Maxime R. Vitale

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.

Combined InCl3- and Amine-Catalyzed Intramolecular Addition of α-Disubstituted Aldehydes onto Unactivated Alkynes

The combination of enamine-type catalysis to the indium-catalyzed activation of alkynes allows the efficient preparation of functionalized cyclopentanes bearing a quaternary stereogenic center. A broad range of formylalkynyl derivatives has been prepared. The InCl(3)/(Cy)(i-Pr)NH system efficiently promotes the carbocyclization reaction of alpha-disubstituted aldehydes in good to excellent yields.

Homologation of boronic esters with lithiated epoxides for the stereocontrolled synthesis of 1,2- and 1,3-diols and 1,2,4-triols.

Lithiated epoxides react stereospecifically with boronic esters to give syn-1,2-diols, a process that can be used iteratively to create triols containing four stereogenic centers.

InCl3/CyNH2 Cocatalyzed Carbocyclization Reaction: An Entry to α-Disubstituted exo-Methylene Cyclopentanes

An efficient and cheap synthetic approach to functionalized exo-methylene cyclopentanes has been developed from α-disubstituted formyl-alkynes by merging amine catalysis with the indium activation of alkynes. We uncovered the crucial role of the amine cocatalyst and the development of a new cooperative catalytic system allowed the cyclization of a broad range of substrates. A mechanistic study was realized in order to rationalize the determining influence of the amine cocatalyst.

An Aptly Positioned Azido Group in the Spacer of a Protein Cross‐Linker for Facile Mapping of Lysines in Close Proximity

Cross‐links between amino acid residues in close proximity can provide distance constraints for the validation of models of the 3D structure proteins. The mapping of cross‐links by the identification of linked peptides in proteolytic digests is facilitated by cleavable cross‐linkers that enable isolation of the cleavage products while preserving information about the linkage. We present an amine‐specific cross‐linker, bis(succinimidyl)‐3‐azidomethyl glutarate (BAMG), that fulfils these requirements. Two parallel reaction pathways are induced by tris(carboxyethyl)phosphine (TCEP) in cross‐linked peptides from BAMG‐treated cytochrome c. One pathway leads to cleavage of the cross‐linked species, while in the other the azido group of BAMG is reduced to an amino group without cleavage. Cross‐linked peptides and peptides modified by partially hydrolysed BAMG yield distinct sets of TCEP‐induced reaction products. These can be isolated by reversed‐phase diagonal chromatography and identified by mass spectrometry to reveal the identity of the parent compounds. The ease with which cross‐link‐derived reaction products can be isolated and identified indicates that the mapping of cross‐links in complex biological assemblies and mixtures of protein complexes might become feasible in the near future.

Chiral undecagold clusters: synthesis, characterization and investigation in catalysis

Enantiopure undecagold clusters protected by chiral atropisomeric diphosphine ligands (P^P) have been synthesized by the stoichiometric reduction of the corresponding (P^P)(AuCl)(2) complexes with NaBH(4). The molecular mono-disperse [Au(11)(P^P)(4)Cl(2)]Cl species have been thoroughly characterized using an array of analytical techniques. (31)P NMR experiments suggested the presence of a slow intramolecular ligand exchange process. Circular dichroism measurements showed that enantiomeric clusters display mirror-image chiroptical activity. Such undecagold clusters containing two chloride ligands bound to the peripheral Au(I) atoms were expected to display a carbophilic Lewis acidity similar to the well-documented molecular Au(I) complex catalysts. Chloride abstraction, performed to generate active Au(+) sites, induced the Au(11) cluster evolution to larger gold clusters and nanoparticles, together with Au(I) complexes, which, in fact, perform the catalysis. This result was corroborated by running an asymmetric tandem hydroarylation-carbocyclization reaction, for which the enantiomeric excesses obtained with Au(11) clusters are similar to those reported using Au(I) complexes.

New Picropodophyllin Analogs via Palladium-Catalyzed Allylic Alkylation-Hiyama Cross-Coupling Sequences

Unsaturated malonyl esters underwent Pd-catalyzed intramolecular allylic alkylation to give 4-vinyl-substituted gamma-lactones. In contrast to the formerly studied cyclization of malonamides, this reaction could be achieved only with a substrate incorporating a suitably positioned silicon moiety, which directs the ionization toward the desired eta(3)-allylpalladium complex. The resulting 4-[dimethyl-(2-thienyl)silylvinyl]lactone could be subsequently engaged into Hiyama couplings with various iodoarenes, to give the corresponding 4-(alpha-styryl)-gamma-lactones. The use of a specifically substituted iodoarene generated an advanced tetracyclic lactone intermediate incorporating rings A-D of lignans belonging to the podophyllotoxin family. Subsequent electrophilic aromatic substitution with a variety of electron-rich arenes afforded the target picropodophyllin analogs.

Palladium(0)-Catalyzed Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with Vinylcyclopropanes: An Entry to Stereodefined 2,3-Fused Cyclopentannulated Indoline Derivatives

The palladium(0)-catalyzed diastereoselective dearomative cyclopentannulation of 3-nitroindoles with vinylcyclopropanes is described. This straightforward and highly atom-economical method leads to a wide range of functionalized indolines in good yields and diastereoselectivities and represents an unprecedented entry toward the valuable 2,3-fused cyclopentannulated indoline scaffold.

Copper(I)-amine metallo-organocatalyzed synthesis of carbo- and heterocyclic systems.

The efficient and atom economical synthesis of 5-membered cyclic structures has been achieved through the combination of amino catalysis and metal catalysis. The discovery of a novel metallo-organocatalytic system merging the use of a catalytic copper(I) complex and a catalytic amount of cyclohexylamine allowed the room temperature preparation of a broad range of skeletons such as cyclopentanes, indanes, pyrrolidines and tetrahydrofuran, important structural cores of many biologically relevant molecules. Mechanistic studies were presented.

Enantiopure alkylidene-1,1-bis-p-tolylsulfoxides as new partners in diastereoselective radical cyclizations

Enantiopure alkylidene-1,1-bis-p-tolylsulfoxides have been used as new partners in diastereoselective radical cyclizations. An efficient and highly diastereoselective 6-exo-trig cyclization was observed.