Dr Philippe Belmont

Prof. Joëlle Prunet Phannarath Phansavath

Prof Giang Vo

Dr Guillaume Vincent

Dr Nicolas Rabasso

Dr Valérie Alezra

Prof David Bonnaffé

Yingchao, Remi, Audrey, Shanyu Nicolas Hussein

Bocheng Wei Flavie

Antoine Guillaume

Diels-Alder Cycloaddition Of 2-Pyrones

Chapter I Methodologies Involving Inverse-Electron-Demand

The road leading to a doctor's degree is full of thorns. No single

Title : Asymmetric inverse-electron-demand Diels-Alder cycloaddition between 2-pyrones and acyclic enol ethers: gram-scale total synthesis of (+)-lucidumone Keywords : Diels-Alder cycloaddition, natural product, organic chemistry, total synthesis Abstract : The inverse-electron-demand Diels-Alder (IEDDA) cycloaddition of electron-poor 2-pyrones as electrophilic dienes has been extensively studied in the past fifty years. The reaction provides an efficient access to bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3cyclohexadienes after CO2 extrusion and polysubstituted aromatic compounds through elimination. Thus, the IEDDA cycloaddition has been used for the synthesis of many biologically active natural products and drug candidates. This thesis focused on the inverse-electron-demand Diels-Alder reaction of electron-poor 2-pyrones and its appliactions in total synthesis. We developed a broadly applicable diastereo-and enantioselective inverse-electron-demand Diels-Alder reaction of 2-pyrones and acyclic enol ethers. Using a copper(II)-BOX catalytic system, numerous bridged bicyclic lactones were obtained in very high yields (up to 99% yield) and enantioselectivities (up to 99% ee). Mechanistic experiments as well as DFT calculations indicate the occurrence of a stepwise mechanism. To showcase the synthetic utility of this methodology, we developed a gram-scale total synthesis of (+)-Lucidumone. The features of the total synthesis involve the formation of a bridged bicyclic lactone by the IEDDA cycloaddition, C-O bond formation under Mitsunobu conditions and a one-pot CO2 extrusion/intramolecular Diels-Alder cycloaddition cascade.

General Introduction

The inverse-electron-demand Diels-Alder (IEDDA) cycloaddition of electron-poor 2-pyrones as electrophilic dienes has been extensively studied in the past fifty years. The IEDDA cycloaddition provides an efficient access to bridged bicyclic lactones that have been used for the synthesis of many biologically active natural products and drug candidates, which has captured the imagination of synthetic chemists. In this thesis, we present four chapters, including recent advances in the IEDDA cycloaddition of electrophilic 2-pyrones and its applications in the first two chapters as well as our research results in the last two chapters.

The first chapter of this thesis deals with a comprehensive review in methodologies involving the IEDDA cycloaddition of 2-pyrones as electrophilic dienes with activated alkenes. These methods generate various bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3-cyclohexadienes after CO2 extrusion and polysubstituted aromatic compounds through elimination. Both non-catalyzed and catalyzed IEDDA cycloadditions of electrophilic 2-pyrones are described. This chapter also discusses the chemical reactivity of different 2-pyrones, as well as the chemo-and stereoselectivity of such IEDDA cycloaddition.

The second chapter is devoted to applications of the above IEDDA cycloaddition to the total synthesis of natural products and drug candidates. The resulting [2.2.2]-bicyclic lactone is a versatile precursor for synthesizing polysubstituted cyclohexene, 1,3-cyclohexadiene as well as bicyclic fused lactone. The four contiguous stereocenters are fixed in a single step, which endows the IEDDA cycloaddition with broad applications in total synthesis.

Our latest research on the development of an asymmetric IEDDA cycloaddition between 2pyrones and acyclic enol ethers is described in the next chapter. Using a Cu II -BOX catalytic system, bridged bicyclic lactones are obtained in excellent yields (up to 99% yield) and enantioselectivities (up to 99% ee) from diversely substituted 2-pyrones and acyclic enol ethers (Scheme 1). Mechanistic experiments as well as density functional theory (DFT) calculations indicate the occurrence of a stepwise mechanism. The synthetic potential of the bridged bicyclic lactones is showcased by the enantioselective synthesis of polyfunctional cyclohexenes and cyclohexadienes, as well as a carbasugar unit.

X Scheme 1. Asymmetric IEDDA cycloaddition between 2-pyrones and acyclic enol ethers.

Chapter IV discusses our latest research on the gram-scale total synthesis of (+)-lucidumone.

The key steps involve the formation of a bridged bicyclic lactone by an enantioselective IEDDA cycloaddition, a key C-O bond formation to assemble two fragments and a one-pot CO2 extrusion/intramolecular Diels-Alder (IMDA) cycloaddition cascade. Late-stage modifications allow to achieve the total synthesis of (+)-lucidumone on gram scale (Scheme 2).

Scheme 2. Gram-scale total synthesis of (+)-lucidumone.

Finally, the thesis ends up with a general conclusion on the previous four chapters as well as our perspectives on the future development of IEDDA cycloaddition of electrophilic 2-pyrones.

We anticipate that this thesis will inspire the development of novel synthetic methodologies in the future, along with their applications to enantioselective natural product synthesis.

can raise the HOMO level, and in contrast an electron-withdrawing group can lower the LUMO level.

Scheme 3. Difference between NEDDA and IEDDA cycloadditions in π molecular orbitals.

Despite its aromaticity, 2-pyrone can be treated as a 1,3-butadiene bearing an electronwithdrawing carboxyl group on one side and an electron-donating acyloxy group on the other side. Therefore, 2-pyrone can react with both electron-rich and electron-poor dienophiles, making them ambiphilic. However, the cycloaddition of unsubstituted 2-pyrone is usually plagued by self-polymerization under thermal conditions. 5 Fortunately, substituted 2-pyrones are suitable for DA cycloadditions, and the electronic property of the substituent on the pyrone ring decides which type of DA cycloaddition happens. It has been recognized that electron-rich 2-pyrones are good dienes for the NEDDA cycloaddition. On the other hand, electron-poor 2pyrones can participate in the DA cycloaddition as electrophilic dienes in an inverse-electrondemand manner with higher reactivity because the electron-withdrawing group on the pyrone ring destroys the internal electron delocalization (less aromaticity) and lowers the LUMO level.

It should be noted that bromo-and dibromo-substituted 2-pyrones can carry out both NEDDA cycloaddition and IEDDA cycloaddition flexibly (Scheme 4). Scheme 4. Ambiphilic capacity of 2-pyrones.

In the past few decades, much effort has been focused on the development of IEDDA cycloadditions and their synthetic applications. 7 Among those, 2-pyrone derivatives captured the attention of chemists, due to the synthetic attractiveness of the resulting bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3-cyclohexadienes after CO2 extrusion and polysubstituted aromatic compounds through loss of a small molecule. 8 Initially, numerous non-catalytic IEDDA cycloadditions were developed, which were usually promoted by direct heating or by high pressure. Despite their high efficiency, however, these reactions generated bridged bicyclic lactones as racemic mixtures, which intrinsically limits their applications in total synthesis. In contrast, catalytic IEDDA cycloadditions by Lewis acids and organocatalysts allowing the efficient preparation of various chiral bridged bicyclic lactones not accessible by non-catalytic IEDDA cycloadditions have attracted much attention in the past 30 years.

Herein, we will begin with a brief description about the mechanism of the IEDDA cycloaddition of electrophilic 2-pyrones and then individually discuss non-catalytic, Lewis acid-catalyzed and organocatalytic IEDDA cycloadditions of electrophilic 2-pyrones with activated alkenes in the following sections.

7 a) X. Jiang, R. Wang, Chem. Rev. 2013, 113, 5515-5546;b)

Mechanism

The electron density distribution of 2-pyrone and its derivatives is shown in Scheme 5, indicating that C 3 and C 5 positions have a large electron density but C 4 and C 6 positions have a deficiency of electron density. Therefore, 2-pyrone is electrophilic at C 6 position and nucleophilic at C 3 position, making it an excellent diene for the IEDDA cycloaddition.

It is widely recognized that the DA cycloaddition between highly polarized 2-pyrone derivatives and dienophiles proceeds in a stepwise fashion instead of a conventional concerted fashion, as shown in Scheme 5. 9 Indeed, the reaction of a Z or E dienophile with 2-pyrone 1 under thermal or catalytic conditions usually results in the formation of trans-3 as a major product. This can be explained by the formation of intermediate 2, which in the case of a Z dienophile rotates from conformer 2a to more stable conformer 2b, ultimately affording product trans-3. From the perspective of electron density, electron-withdrawing groups on the pyrone ring can accelerate the IEDDA cycloaddition. Meanwhile, reaction intermediates from 3substituted and 5-substituted 2-pyrones are more stable than those from 4-substituted and 6substituted 2-pyrones in agreement with the resonance stabilization, which is consistent with the observed results of the IEDDA cycloaddition of substituted 2-pyrones (Scheme 6).

Scheme 5.

Stepwise mechanism of the IEDDA cycloaddition of 2-pyrone. Scheme 6. Comparison of the stability of different reaction intermediates.

On the other hand, Posner and Cho pointed out that the high pressure-promoted IEDDA cycloaddition of 3-substituted 2-pyrones occurred in a concerted fashion. They observed that cis products 5 were obtained exclusively from the cycloaddition of 3-substituted 2-pyrones 4

with (Z)-1,2-disubstituted alkenes and only trans products 6 were isolated from the cycloaddition of 3-substituted 2-pyrones 4 with (E)-1,2-disubstituted alkenes under high pressure (Scheme 7).

Scheme 7. Stereospecificity of the pressure-promoted IEDDA cycloaddition.

3 Non-Catalytic IEDDA Cycloaddition

Non-catalytic IEDDA cycloaddition of electrophilic 2-pyrones has been frequently investigated in the past 50 years, the dienes of which mainly include carbonyl-substituted 2-pyrones, bromosubstituted 2-pyrones and sulfur-substituted 2-pyrones. For dienophiles, ketene acetals, enamines, and vinyl ethers are commonly used for such IEDDA cycloaddition. The IEDDA cycloaddition can be promoted by direct heating or by high pressure.

It should be noted that initially formed bridged bicyclic products are labile at high temperature, and CO2 extrusion occurs through a retro-DA cycloaddition to provide highly functionalized cyclohexadienes which can be further converted into a series of substituted arenes by loss of a small molecule (Scheme 8).

Scheme 8. Conversion of bridged bicyclic lactones under thermal conditions.

In recent years, the emergence of microwave technology as well as the use of new dienophiles have led to many advances, which will be included in this section.

IEDDA Cycloaddition of Carbonyl-Substituted 2-Pyrones

As mentioned above, 3-substituted and 5-substituted 2-pyrones are more reactive than 4substituted and 6-substituted 2-pyrones for the IEDDA cycloaddition because of the resonance stabilization of the reaction intermediates. The classes of 2-pyrone bearing a carbonyl group at different positions are discussed in the following subsections.

IEDDA Cycloaddition of 5-Carbonyl-2-Pyrones

The first example of IEDDA cycloaddition of 2-pyrones was reported by Behringer and coworker in 1969, employing alkyl coumalates 12 to react with various electron-rich dienophiles. 10 When 1,1-dialkoxyethenes 13 were used as dienophiles, the reaction afforded bridged bicyclic compounds 14 exclusively in good yields and without the detection of regioisomer 15 (Scheme 9a). The similar result was observed between 2-pyrones 12 and ethyl vinyl ether 16a, but cycloadducts 18 were thermally unstable at 160 °C and performed a retro-DA cycloaddition to give cyclohexadienes 19 followed by the cycloaddition with another equivalent of ethyl vinyl ether 16a to give 1:2-adducts 17. The authors failed to characterize the exact position of the second ethoxy group of adducts 17 because of the lack of highresolution NMR technology (Scheme 9b). Further exploration of other substrates did not provide the expected bicyclic adducts. For example, 1,1-dimorpholinoethylene 20 and 1dimethylamino-1-ethoxyethylene 22 reacted with 2-pyrones to give corresponding aromatic compounds 21 and 23 (Scheme 10a and Scheme 10b). Likewise, increasing the electron density and steric hindrance of the pyrone ring also accelerated the conversion of bridged bicyclic adducts to aromatic compounds. Interestingly, boiling the mixture of methyl coumalate 12a and N,N-dimethyl-4-vinylaniline 24 in benzene furnished adduct 25 which was considered as positive evidence for the stepwise mechanism (Scheme 10c).

Scheme 9. Thermal IEDDA cycloaddition of alkyl coumalates with alkoxyethenes.

Scheme 10. Thermal IEDDA cycloaddition of alkyl coumalates with substituted alkenes.

Likewise, the good leaving ability of morpholine was observed by Van Saun and co-workers in 1983, when they investigated the regioselectivity of the IEDDA cycloaddition of 2-pyrones with morpholine enamines. 11 Under thermal conditions, 2-pyrones 26 underwent the IEDDA cycloaddition with substituted morpholine enamines 27 followed by CO2 extrusion via a retro-DA cycloaddition and subsequent aromatization via morpholine elimination, preparing a series of highly functionalized benzoates 28 with complete regioselectivities (Scheme 11a). In two cases, cyclohexadiene intermediates 29 could be isolated and characterized, and further transformed into benzoates upon thermolysis (Scheme 11b).

Scheme 11. Thermal IEDDA cycloaddition of 2-pyrones with morpholine enamines.

The cycloaddition of 2-pyrones provides a renewable access to highly functionalized aromatic compounds primarily derived from diminishing petroleum-based sources. Indeed, methyl coumalate is easily obtained by dimerization of malic acid which is produced by glucose fermentation. Kraus and co-workers have explored various dienophiles to react with methyl coumalate 12a for sustainable access to substituted benzoates 12 and milder conditions for conversion of malic acid into coumalic acid. 13 Several vinyl ethers, ketals, and orthoesters were 11 H. L. Gingrich, D. M. Roush, W. A. Van Saun, J. Org. Chem. 1983, 48, 4869-4873. 12 a) J. J. Lee, G. A. Kraus, Tetrahedron Lett. 2013, 54, 2366-2368;b) J. J. Lee, G. A. Kraus, Green Chem. 2014, 16, 2111-2116. tested, as shown in Scheme 12. In 2013, Kraus and co-worker investigated the cycloaddition of methyl coumalate 12a with vinyl ethers (16,30,35,36) and masked vinyl ethers, such as ketals (31,33) and orthoesters (32), under thermal conditions. 12a The transformation occurred in a domino sequence involving IEDDA cycloaddition/CO2 evolution/alcohol elimination to afford a great number of aromatic compounds.

In the plastic industry, dimethyl terephthalate (DMT, 42) is commonly used for large-scale preparation of bis (2-hydroxyethyl) terephthalate (BHET), a monomer for producing polyethylene terephthalate (PET) which is the most common thermoplastic polymer in our daily life. In 2014, a renewable route for accessing DMT by using an IEDDA cycloaddition of methyl coumalate 12a with captodative ketal 34 was disclosed by Kraus and co-worker. 12b This protocol represents an alternative for reducing the dependence on petroleum products. Moreover, exposure of the resulting bridged bicyclic lactone to microwave irradiation without DABCO resulted in a mixture of cyclohexadiene and aromatic compound with a ratio of 7:1, whereas with the addition of DABCO under otherwise identical reaction conditions the bridged bicyclic lactone was fully converted into corresponding aromatic compound. co-workers developed a microwave-assisted IEDDA cycloaddition of 5-carboethoxy-2-pyrone 45a bearing a trifluoromethyl group at C 6 position with acyclic vinyl ethers 50. By adjusting the reaction conditions, bridged bicyclic adducts 51, cyclohexadienes 52 and aromatic compounds 53 were achieved rapidly (Scheme 14a). 15 Later, the authors expanded the substrate scope to cyclic vinyl ethers 30. These cyclic vinyl ethers underwent the IEDDA cycloaddition with 45a, providing an access to substituted dihydrobenzofuran 54a and chromane 54b in good yields (Scheme 14b). 16 Scheme 14. Microwave-assisted IEDDA cycloaddition of 2-pyrone with acyclic and cyclic vinyl ethers.

Electron-rich heteroarenes, such as furans and indoles, with a masked moiety of O- dienophile, providing bridged lactones 56 with high regioselectivities (Scheme 15). 17 For example, the IEDDA cycloaddition between methyl coumalate 12a and 3,4-dimethoxyfuran 55a was carried out in boiling methanol for 2 hours to furnish cycloadducts 56a as a 1:1 mixture of endo/exo isomers (Scheme 15a). It should be noted that the formation of cycloadduct 57

substituted
arising from a second Diels-Alder reaction from 56b was observed when two analogous components 12c and 55b were used in an equimolar ratio for the cycloaddition. By modifying the ratio of starting materials 12c and 55b to 10:1, this obstacle was overcome and only a trace amount of over-addition product 57 was detected (Scheme 15b).

Scheme 15. Thermal IEDDA cycloaddition of alkyl coumalates with 3,4-dialkoxyfurans.

In 2000, Liao and co-worker reported a similar reaction in which 2-methoxyfuran 59 acted as the dienophile (Scheme 16). Liao, Org. Lett. 2000, 2, 2049-2052. shorter than that between C 3 -C 8 (Scheme 16b). 1973, 95, 2303-2311. copaene and (±)-β-ylangene (Scheme 19).

Scheme 19.

Thermal IEDDA cycloaddition of 3-carbomethoxy-2-pyrone with 4-methyl-3cyclohexenone.

In the presence of a good leaving group on the dienophile, the domino sequence of IEDDA cycloaddition/CO2 extrusion/aromatization can afford substituted aromatic compounds. This Owing to the similarity between selenium and oxygen, vinylselenides were also employed to react with 3-carbomethoxy-2-pyrone. This transformation was first achieved by Markó and co-workers, through a high pressure-promoted IEDDA cycloaddition of 3-carbomethoxy-2pyrone 71a with various vinylselenides 100, leading to bridged lactones 101 with complete regio-and endo-selectivity. 28 It should be noted that the reaction was also diastereospecific, as Scheme 28a. 31 Later, Martin and co-workers reported the total synthesis of indole alkaloids (±)α-yohimbine and (±)-reserpine by application of a similar strategy for the construction of a functionalized hydroisoquinoline subunit (Scheme 28b and Scheme 28c). 32

Scheme 28. Thermal IEDDA cycloaddition of 6-carbonyl-2-pyrones.

IEDDA Cycloaddition of Bromo-Substituted 2-Pyrones

The role of halogen substituents (Cl, Br, I) at different positions of 2-pyrone was systematically investigated by Afarinkia and co-workers in 2005. 33 As shown in Scheme 29, the cycloaddition of 2-pyrone bearing a bromine atom at C 3 , C 5 or C 4 position with various dienophiles was carried out under thermal conditions, leading to various bridged bicyclic lactones. Interestingly, 3-bromo-2-pyrone 114a and 5-bromo-2-pyrone 114b, both easily prepared by the bromination of 5,6-dihydro-2H-pyran-2-one and subsequent oxidation, were ambiphilic and underwent both IEDDA cycloaddition with electron-rich dienophiles and NEDDA cycloaddition with electronpoor dienophiles. In contrast, 4-bromo-2-pyrone 114c preferred to participate in the NEDDA cycloaddition with electron-poor dienophiles. Furthermore, in most cases, the cycloaddition of 3-bromo-2-pyrone or 5-bromo-2-pyrone proceeded with good regio-and stereoselectivity 31 E. Ciganek, J. Am. Chem. Soc. 1981, 103, 6261-6262. 32 S. F. Martin, H. Rüeger, S. A. Williamson, S. Grzejszczak, J. Am. Chem. Soc. 1987, 109, 6124-6134. favoring 5-endo cycloadducts predominantly, whereas the reaction of 4-bromo-2-pyrone proceeded with good stereoselectivity but without regioselectivity generating 5-endo and 6endo cycloadducts in nearly 1:1 ratio. Similar results were also obtained by observing the cycloaddition of chloro-substituted 2-pyrones and iodo-substituted 2-pyrones. Moreover, the regio-and stereoselectivity of these reactions were rationalized by using DFT calculations.

Scheme 29. Thermal cycloaddition of bromo-substituted 2-pyrones with various alkenes.

Although the efficiency and selectivity of these reactions are not significantly influenced by the nature of the halogen atom, bromo-substituted 2-pyrones have been more widely investigated than chloro-and iodo-substituted 2-pyrones in the past decades. There are two main factors accounting for this observation. Bromo-substituted 2-pyrones are more easily prepared than chloro-and iodo-substituted 2-pyrones. On the other hand, the late-stage reductive debromination of the resulting cycloadducts allows bromo-substituted 2-pyrones to be treated as the synthetic equivalent of 2-pyrone, the potential of which has been proved by a number of alkaloid total syntheses.

The introduction of bromine atom could enhance the reactivity of 2-pyrones. Generally, the reactivity of bromo-substituted 2-pyrones would be as follows: 3,5-dibromo-2-pyrone > 5bromo-2-pyrone > 3-bromo-2-pyrone, which will be discussed in the following subsections.

IEDDA Cycloaddition of 5-Bromo-2-Pyrones

Early investigations of the efficiency and stereoselectivity of dienophiles participating in the thermal IEDDA cycloaddition with 5-bromo-2-pyrone were undertaken by Posner and Afarinkia. 34 As outlined in Scheme 30, by adjusting the substituent of dienophiles, the IEDDA cycloaddition proceeded with variable stereoselectivities and afforded either predominantly endo or exo cycloadducts. For example, vinyl ethers acted as nucleophilic dienophiles to react with 5-bromo-2-pyrone, mainly providing kinetically favored endo cycloadducts. Although exo cycloadducts were thermodynamically favored, these were not obtained at higher temperature because of further CO2 extrusion. In contrast, the cycloaddition of 5-bromo-2-pyrone with sterically hindered N-vinylpyrrolidinone or N-vinylphthalimide was highly exo-selective because secondary orbital interactions were prevented by steric hindrance.

Scheme 30. Thermal IEDDA cycloaddition of 5-bromo-2-pyrone with electron-rich alkenes.

34 a) K. Afarinkia, G. H. Posner, Tetrahedron Lett. 1992, 33, 7839-7842;b) K. Afarinkia, N. T. Daly, S. Gomez-Farnos, S. Joshi, Tetrahedron Lett. 1997, 38, 2369-2372. A similar reaction was also developed by Cho and co-workers in 2002 with the use of 5bromo-2-pyrones bearing a substituent at C 3 position as the electrophilic diene (Scheme 31). 35 Later, the synthetic potential of this strategy was demonstrated by the total synthesis of (±)joubertinamine, 36 (±)-crinine, 37 (±)-crinamine, (±)-6a-epi-crinamine, 38 (±)-narwedine, (±)lycoraminone, (±)-galanthamine 39 and (±)-aspidospermidine. 40 Scheme 31. Thermal IEDDA cycloaddition of 5-bromo-2-pyrone with enol ethers.

IEDDA Cycloaddition of 3-Bromo-2-Pyrones

The first thermal IEDDA cycloaddition of

IEDDA Cycloaddition of 3-Sulfinyl-2-Pyrone

The first example of the IEDDA cycloaddition between 3-sulfinyl-2-pyrone 133 and 1,1dimethoxyethylene 13a was achieved by Posner and co-worker in 1985, leading to bridged bicyclic lactone 134 in good yield (Scheme 35a). It should be noted that the stereogenic sulfinyl group induces a certain extent of diastereoselectivity, as the cycloadduct 134 was isolated as a mixture of two diastereomers (88:12 dr). 45 Later, the same group expanded the substrate scope by using vinyl thioethers 135 as electron-rich dienophiles under high pressure at room temperature, as shown in Scheme 35b, providing bridged lactones 136. 46 45 G. H. Posner, W. Harrison, J. Chem. Soc., Chem. Commun. 1985, 1786-1787. Scheme 35. IEDDA cycloadditions of 3-sulfinyl-2-pyrone with electron-rich dienophiles. 36). 47 These resulting bridged bicyclic lactones could be used as precursors for efficient preparation of enantioenriched polyfunctionalized cyclohexenes. The synthetic potential of this cycloaddition was demonstrated by the total synthesis of (-)-methyl triacetyl-4-epishikimate. 48

Scheme 36. Thermal IEDDA cycloaddition of 3-sulfonyl-2-pyrone with enantioenriched vinyl ethers.

In 1990, the same group reported an IEDDA cycloaddition of 3-sulfonyl-2-pyrone 137 with electron-rich 1,3-dioxoles 121 for accessing bridged bicyclic lactones 139 (Scheme 37). 49 The 47 G. H. Posner, D. G. Wettlaufer, Tetrahedron Lett. 1986, 27, 667-670. 48 G. H. Posner, D. G. Wettlaufer, J. Am. Chem. Soc. 1986, 108, 7373-7377. cycloaddition could be easily triggered by heating or by high pressure. The reaction outcome was considerably influenced by the steric hindrance of dienophiles, in which more sterically hindered 1,3-dioxoles, such as 2,2-diisopropyldioxole, proved less reactive than unsubstituted (11-12 kbar) and a catalytic amount of (+)-Yb(tfc)3, allowing to furnish racemic bridged bicyclic lactone 142 with complete regio-and diastereoselectivity (Scheme 41). 52 Control experiments illustrated the importance of the reaction conditions in the transformation. Undesired results occurred at atmospheric pressure with a catalytic amount of (+)-Yb(tfc)3 or under high pressure without the catalyst.

Moreover, although chiral (+)-Yb(tfc)3 was used as catalyst, no asymmetric induction was observed. This result was remarkable as it represents the first example of the catalytic IEDDA cycloaddition using unsubstituted 2-pyrone as the diene.

Scheme 41. Yb(tfc)3-catalyzed IEDDA cycloaddition of 2-pyrone with benzyl vinyl ether.

In 1994, Markó and co-worker investigated the Eu(hfc)3-catalyzed IEDDA cycloaddition of

Enantioselective IEDDA Cycloaddition of 2-Pyrones

The highly diastereoselective, catalytic IEDDA cycloaddition for preparation of chiral bridged bicyclic lactones can be achieved by using the auxiliary-based approach. However, this strategy is plagued by the tedious pre-installation and post-removal of the chiral auxiliary. Therefore, the direct asymmetric induction by enantioselective catalysis has attracted intensive research focus in the past decades.

The first example of catalytic enantioselective IEDDA cycloaddition of 3-carbomethoxy-2pyrone with vinyl ethers and vinyl thioethers was realized by Markó and co-workers in 1994. 60 Under the catalysis of Yb(OTf)3 and (R)-BINOL, the reaction proceeded under mild conditions, The bridged ring of 205 was assembled by a Pictet-Spengler reaction of 204. Finally, the removal of bromine atom followed by the stereochemical inversion of the hydroxyl group furnished (±)-crinine 207, as illustrated in Scheme 58. 37

Scheme 58. Total synthesis of (±)-crinine.

Considering the structural similarity between crinine and crinamine, the authors attempted to install a hydroxyl group stereoselectively on the above intermediates by a sequence of epoxidation/epoxide opening for total synthesis of crinamine. 38 As illustrated in Scheme 59, this strategy commenced with the ring-opening reaction of lactone endo-120b and then protection of the resulting hydroxyl group as a methyl ether to afford ester 209 which was reduced by LiAlH4 to give the corresponding primary alcohol. Aldehyde 210 was installed by Dess-Martin oxidation, followed by epoxidation with diiodomethane in the presence of lithium methoxide to provide epoxides 211a and 211b as an inseparable diastereomeric mixture in 6:1 ratio. The subsequent ring opening of epoxide by the treatment of sodium azide allowed to access two inseparable alcohols 212a and 212b (212a:212b = 6:1). However, the authors failed to determine the relative stereochemistry of the major isomer 212a at that time. Starting from alcohol 212a, similar operations for the synthesis of (±)-crinine were carried out, allowing an access to (±)-6a-epi-crinamine 218a (Scheme 60). Unfortunately, all attempts to epimerize the hydroxyl group at C 6a position of 218a failed to provide (±)-crinamine 218b. Therefore, the authors decided to use the minor isomer 212b as the starting material. After investigating the epimerization of 212a, the authors discovered that the diastereomeric ratio of 212a and 212b could be improved to 1:3 by an oxidation/reduction sequence (Entry 3, Scheme 59).

Scheme 59. Synthesis of the key intermediates for crinamine and 6a-epi-crinamine.

As outlined in Scheme 60, upon protection of alcohol 212a and 212b with MOMCl, two diastereomers 213a and 213b were isolated in 25% and 68% yields, respectively. Reduction of azide 213b with PPh3/THF/H2O followed by Boc protection afforded amine 214b which was subjected to desilylation and subsequent oxidation to furnish ketone 215b. The cyclization of 215b in the presence of ZnBr2 provided an imine which was treated with LiAlH4 to deliver amine 216b. The key tetrahydroisoquinoline ring was constructed by a Pictet-Spengler reaction, leading to precursor 217b. The final conversion of 217b to natural product (±)-crinamine 218b

was accomplished by the removal of the bromine atom. 38

Scheme 60. Total synthesis of (±)-crinamine and (±)-6a-epi-crinamine.

Total Synthesis of (±)-Narwedine, (±)-Lycoraminone and (±)-Galanthamine by Cho and Co-Workers

The intramolecular IEDDA cycloaddition of 5-bromo-3-aryl-2-pyrone bearing a vinyl ether moiety on the aryl ring was investigated by Cho and co-workers for the synthesis of (±)narwedine, (±)-lycoraminone and (±)-galanthamine. 39 Under thermal conditions, the reaction Dess-Martin oxidation of 225 followed by Zn-promoted debromination afforded (±)-narwedine 226 and an over-reduction product (±)-lycoraminone 227 in 55% and 20% yields, respectively.

The final reduction of (±)-narwedine by L-selectride was accomplished, furnishing (±)galanthamine 228 which is a commercially available drug used for the treatment of Alzheimer's disease (Scheme 61).

Scheme 61. Total synthesis of (±)-narwedine, (±)-lycoraminone and (±)-galanthamine.

Total Synthesis of (±)-Aspidospermidine by Cho and Co-Workers

Aspidosperma alkaloid is one of the largest groups of indole alkaloids with more than 250 members, the common framework of which is a complicated pentacyclic skeleton. The total synthesis of (±)-aspidospermidine was completed by Cho's group in 2010, starting from an IEDDA cycloaddition of 3-ethyl-5-bromo-2-pyrone 119c with vinyl sulfide 135b. 40

Total Synthesis of Sendaverine by Boger and Co-Worker

Sendaverine alkaloid was isolated from Corydalis aurea, the structure of which possesses a selectively protected o-catechol which could be synthesized by utilizing an IEDDA cycloaddition of 3-carbomethoxy-2-pyrone. The total synthesis of sendaverine by this strategy was reported by Boger and co-worker in 1984. 50 4 Radical Rearrangement

Total Synthesis of (+)-Gelsemiol by Gademann and Co-Workers

The enantioselective IEDDA cycloaddition of 3-carbomethoxy-2-pyrone with vinylselenide was applied by Gademann and co-workers to complete the total synthesis of (+)-gelsemiol, an oxidized iridoid first isolated from Gelsemium sempervirens. 75 As shown in Scheme 73, bridged bicyclic lactone 323 was obtained in 91% yield and with 84% ee by a Cu(OTf)2/BOX-catalyzed

enantioselective IEDDA cycloaddition under reduced pressure, followed by radical-mediated and acid-catalyzed skeletal rearrangements to deliver bicyclic fused lactones 324a and 324b as a diastereomeric mixture. Subsequently, lactones 324 underwent a three-step procedure involving a cascade reaction of methylation/lactone opening, hydrolysis of ester 325 and iodolactonization of 326 to furnish highly functionalized bicyclic fused lactone 327. Reduction of carboxylic acid with excess BH3

Conclusion

To conclude, to date a great number of bridged lactones have been used for the construction of natural products and biologically relevant molecules, which is due to their versatile postfunctionalization (Scheme 74). The CO2 bridge could be attacked by a nucleophilic reagent to furnish densely functionalized cyclohexenes, for example transesterification. Under thermal conditions, the rigid lactone-bridged structure could readily undergo CO2 extrusion via a retro-DA cycloaddition to forge densely functionalized 1,3-cyclohexadienes and subsequent aromatization to afford polysubstituted aromatic compounds through loss of a small molecule.

Moreover, the bridged lactones could also undergo radical skeletal rearrangement to deliver bicyclic fused lactones. These features endowed bridged lactones prepared by IEDDA cycloadditions with wide applications in total synthesis.

Scheme 74.

Versatile post-functionalization of bridged lactones.

Chapter III Asymmetric Inverse-Electron-Demand Diels-Alder Cycloaddition between 2-Pyrones and Acyclic Enol Ethers 1 Introduction

As described in Chapter I, electron-deficient 2-pyrone derivatives are notoriously good partners for IEDDA cycloadditions, affording bridged lactone structures. These versatile intermediates offer many possibilities for further functionalization, including CO2 extrusion, ring opening, radical rearrangement and aromatization. Thus, these reactions were featured in various natural product syntheses, although largely limited to racemic form or the synthesis of achiral natural products, as shown in Chapter II. Asymmetric IEDDA cycloadditions involving 2-pyrone derivatives were developed in the 1990s by the groups of Posner and Markó, using chiral Lewis acid catalysis (Scheme 75a). 60-61,63-65 However, until recently these reactions were limited to non-substituted enol ethers. A huge step forward was taken when the group of Cai reported the enantioselective IEDDA cycloaddition of 2-pyrones and cyclic dienophiles using a combination of Yb(OTf)3 and a modified BINOL ligand (Scheme 75b). 62,74 However, the enantioselective IEDDA cycloaddition of 2-pyrones with acyclic 1,2disubstituted dienophiles remains elusive. Only one example was reported by Gademann and co-workers, where an alkenyl selenide underwent an IEDDA cycloaddition with a 2-pyrone derivative under vacuum, affording the corresponding bridged bicyclic lactone with 84% ee (see Scheme 73). 75 Unlike cyclic dienophiles, the use of acyclic 1,2-disubstituted dienophiles presents additional challenges of diastereoselectivity (endo or exo) and diastereospecificity (cis or trans product for Z or E substrates), in addition to the enantioselectivity issue.

Counterintuitively, IEDDA cycloadditions of 2-pyrone are not always diastereospecific, as both pericyclic and stepwise mechanisms can occur. 58-59 Attracted by the potential of this reactionhighlighted by the many possible applications in total synthesis-we decided to tackle this important issue. Herein, we propose a broadly applicable method for enantio-and diastereoselective IEDDA cycloaddition involving 2-pyrones and acyclic 1,2-disubstituted dienophiles (Scheme 75c). The procedure for synthesis of 5-alkyl-3-carbomethoxy-2-pyrones 71q-71s was similar to that of 3-carboalkoxy-2-pyrones. ZnCl2-catalyzed Aldol condensation between aldehydes 336 and diethyl malonate 330b gave intermediates 337 which was refluxed in aqueous formic acid to deliver 2-pyrones 71q-71s via an acid-mediated lactonization. On the other hand, the preparation of 5-aryl-3-carbomethoxy-2-pyrones 71t-71w started from a conjugate addition of aryl acetaldehyde 338 onto dimethyl methoxymethylenemalonate 339 under basic conditions, followed by one-pot acid-promoted enolization of the generated aldehyde 340 and lactonization (Scheme 79). 62

Scheme 79. Synthesis of 5-substituted 2-pyrones.

Synthesis of Enol Ethers

We then started to synthesize various enol ethers (Scheme followed by reduction and subsequent protection (Scheme 81a). Moreover, trisubstituted enol ether 334r could be obtained from ethyl acetoacetate 347 in three steps. An acid-mediated enol etherification of ethyl acetoacetate 347 with trimethyl orthoformate gave enol ether 348. 80 Subsequent reduction and protection afforded desired enol ether 344r (Scheme 81b).

Scheme 81. Synthesis of Z-disubstituted and trisubstituted enol ethers.

Optimization of Reaction Conditions

After that, we studied the IEDDA cycloaddition of electron-deficient pyrone 71a with acyclic enol ether 344a. To evaluate the possibility of this cycloaddition, thermal conditions were used and the reaction gave cycloadduct 350a as an endo isomer in 11% yield (entry 1, Table 1).

Despite the low yield, we were greatly encouraged by this observation because it still proved the stability of the starting acyclic enol ether for this transformation. Then we began to investigate the catalytic version of this reaction with the use of Lewis acids. Initially, screening of zinc catalysts, such as ZnBr2 and Zn(OTf)2, did not give a delightful result, even though zinc catalysts have been commonly used in catalytic DA cycloadditions in the past (entries 2-3, Table 1). 81 Then several lanthanide catalysts were examined as Lewis acids, indicating that these catalysts could not provide enantioinduction without any additional chiral ligand, despite good isolated yields observed in some cases (entries 4-9, Table 1). Replacing the reaction solvent with DCM could sharply increase the yield, which could be attributed to the excellent solubility of lanthanide catalysts in DCM (entry 5 vs entry 7, entry 6 vs entry 8, Table 1). It should be noted that the relative configuration of exo-isomer 351a was unambiguously Next, we studied the role of the counterion of Cu II -BOX complex in the IEDDA cycloaddition. According to previous reports, the counterion could dramatically affect the efficiency and stereoinduction of Cu II -BOX catalyst. 83 The counterion effect was then evaluated by varying copper salts, indicating that SbF6 -was the optimal counterion. The catalyst prepared in situ from CuCl2 and AgSbF6 afforded bridged lactone 350a in 98% yield with 87% ee (entry 8, Table 4). After that the solvent effect was studied. The challenge at this part is the solubility of the prepared Cu II -BOX catalyst. Non-chlorinated solvents could not fully dissolve the catalyst, resulting in unsatisfying results (entry 2, Table 5). Therefore, several chlorinated solvents were screened, such as chloroform and DCE, but these solvents did not improve the reaction outcome (entries 3-5, Table 5). The effect of concentration was also investigated, in which high concentration could slightly improve the yield without any erosion of the ee value (entry 6, Table 5). To our delight, the mixed solvent of DCM and substituted arenes led to the enhanced enantioselectivity (entries 8-13, Table 5). Adjusting the ratio of DCM and toluene suggested that when the portion of DCM decreases, the yield falls but the ee slightly increases. Particularly, the reaction with a mixed solvent of DCM/toluene (1:2) gave a well-balanced outcome, providing 350a in 92% yield with 95% ee (entry 12, Table 5). Subsequently, the reaction temperature was optimized (entries 1-5, Table 6). In particular, the reaction at -40 o C afforded the best result, providing bridged lactone 350a in 96% isolated yield with 97% ee (entry 4, Table 6). Finally, optimizing the catalyst loading and the reaction concentration suggested that the optimal conditions of this IEDDA cycloaddition included 5 mol% of Cu II -BOX as catalyst, 150 mol% of enol ether as reaction partner, 1:2 of DCM and toluene as the mixed solvent, -40 o C as temperature with 4Å MS under argon atmosphere (entry 7, Table 6).

Substrate Scope

With these optimal conditions in hand, we started exploring the scope of the reaction (Scheme 82). Various ester moieties were well tolerated in C 3 position, from non-bulky Me ester to sterically demanding tBu ester (350a-350d), although longer reaction times were needed in the latter case. Benzyl ester, which can be converted to the corresponding carboxylic acid under classical saponification conditions, also performed well (350e). 84 Testosterone and cholesterol derivatives could also undergo the IEDDA reaction efficiently (350f-350g), proving its applicability to complex structures. We were disappointed to see that amides were not reactive enough to undergo the cycloaddition. Substitution in C 4 position was well tolerated in general, with both alkyl (350h) and aryl substituents (350i-350p). Moreover, both electron-rich (350j, 350n) and electron-deficient (350k-350m) aryl substituents performed well, although with somewhat lower ee in some cases. Substitution was also possible in ortho and meta position of We then studied our reaction with different enol ethers (Scheme 83). Various O-substituents were well tolerated, with ethyl and isopropyl enol ethers providing the corresponding bridged bicyclic lactones 350x-350y with excellent enantioselectivities. Classical protecting groups, such as benzyl, allyl and TBS, were also well tolerated (350z-350ad). Regarding the substitution at C 2 position, various alkyl substituents were tolerated (350ab-350ad), including non-bulky Me group (350ab) and more sterically demanding Bn group (350ad). Good results

were also observed in the presence of protected alcohols (350ae-350ai). Remarkably, a highly sensitive TMS protecting group survived on a primary alcohol in the reaction conditions, underlying the mildness of the reaction conditions. To test the diastereocontrol ability of our catalytic system, we evaluated the influence of a mismatched chiral dienophile in the reaction conditions (Scheme 84). Thus, (-)-menthyl-enol ether 344n was subjected to the reaction conditions using an achiral ligand. Compound 350aj' was obtained as a major diastereomer with 5:1 dr. Conversely, when our catalytic system was employed, the diastereomeric ratio was reversed, and another diastereomer 350aj was obtained as the major one with 6:1 dr, highlighting the stereoinducing power of our catalytic system.

Scheme 84. Influence of a mismatched chiral dienophile.

We were also interested in the reaction diastereospecificity. A quick reoptimization was needed for the case of Z enol ethers, allowing us to highlight L15 as the optimal ligand for Z enol ethers (Table 7). When subjecting Z enol ethers 344o and 344p to the reaction conditions, only cis-diastereomers 350ak-350al were observed (Scheme 85). However, the cycloaddition involving Z enol ether 344q provided a 28:1 mixture of cis and trans diastereomers.

Interestingly, the two diastereomers 350am and 351a were isolated with different ee. It should be noted that isomerization of Z and E enol ethers cannot be invoked to explain this result, as the minor trans isomer is 351a and not 350a. Scheme 85. Diastereospecificity of the reaction with Z enol ethers.

On the other hand, when 1,1',2-trisubstituted enol ether 344r reacted with 71a, four diastereomers were obtained, with a poor diastereoselectivity. Each diastereomer could be isolated separately. Remarkably, each pair of epimer 350an-350aq and 350ao-350ap had the same ee (Scheme 86). These results are strongly positive to the occurrence of a stepwise mechanism, although we could not rule out a competing concerted mechanism at this point.

More control experiments and DFT calculations were undertaken to give an insight into this reaction, as described in the following sections.

Scheme 86. Diastereodivergency of the reaction with 1,1',2-trisubstituted enol ether.

Mechanistic Experiments

To better understand the diastereodivergent results with Z-disubstituted and trisubstituted enol ethers, we resubjected the isolated enantioenriched bridged lactones to the reaction conditions.

Bridged lactone trans-350a remained intact under the standard conditions. However, trans-351a was isolated with the use of cis-350am as the starting lactone, confirming the reversibility of the cyclization step (Scheme 87). Interestingly, the observed difference of ee between the starting 350am and the resulting 351a indicates the different epimerization rate of two enantiomers of 350am under catalytic asymmetric reaction conditions, in comparison with the result under racemic conditions.

Scheme 87. Observation consistent with a stepwise and reversible cyclization.

For enantioenriched bridged lactones 350an-350aq, we also observed epimerization at ether-bearing stereogenic center, but without significant change in ee (Table 8). This result strongly points towards not only the reversibility of the cyclization but also a stepwise mechanism. We also performed a kinetic study of the reaction, showing that the ratio of each diastereomer was constant over the reaction course (Table 9 and Figure 1). These observations were also confirmed by DFT calculations.

DFT Calculations

We were sufficiently intrigued by the experimentally observed diastereoselectivity and epimerization. These remarkable observations indicate two key points of the IEDDA reaction:

(i) the cyclization step is reversible, and (ii) the reaction occurs in a stepwise fashion.

Meanwhile, we were also curious about the observed difference between cis-lactone and translactone in the IEDDA reaction and in the epimerization process, as well as the poor diastereoselectivity observed in the IEDDA reaction with trisubstituted enol ether. To gain a better insight into this reaction, we cooperated with Dr. Boris Maryasin in performing DFT calculations. Figure 2 shows the computed reaction profiles for the reactions of the malonate model complex of the bis(oxazoline) ligand A-Cu with the (E)-1-methoxyprop-1-ene B_E (Figure 2A) and (Z)-1-methoxyprop-1-ene B_Z (Figure 2B). The malonate complex A-Cu associates with enol ethers B_E and B_Z to yield 3.1 and 2.8 kcalmol -1 stabilized reactant complexes. The strong intermolecular interaction between the copper and the oxygen atoms of the methoxy groups of enol ethers is the reason for the computed free energy lowering compared to the separately considered reactants. The next step is the attack of the enol ethers.

We explored both concerted and stepwise mechanisms for this event, and the calculations

Chapter IV Gram-Scale Total Synthesis of (+)-Lucidumone 1 Introduction

Meroterpenoids are an important class of natural products, displaying a partially terpenic skeleton, along with a part from different biogenetic origin, often polyketide. Due to their interesting structure and often powerful biological activities, meroterpenoids have attracted the interest of synthetic chemists for decades. 86 Lucidumone (370) is a meroterpenoid isolated in 2019 from the fruiting bodies of Ganoderma lucidum, a mushroom commonly used in traditional medicine in China and Japan. 87 This natural product presents an unprecedented 6/5/6/6/5 caged pentacyclic structure, with a hydroquinone, one secondary alcohol and two ketone motifs. Its structural complexity can be highlighted by the six contiguous stereogenic centers on the bicyclo[2.2.2]octane subunit. Moreover, preliminary studies indicate that lucidumone selectively inhibits COX-2 by directely binding with Tyr385 and Ser530 residues, providing it with an interesting therapeutic potential for the treatment of inflammation. 88 Interestingly, although lucidumone is produced as an enantiomeric mixture by Ganoderma lucidum, only one enantiomer displayed the selective COX-2 inhibitory activity. Nevertheless, this natural product was isolated in sub-mg scale (extraction yield of 1.5 10 -8 , 0.4 mg of (+)-370 isolated), which hampers in-depth biological activity study.

As shown in Scheme 91, the authors proposed that the plausible pathway for biosynthesis of lucidumone originates from two common terpenoid precursor units, dimethylallyl Recently, She and co-workers reported a synthetic study allowing the racemic construction of the pentacyclic flamework of lucidumone in 18 steps (Scheme 92). 90 Inspired by the work Harrison, Nat. Prod. Rep. 1988, 5, 387-415;d) L. Heide, Curr. Opin. Chem. Biol. 2009, 13, 171-179. 90 S. Ma, Z. Li, P. Yu, H. Shi, H. Yang, J. Yi, Z. Zhang, X. Duan, X. Xie, X. She, Org. Lett. 2022, 24, 5541-5545. reported by Liao's group 91 However, the total synthesis of lucidumone has never been achieved to date. Attracted by the structural complexity as well as the therapeutic potential of this natural product, we decided to engage in its total synthesis.

Retrosynthetic Analysis

As describe in Scheme 93, our retrosynthetic analysis allowed us to identify C 2' -C 3' and C 6' -C 7' as key disconnections, which could be achieved through an IMDA cycloaddition, providing that C 8' -C 9' is a double bond which can be reduced in the late-stage modification. This key disconnection could greatly simplify the structure into synthon 383, bearing an indenone and a cyclohexadiene moieties for the key cycloaddition. Given the high instability of the cyclohexadiene, we would mask this function as a bridged bicyclic lactone 384, which could regenerate the desired cyclohexadiene by CO2 extrusion. Fragment 384 would be obtained by C-O bond formation from two fragments 385 and 386. To allow an enantioselective synthesis, fragment 386 should be obtained enantioselectively, for which we envisaged an inverse-electron-demand Diels-Alder (IEDDA) reaction involving a 2-pyrone (387 or 71a) and an enol ether 344d. The introduction of the methyl ketone moiety can be envisaged either in the early steps of the synthesis or in the endgame. This approach presents three key steps/challenges. (i) The late-stage IMDA reaction presents an unfavorable electron demand, as the electrondeficient site of the diene C 6' will meet the electron-deficient site of the dienophile C 7' , and likewise for the electron-rich sites C 2' and C 3' . (ii) The C-O bond coupling between fragments 385 and 386 will also be an important challenge, as the formation of β-keto enol ethers typically requires the use of excess hydroxy partner, making it unsuitable for fragment coupling. 92 (iii)

The challenge of enantioselective IEDDA reaction involving 2-pyrones for the synthesis of bridged bicyclic lactones had already been solved through the development of the IEDDA reaction described in Chapter III. 93 Scheme 93. Our retrosynthetic analysis for enantioselective total synthesis of lucidumone. anhydride 389 in 82% isolated yield over two steps. 94 Phthalic anhydride 389 could be converted to unprotected 1,3-indandione 390 by reacting with ethyl acetoacetate (347) in the presence of Et3N followed by acid hydrolysis. 95 Scheme 94. Synthesis of unprotected indandione.

Preparation of Indandione

The original thought was to protect the hydroxyl groups as benzyl ethers because (i) it can shorten the synthetic route, as Pd/C reduction can not only reduce C-C double bond but can also remove three benzyl protecting groups at the same time in a single operation; (ii) benzyl protecting group has a good balance between stability and leaving ability, by contrast with too stable methyl group and too labile silyl group. However, the screening of the reaction conditions reveals that the α-position of 1,3-dione moiety is more nucleophilic than the hydroxyl groups (Table 10). The protection of hydroxyl groups as benzyl ethers before the formation of indandione may provide a solution for the selectivity issue. Firstly, substituted hydroquinone 388 reacted with benzyl bromide to give protected product 394 in 81% yield. However, compound 394 is highly insoluble in all solvents, for which further basic hydrolysis of the dinitrile moiety of 394 only gave a trace of diacid 395. Acid hydrolysis of 394 also failed to give diacid 395 and corresponding anhydride 396 (Scheme 95).

Scheme 95. Benzyl protection of hydroquinone.

Therefore, we decided to protect the hydroxyl groups as TBS ethers. A series of the previously reported conditions for protection of hydroquinone was investigated, as shown in Table 11. When TBSCl was used as TBS source and Et3N was used as base, the protection reaction proceeded smoothly to provide di-TBS protected 1,3-indandione 385 in 65% isolated yield. cyclohexanemethanol 398 proved ineffective. 96 The Williamson ether synthesis was also evaluated. All attempts to trap the enolate ion generated in situ from 1,3-indandione 385 and various bases with iodide 399 to provide O-alkylation product only led to a trace of C-alkylation product. 97 According to the hard and soft acids and bases principle, hard alkylating agents, such as tosylate, favor O-alkylation. 98 Therefore, we prepared tosylate 400 as electrophilic reagent for C-O bond formation, but no desired product was formed. Moreover, O-methylation of 1,3indandione was realized by Commeiras and co-workers with the use of dimethyl sulfate 401 as alkylating reagent. 99 The same conditions were carried out with 385 as the starting material, leading to O-methylation product (397a, 402 and 403) in 75% combined yield, although the

Brief Summary: Obstacles and Solutions

From the failure described above, we considered that we were plagued by several issues. (i) The first is the instability of the alcohol and TBS-protected indandione under harsh conditions, Regarding the cyclohexadiene fragment, our first idea was to achieve the cycloaddition with a 2-pyrone derivative already bearing the methylketone functionality at C 3 position. Inspired by the construction of 3-carbomethoxy-2-pyrone 71a, we speculated that 3-acetyl-2-pyrone 387 could be obtained directly through the lactonization of 420 or 421 which could be prepared from acetoacetates 422 and 347. However, the condensation step did not work as expected. We also conducted the same conditions reported by Al-Matar's group for preparation of C Am. Chem. Soc. 1983, 105, 1988-2006. formation of a stable five-membered chelate complex. When methyllithium was used for this reaction, only a trace of β-methylated by-product 426 was detected, whereas an inseparable mixture of 387 and 426 was isolated in 1:10 ratio with the use of methylmagnesium bromide as nucleophilic reagent (Scheme 104). Although much effort had been invested in seeking the reaction conditions for preparation of 3-acetyl-2-pyrone 387, we were disappointed by the complex reaction outcome and β-methylation. Therefore, we decided to install the methyl ketone in the final stage.

Scheme 104. Attempts for preparation of 3-acetyl-2-pyrone from corresponding Weinreb amide.

6 Total Synthesis of (±)-Lucidumone 6.1 Assembly of the Core Framework of (±)-Lucidumone

After the preliminary attempts, we commenced to synthesize (±)-lucidumone starting from a catalytic IEDDA reaction of 3-carbomethoxy-2-pyrone 71a with benzyl enol ether 344d.

Bridged lactone (±)-350z could be obtained in almost quantitative yield as a single diastereomer, followed by TBAF deprotection of the primary alcohol to afford (±)-386b in almost quantitative yield (Scheme 105).

Scheme 105. Preparation of lactone (±)-386b.

The Mitsunobu conditions described above were used to assemble the C-O bond between lactone (±)-386b and di-TBS protected indandione 385, leading to (±)-384b in 36% yield.

Refluxing (±)-384b in chlorobenzene resulted in a cascade of CO2 extrusion/IMDA cycloaddition, which furnished the core framework of lucidumone (427) in 66% yield (Scheme 106). Remarkably, the disfavored electron demand could be overcome without the need of functional group transformation. This is probably due to the spatial proximity between the diene and dienophile, thanks to the alkoxy tether.

Scheme 106. Assembly of the core framework of lucidumone.

Attempts for Installation of Methyl Ketone from Corresponding Ester

Next, we needed to introduce the methyl ketone moiety by converting the ester moiety of (±)-

427.

Many protocols for preparing methyl ketone from corresponding ester have been reported, as concluded in Scheme 107.

Scheme 107. Feasible synthetic routes to methyl ketone from corresponding ester.

The most popular is Weinreb ketone synthesis, in which Weinreb amide was prepared from corresponding acid derivatives before the nucleophilic addition of organometallic reagents, such as Grignard reagent, organolithium reagent, and organocopper. However, we failed to synthesize Weinreb amide (±)-428 in one step, which is presumably due to the steric hindrance of the ester moiety (Scheme 108). Moreover, we observed that the deprotected by-product (±)-437 was formed when nBuLi was used, which illustrated the instability of TBS-protected indandione under basic conditions. To better understand the competition between two carbonyl groups, we subjected (±)-427 to an excess amount of methylmagnesium bromide. Although the reaction was run at room temperature overnight, we still recovered 83% of starting (±)-427, indicating that both of two carbonyl groups are difficult to be attacked by organometallic reagents (Scheme 109). Similarly, direct thioesterification of (±)-427 was also plagued by the deprotection and failed to provide the thioester (Scheme 110).

Scheme 108. Attempts for preparation of Weinreb amide from corresponding ester.

Scheme 109. Control experiment of methyl ketone with excess Grignard reagent.

Scheme 110. Attempts for preparation of thioester from corresponding ester.

As shown in Scheme 107, the multistep amide synthesis requires hydrolysis of ester into carboxylic acid. Moreover, carboxylic acid is the essential precursor to synthesize thioester and acid chloride, both of which could furnish methyl ketone through coupling reactions. 105,107 Particularly, the condensation reaction between carboxylic acid and amine has been widely reported. This transformation could be promoted by the use of activating reagents, such DCC, through the formation of more reactive acylating intermediate in situ from carboxylic acid. 108 Alternatively, the catalytic condensation of carboxylic acid and amine also caught our attention because of its mild reaction conditions 109 , although we were concerned about the stability issue of TBS-protecting groups of (±)-427. Therefore, we attempted to prepare carboxylic acid (±)-429 by hydrolysis of ester (±)-427 (Scheme 111). Disappointingly, we observed a quick deprotection of (±)-427 in aqueous LiOH at 40 o C. We also failed to retard the occurrence of deprotection by lowering the reaction temperature.

Scheme 111. Attempts to prepare carboxylic acid by hydrolysis of corresponding ester.

From the above experiments, we concluded that (i) the ester moiety of (±)-427 is too sluggish towards nucleophilic addition reaction, and (ii) TBS-protecting groups of (±)-427 are labile 107 a) H. under basic conditions at high temperature or even at room temperature. Therefore, we thought that the conversion of ester (±)-427 to aldehyde (±)-434 could increase the reactivity towards nucleophilic addition, although a longer synthetic route would be required. Ester (±)-427 was exposed to LiAlH4 at 0 o C, resulting in the formation of alcohol (±)-433, followed by DMP oxidation to provide aldehyde (±)-434. Nucleophilic addition of methylmagnesium bromide onto (±)-434 at low temperature only gave secondary alcohol (±)-435 without any influence on the ketone moiety. Reoxidation of alcohol (±)-435 with Dess-Martin periodinane afforded methyl ketone (±)-436 (Scheme 112).

Scheme 112. Attempts for preparation of methyl ketone from corresponding ester.

Endgame of the Total Synthesis of (±)-Lucidumone

In the endgame, subjecting (±)-436 to Pd/C hydrogenation could reduce the C-C double bond completely within 2 hours, but debenzylation occurred slowly in a mixed solvent of MeOH and EtOAc. By changing the reaction solvent with THF, the reaction rate could be improved and (±)-439 was synthesized in 90% yield. The TBS-protecting groups were removed with TBAF, furnishing natural product (±)-lucidumone (370) in 97% yield (Scheme 113).

Scheme 113. Endgame of the total synthesis of (±)-lucidumone.

Optimization of Reaction conditions

To achieve gram-scale synthesis of optically active natural product, we decided to optimize reaction conditions for some steps with low yields. Firstly, we reoptimized the reaction conditions for protection of hydroquinone 390. Screening of solvents and bases could improve the yield slightly to 66% (entries 3-4 and 7, Table 12). Further optimization of the ratio of TBSCl and Et3N gave the optimal condition, providing di-TBS protected hydroquinone 385 in 74% isolated yield (entry 5, Table 13). Surprisingly, we found that compound (±)-384b was labile at room temperature because the reaction for C-O bond formation is revisable. By shortening the reaction time, (±)-384b could be obtained in 50% yield (entry 2, Table 14). The use of DIAD to replace DEAD could improve the yield slightly (entry 3, Table 14). Several phosphines were then screened, but none of them could improve the yield (entries 4-5, Table 14). We also optimized the amount of PPh3 and DIAD, in which two equivalents of PPh3 and DIAD gave (±)-384b in 65% yield (entry 7, Table 14). By fine tuning the reaction temperature, (±)-384b could be isolated in 68% yield (entry 8, Table 14). Finally, the reduction for preparation of diol 433 was optimized. The original conditions could not be used for the scale-up reaction because this reaction was plagued by the deprotection of desired product (entry 1 vs entry 2, Table 15), but this problem could be tackled by changing the addition order (entry 3, Table 15). To further improve the yield, we decided to decrease the amount of reductant, which showed that 1.5 equivalents of LiAlH4 were sufficient for the reduction (entry 5, Table 15). Lowering the temperature to -20 o C could improve the yield slightly to 73%, whereas the reaction with -40 o C decreased the yield dramatically (entry 6 vs entry 7, Table 15). To fully convert the unreactive starting ester, we prolonged the reaction time to 1 hour, which could provide higher yield (entry 8, Table 15). The reaction with much longer reaction time did not improve the yield, but almost 6% of starting ester was recovered (entry 9, Table 15). To tackle this issue, more LiAlH4 was used, resulting in lower yield (entry 10, Table 15). To our delight, the reaction with Et2O could proceed more cleanly and gave 433 in 83% yield (entry 11, Table 15). By changing the addition order, the reaction could be scaled up to 15 mmol (entry 12, Table 15). a Ester/THF was added into LiAlH4/THF. b LiAlH4/Et2O(or THF in entry 3) was added into ester/Et2O(or THF in entry 3). c The isolated yield was based on the recovered starting material.

8 Gram-Scale Total Synthesis of (+)-Lucidumone

Our total synthesis began with the preparation of benzyl enol ether 344d (Scheme 114).

DABCO-catalyzed Michael addition of methyl propiolate (341) with benzyl alcohol gave enol ether 342d in quantitative yield. Reduction of 342d with excess DIBAL-H provided alcohol 343d in 95% yield, followed by TBS protection to afford benzyl enol ether 344d in good yield.

Scheme 114. Synthesis of benzyl enol ether 344d.

On the other hand, the synthesis of indandione fragment 385 was achieved starting from cycloaddition and subsequent IMDA cycloaddition could be achieved in one pot by refluxing (-)-384b in chlorobenzene, leading to the core framework (-)-427 in 77% yield. To introduce the methyl ketone, the multistep sequence described above, involving reduction of both the ester and the benzylic ketone using LiAlH4, Dess-Martin oxidation, Grignard addition and reoxidation was used. This sequence, although requiring 4 steps, is high yielding (65% over 4 steps) and can be performed in only two days as the reaction time for each step is short (30 min to 2 h). Moreover, the synthesis can be performed on multigram scale, and 4.49 g of intermediate (-)-436 can be easily obtained. From (-)-436 having all the carbon skeleton of lucidumone, reduction of the C 8' -C 9' olefin and cleavage of the benzyl protecting group could be achieved in one pot under hydrogenation conditions. It should be noted that although reduction of the alkene was completed in 2 hours, longer reaction times were required for the benzyl deprotection. Finally, deprotection of the phenol moieties allowed to complete the total synthesis of (+)-lucidumone (370), with high optical purity. Remarkably, the synthesis was highly scalable, as 1.61 g of natural product was obtained in one batch (Scheme 117).

Scheme 117. Gram-scale total synthesis of (+)-lucidumone.

Conclusion

To conclude, the first enantioselective total synthesis of (+)-lucidumone was achieved in 13 steps in the longest linear sequence with 25.8% overall yield from commercially available 341 (15.8% in 12 steps from 388). The synthesis was enabled by an enantioselective IEDDA reaction described in Section III, a key C-O bond formation for fragment assembly and a onepot CO2 extrusion/IMDA cycloaddition cascade. The sequence could be performed on gram scale, and over 1.6 g of natural product was synthesized in one batch, providing enough material for in-depth biological evaluation (Scheme 118).

Scheme 118.

General view of gram-scale total synthesis of (+)-lucidumone.

Conclusion and Perspectives

To date, much effort has been focused on exploiting IEDDA cycloadditions of 2-pyrones and their synthetic applications. In this thesis, we started with a comprehensive review in IEDDA cycloadditions of electron-deficient 2-pyrones with activated alkenes in the Chapter I, in which IEDDA cycloadditions could be divided into two types including non-catalytic IEDDA cycloaddition and catalytic IEDDA cycloaddition. Non-catalytic IEDDA cycloadditions promoted by direct heating or by high pressure were well developed. However, the poor thermostability of rigid structure in the initially formed bridged bicyclic lactones led to the formation of aromatic compounds under thermal conditions, which intrinsically limits their applications to the total synthesis (Scheme 119a).

To tackle this issue, two strategies have been explored, based on activating either dienes or Nevertheless, catalytic IEDDA reactions based on LUMO-activation strategy usually rely on 3-substituted 2-pyrones, the 1,3-dicarbonyl structure of which can serve as a good handle for the catalyst, but other substitution patterns of the 2-pyrone are not suitable for this type of activation. Delightfully, the HOMO-activation approach through organocatalysis provides a complement to this issue with broader substrate scope including 5-substituted 2-pyrones and α,β-unsaturated carbonyl compounds, although still in its infancy.

Moreover, the synthetic potential of IEDDA reactions of electrophilic 2-pyrones was greatly constricted by racemic bridged bicyclic adducts. Before the emergence of catalytic asymmetric IEDDA reactions of electrophilic 2-pyrones, the synthesis of enantioenriched bridged bicyclic lactones could only rely on chiral pool-based strategy. As the research in catalytic asymmetric IEDDA reactions progresses, we envision that more applications with the use of chiral bridged bicyclic lactones to the synthesis of natural products will emerge.

Therefore, the development of efficient catalytic systems for IEDDA reactions of electrophilic 2-pyrones with excellent chemo-, regio-and stereoselectivies, and further applications of these practical protocols remain a promising area that is worth deeply researching. We hope that this thesis will inspire the development of many new synthetic methodologies in the future, along with their applications to enantioselective natural product synthesis.

Experimental Section singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz), integration. Data for 13 C NMR and 19 F NMR were reported in chemical shift (ppm). ESI technique was used for the high-resolution mass (HRMS) measurements using Bruker Daltonics MicroTOF-Q spectrometer. The enantiomeric excesses were determined by HPLC analysis on Dionex Ultimate 3000 employing a chiral stationary phase column specified in the individual experiment, by comparing the samples with the corresponding racemic mixture.

Specific rotations were measured on Anton Paar MCP150 polarimeter, in which concentrations were synthesized according to the previous reports.

Synthesis of 2-Pyrones

Synthesis of 2-Pyrones 71a-71c, 71e

The synthesis of 2-pyrones 71a-71c and 71e was reported previously 22b,62 and taking the synthesis of 71a as an example.

Step one: To a stirred mixture of 1,1,3,3-tetramethoxypropane 331a (49.3 g, 300 mmol), anhydrous zinc chloride (409 mg, 3 mmol) and acetic anhydride (100 mL) was added dimethyl malonate 330a (39.6 g, 300 mmol) dropwise at room temperature. The reaction mixture was refluxed at 130 o C for 12 h and then cooled down to room temperature. The excess acetic anhydride was removed under reduced pressure (70 o C, 20 mbar) and the resulting reddish dark oil was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 9:1) to give a yellow oil.

Step two: The above product was dissolved in formic acid (88% aq., 100 mL) and then refluxed at 105 o C for 1 h. The resulting mixture was concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1→2:1) to afford 71a as a yellow solid (17.90 g, 39% over two steps).

Compound 71a:

Yellow solid (17.90 g, 39% over two steps).

Rf = 0.12 (petroleum ether/EtOAc = 1:1).

1 H NMR (300 MHz, CDCl3) δ 8.10 (dd, J = 6.9, 2.3 Hz, 1H), 7.65 (dd, J = 5.0, 2.3 Hz, 1H), 6.34 (dd, J = 6.9, 5.0 Hz, 1H), 3.74 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 163. 3, 157.3, 156.6, 148.9, 117.2, 105.9, 52.4. Analytical data were consistent with previously reported data. 62

Compound 71b:

Compound 71b was prepared in the same manner of 71a, except that diethyl malonate 330b and 1,1,3,3-tetraethoxypropane 331b were used as the starting materials.

Yellow solid (865 mg, 52% over two steps). Rf = 0.18 (petroleum ether/EtOAc = 1:1).

1 H NMR (360 MHz, CDCl3) δ 8.13 (dd, J = 6.7, 1.7 Hz, 1H), 7.66 (dd, J = 5.0, 1.7 Hz, 1H), 6.35 (dd, J = 6.7, 5.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C NMR (90 MHz, CDCl3) δ 163.0, 157. 4, 156.4, 148.5, 117.9, 105.9, 61.7, 14.1. Analytical data were consistent with previously reported data. 62

Compound 71c:

Compound 71c was prepared in the same manner of 71a, except that diisopropyl malonate 330c and 1,1,3,3-tetramethoxypropane 331a were used as the starting materials.

Yellow oil (724 mg, 40% over two steps).

Rf = 0.39 (petroleum ether/EtOAc = 1:1).

1 H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 6.8, 2.3 Hz, 1H), 7.65 (dd, J = 5.0, 2.3 Hz, 1H), 6.33 (dd,J = 6.8,5.0 Hz,1H),1H),1.33 (d,J = 6.3 Hz,6H). 13 C NMR (100 MHz, CDCl3) δ 162. 6, 157.4, 156.2, 147.9, 118.7, 105.8, 69.6, 21.9.

HRMS (ESI) m/z Calcd for C9H11O4

[M+H] + : 183.0652, found: 183.0644.

Compound 71e:

Compound 71e was prepared in the same manner of 71a, except that dibenzyl malonate 330e and 1,1,3,3-tetramethoxypropane 331a were used as the starting materials.

Yellow solid (845 mg, 37% over two steps).

Rf = 0.15 (petroleum ether/EtOAc = 1:1). 2H),3H),6.33 (dd,J = 6.8,5.1 Hz,1H),5.34 (s,2H). 13 C NMR (100 MHz, CDCl3) δ 162. 9, 157.3, 156.6, 148.7, 135.5, 128.6, 128.4, 128.2, 117.7, 105.8, 67.3. Analytical data were consistent with previously reported data. 62

Synthesis of 2-Pyrones 71d, 71f-71g

The synthesis of 2-pyrone-3-carbonyl chloride 334 was reported previously. 60a

Step one: A mixture of 71a (3.10 g, 20 mmol) and 12 M HCl (10 mL) was heated at 45°C overnight. Then water (20 mL) was added and the resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were concentrated under reduced pressure to give a dark viscous oil 333 which was used directly for the next step. 1 H NMR (360 MHz, CDCl3) δ 10.40 (br,1H),8.53 (d,J = 6.8 Hz,1H),1H), 6.67 (t, J = 5.9 Hz, 1H).

Step two: The above acid was heated with thionyl chloride (8 mL) at 80 o C overnight. The excess thionyl chloride was removed by atmospheric distillation (80 o C) to give acid chloride 334 as a brown solid which was dissolved in DCM (20 mL) and used directly for the next step.

Step three: (taking the synthesis of 71d as an example) To a mixture of tert-butanol (1.78 g, 24 mmol), triethylamine (3.4 mL, 24 mmol) in DCM (20 mL) under argon was added the above acid chloride solution dropwise at 0 o C. After being stirred at room temperature for 2 h, the resulting mixture was quenched with water (20 mL) and then extracted with DCM (3 × 20 mL).

The combined organic layers were concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 3:1→1:1) to give compound 71d (775 mg, 20% over three steps) as a yellow solid.

Compound 71d:

Yellow solid (775 mg, 20% over three steps).

Rf = 0.48 (petroleum ether/EtOAc = 1:1).

1 H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 6.8, 2.1 Hz, 1H), 7.61 (dd, J = 5.0, 2.2 Hz, 1H), 6.29 (dd, J = 6.8, 5.0 Hz, 1H), 1.49 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 161. 9, 157.6, 155.9, 147.4, 119.3, 105.7, 82.5, 28.0.

HRMS (ESI) m/z Calcd for C10H12NaO4

[M+Na] + : 219.0628, found: 219.0619.

Compound 71f:

White solid (225 mg, 11% over three steps).

Rf = 0.23 (petroleum ether/EtOAc = 1:1). .91 -1.80 (m, 2H), 1.74 -1.54 (m, 5H), 1.48 -1.33 (m, 2H), 1.27 -1.20 (m, 1H), 1.19 (s, 3H), 1.16 -0.96 (m, 3H), 0.94 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 199. 5, 171.0, 163.2, 157.2, 156.4, 148.1, 124.1, 118.5, 105.8, 84.1, 53.8, 50.3, 43.0, 38.7, 36.7, 35.8, 35.5, 34.0, 32.8, 31.6, 27.7, 23.7, 20.6, 17.5, 12.3.

HRMS (ESI) m/z

Calcd for C25H31O5 [M+H] + : 411.2166, found: 411.2151.

[α]D 25 = + 135.0 o (c = 1.00, CHCl3).

Compound 71g:

White solid (467 mg, 9% over three steps).

Rf = 0.48 (petroleum ether/EtOAc = 1:1). 5, 157.4, 156.2, 148.0, 139.6, 123.0, 118.7, 105.7, 75.7, 56.8, 56.3, 50.2, 42.4, 39.8, 39.6, 38.1, 37.1, 36.7, 36.3, 35.9, 32.0, 32.0, 28.3, 28.1, 27.8, 24.4, 24.0, 22.9, 22.7, 21.2, 19.5, 18.8, 12.0.

HRMS (ESI) m/z Calcd for C33H48NaO4

[M+Na] + : 531.3445, found: 531.3424.

[α]D 25 = -15.0 o (c = 1.00, CHCl3).

Synthesis of 2-Pyrone 71h

The synthesis of 2-pyrone 71h was reported previously. 76 To a solution of 2-pyrone 71a (1.0 g, 6.5 mmol) in DCM (20 mL) at 0 o C was added ethereal diazomethane slowly by an addition funnel. The mixture was stirred at room temperature for 6

h and then quenched with acetic acid (5 mL). The resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 1:1) to give compound 71h (0.83 g, 76%) as a yellow solid.

Compound 71h:

Yellow solid (0.83 g, 76%). Rf = 0.38 (petroleum ether/EtOAc = 1:1). 13 C NMR (100 MHz, CDCl3) δ 164. 9, 158.7, 155.5, 151.4, 119.3, 109.8, 52.6, 20.1. Analytical data were consistent with previously reported data. 76

Synthesis of 2-Pyrones 71i-71p

The synthesis of 2-pyrones 71i-71p was reported previously 62 and taking the synthesis of 71i as an example.

Step one: To a solution of 2-pyrone 71a (1.54 g, 10 mmol) in anhydrous THF (100 mL) under argon at -20 o C was added freshly prepared PhMgBr (0.1 M in THF, 100 mL) dropwise by an addition funnel. The mixture was stirred at -20 o C for 1 h and then quenched with NH4Cl (5% aq., 100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to give compound 335i (0.55 g, 24%) as a pale-yellow oil.

Step two: To a solution of above 335i (0.55 g, 2.37 mmol) in 1,4-dioxane ( 20

Compound 71i:

Yellow solid (0.55 g, 24% over two steps).

Rf = 0.14 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 7.56 (d,J = 5.4 Hz,1H),5H),6.38 (d,J = 5.4 Hz, 1H), 3.69 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 165. 2, 159.2, 154.0, 151.6, 135.4, 130.6, 129.1, 127.3, 119.2, 108.6, 52.8.

Analytical data were consistent with previously reported data. 62

Compound 71j:

Yellow solid (0.57 g, 22% over two steps).

Rf = 0.08 (petroleum ether/EtOAc = 3:1). 7, 161.7, 159.5, 153.4, 151.3, 129.1, 127.4, 118.1, 114.6, 108.5, 55.5, 52.9.

HRMS (ESI) m/z Calcd for C14H13O5

[M+H] + : 261.0757, found: 261.0753.

Compound 71k:

White solid (0.36 g, 14% over two steps).

Rf = 0.04 (petroleum ether/EtOAc = 5:1).

1 H NMR (400 MHz, CDCl3) δ 7.56 (d,J = 5.4 Hz,1H),7.42 (d,J = 8.7 Hz,2H),7.34 (d,J = 8.7 Hz,2H),6.33 (d,J = 5.4 Hz,1H),3.71 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 164. 9, 158.9, 152.7, 151.8, 136.9, 133.8, 129.4, 128.7, 119.4, 108.2, 52.9.

Analytical data were consistent with previously reported data. 62

Compound 71l:

White solid (0.38 g, 8% over two steps). Rf = 0.10 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 7.55 (d,J = 5.4 Hz,1H),2H),2H),6.35 (d,J = 5.4 Hz,1H),3.67 (s,3H). 13 C NMR (90 MHz, CDCl3) δ 165. [START_REF]) δ 7[END_REF]163.9 (d,J = 251.9 Hz),159.1,152.9,151.7,131.4 (d,J = 2.9 Hz),129.4 (d,J = 8.9 Hz),119.0,116.3 (d,J = 22.1 Hz),108.4,52.8.

Compound 71m:

White solid (0.21 g, 7% over two steps).

Rf = 0.09 (petroleum ether/EtOAc = 3:1). 6, 158.7, 152.7, 152.2, 139.0, 132.2 (q, J = 32.9 Hz), 127.7, 126.0 (q, J = 3.4 Hz), 123.6 (q, J = 272.1 Hz), 119.8, 108.1, 52.9.

19 F NMR (235 MHz, CDCl3) δ - 62.7 --63.3 (m).

HRMS (ESI) m/z Calcd for C14H10F3O4

[M+H] + : 299.0526, found: 299.0527.

Compound 71n:

Brown solid (0.59 g, 22% over two steps).

Rf = 0.10 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 7.51 (d,J = 5.5 Hz,1H),1H),2H),6.33 (d,J = 5.5 Hz,1H),6.01 (s,2H),3.73 (s,3H). 13 C NMR (90 MHz, CDCl3) δ 165. 5, 159.3, 153.3, 151.4, 149.8, 148.5, 129.0, 122.1, 118.3, 108.9, 108.5, 107.5, 101.9, 52.9.

Analytical data were consistent with previously reported data. 62

Compound 71o:

Yellow oil (0.33 g, 14% over two steps).

Rf = 0.10 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 7.56 (d,J = 5.4 Hz,1H),2H),7.21 (d,J = 7.8 Hz, 2H), 6.41 (d, J = 5.4 Hz, 1H), 3.69 (s, 3H), 2.39 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 165. 2, 159.2, 154.1, 151.5, 138.9, 135.2, 131.3, 128.9, 127.7, 124.2, 118.8, 108.5, 52.6, 21.3.

HRMS (ESI) m/z Calcd for C14H13O4

[M+H] + : 245.0808, found: 245.0805.

Compound 71p:

Colorless oil (0.23 g, 10% over two steps). Rf = 0.15 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 7.57 (d,J = 5.4 Hz,1H),3H), 7.10 (dd, J = 7.5, 0.9 Hz, 1H), 6.24 (d,J = 5.4 Hz,1H),3.56 (s,3H),2.26 (s,3H). 13 C NMR (90 MHz, CDCl3) δ 164. 3, 158.9, 156.3, 151.4, 135.4, 134.4, 130.5, 129.5, 126.8, 125.9, 120.3, 109.2, 52.4, 19.7.

HRMS (ESI) m/z Calcd for C14H13O4

[M+H] + : 245.0808, found: 245.0804.

Synthesis of 2-Pyrones 71q-71s

The synthesis of 2-pyrones 71q-71s was reported previously 62 and taking the synthesis of 71q as an example.

Step one: To a stirred mixture of 336q (450 mg, 3.95 mmol) in acetic anhydride ( 10 and the residue 337q was used directly for the next step without further purification.

Step two: The above product was dissolved in formic acid (88% aq., 5 mL) and then refluxed at 105 o C for 1 h. The resulting mixture was concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1→2:1) to afford 71q as a pale-yellow solid (0.18 g, 24% over two steps).

Compound 71q:

Pale-yellow solid (0.18 g, 24% over two steps).

Rf = 0.09 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 7.99 (s, 1H), 7.41 (s, 1H), 4.26 (q, J = 7.0 Hz, 2H), 1.99 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H). 13 C NMR (90 MHz, CDCl3) δ 163. 1, 157.5, 152.3, 151.6, 116.9, 114.7, 61.6, 14.4, 14.1.

HRMS (ESI) m/z Calcd for C9H11O4

[M+H] + : 183.0652, found: 183.0649.

Analytical data were consistent with previously reported data. 62

Compound 71r:

Yellow oil (0.36 g, 23% over two steps).

Rf = 0.30 (petroleum ether/EtOAc = 1:1).

1 H NMR (360 MHz, CDCl3) δ 7.99 (s, 1H), 7.38 (s, 1H), 4.22 (q, J = 7.0 Hz, 2H), 2.29 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.6 Hz, 3H). 13 C NMR (90 MHz, CDCl3) δ 163.0, 157. 5, 151.8, 150.4, 120.5, 117.1, 61.5, 22.2, 14.0, 13.7.

HRMS (ESI) m/z Calcd for C10H13O4

[M+H] + : 197.0808, found: 197.0806.

Compound 71s:

Yellow oil (0.37 g, 35% over two steps).

Rf = 0.27 (petroleum ether/EtOAc = 1:1). 6, 157.9, 151.3, 149.4, 125.1, 117.7, 61.9, 28.7, 22.4, 14.3.

HRMS (ESI) m/z Calcd for C11H15O4

[M+H] + : 211.0965, found: 211.0962.

Synthesis of 2-Pyrones 71t-71w

The synthesis of 2-pyrones 71t-71w was reported previously 62 and taking the synthesis of 71t as an example.

Step one: To a stirred mixture of NaH (60% in mineral oil, 0. 44 g, 11 mmol) and activated 4 Å molecular sieves (0.80 g) was added a solution of aldehyde 338t (1.20 g, 10 mmol) in DMSO (10 mL). The mixture was stirred at room temperature for 1 h and then dimethyl methoxymethylenemalonate 339 (2.10 g, 12 mmol) in DMSO (10 mL) was added. After being stirred at room temperature for 22 h, the mixture was quenched with aqueous 1 M HCl to pH = 4 at 0 o C and diluted with water (150 mL). The resulting mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was used directly for the next step without further purification.

Step two: The above product was dissolved in acetic acid (20 mL) and then refluxed at 120 o C for 16 h. The resulting mixture was concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1→3:1) to afford 71t as a yellow solid (0.76 g, 33% over two steps).

Compound 71t:

Yellow solid (0.76 g, 33% over two steps).

Rf = 0.31 (petroleum ether/EtOAc = 2:1). 7, 157.0, 152.6, 149.5, 132.4, 129.4, 128.7, 126.0, 120.5, 117.0, 52.9.

Analytical data were consistent with previously reported data. 62

Compound 71u:

Yellow solid (0.82 g, 70% over two steps).

Rf = 0.23 (petroleum ether/EtOAc = 2:1). 8, 157.1, 152.2, 149.6, 138.7, 130.0, 129.4, 125.8, 120.5, 116.9, 52.8, 21.1. Analytical data were consistent with previously reported data. 62

Compound 71v:

Yellow solid (0.41 g, 26% over two steps).

Rf = 0.23 (petroleum ether/EtOAc = 2:1). 8, 156.8, 152.7, 149.1, 132.7, 131.5, 127.7, 123.2, 119.8, 117.4, 53.1. Analytical data were consistent with previously reported data. 62

Compound 71w:

Yellow solid (0.38 g, 18% over two steps).

Rf = 0.26 (petroleum ether/EtOAc = 2:1). 6,163.0 (d,J = 248.7 Hz),156.8,152.5,149.3,128.6 (d,J = 3.5 Hz),127.9 (d,J = 8.4 Hz),119.7,117.0,116.4 (d,J = 21.7 Hz), 52.9.

19 F NMR (235 MHz, CDCl3) δ - 112.5 --112.7 (m).

HRMS (ESI) m/z Calcd for C13H10FO4

[M+H] + : 249.0558, found: 249.0557.

Synthesis of Enol Ethers

Synthesis of Enol Ethers 344a-344e, 344j-344l, 344n

The synthesis of allyl alcohols 343 was reported previously. 77 Step one: To a stirred mixture of DABCO (10 mol%) and alcohol (1.1 equiv.) in THF ( 2mL/mmol based on methyl propiolate) at room temperature was added methyl propiolate 341

(1.0 equiv.) dropwise by an addition funnel. The mixture was stirred at room temperature for an additional 30 min and then NaOH (1.0 M aqueous solution, 2 mL/mmol based on methyl propiolate) was added. The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure (rotavapor conditions: 400 mbar, 38 o C) to give ester 342 as a colorless liquid which was used directly for the next step.

Step two: To a stirred mixture of ester 342 (1.0 equiv.) prepared in the Step one in DCM (0.5 mL/mmol based on methyl propiolate) at -78 o C under argon was added DIBAL-H (2.2 equiv.,

1.0 M in hexane) dropwise. This mixture was stirred at -78 o C for 1 h and at room temperature for an additional 1 h, then quenched with MeOH (0.5 mL/mmol based on methyl propiolate).

After that Rochelle's salt (10% aqueous solution, 2 mL/mmol based on methyl propiolate) was added at -78 o C and the mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure (rotavapor conditions: 400 mbar, 38 o C) and further purified by flash column chromatography (silica gel, pentane/Et2O = 1:1→Et2O) to afford alcohol 343.

Step three: To a stirred mixture of alcohol 343 (1.0 equiv.) in DCM (1 mL/mmol based on 343) at 0 o C was added imidazole (2 equiv.) and [Si]-Cl (1.5 equiv.). The mixture was stirred at 0 o C for 10 min and at room temperature for an additional 1 h. Then H2O (2 mL/mmol based on 343)

was added. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure (rotavapor conditions: 300 mbar, 38 o C) and further purified by flash column chromatography (silica gel, pentane/Et2O/Et3N = 50:5:1) to afford enol ether 344a-344e, 344j-344l, 344n.

Compound 344a:

Colorless oil (8.98 g, 74% over three steps).

Rf = 0.70 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6.48 (d,J = 12.6 Hz,1H),4.89 (dt,J = 12.6,6.9 Hz, 1H), 4.10 (dd, J = 6.9, 1.1 Hz, 2H), 3.52 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 149. 7, 102.3, 61.3, 55.9, 26.1, 18.5, -4.9.

HRMS (ESI) m/z

Calcd for C10H21O2Si [M-H] -: 201.1316, found: 201.1299.

Compound 344b:

Colorless oil (1.80 g, 83% over three steps).

Rf = 0.70 (petroleum ether/EtOAc = 5:1). (dd, J = 6.9, 0.9 Hz, 2H), 3.74 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 148.8, 103.2, 64.8, 61.4, 26.2, 18.6, 14.8, -4.8.

HRMS (ESI) m/z Calcd for C11H24NaO2Si

[M+Na] + : 239.1438, found: 239.1427.

Compound 344c:

Colorless oil (1.38 g, 60% over three steps).

Rf = 0.64 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6.29 (d,J = 12.4 Hz,1H),4.99 (dt,J = 12.4,6.9 Hz, 1H), 4.08 (dd, J = 6.9, 1.1 Hz, 2H), 4.05 -3.93 (m, 1H), 1.22 (d, J = 6.2 Hz, 6H), 0.89 (s, 9H), 0.06 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 147. 6, 104.8, 72.8, 61.4, 26.1, 22.2, 18.5, -4.8.

HRMS (ESI) m/z Calcd for C12H26NaO2Si

[M+Na] + : 253.1594, found: 253.1585.

Compound 344d:

Colorless oil (2.64 g, 95% over three steps).

Rf = 0.68 (petroleum ether/EtOAc = 5:1). 5, 136.9, 128.6, 128.0, 127.7, 104.1, 71.2, 61.3, 26.1, 18.5, -4.9.

HRMS (ESI) m/z Calcd for C16H26NaO2Si

[M+Na] + : 301.1594, found: 301.1584.

Compound 344e:

Colorless oil (1.29 g, 56% over three steps).

Rf = 0.56 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6.44 (d,J = 12.6 Hz,1H),1H),1H),1H),4.96 (dt,J = 12.6,6.8 Hz,1H),4.22 (dt,J = 5.4,1.3 Hz,2H), 4.09 (dd, J = 6.8, 1.2 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 148. 3, 133.4, 117.7, 103.9, 70.1, 61.3, 26.1, 18.5, -4.9.

HRMS (ESI) m/z Calcd for C12H24NaO2Si

[M+Na] + : 251.1438, found: 251.1429.

Compound 344j:

Colorless oil (0.69 g, 56% over three steps).

Rf = 0.65 (petroleum ether/EtOAc = 3:1). Poor thermostability prevented ESI-HRMS analysis.

Compound 344k:

Colorless oil (1.14 g, 73% over three steps).

Rf = 0.63 (petroleum ether/EtOAc = 3:1).

1 H NMR (400 MHz, CDCl3) δ 6.50 (d,J = 12.6 Hz,1H),4.92 (dt,J = 12.6,7.2 Hz, 1H), 4.09 (dd, J = 7.2, 0.7 Hz, 2H), 3.54 (s, 3H), 0.96 (t, J = 8.0 Hz, 9H), 0.61 (q, J = 8.0 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 149. 9, 102.3, 60.9, 56.0, 6.9, 4.7.

Poor thermostability prevented ESI-HRMS analysis.

Compound 344l:

Colorless oil (1.44 g, 74% over three steps).

Rf = 0.69 (petroleum ether/EtOAc = 3:1).

1 H NMR (400 MHz, CDCl3) δ 6.51 (d,J = 12.6 Hz,1H),4.93 (dt,J = 12.6,6.6 Hz,1H),4.18 (dd, J = 6.6, 0.8 Hz, 2H), 3.54 (s, 3H), 1.14 -1.04 (m, 21H). 13 C NMR (100 MHz, CDCl3) δ 149. 4, 102.6, 61.4, 56.0, 18.2, 12.2.

HRMS (ESI) m/z Calcd for C13H28NaO2Si

[M+Na] + : 267.1751, found: 267.1746.

Compound 344n:

Colorless oil (2.98 g, 91% over three steps). 3, 104.4, 80.7, 61.5, 47.9, 41.2, 34.5, 31.6, 26.2, 25.8, 23.5, 22.3, 20.9, 18.5, 16.4, -4.8.

Rf

HRMS (ESI) m/z Calcd for C19H38NaO2Si

[M+Na] + : 349.2533, found: 349.2516.

[α]D 25 = -32.0 o (c = 1.00, CHCl3).

Synthesis of Enol Ethers 344f-344g, 344o-344p

The synthesis of enol ethers 344f-344g and 344o-344p was reported previously 78 and taking the synthesis of 344f and 344o as an example.

To a stirred mixture of propionaldehyde (1.16 g, 20 mmol) in DCM (20 mL) at 0 o C was added DBU (3.65 g, 24 mmol) and TBSCl (3.31 g, 22 mmol). The mixture was stirred at room temperature for 12 h and then H2O (15 mL) was added. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure (rotavapor conditions: 400 mbar, 38 o C) and further purified by flash column chromatography (silica gel, pentane/Et3N = 200:1) to afford two enol ethers 344f and 344o as colorless oil.

Compound 344f:

Colorless oil (1. 62 g, 47%). Rf = 0.39 (petroleum ether).

1 H NMR (360 MHz, CDCl3) δ 6.22 (dq, J = 11.8, 1.5 Hz, 1H), 4.98 (dq, J = 11.8, 6.8 Hz, 1H), 1.51 (dd, J = 6.8, 1.6 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 140. 6, 105.8, 25.9, 18.4, 12.3, -5.1. Analytical data were consistent with previously reported data. 119

Compound 344o:

Colorless oil (1. 20 g, 35%). Rf = 0.52 (petroleum ether).

1 H NMR (360 MHz, CDCl3) δ 6.19 (dq, J = 6.0, 1.8 Hz, 1H), 4.50 (dq, J = 6.8, 6.0 Hz, 1H), 119 T. Amatov, N. Tsuji, R. Maji, L. Schreyer, H. Zhou, M. Leutzsch, B. List, J. Am. Chem. Soc. 2021, 143, 14475-14481.

1.58 (dd, J = 6.8, 1.8 Hz, 3H), 0.93 (s, 9H), 0.13 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 139. 4, 105.0, 25.8, 18.5, 9.1, -5.2.

Analytical data were consistent with previously reported data. 119

Compound 344g:

Colorless oil (0. 48 g, 13%).

Rf = 0.27 (petroleum ether).

1 H NMR (360 MHz, CDCl3) δ 6.23 (dt, J = 11.9, 1.3 Hz, 1H), 5.02 (dt, J = 11.9, 7.2 Hz, 1H), 1.90 (pd, J = 7.3, 1.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 139. 7, 113.6, 25.9, 20.9, 18.5, 15.3, -5.1.

HRMS (ESI) m/z Calcd for C20H44NaO2Si2

[2M+Na] + : 395.2778, found: 395.2773.

Compound 344p:

Colorless oil (0.33 g, 9%). Rf = 0.36 (petroleum ether).

1 H NMR (360 MHz, CDCl3) δ 6.14 (dt, J = 5.8, 1.5 Hz, 1H), 4.45 (td, J = 7.1, 5.9 Hz, 1H), 2.10 (pd, J = 7.5, 1.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 138. 1, 112.8, 25.8, 18.5, 17.2, 14.5, -5.3.

Poor thermostability prevented ESI-HRMS analysis.

Synthesis of Enol Ether 344h

To a stirred mixture of 3-phenylpropionaldehyde (1.34 g, 10 mmol) and TBSCl (1.81 g, 12 mmol) in CH3CN (10 mL) at 0 o C was added DBU (1. 83 g, 12 mmol) dropwise. This mixture was stirred at 65 o C for 12 h and then H2O (20 mL) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/Et3N = 200:1) to afford enol ether 344h as colorless oil.

Compound 344h:

Colorless oil (0. 83 g, 33%).

Rf = 0.13 (petroleum ether).

1 H NMR (360 MHz, CDCl3) δ 7.37 -7.15 (m, 5H), 6.38 (dt, J = 11.9, 1.3 Hz, 1H), 5.20 (dt, J = 11.9, 7.5 Hz, 1H), 3.27 (d, J = 7.5 Hz, 2H), 0.97 (s, 9H), 0.18 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 141. 7, 141.5, 128.4, 128.4, 126.0, 110.3, 33.8, 25.9, 18.5, -5.0.

HRMS (ESI) m/z Calcd for C30H48NaO2Si2

[2M+Na] + : 519.3091, found: 519.3070.

Synthesis of Enol Ethers 344i and 344m

To an oven-dried flask with a magnetic stir bar was added NaH (60 % in mineral oil, 0.28 g, 7.0 mmol). This flask was evacuated and then refilled with argon. THF (5 mL) was added. The mixture was stirred at 0 o C and a solution of alcohol 343a (0.50 g, 5.6 mmol) in THF (5 mL) was added. This mixture was stirred at 0 o C for 5 min followed by the addition of alkyl halide (8.5 mmol). The resulting mixture was stirred at room temperature for 2 h and then quenched with H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure (rotavapor conditions for 344i: 560 mbar, 37 o C; for 344m: 70 mbar, 37 o C).

Compound 344i:

Iodomethane was used as alkyl halide. The boiling point of 344i is so low that 344i could not be purified by flash column chromatography. Therefore, 344i was used directly without purification.

Colorless oil (0.52 g, ca. 56 wt% in the mixture, 50% yield).

Rf = 0.38 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 6.52 (d,J = 12.7 Hz,1H),4.85 (dt,J = 12.7,7.4 Hz, 1H), 3.79 (dd, J = 7.4, 0.7 Hz, 2H), 3.52 (s, 3H), 3.25 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 151. 6, 98.7, 70.0, 57.1, 55.9.

Poor thermostability prevented ESI-HRMS analysis.

Compound 344m:

Benzyl bromide was used as alkyl halide. The crude product was purified by flash column chromatography (silica gel, pentane/Et2O/Et3N = 50:5:1).

Colorless oil (1.00 g, 99%). Rf = 0.45 (petroleum ether/EtOAc = 3:1). 7, 138.5, 128.5, 127.9, 127.6, 98.9, 71.5, 67.8, 55.9.

HRMS (ESI) m/z Calcd for C11H14NaO2

[M+Na] + : 201.0886, found: 201.0883.

Synthesis of Enol Ether 344q

The synthesis of ester 345 was reported previously. 79 To a stirred mixture of AgOTf (257 mg, 1 mmol) in methanol (5.0 mL) was added methyl propiolate (0.90 mL, 10 mmol) slowly. This mixture was stirred at room temperature for 20 h and then saturated NaCl aqueous solution (5 mL) was added. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure (rotavapor conditions: 400 mbar, 38 o C) to give crude 345 as a colorless liquid which was used directly for DIBAL-H reduction and TBS-protection described above to afford 344q as a colorless oil (1.53 g, 76% over three steps).

Compound 344q:

Colorless oil (1.53 g, 76% over three steps).

Rf = 0.60 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 5.89 (d, J = 6.2 Hz, 1H), 4.55 (q, J = 6.5 Hz, 1H), 4.26 (d, J = 6.7 Hz, 2H), 3.59 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 146.9, 106.9, 59.9, 56.9, 26.1, 18.5, -5.0.

HRMS (ESI) m/z Calcd for C10H22NaO2Si

[M+Na] + : 225.1281, found: 225.1273.

Synthesis of Enol Ether 344r

The synthesis of allyl alcohol 349 was reported previously. 80 To a stirred mixture of ethyl acetoacetate (3.20 mL, 25 mmol) and trimethyl orthoformate (2.74 mL, 25 mmol) at 0 o C was added concentrated H2SO4 (0.10 mL) dropwise. The mixture was stirred at room temperature for 36 h and then quinoline (0.25 mL) was added. The residue was purified by flash column chromatography (silica gel, pentane/Et2O = 20:1) to give the corresponding ester as a colorless oil (1.40 g, 39%) which was used for DIBAL-H reduction and TBS-protection described above to afford 344r as a colorless oil (1.42 g, 66% over two steps).

Compound 344r:

(0.5 mL). This mixture was cooled at 0 o C and DIPEA (6.2 mg, 0.048 mmol) was added. The

Asymmetric IEDDA Cycloaddition

Preparation of catalyst: To an oven-dried microwave vial with a magnetic stir bar was added CuCl2 (2.1 mg, 0.015 mmol), BOX ligand L9 (4.6 mg, 0.015 mmol) and DCM (0.2 mL). This solution was stirred at room temperature for 1 h to afford a green solution. Then AgSbF6 (10 mg, 0.030 mmol) was added to this green solution and the mixture was further stirred at room temperature without light for 1 h to afford a deep green suspension. This suspension was filtered through a short column of Celite and rinsed with DCM (0.3 mL) to give a deep green solution which should be used immediately for the cycloaddition.

To another oven-dried microwave vial with a magnetic stir bar was added 2-pyrone 71 (0.30 mmol) and activated 4Å molecular sieves (45 mg). This vial was evacuated, refilled with argon and cooled at -78 o C. The above prepared catalyst solution was added to this mixture by syringe.

After being stirred at - 5, 167.5, 130.8, 130.1, 77.6, 75.2, 62.6, 61.6, 57.9, 53.1, 49.2, 25.9, 18.4, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C17H28NaO6Si

[M+Na] + : 379.1547, found: 379.1538.

[α]D 25 = -33.0 o (c = 1.00, CHCl3).

Racemic compound 351a:

White solid. This bridged bicyclic lactone was crystallized from EtOAc, and its stereochemistry was established by X-ray crystallography. Rf = 0.18 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6.53 (dd, J = 7.7, 5.0 Hz, 1H), 6.39 (dd, J = 7.7, 1.8 Hz, 1H), 5.18 (s, 1H), 3.89 (s, 3H), 3.54 (dd, J = 10.2, 7.1 Hz, 1H), 3.45 -3.30 (m, 5H), 2.61 -2.47 (m, 1H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168. 6, 166.8, 132.6, 130.3, 78.9, 75.3, 64.3, 60.0, 58.2, 53.1, 49.1, 25.9, 18.3, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C17H29O6Si

[M+H] + : 357.1728, found: 357.1716.

Compound 350b:

White solid (88.4 mg, 80% yield, 96% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 220 nm, t 1 = 6.64 min (major), t 2 = 8.15 min (minor).

Rf = 0.42 (petroleum ether/EtOAc = 3:1). 6, 167.0, 130.8, 130.3, 77.6, 75.2, 62.7, 62.2, 61.6, 58.0, 49.4, 26.0, 18.4, 14.2, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C18H31O6Si

[M+H] + : 371.1884, found: 371.1874.

[α]D 25 = -18.0 o (c = 1.00, CHCl3).

Compound 350c:

Pale-yellow oil (89.7 mg, 78% yield, 96% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 220 nm, t 1 = 8.87 min (major), t 2 = 11.30 min (minor). Rf = 0.30 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6.77 (d,J = 7.7 Hz,1H),1H),2H), 3.77 -3.61 (m, 3H), 3.30 (s, 3H), 2.00 (t, J = 8.1 Hz, 1H), 1.32 (dd, J = 10.3, 6.3 Hz, 6H), 0.89 (s, 9H), 0.07 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 168. 6, 166.4, 130.7, 130.3, 77.5, 75.1, 69.9, 62.7, 61.4, 57.9, 49.4, 25.9, 21.8, 18.4, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C19H33O6Si

[M+H] + : 385.2041, found: 385.2034.

[α]D 25 = -28.0 o (c = 1.00, CHCl3).

Compound 350d:

White solid (110.0 mg, 92% yield, 99% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 220 nm, t 1 = 6.14 min (major), t 2 = 8.60 min (minor).

Rf = 0.44 (petroleum ether/EtOAc = 5:1). 13 C NMR (90 MHz, CDCl3) δ 168.9, 165.9, 130.6 (two peaks), 82.9, 77.8, 75.1, 62.7, 61.9, 58.1, 49.5, 28.1, 26.0, 18.4, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C20H35O6Si

[M+H] + : 399.2197, found: 399.2179.

[α]D 25 = -29.0 o (c = 1.00, CHCl3).

Compound 350e:

White solid (97.5 mg, 75% yield, 95% ee). The enantiomeric excess was determined by chiral 13 C NMR (90 MHz, CDCl3) δ 168. 4, 166.9, 135.4, 130.8, 130.1, 128.6, 128.5, 128.3, 77.5, 75.2, 67.8, 62.6, 61.7, 57.8, 49.2, 26.0, 18.4, -5.4, -5.4.

HRMS (ESI) m/z Calcd for C23H33O6Si

[M+H] + : 433.2041, found: 433.2031.

[α]D 25 = -35.0 o (c = 1.00, CHCl3).

Compound 350f:

White solid (139.0 mg, 76% yield, >20:1 dr).

Rf = 0.42 (petroleum ether/EtOAc = 1:1). 13 C NMR (100 MHz, CDCl3) δ 199. 5, 171.0, 168.5, 166.9, 130.7, 130.3, 124.1, 84.0, 77.7, 75.3, 62.8, 61.7, 58.0, 53.8, 50.4, 49.5, 43.1, 38.7, 36.6, 35.8, 35.6, 34.0, 32.8, 31.6, 27.4, 26.0, 23.6, 20.6, 18.4, 17.5, 12.1, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C35H53O7Si

[M+H] + : 613.3555, found: 613.3525.

[α]D 25 = + 54.0 o (c = 1.00, CHCl3).

Compound 350g:

White solid (143.4 mg, 67% yield, >20:1 dr). Rf = 0.48 (petroleum ether/EtOAc = 5:1). 6, 166.4, 139.5, 130.7, 130.5, 123.1, 77.6, 76.0, 75.2, 62.8, 61.6, 58.1, 56.8, 56.3, 50.2, 49.6, 42.5, 39.9, 39.7, 38.0, 37.1, 36.8, 36.3, 35.9, 32.1, 32.0, 28.4, 28.2, 27.8, 26.0, 24.4, 24.0, 23.0, 22.7, 21.2, 19.5, 18.9, 18.5, 12.0, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C43H71O6Si

[M+H] + : 711.5014, found: 711.5005.

[α]D 25 = -28.0 o (c = 1.00, CHCl3).

Compound 350h:

White solid (87.6 mg, 79% yield, 92% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 10 o C, λ = 210 nm, t 1 = 8.24 min (major), t 2 = 9.59 min (minor).

Rf = 0.43 (petroleum ether/EtOAc = 3:1). 2, 167.5, 140.2, 124.8, 77.8, 74.2, 64.5, 62.7, 57.8, 52.7, 49.4, 26.0, 20.7, 18.4, -5.4, -5.4.

HRMS (ESI) m/z Calcd for C18H31O6Si

[M+H] + : 371.1884, found: 371.1883.

[α]D 25 = -49.0 o (c = 1.00, CHCl3).

Compound 350i:

White solid (130.0 mg, >99% yield, 96% ee). The enantiomeric excess was determined by 7, 167.5, 143.7, 137.5, 128.1, 128.0, 126.8, 126.7, 76.6, 74.4, 65.3, 62.6, 58.0, 52.3, 50.2, 26.0, 18.4, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C23H33O6Si

[M+H] + : 433.2041, found: 433.2032.

[α]D 25 = + 64.0 o (c = 1.00, CHCl3).

Compound 350j:

White solid (128.3 mg, 92% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 240 nm, t 1 = 10.04 min (minor), t 2 = 14.03 min (major).

Rf = 0.37 (petroleum ether/EtOAc = 3:1). 8, 167.7, 159.5, 143.2, 129.9, 127.9, 125.6, 113.5, 76.7, 74.5, 65.2, 62.6, 57.9, 55.3, 52.4, 50.2, 26.0, 18.4, -5.4, -5.4.

HRMS (ESI) m/z Calcd for C24H35O7Si

[M+H] + : 463.2147, found: 463.2147.

[α]D 25 = + 52.0 o (c = 1.00, CHCl3).

Compound 350k:

White solid (140.2 mg, >99% yield, 86% ee). The enantiomeric excess was determined by (s, 3H), 3.51 (s, 3H), 2.18 -2.02 (m, 1H), 0.92 (s, 9H), 0.10 (s, 3H), 0.10 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168. 5, 167.3, 142.7, 136.0, 134.0, 128.3, 128.2, 127.4, 76.5, 74.4, 65.2, 62.5, 57.9, 52.5, 50.0, 26.0, 18.4, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C23H32ClO6Si

[M+H] + : 467.1651, found: 467.1640.

[α]D 25 = + 95.0 o (c = 1.00, CHCl3).

Compound 350l:

White solid (135.2 mg, >99% yield, 87% ee). The enantiomeric excess was determined by 76.6, 74.4, 65.3, 62.5, 58.0, 52.4, 50.1, 25.9, 18.4, -5.3, -5.4.

19 F NMR (235 MHz, CDCl3) δ -113.9 --114.1 (m).

HRMS (ESI) m/z Calcd for C23H32FO6Si

[M+H] + : 451.1947, found: 451.1941.

[α]D 25 = + 84.0 o (c = 1.00, CHCl3).

Compound 350m:

White solid (151.0 mg, >99% yield, 88% ee). The enantiomeric excess was determined by 3, 167.1, 142.6, 141.2, 130.0 (q, J = 32.7 Hz), 128.6, 127.2, 125.1 (q, J = 3.4 Hz), 124.2 (q, J = 272.0 Hz), 76.5, 74.3, 65.2, 62.5, 58.0, 52.5, 50.0, 26.0, 18.4, -5.3, -5.4.

19 F NMR (235 MHz, CDCl3) δ -62.5.

HRMS (ESI) m/z Calcd for C24H32F3O6Si

[M+H] + : 501.1915, found: 501.1892.

[α]D 25 = + 79.0 o (c = 1.00, CHCl3).

Compound 350n:

White solid (137.0 mg, 96% yield, 87% ee). 6, 167.4, 147.5, 147.4, 143.2, 131.5, 126.1, 120.5, 108.0, 107.3, 101.2, 76.6, 74.3, 65.3, 62.5, 57.9, 52.4, 50.1, 25.9, 18.4, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C24H33O8Si

[M+H] + : 477.1939, found: 477.1940.

[α]D 25 = + 112.0 o (c = 1.00, CHCl3).

Compound 350o:

White solid (125.2 mg, 93% yield, 85% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 240 nm, t 1 = 6.24 min (minor), t 2 = 8.08 min (major). Rf = 0.46 (petroleum ether/EtOAc = 3:1). 123.8, 76.6, 74.4, 65.3, 62.6, 58.0, 52.3, 50.2, 26.0, 21.5, 18.4, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C24H35O6Si

[M+H] + : 447.2197, found: 447.2183.

[α]D 25 = + 92.0 o (c = 1.00, CHCl3).

Compound 350p:

White solid (121.6 mg, 91% yield, 92% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 6.98 min (minor), t 2 = 8.13 min (major).

Rf = 0.50 (petroleum ether/EtOAc = 3:1).

, 1H), 0.94 (s, 9H), 0.12 (s, 3H), 0.12 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168.9, 166.9, 142. 1, 137.0, 136.2, 129.8, 128.5, 127.6, 127.1, 125.2, 76.9, 74.2, 65.6, 62.7, 57.9, 52.2, 49.6, 26.0, 20.6, 18.4, -5.3, -5.4.

HRMS (ESI) m/z Calcd for C24H35O6Si

[M+H] + : 447.2197, found: 447.2186.

[α]D 25 = + 83.0 o (c = 1.00, CHCl3).

Compound 350q:

White solid (108.2 mg, 94% yield, 92% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.73 min (major), t 2 = 8.58 min (minor). Rf = 0.46 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 6. 39 -6.30 (m, 1H), 4.93 -4.86 (m, 1H), 4.44 -4.25 (m, 2H), 3.77 -3.61 (m, 3H), 3.31 (s, 3H), 2.01 -1.93 (m, 4H), 1.33 (t, J = 7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 169. 1, 167.2, 140.6, 122.1, 79.4, 78.5, 62.7, 62.1, 61.2, 58.0, 49.0, 26.0, 18.4, 17.7, 14.2, -5.3, -5.4. 3, 167.3, 146.2, 120.1, 78.6, 78.4, 62.7, 62.1, 61.2, 58.0, 49.4, 26.0, 25.0, 18.4, 14.2, 11.2, -5.3, -5.4.

HRMS (ESI

HRMS (ESI) m/z Calcd for C20H35O6Si

[M+H] + : 399.2197, found: 399.2193.

[α]D 25 = -6.0 o (c = 1.00, CHCl3).

Compound 350s:

Colorless oil (102.8 mg, 83% yield, 94% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 10 o C, λ = 210 nm, t 1 = 6.34 min (minor), t 2 = 7.48 min (major).

Rf = 0.50 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 6. 32 -6.24 (m, 1H), 5.12 -5.04 (m, 1H), 4.46 -4.26 (m, 2H), 3.79 -3.60 (m, 3H), 3.30 (s, 3H), 2.60 -2.44 (m, 1H), 1.95 -1.86 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.10 (dd, J = 6.8, 5.1 Hz, 6H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 169. 5, 167.4, 150.1, 119.0, 78.2, 77.4, 62.7, 62.1, 61.2, 58.0, 49.8, 30.9, 25.9, 20.3, 20.1, 18.3, 14.2, -5.3, -5.4. 6, 167.6, 142.6, 133.7, 129.1, 129.0, 125.2, 122.0, 78.4, 77.1, 62.6, 61.9, 57.9, 53.2, 49.4, 25.9, 18.4, -5.3, -5.4. 7, 167.7, 142.5, 139.1, 130.8, 129.7, 125.1, 120.8, 78.4, 77.1, 62.6, 61.8, 57.9, 53.1, 49.3, 25.9, 21.3, 18.3, -5.3, -5.4.

HRMS (ESI

HRMS (ESI

HRMS (ESI) m/z Calcd for C24H35O6Si

[M+H] + : 447.2197, found: 447.2185.

[α]D 25 = + 63.0 o (c = 1.00, CHCl3).

Compound 350v:

White solid (117.3 mg, 76% yield, 96% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 260 nm, t 1 = 6.42 min (major), t 2 = 7.98 min (minor).

Rf = 0.44 (petroleum ether/EtOAc = 3:1).

1 H NMR (360 MHz, CDCl3) δ 7.53 (d,J = 8.6 Hz,2H),7.32 (d,J = 8.6 Hz,2H),1H),1H),3.94 (s,3H),3H),3.31 (s,3H),1H), 0.92 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168. 3, 167.4, 141.7, 132.6, 132.3, 126.8, 123.2, 122.8, 78.3, 76.8, 62.5, 62.0, 58.0, 53.3, 49.5, 26.0, 18.4, -5.3, -5.4.

HRMS (ESI)

m/z Calcd for C23H31BrNaO6Si [M+Na] + : 533.0965, found: 533.0958.

[α]D 25 = + 52.0 o (c = 1.00, CHCl3).

Compound 350w:

White solid (96.0 mg, 71% yield, 97% ee). (m, 1H), 0.92 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168. 5,167.5,163.2 (d,J = 249.6 Hz),141.8,130.0 (d,J = 3.0 Hz),127.1 (d,J = 8.5 Hz),121.9,116.2 (d,J = 21.8 Hz),78.4,77.1,62.6,61.9,58.0,53.3,49.5,26.0,18.4,5.4. 7, 167.6, 130.7, 130.2, 75.8, 75.2, 65.8, 62.5, 61.7, 53.0, 49.8, 25.9, 18.4, 15.2, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C18H30NaO6Si

[M+Na] + : 393.1704, found: 393.1697.

[α]D 25 = -33.0 o (c = 1.00, CHCl3).

Compound 350y:

White solid (105.6 mg, 92% yield, 99% ee). 1 H NMR (360 MHz, CDCl3) δ 6. 1H),6.59 (dd,J = 7.8,5.1 Hz,1H),5.21 (dt,J = 5.1,1.4 Hz,1H),4H),3H),1H), 1.03 (dd, J = 9.6, 6.1 Hz, 6H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168.8, 167.6, 130.5 (two peaks), 75.2, 74.0, 71.4, 62.4, 61.8, 52.9, 50.5, 25.9, 23.3, 21.5, 18.4, -5.4, -5.5. 6, 167.5, 137.4, 130.9, 130.2, 128.5, 128.1, 128.0, 75.5, 75.2, 72.4, 62.0, 61.7, 53.0, 49.9, 25.9, 18.4, -5.4, -5.4. 1 H NMR (360 MHz, CDCl3) δ 6. 1H),6.61 (dd,J = 7.8,5.2 Hz,1H),1H),3H),1H),5H),3.75 (dd,J = 10.1,6.9 Hz, 1H), 3.65 -3.55 (m, 1H), 2.08 -1.95 (m, 1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168. 6, 167.5, 134.1, 130.8, 130.2, 117.6, 75.4, 75.1, 71.3, 62.2, 61.6, 53.0, 49.7, 25.9, 18.4, -5.4, -5.5. 9, 167.7, 130.8, 129.3, 79.5, 74.3, 63.0, 52.8, 43.8, 25.4, 17.7, 16.2, -4.4, -5.5.

HRMS (ESI) m/z

HRMS (ESI

HRMS (ESI

HRMS (ESI) m/z Calcd for C16H27O5Si

[M+H] + : 327.1622, found: 327.1619.

[α]D 25 = -36.0 o (c = 1.00, CHCl3).

Compound 350ac:

White solid (94.4 mg, 92% yield, 86% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® IF-3 (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 13.61 min (major), t 2 = 14.73 min (minor). This bridged bicyclic lactone was crystallized from acetone/EtOH (1:1), and its absolute configuration was established by X-ray crystallography.

Rf = 0.41 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6. 76 -6.70 (m, 1H), 6.58 (dd, J = 7.8, 5.2 Hz, 1H), 5.06 (d, J = 5.1 Hz, 1H), 4.17 (s, 1H), 3.85 (s, 3H), 1.78 -1.62 (m, 1H), 1.58 -1.43 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.76 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 169. 1, 167.8, 130.4, 130.0, 76.0, 73.8, 63.1, 52.8, 51.0, 25.5, 23.4, 17.9, 12.1, -4.3, -5.4.

HRMS (ESI) m/z Calcd for C17H28NaO5Si

[M+Na] + : 363.1598, found: 363.1586.

[α]D 25 = -27.0 o (c = 1.00, CHCl3).

Compound 350ad:

Colorless oil (102.9 mg, 85% yield, 89% ee). 1, 167.6, 138.2, 130.4, 130.2, 129.2, 128.9, 127.0, 75.5, 73.3, 63.1, 52.9, 51.3, 36.4, 25.5, 17.8, -4.1, -5.4. 5, 167.4, 130.8, 130.0, 77.8, 75.3, 71.8, 61.5, 59.3, 57.9, 53.1, 47.1.

HRMS (ESI

HRMS (ESI) m/z Calcd for C12H16NaO6

[M+Na] + : 279.0839, found: 279.0837.

[α]D 25 = -36.0 o (c = 1.00, CHCl3).

Compound 350af:

Colorless oil (82.4 mg, 87% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 95/5, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 6.23 min (major), t 2 = 13.38 min (minor).

Rf = 0.34 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 6. 1H),6.59 (dd,J = 7.8,5.2 Hz,1H),1H),3.88 (s,3H),3H),3.27 (s,3H),1H), 0.11 (s, 9H). 13 C NMR (90 MHz, CDCl3) δ 168. 5, 167.4, 130.8, 130.0, 77.5, 75.1, 61.7, 61.6, 57.8, 53.1, 49.1, -0.7.

HRMS (ESI) m/z Calcd for C14H22NaO6Si

[M+Na] + : 337.1078, found: 337.1073.

[α]D 25 = -38.0 o (c = 1.00, CHCl3).

Compound 350ag:

Colorless oil (106.3 mg, >99% yield, 96% ee). The enantiomeric excess was determined by J = 8.0 Hz, 9H), 0.60 (q, J = 8.0 Hz, 6H). 13 C NMR (90 MHz, CDCl3) δ 168. 5, 167.5, 130.8, 130.1, 77.5, 75.2, 62.1, 61.6, 57.8, 53.1, 49.3, 6.8, 4.3.

HRMS (ESI) m/z Calcd for C17H29O6Si

[M+H] + : 357.1728, found: 357.1718.

[α]D 25 = -25.0 o (c = 1.00, CHCl3).

Compound 350ah:

White solid (119.5 mg, >99% yield, 96% ee). 167.8, 130.7, 130.5, 79.5, 74.8, 73.7, 62.2, 61.3, 52.9, 51.5, 48.7, 42.1, 34.3, 31.4, 26.0, 25.0, 23.0, 22.4, 21.4, 18.4, 16.2, -5.4, -5.4. 9, 167.6, 131.0, 130.0, 76.3, 75.6, 72.4, 63.1, 61.9, 52.8, 50.0, 48.3, 39.8, 34.4, 31.5, 26.1, 25.2, 23.2, 22.5, 21.3, 18.5, 16.2, -5.3, -5.4.

Compound 350ak:

This compound was synthesized from cycloaddition of 2-pyrone 71a (0. 167.7, 130.4, 129.2, 78.7, 69.3, 63.4, 52.9, 39.6, 25.8, 18.2, 13.3, -3.7, -5.0.

HRMS (ESI) m/z Calcd for C16H26NaO5Si

[M+Na] + : 349.1442, found: 349.1436.

[α]D 25 = + 6.6 o (c = 1.22,CHCl3).

Compound 350al:

This compound was synthesized from cycloaddition of 2-pyrone 71a (0. 1 H NMR (360 MHz, CDCl3) δ 6. 1H),6.50 (dd,J = 7.8,5.1 Hz,1H),1H),4.73 (dd,J = 7.5,0.8 Hz,1H),3.86 (s,3H),1H),1H),4H), 0.78 (s, 9H), 0.04 (s, 3H), 0.00 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 169. 2, 167.8, 130.7, 128.8, 76.2, 69.7, 63.5, 52.9, 46.8, 25.9, 20.6, 18.3, 12.1, -3.8, -4.8.

HRMS (ESI) m/z Calcd for C17H29O5Si

[M+H] + : 341.1779, found: 341.1776.

[α]D 25 = + 8.0 o (c = 1.00, CHCl3).

Compound 350am:

This compound was synthesized from cycloaddition of 2-pyrone 71a (0. 8, 167.7, 130.4, 129.7, 77.1, 76.0, 62.1, 61.1, 60.5, 53.0, 46.4, 25.9, 18.2, -5.4, -5.5. 5.18 (s, 1H), 3.89 (s,3H),3.54 (dd,J = 10.2,7.1 Hz,1H),5H),1H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168. 6, 166.8, 132.6, 130.3, 78.9, 75.3, 64.3, 60.0, 58.2, 53.1, 49.1, 25.9, 18.3, -5.4, -5.5. 6, 168.7, 133.1, 129.9, 80.2, 76.2, 65.4, 61.7, 57.5, 53.0, 52.5, 26.2, 23.2, 18.8, -5.3, -5.4. Rf = 0.34 (petroleum ether/EtOAc = 3:1).

HRMS (ESI

HRMS (ESI

HRMS (ESI

1 H NMR (360 MHz, acetone-d6) δ 6. 2H),5.29 (dd,J = 4.4,2.1 Hz,1H),3.92 (dd,J = 10.3,7.1 Hz,1H),3.80 (s,3H),3.71 (dd,J = 10.1,8.7 Hz,1H),3.15 (s,3H), 2.12 -2.06 (m, 1H), 1.61 (s, 3H), 0.93 (s, 9H), 0.13 (s, 6H). 13 C NMR (90 MHz, acetone-d6) δ 169. 3, 167.6, 131.8, 131.6, 78.8, 76.2, 65.7, 62.9, 52.7, 51.0, 50.8, 26.2, 18.7, 17.2, -5.4, -5.4. 1 H NMR (400 MHz, acetone-d6) δ 6.70 (dd, J = 7.8, 5.1 Hz, 1H), 6.64 (dd, J = 7.8, 2.2 Hz, 1H), 5.22 (dd, J = 5.0, 1.6 Hz, 1H), 3.93 (dd,J = 10.2,5.8 Hz,1H),3.82 (s,3H),3.73 (dd,J = 8.6,7.6 Hz,1H),3.41 (s,3H),1.84 (ddd,J = 9.0,5.8,0.5 Hz,1H),1.44 (s,3H), 0.92 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H). 13 C NMR (100 MHz, acetone-d6) δ 168. 6, 168.6, 134.3, 131.6, 78.3, 75.5, 66.7, 60.8, 54.6, 53.5, 52.7, 26.3, 20.9, 18.8, -5.2, -5.3. 2, 167.4, 131.5, 131.1, 80.9, 75.5, 65.0, 62.7, 53.1, 51.0, 49.6, 25.9, 18.2, 16.2, -5.4, -5.5.

HRMS (ESI

HRMS (ESI

HRMS (ESI) m/z Calcd for C18H31O6Si

[M+H] + : 371.1884, found: 371.1870.

[α]D 25 = -8.0 o (c = 1.00, CHCl3).

Procedures for Post-Functionalization

Removal of TBS-Protecting Group

To a stirred solution of cycloadduct 350a (107 mg, 0.3 mmol) in THF (2 mL) was added TBAF

(1.0 M in THF, 0.45 mL, 0.45 mmol) dropwise. This mixture was stirred at room temperature for 30 min before H2O (5 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 1:2) to afford alcohol 352 as a colorless oil.

Compound 352:

Colorless oil (73.0 mg, >99% yield, 97% ee). 8, 167.5, 130.9, 130.1, 77.6, 75.4, 62.1, 61.6, 58.0, 53.3, 48.8.

HRMS (ESI

Ring-Opening Reaction via CO2 Extrusion

To a 25 mL Schlenk tube with a magnetic stir bar and a condenser was added cycloadduct 350a

(107 mg, 0.3 mmol). The Schlenk tube was evacuated and then refilled with argon. After that chlorobenzene (3 mL) was added and the mixture was refluxed at 140 o C for 3 h. The residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford cyclohexadiene 353 as a colorless oil. 134.6, 134.4, 125.3, 123.5, 70.9, 61.7, 56.1, 51.9, 43.2, 25.9, 18.4, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C16H28NaO4Si

[M+Na] + : 335.1649, found: 335.1638.

[α]D 25 = -418.0 o (c = 1.00, CHCl3).

Ring-Opening Reaction via Transesterification

To an oven-dried 25 mL Schlenk tube with a magnetic stir bar was added cycloadduct 350a

(107 mg, 0.3 mmol). This Schlenk tube was evacuated, refilled with argon and then anhydrous 3, 168.7, 132.3, 125.7, 75.8, 67.2, 62.7, 62.2, 60.3, 53.0, 52.8, 42.1, 25.9, 18.1, -5.5.

HRMS (ESI) m/z Calcd for C18H33O7Si

[M+H] + : 389.1990, found: 389.1985.

[α]D 25 = -61.0 o (c = 1.00, CHCl3).

Pd/C Reduction with Hydrogen

To an oven-dried flask with a magnetic stir bar was added cycloadduct 350a (107 mg, 0.3 mmol) and 10% Pd/C (50 wt% based on 350a, 54 mg) and EtOAc (12 mL). This mixture was stirred under hydrogen bubbling at room temperature for 2 h. This suspension was filtered through a short column of Celite and rinsed with EtOAc. The organic solvent was evaporated under reduced pressure to afford bridged lactone 355 as a white solid.

Compound 355:

White solid (108.0 mg, >99% yield, 97% ee). The enantiomeric excess was determined by 1, 169.3, 77.6, 76.1, 62.9, 57.7, 55.1, 52.8, 47.8, 26.0, 24.4, 18.4, 18.4, -5.4, -5.4.

HRMS (ESI) m/z Calcd for C17H31O6Si

[M+H] + : 359.1884, found: 359.1877.

[α]D 25 = -24.0 o (c = 1.00, CHCl3).

Dihydroxylation with OsO4

To an oven-dried microwave vial with a magnetic stir bar was added cycloadduct 350a (107 mg, 0.3 mmol), THF (1.5 mL), H2O (0.5 mL) and 4-methylmorpholine N-oxide (NMO, 53 mg, 0.45 mmol). This mixture was stirred at room temperature while OsO4 (2.5 wt% in tBuOH, 0.20 mL, 0.015 mmol) was added. The resulting mixture was stirred at room temperature for another 10 h and then quenched with saturated Na2SO3 aqueous solution (2 mL). The aqueous mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), concentrated under reduced pressure and further purified by flash column chromatography (silica gel, DCM/EtOAc = 5:1) to afford diol 356a as a white solid and diol 356b as a colorless oil.

Compound 356a:

White solid (55.1 mg, 47% yield, 97% ee). 4, 167.2, 81.6, 77.3, 66.8, 64.8, 62.1, 61.4, 57.7, 53.5, 45.2, 25.9, 18.4, -5.4, -5.5.

HRMS (ESI) m/z Calcd for C17H31O8Si

[M+H] + : 391.1783, found: 391.1772.

[α]D 25 = + 22.0 o (c = 1.00, CHCl3).

Compound 356b:

Colorless oil (30.8 mg, 26% yield, 97% ee). The enantiomeric excess was determined by chiral 7, 167.3, 79.8, 78.4, 77.5, 76.7, 62.1, 60.4, 58.8, 53.3, 46.7, 26.0, 18.4, -5.4, -5.4.

HRMS (ESI) m/z Calcd for C17H31O8Si

[M+H] + : 391.1783, found: 391.1770.

[α]D 25 = -4.0 o (c = 1.00, CHCl3).

Synthesis of a Carbasugar Unit

(-)-350ab (602.8 mg, 92% yield, 89% ee) was synthesized according to the general procedure on 2 mmol scale.

Preparation of lithium allyloxide:

To an oven-dried microwave vial with a magnetic stir bar under argon was added allyl alcohol (3 mL). This solution was stirred at 0 o C and nBuLi (2.5 M in hexanes, 2.2 mL) was added dropwise. The resulting solution was continually stirred at 0 o C for 5 min to give lithium allyloxide/allyl alcohol solution.

To another oven-dried flask with a magnetic stir bar was added lactone (-)-350ab (588.6 mg, 1.8 mmol). This flask was evacuated, refilled with argon and cooled at 0 o C. Allyl alcohol (7 mL) was added, followed by addition of the above prepared lithium allyloxide solution. The mixture was stirred at 0 o C for 2 h before saturated NH4Cl aqueous solution (10 mL) was added.

The aqueous mixture was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (10 mL), concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1) to afford cyclohexene (+)-357 as a white solid.

Compound (+)-357:

White solid (581.2 mg, 84% yield, 89% ee). 7, 168.6, 131.8, 131.6, 124.7, 118.8, 72.7, 66.9, 66.4, 61.1, 52.7, 39.0, 26.1, 18.3, 12.2, -4.3, -4.6.

HRMS (ESI) m/z Calcd for C19H33O6Si

[M+H] + : 385.2041, found: 385.2040.

[α]D 25 = + 9.0 o (c = 1.00, CHCl3).

To an oven-dried flask with a magnetic stir bar was added alcohol (+)-357 (495 mg, 1.29 mmol).

This flask was evacuated, refilled with argon and cooled at 0 o C. Then DCM (10 mL) and 2,6lutidine (0.37 mL, 3.20 mmol) were added, followed by slow addition of TBSOTf (0.74 mL, 3.20 mmol). The mixture was stirred at 0 o C for 10 min before water (10 mL) was added. The aqueous mixture was extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 20:1) to afford cyclohexene (+)-358 as a colorless oil.

Compound (+)-358:

Colorless oil (639.8 mg, >99% yield). Rf = 0.56 (petroleum ether/EtOAc = 5:1). 4, 132.9, 131.6, 123.0, 118.6, 73.2, 66.8, 66.2, 60.5, 52.6, 40.1, 26.0, 25.9, 18.2, 12.3, -4.1, -4.4, -4.7, -4.9. Step one: To an oven-dried flask with a magnetic stir bar and a condenser was added malonate (+)-358 (607 mg, 1.22 mmol), Pd(OAc)2 (14 mg, 0.06 mmol) and PPh3 (64 mg, 0.24 mmol).

HRMS (ESI

The flask was evacuated and then refilled with argon. Then formic acid (56 µL, 1.50 mmol), triethylamine (0.23 mL, 1.65 mmol) and 1,4-dioxane (10 mL) were added. After being stirred at 100 o C for 8 h. The mixture allowed to cool down to room temperature. DBU (0.5 mL) was added and the mixture was continually stirred at room temperature for 1 h. This suspension was filtered through a short column of silica gel and rinsed with EtOAc. The organic solution was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford a colorless oil (300.2 mg).

Step two: To a stirred mixture of ester (300.2 mg) prepared in the Step one in DCM (10 mL) at -78 o C under argon was added DIBAL-H (1.0 M in hexane, 1.81 mL, 1.81 mmol) dropwise.

This mixture was stirred at -78 o C for 1 h and at room temperature for an additional 1 h, then quenched with MeOH (2 mL). After that Rochelle's salt (10% aqueous solution, 10 mL) was added at -78 o C and the mixture was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford alcohol (-)-361 as a colorless oil.

Compound (-)-361:

Colorless oil (268.2 mg, 57% over two steps).

Rf = 0.34 (petroleum ether/EtOAc = 5:1). 8, 125.0, 73.1, 66.3, 65.4, 42.3, 30.7, 26.0, 18.2, 18.1, 9.6, -4.2, -4.5, -4.6, -4.8. 2.6 X-ray Single Crystal Diffraction Analysis Hydrogen atoms were located on a difference Fourier map and introduced into the calculations as a riding model with isotropic thermal parameters. All calculations were performed by using the Crystal Structure crystallographic software package WINGX 122 .

HRMS (ESI

The crystal data collection and refinement parameters are given in Table 16.

Absolute configuration of compounds 350ac, 350al and 350r has been established by anomalous-dispersion effects in diffraction measurements on the crystal (using a large number of Friedel's pairs).

CCDC 2160985-2160988 contains the supplementary crystallographic data for this thesis.

These data can be obtained free of charge from the Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe via http://www.ccdc.cam.ac.uk/structures/.

Synthesis of Anhydride 389

Step one: To a flask equipped with a stir bar and a condenser was added 3,6dihydroxyphthalonitrile 388 (14. 40 g, 90 mmol), KOH (64.00 g, 1.14 mol) and H2O (64 mL).

This mixture was refluxed at 105 o C for 2 h, cooled down to room temperature, and then acidified with 20% aqueous H2SO4 (200 mL) at 0 o C. After that the aqueous mixture was diluted with H2O (400 mL) and extracted with EtOAc (5 × 200 mL). The combined organic layers were concentrated under reduced pressure to afford crude 3,6-dihydroxyphthalic acid as a brown solid which was used directly without further purification.

Step two: The above crude

Synthesis of 1,3-Indandione 390

to afford allyl alcohol 343d as a colorless oil (12.47 g, 95%). Rf = 0.08 (petroleum ether/EtOAc = 5:1). 7, 128.7, 128.2, 127.7, 103.7, 71.4, 60.8.

Analytical data were consistent with previously reported data. 77a To a stirred mixture of allyl alcohol 343d (11.77 g, 71.7 mmol) in DCM (100 mL) at 0 o C was added imidazole (9.76 g, 143.4 mmol) and TBSCl (16.21 g, 107.6 mmol). The mixture was stirred at 0 o C for 10 min and at room temperature for an additional 30 min. Then H2O (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/Et2O/Et3N = 50:5:1) to afford enol ether 344d as a colorless oil (19.98 g, >99%). Rf = 0.68 (petroleum ether/EtOAc = 5:1). 5, 136.9, 128.6, 128.0, 127.7, 104.1, 71.2, 61.3, 26.1, 18.5, -4.9.

HRMS (ESI) m/z Calcd for C16H26NaO2Si

[M+Na] + : 301.1594, found: 301.1584.

Synthesis of 2-Pyrones 333, 334 and 425

The synthesis of 2-pyrone-3-carboxylic acid 333 and corresponding acid chloride 334 were reported previously. 60a

Step one: A mixture of 2-pyrone 71a (3.10 g, 20 mmol) and 12 M HCl (10 mL) was heated at 45°C overnight. Then water (20 mL) was added and the resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were concentrated under reduced pressure to give 2-pyrone-3-carboxylic acid 333 as a brown solid which was further dried under vacuum for 12 h before use. Step two: The above acid was heated with thionyl chloride (8 mL) at 80 o C overnight. The excess thionyl chloride was removed by atmospheric distillation (80 o C) to give acid chloride 334 as a brown solid which was dissolved in DCM (20 mL) and used directly for the next step.

Step 7, 158.3, 153.2, 141.8, 124.8, 105.8, 61.4, 32.3.

HRMS (ESI) m/z Calcd for C8H10NO4

[M+H] + : 184.0604, found: 184.0605.

Synthesis of Bridged Lactone (-)-350z

Preparation of catalyst: To an oven-dried flask equipped with a stir bar was added CuCl2 (269 mg, 2 mmol), BOX ligand L9 (613 mg, 2 mmol) and DCM (15 mL). This solution was stirred at room temperature for 1 h to afford a green solution. Then AgSbF6 (1. 37 g, 4 mmol) was added to this green solution and the mixture was further stirred at room temperature without light for 1 h to afford a deep green suspension. This suspension was filtered through a short column of Celite and rinsed with DCM (18 mL) to give a deep green solution which should be used immediately for the cycloaddition.

Asymmetric cycloaddition: To another oven-dried flask equipped with a stir bar was added 2pyrone 71a (6.17 g, 40 mmol) and activated 4Å molecular sieves (6.00 g). This flask was evacuated, refilled with argon and cooled at -78 o C. The above prepared catalyst solution was added to this mixture by syringe. After being stirred at -78 o C for 5 min, a solution of enol ether 344d (16.71 g, 60 mmol) in PhMe (67 mL) was added and the resulting mixture was stirred at -78 o C for 5 min to give a green suspension which was further stirred at -40 o C for 20 h. The crude mixture was filtered through a short column of silica gel and rinsed with EtOAc. After that the organic solution was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford enantioenriched bridged lactone (-)-350z as a white solid (17.31 g, >99% yield, dr = 48:1, 97% ee).

Racemic cycloaddition: the same procedure was carried out, except that 10 mol% Cu(SbF6)2/L21 was used as catalyst and only DCM was used as reaction solvent, and the reaction was runed at room temperature for 10 h.

Synthesis of Cycloadduct (-)-427

To an oven-dried flask equipped with a stir bar and a condenser was added enol ether (-)-384b (14.14 g, 20 mmol). This flask was evacuated and then refilled with argon. PhCl (60 mL) was added and the mixture was refluxed at 140 o C for 3 h. The reaction was then allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to give cycloadduct (-)-427 as a white solid (10.18 g, 77%). Rf = 0.58 (petroleum ether/EtOAc = 3:1).

Synthesis of Alcohol (-)-433

To an oven-dried flask equipped with a stir bar and an addition funnel was added ester (-)-427 (9. 94 g, 15 mmol) and Et2O (90 mL) under argon. The mixture was stirred at -20 o C for 5 min.

Then a solution of LiAlH4 (854 mg, 22.5 mmol) in Et2O (30 mL) was added slowly through addition funnel. The resulting mixture was stirred at -20 o C for another 1 h, followed by addition of cold water (10 mL) and aqueous HCl solution (1 M, 100 mL) to quench the reaction. The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 4:1→1:1)

to afford alcohol (-)-433 as a white solid (7.85 g, 82%), alcohol (-)-433' as a yellow solid (0.46 g, 5%) and to recover starting material (-)-427 (1. 28 g, 13%).

Alcohol (-)-433:

Rf = 0.34 (petroleum ether/EtOAc = 3:1).

Alcohol (-)-433':

Rf = 0.13 (petroleum ether/EtOAc = 1:1).

Synthesis of Aldehyde (-)-434

To a flask equipped with a stir bar was added alcohol (-)-433 (7.21 g,11.3 mmol),NaHCO3 (4.75 g,56.5 mmol), Dess-Martin periodinane (12.00 g, 28.3 mmol) and DCM (80 mL). The mixture was stirred at room temperature for 2 h followed by addition of saturated Na2S2O3 aqueous solution (50 mL) and H2O (50 mL) to quench the reaction. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford aldehyde (-)-434 as a yellow solid (6. 99 g, 98%).

Rf = 0.28 (petroleum ether/EtOAc = 5:1).

1 H NMR (400 MHz, CDCl3) δ 10. 16 (s,1H,3H,ArH),2H,ArH),6.90 (d,J = 8.7 Hz,1H,6.67 (d,J = 8.7 Hz,1H,6.58 (d,J = 8.3 Hz,1H,6.05 (dd,J = 8.1,6.8 Hz,1H,4.50 (d,J = 11.9 Hz,1H,ArCH2),4.40 (d,J = 11.9 Hz, 1H, ArCH2), 4.22 (dd, J = 8.6, 5.1 Hz, 1H, H-10'), 3.94 (s,1H,3.69 (d,J = 8.6 Hz,1H,1H,, 2.81 (s, 1H, H-2'), 2.46 (t, J = 4.6 Hz, 1H, H-5'), 1.04 (s, 9H, SiC(CH3)3), 0.97 (s, 9H, SiC(CH3)3), 0.28 (s, 6H, Si(CH3)2), 0.14 (s, 3H, SiCH3), 0.12 (s, 3H, SiCH3).

Synthesis of Methyl Ketone (-)-436

To a flask equipped with a stir bar was added alcohol (-)-435 (4. 75 g, 7.3 mmol), NaHCO3

(1.84 g, 21.9 mmol), Dess-Martin periodinane (4. 66 g, 11.0 mmol) and DCM (50 mL). The mixture was stirred at room temperature for 30 min followed by addition of saturated Na2S2O3 aqueous solution (30 mL) and H2O (30 mL) to quench the reaction. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford methyl ketone (-)-436 as a yellow solid (4. 49 g, 95%). Rf = 0.20 (petroleum ether/EtOAc = 10:1).

1 H NMR (400 MHz, CDCl3) δ 3H,ArH),2H,ArH),6.90 (d,J = 8.7 Hz,1H,6.67 (d,J = 8.7 Hz,1H,6.63 (d,J = 8.5 Hz,1H,5.97 (dd,J = 8.3,6.9 Hz,1H,4.50 (d,J = 11.9 Hz,1H,ArCH2),4.35 (d,J = 11.9 Hz,1H,ArCH2),4.23 (dd,J = 8.4,5.0 Hz,1H,3.90 (s,1H,3.72 (d,J = 8.5 Hz,1H,1H, 1.05 (s, 9H, SiC(CH3)3), 0.97 (s, 9H, SiC(CH3)3), 0.29 (s, 3H, SiCH3), 0.28 (s, 3H, SiCH3), 0.14 (s, 3H, SiCH3), 0.12 (s, 3H, SiCH3). 4.6 (SiCH3).

1 H NMR (400 MHz, MeOD) δ 7. 5H,ArH),7.03 (d,J = 8.7 Hz,1H,6.76 (d,J = 8.7 Hz,1H,6.56 (d,J = 8.4 Hz,1H,5.92 (dd,J = 8.3,6.9 Hz,1H,4.51 (d,J = 11.9 Hz,1H,ArCH2),4.32 (d,J = 11.9 Hz,1H,ArCH2),4.27 (dd,J = 8.5,5.0 Hz,1H,3.92 (s,1H,3.77 (d,J = 8.6 Hz,1H,1H,

Synthesis of Alcohol (+)-439

To a flask equipped with a stir bar was added methyl ketone (-)-436 (4.22 g, 6.5 mmol), THF (100 mL) and 10% Pd/C (2.11 g). This mixture was stirred vigorously under hydrogen (balloon) at room temperature for 6 d. This suspension was filtered through a short column of Celite and rinsed with EtOAc. The organic solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1→1:1)

to give benzyl ether (+)-439' as a white solid (244 mg, 7%) and alcohol (+)-439 as a white solid (3.12 g, 86%).

Note: Hydrogenation of C=C with Pd/C proceeded completely within 2 hours in quantitative yield, but debenzylation occurred slowly. We also attempted to raise the reaction temperature to 50 o C, but it resulted in complex mixture.

Benzyl ether (+)-439': Rf = 0.56 (petroleum ether/EtOAc = 3:1).

1 H NMR (400 MHz, CDCl3) δ 7. 5H,ArH),6.92 (d,J = 8.6 Hz,1H,6.72 (d,J = 8.6 Hz,1H,4.58 (d,J = 11.7 Hz,1H,ArCH2),4.41 (d,J = 11.7

Alcohol (+)-439:

Rf = 0.20 (petroleum ether/EtOAc = 3:1). 2.36 (s, 3H, H-12'), 2.18 -2.07 (m, 1H, H-9'), 1.87 -1.76 (m, 1H, H-8'), 1.37 -1.26 (m, 1H, H-9'), 1.12 -1.04 (m, 1H, H-8'), 1.00 (s, 9H, SiC(CH3)3), 0.99 (s, 9H, SiC(CH3)3), 0.26 (s, 3H, SiCH3), 0.25 (s, 3H, SiCH3), 0.17 (s, 3H, SiCH3), 0.16 (s, 3H, SiCH3). 1 H NMR (400 MHz, MeOD) δ 7.08 (d,J = 8.7 Hz,1H,6.83 (d,J = 8.7 Hz,1H,4.21 (dd,J = 8.4,5.0 Hz,1H,3.89 (s,1H,3.74 (d,J = 8.3 Hz,1H,

Synthesis of (+)-Lucidumone (370)

To a flask equipped with a stir bar was added alcohol (+)-439 (2.80 g, 5 mmol) and THF (80 mL). Then TBAF (1.0 M in THF, 12.5 mL, 12.5 mmol) was added dropwise by an addition funnel. This mixture was stirred at room temperature for 30 min. Then saturated NaCl aqueous solution (100 mL) and H2O (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et2O (5 × 100 mL). The combined organic layers were concentrated under reduced pressure and further purified by flash column chromatography (silica gel, DCM/MeOH = 10:1) to afford (+)-lucidumone (370) as a yellow solid (1.61 g, 97% yield, >99% ee). Rf = 0.38 (DCM/MeOH = 10:1).

1 H NMR (400 MHz, MeOD) δ 7.01 (d,J = 8.7 Hz,1H,6.74 (d,J = 8.7 Hz,1H,4.24 (dd,J = 8.2,4.9 Hz,1H,3.90 (s,1H,3.76 (d,J = 8.3 Hz,1H,2.89 (d,J = 1.9 Hz,1H,2.67 (dd,J = 6.4,3.3 Hz,1H,2.35 (t,J = 4.4 Hz,1H,2.28 (s,3H,1H,1H,1H,), 1.12 -0.97 (m, 1H, H-8').

Synthesis of β-Bromoindenone 412

To a flask equipped with a stir bar and a condenser was added indanone 411 (192 mg, 1 mmol), NBS (356 mg, 2 mmol), CCl4 (10 mL) and AIBN (3 mg, 0.02 mmol). This mixture was stirred at 80 o C under visible light (12 V, 50 W). After 2 h, Et3N (0.5 mL, 3.5 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for another 12 h. The crude mixture was concentrated under reduced pressure and the residue was dissolved in aqueous HCl solution (0.1 N, 20 mL). After that the aqueous mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:2) to give β-Bromoindenone 412 as a yellow solid (223.6 mg, 83%).

Rf = 0.19 (petroleum ether/EtOAc = 1:1). 4, 150.7, 148.4, 142.8, 128.1, 128.0, 122.5, 118.0, 117.1, 56.9, 56.5.

HRMS (ESI) m/z Calcd for C11H10BrO3

[M+H] + : 268.9808, found: 268.9813.

Analytical data were consistent with previously reported data. 132

Synthesis of Iodide 399

To a flask equipped with a stir bar was added PPh3 (3.15 g, 12 mmol) and imidazole (0. 89 g, 13 mmol). This flask was evacuated and then refilled with argon. DCM (10 mL) was added and the mixture was stirred at 0 o C. After 5 min, the rubber septum was partly removed and iodine dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether) to afford iodide 399 as a colorless oil (2.12 g, 95%). Rf = 0.66 (petroleum ether).

1 H NMR (360 MHz, CDCl3) δ 3.09 (d,J = 6.4 Hz,2H),2H),2H),1H),1H),3H), 1.00 -0.87 (m, 2H). 13 C NMR (90 MHz, CDCl3) δ 40. 1, 33.6, 26.2, 26.1, 16.4.

Analytical data were consistent with previously reported data. 133

Synthesis of Tosylate 400

To an oven-dried flask equipped with a stir bar and an addition funnel was added 4toluenesulfonyl chloride (3.81 g, 20 mmol) and DCM (50 mL) under argon. This mixture was stirred at 0 o C. Another mixture of alcohol 398 (2.28 g, 20 mmol) and Et3N (5.6 mL, 40 mmol) in DCM (15 mL) was added dropwise by the addition funnel. The resulting mixture was stirred at 0 o C for 10 min and then at room temperature for 12 h, followed by addition of water (50 mL) to quench the reaction. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were washed sequentially with aqueous HCl solution (3 M, 50 mL), saturated NaHCO3 solution (50 mL) and water (50 mL), dried over MgSO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1) to afford tosylate 400 as a colorless oil (5.00 g, 93%). Rf = 0.40 (petroleum ether/EtOAc = 5:1). 7, 133.4, 129.9, 128.0, 75.5, 37.3, 29.2, 26.2, 25.5, 21.7. 133

Table of Figures

Résumé en Langue Française

Les cycloadditions de Diels-Alder à demande inverse en électrons impliquant des 2-pyrones déficientes en électrons en tant que diène électrophile ont été étudiées en détail au cours des 50 Enfin, la thèse se termine par une conclusion générale sur les quatre chapitres précédents ainsi que nos perspectives sur les futurs développements de Diels-Alder à demande inverse en électrons impliquant des 2-pyrones électrophiles. Nous espérons que cette thèse inspirera le développement de nouvelles méthodes de synthèse dans le futur, ainsi que leurs applications en synthèse totale de produits naturels.

Titre:

  Cycloaddition de Diels-Alder à demande inverse en électron asymétrique entre une 2-pyrone et un éther d'énol acyclique et synthèse totale de la (+)-lucidumone à l'échelle du gramme Mots clés : cycloaddition de Diels-Alder, produit naturel, chimie organique, synthèse totale Résumé : Les cycloadditions de Diels-Alder à demande inverse en électron impliquant des 2pyrones appauvries en électrons en tant que diène électrophile on fait l'objet de nombreuses études au cours des 50 dernières années. Cette réaction offre une voie d'accès efficace à des lactones bicycliques pontées et leurs dérivés, tels que des 1,3cyclohexadiènes hautement fonctionnalisés après extrusion de CO2 est des composés aromatiques polysubstitués après élimination. Ainsi, les Diels-Alder à demande inverse ont été utilisées pour la synthèse de nombreuses molécules bioactives et/ou naturelles ainsi que des candidats médicaments. Cette thèse s'intéresse à la Diels-Alder à demande inverse en électrons entre une 2-pyrone appauvrie en électrons et un éther d'énol acyclique. En utilisant un système catalytique comportant un complexe Cu(II)-BOX, de nombreuses lactones bicycliques sont obtenues avec d'excellents rendements (jusqu'à 99%) et énantiosélectivités (jusqu'à 99% d'excès). Une étude mécanistique ainsi que des calculs de DFT indiquent que le mécanisme à lieu en deux étapes. Le potentiel synthétique des lactones bicycliques est mis en évidence par la synthèse totale à l'échelle du gramme de la (+)lucidumone. Les étapes clés comportent la formation d'une lactone bicyclique pontée par la cycloaddition énantiosélective susmentionnée, formation d'une liaison C-O pour assembler deux fragments dans des conditions de Mitsunobu, et une cascade d'extrusion de CO2/cycloaddition [4+2] intramoléculaire.

Scheme 12 .

 12 Scheme 12. Thermal IEDDA cycloaddition of methyl coumalate with vinyl ethers, ketals, and orthoesters. Conventional thermal conditions for the IEDDA cycloaddition to access aromatic compounds always involve either high temperature (up to 220 °C) or long reaction time (up to

Scheme 13 .

 13 Scheme 13. Comparison of microwave-assisted and high pressure-promoted IEDDA cycloadditions of 2-pyrones.Attracted by the relevance of the trifluoromethyl group in bioactive molecules, Haufe and

  or N-substituted alkene, are good dienophiles for the IEDDA cycloaddition with 2pyrones, in spite of the stability provided by the aromatic character. Jung and co-workers discovered in 1986 that alkyl coumalates 12 underwent a [4+2] cycloaddition with 3,4dialkoxyfurans 55 in an inverse-electron-demand fashion in which alkyl coumalates 12 acted as the electrophilic diene and the dialkoxyethene moiety of 3,4-dialkoxyfurans 55 acted as the 15 I. S. Kondratov, N. A. Tolmachova, V. G. Dolovanyuk, I. I. Gerus, K. Bergander, C.-G. Daniliuc, G. Haufe, Eur. J. Org. Chem. 2014, 2443-2450. 16 I. S. Kondratov, N. A. Tolmachova, V. G. Dolovanyuk, I. I. Gerus, C.-G. Daniliuc, G. Haufe, Eur. J. Org. Chem. 2015, 2482-2491.

Scheme 16 . 20 Scheme 17 .

 162017 Scheme 16. IEDDA cycloaddition of 2-pyrones with 2-methoxyfuran. Substituted indoles 63 as dienophiles in the IEDDA cycloaddition with methyl coumalate 12a for accessing highly functionalized carbazoles 64 were initially investigated byKraus and co-workers in 2014 (Scheme 17a).19 This transformation involved a cascade sequence of IEDDA cycloaddition/CO2 extrusion/HCl elimination. To overcome the aromaticity of indoles, a good leaving group chloride was installed at C 3 position of indoles. Although the IEDDA cycloaddition step is kinetically and thermodynamically disfavored, the elimination of both HCl and CO2 makes the IEDDA cycloaddition step irreversible. In addition, the alkyl protecting group at nitrogen atom played a key role in attenuating the decomposition of indoles under harsh conditions (up to 200 °C). In 2015, Domingo and co-workers used DFT calculations to elucidate the possible pathway in this methodology. DFT calculations suggested that the IEDDA cycloaddition proceeded with slight exo stereoselectivity and the initial HCl elimination in the aromatization step was kinetically favored over the extrusion of CO2 (Scheme

Scheme 20 . 26 Scheme 24 .

 202624 Scheme 20. The IEDDA cycloaddition/CO2 extrusion/aromatization sequence of 2-pyrone derivative with various dienophiles.In 1993, Markó and co-workers reported an interesting comparison between 3carbomethoxy-2-pyrone and 5-carbomethoxy-2-pyrone in the IEDDA cycloaddition.24 Their thermal IEDDA cycloaddition with various vinyl ethers 84 proceeded smoothly at atmospheric pressure, leading to bridged bicyclic compounds 85 and 87, respectively. It should be noted that the IEDDA cycloaddition of 3-carbomethoxy-2-pyrone 71a provided endo-specific compounds 85 (Scheme 21). This result is in sharp contrast with that of 5-carbomethoxy-2-pyrone 12a which usually furnished a mixture of endo and exo isomers (Scheme 22). Moreover, heating the resulting bridged bicyclic compounds 85 in toluene at 110 °C afforded oxygenated cyclohexadienes 86 via CO2 extrusion.

  Z)-vinylselenide 100b led to cis-substituted bridged lactone 101b, while (E)-vinylselenide 100c led to trans-substituted bridged bicyclic lactone 101c, in agreement with the concerted mechanism usually observed for the high pressure-promoted IEDDA cycloaddition. The resulting bridged lactones 101 could be readily converted into corresponding bicyclic fused lactones 102 by a two-step sequence of radical-mediated and acid-catalyzed (or palladiumcatalyzed) skeletal rearrangements (Scheme 26).

Scheme 26 .

 26 Scheme 26. High pressure-promoted IEDDA cycloaddition of 3-carbomethoxy-2-pyrone with vinylselenides.

Scheme 32 .Scheme 33 .

 3233 Scheme 32. Thermal IEDDA cycloaddition of 3-bromo-2-pyrone with electron-rich dienophiles.Tandem DA cycloadditions have attracted much synthetic attention in the past decades because of their powerful potential to rapidly increase molecular complexity in a single operation. In 2006, Cho and co-workers reported that 3-bromo-5-vinyl-2-pyrones 125 underwent a tandem DA cycloaddition with allyl vinyl ethers 124 to prepare various tetracyclic lactones.42 Interestingly, the stereochemistry of the ester group in the reaction outcome was only influenced by the configuration of acrylate fragment at C 5 position of 3-bromo-2-pyrones.For example, the tandem DA cycloaddition of (Z)-125 with vinyl ethers 124 provided tetracyclic lactones 126, whereas the tandem DA cycloaddition of (E)-125 with vinyl ethers 124 afforded tetracyclic lactones 127. Moreover, the configuration of the allyl group in dienophiles could not affect the orientation of substituents R 1 and R 2 in the resulting lactones (Scheme 33a). By running the reaction at room temperature, lactone endo-128a was isolated, which illustrates that the first step involves an IEDDA cycloaddition. Heating the lactone endo-128a in toluene at 110 °C afforded tetracyclic lactone 126a (Scheme 33b).

2. 2

 2 Total Synthesis of (±)-Crinine, (±)-Crinamine and (±)-6a-epi-Crinamine byCho and Co-Workers Crinane-type alkaloids, including crinine and crinamine, belonging to the family of amarylidaceae natural products, have been of interest to organic chemists due to their potential antitumor activities. In 2008, Cho's group reported the total synthesis of (±)-crinine, (±)-6a-epicrinamine and (±)-crinamine from cycloadduct 120b. Similarly, bridged bicyclic lactone 120b was achieved as a mixture of endo/exo isomers by a sequence of C3 -selective Stille coupling reaction and IEDDA cycloaddition. Subsequently, the ring opening of lactone 120b and then protection of the resulting hydroxyl group as a MOM ether gave ester 199. Reduction of 199 to corresponding primary alcohol by excess DIBAL-H followed by the treatment of mesyl chloride provided mesylate 200. Cyanation of 200 was followed by LiAlH4 reduction of the resulting nitrile group and then Boc protection of the primary amine to deliver amine 202. Deprotection of TBS ether and subsequent oxidation of the resulting alcohol by Dess-Martin periodinane furnished ketone 203. Under the treatment of ZnBr2 in DCM, ketone 203 was converted into a cyclic imine which was further reduced by LiAlH4 to afford cyclic amine 204.

of 3 , 5 -

 35 dibromo-2-pyrone 129 with aryltin 219 allowed to furnish tetracyclic lactones endo-220 and exo-220 directly rather than the expected Stille coupling product. The ring opening of endo-220 followed by protection of the resulting hydroxyl group as a MOM ether afforded aldehyde 221. The subsequent reductive amination of aldehyde 221 with methylamine provided a secondary amine which was then protected with a Boc group to give ester 222. Ester 222 was converted into aldehyde 223 in a two-step manipulation involving reduction by DIBAL-H and further oxidation by Dess-Martin periodinane. By employing the Wittig olefination of 223 with methoxymethyl phosphorus ylide, compound 224 was obtained as an enol ether which was subjected to acid-promoted hydrolysis in the presence of TFA to provide the corresponding aldehyde, along with the removal of both Boc and MOM protecting groups. The resulting aldehyde underwent an intramolecular reductive amination to construct cyclic amine 225.

Scheme 62 .Scheme 63 .Scheme 64 . 66 Scheme 65 .Scheme 66 .

 626364666566 Scheme 62. Total synthesis of (±)-aspidospermidine.

3. 3 Scheme 68 .Scheme 69 .Scheme 70 .Scheme 71 .Scheme 72 .

 36869707172 Scheme 68. Total synthesis of rufescine and imeluteine.

Scheme 75 .Scheme 76 .Scheme 77 . 62 Scheme 78 .

 7576776278 Scheme 75. Advances and challenges in catalytic enantioselective IEDDA cycloadditions of 2-pyrones with activated alkenes.

Scheme 82 .

 82 Scheme 82. Scope of the reaction regarding 2-pyrone derivatives. a The reaction was conducted at -40 o C for 40 h then at room temperature for 2 h. b The reaction was conducted at -40 o C for 60 h then at room temperature for 2 h.cThe reaction was conducted at room temperature for3 d.

Scheme 83 .

 83 Scheme 83. Scope of the reaction regarding enol ethers. a The reaction was conducted at -40 o C for 40 h then at room temperature for 2 h. b The reaction was conducted at -40 o C for 60 h then at room temperature for 2 h.

Figure 1 .

 1 Figure 1. A) the relationship between yield and reaction time. B) the relationship between ee and reaction time.

  strongly deny the concerted mechanism. The endo attack of the enol ethers leads to the formation of the Int1_E and Int1_Z via low barrier transition states TS1_E (ΔG ‡ = 15.0 kcalmol -1 , the optimized 3d structure is also shown in Figure 2A) and TS1_Z (ΔG ‡ = 15.4 kcalmol -1 ) respectively. The conformational flexibility of the intermediates Int1_E and Int1_Z allows two types of structures regarding Me and OMe groups orientation: Int1_trans and Int1_cis. As shown in Figure 2, the trans form of the intermediate Int1 is more stabilized than the cis form in the case of the E enol ether, while vice versa the cis form is thermodynamically more favorable for the Z enol ether.

Figure 2 .

 2 Figure 2. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the E and Z enol ethers.

Figure 3 .Scheme 89 .

 389 Figure 3. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the trisubstituted dienophile.

  86 a) S. Toshiaki, S. Ōmura, Chem. Rev. 2005, 105, 4559-4580; b) L. A. M. Murray, S. M. K. McKinnie, B. S. Moore, J. H. George, Nat. Prod. Rep. 2020, 37, 1334-1366; c) J. H. George. Acc. Chem. Res. 2021, 54, 1843-1855; d) Y.Matsuda, I. Abe, Nat. Prod. Rep. 2016, 33, 26-53.

  87 a) Y.-M. Yan, H.-X. Zhang, H. Liu, Y. Wang, J.-B. Wu, Y.-P. Li, Y.-X. Cheng, Org. Lett. 2019, 21, 8523-8527; b) X. Peng, M. Qiu, Nat. Prod. Bioprospect. 2018, 8, 137-149; c) B. Boh, M. Berovic, J. Zhang, Z.-B. Lin, Biotechnol. Annu. Rev. 2007, 13, 265-301; d) B. S. Sanodiya, G. S. Thakur, R. K. Baghel, G. B.K.S. Prasad, P. S. Bisen, Curr. Pharm. Biotechnol. 2009, 10, 717-742; e) P. Batra, A. K. Sharma, R. Khajuria, Int. J. Med. Mushrooms 2013, 15, 127-143.

Scheme 91 .

 91 Scheme 91. Proposed biosynthesis of lucidumone.

  89 a) R. Boehm, S. Sommer, S.-M. Li, L. Heide, Plant Cell Physiol. 2000, 41, 911-919; b) K. Yazaki, M. Kunihisa, T. Fujisaki, F. Sato, J. Biol. Chem. 2002, 277, 6240-6246; c) D. M.

  , the authors started the synthesis from intermediate 373 prepared by a sequence of oxidative dearomatization/IMDA cascade, reductive deoxygenation with SmI2 and TBS protection. The installation of a directing group followed by Cu-mediated remote C(sp 3 )-H hydroxylation and subsequent protection of the hydroxyl group furnished intermediate 375 which was subjected to a Wittig reaction to give intermediate 376 with an allylic motif. Allylic oxidation of 376 with SeO2 gave an allylic alcohol which was oxidized by Dess-Martin periodinane to generate α,β-unsaturated ketone 377. Intermediate 378 could be obtained as a diastereomeric mixture at α-position of ketone via a Cu-mediated Michael addition of 377 with a bromoarene. After deprotection of 378 with TBAF, the resulting alcohol was subjected to TfOH to form the carbon skeleton of lucidumone in good yield because of the simultaneous dynamic kinetic resolution. The methyl ketone could be installed through a sequence involving DMP oxidation, the addition of Grignard reagent and DMP reoxidation. Later, the C-C double bond was reduced with Pd/C under hydrogen to give 381. Benzylic bromination of 381 followed by the treatment of Dess-Martin periodinane completed the synthesis of the core framework of lucidumone in racemic form.

  Scheme 92. She's research work for racemic synthesis of the core skeleton of lucidumone.

  At the beginning of the project, we decided to synthesize indandione 385 for testing C-O bond formation. As shown in Scheme 94, our synthesis commenced with the preparation of phthalic anhydride 389 in two steps from phthalonitrile 388. The phthalic acid was obtained by basic hydrolysis of phthalonitrile 388, followed by the treatment of acetic anhydride to give phthalic 92 a) A. Böhm, T. Bach, Chem. Eur. J. 2016, 22, 15921-15928; b) M. K. Das, B. K. Dinda, V. Bisai, Tetrahedron Lett. 2019, 60, 2039-2042; c) A. M. Harned, B. M. Stoltz, Tetrahedron 2019, 75, 3166-3177.93 G. Huang, R. Guillot, C. Kouklovsky, B. Maryasin, A. de la Torre, Angew. Chem. Int. Ed. 2022, e202208185.

a

  Reaction conditions: 390 (0.5 mmol), TBSX(1.25 mmol), base(1.25 mmol), solvent(1.5 mL), argon, room temperature, 24 h. Isolated yield. b The reaction was conducted at 50 o C. c DMAP (10 mol%) was added. d The reaction was conducted at 0 o C. 4 Attempts for C-O Bond Formation 4.1 Attempts for Preparation of β-Keto Enol Ether from 1,3-Indandione With 1,3-indandione 385 in hand, we set out to evaluate the feasibility of C-O bond formation by model reactions. Initially, direct C-O bond formation was surveyed. Although numerous protocols have been established for the direct transformation of 1,3-diketones into β-keto enol ethers, the reaction with 1,3-indandione 385 as the starting material had never been studied. As depicted in Scheme 96, acid-catalyzed dehydration of 1,3-indandione 385 with

  96 a) A. R. Matlin, B. E. Turk, D. J. McGarvey, A. A. Manevich, J. Org. Chem. 1992, 57, 4638-4644; b) Y. Li, Y.-C. Hu, D.-W. Ji, W.-S. Zhang, G.-C. He, Y.-F. Cong, Q.-A. Chen, Chinese J. Catal. 2020, 41, 1401-1409; c) A. Clerici, N. Pastori, O. Porta, Tetrahedron 2001, 57, 217-225; d) M.

  Scheme 100. Mohr's research work for synthesis of aspergillusene B.

123 Scheme 119 .(Scheme 120 ) 120 .Scheme 121 .Scheme 122 .

 123119120120121122 Scheme 119c).

  mL) was added DDQ(1.08 g, 4.75 mmol) and K2CO3 (0.66 g, 4.75 mmol). The reaction mixture was refluxed at 105 o C for 2 h. Then the mixture was quenched with saturated Na2S2O3 aqueous solution (10 mL) and further diluted with water (20 mL). The resulting aqueous layer was extracted with DCM (3 × 20 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1) to afford 71i (0.55 g, quant.) as a yellow solid.

1 H

 1 NMR (400 MHz, CDCl3) δ 7.52 (d, J = 5.5 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.37 (d, J = 5.5 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H).

1 H

 1 NMR (360 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 5.4 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 6.36 (d, J = 5.4 Hz, 1H), 3.68 (s, 3H).

  mL) was added diethyl malonate 330b (949 mg, 5.93 mmol) and anhydrous zinc chloride (27 mg, 0.2 mmol). The reaction mixture was refluxed at 150 o C for 4 h and then cooled down to room temperature. The excess acetic anhydride was removed under reduced pressure(70 o C, 20 mbar)

  = 0.70 (petroleum ether/EtOAc = 5:1).1 H NMR (300 MHz, CDCl3) δ 6.30(d, J = 12.3 Hz, 1H), 5.01 (dt, J = 12.4, 7.0 Hz, 1H), 4.08 (dd, J = 7.0, 1.0 Hz, 2H),3.46 (td, J = 10.7, 4.3 Hz, 1H), 2H), 2H), 2H), 0.93 -0.86 (m, 18H), 0.76 (d, J = 6.9 Hz, 3H), 0.06 (s, 6H).

1 H

 1 NMR (360 MHz, CDCl3) δ 7.43 -7.25 (m, 5H), 6.58 (d, J = 12.7 Hz, 1H), 4.96 (dt, J = 12.7, 7.4 Hz, 1H), 4.51 (s, 2H), 3.97 (dd, J = 7.4, 0.7 Hz, 2H), 3.58 (s, 3H).

  resulting mixture was stirred at 0 o C for 30 min to give a pale-yellow suspension. Then a solution of 2-pyrone 71 (0.2 mmol) in DCM (0.5 mL) was added. After being stirred at 0 o C for 10 min, a solution of enol ether 344 (0.6 mmol) in DCM (0.5 mL) was added. This new mixture was stirred at 0 o C for 10 min and then stirred at 60 o C for 25 h. The crude mixture was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1→2:1) to afford racemic bridged lactone (±)-350.a Isolated yield. dr was determined by 1 H NMR spectroscopy. b Lactone (±)-350q was synthesized by General Procedure B, other lactones were synthesized by General Procedure A. c Cu(SbF6)2 was used as Lewis acid for the synthesis of (±)-350z.d The reaction for synthesizing lactones (±)-350ac and (±)-350al was run at 60 o C for 2 d. e The reaction for synthesizing lactone (±)-350ad was run at 60 o C for 3 d.

  78 o C for 5 min, a solution of enol ether 344 (0.45 mmol) in PhMe (1.0 mL) was added and the resulting mixture was stirred at -78 o C for 5 min to give a green suspension which was further stirred at -40 o C for 20 h (or 40/60 h for different cases) and then at room temperature for an additional 2 h. The crude mixture was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1→2:1) to afford chiral bridged lactone 350. Compound 350a: White solid (1.70 g, 95% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 0.8 mL/min, temperature = 5 o C, λ = 220 nm, t 1 = 7.79 min (major), t 2 = 10.81 min (minor). Rf = 0.35 (petroleum ether/EtOAc = 5:1).

  HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 95/5, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.85 min (major), t 2 = 12.31 min (minor).

  chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 240 nm, t 1 = 7.11 min (minor), t 2 = 8.48 min (major). Rf = 0.47 (petroleum ether/EtOAc = 3:1). 1 H NMR (360 MHz, CDCl3) δ 7.35 -7.20 (m, 5H), 6.48 (d, J = 5.5 Hz, 1H), 5.27 (dd, J = 5.5, 1.4 Hz, 1H), 3.87 (d, J = 1.4 Hz, 1H), 3.83 -3.67 (m, 2H), 3.53 (s, 3H), 3.51 (s, 3H), 2.17 -2.06 (m, 1H), 0.93 (s, 9H), 0.11 (s, 3H), 0.11 (s, 3H).

13 C

 13 NMR (90 MHz, CDCl3) δ 168.

  (91 MHz, CDCl3) δ 168.

  chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 97/3, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 240 nm, t 1 = 9.38 min (minor), t 2 = 10.47 min (major). Rf = 0.48 (petroleum ether/EtOAc = 3:1).1 H NMR (360 MHz, CDCl3) δ 7.28(d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 5.4 Hz, 1H), 5.27 (dd, J = 5.4, 1.4 Hz, 1H), 3.86 (d, J = 1.3 Hz, 1H), 2H), 3.56

  chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 240 nm, t 1 = 7.44 min (minor), t 2 = 8.62 min (major). Rf = 0.39 (petroleum ether/EtOAc = 3:1).1 H NMR (360 MHz, CDCl3) δ 7.20 (dd, J = 8.3, 5.5 Hz, 2H), 6.99 (t, J = 8.6 Hz, 2H), 6.45(d, J = 5.4 Hz, 1H), 5.26 (d, J = 5.4 Hz, 1H),3.86 (s, 1H), 3.82 -3.66 (m, 2H), 3.54 (s, 3H), 3.51 (s, 3H), 2.10 (t, J = 8.1 Hz, 1H), 0.92 (s, 9H), 0.10 (s, 6H).

  δ 168.6, 167.4, 162.7 (d, J = 247.2 Hz), 142.8, 133.6 (d, J = 3.0 Hz), 128.6 (d, J = 8.0 Hz), 127.0, 115.1 (d, J = 21.7 Hz),

  chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 240 nm, t 1 = 6.97 min (minor), t 2 = 8.35 min (major). Rf = 0.43 (petroleum ether/EtOAc = 3:1). 1 H NMR (360 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 5.4 Hz, 1H), 5.30 (d, J = 5.4 Hz, 1H), 3.89 (s, 1H), 3.84 -3.67 (m, 2H), 3.54 (s, 3H), 3.51 (s, 3H), 2.11 (t, J = 8.1 Hz, 1H), 0.92 (s, 9H), 0.11 (s, 6H).

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 13.24 min (minor), t 2 = 17.95 min (major). Rf = 0.37 (petroleum ether/EtOAc = 3:1).1 H NMR (360 MHz, CDCl3) δ 6. 3H), 6.39 (d, J = 5.5 Hz, 1H), 5.93 (d, J = 3.5 Hz, 2H), 5.23(d, J = 5.5 Hz, 1H), 3.83 (s, 1H), 2H), 3.59 (s, 3H), 3.49 (s, 3H), 2.09 (t, J = 8.1 Hz, 1H), 0.91 (s, 9H), 0.09 (s, 6H).

13 C

 13 NMR (90 MHz, CDCl3) δ 168.

  (s, 6H), 2.33 (s, 3H), 2.11 (t, J = 8.1 Hz, 1H), 0.93 (s, 9H), 0.11 (s, 6H).

  ) m/z Calcd for C19H33O6Si [M+H] + : 385.2041, found: 385.2038. White solid (109.0 mg, 91% yield, 95% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® IF-3 (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 10.70 min (minor), t 2 = 11.05 min (major). This bridged bicyclic lactone was crystallized from acetone/EtOH (1:1), and its absolute configuration was established by X-ray crystallography. Rf = 0.46 (petroleum ether/EtOAc = 3:1).1 H NMR (360 MHz, CDCl3) δ 6. 1H), 1H), 2H), 3H), 3.30 (s, 3H), 2.28 (qd, J = 7.4, 1.5 Hz, 2H), 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.4 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H).

  ) m/z Calcd for C21H37O6Si [M+H] + : 413.2354, found: 413.2341.[α]D 25 = -4.0 o (c = 1.00, CHCl3).Compound 350t:Colorless oil (123.3 mg, 95% yield, 95% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 260 nm, t 1 = 5.19 min (major), t 2 = 5.66 min (minor). Rf = 0.44 (petroleum ether/EtOAc = 3:1).

  ) m/z Calcd for C23H33O6Si [M+H] + : 433.2041, found: 433.2025. [α]D 25 = + 38.0 o (c = 1.00, CHCl3).

  White solid(131.4 mg, 98% yield, 96% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 260 nm, t 1 = 5.61 min (major), t 2 = 6.59 min (minor). Rf = 0.44 (petroleum ether/EtOAc = 3:1).

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 260 nm, t 1 = 6.01 min (major), t 2 = 6.91 min (minor). Rf = 0.44 (petroleum ether/EtOAc = 3:1).

  White solid(103.6 mg, 93% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.18 min (major), t 2 = 11.08 min (minor). Rf = 0.31 (petroleum ether/EtOAc = 5:1).

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 5.32 min (major), t 2 = 6.70 min (minor). Rf = 0.35 (petroleum ether/EtOAc = 5:1).

  Calcd for C19H33O6Si [M+H] + : 385.2041, found: 385.2031. White solid (130.4 mg, >99% yield, 98% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 97/3, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 5.40 min (major), t 2 = 8.45 min (minor). Rf = 0.41 (petroleum ether/EtOAc = 5:1).

  ) m/z Calcd for C23H33O6Si [M+H] + : 433.2041, found: 433.2027. White solid (104.4 mg, 91% yield, 98% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.08 min (major), t 2 = 12.22 min (minor). Rf = 0.38 (petroleum ether/EtOAc = 5:1).

  ) m/z Calcd for C19H31O6Si [M+H] + : 383.1884, found: 383.1874. White solid (90.2 mg, 92% yield, 89% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® IF-3 (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 19.93 min (major), t 2 = 21.43 min (minor). Rf = 0.39 (petroleum ether/EtOAc = 3:1).

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® IF-3 (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 13.13 min (minor), t 2 = 14.40 min (major). Rf = 0.38 (petroleum ether/EtOAc = 5:1).

  ) m/z Calcd for C22H30NaO5Si [M+Na] + : 425.1755, found: 425.1744. White solid (40.3 mg, 53% yield, 88% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 90/10, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 8.80 min (major), t 2 = 10.06 min (minor). Rf = 0.35 (petroleum ether/EtOAc = 1:1).

  chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 97/3, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 5.90 min (major), t 2 = 9.46 min (minor). Rf = 0.35 (petroleum ether/EtOAc = 5:1).

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 97/3, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 4.90 min (major), t 2 = 5.93 min (minor). Rf = 0.41 (petroleum ether/EtOAc = 5:1).

  [α]D 25 = -83.0 o (c = 1.00, CHCl3

  [α]D 25 = -17.0 o (c = 1.00, CHCl3). HRMS (ESI) m/z Calcd for C26H44NaO6Si [M+Na] + : 503.2799, found: 503.2778.

  1 mmol) with Z-enol ether 344p with catalysis of Cu(SbF6)2/L15 (10 mol%) at -40 o C for 40 h and then at room temperature for 2 h. White solid (30.5 mg, 90% yield, 91% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® IF-3 (250 × 4.6 mm), hexane/iPrOH = 90/10, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.81 min (minor), t 2 = 9.12 min (major). This bridged bicyclic lactone was crystallized from acetone/EtOH (1:1), and its absolute configuration was established by X-ray crystallography. Rf = 0.33 (petroleum ether/EtOAc = 5:1).

  ) m/z Calcd for C17H29O6Si [M+H] + : 357.1728, found: 357.1722.[α]D 25 = + 10.0 o (c = 1.00, CHCl3).Chiral compound 351a:White solid (3.7 mg, 3% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 95/5, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm), t 1 = 7.53 min (major), t 2 = 8.51 min (minor). Rf = 0.18 (petroleum ether/EtOAc = 5:1).

  ) m/z Calcd for C17H29O6Si [M+H] + : 357.1728, found: 357.1716. White solid (13.3 mg, 12% yield, 90% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 98/2, flow rate = 0.8 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 5.95 min (major), t 2 = 7.18 min (minor). Rf = 0.43 (petroleum ether/EtOAc = 3:1).

  ) m/z Calcd for C18H31O6Si [M+H] + : 371.1884, found: 371.1890. White solid (15.6 mg, 14% yield, 86% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 5.78 min (major), t 2 = 8.65 min (minor).

  ) m/z Calcd for C18H31O6Si [M+H] + : 371.1884, found: 371.1873. White solid (23.3 mg, 21% yield, 85% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 6.58 min (major), t 2 = 7.42 min (minor). Rf = 0.29 (petroleum ether/EtOAc = 3:1).

  ) m/z Calcd for C18H31O6Si [M+H] + : 371.1884, found: 371.1877. White solid (22.1 mg, 20% yield, 90% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 95/5, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 6.66 min (minor), t 2 = 8.59 min (major). Rf = 0.16 (petroleum ether/EtOAc = 3:1).

  ) m/z Calcd for C11H15O6 [M+H] + : 243.0863, found: 243.0863. [α]D 25 = -47.0 o (c = 1.00, CHCl3).

  Colorless oil(92.3 mg, 98% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 97/3, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 280 nm, t 1 = 3.97 min (minor), t 2 = 4.54 min (major). Rf = 0.30 (petroleum ether/EtOAc = 5:1).

MeOH ( 4 . 5 ×

 45 8 mL) was added. The solution was stirred at 0 o C and NaOMe (0.5 M in MeOH, 1.2 mL, 0.6 mmol) was added dropwise. The mixture was stirred at 0 o C for 2 h before saturated NH4Cl aqueous solution (5 mL) was added. The aqueous mixture was extracted with DCM (20 mL). The combined organic layers were washed with brine (10 mL), concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1→6:1) to afford cyclohexene 354 as a colorless oil.Compound 354:Colorless oil (102.1 mg, 88% yield, 97% ee). The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 6.75 min (minor), t 2 = 8.51 min (major). Rf = 0.13 (petroleum ether/EtOAc = 5:1).

  chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 95/5, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 4.63 min (major), t 2 = 5.07 min (minor). Rf = 0.27 (petroleum ether/EtOAc = 5:1).

  HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 90/10, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 9.61 min (minor), t 2 = 13.39 min (major). Rf = 0.23 (DCM/EtOAc = 3:1).

  ) m/z Calcd for C25H47O6Si2 [M+H] + : 499.2906, found: 499.2905. [α]D 25 = + 5.2 o (c = 1.16, CHCl3).

  ) m/z Calcd for C20H43O3Si2 [M+H] + : 387.2745, found: 387.2746. [α]D 25 = -35.1 o (c = 1.34, CHCl3).

Figure 4 .

 4 Figure 4. An ORTEP drawing of compound 350ac. Thermal ellipsoids are shown at the 30% level.

Figure 5 .

 5 Figure 5. An ORTEP drawing of compound 350al. Thermal ellipsoids are shown at the 30% level.

Figure 6 .

 6 Figure 6. An ORTEP drawing of compound 350r. Thermal ellipsoids are shown at the 30% level.

Figure 7 .

 7 Figure 7. An ORTEP drawing of compound 351a. Thermal ellipsoids are shown at the 30% level.X-ray diffraction data for compounds 350ac, 350al and 350r were collected by using a Kappa X8 APPEX II Bruker diffractometer with graphite-monochromated MoKα radiation (λ = 0.71073 Å). X-ray diffraction data for compound 351a were collected by using a VENTURE PHOTON100 CMOS Bruker diffractometer with Micro-focus IuS source CuKα radiation (λ =

  three: To a mixture of N,O-dimethylhydroxylamine hydrochloride(1.07 g, 11 mmol), triethylamine(3.5 mL, 25 mmol) in DCM (10 mL) under argon was added the above acid chloride solution (10 mL, 10 mmol) dropwise at 0 o C. After being stirred at room temperature for 2 h, the resulting mixture was quenched with water (10 mL) and then extracted with DCM(3 × 20 mL). The combined organic layers were concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 3:1→1:3) to give compound 425 as a yellow solid (265 mg, 15% over three steps). Rf = 0.16 (petroleum ether/EtOAc = 1:3) 1 H NMR (360 MHz, CDCl3) δ 7.54 (dd, J = 5.1, 2.1 Hz, 1H), 7.50(d, J = 5.4 Hz, 1H), 6.30 (dd, J = 6.5, 5.3 Hz, 1H), 3.67 (s, 3H), 3.29 (s, 3H).

(

  Calcd for C38H51O9Si2 [M+H] + : 707.3066, found: 707.3044.[α]D 20 = -126.0 o (c = 1.00, CHCl3).

5 (

 5 C-8'),126.1 (C-5),122.3 (C-6), 87.9 71.3 (ArCH2), 61.1 (C-2'), 52.3 (OCH3), 51.0 (C-3'), 45.7 (C-5'), 43.5 (C-6'), 25.9 (SiC(CH3)3), 18.Calcd for C37H51O7Si2 [M+H] + : 663.3168, found: 663.3139. [α]D 20 = -59.4 o (c = 1.01, CHCl3).

  Calcd for C36H52NaO6Si2 [M+Na] + : 659.3195, found: 659.3161. [α]D 20 = -63.4 o (c = 1.01, CHCl3).

  ), 130.2(C-3),128.7 (ArCH2), 128.2 (ArCH2), 128.1 (ArCH2),, 117.1 (C-6), 96.8 (C-7'), 88.2 (C-4'), 72.8 (C-1'), 71.5 (C-10'), 70.8 (ArCH2), 65.1 (C-11'), 57.2 (C-2'), 46.0 (C-3'), 45.7 (C-5'), 43.2 (C-6'), 26.1 (SiC(CH3)3), 18.5 (SiC(CH3)3), -3Calcd for C30H38NaO6Si [M+Na] + : 545.2330, found: 545.2311. [α]D 20 = -95.1 o (c = 1.01, CHCl3).

5 (

 5 ),126.6 (C-5),122.4 (C-6), 71.7 (ArCH2),, 26.0 (SiC(CH3)3), 25.9 (SiC(CH3)3), 18.SiC(CH3)3), 18.5 (SiC(CH3)3), -3.8 (SiCH3), -4.0 (SiCH3), -4.4 (SiCH3), -4.5 (SiCH3).HRMS (ESI) m/zCalcd for C36H49O6Si2 [M+H] + : 633.3062, found: 633.3080. Calcd for C37H53O6Si2 [M+H] + : 649.3375, found: 649.3385. [α]D 20 = -33.0 o (c = 1.06, CHCl3).

  C-2'),55.9 (C-3'), 45.5 (C-5'), 43.7 (C-6'), 29.2 (C-12'), 25.9 (SiC(CH3)3), 25.8 (SiC(CH3)3), 18.4 (SiC(CH3)3), 18.4 (SiC(CH3)3), -3.9 (SiCH3), -4.1 (SiCH3), -4.6 (SiCH3), -

3 (

 3 C-5),127.7 (C-8'),123.4 (C-6),89.3 (C-4'), 87.5 (C-7'), 72.9 (C-10'), 71.8 (ArCH2), 63.1 (C-2'), 57.4 (C-3'), 46.5 (C-5'), 45.0 (C-6'), 28.5 (C-12'), 26.4 (SiC(CH3)3), 26.SiC(CH3)3), 19.2 (SiC(CH3)3), 19.2 (SiC(CH3)3), -3.8 (SiCH3), -4.0 (SiCH3), -4.3 (SiCH3), -4.4 (SiCH3). HRMS (ESI) m/z Calcd for C37H51O6Si2 [M+H] + : 647.3219, found: 647.3204. [α]D 20 = -32.7 o (c = 1.04, CHCl3).

13 C 9 (

 139 NMR (100 MHz, CDCl3) δ 212.9(C-11'), 198.6 (C-1'), 148.3 (C-1), 147.3(C-4), 139.Calcd for C33H53O6Si2 [M+H] + : 649.3375, found: 649.3347. [α]D 20 = + 61.0 o (c = 1.05, CHCl3).

13 C

 13 NMR (100 MHz, CDCl3) δ 213.8 (C-11'), 198.7 (C-1'), 148.3 (C-1), 147.4 (C-4), 139.8 (C-3), 130.1 (C-2), 126.7 (C-5), 122.6 (C-6), 85.5 (C-7'), 78.1 (C-4'), 72.9 (C-10'), 61.2

13 C

 13 NMR (100 MHz, MeOD) δ 215.1 (C-11'), 200.5 (C-1'), 149.6 (C-4), 148.5 (C-1), 141.1 (C-3), 131.0 (C-2), 128.1 (C-5), 123.7 (C-6), 86.6 (C-7'), 79.6 (C-4'), 74.0 (C-10'), 62.7 (C-2'), 52.7 (C-3'), 49.1 (C-5'), 39.2 (C-6'), 28.5 (C-12'), 26.3 (SiC(CH3)3), 26.3 (SiC(CH3)3Calcd for C30H47O6Si2 [M+H] + : 559.2906, found: 559.2883. [α]D 20 = + 31.1 o (c = 1.03, CHCl3).

  , 52.6 (C-3'), 49.1 (C-5'), 39.1 (C-6'),28.4 (C-12'), 16.1 (C-8'), 15.8 (C-9').

  ) m/z Calcd for C18H19O6 [M+H] + : 331.1176, found: 331.1171. [α]D 20 = + 68.9 o (c = 1.03, MeOH). The specific rotations of natural lucidumone reported by Cheng's work: {[α]D 20 = + 29.6 o (c = 0.027, MeOH) for (+)-370; [α]D 20 = -70.6 o (c = 0.017, MeOH) for (-)-370}. 87a

( 3 .

 3 05 g, 12 mmol) was added under argon. After being stirred at 0 o C for 15 min, then alcohol 398(1.15 g, 10 mmol) in DCM (10 mL) was added. The reaction was stirred at 0 o C for another 30 min and then allowed to stir at room temperature for 16 h. After that saturated Na2S2O3 aqueous solution (20 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with DCM(3 × 20 mL). The combined organic layers were132 H. Tsukamoto, Y. Nomura, T. Doi, Heterocycles 2019,99, 549-565.

  COSY spectrum of (+)-lucidumone (in MeOD) HSQC spectrum of (+)-lucidumone (in MeOD) HMBC spectrum of (+)-lucidumone (in MeOD) Partial HMBC spectrum of (+)-lucidumone (in MeOD) HSQC spectrum of (+)-lucidumone (in DMSO-d6) Partial HSQC spectrum of (+)-lucidumone (in DMSO-d6) HMBC spectrum of (+)-lucidumone (in DMSO-d6) Partial HMBC spectrum of (+)-lucidumone (in DMSO-d6) Partial HMBC spectrum of (+)-lucidumone (in DMSO-d6) ROESY spectrum of (+)-lucidumone (in

Figure 1 .

 1 Figure 1. A) the relationship between yield and reaction time. B) the relationship between ee and reaction time. ...................................................................................................................................Figure 2. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the E and Z enol ethers. ........................................... Figure 3. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the trisubstituted dienophile. ...................................Figure 4. An ORTEP drawing of compound 350ac. .....................................................................Figure 5. An ORTEP drawing of compound 350al. .....................................................................Figure 6. An ORTEP drawing of compound 350r. .......................................................................Figure 7. An ORTEP drawing of compound 351a. ......................................................................

  Figure 1. A) the relationship between yield and reaction time. B) the relationship between ee and reaction time. ...................................................................................................................................Figure 2. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the E and Z enol ethers. ........................................... Figure 3. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the trisubstituted dienophile. ...................................Figure 4. An ORTEP drawing of compound 350ac. .....................................................................Figure 5. An ORTEP drawing of compound 350al. .....................................................................Figure 6. An ORTEP drawing of compound 350r. .......................................................................Figure 7. An ORTEP drawing of compound 351a. ......................................................................

Figure 2 .Figure 3 .

 23 Figure 1. A) the relationship between yield and reaction time. B) the relationship between ee and reaction time. ...................................................................................................................................Figure 2. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the E and Z enol ethers. ........................................... Figure 3. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the trisubstituted dienophile. ...................................Figure 4. An ORTEP drawing of compound 350ac. .....................................................................Figure 5. An ORTEP drawing of compound 350al. .....................................................................Figure 6. An ORTEP drawing of compound 350r. .......................................................................Figure 7. An ORTEP drawing of compound 351a. ......................................................................

Figure 4 .Figure 5 .Figure 6 .

 456 Figure 1. A) the relationship between yield and reaction time. B) the relationship between ee and reaction time. ...................................................................................................................................Figure 2. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the E and Z enol ethers. ........................................... Figure 3. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the trisubstituted dienophile. ...................................Figure 4. An ORTEP drawing of compound 350ac. .....................................................................Figure 5. An ORTEP drawing of compound 350al. .....................................................................Figure 6. An ORTEP drawing of compound 350r. .......................................................................Figure 7. An ORTEP drawing of compound 351a. ......................................................................

Figure 7 .

 7 Figure 1. A) the relationship between yield and reaction time. B) the relationship between ee and reaction time. ...................................................................................................................................Figure 2. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the E and Z enol ethers. ........................................... Figure 3. Computed reaction profiles (ωB97X-D/def2-TZVP//ωB97X-D/6-31G(d),LanL2DZ, ΔG298,toluene, kcalmol -1 ) for the reaction with the trisubstituted dienophile. ...................................Figure 4. An ORTEP drawing of compound 350ac. .....................................................................Figure 5. An ORTEP drawing of compound 350al. .....................................................................Figure 6. An ORTEP drawing of compound 350r. .......................................................................Figure 7. An ORTEP drawing of compound 351a. ......................................................................

  dernières années. Ces cycloadditions permettent d'accéder efficacement à des lactones bicycliques pontées qui ont été utilisée pour la synthèse de nombreux produits naturels bioactifs et candidats-médicament. Dans cette thèse nous présentons 4 chapitres, dont les deux premiers décrivent les récentes avancées de ce type de cycloaddition et leur application, et les deux derniers concernent nos résultats de recherche.Le premier chapitre de cette thèse décrit une revue exhaustive des méthodes décrites dans la littérature de cycloadditions à demande électronique inverse des 2-pyrones en tant que diènes électrophiles avec des alcènes activés. Ces exemples se divisent en deux catégories : cycloadditions non-catalysées (thermiques ou sous haute pression) et cycloadditions catalysées.La première de ces deux catégories a été l'objet de nombreux développements mais est handicapée par la faible stabilité thermique des cycloadduits, ainsi que pas le manque de contrôle de l'énantiosélectivité, ce qui limité don potentiel synthétique. En revanche, les cycloaddition catalysées permettent de surmonter ces difficultés, par activation soit du diène, soit du diénophile. Le système 1,3-dicarbonylé des 3-carbanoly-2-pyrones est susceptible de chélater des acides de Lewis afin d'abaisser le niveau de l'orbitale BV et donc de réaliser des cycloadditions avec des diénophiles électroniquement enrichis dans des conditions douces, pour conduire à la formation exclusive de lactones bicycliques. L'organocatalyse a été également employée pour ces cycloadditions : l'utilisation da catalyseurs aminés permet d'inclure les dérivés carbonylés -insaturés comme diénophiles dans la mesure où ils conduisent à des diénamines chirales par condensation. L'utilisation de chaque type de catalyseur permet de s'affranchir des méthodes conventionnelles utilisant des auxiliaires chiraux pour réaliser une induction asymétrique directe.Le deuxième chapitre concerne les applications de ces cycloadditions en synthèse totale de produits naturels et de candidats-médicament. Les lactones bicycliques sont des précurseurs flexibles pour la synthèse de nombreuses substances naturelles en raison de leurs possibilités de post-fonctionnalisation : l'ouverture par des lactones nucléophiles (comme par exemple une transestérification) conduit à des cyclohexènes densément fonctionnalisés, tandis que l'extrusion de CO2 par réaction de retro-Diels-Alder conduit à des cyclohexadiènes, lesquels peuvent être aromatisés. De surcroit, de nouvelles lactones polycycliques peuvent être obtenues par des transpositions radicalaires des cycloadduits. L'ensemble de ces réaction confère à ces lactones préparées par cycloaddition à demande électronique inverse un très fort potentiel synthétique. Nos derniers résultats de recherche sur le développement d'une réaction de Diels-Alder à demande inverse en électrons asymétrique entre des 2-pyrones et des éthers d'énol acycliques sont décrits dans le chapitre suivant. L'utilisation d'un système catalytique Cu II -BOX permet l'obtention des lactones bicycliques correspondantes avec d'excellents rendements (jusqu'à 99%) et d'excellents excès énantiomériques (jusqu'à 99%) à partir de 2-pyrones diversement substituées et d'éthers d'énol acycliques. Une étude mécanistique appuyée par des calculs de théorie de la fonctionnelle de la densité (DFT) indiquent que le mécanisme se décompose en deux étapes. Le potentiel synthétique des lactones bicycliques pontées est mis en avant par la synthèse énantiosélective de cyclohexènes et cyclohexadiènes polysubstitués ainsi que d'une unité carbasucre. Le chapitre 4 présente nos derniers travaux pour une synthèse totale énantiosélective de la (+)-lucidumone à l'échelle du gramme. Les étapes-clés de cette synthèse impliquent la formation d'une lactone bicyclique par une réaction de Diels-Alder à demande inverse en électrons énantiosélective, la formation d'une liaison C-O pour assembler deux fragments et une cascade d'extrusion de CO2 / Diels-Alder intramoleculaire. Des modifications de groupements fonctionnels en fin de synthèse permettent de compléter la synthèse totale de la (+)-lucidumone à l'échelle du gramme.

  R. A. A. Foster, M. C. Willis, Chem. Soc. Rev. 2013,

	42, 63-76; c) A.-C. Knall, C. Slugovc, Chem. Soc. Rev. 2013, 42, 5131-5142; d) M. Xie, L. Lin, X. Feng, Chem.
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8 a) B. T. Woodward, G. H. Posner in Advances in Cycloadditions, Vol. 5 (Ed: M. Harmata), JAI Press, 1999, pp 47-83; b) K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner, Tetrahedron 1992, 48, 9111-9171; c) Q. Cai, Chin.

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silyl enol ether 16c could proceed easily in the presence of catalytic zinc salt, leading to bridged bicyclic lactone 141 in 74% yield with 98:2 dr (Scheme 40). 51

	the addition of Lewis acid combining with chiral ligands allows to realize the asymmetric
	variant of IEDDA cycloaddition, which is impossible under non-catalytic conditions.
	Scheme 40. ZnBr2-catalyzed IEDDA cycloaddition of 3-carbomethoxy-2-pyrone with silyl
	enol ether.
	Lanthanides are efficient catalysts for the IEDDA cycloaddition of 3-carbomethoxy-2-
	pyrone with a great number of electron-rich dienophiles. In 1994, Posner and co-worker
	reported an efficient IEDDA cycloaddition of unsubstituted 2-pyrone 1 with electron-rich
	benzyl vinyl ether 16d with the combination of high pressure
	Scheme 38. Comparable results between thermal and Lewis acid-catalyzed IEDDA
	cycloadditions.
	4.1.1 Racemic IEDDA Cycloaddition of 2-Pyrones
	In 1987, Posner and co-workers reported that the IEDDA cycloaddition of 3-sulfinyl-2-pyrone
	133 with ethyl vinyl ether 16a could be promoted by zinc bromide at room temperature, as
	shown in Scheme 39. The resulting bridged bicyclic lactone 140 was obtained in good yield.
	However, in this example stoichiometric amount of zinc bromide was required. 46 In 2013, the
	same team disclosed that the IEDDA cycloaddition of 3-carbomethoxy-2-pyrone 71a with more
	disubstituted 3-carbomethoxy-2-pyrone 77 was treated with 1,1-dimethoxyethylene 13a in the electron-rich Scheme 39. ZnBr2-promoted IEDDA cycloaddition of 3-sulfinyl-2-pyrone with ethyl vinyl
	presence of catalytic Ni(acac)2 at room temperature, despite the lower yield in comparison with ether.
	the thermal IEDDA reaction (Scheme 38). 50 Generally, the role of Lewis acid in the mild
	catalytic IEDDA cycloaddition is to lower the LUMO level of 2-pyrone. It should be noted that
	50 D. L. Boger, M. D. Mullican, J. Org. Chem. 1984, 49, 4033-4044. 51 R. D. Slack, M. A. Siegler, G. H. Posner, Tetrahedron Lett. 2013, 54, 6267-6270.

4 Catalytic IEDDA Cycloaddition 4.1 Lewis Acid-Catalyzed IEDDA Cycloaddition of 2-Pyrones As mentioned above, the [2.2.2]-bicyclic lactones prepared from the IEDDA cycloaddition of 2-pyrones with dienophiles are usually so labile under thermal conditions that the cycloaddition is easily plagued by CO2 extrusion and subsequent aromatization. To avoid CO2 extrusion from the initially formed cycloadducts, relatively milder reaction conditions are required to replace the previous harsh conditions. Since the first example of Lewis acid-catalyzed IEDDA cycloaddition of 2-pyrone was discovered by Boger and co-worker in 1984, chemists have realized that Lewis acids are capable of catalyzing the IEDDA cycloaddition of 2-pyrones under mild conditions. In this first report, only aromatic cycloadduct 81 was isolated when 5,6-

the rigidity of the seven-membered structure in 153 and 154 blocked the attack of dienophiles from Si-face because of the steric effect of α- methyl substituents. This chelated intermediate 154 also rationalizes the same levels of

	Scheme 44. Diastereoselective IEDDA cycloadditions by the installation of a chiral auxiliary
	Scheme 43. Eu(hfc)3-catalyzed IEDDA cycloaddition of 2-pyrones with α,β-unsaturated on 2-pyrone or on the dienophile.
	hydrazones. In 1994, Markó and co-worker also investigated the catalytic IEDDA cycloaddition of
	Scheme 42. Comparable results between thermal and Eu(hfc)3-catalyzed IEDDA 4.1.2 Diastereoselective IEDDA Cycloaddition of 2-Pyrones Using Chiral Auxiliaries several chiral 3-carbonyl-2-pyrones and discovered that (R)-pantolactone auxiliary provided
	cycloadditions of 3-carbomethoxy-2-pyrone. excellent yields and diastereoselectivities. 57 Mono-substituted dienophiles reacted with (R)-150
	The installation of a chiral auxiliary on 2-pyrone or on the dienophile, prior to the IEDDA The transformation of α,β-unsaturated aldehydes to α,β-unsaturated hydrazones results in to deliver bridged bicyclic lactones endo-151 as the major diastereomer with good to excellent
	cycloaddition, provides a route to optically active bridged bicyclic lactones as a separable umpolung, for which the HOMO level of the resulting α,β-unsaturated hydrazones could match diastereoselectivities, whereas the reaction with dihydrofuran as the dienophile gave a Scheme 45. Diastereoselective IEDDA cycloaddition of chiral 3-carbonyl-2-pyrone with
	diastereomeric mixture. In 1990, Posner and co-worker used enantioenriched vinyl ether (S)-with the LUMO level of electron-poor 2-pyrones. In 2018, Tamura and co-workers reported an 146 as the dienophile for an aluminium-catalyzed IEDDA cycloaddition with 3-sulfonyl-2-diastereomeric mixture of 151 and 152 in nearly 1:1 dr (Scheme 45a). Remarkably, the major various dienophiles. Scheme 46. Intramolecular diastereoselective IEDDA cycloaddition of 2-pyrones bearing a Eu(hfc)3-catalyzed IEDDA cycloaddition of 3-carbomethoxy-2-pyrone 71a or 3-sulfonyl-2-(endo-149, Scheme 44b), which could be rationalized by chelated intermediates 153 and 154. Posner and co-workers in 1995, as shown in Scheme 46. 58 The chiral 1,3-butanediol auxiliary pyrone 137 with α,β-unsaturated hydrazones 144 for accessing bridged bicyclic lactones 145 pyrone 137, leading to chiral bridged bicyclic lactone endo-147 as the major diastereomer in diastereomer possesses the opposite absolute configuration to that obtained by Posner et al. An intramolecular diastereoselective IEDDA cycloaddition of 2-pyrones was explored by chiral auxiliary.
	good isolated yield with excellent diastereoselectivity (Scheme 44a). 55 Later, an alternative (Scheme 43). In contrast, no cycloaddition occurred when acrolein was directly used as the The chelated intermediate 153 is disfavored because of the dipole-dipole repulsion between acted as a linker between trans-silyl enol ethers and 2-pyrone-3-carboxylate. The
	3-carbomethoxy-2-pyrone 71a with electron-rich dienophiles in comparison with the thermal route to optically active bridged bicyclic lactones was achieved by the same group, in which 2-dienophile, which illustrates that the reaction proceeded in an inverse-electron-demand fashion. 54 pyrone 148 bearing a chiral side chain at C 3 position was used as the electrophilic diene in the catalytic IEDDA cycloaddition with benzyl vinyl ether 16d (Scheme 44b). 56 intramolecular IEDDA cycloaddition of such 2-pyrones (S)-155 and (R)-157 were promoted by zinc bromide and proceeded in a stepwise, asynchronous fashion to give optically active cis-bridged lactones exclusively with acceptable exo/endo ratios. Interestingly, both exo and endo two carbonyl groups at the same side. Moreover, diastereoselectivity observed by using achiral Eu(fod)3 and chiral (+)-Eu(hfc)3 as catalysts. cycloadducts were diastereomerically pure (>99:1 dr), which could be rationalized by the
	IEDDA cycloaddition. 53 As shown in Scheme 42, a range of dienophiles showed lower orientation of the methyl group in the transition state. For example, the transition state TS-158
	reactivities in the thermal IEDDA cycloaddition. However, in the presence of a catalytic amount with the methyl group in pseudo-equatorial position would be more stable than TS-158' with
	of Eu(hfc)3, bridged bicyclic lactones 143 were obtained in good isolated yields with these the methyl group in pseudo-axial position (Scheme 46c). 59 The energy difference in the
	dienophiles. transition states resulted in the predominant formation of one diastereomer.
	58 G. H. Posner, C.-G. Cho, T. E. N. Anjeh, N. Johnson, R. L. Horst, T. Kobayashi, T. Okano, N. Tsugawa, J. Org.
	52 G. H. Posner, Y. Ishihara, Tetrahedron Lett. 1994, 35, 7545-7548. 55 G. H. Posner, C. M. Kinter, J. Org. Chem. 1990, 55, 3967-3969. Chem. 1995, 60, 4617-4628.
	53 I. E. Markó, G. R. Evans, Synlett 1994, 431-433. 54 Y. Hashimoto, R. Abe, N. Morita, O. Tamura, Org. Biomol. Chem. 2018, 16, 8913-8916. 57 I. E. Markó, G. R. Evans, Tetrahedron Lett. 1994, 35, 2767-2770. 59 C.-G. Cho, G. H. Posner, Bull. Korean Chem. Soc. 1998, 19, 957-961.

pyrone 71a with vinylselenide 167, affording the corresponding bridged bicyclic lactone 169 in good isolated yield but with moderate ee (Scheme 50

	providing a great number of optically active bicyclic adducts 159 with variable the cycloaddition of 4,5-disubstituted-3-carboalkoxyl-2-pyrones 160 with 2,2-dimethyl-1,3-workers focused on the chiral titanium complex-promoted enantioselective IEDDA 4.2 Organocatalytic IEDDA Cycloaddition of 2-Pyrones of corresponding α,β-unsaturated esters 189 in good yields as well as excellent diastereo-and LUMO level, for which corresponding IEDDA cycloadditions with electron-rich dienophiles
	enantioselectivities (Scheme 47). Interestingly, Yb(OTf)3 could not catalyze this cycloaddition dioxole 121a proceeded well to provide bridged bicyclic lactones 162 with excellent cycloaddition of 3-carbomethoxy-2-pyrone 71a with vinyl ethers 16. As shown in Scheme 49, For decades, catalytic IEDDA cycloaddition of 2-pyrones only relied on LUMO-activation enantioselectivities. could occur under milder reaction conditions and provide bridged lactones exclusively. On the
	independently, indicating that a more suitable enantioselective catalyst was formed by the enantioselectivities (Scheme 48a), whereas the cycloaddition of more encumbered 6-the combination of Ti(OiPr)2Cl2 and chiral diol ligands could induce this cycloaddition strategy. Recently, chiral amine-catalyzed asymmetric IEDDA cycloaddition of α,β-unsaturated other hand, HOMO-activation strategy could be also used for IEDDA cycloadditions, in which
	combination of Yb(OTf)3 and (R)-BINOL. Later, the same group disclosed that the addition of substituted-3-carboalkoxyl-2-pyrones 163 with 2,2-dimethyl-1,3-dioxole 121a did not afford enantioselectively. For example, under catalysis by stoichiometric (4R,5R)-TADDOL-TiCl2 carbonyl compounds based on HOMO-activation strategy has attracted considerable attention. the use of aminocatalyst allowed to expand the substrate scope to α,β-unsaturated carbonyl
	THF, in the absence of molecular sieves, led to dramatically improved enantioselectivities in bridged bicyclic lactones 164 but directly generated arene cis-dihydrodiols 165 with excellent complex, the cycloaddition afforded optically active endo-adduct 166d, albeit in moderate yield As outlined in Scheme 52, the condensation of α,β-unsaturated carbonyl compounds 176 with compounds because of the formation of electron-rich dienamine intermediates via condensation.
	several cases, which is presumably due to the generation of a new active ytterbium catalyst enantioselectivities (Scheme 48b). Both the congested scaffold of intermediates TS-165 and the and enantioselectivity (Scheme 49a). 63 Gratifyingly, after considerable condition optimization, chiral aminocatalysts would generate dienamines 177 which have proved to be excellent Remarkably, both Lewis acid catalysis and aminocatalysis could realize direct asymmetric
	after coordinating with THF. 61 stabilization of C 6 -carbocation by substituents favored CO2 extrusion under very mild highly enantioenriched bridged bicyclic lactones 166a and 166b were obtained on gram scale intermediates for the IEDDA cycloaddition. induction, avoiding tedious operations in the conventional auxiliary-based approach, which has
	conditions. DFT calculations indicated that a lower energy barrier for CO2 extrusion was using stoichiometric amounts of chiral (R)-BINOL-TiCl2 complex (Scheme 49b). 64 Scheme 50. Enantioselective IEDDA cycloaddition of 3-carbomethoxy-2-pyrone with captured the imagination of synthetic chemists (Scheme 55b and Scheme 55c).
	observed when increasing the size of R 4 , in agreement with experimental results. The thermal vinylselenide.
	CO2 extrusion of bridged bicyclic lactones 162 generated from 4,5-disubstituted-3-More recently, a novel enantioselective catalytic system was developed by Feng's group for Scheme 53. Organocatalytic asymmetric IEDDA cycloaddition of 3-carbomethoxy-2-pyrone
	carboalkoxyl-2-pyrones 160 had to be conducted in chlorobenzene with very low concentration the IEDDA cycloaddition of 2-pyrones 172 with achiral pyrroline derivatives 173, as illustrated with 2,5-dienones.
	to prevent the dimerization of the generated cyclohexadienes, leading to the isolation of arene in Scheme 51. This IEDDA cycloaddition catalyzed by a complex of Mg(OTf)2 and chiral N,N'-Scheme 52. HOMO-activation of α,β-unsaturated carbonyl compounds. Diarylprolinol silyl ethers have been widely used as chiral organocatalysts in the
	cis-dihydrodiols in good yields without any erosion of ee values. This powerful method dioxide ligand 174 delivered numerous optically active bridged bicyclic adducts 175 with good By using this strategy, Chen and co-workers reported in 2018 the first example of enantioselective transformation of aldehydes. Recently, a novel organocatalytic asymmetric
	represents the first asymmetric chemical catalytic synthesis of arene cis-dihydrodiols and to excellent enantioselectivities. Further transformation of the obtained bridged lactones 175 organocatalytic asymmetric IEDDA cycloaddition of 3-carbomethoxy-2-pyrone 71a (Scheme IEDDA cycloaddition of electron-poor 2-pyrones 182 with 3,3-disubstituted α,β-unsaturated
	provides an efficient alternative to traditional enzymatic catalysis. allowed to achieve the formal synthesis of (+)-minovincine. 66 53). Under the catalysis of primary amine 179 derived from cinchona alkaloid, trienamine aldehydes 183 was achieved by Snyder and co-workers. 68 As shown in Scheme 54a, the Scheme 54. Organocatalytic asymmetric IEDDA cycloadditions of 2-pyrones with α,β-
	Scheme 49. Enantioselective IEDDA cycloaddition of 3-carbomethoxy-2-pyrone promoted intermediates were generated in situ from 2,5-dienones 178, the distal C-C double bond of cycloaddition between dienamine species, generated in situ from α,β-unsaturated aldehydes 183 unsaturated aldehydes.
	by chiral titanium complex. which underwent the cycloaddition with 3-carbomethoxy-2-pyrone 71a from the Re-face by condensation with aminocatalyst 184, and electron-poor 2-pyrones 182 afforded an array of
	Scheme 47. Enantioselective IEDDA cycloaddition of 3-carbomethoxy-2-pyrone with vinyl In 2000, Markó and co-workers disclosed that a combination of copper(II) triflate and chiral approach, leading to a series of bridged bicyclic lactones 181 in good yields and with excellent optically active bridged bicyclic lactones 185 in moderate to good yields (46-96% yield) with 5 Conclusion
	BOX ligand 168 was suitable for the enantioselective catalytic IEDDA cycloaddition of 3-diastereo-and enantiocontrol. 67 variable stereoselectivities (1.1:1 dr to >20:1 dr, 21% ee to 99% ee). Because of the secondary ethers and vinyl thioethers. To conclude, great progress has been made in IEDDA cycloadditions of electron-poor 2-
	More recently, an improved and efficient version of this reaction was achieved by Cai and orbital overlap between 2-pyrones and trienamines in the transition state TS-endo-185, bridged pyrones as electrophilic dienes with activated alkenes for the construction of a great number of carbomethoxy-2-). The resulting bicyclic lactones endo-185 were obtained as the major diastereomer in each case. It should be co-workers, in which a series of bridged bicyclic lactones 162 and arene cis-dihydrodiols 165 bridged lactones in the past few decades. Numerous non-catalytic IEDDA cycloadditions
	bridged lactone 169 readily underwent a two-step sequence including radical-mediated and noted that the use of 3,3-disubstituted α,β-unsaturated aldehydes is essential to the isolation of were obtained in good yields with excellent enantioselectivities (Scheme 48). 62 After extensive promoted by direct heating or by high pressure were developed. However, under thermal
	acid-catalyzed skeletal rearrangements to provide bicyclic fused lactones 171a and 171b in desired products. Later, a similar reaction using 2,3-disubstituted α,β-unsaturated aldehydes screening of chiral ligands in combination with Yb(OTf)3, they found that the introduction of conditions the rigid lactone-bridged structure in the initially formed cycloadducts could readily
	15:1 ratio. 65 Scheme 51. Enantioselective IEDDA cycloaddition of 3-carboalkoxyl-2-pyrones with 186 as dienophiles was developed by Albrecht and co-workers (Scheme 54b). 69 However, the pentafluorophenyl groups on 3,3'-positions of (R)-BINOL resulted in dramatical increase of the undergo CO2 extrusion via a retro-DA cycloaddition to forge densely functionalized 1,3-
	pyrroline derivatives. resulting bridged bicyclic lactones 188 were not stable enough for purification. Further yield and ee value. Interestingly, using a combination of Yb(OTf)3 and chiral ligand (R)-161, cyclohexadienes and subsequent aromatization through loss of a small molecule to afford
	transformation of cycloadducts 188 via a Wittig reaction in one pot allowed to isolate a number Scheme 55. Summary of recent advances in IEDDA cycloadditions of 2-pyrones.
	polysubstituted aromatic compounds, which intrinsically limits their applications in total
	60 a) I. E. Markó, G. R. Evans, J.-P. Declerq, Tetrahedron 1994, 50, 4557-4574; b) I. E. Markó, G. R. Evans, 61 I. E. Markó, I. Chellé -Regnaut, B. Leroy, S. L. Warriner, Tetrahedron Lett. 1997, 38, 4269-4272. Scheme 48. Enantioselective IEDDA cycloaddition of 3-carboalkoxyl-2-pyrones with 2,2-dimethyl-1,3-dioxole. 63 G. H. Posner, J.-C. Carry, J. K. Lee, D. S. Bull, H. Dai, Tetrahedron Lett. 1994, 35, 1321-1324. 64 a) G. H. Posner, F. Eydoux, J.-K. Lee, D. S. Bull, Tetrahedron Lett. 1994, 35, 7541-7544; b) G. H. Posner, H. synthesis (Scheme 55a).
	Tetrahedron Lett. 1994, 35, 2771-2774; c) I. E. Markó, G. R. Evans, Bull. Soc. Chim. Belg. 1994, 103, 295-297; d) I. E. Markó, G. R. Evans, P. Seres, I. Chellé , Z. Janousek, Pure & Appl. Chem. 1996, 68, 113-122. 62 X.-W. Liang, Y. Zhao, X.-G. Si, M.-M. Xu, J.-H. Tan, Z.-M. Zhang, C.-G. Zheng, C. Zheng, Q. Cai, Angew. Chem. 2019, 131, 14704-14709; Angew. Chem. Int. Ed. 2019, 58, 14562-14567. 65 I. E. Markó, S. L. Warriner, B. Augustyns, Org. Lett. 2000, 2, 3123-3125. 66 F. Zhang, B.-T. Ren, Y. Zhou, Y. Liu, X. Feng, Chem. Sci. 2022, 13, 5562-5567. While Markó and co-workers studied enantioselective lanthanide catalysis, Posner and co-Dai, D. S. Bull, J.-K. Lee, F. Eydoux, Y. Ishihara, W. Welsh, N. Pryor, S. Petr, J. Org. Chem. 1996, 61, 671-676. 68 C. J. F. Cole, L. Fuentes, S. A. Snyder, Chem. Sci. 2020, 11, 2175-2180. The use of Lewis acid catalysts could activate electrophilic 2-pyrones by lowering their

Chapter II Total Synthesis Employing Inverse-Electron- Demand Diels-Alder Cycloaddition of 2-Pyrones

	2 Ring Opening of Bridged Bicyclic Lactones
	2.1 Total Synthesis of (±)-Joubertinamine by Cho and Co-Worker
	Joubertinamine is a seco-congener of mesembrine alkaloids which have proved potentially
	1 Introduction useful in the treatment of mental illnesses, such as depressive disorder. In 2007, Cho and co-
	The IEDDA cycloaddition of 2-pyrone derivatives has found numerous applications in the total worker reported a new efficient synthetic route to (±)-joubertinamine in which the key
	synthesis of natural products and drug candidates. This can be explained by many possibilities cyclohexene fragment was introduced by a thermal IEDDA cycloaddition of 5-bromo-3-aryl-
	for further functionalization of the [2.2.2]-bicyclic lactone. Firstly, the ring opening of the 2-pyrone 119a prepared by a C 3 -selective Stille coupling between 3,5-dibromo-2-pyrone 129
	bridged lactone moiety attacked by a nucleophilic reagent can furnish a polysubstituted and aryltin (Scheme 57). 36 5-Bromo-3-aryl-2-pyrone 119a underwent the IEDDA cycloaddition
	cyclohexene (Scheme 56a). Secondly, CO2 extrusion can readily happen upon thermolysis of with vinyl sulfide 135b, providing bridged lactone 120a as a mixture of endo/exo isomers in
	2:1 ratio. The ring opening of lactone endo-120a in the presence of sodium methoxide and then the bridged lactone, leading to a complex 1,3-cyclohexadiene which is a versatile synthon for Scheme 57. Total synthesis of (±)-joubertinamine.
	further transformations, such as aromatization and cycloaddition (Scheme 56b). Finally, the protection of the resulting secondary alcohol 190 afforded silyl ether 191. Reduction of 191
	bridged lactone can undergo a radical skeletal rearrangement to deliver bicyclic fused lactone was completed by the treatment of LiAlH4, which was accompanied by the removal of bromine
	(Scheme 56c). In this section, we will discuss applications of the above IEDDA cycloadditions atom to deliver sulfide 192. The subsequent removal of thiophenyl group with Raney nickel
	in total synthesis of natural products and drug candidates. under hydrogen atmosphere generated alcohol 193. PCC oxidation of primary alcohol 193 to
	aldehyde 194 followed by a Wittig olefination provided vinyl ether 195 which was further
	treated with p-toluenesulfonic acid to furnish aldehyde 196. The final conversion of 196 to (±)-
	joubertinamine 197 was accomplished by the reductive amination with methylamine
	hydrochloride. According to a known procedure, (±)-joubertinamine could be easily converted
	into (±)-mesembrine 198 by MnO2 oxidation.
	Scheme 56. Multiple characteristics of bridged lactone.

  Reduction of the methyl ester moiety of enol ethers 342 with excess DIBAL-H provided alcohols 343,77 followed by protection of the hydroxyl group as silyl ethers or alkyl ethers to afforded a series of E enol ethers 344 in good yield (Scheme 80a and Scheme 80b). We also tried to synthesize several silyl enol ethers by trapping the enolate ion generated in situ from corresponding aldehydes under basic conditions with TBSCl (Scheme 80c).78 Despite the poor E/Z selectivity, both of two isomers could be isolated completely by flash column chromatography.

	Chem. Int. Ed. 2016, 55, 16153-16155; b) J. P. Tellam, G. Kociok-Köhn, D. R. Carbery, Org. Lett. 2008, 10, 5199-
	5202.

80 and Scheme 81)

. Firstly, an E-selective DABCO-catalyzed conjugated addition of methyl propiolate 341 with various alcohols

(MeOH, EtOH, iPrOH, BnOH, allyl alcohol and menthol)

could give E enol ethers 342.

Scheme 80. Synthesis of enol ethers.

In order to compare with E enol ether, we also synthesized Z enol ether 344q, starting from a Z-selective AgOTf-catalyzed conjugated addition of methyl propiolate 341 with MeOH 79 77 a) S. Dochain, F. Vetica, R. Puttreddy, K. Rissanen, D. Enders, Angew.

Chem. 2016, 128, 16387-16389

; Angew.

78

F. Schäfers, L. Quach, J. L. Schwarz, M. Saladrigas, C. G.

Daniliuc, F. Glorius, ACS Catal. 2020, 10, 11841- 11847.

Table 1 .

 1 by X-ray single crystal diffraction analysis. According to previous reports, the combination of ytterbium catalyst and chiral diol ligands, such as BINOL and TADDOL, could induce the stereocontrol in such IEDDA reaction, but in this reaction, all failed to give an acceptable ee value (Table2). Screening of Lewis acids a

	Entry	Lewis acid	dr (endo/exo)	Yield of 350a (%)	ee (%)
	1	no	>20:1	11	0
	2	ZnBr2	>20:1	33	0
	3 b	Zn(OTf)2	>20:1	21	0
	4	Eu(fod)3	>20:1	19	0
	5	(+)-Eu(hfc)3	-	ND	-
	6	(+)-Eu(tfc)3	>20:1	17	4
	7 b	(+)-Eu(hfc)3	13:1	65	8
	8 b	(+)-Eu(tfc)3	>20:1	83	2
	9 b	Yb(OTf)3	>20:1	52	0

80

Y.

Zhu, K. Burgess, Adv. Synth. Catal. 2008, 350, 979-983. 81 H. Pellissier, Coordin. Chem. Rev. 2021, 439, 213926

. established a Reaction conditions: 71a (0.1 mmol), 344a (1.2 mmol), Lewis acid (10 mol%), THF (1.5 mL), air, 60 o C, 25 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC. ND = not detected.

b THF was replaced by DCM.

Table 2 .

 2 Preliminary screening of ligands (with Yb(OTf)3) a unsatisfying reaction outcome obtained from the lanthanide catalytic system led us to investigate Cu II -BOX catalytic system. To our delight, the IEDDA reaction gave a promising outcome, resulting in 350a in 76% yield with 72% ee under the catalysis of Cu(OTf)2 and BOX ligand L1. After that the effects of different substituents at C 4 position in the oxazoline ring and at the bridgehead carbon between two oxazolines were surveyed, as shown in Table3. The primary variation in the structure of BOX ligand was the substituents at C 4 position. tBu group was replaced by other substituents, including less sterically hindered groups (iBu, Me, iPr) and more sterically encumbered groups (Bn, Ph), but none of them could improve yield or ee (L2-L7). Then we focused on the modification of BOX ligand at the bridged methylene and

	Entry	Ligand	Yield (%)	ee (%)
	1	(R)-BINOL	83	5
	2	(4S, 5S)-TADDOL	22	0

a Reaction conditions: 71a (0.2 mmol), 344a (0.6 mmol), Yb(OTf)3

(10 mol%)

, Ligand

(12 mol%)

, DIPEA

(24 mol%)

, 4Å molecular sieves (MS, 50 mg), DCM

(1.5 mL)

, air, 60 o C, 20 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC.

The prepared a series of BOX ligands L8-L18. Firstly, we were intrigued by spirocyclic BOX ligands (L8-L11) because previous reports proved the correlation between enantioselectivity and the geometries, specifically bridge angle Φ and chelate bite angle θ, of spirocyclic BOX ligands in the copper-catalyzed DA cycloaddition.

82

Among them, L9 with a spiro-cyclobutane motif at the bridgehead carbon gave a well-balanced result between yield and ee (75% yield, 73% ee), although BOX ligands L8 and L10 could give better enantioselectivities with lower yields. It should be noted that the addition of 4Å molecular sieves could increase the yield dramatically without any erosion of enantioselectivity (75% yield vs 93% yield). Further optimization of BOX ligand with different groups at the bridgehead carbon could not enhance the reactivity and stereoselectivity of this reaction (L12-L18). Moreover, PyOX and PyBOX ligands also proved unsuitable for this cycloaddition (L19-L20). Therefore, BOX ligand L9

was selected for subsequent optimization. 82 a) I. W. Davies, L. Gerena, L. Castonguay, C. H. Senanayake, R. D. Larsen, T. R. Verhoeven, P. J. Reider, Chem. Commun. 1996, 1753-1754; b) I. W. Davies, R. J. Deeth, R. D. Larsen, P. J.

Reider, Tetrahedron Lett.1999, 40, 1233-1236.

Table 3 .

 3 Screening of ligands (with Cu(OTf)2) a

a Reaction conditions: 71a (0.2 mmol), 344a (0.6 mmol), Cu(OTf)2 (10 mol%), Ligand (12 mol%), DCM (1.5 mL), air, room temperature, 20 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC.

b

The reaction was conducted in the presence of 4Å MS (30 mg) under argon.

Table 4 .

 4 Screening of copper salts a

	Entry	Cu salt	Yield (%)	ee (%)
	1	Cu(OTf)2	93	73
	2	CuCl2	NR	-
	3	Cu(OAc)2	NR	-
	4	Cu(ClO4)2•6H2O	91	81
	5	Cu(acac)2	NR	-
	6	[Cu(CH3CN)4]•PF6	trace	-
	7	[Cu(CH3CN)4]•BF4	trace	-
	8 b	Cu(SbF6)2	98	87
	9 c	Cu(BF4)2	28	82
	10 d	Cu(PF6)2	NR	-

a Reaction conditions: 71a (0.2 mmol), 344a (0.6 mmol), Cu salt (10 mol%), L9 (12 mol%), 4Å MS (30 mg), DCM (1.5 mL), argon, room temperature, 20 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC. NR = no reaction. b Cu(SbF6)2 was prepared in situ from CuCl2 and AgSbF6. c Cu(BF4)2 was prepared in situ from CuCl2 and AgBF4. d Cu(PF6)2 was prepared in situ from CuCl2 and AgPF6.

Table 5 .

 5 Screening of solvents a

	Entry	Solvent	Volume (mL)	Yield (%)	ee (%)
	1	DCM	1.5	98	87
	2	THF	1.5	23	85
	3	CHCl3	1.5	trace	-
	4	1,2-DCE	1.5	95	82
	5	1,1-DCE	1.5	NR	-
	6	DCM	1.0	quant.	88
	7	DCM	4.0	39	86
	8	DCM:PhMe = 1:1	2.0	quant.	93
	9	DCM:PhF = 1:1	2.0	98	92
	10	DCM:PhCl = 1:1	2.0	quant.	92
	11	DCM:PhMe = 2:1	2.0	98	91
	12	DCM:PhMe = 1:2	2.0	92	95
	13	DCM:PhMe = 1:4	2.0	91	94

a Reaction conditions: 71a (0.2 mmol), 344a (0.6 mmol), Cu(SbF6)2 (10 mol%), L9 (10 mol%), 4Å MS (30 mg), solvent shown in the table, argon, room temperature, 20 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC.

Table 6 .

 6 Screening of reaction temperature a

	Entry	Temperature ( o C)	Yield (%)	ee (%)
	1	r.t.	92	95
	2	0	94	95
	3	-20	95	96
	4	-40	96	97
	5	-60	87	95
	6 b	-40	89	97
	7 b,c	-40	95	97

a Reaction conditions: 71a (0.2 mmol), 344a (0.3 mmol), Cu(SbF6)2 (10 mol%), L9 (10 mol%), 4Å MS (30 mg), DCM:PhMe = 1:2 (2 mL), argon, temperature shown in the table, 20 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC. b 5 mol% of Cu(SbF6)2 and 5 mol% of L9 were used as cocatalyst. c 1 mL of solvent was used.

  C 4 aryl substituent (350o-350p). C 5 -substituted 2-pyrones gave the corresponding bridged bicyclic lactones in very high yields with excellent enantioselectivities, both in the case of alkyl

	(331q-350s) and aryl substituents (350t-350w). However, C 6 -substituted 2-pyrones proved
	unreactive in this reaction. The absolute configuration of 350r was unambiguously established
	by X-ray single crystal diffraction analysis.

84 a) P. K.

Mandal, J. S. McMurray, J. Org. Chem. 2007, 72, 6599-6601; b)

J. M. Khurana, R. Arora, Synthesis 2009, 1127-1130; c) F.-X.

Felpin, E. Fouquet, Chem. Eur. J. 2010, 16, 12440-12445.

the

Table 7 .

 7 Rescreening of ligands for the reaction between 71a and Z-enol ether 344q a

a Reaction conditions: 71a (0.2 mmol), 344q (0.3 mmol), Cu(SbF6)2 (5 mol%), Ligand (5 mol%), 4Å MS (30 mg), DCM:PhMe = 1:2 (1 mL), argon, -40 o C, 20 h. Isolated yield. dr was determined by 1 H NMR spectroscopy. ee was determined by chiral HPLC.

Table 8 .

 8 Observation consistent with a stepwise and reversible cyclization a

	Starting		Resulting lactones		Yield of 71a
	lactone	350an	350ao	350ap	350aq
	350an	22% yield	-	-	42% yield	trace
	(90% ee)	90% ee			87% ee

a Isolated yield. ee was determined by chiral HPLC.

Table 9 .

 9 Reaction results with different reaction time a

	Entry	Time (h)	350an	350ao	350ap	350aq	71a
	1	0	-	-	-	-	100%
	2	2	6% yield,	7% yield,	13% yield,	14% yield,	56%
			90% ee	86% ee	86% ee	90% ee
	3	5	7% yield,	10% yield,	15% yield,	17% yield,	44%
			90% ee	86% ee	86% ee	90% ee
	4	8	7% yield,	10% yield,	17% yield,	18% yield,	42%
			90% ee	86% ee	87% ee	91% ee
	5	11	8% yield,	10% yield,	21% yield,	20% yield,	35%
			92% ee	86% ee	86% ee	91% ee
	6	14	9% yield,	12% yield,	22% yield,	21% yield,	34%
			90% ee	86% ee	87% ee	90% ee
	7	17	10% yield,	12% yield,	23% yield,	21% yield,	34%
			91% ee	86% ee	85% ee	91% ee
	8	20	12% yield,	14% yield,	21% yield,	20% yield,	32%
			90% ee	86% ee	85% ee	90% ee

a Isolated yield. ee was determined by chiral HPLC.

Table 10 .

 10 Screening of reaction conditions for protection of hydroquinone as benzyl ether a

	Entry	x	y	Solvent	Temp.	Time		Yield (%)
					( o C)	(h)	391	392	393
	1	5	5	acetone	60	18	58	ND	ND
	2	2	2	acetone	60	18	29	ND	ND
	3	2	2	acetone	r.t.	72	mixture (391 and 392)	ND
	4	2	2	toluene	r.t.	48	only 391	ND	ND
	5	2	2	DMF	r.t.	18	mixture (391 and 392)	ND

a Isolated yield. ND = not detected. 94 a) T. Murata, T. Kuboki, R. Ishikawa, T. Saito, S. Taguchi, K. Takeuchi, E. Hatano, M. Shimonaka, I. Shiina, J. Nat. Prod. 2018, 81, 2364-2370; b) S. Wang, G. A. Kraus, Synlett 2019, 30, 353-355. 95 D. R. Buckle, N. J. Morgan, J. W. Ross, H. Smith, B. A. Spicer, J.

Med. Chem. 1973, 16, 1334-1339.

Table 11 .

 11 Screening of reaction conditions for protection of hydroquinone as TBS ether a

	Entry	X	Base	Solvent	Yield (%)
					385	385'
	1 b	Cl	imidazole	DMF	33	trace
	2 c	Cl	imidazole	DMF/DCM (1:1)	22	12
	3 c	Cl	Et3N	DMF	29	trace
	4	Cl	Et3N	THF	65	trace

  Subsequently, much effort had been invested in seeking the reaction conditions for C-O bond coupling with cyclohexanemethanol 398 as model substrate, but all attempts failed to give any C-O bond coupling product. We also carried out the Williamson ether synthesis between bromide 412 and alcohol (±)-352 or (±)-406, but we did not obtain the desired products 413.

	Curini, F. Epifano, S. Genovese, Tetrahedron
	Lett. 2006, 47, 4697-4700; e) B. Banerjee, S. K. Mandal, S. C. Roy, Chem. Lett. 2006, 35, 16-17; f) R. S. Bhosale,
	S. V. Bhosale, S. V. Bhosale, T. Wang, P. K. Zubaidha, Tetrahedron Lett. 2004, 45, 7187-7188.

97

H.

Schick, H. Schwarz, A. Finger, S. Schwarz, Tetrahedron 1982, 38, 1279-1283. 98

S. Damoun, G. Van de Woude, K. Choho, P. Geerlings, J. Phys. Chem. A 1999, 103, 7861-7866. 99 A.-D. Manick, B. Salgues, J.-L. Parrain, E. Zaborova, F. Fages, M. Amatore, L. Commeiras, Org. Lett. 2020, 22, 1894-1898. Scheme 98. Synthesis of β-bromoindenone. A trace of aromatic product 414 was detected, illustrating that both (±)-352 and (±)-406 are labile in the presence of bases, for which we have to explore milder reaction conditions for C-O bond formation (Scheme 99). Scheme 99. Attempts for preparation of β-keto enol ether from β-bromoindenone.

  6 substituted 3-acetyl-2-pyrones to the reaction of 347 with 423 in the presence of chitosan as a catalyst, but no desired compound 387 was produced (Scheme 102). The protocols have been well developed.104,105 Disappointingly, only a trace of β-methylated by-product 424 was detected in all cases, illustrating that C 4 position of 2pyrone derivatives is easily attacked by nucleophiles, which was also observed by Ireland's group (Scheme 103). The addition of organometallic reagents, such as Grignard reagent, organolithium reagent, and organocopper, to Weinreb amides prepared from corresponding acid derivatives proved effective to prepare ketones in good yield without over-addition products because of the 104 a) D. Sahoo, S. Sarkar, S. Jana, Tetrahedron Lett. 2019, 60, 151084; b) R. Murata, K. Hirano, M. Uchiyama,

	Chem. Asian J. 2015, 10, 1286-1290; c) D. T. Genna, G. H. Posner, Org. Lett. 2011, 13, 5358-5361.
	105 a) R. K. Dieter, Tetrahedron 1999, 55, 4177-4236; b) A. K. Pandey, ChemCatChem 2022, 14, e202101982; c)
	D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636-3638; d) D. Milstein, J. K. Stille, J. Org. Chem. 1979,

103 Scheme 102. Attempts for preparation of 3-acetyl-2-pyrone from acetoacetates. Then we explored the direct conversion of carboxylic acid 333 or acid chloride 334 into 103 K. Khalil, H. Al-Matar, M. Elnagdi, Eur. J. Chem. 2010, 1, 252-258. methyl ketone 387. 106 Scheme 103. Attempts for preparation of 3-acetyl-2-pyrone from carboxylic acid or acid chloride.

The Weinreb ketone synthesis is a classical textbook reaction to transform acid derivatives to ketones.

44, 1613-1618; e) J. Cason, K. W.

Kraus, J. Org. Chem. 1961, 26, 1768-1772

; f) R. A.

Grey, J. Org. Chem. 1984, 49, 2288-2289. 106

R. E. Ireland, R. C. Anderson, R. Badoud, B. J. Fitzsimmons, G. J. McGarvey, S. Thaisrivongs, C. S. Wilcox, J.

Table 12 .

 12 Screening of reaction conditions for protection of hydroquinone a

	Entry	Base	Solvent	Yield (%)
				385	385'
	1	Et3N	THF	65	trace
	2	Et3N	PhMe	55	trace
	3	Et3N	DCM	66	trace
	4	imidazole	DCM	66	trace
	5	DIPEA	DCM	64	trace
	6	2,6-lutidine	DCM	trace	much
	7	DIPA	DCM	66	trace
	8	TMEDA	DCM	62	trace
	a Reaction conditions: 390 (0.5 mmol), TBSCl (1.25 mmol), base (1.25 mmol), solvent (1.5 mL), argon, room
	temperature, 24 h. Isolated yield.

Table 13 .

 13 Screening of reactant ratios for protection of hydroquinone a

	Entry	x	y	Yield (%)
				385	385'
	1	2.5	2.5	66	trace
	2	2.5	2.0	44	trace
	3	2.5	4.0	60	trace
	4	2.5	6.0	40	trace
	5	3.0	2.5	74	trace
	6	4.0	2.5	66	trace

a Reaction conditions: 390 (0.5 mmol), TBSCl (x equiv.), Et3N (y equiv.), DCM (1.5 mL), argon, room temperature, 24 h. Isolated yield.

Table 14 .

 14 Screening of reaction conditions for C-O formation a

	Entry	Conditions	Yield (%)
	1	PPh3 (1.5 equiv.

), DEAD

(1.5 equiv.)

, THF, -20 o C, 1 d 44 2 PPh3 (1.5 equiv.), DEAD (1.5 equiv.), THF, -20 o C to r.t. over 2 h, then r.t., 12 h a Isolated yield.

Table 15 .

 15 Screening of reaction conditions for reduction of ester a

	Entry	Conditions	Isolated yield (%)

  led to anhydride 389 which was converted to indandione 390 in the presence of ethyl acetoacetate (347) under basic conditions. The phenolic moieties were protected as TBS ethers, affording 385 in 4 steps and 56% yield. Remarkably, this synthesis was easily scalable, as 24.87 g of fragment 385 was obtained in one batch.

3,6dihydroxyphthalonitrile 388 (Scheme 115). Hydrolysis of the dinitrile followed by dehydration and acetylation Scheme 115. Synthesis of indandione 385. The Cu II -BOX catalyzed enantioselective IEDDA reaction of 3-carbomethoxy-2-pyrone 71a with benzyl enol ether 344d could be efficiently performed on decagram scale, providing (-)-350z in quantitative isolated yield with 97% ee. It should be noted that on such a scale, the minor diastereomer could be observed (dr = 48:1), although easily separated by column chromatography after the next step. Deprotection of the primary alcohol afforded (-)-386b in excellent yield, with 12.11 g easily obtained in one batch (Scheme 116). Scheme 116. Synthesis of lactone (-)-386b. The C-O bond assembly proved efficient under Mitsunobu reaction conditions and (-)-384b could be synthesized on decagram scale in 68% yield. The key CO2 extrusion via a retro-DA

1 H NMR (360 MHz, CDCl3)

	6, 7.2 Hz, 1H), 4.06
	(dd, J = 7.2, 0.8 Hz, 2H), 3.54 (s, 3H), 0.12 (s, 9H).

δ 6.51

(d, J = 12.6 Hz, 1H), 4.91 (dt, J = 12.

1 H NMR (400 MHz, CDCl3

  ) δ 6.79(d, J = 7.6 Hz, 1H), 6.61 (dd, J = 7.7, 5.2 Hz, 1H), 5.42 (d, J = 5.0 Hz, 1H), 5.21(d, J = 5.1 Hz, 1H), 1H), 3H), 3.32 (s,

	3H), 2.56 -2.36 (m, 2H), 2.06 -1.94 (m, 4H), 1.91 -1.79 (m, 2H), 1.73 -1.07 (m, 20H), 1.03
	(s, 3H), 0.97 -0.89 (m, 13H), 0.87 (d, J = 1.5 Hz, 3H), 0.86 (d, J = 1.6 Hz, 3H), 0.68 (s, 3H),
	0.10 (s, 6H).

13

C NMR (100 MHz, CDCl3) δ 168.

1 H NMR (360 MHz, CDCl3) δ

	6.26 -6.17 (m, 1H), 5.08 (dd, J = 5.4, 1.3 Hz, 1H), 3.89 (s,
	3H), 3.76 (d, J = 1.4 Hz, 1H), 3.72 -3.58 (m, 2H), 3.33 (s, 3H), 2.06 (d, J = 1.6 Hz, 3H), 2.00
	-1.92 (m, 1H), 0.89 (s, 9H), 0.07 (s, 6H).

13

C NMR (90 MHz, CDCl3) δ 169.

  ).

	331aj': 1 H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 7.8 Hz, 1H), 6.58 (dd, J = 7.8, 5.2 Hz, 1H),
	5.20 (d, J = 5.1 Hz, 1H), 4.05 (s, 1H), 3.88 (s, 3H), 3.68 (dd, J = 8.0, 3.3 Hz, 2H), 3.17 (td, J =
	10.4, 4.2 Hz, 1H), 2.11 -2.04 (m, 1H), 1.99 -1.91 (m, 2H), 1.66 -1.55 (m, 3H), 1.37 -1.23
	(m, 1H), 1.09 -1.02 (m, 1H), 0.91 (s, 9H), 0.90 (s, 3H), 0.83 (d, J = 7.1 Hz, 3H), 0.81 -0.74
	(m, 2H), 0.69 (d, J = 7.0 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ
	168.

NMR (100 MHz, acetone-d6) δ 169.

	1 H NMR (400 MHz, acetone-d6) δ 6.81 (dd, J = 7.8, 1.9 Hz, 1H), 6.65 (dd, J = 7.8, 5.1 Hz,
	1H), 5.28 -5.19 (m, 1H), 3.84 (s, 3H), 3.81 (dd, J = 10.6, 5.7 Hz, 1H), 3.39 -3.32 (m, 1H),
	3.14 (s, 3H), 2.45 -2.39 (m, 1H), 1.73 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H).

13 C

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/iPrOH = 90/10, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.86 min (major), t 2 = 8.54 min (minor).

	Rf = 0.42 (DCM/EtOAc = 3:1).

  The enantiomeric excess was determined by chiral HPLC: CHIRALPAK ® AD-H (250 × 4.6 mm), hexane/EtOH = 98/2, flow rate = 1.0 mL/min, temperature = 25 o C, λ = 210 nm, t 1 = 7.50 min (major), t 2 = 8.60 min (minor).

	Rf = 0.13 (petroleum ether/EtOAc = 5:1).
	1 H NMR (300 MHz, CDCl3) δ 6.04 -5.78 (m, 3H), 5.41 -5.14 (m, 2H), 4.76 (d, J = 6.7 Hz,
	1H), 4.72 -4.53 (m, 2H), 4.40 (s, 1H), 3.69 (s, 3H), 2.39 -2.18 (m, 1H), 1.72 (br, 1H), 0.93 (d,
	J = 7.1 Hz, 3H), 0.84 (s, 9H), 0.14 (s, 3H), 0.05 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 168.

Table 16 .

 16 Crystallographic data and structure refinement details of 350ac and 350al

	Compound	350ac	350al
	CCDC	2160985	2160988
	Empirical Formula	C17 H28 O5 Si	C17 H28 O5 Si
	Mr	340.48	340.48
	Crystal size, mm 3	0.34 x 0.27 x 0.19	0.31 x 0.08 x 0.06
	Crystal system	orthorhombic	orthorhombic
	Space group	P 21 21 21	P 21 21 21
	a, Å	9.4115(3)	7.0912(3)

Table 17 .

 17 Crystallographic data and structure refinement details of 350r and 351a

	Compound	350r	351a
	CCDC	2160986	2160987

1 H NMR (400 MHz, CDCl3)

	4.55 (d, J = 12.2 Hz, 1H, ArCH2), 4.44 (d, J = 12.2 Hz, 1H, ArCH2), 4.22 (dd, J = 8.5, 5.0 Hz,
	1H, H-10'), 3.96 (s, 1H, H-4'), 3.85 (s, 3H, OCH3), 3.71 (d, J = 8.5 Hz, 1H, H-10'), 3.59 -3.51
	(m, 1H, H-6'), 2.83 (s, 1H, H-2'), 2.43 (t, J = 4.6 Hz, 1H, H-5'), 1.04 (s, 9H, SiC(CH3)3), 0.97
	(s, 9H, SiC(CH3)3), 0.28 (s, 3H, SiCH3), 0.28 (s, 3H, SiCH3), 0.15 (s, 3H, SiCH3), 0.12 (s, 3H,
	SiCH3).

 5H, ArH), 6.89 (d, J = 8.6

Hz, 1H, H-5), 6.67

(d, J = 8.7 Hz, 1H, 6.63 (d, J = 8.4 Hz, 1H, 5.93 (dd, J = 8.3, 6.8 Hz, 1H,

  , 2.92 (s, 1H, H-2'), 2.43 (t, J = 4.8 Hz, 1H, H-5'), 2.43 (s, 3H, H-12'),

  ,2.87 (s, 1H, 2.50 (t, J = 4.4 Hz, 1H, 2.34 (s, 3H,, 1.06 (s, 9H, SiC(CH3)3), 0.97 (s, 9H, SiC(CH3)3), 0.30 (s, 6H Si(CH3)2), 0.14 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3).

  Hz, 1H, ArCH2),4.18 (dd, J = 8.3, 4.9 Hz, 1H, 3.72 (s, 1H, 3.65 (d, J = 8.3 Hz, 1H, 2.85 (d, J = 1.8 Hz, 1H, H-2'), 2.69 (dd, J = 6.3, 3.5 Hz, 1H, H-6'), 2.50 (t, J = 4.5 Hz, 1H, H-5'), 2.27 (s, 3H, H-12'), 2.24 -2.15 (m, 1H, H-9'),1.89 -1.78 (m, 1H, H-8'), 1.54 -1.44 (m, 1H, H-9'), 1.14 -1.05 (m, 1H, H-8'), 1.01 (s, 9H, SiC(CH3)3), 0.99 (s, 9H, SiC(CH3)3), 0.27 (s, 3H, SiCH3), 0.25 (s, 3H, SiCH3), 0.17 (s, 3H, SiCH3), 0.17 (s, 3H, SiCH3).

  CDCl3) δ 6.92(d, J = 8.6 Hz, 1H, 6.72 (d, J = 8.7 Hz, 1H, 4.18 (dd, J = 8.4, 4.9 Hz, 1H, H-10'), 3.91 (s, 1H, H-4'), 3.72(d, J = 8.4 Hz, 1H, H-10'), 2.84 (d, J = 2.1 Hz, 1H, H-2'), 2.66 (dd, J = 6.3, 3.5 Hz, 1H, H-6'), 2.37 (t, J = 4.6 Hz, 1H, H-5'),

1 H NMR (400 MHz,

  , 2.81(d, J = 2.1 Hz, 1H, 2.69 (dd, J = 6.8, 3.2 Hz, 1H, 2.34 (t, J = 4.5 Hz, 1H,, 2.28 (s, 3H, H-12'), 2.21 -2.10 (m, 1H, H-9'), 1.91 -1.79 (m, 1H, H-8'), 1.33 -1.26 (m, 1H, H-9'), 1.07 -1.03 (m, 1H, H-8'), 1.03 (s, 9H, SiC(CH3)3), 1.01 (s, 9H, SiC(CH3)3), 0.29 (s, 3H, SiCH3), 0.28 (s, 3H, SiCH3), 0.19 (s, 3H, SiCH3), 0.17 (s, 3H, SiCH3).

  9.13 (br, 2H, Ar(OH)2), 6.97(d, J = 8.6 Hz, 1H, H-5), 6.72(d, J = 8.6 Hz, 1H, 5.31 (br, 1H, CHOH), 4.06 (dd, J = 7.9, 4.8 Hz, 1H, 3.76 (s,

1 H NMR (400 MHz, DMSO-d6) δ 1H, H-4'), 3.64 (d, J = 8.0 Hz, 1H, H-10'), 2.71 (d, J = 1.1 Hz, 1H, H-2'), 2.56 (dd, J = 6.2, 3.1

Hz, 1H, H-6'), 2.25 (t, J = 4.2 Hz, 1H, H-5'),

2.16 (s, 3H, H-12'), 2.07 -1.93 (m, 1H, H-9'), 1.78 -1.65 (m, 1H, H-8'), 1.16 -1.04 (m, 1H, H-9'), 0.93 -0.80 (m, 1H, H-8')

.

  CDCl3) δ 7.01 (d, J = 9.3 Hz, 1H), 6.89 (d, J = 9.3 Hz, 1H), 6.04 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H).

1 H NMR (400 MHz,

13

C NMR (100 MHz, CDCl3) δ 192.

  .3 Comparison of the Spectra of Isolated and Synthetic Lucidumone

	no.	1 H NMR [δ (ppm), mult, J (Hz)] in DMSO-d6	13 C NMR (δ, ppm) in DMSO-d6
		Isolated 87a	Synthetic	Δδ	Isolated 87a	Synthetic	Δδ
	no.	1 H NMR [δ (ppm), mult, J (Hz)] in MeOD (600 MHz) (400 MHz)		13 C NMR (δ, ppm) in MeOD (150 MHz)	(100 MHz)
	1	Isolated 87a	Synthetic	Δδ	Isolated 87a 148.3 (misassigned, 147.7) 148.2 Synthetic	Δδ 0.5
	2	(600 MHz)	(400 MHz)		(150 MHz) 125.2 (misassigned, 124.9) 124.9 (100 MHz)	0.0
	1 3				150.8 (misassigned, 149.5) 149.4 135.2 135.2	-0.1 0.0
	2 4				125.4 147.7 (misassigned, 148.3) 148.9 125.3	-0.1 0.6
	3 5	6.97 d (8.6)	6.97 d (8.6)	0.00	135.4 124.9 (misassigned, 125.2) 125.2 135.3	-0.1 0.0
	4 6	6.71 d (8.6)	6.72 d (8.6)	0.01	149.5 (misassigned, 150.8) 150.7 118.1 118.1	-0.1 0.0
	5 1'	7.01 d (8.7)	7.01 d (8.7)	0.00	126.4 201.0	126.5 201.1	0.1 0.1
	6 2'	6.75 d (8.7) 2.70 d (2.2)	6.74 d (8.7) 2.71 d (1.1)	-0.01 118.6 0.01 61.2	118.6 61.1	0.0 -0.1
	1' 3'				204.2 51.3	204.2 51.3	0.0 0.0
	2' 4'	2.88 d (2.2) 3.75 brs	2.89 d (1.9) 3.76 s	0.01 0.01	62.3 77.6	62.3 77.7	0.0 0.1
	3' 5'	2.24 t-like (4.5)	2.25 t (4.2)	0.01	52.7 47.8	52.6 47.8	-0.1 0.0
	4' 6'	3.90 brs 2.55 q-like (3.5)	3.90 s 2.56 dd (6.2, 3.1)	0.00 0.01	79.5 37.5	79.4 37.6	-0.1 0.1
	5' 7'	2.35 t-like (4.5)	2.35 t (4.4)	0.00	48.7 85.3	49.1 85.3	0.4 0.0
	6' 8'	2.69 q-like (3.4) Ha 1.71 m	2.67 dd (6.4, 3.3) Ha 1.72 m	-0.02 39.1 0.01 15.5	39.1 15.5	0.0 0.0
	7'	Hb 0.86 m	Hb 0.87 m	0.01	87.4	87.4	0.0
	8' 9'	Ha 1.86 m Ha 1.99 m	Ha 1.85 m Ha 2.00 m	-0.01 0.01	16.2 14.8	16.1 14.8	-0.1 0.0
		Hb 1.06 m Hb 1.08 m	Hb 1.05 m Hb 1.10 m	-0.01 0.02
	9' 10'	Ha 2.17 m Ha 4.05 dd (8.1, 4.8)	Ha 2.16 m Ha 4.06 dd (7.9, 4.8)	-0.01 0.01	15.8 72.8	15.8 72.8	0.0 0.0
		Hb 1.33 m Hb 3.64 d (8.1)	Hb 1.32 m Hb 3.64 d (8.0)	-0.01 0.00
	10' 11'	Ha 4.25 dd (8.3, 4.9)	Ha 4.24 dd (8.2, 4.9)	-0.01	74.3 211.5	74.2 211.4	-0.1 -0.1
	12'	Hb 3.77 d (8.3) 2.16 s	Hb 3.76 d (8.3) 2.16 s	-0.01 0.00	28.1	28.0	-0.1
	11'				214.8	214.8	0.0
	12'	2.26 s	2.28 s	0.02	28.5	28.4	-0.1

U. Huynh, S. L. McDonald, D. Lim, M. N. Uddin, S. E. Wengryniuk, S. Dey, D. M. Coltart, J. Org. Chem. 2018, 83, 12951-12964.

3

Table 15 .

 15 Screening of reaction conditions for reduction of ester a ...............................................

Table 16 .

 16 Crystallographic data and structure refinement details of 350ac and 350al .................

Table 17 .

 17 Crystallographic data and structure refinement details of 350r and 351a ....................

a) R.Gompper, Angew. Chem. 1969, 81, 348-363; Angew. Chem. Int. Ed. 1969, 8, 312-327; b) J. Sauer, R.Sustmann, Angew. Chem. 1980, 92, 773-801; Angew. Chem. Int. Ed. 1980, 19, 779-807.

H.Behringer, P. Heckmaier, Chem. Ber. 1969, 102, 2835-2850.

L. R. Domingo, J. A. Sá ez, S. R. Emamian, Org.Biomol. Chem. 2015, 13, 2034-2043.

G. A.Kraus, H. Yu, Arkivoc 2018, iv, 70-75.

I. E.Markó, G. R. Evans, Tetrahedron Lett. 1993, 34, 7309-7312.

H. B. Jeon, G. H. Posner, Tetrahedron 2009, 65, 1235-1240.

a) G. H.Posner, N. Johnson, J. Org. Chem. 1994, 59, 7855-7861; b) G. H. Posner, B. T. Woodard, K. R. Crawford, S. Peleg, A. J. Brown, P. Dolan, T. W.Kensler, Bioorg. Med. Chem. 2002, 10, 2353-2365.

G. H. Posner, T. D. Nelson, C. M. Kinter, K.Afarinkia, Tetrahedron Lett. 1991, 32, 5295-5298.

Attempts for Preparation of 3-Acetyl-2-Pyrone

C NMR (90 MHz, CDCl3) δ 168.8, 167.6,

143.8, 137.7, 137.4, 128.8, 128.0, 127.4, 126.5,

C NMR (90 MHz, CDCl3) δ 168.5, 167.5, 130.8, 130.1, 77.4, 75.1, 62.9, 61.6, 57.8, 53.1,

H NMR (360 MHz, CDCl3) δ 6.53 (dd, J = 7.7, 5.0 Hz, 1H),6.39 (dd, J = 7.7, 1.8 Hz, 1H),

G. M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution, University of Göttingen, Göttingen, Germany, 1997.

G. M.Sheldrick, Acta Crystallogr. A 2008, 64, 112-122.

L. J.Farrugia, J. Appl. Cryst. 1999, 32, 837-838.

G.Bernardinelli, H. D. Flack, Acta Crystallogr. A 1985, 41, 500-511.

ROESY spectrum of (+)-lucidumone (in MeOD)[START_REF]) δ 7[END_REF] H NMR spectrum of (+)-lucidumone (in

C NMR spectrum of (+)-lucidumone (in DMSO-d6) COSY spectrum of (+)-lucidumone (in

Acknowledgements

This thesis is based on the frame of Memorandum of Understanding between the Chinese Scholarship Council and Université Paris-Saclay. I greatly appreciate the Chinese Scholarship Council for providing my PHD fellowship. We truly acknowledge Université Paris-Saclay and CNRS for financial support.

desired product underwent further deprotection in this process (Scheme 96). Scheme 96. Attempts for preparation of β-keto enol ether from 1,3-indandione.

Inspired by this result, we attempted to synthesize sulfate (±)-408 for the transformation (Scheme 97a). Refluxing of (±)-350a in chlorobenzene resulted in CO2 extrusion via a retro-DA cycloaddition, providing cyclohexadiene (±)-353 in 98% yield. Exposure of (±)-353 to a catalytic amount of acetyl chloride could afford alcohol (±)-406. Dialkyl sulfite (±)-407 was obtained from alcohol (±)-406 by reacting with thionyl chloride in the presence of Et3N.

Unfortunately, the final oxidation of sulfite (±)-407 did not occur as expected to afford sulfate (±)-408. We also attempted to synthesize sulfate 409 by using an exchange reaction between iodide 399 and silver sulfate, but only a trace of desired product was detected (Scheme 97b). Scheme 97. Attempts for preparation of dialkyl sulfates.

Attempts for Preparation of β-Keto Enol Ether from β-Bromoindenone

Transition metal-catalyzed C-O bond coupling reaction provides an alternative for preparation of alkyl aryl ether. To date palladium and copper-based catalytic systems have been broadly developed for intermolecular coupling reactions of aryl halides with aliphatic alcohols. 100 In order to achieve this goal, we started to synthesize β-bromoindenone derivative 412 to test the coupling reaction. Acid-promoted cyclization of substituted hydrocinnamic acid 410 afforded indanone derivative 411 in 69% yield. Benzylic bromination of indanone derivative 411 followed by the treatment of Et3N gave β-bromoindenone derivative 412 in 83% yield (Scheme 98). 100 a) M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 3395-3396;b) J. F. Hartwig, Angew. Chem. 1998, 110, 2154-2177;Angew. Chem. Int. Ed. 1998, 37, 2046-2067;c) K. E. Torraca, X. Huang, C. A. Parrish, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 10770-10771;d) N. Kataoka, Q. Shelby, J. P. Stambuli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553-5566;e) A. V. Vorogushin, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 8146-8149;f) M. Wolter, G. Nordmann, G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 973-976;[START_REF] Sheldrick | SHELXS-97, Program for Crystal Structure Solution[END_REF]

A. Altman, A. Shafir, A. Choi, P. A. Lichtor, S. L. Buchwald, J. Org. Chem. 2008, 73, 284-286;h) A. B. Naidu, G. Sekar, Tetrahedron Lett. 2008, 49, 3147-3151. Colorless oil (1.42 g, 66% over two steps). Rf = 0.57 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 4. 60 (t,J = 7.3 Hz,1H),4.19 (d,J = 7.3 Hz,2H),3.50 (s,3H), 1.80 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H). 13 C NMR (90 MHz, CDCl3) δ 156. 2, 96.7, 60.2, 54.3, 26.2, 18.6, 16.5, -4.8.

Poor thermostability prevented ESI-HRMS analysis.

General Procedures for IEDDA Cycloaddition of 2-Pyrones with Enol Ethers

Racemic IEDDA Cycloaddition

General Procedure A

To an oven-dried microwave vial with a magnetic stir bar was added Cu(OTf)2 (3.7 mg, 0.01 mmol), BOX ligand L21 (2.2 mg, 0.012 mmol) and activated 4Å molecular sieves (15 mg).

The vial was evacuated and then refilled with argon. After that DCM (0.5 mL) was added and the mixture was stirred at room temperature for 1 h to give a blue solution. This blue solution was cooled at -78 o C, and a solution of 2-pyrone 71 (0.1 mmol) in DCM (0.5 mL) was added followed by the addition of a solution of enol ether 344 (0.3 mmol) in DCM (0.5 mL). The resulting green solution was stirred at room temperature for 20 h and was further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1→2:1) to afford racemic bridged lactone (±)-350.

General Procedure B

To an oven-dried microwave vial with a magnetic stir bar was added Yb(OTf)3 (12.4 mg, 0.02 mmol), (±)-BINOL (6.9 mg, 0.024 mmol) and activated 4Å molecular sieves (30 mg) and DCM

DFT Calculations

The conformational space of all molecules has been initially searched using meta-dynamics simulations based on generic force field GFN-FF 124 calculations as implemented in Conformer-Rotamer Ensemble Sampling Tool CREST 125 .

The structures located with the CREST have then been subjected to ωB97X-D 126 geometry optimization. The LanL2DZ basis set with effective core potential (ECP) 127 was used for Cu, and the 6-31G(d) 128 basis set was applied for other atoms.

The nature of all stationary points (minima and transition states) was verified through the computation of the vibrational frequencies. The thermal corrections to the Gibbs free energy were combined with the single point energies calculated at the ωB97X-D/def2-TZVP 129 to yield ωB97X-D/def2-TZVP//ωB97X-D/6-31G (d),LanL2DZ Gibbs free energies ("G298") at 298.15 K. All energies are reported in kcal•mol -1 .

The polarizable continuum model (PCM) with SMD parameters 130 was applied to consider solvent (toluene) effects for single point energy calculations. Free energies in solution have been corrected to a reference state of 1 mol l -1 at 298.15 K through the addition of RTln (24.46) = +7.925 kJ mol -1 to the gas phase (1 atm) free energies.

The calculations have been performed with the Gaussian 16 program package. 131 124 S. Spicher, S. Grimme, Angew. Chem. 2020, 132, 15795-15803;Angew. Chem. Int. Ed. 2020, 59, 15665-15673. 125 a) P. Pracht, F. Bohle, S. Grimme, Phys. Chem. Chem. Phys. 2020, 22, 7169-7192;b) S. Grimme, J. Chem. Theory Comput. 2019, 15, 2847-2862. 126 J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10, 6615-6620. 127 P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82, 299-310. 128 R. Ditchfield, W. J. Hehre, J. A. Pople, J. Chem. Phys. 1971, 54, 724-728. 129 F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297-3305. 130 a) E. Cancè s, B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 107, 3032-3041;b) A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113, 6378-6396. 131 Frisch, M. J. et al. Gaussian 16,Revision A.03. To a flask equipped with a stir bar was added phthalic anhydride 389 (19.60 g, 74 mmol), acetic anhydride (37 mL), triethylamine (37 mL) and ethyl acetoacetate 347 (11.3 mL, 89 mmol). This mixture was stirred at room temperature overnight. Then aqueous HCl (6 N, 74 mL) was added slowly and the mixture was stirred at 75 o C for 1 h. After that the aqueous mixture was extracted with EtOAc (5 × 200 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 2:1→EtOAc 100%) to give 1,3-indandione 390 as a reddish solid (12.11 g, 92%). Rf = 0.26 (petroleum ether/EtOAc = 2:1).

1 H NMR (360 MHz, DMSO-d6) δ 9.91 (s, 2H), 7.11 (s, 2H), 3.18 (s, 2H). 13 C NMR (90 MHz, DMSO-d6) δ 197. 1, 148.1, 126.8, 125.9, 46.1.

HRMS (ESI) m/z

Calcd for C₉H₅O₄ [M-H] -: 177.0193, found: 177.0192.

Synthesis of 1,3-Indandione 385

To a flask equipped with a stir bar was added 1,3-indandione 390 (14. 80 g, 83 mmol) and TBSCl (37.60 g, 249 mmol) and DCM (100 mL) under argon. The mixture was stirred at 0 o C and Et3N (28.90 mL, 208 mmol) was added dropwise. The mixture was stirred at 0 o C for 10 min and then at room temperature for an additional 24 h. After that the resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 50:1) to give 1,3-indandione 385 as a yellow solid (24.87 g, 74%). Rf = 0.43 (petroleum ether/EtOAc = 10:1).

1 H NMR (400 MHz, CDCl3) δ 7.04 (s, 2H), 3.08 (s, 2H), 1.04 (s, 18H), 0.23 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ 195. 3, 147.4, 132.8, 129.4, 46.4, 25.8, 18.5, -4.3. + : 407.2068, found: 407.2062.

HRMS (ESI) m/z Calcd for C₂₁H₃₅O₄Si₂ [M+H]

Synthesis of Enol Ether 344d

The synthesis of ester 342d was reported previously. 77b To a stirred mixture of DABCO (1.12 g, 10 mmol) and benzyl alcohol (11.4 mL, 110 mmol) in THF (100 mL) at room temperature was added methyl propiolate 341 (8.9 mL, 100 mmol) dropwise by an addition funnel over 10 min. The mixture was stirred at room temperature for an additional 30 min and then NaOH (1.0 M aqueous solution, 150 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1) to afford ester 342d as a colorless oil (19.20 g, >99%). Rf = 0.35 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 7.69 (d,J = 12.6 Hz,1H),5H),5.33 (d,J = 12.6 Hz, 1H), 4.88 (s, 2H), 3.69 (s, 3H). 13 C NMR (90 MHz, CDCl3) δ 168.0, 162. 1, 135.2, 128.7, 128.6, 127.7, 97.1, 72.8, 51.1. Analytical data were consistent with previously reported data. 77b The synthesis of allyl alcohol 343d was reported previously. 77a A slightly modified procedure was used as follows: to a stirred mixture of ester 342d (15.38 g, 80 mmol) in DCM (20 mL) at -78 o C under argon was added DIBAL-H (1.0 M in hexane, 176 mL) dropwise by an addition funnel. This mixture was stirred at -78 o C for 1 h and at room temperature for an additional 1 h, then quenched with MeOH (25 mL) slowly. After that Rochelle's salt (10% aqueous solution, 100 mL) was added slowly at -78 o C and the mixture was stirred at room temperature for 1 h.

The organic layer was separated and the aqueous layer was extracted with DCM (3 × 50 mL).

The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, pentane/Et2O = 1:1→Et2O 100%) Rf = 0.41 (petroleum ether/EtOAc = 5:1).

1 H NMR (360 MHz, CDCl3) δ 7. 5H,ArH),1H,6.63 (dd,J = 7.8,5.2 Hz,1H,1H,4.58 (d,J = 11.8 Hz, 1H, ArCH2), 4.49 (d, J = 11.8 Hz, 1H, ArCH2), 3.95 (s,1H,3.86 (s,3H,OCH3),2H, H-10'), 2.13 -2.02 (m, 1H, H-5'), 0.91 (s, 9H, SiC(CH3)3), 0.07 (s, 6H, Si(CH3)2).

Synthesis of Bridged Lactone (-)-386b

To a stirred solution of cycloadduct (-)-350z (17 g, 39.3 mmol) in THF (80 mL) was added TBAF (1.0 M in THF, 59 mL, 59 mmol) dropwise. This mixture was stirred at room temperature for 30 min before adding H2O (50 mL) and saturated NaCl aqueous solution (50 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 1:2) to afford alcohol (-)-386b as a pale-yellow oil (12.11 g, 97%). Rf = 0.33 (petroleum ether/EtOAc = 1:2).

HRMS (ESI) m/z Calcd for C17H19O6

[M+H] + : 319.1176, found: 319.1170.

[α]D 20 = -40.9 o (c = 1.10, CHCl3).

Synthesis of Bridged Lactone (-)-384b

To an oven-dried flask equipped with a stir bar was added PPh3 (18.89 g, 72 mmol) and THF (30 mL). This flask was evacuated, refilled with argon and cooled at -20 o C. Then a solution of DIAD (14. 56 g, 72 mmol) in THF (20 mL) was added dropwise, followed by the addition of alcohol (-)-386b (11.46 g, 36 mmol) in THF (50 mL). After that 1,3-indandione 385 (17.57 g, 43.2 mmol) in THF (100 mL) was added. The reaction was allowed to warm to room temperature over 3 h and stirred at room temperature for another 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 10:1→6:1) to give enol ether (-)-384b as a yellow solid (17.23 g, 68%). Rf = 0.38 (petroleum ether/EtOAc = 3:1). To an oven-dried flask equipped with a stir bar and an addition funnel was added aldehyde (-)-434 (6.45 g, 10.2 mmol) and Et2O (80 mL) under argon. The mixture was stirred at 0 o C for 5 min. Then a solution of CH3MgBr (3.0 M in Et2O,5.10 mL,15.3 mmol) was added slowly through addition funnel. The resulting mixture was stirred at 0 o C for 30 min, followed by addition of saturated NH4Cl aqueous solution (20 mL) and H2O (50 mL) to quench the reaction.

The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 50 mL).

The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and further purified by flash column chromatography (silica gel, petroleum ether/EtOAc = 5:1) to afford two inseparable diastereomers (-)-435 as a yellow solid (5.59 g, 85%, dr = 1.2:1). Rf = 0.49 (petroleum ether/EtOAc = 3:1).

Major diastereomer: 1 H NMR (400 MHz, CDCl3) δ 7. 5H,ArH),6.93 (d,J = 8.7 Hz,1H,6.67 (d,J = 8.7 Hz,1H,6.55 (d,J = 8.3 Hz,1H,5.92 (dd,J = 8.2,6.8 Hz,1H,4.95 (d,J = 12.0 Hz, 1H, OH), 4.61 (d,J = 12.1 Hz,1H,ArCH2),1H,4.32 (d,J = 12.1 Hz,1H,ArCH2),4.21 (dd,J = 8.1,4.6 Hz,1H,3.64 (d,J = 8.1 Hz,1H,1H,3.30 (s,1H,2.51 (t,J = 4.3 Hz, 1H, H-5'), 2.49 (s, 1H, H-2'), 1.13 (d,J = 6.5 Hz,3H,, 1.05 (s, 9H, SiC(CH3)3), 0.98 (s, 9H, SiC(CH3)3), 0.28 (s, 6H, Si(CH3)2), 0.12 (s, 6H, Si(CH3)2).

Minor diastereomer: 1 H NMR (400 MHz, CDCl3) δ 7. 5H,ArH),6.89 (d,J = 8.7 Hz,1H,6.67 (d,J = 8.7 Hz,1H,6.43 (d,J = 8.3 Hz,1H,5.95 (dd,J = 8.1,6.9 Hz,1H,1H,4.62 (d,J = 11.4 Hz,1H,ArCH2),4.40 (d,J = 11.4 Hz,1H,ArCH2),4.26 (dd,J = 8.2,4.7 Hz,1H,3.92 (d,J = 10.4 Hz, 1H, OH), 3.88 (s,1H,3.72 (d,J = 8.2 Hz,1H,1H,2.46 (t,J = 4.3 Hz, 1H, H-5'), 2.11 (s,1H,1.27 (d,J = 6.5 Hz,2H,, 1.05 (s, 9H, SiC(CH3)3), 0.98 (s, 9H, SiC(CH3)3), 0.29 (s, 6H, Si(CH3)2), 0.15 (s, 6H, Si(CH3)2). 13 C NMR (100 MHz, CDCl3) δ 202. 2, 198.3, 147.5, 147.4, 147.4, 146.9, 141.4, 140.0, 137.4, 136.4, 133.8, 133.7, 130.8, 130.0, 128.7, 128.5, 128.5, 128.4, 128.4, 128.0, 126.9, 126.4, 126.1, 125.7, 122.2, 122.1, 87.8, 86.5, 86.2, 85.0, 71.9, 71.7, 70.5, 70.3, 68.3, 66.4, 59.4, 58.9, 49.2, 47.8, 46.2, 43.9, 43.2, 43.1, 25.9, 25.9, 25.8, 18.7, 18.5, 18.5, 18.4, 18.4, 18.4, -3.9, -4.0, -4.1, Analytical data were consistent with previously reported data. 134

Synthesis of Bridged Lactone (±)-419

Bridged lactone (±)-419 was synthesized according to the procedure for bridged lactone (-)-384b, except that DEAD was used instead of DIAD.

Yellow oil (644 mg, 51%). Rf = 0.28 (petroleum ether/EtOAc = 3:1). Table 1.

Table of Tables

List of Publications

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G. Huang, C. Kouklovsky, A. de la Torre*, Gram-Scale Enantioselective Synthesis of (+)-Lucidumone, J. Am. Chem. Soc. 2022, 144, 17803-17807. This work was highlighted by ChemistryViews, Synfacts, ChemBeanGo.