Agathe C A D'hollander

Laure Peilleron

Tatyana D Grayfer

Kevin Cariou
email: kevin.cariou@cnrs.fr

Halonium-Induced Polyene Cyclizations

Keywords: Asymmetric Reactions 6. Total Synthesis of Halogenated Natural Products 7 halogenation, polyenes, biomimetic synthesis, cascade cyclization, asymmetric synthesis, natural products

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Introduction

The intricate polycyclic structures that living organism produce have been a tremendous source of inspiration for chemists, often leading to the development of powerful synthetic methods. From this standpoint, the electrophilic cyclization of polyenes, as pioneered by Stork 1 and Eschenmoser 2 in the 50s, remain a striking example of chemists rivalling Nature in terms of efficiency and selectivity and constitute a landmark for the field of biomimetic synthesis. 3 Halogenated derivatives 4 constitute a particular sub-class of polycyclic natural compounds which, because of their complex and original structures and their therapeutic potential, 5 fueled the development of many synthetic methods. 6 In Nature the synthesis of these molecules from linear terpenes is achieved through various enzymatic machineries, 7 that, following initial halogenation of a trisubstituted alkene, can readily achieve halogen-induced carbocyclizations, oxy-halogenations or polyhalogenations. Several of these transformations sometimes occur for the same substrate. For instance, the brominated terpenoid bromophycolide A, 8 that exhibits three different bromination patterns (including a cyclic one) could basically arise from three distinct electrophilic brominations of a geranylgeranyl starting material (Scheme 1). Yet, what enzymes have evolved to achieve can raise complex chemo-, regio-, and stereoselectivity issues for the synthetic chemist, especially considering that all patterns could come from a common intermediate.

Scheme 1 Schematic biosynthesis of bromophycolide A

Indeed, the first step in the electrophilic bromination of a geranyl derivative 1 would lead to a key bridged halonium intermediate 2, which can evolve following different pathways (Scheme 2). Elimination of one proton would yield allylic halide 3 while nucleophilic opening by an external nucleophile (such as water or a halide) would give disubstituted product 4. Eventually, trapping by the proximal double bond would lead to 6-membered carbocation 5 that can then follow various routes such as elimination, trapping or cascade process. This carbocyclization pathway, when not triggered by a suitable enzyme, is generally the most difficult to favor compared to the other two major options. It is important to note that for the halocyclization of a linear terpene, such as geranyl derivative 1, the relative cisconfiguration of the resulting cyclohexyl cation 5 is dictated by the configuration of the bridged halonium 2 since the cyclization would take place through an SN2-type mechanism on a preorganized (most often chair-like) transition state (Scheme 3).

The aim of this review is to present the different methods that chemists have developed to efficiently initiate the direct halonium induced cyclization of polyenes, from seminal works to the most recent breakthroughs, including asymmetric variations and applications for the total synthesis of natural products. 10

Pioneering Studies

In 1966, Van Tamelen reported that, unlike most terpene derivatives that would give bromohydrins under the same conditions, treatment of methyl farnesate 6 with NBS in a water/THF mixture also produced minor amounts of bromocyclized products 7 and 8 (Scheme 4, eq. 1). 11 These compounds were identified as the major components of a fraction representing 12-15% yield. After selective saponification and further purification, only 4-5% of this fraction were found to be the bicyclic products 7. A similar cyclization was observed in 1975 by Nasipuri for the more nucleophilic m-anisyl derivative 9a (Scheme 4, eq. 2), which led to tricycle 10a in 10% yield under the same conditions (the major products being the acyclic dibromohydrins). 12

Scheme 4 First examples of bromocyclization of polyenes mediated by NBS

The following year Faulkner described the bromocyclization of geranyl acetate 11a using bromine (Scheme 5, eq. 1). 13 The use of bromine along with tin(IV) bromide mostly led to dibrominated products although 16% of cyclized product 12a could be isolated. Instead of SnBr4, silver(I) tetrafluoroborate was used to scavenge the bromide ions responsible for the dibromination of the olefin allowed the yield to reach 20%. Applying this second protocol to geranylacetone 13 gave bicyclic enol ether 14 in 20% yield (Scheme 5, eq. 2). Hydrolysis of the enol, vinylation of the resulting ketone followed by acidic treatment eventually furnished 10-bromo--chamigrene (15). Scheme 5 Faulkner's bromocyclization of geranyl acetate and total synthesis of 10-bromo--chamigrene These seminal studies showed that the total synthesis of halogenated polycyclic natural products could be achieved by a straightforward biomimetic strategy. Yet, they also highlighted that, while feasible using standard reagents such as Br2 or NBS, the bromocyclization pathway was not favored and would require some kind of additive (a silver salt for Faulkner) or specifically designed reagents to increase its efficiency.

Use of Specific Reagents

TetraBromoCyclohexadienOne (TBCO)

As the initial electrophilic halogenation of the terminal double bond would yield a highly reactive cationic intermediate, to promote carbocyclization other species in the reaction need to be less nucleophilic than the internal olefin. Taking this into consideration, Kato proposed a combination of 2,4,4,6tetrabromo-2,5-cyclohexadienone 16 (TBCO) and an aluminum(III) halide to promote the bromocyclization of polyenes. 14 The Lewis acid would trigger the generation of a bromonium ion along with aluminate complex 17 which is a rather poor nucleophile (Scheme 6, eq. 1). When applied to Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 3 of 17 geranyl cyanide 18, these conditions gave 15% of the bromocyclized products 19 (Scheme 6, eq. 2). In this setting, the nucleophilic trapping of the carbocation by a bromide only happens after the cyclization. In the absence of AlBr3, no cyclization took place and the dibromination of the terminal double bond of 18 occurred quantitavely. 15 In contrast, the conditions reported by Van Tamelen (Scheme 4, eq. 1) 11 only gave the corresponding bromohydrin. Additionally, if TBCO is used in conjunction with cetyltrimethylammonium bromide, only the dibromination takes place. 16 Scheme 6 Activation of TBCO with AlBr3 and bromocyclization of geranyl cyanide TBCO was also used for the biomimetic synthesis of natural products, which will be covered in the dedicated section below.

Bis(pyridine)iodonium tetrafluoroborate

Bis(pyridine)iodonium tetrafluoroborate was developed in 1985 by Barluenga as a practical reagent for the 1,2iodofunctionalization of olefins, 17 and it proved suitable for the iodocarbocyclization of several polyenes. When very simple dienes such as hexa-1,5-diene 20a and hepta-1,6-diene 20b were subjected to the Barluenga's reagents and tetrafluoroboric acid the iodocyclization took place in a 6-endo or 6-exo fashion to give fluorocyclohexanes 21 or 22 respectively (Scheme 7). 18 While iodocarbocyclization had been previously described with molecular iodine in CCl4, it was limited to one 1,6-diene containing a central gem-dialkyl carbon. Under these conditions, 20a and 20b only led to linear polyiodinated products. 19 Scheme 7 Iodocyclization of dienes When phenyl-geranyl ether 23 was submitted to Barluenga's reagent, iodo-chromane 24 was obtained with an excellent yield. 20 To explain the formation of 24 and other rearranged products the authors proposed that the iodocarbocyclization would initially lead to an oxetanium intermediate. Substrate 23 would thus give 25 that can then yield 24 (Scheme 8, eq. 1). This protocol can even be applied to longer polyenes such as farnesyl derivative 26 to give tetracyclic tetrahydroquinoline 27 in 41% yield, in this case without rearrangement (Scheme 8, Eq.2).

Scheme 8 Iodocyclization of geranyl and farnesyl derivatives with Barluenga's reagent

Use of Halodiethylsulfoniums

Bromodiethylsulfonium Bromopentachloro antimonate (BDSB)

For the development of bromodiethylsulfonium bromopentachloroantimonate (BDSB) in 2009, the group of Snyder hypothesized that a controlled polyene cyclization required a highly activated cationic bromonium source without any nucleophilic anionic species being present. 21 For this purpose they chose to synthetize and study the reactivity of various bromosulfoniums salts and eventually selected BDSB. BDSB is obtained by reaction of Br2 with SbCl5 and Et2S in 1,2dichloroethane at -30 °C (Scheme 9), 22 it is fairly convenient to isolate and can be stored for some time before being used. This specifically designed reagents turned out to give exquisite results in terms of chemoselectivity and yields on a very broad range of substrates, especially compared to the existing methods at that time (Table 1). Ten years later, it remains the gold standard for the racemic bromo-cyclization of polyenes. Electron-poor substrates such as geranyl cyanide 18 or geraniol esters 11a, b and carbonate 11c selectively gave the corresponding monocyclic products with excellent yields (entries 1-4). Stronger electron-withdrawing groups (CN, OCOCF3) favored a final elimination to give cyclohexenes 28 and 29 (entries 1, 3), whereas internal nucleophilic trapping occurred for acetate 11a and carbonate 11c to give alcohol 12a (after hydrolysis) and cyclic carbonate 30, respectively (entries 2, 4).

Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 4 of 17 [a] Isolated as a mixture of alkene stereoisomers. [b] All yields deriving from this reagent were determined by NMR analysis using nitrobenzene as an internal standard since the desired material co-elutes with undesired side products. [c] Generated alongside some very minor diastereomers. [d] Yield includes partially cyclized material. [e] Complete cyclization promoted by the addition of CH3SO3H at the end of the reaction.

Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 5 of 17

Homogeranic acid 31 and its t-butyl ester 32 reacted equally well to give 6,5-bicyclic lactone 33 (entries 5, 6). One striking feature of BDSB is that it can directly convert electron-rich substrates such as homogeranylphenyl derivatives 9b, c and even farnesyl substrate 34 to the fully cyclized products 10b, c and 35 without having to resort to an additional acidic treatment (entries 7-9).

IDSI and CDSC

Following the development of BDSB, the group of Snyder studied the synthesis of iodo-and chloro-variants of their reagent. 23 Reaction of iodine with pentachloroantimonate and diethyl sulfide was optimized to allow the isolation of a chlorinebridged dimer that was termed IDSI (Scheme 9, eq. 1). This dimer was less stable than BDSB -a quick decomposition occurred at room temperature to give ICl, SbCl5 and Et2S -but suitable to carry out iodination reactions (see below). Following a similar protocol with chlorine gave chlorodiethylsulfonium hexachloroantimonate (CDSC), which was structurally analogous to BDSB (Scheme 9, eq. 2).

Scheme 10 Synthesis of IDSI and CDSC.

Despite its minor drawbacks, IDSI could be used for the cyclization of several polyenes (Table 2, entries 1-3). For electron-rich benzylgeranyl 9c, d and for benzylfarnesyl 34 the desired tri-and tetracycles 36c, d and 37 respectively were obtained in good yields (entries 1-3)., even though for the latter the final cyclization required the addition of methane sulfonic acid. Protected phenolic derivative 38 underwent a cascade cyclization process to give tricycle 39 (with the loss of one MOM group, entry 4), Electron-poor compounds such as nitrile 18, geranyl acetate 11a and carbonate E-11c reacted in a similar fashion to that observed with BDSB, yielding cyclohexenes 40, tertiary alcohol 41a and cyclic carbonate 42, respectively (entries 5-7). Finally, neryl carbonate Z-11c also reacted to give the trans, cis isomer 42' in moderate yield, thus confirming the stereospecificity of the transformation (entry 8).

The CDSC reagent could also be applied for various cyclizations, which, although the scope was more limited and the yields more modest, represented the first report of an ionic chloronium induced polyene cyclization (Table 3). Hence, homogeranylbenzene 9b gave the chlorinated tricycle 43b in 46% yield (entry 1). The reagent also promoted the cyclization of electron-poor substrates such as geranyl acetate 11a to give 44 (entry 2), or homogeranic acid 31 and its t-butyl ester 32, both yielding lactone 45 with modest yields (entries 3, 4).

Miscellaneous

Trimethylphenylammonium perbromide

Trimethylphenylammonium perbromide (TMPAP) is a soluble and stable electrophilic bromination reagent, 24 which has been used for the transannular bromocyclization of costunolide 46 (Scheme 11). 25 An excellent overall yield of 95% was obtained for the formation of tricyclic 47 as a mixture of olefin isomers with the major one (70%) being the exo-isomer. The use of TMPAP greatly increases the efficiency of the product formation compared to NBS, which had previously been reported to give a very complex mixture after reaction with the analogous dihydrocostunolide. 26 Water was excluded to prevent the formation of the tertiary alcohol by nucleophilic trapping of the carbocation and pyridine was added to scavenge any strong acid that would lead to the corresponding proton-induced transannular cyclization. 25 Scheme 11 Transannular bromocyclization with TMPAP

Vanadium bromoperoxidase

Since the aforementioned bromocyclizations were modeled after Nature's, it was somewhat tempting to try and reproduce those transformations using a halogenase enzyme as catalyst. 27 The group of Butler isolated and cloned a vanadium bromoperoxidase (V-BrPO) from red algae and submitted several linear terpenes to this enzyme in the presence of potassium bromide and hydrogen peroxide. 28 Thus, geranyl acetate 11a gave a racemic mixture of endo-and exo-bromocyclohexenes 48 in moderate yield (10-20%, Scheme 12, eq 1) and geranyl acetone 13 gave the racemic bicycle 14 (Scheme 12, eq 2) that was previously reported by Faulkner (Scheme 5, eq. 2). 13 Scheme 12 Butler's enzymatic bromocyclization of geranyl acetate and geranyl acetone

Bromiranium

Following the strategy of having a stabilized bromonium with a weakly coordinating anion, the group of Hennecke designed the synthesis of the (stable) bromiranium salt of adamantylidene adamantane with a BArF (tetrakis[3,5bis(trifluoromethyl)phenyl]borate) counterion (Scheme 13). 29 This reagent promoted the bromination of phosphines and was also used for the bromocyclization of three homogeranylarene derivatives (9) to give the corresponding tricyclic products 10 with modest to good yields. Hexamethyldisilazane was used to prevent the formation of the very strong acid HBArF that can induce cationic cyclization of the substrates.

Scheme 13 Bromocyclization induced by a stable bromiranium (after column chromatography the products are obtained with ca 90% purity, yields in brackets are after recrystallization from acetone)

Bis(tert-butylcarbonyloxy)iodobenzene/Triethylsilylbromide

Synthesis

Review / Short Review Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 7 of 17

In order to generate an electrophilic bromination species that would selectively trigger the cyclization of polyenes and suppress the formation of the unwanted linear brominated products, the group of Cariou screened various combinations of hypervalent iodine(III) reagents 30 as oxidants with different bromide sources. 31 The rather soluble bis(tertbutylcarbonyloxy) iodobenzene was selected so the reaction could be run at low temperature (-78 °C) in nitroethane, thus preventing undesired side reactions, and because the oxidation of the bromide would liberate pivalate, a rather mediocre nucleophile that would not compete with the internal double bond. As for the bromide source, triethylsilylbromide was chosen because it was soluble and relatively easy to handle. Using this combination of reagents allowed to selectively promote the carbocyclization process of various homogeranylbenzenes 9 and, after treatment of the crude with a strong acid, the desired tricyclic products 10 were isolated in moderate to good yields (Scheme 14).

Scheme 14 Iodine(III)/bromide induced cyclization of homogeranylbenzene derivatives.

The reaction conditions could also be applied to geranylaryl derivatives 4 to give snyderol type bromocyclohexenes 49a, b or, if an o-phenol moiety was present, to an isocymobarbatol 32 like bromo-hexahydroxanthene 50a (Scheme 15). Additionally, homofarnesyl derivative 34 could be converted into tetracyclic compound 35, albeit with a modest yield.

Scheme 15 Iodine(III)/bromide induced cyclization of geranyl and homofarnesyl substrates

Finally, it is worth noting that while this combination of reagents specifically promotes the polyene cyclization process, the use of other iodine(III) reagents with other bromides, 31 chlorides or iodides, 33 rather leads to various possible linear halogenated products in a selective fashion.

Use of N-Halo Amides

Activation with a phosphorus derivative

Phosphines

A considerable breakthrough in the field of halocyclization of polyenes came in 2007 when Ishihara described the iodo-and bromo-cyclization of benzyl-geranyl derivatives using a combination of the corresponding N-halosuccinimide with a nucleophilic promoter such as a phosphine. 34 In sharp contrast with what had previously been observed, 11 reacting homogeranyltoluene 9f with NBS or NIS in dichloromethane in the presence of 30% of tri-n-butylphosphine allowed, after acidic treatment, the isolation of the desired iodo-(36f) and bromo (10f) tricycles in good to quantitative yields (Scheme 16). Other phosphines and phosphites could also promote the reaction, with lower yields, but nucleophilic amines such as DBCO and DMAP were inefficient.

Scheme 16 Halocyclization with NXS promoted by a phosphine

Ishihara proposed that the nucleophilic activation of the Nhalosuccinimide by the phosphine would give phosphonium salt 52 as the actual halogenation species that would then react with the polyenic substrates 9 (Scheme 17). The close vicinity between the nucleophilic promoter and the halogen in the active species was considered determinant for the development of an asymmetric version of this reaction by the same authors (see dedicated section below). Setting the absolute configuration of haliranium 53 then induces the configuration of the stereogenic centers formed during the subsequent stereospecific cyclization process.

Scheme 17 Mechanism proposal for the nucleophilic activation of NXS

Phosphite-urea

The major drawbacks of Ishihara's protocol were the need for high catalyst loading (up to 100 mol% for the asymmetric variant) and the inferior (in terms of yield and ee) results

Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 8 of 17 obtained for the bromination reaction with NBS. 34 In order to overcome these limitations they later designed bifunctionnal phosphite-urea catalyst 54 (Scheme 18). 35 Its reaction with NBS or with the more reactive 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) would give complex 55 that would simultaneously bear the phosphonium bromide reactive center and sequestrate the imidate to prevent unwanted side-reactions. In particular, addition of the imidate onto the phosphonium would be detrimental since it would liberate bromides that might lead to the formation of the dibromo products.

Scheme 18 Dual activation of DBDMH with a phosphite-urea catalyst

This carefully designed system allowed to perform the reaction with a low catalyst loading (0.5 mol%) and a high efficiency for several homogeranylarenes 9, yielding the desired tricyclic products 10 in the 90% yield range after full cyclization in acidic conditions (Scheme 19).

Scheme 19 Bromocyclization with DBDMH and a phosphite-urea catalyst

These conditions were subsequently applied to 2geranylphenols to give isocymobarbatol-like bromohexahydroxanthenes. 36

Phosphoramidite

Shortly after Ishihara's report, McErlean disclosed the use of phosphoramidite (S)-TCPT (56) as a promoter for the monocyclization of various geranyl derivatives with NBS. 37 In toluene the reaction led to the cyclohexene derivatives as major product in all cases (Scheme 20). In contrast to BDSB (see Table 1), benzyl derivative 9b and acylgeraniols 11a, d afforded cyclohexenes 58b and 48a, d. Unfortunately, although the promoter is chiral, no optically active products could be isolated.

Scheme 20 Bromocyclization with NBS promoted by a phosphoramidite.

Activation with an amine

While Ishihara had shown that neither DABCO nor DMAP were suitable activators, the group of Yamamoto briefly reported that 2,4,6-trimethylaniline could promote the bromocyclization of 9b into 10b in 66% yield (after acidic treatment). 38 After this single example the group of Gulder recently showed that hexafluoroisopropanol (HFIP) had a dramatic positive effect for the halocyclization of polyenes using N-haloamides such as NBS (42% of 10b from 9b in HFIP vs 8% in DCM). Even better yields (78%) could be achieved in the presence of morpholine (as its HFIP salt). 39 Using this simple setting a broad range of polyenes could undergo bromocyclization with excellent yields that compare favorably with those obtained with BDSB (Scheme 21).

Scheme 22 Iodocyclization with NIS-morpholine in HFIP

One key feature of this morpholine-HFIP system is that it could also be applied for the chlorocyclization of polyenes, using 1,3dichloro-5,5-dimethylhydantoin (DCDMH) instead of NCS.

Although the scope and the yields are modest it represents a major improvement as until then only the CSDC was known to promote this type of chlorocyclization. In addition to the tricyclic chloro-products 43, previously obtained by Snyder, tetracycle 61 and oxygenated tricycle 62 could also be synthetized (Scheme 23).

Based on various mechanistic studies, the authors suggest several beneficial roles for the HFIP. First, as a strong hydrogen-bond donor it would stabilize the N-halo morpholine species, that was proposed as key reactive intermediate for halocyclization. Moreover, its high polarity would induce a prearrangement of the polyene through hydrophobic interactions. The apolar hydrocarbon chain would thus adopt a tight chair-like conformation, readily poised for cyclization.

Scheme 23 Chlorocyclization with DCDMH-morpholine in HFIP

Asymmetric Reactions

The direct halonium-induced cyclization of polyenes already a challenge se, rendering this transformation enantioselective was even more arduous. 40 Despite many accomplishments for the asymmetric halofunctionalization of alkenes, [START_REF] Kuester | [END_REF] including cyclizations [START_REF] Che N | speci fically on this topi c[END_REF] and dihalogenation, [START_REF] Eey | For key reviews specifi cally on this topic, se e: (a ) Cres swell[END_REF] the asymmetric cyclization of polyenes remained elusive until 2007 and the work of Ishihara. 3444

Ishihara's strategy

Iodocyclization

After successfully devising conditions to activate NIS with a phosphorous nucleophile for the direct iodocyclization of polyene, the group of Ishihara went further by probing chiral inductors for the asymmetric version.

Scheme 24 Asymmetric iodocyclization of polyenes.

A binol-derived phosphoramidite 62 was found to be the best promoter. Using one equivalent of 62 in combination with NIS in toluene, tricycles 36b, c, k and tetracycle 63 were obtained in good yields (after acidic treatment) and with enantiomeric excesses up to 99% (Scheme 24). As mentioned previously, Ishihara's mechanistic proposal stated that a phosphonium salt is the actual halogenation species. In toluene, reaction between NIS and promoter 62 would give a tight ion pair 64 which can be represented as 64' in Newman projection along the P-I bond (Figure 1). In this view, three segments of space can be delimited depending on steric hindrance. Iodination of the most reactive prenyl double bond, within the least hindered space would take place by a Si-face approach leading to the observed Sconfiguration in the final product. The subsequent stereocenters would be set during the following stereospecific cyclization process, whether it directly happens during the course of the reaction or only after treatment with a strong acid.

Bromocyclization

After successfully rendering the bromocyclization of polyenes catalytic by using a phosphite-urea bifunctionnal catalyst (54, Figure 2), the group of Ishihara reported an enantioselective version of their strategy. 45 The catalyst backbone of 54 was expanded from a bi-phenyl to a bi-naphthyl and the 3,5diphenylphenyl substituents were exchanged for 3,5dipentafluorosulfanylphenyl groups (65). Using 10 mol% of this catalyst 65 with N-bromophthalimide NBP (instead of the succinimide), cyclization of 2geranylphenols 66a-f afforded the monocyclized bromocyclohexenes 67a-f in good yields and moderate ee (Scheme 25). Tricycles 50a-e, 57 were also formed in the reaction and isolated in significantly lower yields and enantiomeric excess.

Scheme 25 Asymmetric bromocyclization of geranylphenols

However, when the monocyclic compounds 67 were converted to the tricyclic products 50, using triflic acid at low temperature in i-PrNO2 the enantiomeric excesses remained unchanged. This observation led the authors to assume that the single cyclization and the cascade cyclization did not arise from the same process, and the transition states involved were likely to be different. The major process, i.e. the monocyclization, would occur via TSmono (Figure 3). In this transition state, an H-bond is established between the phenol and the urea moiety. This stabilizes the TS and precludes O-cyclization, favoring the formation of the enantioenriched monocyclized product. The tricyclic products were proposed to arise from the less stable TScasc, where no hydrogen bond is present and the phenol is thus more nucleophilic.

Yamamoto's Strategy

Ten years after Ishihara's group initial report 34 and taking cues from subsequent studies, 35,36 the group of Yamamoto was eventually able to devise a suitable catalyst for the asymmetric bromocyclization of polyenes. 46 After optimization, binol-based thiophosphoramide 68 was selected as the best catalyst in combination with DBDMH (Figure 4). As with Ishihara's phosphite-urea catalyst, a dual activation of the halogenation reagent was postulated. However, here the Lewis base is the sulfur and not the phosphorous whilst the Brønsted acid is the triflimide. The Lewis basicity of the sulfur is essential as the analogous phosphoramide gave low yield and no selectivity. Additionally, both key moieties are located in close vicinity and inside the chiral pocket that is delineated by the large aromatic groups in the ortho positions of the binol backbone. Using only 5 mol% of catalyst 68 with DBDMH promoted the cyclization of homogeranylarenes 9 leading, after acidic treatment in most cases, to the brominated tricycles 10 with yields ranging from 44% to 98% and enantiomeric ratios up to 97:3 (Scheme 26).

Scheme 26 Asymmetric bromocyclization of homogeranylarenes

When the same reaction conditions were applied to geranylbenzene, a mixture of endo-and exo-monocyclized products 49a and 49a' were obtained in 82% combined yield and 84% ee for the former and only 26% ee for the latter (Scheme 27). In sharp contrast to what was observed by Ishihara with his phosphite-urea catalyst (Scheme 25), when applied to geranylphenols these conditions favor the formation of tricyclic products 50 with moderate to good yields and good enantiomeric excesses.

Scheme 27 Asymmetric bromocyclization of various polyenes

Moreover, for the substrate bearing a 2,4-dimethoxyphenol moiety, the intermediate carbocation was trapped by a C-C bond of the aromatic ring, yielding [6,5,6]-fused tricycle 69 rather than the corresponding oxygenated [6,6,6]-fused system.

Total Synthesis of Halogenated Natural Products

From the onset, the goal of the research on the halocyclization of polyenes was to mimic Nature in order to access structurally complex molecules. Thus, numerous efforts have been devoted to apply this strategy for the total synthesis of natural products incorporating halogen atoms. [START_REF]For seminal and rece nt reviews covering some aspe cts of this se ction[END_REF]

Using NBS

In 1977, the group of Gonzales started their synthesis of snyderol by cyclizing methyl farnesate 6 into diene 8 in 12% yield using NBS with copper(II) acetate (Scheme 28). 48 Reduction of the ester and bromination of the resulting allylic alcohol led to 70 that was then converted into snyderol by an aqueous acidic treatment.

Scheme 28 First total synthesis of snyderol using NBS In 2014, McErlean undertook the synthesis of luzofuran, isolated from the red alga Laurencia luzonensis. 49 Phosphoramidite (S)-TCPT (56) was used to promote the bromocyclization of enantioenriched furanic alcohol 71 with NBS to directly access (+)-luzofuran (Scheme 29, eq.1). 50 The latter was obtained alongside minor amount of its epimer 72, which could in turn be transformed into (-)-ancistrofuran (itself isolated from the defensive secretions of the West African termite Ancistrotermes cavithorax 51 ) by debromination (Scheme 29, eq. 2).

Scheme 29 First total synthesis of Snyderol using NBS

Although the target compounds were effectively obtained, both examples show the poor performance of NBS, even in the presence of a promoter, for bromo-carbocyclizations.

Scheme 30 Total synthesis of aplysistatin using TBCO for the key bromocyclization Hence, many groups turned their attention towards specially designed reagents such as TBCO or BDSB to improve the efficiency of the key cyclization step.

TBCO

To synthetize (-)-aplysistatin, an antineoplastic isolated form the sea hare Aplysia angasi, 52 Prestwich used TBCO as the promoter for the key bromocyclization. 53 Cyclization of enantioenriched geranyl-γ-butyrolactone 73 with TBCO led to the desired tricycle 74 and its bromo-epimer in a combined 12% yield (Scheme 30). This mixture was then converted into (-)aplysistatin (and its bromo-epimer) by a selenation/oxidation/ elimination sequence in 93% yield. The pure natural product could be isolated from the epimer-mixture by HPLC. Although the yield of the cyclization is rather low and the desired diastereoisomer is the minor one formed, this route is, nevertheless, rather straightforward and avoids the use of stoichiometric amount of toxic mercury salt as previously reported by Hoye for the racemic synthesis of aplysistatin. 54 A TBCO-promoted bromocyclization was used by the group of Kato as the key step for the total synthesis of a series of molecules. In 1985, they reported the synthesis of both concinndiol 55 and aplysin 20 56 from a common precursor (Scheme 31). 57 Using acetonitrile as the solvent favored the cyclization of geranylgeranate 75 initiated by TBCO and gave brominated bicylic product 76 in 20% yield (along with 30% of the monocyclic product). Epoxidation of the endo-cyclic double bond led to a 2:1 mixture of isomers 77:78 (Scheme 31, eq. 1). 77 was selectively reduced with aluminum hydride to the corresponding allylic alcohol 79 which was converted into concinndiol in three steps (Scheme 31, eq. 2). Longer exposure to aluminum hydride of the other diastereoisomer 78 triggered the reduction of the ester and the opening of the oxirane to give aplysin-20 in one step (Scheme 31, eq. 3).

A slightly modified strategy was then used for the total synthesis of pinnatol D 58 and isoconcinndiol. 59 Starting from farnesyl derivative 79, TBCO-promoted bromocyclization gave a complex mixture out of which the desired bicyclic product 80 could be isolated in 30% yield as a 1:1 mixture of isomers (Scheme 32, eq. 1). 60 Both the benzoate and the methyl ester were reduced to furnish the two corresponding diastereoisomeric diols, that were separated by chromatography. From diastereoisomer 81, pinnatol D could then be attained by a Grieco elimination. From pinnatol D, epoxidation followed by reduction with aluminum hydride gave conncindiol. Alternatively, after protection of the diol, regio-and stereo-selective hydroboration of the endocyclic double bond followed by oxidation installed the tertiary alcohol of 82 (Scheme 32, eq. 2). Finally, a Grieco elimination was then performed to access isoconcinndiol. In order to access cyclocymopol, 61 Tanaka used TBCO on dimethoxypheny-geranyl derivative which led to the desired methylenebromocyclohexane 67g in 35% yield (Scheme 33). 62 Removal of both methyl groups was carried out in a sequence, starting with silver-mediated oxidation into a benzoquinone that was reduced with sodium hydrosulfite to give cyclocymopol in 20% yield. The TBCO-promoted bromocyclization protocol was applied to the analogous di-MOM-protected geranyl derivative 38. 63 Scheme 31 Total synthesis of concinndiol and aplysin 20 using TBCO for the key bromocyclization Scheme 32 Total synthesis of pinnatol D and isoconcinndiol using TBCO for the key bromocyclization Scheme 33 Total synthesis of cyclocymopol and isocycmobarbatol using TBCO for the key bromocyclization

In this case, concomitantly with the loss of a MOM group, tricyclic product 83 was obtained in 40% yield. Acidic cleavage of the remaining protecting group led to isocycmobarbatol 32 in near quantitative yield.

BDSB

The development of BDSB by Snyder opened promising perspectives for targeting brominated natural products as first exemplified by its use for the synthesis of isocymobarbatol. 21 Compared to TBCO, BDSB proved to be far more efficient since the bromocyclization of compound 38 took place in only five minutes to give 83 with 74% yield (Scheme 34).

Scheme 34 Total synthesis of isocycmobarbatol using BDSB for the key bromocyclization Shortly after, Snyder undertook the total synthesis of peyssonol A, 64 whose relative configuration was unambiguously assigned by performing the same synthetic sequence starting from different trienes. 23 The actual peyssonol A was obtained starting from triene 84 that was submitted to the action of BDSB to give tricyclic carbonate 85 in 56% yield (Scheme 34, eq. 1).

Methanolysis followed by oxidation of the primary alcohol and elimination of the tertiary alcohol led to decaline 86 in 76% yield. The synthesis was completed by adding the aryl moiety as its lithium derivative followed by reduction of the benzylic alcohol, formylation and acidic cleavage of the MOM groups, furnishing peyssonol A in a 15% overall yield. In addition to the various isomers that were synthetized, a iodo-analogue was constructed using IDSI instead of BDSB and all the synthesized compounds were evaluated for their HIV-1 inhibition properties. 65 To access peyssonoic acid A, 66 a slightly different approach was chosen and the bromocyclization was performed on triene 87 that already incorporated the aryl moiety (Scheme 35, eq. 2). This gave tetracycle 88 in 31% yield with a good chemoselectivity since the allyl group was untouched. The later was then fully oxidized to the carboxylic acid, then treatment with boron trichloride cleaved both ethers to deliver peyssonoic acid A. Snyder also disclosed the utility of BDSB to access various bromo-chamigrenes derivatives, albeit unnatural ones. 67 Krauss, decided to use BDSB on macrocylic triene 89 to trigger a transannular bromocyclization, via bromiranium 90, to access bromophycolides 68 derivatives (Scheme 36). Macrocycle 89 was obtained as the S-enantiomer (ee 92%) using a regiospecific Sharpless asymmetric dihydroxylation and a Shiina macrocyclization as the key steps. 69 When submitted to BDSB in a highly polar media (addition of aqueous 1 M LiClO4 to the solvent) the major products obtained were allylic bromides 91 and 91'.

Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 14 of 17

Scheme 35 Total synthesis of peyssonol A and peyssonoic acid A using BDSB for the key bromocyclization

Yet, ca 20% of monocyclized compounds 92 and 93 were also obtained, the latter exhibiting a bromophycolides D skeleton with an exo-cyclic double bond. 68a Unfortunately, the authors were unable to form the bromohydrin on the remaining double bond embedded in the macrocycle, which would have completed the total synthesis.

Conclusion and Perspectives

In more than fifty years after the initial report of a direct bromocyclization of a polyene by Van Tamelen, tremendous improvements have been achieved. The development of reagents such as BDSB allowed to increase yields by tenfold, thus making these transformations sufficiently efficient to tackle the synthesis of complex compounds, including polycyclic halogenated natural products. Additionally, following the seminal report by Ishihara in 2007, catalytic enantioselective versions have also been developed. Nevertheless, the vast majority of literature on the topic deals with cyclizations whilst iodocyclization remains rare,chlorocyclization even more scarce, without mentioning the fact that a direct fluorocyclization of polyene has yet to be described. 70 Therefore, future developments should aim to overcome these limitations.

Scheme 9

 9 Scheme 9 Synthesis of BDSB.

Figure 1

 1 Figure 1 Mechanistic rationale proposed by Ishihara to explain the stereoinduction during asymmetric iodocyclization

Figure 2

 2 Figure 2 Ishihara's chiral phosphite-urea catalyst

Figure 3

 3 Figure 3 Comparison between mono-cyclization and cascade transition states

Figure 4

 4 Figure 4 Activation of DBDMH by a thiophosphoramide

Table 1

 1 Reactivity of BDSB with a variety of polyenes and comparison with other methods

	Entry	Starting material	Product	Conditions (reagent, solvent) Yield (reaction temperature) (time)

Table 2

 2 Reactivity of IDSI with a variety of polyenes

	Entry	Starting material	Product, yield Temp., Time

[a] Isolated as a 2:1 mixture of inseparable stereoisomers about the highlighted carbon atom favoring the drawn diastereoisomer.

[b]

MeSO3H (15 equiv.) added with 1 h of additional stirring to promote the final cyclization.

[c]

Produced as a 8.5:1.4:1.0 mixture of tri, tetra and disubstituted alkene isomers.

Table 3

 3 Reactivity of CDSC with a variety of polyenes

	Entry	Starting material	Product, yield Temp., Time

[a] Isolated as a 1.0:1.0 mixture of inseparable stereoisomers.

[b]

Isolated as a 2.2:1.0 mixture of separable diastereoisomers at the highlighted carbon favoring the drawn product.

[c]

Produced as a 4.0:1.0 mixture of separable diastereomers at the highlighted carbon favoring the drawn product.

  Similar to BDSB (Table1), tricycles 10 were directly obtained from the starting homogeranylarenes 9, the farnesyl derivative 34 being the only one that required an additional acidic treatment to form tetracyclic product 35 (Scheme 21).

	Synthesis	Review / Short Review
	Hexahydroxanthene 50a stemmed from the cyclization of o-
	geranylphenol with one equivalent of NBS whereas the reaction
	with two equivalents of NBS induced an additional bromination
	of the aryl ring (product 57). The reaction of geraniol esters
	gave the monocyclized tertiary alcohols 12a, e-h with good
	yields and stereoselectivities, while geranyl cyanide furnished a
	mixture of cyclohexenes (28). Finally, homogeraniol and
	homogeranic acid underwent a cascade cyclization to give
	tetrahydrofuran 58 and lactone 32, respectively.
	This method was readily extended to the analogous
	iodocyclization with NIS, giving the desired products with good
	yields and diastereomeric ratios up to 95:5 (Scheme 22).
	Homogeranylarene substrates directly yielded the tricyclic
	compounds 36 while o-geranylphenol gave iodo-
	hexahydroxanthene 59. Following the general trend observed
	for bromocyclization, geranyl esters gave tertiary cyclohexanols
	41a, g and geranylcyanide gave cyclohexene 40. If an internal
	nucleophile is present, a cascade cyclization takes place giving
	an additional oxygenated ring, either a carbonate (60) or an
	ether (61).
		Scheme 21 Bromocyclization with NBS-morpholine in HFIP

Template for SYNTHESIS © Thieme Stuttgart • New York 2019-10-07 page 9 of 17

Acknowledgment A. C. D. thanks Labex Lermit for a postdoctoral fellowship, L. P. thanks University Paris Saclay for a PhD fellowship and T. D. G. thanks ICSN for a PhD fellowship. Drs R. H. Dodd and J. Dubois (ICSN) are warmly thanked for their contribution to the group's research in this field. Scheme 36 Synthesis of the bromophycolide D skeleton using BDSB for the key transannular bromocyclization

Funding Information

CNRS, ICSN, Labex Lermit (ANR grant ANR-10-LABX-33 under the program Investissements ANR-11-IDEX-0003-01) and University Paris Saclay.

Biosketches


Keywords: ketenimines, ynamides, rearrangement, cycloaddition, building blocks

Using ynamides as readily available starting materials, a single step can generate highly reactive ketenimines which can then undergo a variety of transformations. The choice of the method for generating the ketenimine dictates the outcome of the reaction that can, moreover, be precisely steered through minor variations of the starting material. This Concept gives an overview of the different existing methodologies for this objective, showcasing the diverse nitrogen-containing frameworks that can be obtained by this highly versatile strategy.

Introduction

Ketenimines, 1 like ynamines, 2 are a particularly attractive subclass of unsaturated nitrogen-containing compounds which can serve as versatile building blocks to incorporate an N, C, C triatomic moiety. Both families share some similarities, such as a strong polarization of the carbon backbone or the central sphybridized carbon and, eventually, ketenimines can be viewed as tautomers of secondary ynamines. This was first demonstrated by the work of Wentrup in the early 80s. 3 In this seminal study, 3a he showed that flash vacuum pyrolysis (FVP) of methylisoxazolone 1 led to N-ethynylaniline 2 which tautomerized to Nphenylketenimine 3 (Scheme 1). While this study illustrated how ynamines could be transformed into ketenimines it also showed how unstable these compounds are. Indeed, neither 2 nor 3 were isolated and both could only be characterized by IR spectroscopy at low temperature (-196 °C and -70 °C, respectively). After workup only N-acetylaniline 4, resulting from the hydrolysis of 3, was isolated.

Scheme 1. Generation of ynamines by FVP, followed by isomerization to ketenimine.

Yet, while ynamine chemistry has witnessed a tremendous increase in interest from the synthetic community over the last 20 years or so, ketenimines remain rather exotic and underemployed substrates despite their synthetic potential. 1 This can be partly explained by the relatively small number of existing methods to generate them. In contrast, for ynamines, by focusing on the more stable subclass of ynamides, 4 many robust and general methods have been developed, allowing access to an ever-increasing range of derivatives. Compared with ynamines, the electron-withdrawing group on the nitrogen of ynamides improves the stability without overly hampering the reactivity. This can be viewed as a particularly seductive entry into ketenimine chemistry since, starting with a readily available ynamide, one single synthetic operation should be sufficient to convert it into a ketenimine (Scheme 2).

Scheme 2. Generation of ketenimines from ynamides. This Concept will give the reader a panorama of the methods that start from preformed ynamides to generate ketenimines and their subsequent transformations. Depending on the mode of generation of the intermediate ketenimine various mechanistic pathways can be triggered or shut down and particular attention will be given to present the key steps and how they influence the outcome of the reactions.

Thermal Rearrangements

Twenty-five years after Wentrup's pioneering study of ynamines, the first thermal rearrangement of an ynamide into a ketenimine was reported by the group of Wudl. 5 By heating compound 5 at 120 °C, N to C migration of the p-tosyl group yielded ketenimine 6 (Scheme 3). The latter could thereafter evolve towards tertiary nitrile 7 through a second N to C migration, this time of the PMB group, or be hydrolyzed to yield amide 8. Scheme 3. Thermal rearrangement of sulfonylynamides into ketenimines.

Similar results were obtained by the Hsung group for the thermal rearrangement of N-allylsulfonylynamide 9, 6 although in this particular case the allyl group is the first one to migrate through an aza-Claisen rearrangement (Scheme 4). The outcome of this process is particularly dependent on the nature of the R group. In the case of a phenyl group (9a) or a protected primary alcohol (9b), the intermediate ketenimine 10 eventually converges towards the corresponding tertiary nitrile 11 by a 1,3-sulfonyl shift (Scheme 4, eq.1). However, a TIPS substituent brings enough 4, eq.2). Under prolonged heating, desilylation of the ketenimine occurs thus triggering its rearrangement into secondary nitrile 11d (Scheme 4, eq.2).

Scheme 4. Aza-Claisen rearrangement of N-allylsulfonylynamides into ketenimines.

Following these initial findings, Hsung further exemplified both the amidine synthesis (with primary and secondary amines) and the nitrile formation (with diverse substitution patterns on the starting ynamide). 7 During this latter study, it was also shown that for suitably poised carboxy-substituted ynamides 9e,f a tandem aza-Claisen/[3,3]-sigmatropic rearrangement reaction could take place to yield imidates 13 (Scheme 5).

Scheme 5. Tandem aza-Claisen/[3,3] sigmatropic rearrangement.

The same author showed that the synthesis of imidate can also be carried out in an intermolecular fashion by prolonged heating of a highly diluted alcohol solution of ynamides (Scheme 6). 8 Use of the alcohol as the solvent was necessary to suppress the 1,3sulfonyl migration that would lead to the corresponding nitriles.

Another strategy devised by the Hsung group to prevent the 1,3shift and explore further synthetic opportunities was to replace the sulfonyl group by a phosphoryl group. 9

Scheme 6. Intermolecular imidate synthesis.

Thus ynamide 15 bearing a neopentylglycol-derived cyclic phosphoramidate moiety could react thermally to give ketenimine 16 which then furnished azetidinimine 17 after a [2+2] cycloaddition with an imine (Scheme 7).

Scheme 7.

Use of an N-phosphorylynamide for the synthesis of an azetidinimine.

Taking advantage of the relative stability granted to the ketenimine intermediate by the N-phosphoryl moiety, a series of carbocyclization cascades leading to intricate structural motifs was developed. 10 First, it was demonstrated that ketenimine 16 was sufficiently electrophilic that a carbocyclization to cyclopentenyl zwitterion 17 could take place (Scheme 8 In this case, the Wagner-Meerwein methyl shift was not operative and deprotonation gave enamine 22 (as a 1:1 mixture of tautomers) with an excellent overall yield. Quite interestingly, bubbling air into a solution of 22 in chloroform for three days gave access to diketone 24, presumably via fragmentation of endoperoxide 23 that results from a [4+2] cycloaddition with oxygen. 10 For ynamide 25 bearing a vinylidenecyclobutane moiety, the aza-Claisen/carbocyclization sequence led to spiro-zwitterion 27 possessing enough ring strain for the 1,2-alkyl shift to take place, furnishing cyclic imine 28 with 84% yield (Scheme 10). 10 Scheme 10. Carbocyclization/ring expansion cascade.

Other complex ring expansions cascades have been developed but, perhaps, the most spectacular results in terms of structural complexity generation came from geranylamine-derived ynamide 29. After initial isomerization to ketenimine 30, two carbocyclizations take place to give bicyclic zwitterion 32 (Scheme 11). The latter can then either evolve through simple elimination to give 33 or through a third carbocylization to give caged tricycle 34 which exhibits four contiguous stereocenters and three all-carbon quaternary centers. Both compounds were isolated as single diastereroisomers with an almost quantitative combined yield. 10

Metal-Catalyzed Rearrangements

Hsung and coworkers not only explored the thermal aza-Claisen rearrangement of N-allyl ynamides but also extensively studied their behavior in the of transition metals. The cornerstone of this chemistry was the demonstration that upon treatment with a Pd(0) complex, oxidative addition into the N-allyl bond led to ynamide-π-allyl complex 35 that lies in equilibrium with ketenimine-π-allyl complex 36 (Scheme 12). 11,[START_REF] Cassidy | The formation of ketenimines from N-metallated ynamides via a Cmetallated ketenimine was developed by Fokin and used for the synthesis of amides: a)[END_REF] The latter could then react in a variety of ways. In their first study, trapping with a primary or secondary amine was considered. Initial addition (37) followed by tautomerization would give amidinyl πallyl complex 38 (Scheme 13). Reductive elimination eventually led to amidine 39, 28 examples of which were prepared. When an excess of the amine was used, a competitive pathway could take place. Thus, deallylation gave palladium hydride 40 and, after reductive elimination, amidine 41 in which the allyl group was not transferred.

Scheme 11. Cationic polyene cascade. This pathway could be suppressed by adjusting the reaction conditions (slow addition of the amine and use of a ligand such as X-Phos or Xantphos that favors reductive elimination before the deallylation). 11 The scope of the deallylative amidine formation was then further exemplified for both primary (8 examples, 30% -95% yields) and secondary (20 examples, 37% -95% yields) using PdCl2(PPh3)2. 7Scheme 13. Trapping of the ketenimine π-allyl complex with an amine.

The case of TIPS-substituted ynamide 9c is noteworthy for how it showcases the influence of the Pd-complex on the course of the reaction after the formation of intermediate 36 (Scheme 14). 11 Using Pd2(dba)3 with Xantphos favored the reductive elimination and therefore the formation of ketenimine 10c obtained with a near-quantitative yield thanks to the silyl group's stabilizing effect. In contrast, using Pd(PPh3)4 as catalyst with a phenol additive ultimately led to the formation of cyclopentenimine 42. 6 The authors showed that the formation of the 5-membered ring did not stem from ketenimine 10c and proposed a series of elementary steps from π-allyl complex 36 to account for its formation. A Pd-[3,3]-sigmatropic rearrangement of the η 1 -form of 36 would yield a palladium carbenoid that can be neutralized by the addition of the phenol. Aza-Rautenstrauch cyclization followed by βelimination and tautomerization would then give cyclopentenimine 42. Scheme 14. Pd-Catalyzed synthesis of ketenimine and cyclopentenimine. This strategy could be extended to a broad range of γ-branched ynamides 43, readily accessible from the parent free ynamide and the corresponding aldehyde. 13 Submitting these to Pd(PPh3)4 catalysis gave a dozen cyclopentenemines 45 with moderate to excellent yields through the aza-Claisen/aza-Rautenstrauch sequence (Scheme 15). Along with their exploration of the Pd(0)-catalyzed formation of amidines, Hsung also designed a vinylogous amidine synthesis. 7 Instead of trapping the intermediate Pd-ketenimine with an amine nucleophile, an enamine was used, resulting in the formation of imino-enamines 46 (Scheme 16). The yields are generally good although in some cases the reaction follows the deallylative pathway.

Scheme 16. Vinylogous amidine synthesis.

Base-Mediated Transformations

Acidic or electrophilic activation of ynamides can give birth to keteniminium ions which have recently witnessed a surge in attention by the synthetic community due to their high electrophilicity and broad reactivity. 14 Much less explored but equally promising is the anionic activation of ynamides to generate ketenimines, [START_REF] Evano | review specifically covering the anionic chemistry of ynamides[END_REF] usually through a reaction at the electron-withdrawing group under basic conditions.

Evano's group has developed efficient procedures to access ynimines, a particular class of ynamides for which the stability is provided by the imino substituent, and subsequently explored their unusual reactivity. They showed that adding an organolithium on ynimine 47 generates ynamide/ketenimine lithium anion 48/49 (Scheme 17), which can then evolve following three distinct reaction pathways. 16 Scheme 17. Carbolithiation of ynimines.

the starting ynimine is substituted by a silyl group (47a), trapping an alkyl halide leads to ketenimines 50 that, as previously observed by Hsung, 11 are stable enough to be isolated with good yields (Scheme 18). 16 Scheme 18. Synthesis of stable silyl-ketenimines.

The outcome is different when the starting ynimine is substituted by an aryl group (47b, Scheme 19). In this case, ketenimine 50 is no longer stable enough to be isolated and homolytically fragments to ketenimine radical 51 and the highly stabilized tertiary radical 52. The latter can recombine with the more stable captodative radical 51' to furnish nitrile 53. The whole dichotomy between silyl-and aryl-substituted ketenimine that can, respectively, be isolated or collapse to the corresponding nitrile is in total agreement with the previous observations of Hsung for the aza-Claisen rearrangement of N-allyl-ynamides. The third reaction pathway requires the use of silylated ynimine 47a as the starting material and of an aldehyde as the electrophile (Scheme 20). Addition of the ketenimine anion to the aldehyde yields ketenimine 54 bearing a β-silyl alkoxide moiety that can undergo a Peterson elimination. This olefination results in the formation of aza-cumulene 55, which, after hydrolysis, delivers α,β-unsaturated amide 56. 16 Scheme 20. Peterson olefination/hydrolysis to give conjugated amides.

Finally, ynimines 47' bearing an alkyl group were subjected to potassium bis(trimethylsilyl)amide to give potassium anion 57 (Scheme 21). Hydrolysis led to transient enamidyl-ketenimine 58 which, according to the authors' proposal, would fragment to a ketenimine radical (59) and a styryl radical (60). Recombination of the latter with α-nitrile radical 59' then gives mixtures of nitriles 61 and 62 with moderate combined yields. If R is an aryl (paramethoxyphenyl) group, then a 3 : 1 ratio of the allylic (61) and conjugated (62) nitriles is obtained. If R is an alkyl (cyclohexyl) group, an E,Z mixture of conjugated nitrile 62 is observed. 16 Scheme 21. Synthesis of stable silyl-ketenimines.

Anionic conditions can also be used to remove the electronwithdrawing group of the ynamide that will eventually generate the corresponding ketenimine. This approach has been simultaneously developed by the groups of Cao and of Dodd & Cariou using different types of starting ynamides. In order to facilitate the cleavage of the protecting group Cao studied the behavior of bis-phenysulfonyl ynamides 63 in the presence of an excess of amine (Scheme 22). [START_REF] Kong | For the original synthesis of bis-sulfonyl ynamides see: b)[END_REF] A first equivalent of amine deprotects the ynamide to give ketenimine 64 which reacts with a second equivalent of amine to give amidine 65. The reaction conditions are remarkably mild although the process is sensitive to steric hindrance on the amine partner, presumably for the initial sulfonyl cleavage step.

Scheme 22. Sulfonyl cleavage followed by nucleophilic addition.

Following up on their initial report, Cao implemented a similar reaction with aldehydes (Scheme 23). 18 A lithium alkoxide base was used to trigger the formation of a ketenimine anion 66 which then added to an aldehyde to give lithium alkoxide 67. The authors propose that this intermediate evolves through intramolecular addition to the ketenimine to give oxetene 68. Conrotatory ring opening followed by hydrolysis then gives rise to α,β-unsaturated amide 69. Contrary to the case of silylated ynamide developed by the Evano group, the Peterson elimination cannot take place here yet the outcome is similar. An interesting variation was also described when the aldehyde is a salicylaldehyde derivative. In the presence of triethylamine, a first equivalent reacts as a phenol to initiate the formation of ketenimine 64 (Scheme 24). Addition to the carbonyl moiety of a second equivalent would yield alcohol 67' which could cyclize on the ketenimine moiety through the phenol to give iminocoumarin 71 after dehydration of bicycle 70. 18 An alternative pathway from 64 to 71 would involve the addition of the phenol followed by cyclization of the resulting enamide on the aldehyde.

Scheme 24. Synthesis of iminocoumarins through a formal [4+2] cycloaddition.

For their part, Dodd and Cariou studied the reaction between indoles and unsubstituted ynamides 72 under basic conditions (Scheme 25). 19 Using sodium tert-butoxide in dimethylformamide triggered the cleavage of the electron-withdrawing group to give phenylketenimine 3, presumably through the intermediacy of sodium indolide as the nucleophile. [START_REF]indole which is then deprotected to give the indolide again[END_REF] Scheme 25. of indolic amidines.

Addition of the anion to the ethenimine then led to indolic amidine 73 in good yields that vary depending on the nature of the electron-withdrawing group.

In order to further expand the potential of this straightforward access to phenylethenimine, Dodd and Cariou sought to trap it in a [2+2] cycloaddition. [START_REF] Romero | [END_REF] Subjecting N-tert-butylcarbamate ynamide 74 to lithium tert-butoxide in dimethylformamide in the presence of an imine under microwave heating led to azetidinimines 76 in moderate to good yields (Scheme 26). This imino-Staudinger synthesis using arylethenimines 75 is complementary to Fokin's method that provides N-sulfonyl-azetidinimines. 12b The compounds obtained can also be further functionalized to access more complex scaffolds, using cross-coupling reactions (Scheme 26, Eq. 1 to give biaryl azetidinimine 77) or strongly acidic or reductive conditions (Scheme 26, Eq. 2, trifluoroacetic acid giving free acid 78 and lithium aluminum hydride yielding benzylic alcohol 79).

Scheme 26. Synthesis of azetidinimines through a [2+2] cycloaddition.

Summary and Outlook

Overall, the use of ynamides as bench-stable feedstock to access ketenimines is a convenient strategy to tame their instability while taking advantage of their reactivity. This is particularly useful to initiate cascade processes such as tandem sigmatropic rearrangements which, as demonstrated by Hsung, can take place through thermal or metal-catalyzed pathways. Using this approach, ionic or radical manifolds can be operative and unusual scaffolds, that would be difficult to prepare otherwise, are within reach. Yet this probably represents only the tip of the iceberg as the chemistry of ketenimines is richer than that summarized in this Concept. Of particular interest for further studies in the field will probably be the implementation of asymmetric variations of these transformations, a challenge which has yet to be taken up.

  des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay Avenue de la Terrasse, 91198 Gif-sur-Yvette, France E-mail: kevin.cariou@cnrs.fr stabilization to allow isolation of ketenimine 10 or its trapping by nucleophilic addition with pyrrolidine to give amidine 12 (Scheme

Scheme 12 .

 12 Scheme 12. Pd-Catalyzed rearrangement of N-allyl ynamides into ketenimines.

Scheme 15 .

 15 Scheme 15. Aza-Claisen/aza-Rautenstrauch sequence.

Scheme 19 .

 19 Scheme 19. Homolytic fragmentation/recombination to give nitriles from ketenimines.

Scheme 23 .

 23 Scheme 23. Oxetene formation/ring opening to give conjugated amides.

Acknowledgements

The authors thank CNRS, ICSN, Labex Lermit (ANR grant ANR-10-LABX-33 under the program Investissements d'Avenir ANR-11-IDEX-0003-01) and University Paris Saclay for financial support. Drs A. Hentz, C. Minard, S. Ventre, M. Benchekroun, E. Romero, P. Retailleau and Prof. Dr V. Gandon are warmly thanked for their contribution to the group research in this field. Frontispiece illustration: © E. Menneteau, CNRS-PRC 2017.

CONCEPT

Entry for the


Tatyana Grayfer

Pascal Retailleau

Robert H Dodd

Joëlle Dubois

Kevin Cariou

Chemodivergent, Tunable, and Selective Iodine(III)-Mediated Bromo-Functionalizations of Polyprenoids

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Chemodivergent, Tunable and Selective Iodine(III)-Mediated Bromo-functionalizations of Polyprenoids.

Tatyana D. Grayfer, Pascal Retailleau, Robert H. Dodd, Joëlle Dubois and Kevin Cariou* Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.

Supporting Information Placeholder

ABSTRACT: Mild oxidation of bromides by iodine(III) reagents generated active electrophilic bromination species that were reacted with polyprenoids. By simple and minor variations of an I(III)/Br combination the reactivity could be selectively steered toward dibromination, oxybromination or bromocyclization, giving access to a wide array of brominated motifs. Brominated terpenoids of marine origin constitute a particularly wide class of natural products that exhibit a vast array of structural diversity 1 and potential therapeutic applications. 2 A myriad of motifs, arising from diverse biosynthetic pathways, 3 can be found in different families and sometimes in the same molecule. For example, just considering the brominated moieties of the bromophycolide A 4 macrocycle (1, Figure 1), fragments arising from a carbobromination, a hydroxybromination and an acyloxybromination (with the opposite regiochemistry) of a geranyl-geranyl chain can be delineated. A carbobromination accounts for the formation of cyclocymopol 2 5 but in this case the double bond lies out of the ring. Isocymobarbatol 3 6 stems from the same linear precursor but through a formal cascade cyclization, resulting in a tricyclic scaffold. This variability could be explained by the intermediacy of one or several halogenating enzymes, 3 but raises complex chemo-, regio-and stereoselectivity issues, which remain challenging for organic chemists. One way to address this challenge is to design specific reagents for one transformation, as shown by Snyder with the development of bromocyclization specific BDSB reagent. 7,[START_REF] Sakakura | For other strategies aimed at the halocyclization of polyenes, including asymmetric versions see[END_REF] Figure 1 Examples of brominated terpenoids of marine origin.

For our part we thought that it would be highly desirable to design a general strategy that would demand only limited modifications of the modus operandi to completely deviate the reactivity in one or another chemical direction. Based on our previous experi-ence 9 with iodine(III)-mediated bromination reactions 10 we believed that when generating the active bromination species by in situ oxidation of a bromide by a hypervalent iodine(III) species 11 several parameters would be easily tunable so as to govern the selectivity of the reaction. Thus, running the reaction in a non-participating solvent in the absence of external nucleophile should favor bromocyclization 9d towards bromocyclohexenyl 5 (Scheme 1, eq 1), while adding an alcohol to the reaction mixture would trigger an oxybromination 9a towards alkyl-bromohydrine 6 (Scheme 1, eq 2).

Scheme 1 Chemoselective iodine(III)-mediated bromination of a geranyl derivative.

Initial experiments were performed on geranyl acetate 4a using a combination of (diacetoxyiodo)benzene (DIB) and lithium bromide in acetonitrile, which led to dibromo derivative 7a with 91% yield (Scheme 2). Running the same reaction in ethanol or in a water/acetonitrile mixture triggered the oxybromination process yielding ethoxy-and hydroxy adducts 6a and 6a', respectively, with satisfying yields. This reactivity switch validated the second half of our premise but despite extensive screening, 12 geranyl acetate, because of the deactivation of the internal double bond, seemed unsuitable to probe the triggering of the cyclization process.

Scheme 2 Solvent effect in the DIB-mediated bromination of geranyl acetate.

In order to circumvent this hurdle, we decided to focus our attention on the reactivity of the electron-rich homogeranylbenzene 4b (Table 1), that has been shown to cyclize more readily towards mono-(5b) and/or tricyclic (8b) adducts under a variety of conditions. 7,[START_REF] Sakakura | For other strategies aimed at the halocyclization of polyenes, including asymmetric versions see[END_REF] The crude reaction mixture (5:2:1 ratio of tetra-, tri-, disubstituted olefins) was recyclized without purification. i Recyclization with MeSO3H, dr = 6:1.

We therefore screened numerous parameters 12 in order to generate the initial bromonium intermediate 9b and selectively orientate its evolutions towards one of the many possible adducts (5-8, 10 and 11). 13 As with geranyl acetate, the combination of DIB and LiBr in MeCN, mainly led to dibromo compound 7b in 63% yield (Table 1, entry 1). 14 Halving the amount of bromide and adding it slowly as the last reagent in order to prevent dibromination only led to a decrease in yield, without changing the reaction course (Table 1, entry 2). However, using this protocol and replacing the DIB by its trifluoroacetoxy analog (PIFA) diverted the reactivity toward bromocyclization giving 5b (as a mixture of isomers) and tricycle 8b in a 39% cumulated yield (Table 1, entry 3). This result could be further improved by using the more soluble TMSBr to give 41% of 5b and 15% of 8b (Table 1, entry 4). Treatment of the mixture of brominated cyclohexenes 5b with chlorosulfonic acid in 2-nitropropane at -78°C 7,8 to give 8b led to a cumulated yield of tricyclic adduct of 46%. Increasing the addition time (Table 1, entry 5) or exchanging trimethylsilylbromide for triethylsilylbromide (Table 1, entry 6) mostly led to complex mixtures of adducts, including allylbromide 10b and cyclopentene 11b. 13 When alkylammonium bromide salts were used, the acyloxybromination pathway was also observed (Table 1, entries 7 and 8), with 6b becoming the major product when tetrabutylammonium bromide was employed (Table 1, entry 8). This could be further improved by increasing slightly the concentration and the addition rate, to obtain 60% of 6b (Table 1, entry 9). Running the reaction in nitromethane with TESBr steered the reactivity back towards cyclization (Table 1, entry 10) and using the bulkier bis(tert-butylcarbonyloxy)iodobenzene completely suppressed the oxybromination pathway (Table 1, entry 11). In order to perform the reaction at a lower temperature (-78 °C), nitroethane was employed instead of nitromethane. This prevented the formation of 10b and directly submitting the crude product to ClSO3H treatment gave 8b in 54% yield over two steps (Table 1, entry 12). Eventually, performing the same sequence with MeSO3H in the second step improved the yield up to 67% in a 6:1 diastereomeric ratio (Table 1, entry 13). 15 This thorough optimization helped define three sets of conditions to selectively access dibromo-oxybromo-and cyclobromo-derivatives. First, the scope of the former two processes was evaluated.

In addition to the above mentioned results on geranyl acetate 4a and homogeranylbenzene 4b, the combination of DIB and LiBr selectively triggered the dibromination of o-homogeranylanisole 4c and geranylbenzene 4d to give 7a-d in good to excellent yields (Table 2, entries 1-4). The same protocol could be applied to geraniol 4e to give 7e in 63% yield without any detectable oxidation of the free alcohol (Table 2, entry 5). Finally, the more challenging bis(benzyloxycarbamate)-guanidine 4f could be selectively dibrominated to yield 7f by using a reverse addition protocol at -78 °C (Table 2, entry 6). The same substrates were also submitted to the PIFA/n-Bu4NBr combination to give the α-bromo trifluoroacetyl adducts 6. Geranyl acetate led to 6a'' and geraniol to 6e in 77% and 57% yield, respectively (Table 2, entries 1 and 5). In addition to 4b, the other aryl derivatives 4c and 4d reacted equally well to give the oxybrominated adducts in 56% and 64% yield (Table 2, entries 3 and 4). Only guanidine 4f reacted sluggishly to yield the desired trifluoroacetoxy adduct 6f in only 25% yield (Table 2, entry 6) along with 13% of 7f and 31% of cyclic guanidine 12 (see Scheme 5). Finally, it was demonstrated that selective cleavage of the trifluoroacetoxy group of 6b could be achieved with NaBH4 to give the corresponding bromohydrine with 79% yield. 12 We then turned our attention towards the third protocol and studied the cyclization of several homogeranyl and geranyl derivatives. First, homogeranylarenes were reacted under the optimized conditions, followed by treatment with sulfonic acid or with tin(IV) chloride, 15 to provide the corresponding tricycles (Scheme 3). Para-toluene 4g, para-anisole 4h and ortho-anisole 4c derivatives led to the desired bromo-octahydrophenanthrenes 8g, 8h and 8c with 40% to 60% yields and moderate to good diastereoselectivities.

Scheme 3 Bromocyclization of homogeranyl-and homofarnesylarenes.

The reaction proceeded even better with meta-anisyl substrate 4i, although the two adducts arising from para and ortho addition (8i + 8i' = 73% yield) were formed. Finally, homofarnesylbenzene 4j was reacted to give bromotetracycle 8j in a low but satisfying yield, considering that one C-Br and three C-C bonds are formed in the sequence.

In the case of phenolic homogeranyl derivatives, PhI(OPiv)2-mediated bromocyclization gave good (59% to 65%) overall yield of bromo-cyclized products, 16 the distribution of which varied depending on the initial substitution pattern (Scheme 4). Starting from ortho-phenol 4k, in addition to the monocyclic cyclohexenes 5k and the expected tricycle 8k, compound 13 embedding a sevenmembered ring was also isolated. 17 For meta-phenol 4l, the cyclohexenes 5l were obtained in 36% yield and the two brominated polycycles arising from para and ortho addition (8l + 8l' = 23% yield) were also formed.

Scheme 4 Bromocyclization of homogeranylphenols.

Finally, the behavior of geranyl compounds was explored (Scheme 5). Geranyl-benzene 4d led to bromocyclohexenes 5d in 43% yield as a mixture of endo/exo adducts. [START_REF]The structure of endo-5d was confirmed by X-ray crystallography[END_REF] The analogous cyclohexenes 5m were obtained in slightly higher yield (51%) from o-geranylanisole 4m along with 24% of bromo-hexahydroxanthene 14 arising from a cascade cyclization and concomitant loss of a methyl group.

Scheme 5 Bromocyclization of geranyl derivatives.

As could be expected, this isocymobarbatol-like adduct became the major product when o-geranylphenol 4n was subjected to the PhI(OPiv)2/TESBr combination. 3-Bromochromane 15, resulting from a phenoxybromination of the internal double bond, was also observed as a minor adduct. This change in chemoselectivity might hint at an active participation of the heteroatom in the cyclization process, presumably via initial ligand exchange between the phenol and the ester on the hypervalent iodine center, followed by oxyhalogenation of the proximal double bond. This was further exemplified by the reaction of guanidine 4f which smoothly led to 12 with 75% yield. Indeed, it is the only substrate that we studied for which the reaction mainly occurred on the internal double bond.

Overall we have shown that using a combination of a (bisacyloxy)iodobenzene and a bromide source three different electrophilic brominations of terpenoids with different outcomes could be triggered. Simple adjustments in the nature of the reagents (all commercially available) and the procedure (temperature, rate and order of addition) could steer the reactivity towards dibromination, oxy-bromination or bromocyclization, including cascade processes. This strategy grants access to various motifs that can be found in several families of natural products. Studies in this direction as well as the implementation of this methodology for other halides are currently being pursued.

Table 1 Optimization of the iodine(III)-mediated dibromination, oxybromination and bromocyclization of homogeranylben- zene 4b. a

 1

	entry	R (x equiv)	M (y equiv)	solvent	[M] b	temp	addition time	5b, yield % c	6b, yield % c	7b, yield % c	8b, yield % c
	1	Ac (1.2)	Li (2.4)	MeCN	0.05	0 °C	5 min d	-	-	63	-
	2	Ac (1.1)	Li (1.1)	MeCN	0.02	0 °C	10 min	-	-	46	-
	3	C(O)CF3 (1.2)	Li (1.1)	MeCN	0.01	0 °C	30 min	17	-	-e	22
	4	C(O)CF3 (1.2)	Me3Si (1.1)	MeCN	0.01	0 °C	20 min	41	-	Traces f	15(46)
	5	C(O)CF3 (1.2)	Me3Si (1.1)	MeCN	0.01	0 °C	30 min	16	-	3 f	19 g
	6	C(O)CF3 (1.2	Et3Si (1.1)	MeCN	0.01	0 °C	20 min	33	-	-f	15 g
	7	C(O)CF3 (1.2)	Et3HN (1.1)	MeCN	0.01	0 °C	10 min	15	6	-f	20
	8	C(O)CF3 (1.2)	Bu4N (1.1)	MeCN	0.01	0 °C	10 min	6	44	-f	8
	9	C(O)CF3 (1.2)	Bu4N (1.1)	MeCN	0.04	0 °C	5 min	-	60	-	-
	10	C(O)CF3 (1.2)	Et3Si (1.1)	MeNO2	0.01	0 °C	10 min	27	4	-f	20
	11	C(O)CMe3 (1.2)	Et3Si (1.1)	MeNO2	0.01	0 °C	10 min	24	-	-f	24
	12	C(O)CMe3 (1.2)	Et3Si (1.1)	EtNO2	0.04	-78 °C	10 min	N/A h	-	-	(54)
	13	C(O)CMe3 (1.2)	Et3Si (1.1)	EtNO2	0.04	-78 °C	10 min	N/A h	-	-	(67) i

a A solution of MBr [2C] was slowly added to a solution of 4b [2C] containing the iodine(III) reagent. b Resulting concentration after addition. c Isolated yields; for 8b overall yield after re-cyclization of 5b with ClSO3H is given in parenthesis. d Direct addition of LiBr and with 4 Å MS. e And 7% of 10b. f And traces of 10b. g And 8% of 11b. h

Table 2 Scope of the dibromination and the trifluoroace- toxybromination.

 2

	entry 4, R	7, yield % a	6, yield % b
	1	4a, OAc	91	77
	2	4b, Bn	63	60
	3	4c, o-MeOBn	52	56
	4	4d, Ph	55	64
	5	4, OHe	63	57
	6	4f, NHC(NZ)NHZ	52 c	25 d
	a Isolated yields for conditions A: PhI(OAc)2 (1.2 equiv), LiBr
	(2.4 equiv), 4 Å MS in MeCN, at 0 °C for 5 min

b

Isolated yields for conditions B: PhI(OCOCF3)2 (1.2 equiv) n-Bu4NBr (2.4 equiv) in MeCN, at 0 °C for 5 min c At -78 °C, using TESBr instead of LiBr. d At -78 °C, + 13 % of 6f and 31% of 12.

ACKNOWLEDGMENT

The authors thank CNRS and ICSN, for financial support. T. D. G. thanks ICSN for a PhD fellowship.

ASSOCIATED CONTENT Supporting Information

Supporting Information contains experimental procedures, analytical data and copies of NMR spectra for all new compounds (pdf) and crystallographic data for 5d, 8b and 13 (cif). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author *kevin.cariou@cnrs.fr

Notes

The authors declare no competing financial interests.


Eugénie Romero

Corinne Minard

Mohamed Benchekroun

Sandrine Ventre

Pascal Retailleau

Robert H Dodd

Kevin Cariou

Base-Mediated Generation of Ketenimines from Ynamides: Direct Access to Azetidinimines by an Imino Staudinger Synthesis

Keywords: ynamides, ketenimines, [2+2] cycloaddition, azetidinimines, Staudinger synthesis

Ynamides were used as precursors for the in situ generation of highly reactive ketenimines which could be trapped with imines in a [2+2] cycloaddition. This imino Staudinger synthesis led to a variety of imino-analogs of β-lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations.

 The strong inherent polarization of the triple bond, that can be visualized by drawing the main mesomeric form 1', generally drives their reactivity towards nucleophilic addition on the α position and reactions with electrophiles at the β position. 1 This trend can be further enhanced by acid activation, since protonation of the substrate yields keteniminium 2 (Scheme 1). 2

Scheme 1. Ynamides: Inherent Polarization vs Acid and Base Activations

For our part, we have shown that using strongly basic conditions [START_REF] Evano | review specifically covering the anionic chemistry of ynamides[END_REF] an unprecedented nucleophilic addition of various heteroarenes at the β position could take place. 4 Moreover, depending on the substitution pattern of the nitrogen atom, the same basic conditions could lead to an α nucleophilic addition, albeit with the loss of the electron-withdrawing group (EWG). In this latter case, base activation would trigger the cleavage of the EWG, leading to an amide that will eventually evolve towards ketenimine 3. 4,5 In order to further expand the potential of this highly reactive intermediate (3), we sought to trap it in a [2+2] cycloaddition. [START_REF] Wang | use of ynamides in ring forming reactions[END_REF] By analogy with the well-established Staudinger synthesis of βlactams, 7 and based on the pioneering studies by Ghosez 8 and Regitz,9 we envisioned that the N-phenylethenimine 3a generated in situ from ynamide 1a would be sufficiently electrophilic to react with imine 4 to ultimately give azetidinimine 5 (Scheme 2). [START_REF] Mostowicz | For other methods to access azetidinimines[END_REF] From our previous experience, an unsubstituted N,N-Boc-aryl-ynamide would be the best precursor for the generation of the ketenimine and we assumed an electron-rich nitrogen atom in the imine would favor the desired cycloaddition.

Scheme 2. In situ Generation of an Ethenimine and Trapping with an Imine

However, direct application of our previously disclosed reaction conditions 4i.e., 1.0 equiv. of ynamide, 1.0 equiv. of t-BuONa as base, DMF as solvent, with molecular sieves at room temperature proved totally ineffective, even after prolonged reaction time (Table 1, entry 1). We reasoned that the cycloaddition process required thermal activation and thus, while traditional heating (entry 2) was unsuccessful, switching to microwave conditions 11 allowed the reaction to take place (entry 3). By replacing the sodium salt by potassium (entry 4) or lithium (entry 5) t-butanolate the desired azetidinimine 5aa could be isolated with 46% and 47% yield, respectively. Doubling the amount of both the ynamide and the base (X = 2) had little effect (entry 6) unless the temperature was raised to 100 °C (entry 7) which allowed 5aa to be isolated in 50% yield. This 50% threshold could be overcome by using silica gel as the additive instead of molecular sieves (entry 8, 54%). These optimized conditions were then applied to pchlorobenzaldehyde-derived imine 4b which led to the isolation of 64% of azetidinimine 5ab (entry 9). Improved formation of the latter was attempted by using a catalytic amount of a Lewis acid as the additive (entry 10, 50%) or as a co-additive (entry 11, 52%) but to no avail.

Having determined the optimal reaction conditions, we then explored the scope of this cycloaddition (Table 2). First, the influence of the substituents on the imine partners was assayed. Unsubstituted diphenyl aldimine 4c allowed formation of the corresponding azetidinimine 5ac in only 22% yield (entry 3). t-BuOLi [b] ZnOTf (10 mol%) 1 h 100 °C µW 50%, 5ab 11 2 4b t-BuOLi [b] SiO2 (1 equiv.) + ZnOTf (10 mol%)

1 h 100 °C µW 52%, 5ab [a] Isolated yields. [b] A 2.2 M solution of t-BuOLi in THF was used.
This result appears consistent with the positive effect of having an electron-donating group on the nitrogen (entries 1,2) and an electron-poor aryl group on the carbon of the imine partner (entry 2). Imines derived from meta-(4d) and ortho-anisidine (4e) were then reacted with ynamide 1a, providing cycloadducts 5ad and 5ae in 26% and 37% yields, respectively (entries 4,5).These yield variations can be accounted for by standard electronic (meta vs. para/ortho) and steric (ortho vs. para) effects. Ph, 4-MeO-C6H4, 4a 54%, 5aa [b] [c] 2 Ph, 1a 4-Cl-C6H4, 4-MeO-C6H4, 4b 64%, 5ab [b] 3 Ph, 1a Ph, Ph, 4c 22%, 5ac [d] 4

Ph, 1a 4-Cl-C6H4, 3-MeO-C6H4, 4d 26%, 5ad [d] 5

Ph, 1a 4-Cl-C6H4, 2-MeO-C6H4, 4e 37%, 5ae [d] 6

Ph, 1a Ph, 3,4,5-triMeO-C6H4, 4f 54%, 5af [b] 7 Ph, 1a 4-MeO-C6H4, 4-MeO-C6H4, 4g 40%, 5ag [b] 8 Ph, 1a

4-Br-C6H4, 4-MeO-C6H4, 4h 63%, 5ah 9
Ph, 1a 4-I-C6H4, 4-MeO-C6H4, 4i 61%, 5ai [c] 10 Ph, 1a 4-MeO2C-C6H4, Ph, 4j 4%, 5aj + 26%, 5aj' [d] 11 4-Cl-C6H4, 1b Ph, 4-MeO-C6H4, 4a 10%, 5ba [c] 12 [c] 20 4-MeO-C6H4, 1f 4-Cl-C6H4, 4-MeO-C6H4, 4b 35%, 5fb

4-Cl-C6H4, 1b 4-Cl-C6H4, 4-MeO-C6H4, 4b 29%, 5bb 13
[a] Isolated yields, using a 2.2 M solution of t-BuOLi in THF. [b] Solid t-BuOLi was used. [c] An X-ray structure was obtained, see Supporting Information for details. 12 [d] 10 mol% of ZnOTf2 was used as the additive instead of silica gel.

Strongly electron-enriched 3,4,5-trimethoxylated imine 4f reacted smoothly with 1a to give 5af in 54% yield (entry 6) while dianisyl imine 4g led to 5ag in 40% yield (entry 7). In order to allow further functionalization, p-bromo-and p-iodobenzaldehydederived imines (4h and 4i) were subjected to the reaction conditions and the desired adducts were obtained in 63% and 61% yields, respectively (entries 8,9). Imine 4j bearing a methoxycarboxylate was then used, leading to an overall 30% yield of cycloaddition adduct 5a, most of which had been transesterified to the corresponding t-butoxycarboxylate 5aj' during the course of the reaction (entry 10). While various substitution patterns on the imine partner were well tolerated, this was not the case for the ketenimine precursor. Indeed, a series of ynamides was evaluated for which no cycloaddition took place (Table 2, topright b). These include: sulfonamides (GP = tosyl, mesyl and pnosyl) and N-alkyl (R = benzyl or allyl) as well as C-substituted (R' = phenyl, n-butyl and triisopropylsilyl) derivatives. The reaction did take place, however, when functionalized aryl groups such as para halo-(Cl, Br and I), trifluoromethyl-and methoxy-phenyl were incorporated on the ynamide partner (1b-f). All of these reacted with both imines 4a and 4b (entries11-20) providing yields of cycloadducts ranging from 10-36% with imine 4a (entries 11, 13, 15, 17 and 19) to 29-40% with imine 4b (entries 12, 14, 16, 18 and 20). Compared with ynamide 1a, yields were systematically lower and this can be attributed to a variety of factors difficult to unambiguously pinpoint since the substitution of this aryl presumably has an influence on both the generation of the active ketenimine and its subsequent stability and reactivity.

Having a wide panel of azetidinimines at our disposal we then turned our attention to their use for further functionalization. Satisfyingly, this unusual four-membered ring proved to be quite tolerant to a broad range of reaction conditions, obviating the necessity of extensive optimization. First, Suzuki coupling was used as a typical Pd-catalyzed cross-coupling reaction. Thus, an additional p-methoxyphenyl moiety could be added with excellent yields on both the C-aryl (6) or iminoaryl (7) part of the scaffold, using either bromo-(5ah & 5ca) or iodo-azetidinimines (5ai & 5da) (Scheme 3).

Scheme 3. Ynamides: Inherent Polarization vs Acid and Base Activations

A strong Lewis acid such as boron tribromide (Scheme 4, Eq. 1) could be employed, without any noticeable degradation of the amidine ring, to selectively cleave the methyl group of 5ab to give phenolic azetidinimine 8. The latter could in turn be alkylated with t-butyl bromoacetate to give 9 in 78% yield. Finally, treatment of carboxylate 5aj' (Eq. 2) with a strong acid such as trifluoroacetic acid or a strong reducing agent such as lithium aluminum hydride gave respectively carboxylic acid 10 (96%) and primary alcohol 11 (82%), leaving the four-member ring untouched. Benzyl alcohol 11 could furthermore be transformed into the corresponding chloride 12 in 70% yield, using methanesulfonyl chloride.

Scheme 4. Further Functionalization around the Azetidinimine Ring

In conclusion, we have taken advantage a specific mode of activation of ynamides under basic conditions to generate Narylethenimines from Boc-aryl-ynamides and react them with imines in a [2+2] cycloaddition. This reaction further ascertains the intermediacy of the ketenimine intermediate and paves the way for other types of cycloadditions. Moreover, the azetidinimines resulting from this imino Staudinger synthesis can undergo a broad array of chemical transformations that leave the 4-membered amidine ring intact. This work should allow for further exploration around this particular heterocyclic scaffold which can be viewed as an imino-analog of monocyclic β-lactams. [START_REF] Ramsey | In the context of antibiotic resistance, monocyclic β-lactam antibiotics (monobactams) such as aztreonam hold a special position due to their unique properties[END_REF] Studies in these directions are currently ongoing in our laboratory and will be reported in due course.

Experimental Section

Imine 4a (63 mg, 0.3 mmol, 1.0 equiv.), ynamide 1a (130 mg, 0.6 mmol, 2.0 equiv.) and SiO2 (18 mg, 0.3 mmol, 1.0 equiv.) were successively added in a microwave sealable tube and placed under argon before the addition of t-BuOLi (48 mg, 0.6 mmol, 2.0 equiv.) followed by extra dry DMF (900 µL). The sealed tube was placed in a microwave apparatus for 1 h at 100 °C. The crude material was purified by flash chromatography on silica gel (10% ethyl acetate in heptane as eluent) to provide azetidinimine 5aa with 54 % yield (53 mg, yellow solid).

Entry for the Table of Contents

  [a] Dr E. Romero, Dr C. Minard, Dr M. Benchekroun, Dr S.Ventre, Dr P. Retailleau, Dr R. H. Dodd,* Dr K. Cariou* Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay Avenue de la Terrasse, 91198 Gif-sur-Yvette, France E-mail: kevin.cariou@cnrs.f r

  Under strong basic conditions ynamides gave highly reactive ketenimines which could be trapped with imines in a [2+2] cycloaddition. This imino Staudinger synthesis led to a variety of imino-analogs of β-lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations. Dr E. Romero, Dr C. Minard, Dr M. Benchekroun, Dr S. Ventre, Dr P. Retailleau, Dr R. H. Dodd,* Dr K. Cariou*

Table 1 .

 1 Optimization

	Entry	X	4	Base	Additive	Time	Heating	Yield, 5
	1	1	4a	t-BuONa	M. S.	24 h	RT	0%
	2	1	4a	t-BuONa	M. S.	24 h	60 °C	Traces
	3	1	4a	t-BuONa	M. S.	1 h	80 °C µW	20% conv.
	4	1	4a	t-BuOK	M. S.	1 h	80 °C µW	46%, 5aa
	5	1	4a	t-BuOLi	M. S.	1 h	80 °C µW	47%, 5aa
	6	2	4a	t-BuOK	M. S.	1 h	°C µW	45%, 5aa
	7	2	4a	t-BuOLi	M. S.	1 h	100 °C µW	50%, 5aa
	8	2	4a	t-BuOLi	SiO2 (1 equiv.)	1 h	100 °C µW	54%, 5aa
	9	2	4b	t-BuOLi	SiO2 (1 equiv.)	1 h	100 °C µW	64%, 5ab
	10	2	4b

of the [2+2] Cycloaddition between Ynamide 1a and Imines 4a,b. a

Table 2 .

 2 Scope and limitations of the [2+2] Cycloaddition with Ynamides 1 and Imines 4.[a]

	Entry	Ar, 1	Ar 2 , Ar 3 , 4	Yield, 5 a
	1	Ph, 1a

Acknowledgements

The authors thank CNRS, ICSN, Labex Lermit (ANR grant ANR-10-LABX-33 under the program Investissements d'Avenir ANR-11-IDEX-0003-01) and FCS Campus Saclay for financial support. E. R., C. M. and S. V thank Labex Lermit and M. B. thanks FCS Campus Saclay for fellowships.

Supporting information for this article is given via a link at the end of the document.

Author Contributions

K. C. and R. H. D. designed and supervised the experiments and wrote the manuscript, C. M. † and S. V. ‡ optimized the reaction conditions and initiated the scope study, E. R. † and M. B. ‡ expanded the scope and performed the functionalization of the compounds. P. R. performed the X-ray crystallography experiments. † These authors contributed equally. ‡ These authors contributed equally. The authors declare no competing financial interests.


Diego R C Silva

Edmilson J Maria

Rosa M Suárez Ordóñez

Josiane Thierry

Kevin Cariou
email: kevin.cariou@cnrs.fr

Robert H Dodd
email: robert.dodd@cnrs.fr

Synthesis of Orthogonally N-Protected, C-4 Functionalized Cyclic Guanidines from L-Serine

Keywords: cyclic guanidine, amino acid, azide, orthogonal protection, Weinreb amide

come

The cyclic guanidine motif is present in a wide range of naturally-occurring compounds, 1 notably as a structural unit of non-proteinogenic amino acids, examples of which are enduracididine (1), 2 its 3-hydroxy derivatives (2), 3 capreomycidine 4 (3) and tetrahydrolathyrin 5 (4) or of alkaloids such as trachycladindole B 6 (5) and its derivatives (Figure 1). These amino acids have been isolated either in their free form or as components of cyclic peptides. Thus, compound 1 is a structural unit of the cyclopeptide enduracidin 2 and of the recently described teixobactin, 7 compound 2 of the mannopeptimycins 3 and compound 3 of capreomycins and tuberactinomycins, 8 all of which display antibiotic or antifungal action. In terms of synthesis, formation of the cyclic guanidine unit usually depends on the generation of a 1,2-or 1,3-diamino motif which classically can then be cyclized using cyanogen bromide, an inexpensive but highly toxic reagent. Alternatively, one of the amino groups can be coupled to a reactive isothiourea derivative which then undergoes cyclization upon heating. 9 Starting from a 1-hydroxyl-2-(or 3-)-guanidine unit, a Mitsunobu-type cyclodehydration has also been used to prepare a 5-(or 6-) membered cyclic guanidine. [10][11][12] We ourselves have recently described the syntheses of both Lenduracididine (1) 13 and tetrahydrolathyrin (4) 14 by way of prior iminoiodane-mediated aziridination of a common, easily accessible starting material, L-allylglycine. Subsequent nucleophilic opening of the aziridine by azide (for enduracididine) or nitrile (for tetrahydrolathyrin) provided the required diamino precursors after reduction. The lack of diasteoselectivity in the aziridination step was, however, a complicating factor in both cases.

Figure 1

Examples of natural products containing a C-4 substituted cyclic guanidine structural unit It occurred to us that a more convergent way of synthesizing cyclic guanidine-containing compounds, be they natural products, analogues thereof or in the context of drug discovery, would consist of preparing a pre-formed cyclic guanidine moiety bearing a functional group which could thereafter be used to link another molecule (e.g., an amino acid, an indole...). Such a tactic was recently described by us whereby halogenated cyclic guanidines were obtained in one step by halocyclization of unsaturated guanidines using a combination of lithium halides and Koser's reagent. 15 We now report herein the efficient preparation, starting from L-serine, of 5-membered cyclic guanidines functionalized at C-4 with an ester, a Weinreb amide or a hydroxymethyl group and in which, moreover, the three guanidine nitrogen atoms are orthogonally protected. The possibility of accessing a mono-N-deprotected cyclic guanidine could be highly valuable, for example, for the introduction of different substituents on each nitrogen atom in the context of a structure-activity relationship study of a particular bio-active molecule.

Template for SYNLETT © Thieme Stuttgart • New York 2016-12-16 page 2 of 4

The success of our methodology was very much dependent on the judicious choice of nitrogen atom protecting groups. [START_REF] Wuts | s Protective Groups in Organic Synthesis, Fourth Edition[END_REF] Indeed, a frequently encountered problem in working with partially N-protected cyclic guanidines is scrambling of the protecting group(s) 17 making characterization and purification of products difficult and lowering yields. For our initial studies starting from L-serine methyl ester ( 6), we thus chose to protect the amine function with a p-methoxybenzyl (PMB) group not prone to migration but easily removed under mild oxidizing conditions (Scheme 1). Additionally, the electron-rich nature of the group should assist in the subsequent cyclization step. Thus, reaction of 6 with p-methoxybenzaldehyde (7) in methanol in the presence of triethylamine followed by sodium borohydridepromoted reduction of the resulting intermediate imine provided the desired N-PMB serine methyl ester 8 in 81% overall yield. Compound 8 in dichloromethane was then treated at -78 °C with thionyl chloride in the presence of pyridine to give the oxathiazolidine derivative 9. The latter was oxidized to the cyclic sulfamidate 10 in 77% overall yield using catalytic ruthenium trichloride and sodium metaperiodate in acetonitrile. 18 Regioselective ring-opening of compound 10 in acetone was very efficiently achieved by the action of aqueous sodium azide (Warning !) at room temperature, furnishing methyl (2S)-3-azido-2-(p-methoxybenzyl)aminopropanoate 11 in 85% yield. 19 Scheme 1 Preparation of the 2-amino-3-azido precursors for cyclic guanidine formation

Transformation of azido derivative 11 into the orthogonally Nprotected cyclic guanidine 4-carboxylic ester 16 is depicted in Scheme 2. Thus, the azido function of 11 was first reduced to the primary amine 12 via a Staudinger reaction using triphenylphosphine in aqueous dichloromethane. This amine was not purified but was reacted directly with 1,3bis(benzyloxycarbonyl)-2-methylisothiourea (13) in the presence of triethylamine in dichloromethane. [START_REF]Methyl (2S)-3-(2,3-bis(benzyloxycarbonyl)guanidino)-2-(pmethoxybenzylamino) propanoate (14): To a solution of amine 12 (669 mg, 2.8 mmol) in CH2Cl2 (15 mL) were successively added at room temperature 1,3-bis(benzyloxycarbonyl)-2methylisothiourea (13, 1.22 g, 3.4 mmol) and triethylamine (0.93 mL, 6.7 mmol). The reaction mixture was stirred overnight, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (EtOAc/heptane, 40:60), providing compound 14[END_REF] The resulting guanidino derivative 14, obtained in 95% overall yield for both steps, underwent cyclization when heated for 2 days at 70 °C in acetonitrile, providing a 75% yield of methyl 2iminoimidazolidine-4-carboxylate 15. [START_REF]Methyl (4S)-2-(benzyloxycarbonylimino)-3-(p-methoxybenzyl)-imidazoledine-4-carboxylate (15): A solution of compound 14 (2.56 g, 4.6 mmol) in acetonitrile (25 mL) was heated at 70 °C for 2 d. The reaction mixture was then cooled to room temperature, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (EtOAc/heptane, 1:1) to provide the cyclic guanidine 15 as[END_REF] Finally, treatment of compound 15 with excess Boc anhydride and DMAP in acetonitrile led to the targeted fully N-protected, C-4 functionalized cyclic guanidine 16 in 73% yield. The latter could furthermore be transformed in 90% yield to the C-4 hydroxymethyl derivative 17 by reduction of the ester with lithium borohydride in ethanol at 0 °C. The orthogonality of our design was illustrated by the selective deprotection of the Cbz of 16 to give 18 by hydrogenolysis. Thus it is possible to go from 2,3 diprotected guanidine (15) to tri-protected ( 16), to 1,3 diprotected guanidine (18). 6) then allowed efficient access to optically pure, N-protected cyclic guanidine derivative 29 having now a Weinreb amide at the C-4 position suitable for further transformations (Schemes 1 and 2). [START_REF]Methyl (2S)-3-(2,3-bis(benzyloxycarbonyl)guanidino)-2-(pmethoxybenzylamino) propanoate (14): To a solution of amine 12 (669 mg, 2.8 mmol) in CH2Cl2 (15 mL) were successively added at room temperature 1,3-bis(benzyloxycarbonyl)-2methylisothiourea (13, 1.22 g, 3.4 mmol) and triethylamine (0.93 mL, 6.7 mmol). The reaction mixture was stirred overnight, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (EtOAc/heptane, 40:60), providing compound 14[END_REF][START_REF]Methyl (4S)-2-(benzyloxycarbonylimino)-3-(p-methoxybenzyl)-imidazoledine-4-carboxylate (15): A solution of compound 14 (2.56 g, 4.6 mmol) in acetonitrile (25 mL) was heated at 70 °C for 2 d. The reaction mixture was then cooled to room temperature, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (EtOAc/heptane, 1:1) to provide the cyclic guanidine 15 as[END_REF] In conclusion, esters 15, 16 or 18 primary alcohol 17 and Weinreb amide 29 represent five functionalized and stereochemically defined cyclic guanidine derivatives which can serve as starting materials for the synthesis of a variety of natural products containing this 5-membered heterocyclic unit. An added feature of the synthetic strategy presented here is that these key compounds can be obtained with each nitrogen atom of the guanidine unit being orthogonally protected allowing their selective deprotection and substitution in the context of a structure-activity study (e.g., N-alkylation as in the trachycladindoles 5) or of total synthesis (e.g., the mannopeptimycins). 10b Such transformations are the object of our ongoing studies.

Scheme

Scheme 3

 3 Scheme Preparation of the C-4 functionalized, N-protected 5membered cyclic guanidines For the preparation of the Weinreb amide analogue of the cyclic guanidine ester 16, the corresponding amide of L-serine (i.e., compound 21) was first synthesized as shown in Scheme 3. This two-step procedure consisted of EDCI-promoted coupling of commercial N-Boc-L-serine(19) with N,Odimethylhydroxylamine in the presence of N-methylmorpholine (NMM) to give amide 20. Removal of the N-Boc protecting group using trifluoroacetic acid in dichloromethane then provided 21 in 72% overall yield.

Acknowledgment

The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) for financial support and D.R.C.S is thankful to CAPES, Brazil for a scholarship. We thank the Institut de Chimie des Substances Naturelles for financial and technical support.

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