Patrick Y. Toullec

Cycloisomerization of 1,n-Enynes: Challenging Metal-Catalyzed Rearrangements and Mechanistic Insights

Metal-catalyzed cycloisomerization reactions of 1,n-enynes have appeared as conceptually and chemically highly attractive processes as they contribute to the highly demanded search for atom economy and allow the discovery of new reactions. Since the pioneering studies with palladium by the research group of Barry Trost in the mid-1980s, several other metals have been identified as excellent catalysts for the rearrangement of enyne skeletons. Moreover, the behavior of 1,n-enynes may be influenced by other functional groups such as alcohols, aldehydes, ethers, alkenes, or alkynes, thus enhancing the molecular complexity of the synthesized products. Apart from the intrinsic rearrangements of 1,n-enynes, several tandem reactions incorporating intramolecular trapping agents or intermolecular partners have been discovered. This Review aims to highlight the main contributions in this field of catalysis and to propose and comment on the mechanistic insights of the recent discoveries.

Asymmetric Gold‐Catalyzed Hydroarylation/Cyclization Reactions

Recent years have witnessed a substantial growth in the number of gold-catalyzed reactions implying C C, C O or C N bond-formation processes. Despite the rapid development of several synthetic applications, the enantioselective aspects still require investigations. Some reports described the transfer of chirality from allenes and propargylic esters, and the asymmetric hydroalkoxylation and hydroamination of allenes. Nevertheless examples are still scarce, most probably due to the linear geometry of chiral gold(I) complexes that explains a lack of steric interactions between the chiral inducer and the activated function of the substrate. Ito and Hayashi s groups pioneered the field of asymmetric gold catalysis by conceiving the addition of isocyanoacetates to aldehydes in the presence of a cationic gold catalyst and a chiral diphosphanyl ferrocene ligand. Other groups have recently challenged to discover new applications of linear chiral gold complexes, but to the best of our knowledge, only two of them implied alkyne activation. In the course of our research on metal-catalyzed cycloisomerization reactions of enynes, we and others have described novel rearrangements in the presence of external nucleophiles such as alcohols, electron-rich aromatic rings, amines, carboxylic acids and 1,3-dicarbonyl compounds (Scheme 1). Despite the fact that these reactions seem mechanistically related, they proved to be highly substrate and nucleophile dependent. This explains the fact that no general asymmetric version was described so far for these tandem atom-economical processes. We described the first asymmetric Pt-catalyzed alkoxycyclization reactions and Echavarren s group published the first analogous gold-catalyzed proACHTUNGTRENNUNGcess.[4a] In both cases, moderate to good enantioselectivities were observed and only one example has been reported with an ee higher than 90 %. We envisaged to study these challenging reactions and wish to present our preliminary results leading to enantiomerically enriched functionalized cyclic alkenes starting from 1,6-enynes. Initial efforts have focused on the optimization of an efficient system starting from enyne 1 a as a model substrate (Table 1). Based on our experience, we reasoned that the addition of electron-rich aromatic rings would be successful as the kinetics were fast and the steric hindrance of the nucleophile would favor an enantioselective process. According to previously described procedures, we prepared chiral Au catalysts with MeOBIPHEP, BINAP and 4MeO-3,5-(tBu)2-MeOBIPHEP ligands. The use of (R)MeOBIPHEP–(AuCl)2 associated with silver salt AgSbF6 in diethyl ether led to the formation of the desired product 2 a in excellent yield and 26 % enantiomeric excess (Table 1, entry 1). The influence of silver salts was investigated (Table 1, entries 2–4), silver triflate and silver bis(trifluoromethanesulfonyl)imidate giving the best results. The use of silver benzoate was particularly striking as no conversion was observed at room temperature for 240 h (Table 1, entry 2). Lowering the temperature to 0 8C increased the re[a] C.-M. Chao, Dr. M. R. Vitale, Dr. P. Y. Toullec, Prof. J.-P. GenÞt, Dr. V. Michelet Laboratoire de Synth se S lective Organique et Produits Naturels UMR 7573, Ecole Nationale Sup rieure de Chimie de Paris rue P. et M. Curie, 75231 Paris cedex 05 (France) Fax: (+33) 144-071-062 E-mail : veronique-michelet@enscp.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200802341. Scheme 1. Metal-catalyzed cycloisomerization of 1,6-enynes in the presence of an external nucleophile.

Cycloisomerization versus Hydration Reactions in Aqueous Media: A Au(III)-NHC Catalyst That Makes the Difference

A novel water-soluble Au(III)-NHC complex has been synthesized and successfully applied in the intramolecular cyclization of γ-alkynoic acids into enol-lactones under biphasic toluene/water conditions, thus representing a rare example of an active and selective catalyst for this transformation in aqueous media. Remarkably, competing alkyne hydration processes were not observed, even during the desymmetrization reaction of challenging 1,6-diyne substrates. In addition, after phase separation, the water-soluble Au(III) catalyst could be recycled 10 times without loss of activity or selectivity.

Fluorescent Phosphane Selenide As Efficient Mercury Chemodosimeter

The synthesis and photophysical properties of a novel fluorescent sensor are described. The phosphorus-selenium moiety allowed a selective mercury salt complexation, followed by the formation of phosphane oxide, which leads to a turn-on of the fluorescence. The sensibility and selectivity toward mercury cations were evaluated (0.18 ppb) and found to be in complete adequation with the targeted level of the World Health Organization, which makes the dye an efficient dosimeter for mercury cations.

Mimicking polyolefin carbocyclization reactions: gold-catalyzed intramolecular phenoxycyclization of 1,5-enynes.

PPh(3)AuNTf(2) promotes highly efficient intramolecular phenoxycyclization reactions on 1,5-enynes under mild conditions. The original tricyclic and functionalized heterocycles were isolated in good to excellent yields. The 6-endo cyclization process is predominant and operates via a biomimetic cascade cation-olefin process. The efficiency of this system was further demonstrated in the cycloisomerization reaction of a 1,5,9-dienyne.

Heterogeneous Gold Catalysts for Efficient Access to Functionalized Lactones

A novel class of heterogeneous gold catalysts supported on zeolite beta-NH4+ was prepared by the deposition-precipitation method. This new class of catalyst showed interesting catalytic activities for the intramolecular cycloisomerization of gamma-acetylenic carboxylic acids leading to functionalized gamma-alkylidene gamma-butyrolactones. Analysis of the supported gold species with in situ X-ray photoelectron spectroscopy (in situ XPS) suggests that cationic Au (possibly AuIII) can play an important role in such reactions. The high discrepancy in catalyst stability in favor of the Au supported on the zeolite system over bulk Au2O3 is explained by 1) the size of the particles and 2) the reversibility of the redox deactivating process (AuIII-->AuI) in the presence of oxygen for the supported system. The efficiency of this system allowed reaction under mild heterogeneous conditions. The potential for catalyst recycling was also highlighted.

Cycloisomerization of 1,n-Enynes Via Carbophilic Activation

Metal-catalyzed cycloisomerization of 1,n-enynes has appeared as a highly attractive methodology for the synthesis of original carbo- and heterocycles. This chapter intends to propose an overview of the recent and seminal advances in 1,n-enynes cycloisomerization reactions in the presence of carbophilic transition metals. The recent mechanistic insights, the enantioselective versions, and the applications in total synthesis are highlighted.

Asymmetric Au-catalyzed cycloisomerization of 1,6-enynes: An entry to bicyclo[4.1.0]heptene.

Summary A comprehensive study on the asymmetric gold-catalyzed cycloisomerization reaction of heteroatom tethered 1,6-enynes is described. The cycloisomerization reactions were conducted in the presence of the chiral cationic Au(I) catalyst consisting of (R)-4-MeO-3,5-(t-Bu)2-MeOBIPHEP-(AuCl)2 complex and silver salts (AgOTf or AgNTf2) in toluene under mild conditions to afford functionalized bicyclo[4.1.0]heptene derivatives. The reaction conditions were found to be highly substrate-dependent, the best results being obtained in the case of oxygen-tethered enynes. The formation of bicyclic derivatives, including cyclopropyl pentasubstituted ones, was reported in moderate to good yields and in enantiomeric excesses up to 99%.

Silver-Catalyzed Domino Hydroarylation/Cycloisomerization Reactions of ortho-Alkynylbenzaldehydes: An Entry to Functionalized Isochromene Derivatives

A Ag-catalyzed versatile and efficient access to 1H,1-arylisochromenes is reported. Starting from ortho-alkynylbenzaldehydes bearing various substitution patterns on the benzaldehyde and alkynyl units, the use of silver triflate (10 mol %) allowed a domino hydroarylation/cycloisomerization reaction process, leading to aryl-functionalized 1H-isochromene (>10 compounds, 80-98% yields). Notably, the reaction conditions were also compatible with benzaldehydes bearing an aliphatic-substituted alkynyl moiety with modest to good yields (34-88%, 10 compounds).

Gold-Catalyzed Oxidative Acyloxylation of Arenes§

A variety of nonactivated hindered aromatic rings are acyloxylated (22 examples, up to 83% yield) in the presence of PPh(3)AuCl as the catalyst and di(acetoxy)iodobenzene as the oxidant. The reaction proceeds at 110 °C in an acid media and allows the formation of both hindered acetoxy and acyloxy derivatives. This methodology nicely complements the Pd-catalyzed arene acyloxylation reaction, which is not operating on hindered substrates and allows the Au-catalyzed unprecedented acyloxylation reaction of arenes, implying various carboxylic acids.