Alexis Pinet

Dr Linh T Nguyen

Bruno Figadère

Dr Laurent Ferrié
email: laurent.ferrie@universite-paris-saclay.fr

Dr ] A Pinet

B Figadère Biocis

Synthesis of 3,5-Disubstituted 1,2-Dioxolanes

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Introduction

Most of synthetic and natural compounds containing peroxy-moiety display a wide range of interesting biological activities. [1] Driven by the success story of artemisinin as antimalarial drug, [2] some other endoperoxide compounds were also brought to a commercial stage (e.g. Arterolane®, Artemether®). Although these compounds appear to be pharmacologically relevant, endoperoxides represent only a small part of the chemical space compared to other heterocycles. [3] For instance, tetrahydrofurans (THF) get millions of output (obviously a lot are furanoses), with a trivial CAS research, while their structurally close peroxidized analogues, the 1,2-dioxolanes get 1000-fold less results. Our group has been involved for a long time in the synthesis of THF and in particular 2,5-disubstituted THF. [4] More recently, we started some research programs in the synthesis of 3,5-disubstituted 1,2-dioxolanes, which can be considered as peroxide analogues of these THF.

The 1,2-dioxolane moiety is commonly found as secondary metabolites in sponges of genus plakortis or plakinastrella, from which plakinic acids A-P (excepted B and I members which contains a 1,2-dioxane ring) were isolated, as well as related compounds such as epiplakinidoic acid, plakortisinic acid, plakortinic acid A or andavadoic acid. [5] These compounds generally display cytotoxicity against some fungi and cancer cell lines, both 3,3,5,5-tetrasubstituted 1,2-dioxolane core and carboxyl group are essential for antifungal activity (Figure 1). [5i],[5p] In 2009, Clardy and co-workers isolated mycangimycin, a new polyene peroxide from some Streptomyces strains living in symbiosis with the southern pine beetle Dendroctonus frontalis. Mycangimycin was found to display antifungal activity equal to or greater than amphotericin B and antimalarial activity close to artemisinin. [6] Earlier, urticic acid, an original endoperoxide derived from pentadecene dioic acid, was isolated from Leucas urticifolia (Labiatae family). This molecule contains an original ketone function on the endoperoxide ring. [7] In 2016 was isolated from herbaceous plant Ophioglossum thermale, thermalic acids A and B, analogous 1,2-dioxolanes of urticic acid. [8] Some significant antibacterial activities were observed for both compounds. These metabolites are the only natural 3,5disubstituted-1,2-dioxolanes known so far, except for prostaglandin H2 (PGH2) and G2 (PGG2), which exhibit a bicyclic structure (with a five and six-membered endoperoxide). These two compounds have been isolated and identified as key intermediates in the biosynthesis of prostaglandins from arachidonic acid (Figure 2). [9] Figure 2. Natural products containing a 3,5-disubstituted 1,2-dioxolane framework.

If the preparation of 3,3,5-tri-and 3,3,5,5-tetrasubstituted 1,2-dioxolanes has been more widely explored, [10] the synthesis of di-substituted 1,2-dioxolanes remains more challenging and much less studied, due to the lack of substitution, which involves generally a decrease of stability of carbocations and alkyl radicals, two major pathways to build this heterocycle. This review will thus focus on the synthesis of 3,5-disubstituted 1,2dioxolanes that were reported in the literature, and the different syntheses will be classified following the key step used in their preparation.

Nucleophilic Substitution with Hydrogen peroxide or Hydroperoxides

Peroxymercuration and Peroxyhalogenation

Activation of a double bond for subsequent nucleophilic substitution with an hydroperoxide can be a valuable strategy to access to endoperoxides. Despite their high toxicity, mercury(II) salts exhibit some high affinity with π-bonds and consequently, peroxymercuration can be an efficient process to produce hydroperoxides and endoperoxides. An interesting example from Bloodworth and co-workers was reported from pentadiene 1, which underwent a double peroxymercuration with hydrogen peroxide to afford mercurated 1,2-dioxolane 2. An oxidative demercuration with bromine afforded dibromide 3, while a reductive demercuration with NaBH4 afforded dioxolane 4. It is noteworthy that this reductant is compatible with the organic peroxide functionality (Scheme 1). [11] Scheme 1. Peroxymercuration of 1,4-pentadiene 1.

Since cyclopropanes possess a π-bond character, peroxymercuration of hydroperoxide containing these rings could be planned. Indeed hydroperoxides 5 underwent a cyclization in presence of perchloric acid and mercury(II) salts to give, in 80% yield, organomercury compounds 6, as intermediates isolated with 60:40 cis:trans ratio. Reduction of the latter with alkaline sodium borohydride afforded the corresponding dioxolanes 7 in 52-60% yields (Scheme 2). [12] Scheme 2. Cycloperoxymercuration of hydroperoxycyclopropanes.

Mechanistically similar to peroxymercuration, peroxyhalogenation is more attractive due to a lower toxicity of the reagents and by-products. [13a] Bloodworth and co-workers reported the synthesis of bicyclic compounds 9a or 9b by using NBS or NIS, respectively, in deuterated methanol from peroxycyclooctene 8 (Scheme 3). [13b] Scheme 3. Cycloperoxyhalogenation of allylic hydroperoxides.

Alkylation

In 1975, Corey and co-workers reported a typical example of direct alkylation of a hydrogen peroxide derivative. [14] This reaction relies first on the formation of an organic hydroperoxide derivative that reacts further in an intramolecular fashion to displace the second leaving group. Thus, treatment of dimesylate 10 with KO2 and 18-crown-6 in DMSO at 25 ºC for 3 minutes afforded the desired peroxide 11 in moderate yield. Following a similar strategy, a certain number of endoperoxides could be prepared from ditriflates and bis-(tributyltin)peroxide. Therefore, dioxolanes 13a and 13b could be prepared from compound 12 in acceptable yields. [15] As demonstrated in these examples, hydroperoxides are not very efficient reagents for alkylation; the scope of the reaction seems limited to low substituted substrates such as those with a methyl group, the critical step being the intermolecular substitution (Scheme 4).

Scheme 4. Cyclization of 1,3-disulfonate derivatives into 1,2-dioxolanes.

Formation of 3,5-disubstituted 1,2-dioxolanes is also possible through the use of 1,3-hydroperoxy halogenated compounds. Bloodworth and co-workers managed to cyclize product 14 into 1,2-dioxolane 15a with endo configuration and inversion of configuration by using Ag2O for 63 h, and 1,2dioxolane 15b with exo configuration and retention of configuration by using silver trifluoroacetate for 1.5 h. No yield was given for these transformations, however the retention of configuration observed for reaction with silver trifluoroacetate was discussed and the author proposed that the formation of a bromonium ion might be probably at the origin of this unexpected process (Scheme 5). [16] Scheme 5. Selective intramolecular alkylation of hydroperoxide into endo-or exo-product.

Similarly, Kishi and co-workers used the same transformation on a cyclopentyl system in their studies towards prostaglandin endoperoxide (PGH2). An oxidative hydroboration was performed on cyclopentene 16 to give hydroperoxide 17. Intramolecular alkylation of the latter with Ag2O afforded endoperoxide 18 in 58% yield (Scheme 6). [17] Scheme 6. Synthesis of endoperoxide 18 as a model study towards prostaglandin-H2.

oxa-Michael addition

Hydrogen peroxide or hydroperoxides are pretty good reagents for Michael addition as illustrated by the Weitz-Scheffer epoxidation of enones. An example of an intramolecular Michael reaction from an hydroperoxide was reported with furan 19. The cyclization to dioxolane 20 was performed in trifluoroethanol in the presence of diethylamine. However, the yield was relatively low (17%), which might be attributed to the basic conditions used during the process, which are not always compatible with organic peroxides, probably leading to the formation of numerous by-products (Scheme 7). [18] Scheme 7. Et2NH mediated Michael intramolecular addition of a hydroperoxide.

In 2008, List and co-workers developed a highly efficient, general, and enantioselective peroxidation of enones 21 with hydrogen peroxide using cinchona alkaloid derivative 20 as an organocatalyst to provide some 1,2-dioxolane-3-ols 22 in a mixture of endoperoxyketal diastereomers. [19] The reaction tolerates a wide scope of aliphatic acyclic α,β-unsaturated ketones, small medium and large ring-sized cyclic α,βunsaturated ketones, and α-branched α,β-unsaturated ketones, giving rise to the expected dioxolanes with an enantiomeric ratio generally above 96:4 er. These dioxolanes could be reduced by TESH in the presence of triflic acid to deliver the corresponding 3,5-disubstituted-1,2-dioxolanes such as compound 23, which was the only example reported. Alternatively, Deng and coworkers disclosed that the asymmetric reaction could even be applied to α,β-unsaturated aldehydes by using some bulky hydroperoxides as nucleophiles, but they did not show any 1,2dioxolane synthesis even if the transformation into these compounds is in theory possible (Scheme 8). [20] Scheme 8. Catalytic asymmetric hydroperoxidation of enones.

Use of Electrophilic Singlet Oxygen

Dussault and co-workers demonstrated in 1995 that singlet oxygen is able to induce the formation of 3,5-disubstituted dioxolane rings from functionalized allyl stannanes 24. In the first step, the oxygen adducts 25 could evolve classically to allyl hydroperoxide 26 through an H-elimination (H-ene) or more surprisingly to 1,2-dioxolane 28 through a 1,2-migration of SnBu3 group (intermediate 27). The selectivity between products 26 and 28 was dependant on the nature of the "X" group (OMOM driving to dioxolane structure 28), as well as the stereochemistry of the double bond, E or Z (Scheme 9). [21] Scheme 9. Addition of singlet oxygen to allyl stannanes: discovery of an unexpected 1,2-migration of SnBu3 group leading to 1,2-dioxolanes.

Use of Triplet Oxygen in Radical Processes

Formation of a radical cation

Oxidation of electron-rich aromatic rings through a single electron transfer can lead to radical cationic species. These radicals can trap triplet oxygen leading to the formation of endoperoxides. Pioneer work was using dicyanoanthracene and photoactivation as oxidant through a single electron transfer, presumably with the formation of a charge transfer-complex. The reaction on disubstituted cyclopropanes could lead to expected 1,2-dioxolanes, but this process was only reserved to electronrich cyclopropanes, where the aromatic ring is substituted with some electron-donor groups such as in compound 29. [22] Presumably oxidation occurs more easily on the heteroatom driving to radical cation 30, which opens the strained cyclopropyl ring by conjugation. Stabilized radical 31 is then reacting with triplet oxygen and further cyclization of the peroxyradical drives to re-aromatization to radical cation 33. An electron transfer from starting molecule 29 takes place in order to propagate the reaction and furnish 1,2-dioxolane 34. Addition of Mg(ClO4)2 was reported to dissociate dicyanoanthracene (DCA) radical anion from the radical cation leading to an overall acceleration of the process (Scheme 10). [22] An improvement of the procedure showed that TiO2 could be used in place of dicyanoanthracene. [23] More recent work of Yoon and co-workers showed also that Ru(bpz)3 2+ ( 35) is a more effective catalyst than dicyanoanthracene, mainly by performing the transformation of cyclopropane 36 into 1,2-dioxolane 37 with simple visible light apparatus at low temperature and with a wider scope of substrates (Scheme 11). [24] Scheme 10. Dicyanoanthracene mediated photooxidation of electron-rich diaryl-cyclopropanes.

Scheme 11. Ruthenium mediated photooxidation of electron-rich diarylcyclopropanes.

Ring-expansion of cyclopropylamines is reported to work with a similar mechanism. Thus, Wimalasena and co-workers found that cyclopropylaniline derivatives can react in a single electron transfer oxidation. [25] For example cyclopropylamine 38 could react in presence of air with different reagents such as some iron complexes or di-tert-butylperoxide and UV to obtain 1,2-dioxolane 42. After oxidation of 38, radical cation 39 was involved in the ring opening of the cyclopropane followed by oxygen trap. Then, propagation of the radical chain reaction through transfert of the radical to starting material 38 maintains the process (Scheme 12). Because of the instability of these endoperoxides, no yield could be given, even if some NMR spectroscopic evidences were reported. Six and co-workers, applied a similar strategy to different substituted cyclopropylamines by using anodic oxidation to produce a single electron transfer. They found notably that more substituted endoperoxides exhibit an improved stability. [26]

Cyclopropyloxy radicals

In 2001, Kulinkovich and co-workers found that oxidation of readily available cyclopropanols by molecular oxygen proceeds effectively in the presence of manganese(II) abietate or manganese(II) acetylacetonate. [27] Using this key step, our group was able to synthesize saturated analogue of mycangimycin 48. Formation of an alkoxy radical from cyclopropanol 43 and superoxocobalt(III) drove to radical 44, which gave peroxyradical 45 after addition of a molecule of oxygen. Ultimately, hydrogen abstraction and propagation led to 1,2-dioxolane 46. A reduction of the peroxyketal with triethylsilane in the presence of triflic acid furnished compound 47 with a decent selectivity towards cis product. After two additional steps, target product 48 was obtained (Scheme 13). [28] Scheme 12. Oxidative ring opening of cyclopropylamines into 1,2-dioxolanes. Scheme 13. Synthesis of a saturated analogue of mycangimycin through a ring expansion of a cyclopropanol into a 1,2-dioxolane.

Isayama-Mukaiyama cobalt catalyzed hydroperoxysilylation

Beside hydrogen abstraction of cyclopropanols, some Cobalt(II) complexes found also their utility into the hydroperoxydation of olefin through the in situ formation of Cobalt(III) hydride species. Indeed, Isayama and Mukayama developed some years ago a new peroxidation of alkenes catalyzed by cobalt(II) acetylacetonate derivatives in presence of triethylsilane, which produced alkyl triethylsilylperoxides. [29] A better investigation of the mechanism was performed by Nojima et al. few years later with an example of a radical domino reaction from a vinyl cyclopropane. Thus, alkene 49 reacted with a cobalt(III) hydride species, formed in situ, through hydrometallation then an homolytic cleavage of the Co-C bond would produce radical species 50, which in turn opened the cyclopropyl ring. Radical 51 reacted with triplet oxygen to furnish dioxolanyl radical 52 and in a second step to give Co(III) peroxy species 53, which could be silylated to furnish compound 54 in 38% yield along with a new cobalt(III) hydride, which could be involved in a new catalytic cycle (Scheme 14). [30] Scheme 14. 1,2-Dioxolane formation from a radical domino reaction in an Isayama-Mukaiyama hydroperoxysilylation.

Thiyl and selenyl radical-mediated domino reactions

In 1989, Feldman and co-workers developed a convenient approach for the formation of 1,2-dioxolanes 56 from 1vinylcyclopropanes 55 bearing phenyl, vinyl or ether substituents at C-2 position of the cyclopropyl ring or alkyl groups at C-1 of the vinyl moiety, through a free radical mediated ring expansion with oxygen. [31] This reaction works as follows: addition of phenylselenide radical to alkene 55 led to cyclopropylmethyl radical 57, which rearranges into homoallyl radical 58 through a β-fragmentation. This alkyl radical is then trapped by O2, providing peroxy radical 59, which after cyclization and loss of phenylselenyl radical, affords desired dioxolane 56. Thus, numerous examples of this reaction have been reported giving yields ranging between 41% and 88%. Some examples are particularly interesting, such as compound 61, which led to product 62 in 38% yield, with formation of three consecutive 1,2dioxolane rings. Sulfur showed to be especially effective in this last transformation compared to selenium (Scheme 15). Scheme 15. Formation of 1,2-dioxolanes from vinyl cyclopropanes through thiyl and selenyl radical-mediated oxygenation.

The authors also applied this methodology to the synthesis of (+/-)-yashabushitriol 66 from vinyl cyclopropane 63 through the reductive opening of 1,2-dioxolane 64 into diol derivative 65 (Scheme 16). [32] Scheme 16. Total synthesis of racemic yashabushitriol.

Using a similar transformation, Beckwith and co-workers studied the addition of thio-radicals on deconjugated triene 67 in presence of oxygen. In a first step, stabilized conjugated radical 68 is formed, followed by the trapping of oxygen, forming peroxy radical 69. Further addition of a molecule of oxygen through the cyclisation of the peroxy-radical on terminal olefin afforded 1,2dioxolane 70 as a minor product (26%) but as a single cis diastereomer (Scheme 17). [33]

Halogen-mediated free radical chain reactions

In 1994, Suarez and co-workers discovered a radical fragmentation of steroids containing a cyclopropane ring, mediated by PhI(OAc)2, I2 and light. Following authors' description, decalin ring-opening of compound 71 into dioxolane 72 was generated from the formation of alkoxyradical 73. Fragmentation of the decalin moiety followed by cyclopropyl ring-opening led to 1,2-dioxolane 76 after reaction with one molecule of oxygen. The resulting radical reacted with an additional molecule of oxygen, and underwent several transformations, among which a hydrogen atom transfer, to form THF ring present in product 72 (Scheme 18). [34] Scheme 17. Formation of 1,2-dioxolanes from a triene through radicalmediated oxygenation.

Two years later, the same authors reported a fragmentation under radical process of 1,2-dioxane steroid derivative 77 to rearranged 1,2-dioxolane 78. The described mechanism passed through a fragmentation of alkoxy radical 79 into species 80. The alkyl radical was reported to trap an iodide presumably from I2 in order to form intermediate 81. Finally, a hydroxide ion might then hydrolyze per-ester function, followed by a final intramolecular cyclization on the iodide. However, the presence of a hydroxide ion is not clear since the reported conditions are neutral (Scheme 19). [35] Scheme 18. Radical fragmentation of steroids into 1,2-dioxolanes. Scheme 19. Radical rearrangement of a 1,2-dioxane to a 1,2-dioxolane on a steroid.

Free-radical oxidation and peroxycyclization

Because prostaglandins are in general very important chemical mediators for human beings, the biosynthetic study of prostaglandins G2 and H2 from arachidonic acid was a primary task for fundamental research as they are precursors of all other prostaglandins, as demonstrated by Porter and co-workers. [36] Thus, γ-linolenic acid 82 was peroxidized using Soybean lipoxygenase followed by a reaction with diazomethane to obtain methyl ester 83. Epoxidation of 83 led directly to the formation of disubstituted 1,2-dioxolane 84. Although the first step is enzymatic, no data was given about enantiopurity of compound 82, no more than the diasteroselectivity for 84 (Scheme 20).

Scheme 20. Synthesis of 3,5-disubstituted-1,2-dioxolane from γ-linolenic acid.

More recently, Brash and co-workers used a quite similar strategy in terms of reactivity for the synthesis of 3,5disubstitued-1,2-dioxolane but they more or less reversed the steps compared to Porter's work. [37] α-Linolenic acid was epoxidized with m-CPBA and after purification on preparative chiral chromatography, enantiopure compound 85 could be obtained, for instance. The oxirane was peroxidised by the use of various lipoxygenases to provide compounds 86, it is interesting to note that only (S) enantiomers were obtained. The buffer was then acidified to pH 5 and an intramolecular nucleophilic substitution occurred leading to the formation of enantiopure 3,5-disubstituted-1,2-dioxolane 87 with an inversion of configuration at C-15 (Scheme 21).

Scheme 21. Synthesis of 3,5-disubstituted-1,2-dioxolane from α-linolenic acid.

In 1982, Carless and co-workers studied the sensitized photooxidation of diene 88 to afford hydroperoxide 89 in 13% yield through an ene-reaction with singlet oxygen. Further radical mediated cyclization of hydroperoxide 89 in presence of triplet oxygen afforded 1,2-dioxolane 90 in 20% yield (Scheme 22). [38] Scheme 22. Radical Peroxy-cyclization.

Peroxycarbenium ions

Formal [3+2] cycloaddition

In 2000, Dussault's group provided an interesting route for the synthesis of poly-substituted 1,2-dioxolanes from hydroperoxy-acetals or ketals, through peroxycarbenium species mediated C-C bond formation, a process which can be considered like a formal [3+2] cycloaddition. [39] Thus, treatment of peroxyacetal 91a or 91b with TiCl4 drove to the formation of peroxycarbenium species 95, which was reacting with allyltrimethylsilane leading to 1,2-dioxolane 92. Usually, Sakurai reaction gives an elimination of a trimethylsilylium ion, but in this particular case hydroperoxide is reacting directly on the carbocationic species 96 to provide 1,2-dioxolane 95. It is important to note that another pathway was involved in the process: the leaving group could be also the hydroperoxide function, leading to the formation of oxycarbenium species 94, which gave major product 93a, meaning hydroperoxide is unfortunately a better leaving group in this reaction. However, when a methoxyethyl ether was used as leaving group in order to clamp titanium species (91b), such by-product was no longer isolated and the yield in dioxolane 92 was also The reaction is working usually with more decent yield when hemiperoxyketals are used in place of hemiperoxyacetals due to a better formation and stabilization of the peroxycarbenium species. Improvement of the method was also investigated by Woerpel and co-workers but only reactions on peroxyketals were reported (Scheme 23). [40] 23. Lewis acid-mediated formal [3+2] cycloaddition between peroxycarbenium species and allyltrimethylsilane.

Similarly, Dussault also showed that ozonide 97 could be the source of 3,5-disubstituted 1,2-dioxolanes 98 and 99 through an acid mediated fragmentation, which led to a statistic mixture of 1,2-dioxolanes after trapping of peroxonium intermediates 101 or 102 (Scheme 24). [41] Scheme 24. Lewis acid-mediated fragmentation of ozonides and reaction of the peroxycarbenium species with allylTMS.

Functionalization of endoperoxyacetals

Recently, we found that 1,2-dioxolanols could be useful intermediates to prepare diversely functionalized 3,5disubstituted 1,2-dioxolanes. Dussault originally reported this process on endoperoxy-ketals derivatives, but since the lack of substitution resulted in a decrease of the reactivity of the endoperoxyacetal function, no example was reported by him or other groups. [42] Indeed, utilization of an ether function as leaving group is inefficient with endoperoxyacetals, and acetate was found to be a more appropriate nucleofuge. However, the protocol of acetylation was crucial, since classical conditions (Ac2O, pyridine or DMAP) were unsuccessful due to the reactivity of peroxides towards amines. Lewis acid catalyzed acetylation was in contrast very effective and could provide these corresponding reactive substrates. Addition of different nucleophiles was performed using SnCl4 or TiCl4 as Lewis acids (0.9 equiv). The reaction was allowed with very diverse nucleophiles, from allylsilanes (103-110) to silyl enol ethers of ketone derivatives (113-114), to silanes (111-112). The results were different by using TiCl4 or SnCl4, the first one giving high trans selectivities but low yields, whereas the second one delivered 1,2-dioxolanes in significant higher yields but with lower diatereoselectivities. It was found that 3,5-disubstituted 1,2-dioxolanes underwent a more pronounced but selective degradation of the cis-diastereomer with TiCl4 rationalizing these results. [43] Slightly later, we reported the same transformation using improved experimental conditions. Utilization of mild Lewis acids such as Sc(OTf)3 or InCl3/TMSCl proved to be very convenient catalysts for such a reaction. [44] Besides the catalytic amounts of Lewis acids used (5 mol%), the room temperature conditions instead of -40°C facilitate the experimental protocol. No significant degradation was observed with these catalysts compared to the previous study. [43] Moreover, it was found these conditions expanded the scope of the reaction to other nucleophiles such as silyl enol ether of esters (119) and thioesters (118&120) (Scheme 26). However, deactivated allylsilanes such as bromo-or chloro-allylsilanes were ineffective with these catalysts (Scheme 25, 106&110). This means, finally, that the two protocols, i.e. stoichiometric amount of a strong Lewis or catalytic amount of a mild Lewis acid, are complementary to each other (Scheme 26).

Conclusion

1,2-Dioxolanes are rarely found in Nature, and specifically for 3,5-disubstituted-1,2-dioxolanes where only few representative examples are known to date. Although organic peroxides have in general a bad reputation, most of 3,5-disubstituted dioxolanes described in this review, with few exceptions, were isolated by chromatography with a determined yield, using classical conditions, meaning these compounds are rather stable under normal conditions of temperature. However, due to their very promising activities as anti-inflammatory, antifungal and antiplasmodial agents, this new class of compounds has attracted some growing interest. In the future, more efficient syntheses in a stereoselective manner must be designed, in order to prepare multi-functionalized 3,5-disubstituted-1,2dioxolanes with a large scope and a high yielding. This review has attempted to present the different approaches that have been studied for this purpose. This will, hopefully, open the path for improvement and creativity towards the synthesis of these exciting new compounds.

Entry the Table of Contents: "Endoperoxides"

Although the synthesis of 3,3',5,5'-tetrasubstituted 1,2-dioxolanes is widely reported in the literature, some specific methods for the synthesis of 3,5-disubstituted 1,2-dioxolanes are more scarcely described. The isolation, these last ten past years, of several natural products containing this framework enhanced the interest in the synthesis of these structures. Thus, we propose herein a tentative exhaustive compilation of the methods reported to build 3,5-disubstituted 1,2-dioxolanes. The reactions are classified according their mechanism, from nucleophilic substitutions with hydroperoxide derivatives to radical reactions with triplet oxygen, reaction with electrophilic singlet oxygen, or reaction and functionalization from peroxycarbenium species.

Institute and/or researcher Twitter usernames: @BioCIS; @BFigadere; @FerrieLaurent; @alexis_pinet

Figure 1 .

 1 Figure 1. Major known 1,2-dioxolanes isolated from marine sponges plakortis or plakinastrella sp.

Alexis

  Pinet received his BSc in Biochemistry from Université de Lyon and a MSc in Organic Chemistry from Université de Montpellier. In 2017 he started a PhD degree in total synthesis and methodology under the supervision of Dr. Laurent Ferrié and Dr. Bruno Figadère in Université Paris-Sud/Paris-Saclay. His research interests focus on the synthesis and functionalization of 1,2-dioxolanes applied to the total synthesis of Mycangimycin. Linh Thuy Nguyen received her PhD in Medicinal Chemistry from the Faculty of Pharmacy at the Université Paris-Sud/Paris-Saclay in 2017. She is currently an NIH post-doc fellow and joint trainee of an NIH D43 international research training program in infectious diseases between the Institute of Marine Biochemistry at the Vietnam Academy of Science and Technology in Vietnam and the University of Illinois at Chicago in the United States. Her research interests include the discovery of bioactive natural products from plants, microorganisms and their synthesis or semi-synthesis of their derivatives. Bruno Figadère graduated in chemistry in 1984 and obtained his PhD in 1987, both from Université Pierre et Marie Curie in Paris. He was a post-doctoral fellow at the University of California at Riverside with Professor William Okamura working on total synthesis of natural products. In 1990 he became Chargé de Recherche in the CNRS at the University of Paris-Sud/Paris-Saclay-Faculty of Pharmacy, and was promoted in 1997 as Directeur de Recherche. His research interests are in the field of natural product chemistry: total synthesis, isolation, structure determination and pharmacomodulation. Laurent Ferrié graduated from Université de Lyon, and then moved from 2004 to Paris at ESPCI to complete his PhD under the supervision of Pr. Janine Cossy. He joined then Pr. Peter Wipf in 2008 at the university of Pittsburgh for a postdoctoral internship and was finally hired in 2009 at CNRS in BioCIS at Université Paris-Sud/Paris-Saclay/. His research interests focus on natural product total synthesis, synthesis of endoperoxides and discovery of new drug candidates for treatment of Parkinson's disease.

Scheme 25 .

 25 Scheme 25. Nucleophilic substitution of 1,2-dioxolan-3-yl acetates mediated by TiCl4 or SnCl4.

Acknowledgements

A.P. thanks gratefully the French government for a MESRI PhD grant and L.T.N. thanks the Vietnamese government for a PhD fellowship


Alexis Pinet

Bruno Figadère

Laurent Ferrié
email: laurent.ferrie@u-psud.fr

Access to Functionalized 3,5-Disubstituted 1,2-Dioxolanes under Mild Conditions through Indium(III) Chloride/Trimethylsilyl Chloride or Scandium(III) Triflate Catalysis

Keywords: Peroxides, Peroxycarbenium, Acetal, Rareearths, Indium

Herein we report the use of catalytic amount of scandium(III) triflate or indium(III) chloride (with trimethylsilyl chloride) for the functionalization of endoperoxyacetals through Sakurai or Mukaiyama reactions. These catalysts allow milder and more practical conditions than those previously reported with improvements in scope and reproducibility. This method allows a full catalytic sequence from cyclopropanols to produce desired functionalized 1,2-dioxolanes.

Endoperoxides are a rich source of natural or unnatural bioactive products, leading to the development of important anti-malarial drugs such as Artemisinin or Arterolane. We were involved these last years in a scientific program towards the total synthesis of mycangimycin, a fatty acid containing a 1,2-dioxolane pattern (Figure 1). [1] [2] Figure 1. Artemisinin, Arterolan and Mycangimycin.

Thereafter, we described a methodology [START_REF] Pinet | yen e nadat i ad e e i[END_REF] to build disubstituted 1,2-dioxolanes through Lewis acid activation of 1,2-dioxolanyl acetates with TiCl 4 or SnCl 4 at low temperature. The corresponding peroxycarbenium species [4] was then trapped with a neutral nucleophile such as an allylsilane or silyl enol ether. We also highlighted the fact that the 1,2dioxolane moiety undergoes two paths of degradation/rearrangement due to activation by strong Lewis acids (mainly TiCl 4 ), leading to lower yields but often higher diastereoselectivities. [START_REF] Pinet | yen e nadat i ad e e i[END_REF] Moreover, this methodology tends to be difficult to control since a slight modification of the Lewis acid stoichiometry can lead to more degradation products (if in excess) or a worse conversion in desired product (if in deficiency), which gives sometimes difficulties to reproduce the experiments. [START_REF] Pinet | yen e nadat i ad e e i[END_REF] Thus, the utilization of a mild Lewis acid under catalytic amount at room temperature would be highly desirable to circumvent the degradations products and the utilization of sub-stoichiometric amount of Lewis acid under low temperature conditions. Scheme 1. Previous work about the synthesis of disubstituted 1,2-dioxolanes.

In order to prepare the dioxolanyl acetate, we transformed some cyclopropanols 1a-g (obtained either from Kulinkovich reaction [5] or chromium (II) mediated cyclization of β-methylene aldehydes [6] ) with two catalytic transformations. Firstly cyclopropanols 1a-g were oxidized to peroxyhemiacetals 2a-g through the formation of a hydroxyl radical mediated by Mn(acac) 3 , followed by cyclopropyl opening and trapping of intermediate radical with triplet oxygen. [7] Peroxy-hemiacetals 2ag were then acetylated with acetic anhydride in the presence of 10 mol% of Yb(OTf) 3 to give acetoxyendoperoxyacetals 3a-g in overall good yields (Scheme 2). Noteworthy is that only 0.5 mol% of Yb(OTf) 3 was found, more recently, to be enough for the transformation. The use of a Lewis acid catalysed acetylation [8] was crucial to the success of this transformation since organic peroxides are reacting with amines, which are used in more common protocols. Both reactions are safe and multi-gram scalable and require low amounts of inexpensive catalysts.

Scheme 2. Synthesis of 1,2-dioxolanyl acetates 3a-g

Then, our attention focused on the functionalization of endoperoxyacetals 3a-g under catalytic conditions. Considering the literature about catalytic Sakurai reactions combining InCl 3 and TMSCl, [9] these reagents were chosen as a starting

In the Sakurai reaction between peroxyacetal 3a and allyl-trimethylsilane 5, InCl 3 or TMSCl were alone unable to catalyse the reaction (Table 1 entries 1 and2). However, when the experiment was run with 10 mol% of InCl 3 and TMSCl (Table 1 entry 3), we obtained expected product 4a in less than 30 min. The amount of both TMSCl and InCl 3 was then reduced gradually until reaching 0.5 mol% of InCl 3 (entry 6). The less the amount of InCl 3 was used, the more the reaction time increased, but this shows the possibility to decrease sensibly the amount of catalyst (entries 5 and 6). Optimal conditions were identified for 5 mol% of InCl 3 and 2.5 equivalent of TMSCl (entry 4). This last result was comparable in term of yield and diastereoselectivity with the use of substoechiometric amount of SnCl 4 at -40 °C (81% vs 80% and 70:30 vs 65:35). [START_REF] Pinet | yen e nadat i ad e e i[END_REF] Table 1. Sakurai reaction study with InCl 3 /TMSCl as catalyst couple on peroxyacetal 3a.

Entry [a] Conditions Stoichiometry (equiv)

Reaction

Time Yield [a] dr [b] trans:cis [a] Isolated yield. [b] Diastereomeric ratios were determined by 1 H NMR.

1 InCl 3 0.1 3 h n.
In parallel to our studies of InCl 3 /TMSCl as a potent mild Lewis acid system, rare-earth metal triflates or more generally metallic triflate of type "M(OTf) 3 " were also promising species since they were reported in catalytic version of Mukaiyama aldol reaction but also for Sakurai allylation. [10] Thus, with these elements in hands, an investigation of metallic triflate was also conducted on peroxyacetal 3a in a Sakurai reaction with allytrimethylsilane 5.

Post-transition metal triflates such as indium(III) or bismuth(III) revealed to be poorly effective as Lewis acid in our reaction (Table 2, entries 1 and 2). In particular, bismuth(III) led to the formation of many degradation products in a very short time, while reactions employing In(OTf) 3 proceeded slowly and extended reaction times brought many side-products without improving the yield of dioxolane 4a. Some popular rare-earth metal triflates in catalysis were also screened at 10% mol. [10a] Reaction employing triflates of Yb(III), Y(III), and La(III) proceeded very slowly (6-48 h) giving modest yields of compound 4a, resulting again in a bad conversion/ degradation ratio (Table 2, entries 5,6 and7). In contrast, scandium(III) gave interesting results, comparable to those obtained with InCl 3 /TMSCl (Table 2,entry 3). Decreasing the amount of catalyst by half did not modify the results (Table 2, entry 4). The improved reactivity of Sc(OTf) 3 towards other tested metal rare-earth triflates is not surprising since Sc(OTf) 3 is known to possess a higher oxophilicity. [11] Table 2. Sakurai reaction study with various metal (III) triflates as catalyst on peroxyacetal 3a.

[a] Isolated yield. [b] Diastereomeric ratios were determined by 1 H NMR.

Because InCl 3 /TMSCl and Sc(OTf) 3 exhibited similar results in term of reaction time, catalyst loading, diastereoselectivities and yields, we chose to Entry [a] Conditions Stoichiometry (equiv)

Reaction

Time Yield [a] dr [b] trans:cis further study these two catalytic systems under the optimized selected conditions (Table 1, entry 4 and Table 2, entry 4). The influence of lateral chain R 1 at position 3 of 1,2-dioxolanyl acetates 3b-g was investigated in the Sakurai reaction with allylTMS (Table 3). InCl 3 /TMSCl and Sc(OTf) 3 behaved similarly to furnish 1,2-dioxolanes 4b-g, giving same selectivity. Only some differences appeared on the yield with sometimes a significant improvement with InCl 3 /TMSCl compared to Sc(OTf) 3 (Table 3, Entries 1 and 7).

When these results are compared to our previous report involving SnCl 4 or TiCl 4 as Lewis acids, [START_REF] Pinet | yen e nadat i ad e e i[END_REF] these two catalytic systems gave overall slightly lower yields than sub-stoichiometric SnCl 4 but it was compensated by a higher selectivity toward trans product.

Table 3. Sakurai reaction with InCl 3 /TMSCl or Sc(OTf) 3 as catalysts on different substrates 3b-g.

[a] Reaction conditions: 3a (1 equiv.), InCl 3 /TMSCl (5/250 mol%) or Sc(OTf) 3 (5 mol%), AllylTMS 5 (3 equiv.), 30-60 min. [b] Isolated yield. [c] Diastereomeric ratios were determined by 1 H NMR.

The nature of the nucleophile was also examined on dioxolanyl acetate 3a for the two selected catalysts (Table 4). Methyl allyltrimethylsilane 6 gave product 15 with similar results for both systems (Table 4, entries 1-2), as well as TMS cyanide 7 and TMS azide 8 (Table 4, entries 3-4 and 5-6), which produced very efficiently compounds 16 and 17. Triethylsilane 9 was able to reduce the acetal function giving dioxolane 18, but the yield was significantly higher with Sc(OTf) 3 (Table 4, entries 7-8). Mukaiyama aldol reaction was also experienced under our two selected conditions. Ketone derivatives gave contrasted results; enol ether 10 from acetophenone gave good conversion in compound 19, in particular with Sc(OTf) 3 (entry 10) but t-butyl methyketone derivative 11 reacted sluggishly giving poor yields (until 28 h) of t-butyl ketone 20 in both cases (Table 4, entries 11-12); this poor yield could be attributed to some steric hindrance in the nucleophile. Silyl enol ether of esters and thioesters proved to react similarly under the two tested conditions affording ester 21, thioesters 22 and 23 in nice yields (Table 4, entries 13-18). Thioesters 22 and 23 are particularly interesting, since some cross coupling reactions could be applied [12] and because of their ease of conversion into the corresponding carboxylic acid. For example, we were able to convert thioester 22 into the corresponding carboxylic acid 24 with H 2 O 2 and LiOH in aqueous THF in 1h at rt in 99% yield.

Table 4. Addition of various nucleophiles to peroxyacetal 3a [a] under catalytic conditions. [a] Reaction conditions: 3a (1 equiv.), InCl 3 /TMSCl (5 /250 mol%) or Sc(OTf) 3 (5 mol%), nucleophile 6-14 (3 equiv.), 30-60 min. [b] Isolated yield. [c] Diastereomeric ratios were determined by 1 H NMR. [d] 20h and 28h reaction time using respectively InCl 3 /TMSCl and Sc(OTf) 3 .

When these results are now compared to the substoichiometric utilization of SnCl 4 as a Lewis acid, [START_REF] Pinet | yen e nadat i ad e e i[END_REF] it can be observed that the yields were overall similar and diastereoselectivities were slightly better towards trans products by using the catalytic versions. Nevertheless, there are some exceptions where strong Lewis acids are superior, such as with t-butyl enol ether 11, which seemed to react better with SnCl 4 due to higher reactivity of this later. [START_REF] Pinet | yen e nadat i ad e e i[END_REF] For the same reason 1-bromo-and 1-chloro-trimethylsilanes were completely inert by using our selected catalytic systems due to a decreased nucleophilicity of these allylsilanes. In contrast, InCl 3 /TMSCl and Sc(OTf) 3 were far superior to SnCl 4 (and TiCl 4 ) in some cases. TMSCN 7 and TMSN 3 8 gave significant higher yields with both catalytic systems. More importantly, enol ether of ester 12 and thioesters 13 and 14 were completely unreactive with SnCl 4 and TiCl 4 , whereas compounds 21, 22, 23 were very efficiently obtained with the catalytic methods, expanding the initial scope of our reaction.

In conclusion, we developed a new catalytic protocol of functionalization for 1,2-dioxolanyl acetates, identifying two efficient systems, namely InCl 3 /TMSCl and Sc(OTf) 3 . Overall the use of InCl 3 /TMSCl or Sc(OTf) 3 over SnCl 4 (and TiCl 4 ) is justified by simpler experimental procedures (room temperature versus -40°C, inert powders versus fumigating and hazardous reagents), atom economy and improvement of diastereoselectivity. Although some poorly reactive species such as deactivated allylsilanes, and hindered nucleophiles work better with SnCl 4 and TiCl 4 , the two new catalytic systems also enlarge the reagents scope to ester and thioester enol ether derivatives, which makes complementary the catalytic and the stoichiometric versions of the studied transformation.

Experimental Section

General Procedure for the preparation of peroxyhemiacetals 2a-g:

To a solution of cyclopropanol 1a-g (1 equiv.) in THF (1 mL/mmol), was added Mn(acac) 3 (0.5 mol%) and the reaction mixture was then stirred under an atmosphere of oxygen. After disappearance of starting material monitored on TLC (usually from 1 to 2 h), pentane was added precipitating most of the manganese salts. The solution was filtrated on a silica pad and was rinsed with Et 2 O several times. Volatiles were removed under reduced pressure without heating to afford peroxy-hemiacetals 2ag. This procedure allows generally excellent yields with sufficiently pure materials for further utilization. In some cases, flash column chromatography might be needed, we advise to perform it in isocratic gradient as fast as possible.

General Procedure for the preparation of acetoxyendoperoxyacetal 3a-g:

To an ice-bath cooled solution of peroxy-hemiacetal 2a-g (1 equiv.) in anhydride acetic (2 mL/mmol) was added Yb(OTf) 3 (10 mol%, but it can be lower to 0.5 mol% such as with 3a; most rare-earth metal triflates are usable with similar results in this reaction). Reaction was monitored by TLC and when no starting material remains (usually 30 min-1 h) the reaction was quenched by pouring the reaction mixture into a saturated solution of NaHCO 3 at 0-5 °C to be stirred 30 min at this temperature. The aqueous phase was extracted with Et 2 O three times and organic layer was washed with brine and dried over MgSO 4 . Volatiles were removed under reduced pressure without heating, and the residue was used in its state without further purification in case of good purity.

When necessary, the residue could be purified on a silica gel flash column chromatography.

General Procedures for the preparation of functionalized 1,2-dioxolanes 4a-g and 15-23 under catalytic conditions:

Prior to use, catalysts were dried (if soggy or old), under high vacuum (0.5 mmHg) and gentle warming with a heatgun.

Using InCl 3 and TMSCl: To a solution of acetoxyendoperoxyacetal 3a-g (1 equiv.) and desired nucleophile (3 equiv.) in dry DCM (4 mL/mmol) was added 5 mol% InCl 3 and TMSCl (2.5 equiv.) sequentially. After disappearance of starting material monitored on TLC (usually 1 h), the reaction mixture was poured into a saturated solution of NaHCO 3 . Aqueous phase was extracted with Et 2 O three times and organic layer was washed with brine and dried over MgSO 4 . Volatiles were removed under reduced pressure and the crude residue was purified by silica gel flash column chromatography to afford the different 3,5-disubstituted 1,2 dioxolanes 4a-g and 15-23.

Using Sc(OTf) 3 : To a solution of acetoxyendoperoxyacetal 3a-g (1 equiv.) and desired nucleophile (1.5-3 equiv.) in dry DCM (4 mL/mmol) was added 5 mol% Sc(OTf) 3 . After disappearance of starting material on TLC (usually 1 h), the reaction mixture was poured into a saturated solution of NaHCO 3 . Aqueous phase was extracted with Et 2 O three times and organic layer was washed with brine and dried over MgSO 4 . Volatiles were removed under reduced pressure and the crude residue was purified by silica gel flash column chromatography to afford the different 3,5-disubstituted 1,2 dioxolanes 4a-g and 15-23.

Acknowledgements

A.P. thanks the MESRI for a PhD fellowship. We thank Karine Leblanc and Jean-Christophe Jullian (BioCIS, Châtenay-Malabry) for HRMS analysis and NMR services, respectively.

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