Javier Adrio

Novel dipolarophiles and dipoles in the metal-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides

The catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides constitutes one of the most powerful and atom economical methods for the enantioselective construction of pyrrolidines. This article highlights the recent developments in this area, with special focus on contributions improving the structural scope at the dipolarophile and azomethine ylide partners.

Bis-sulfonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3 + 2] cycloaddition of azomethine ylides.

Enantioenriched 3-pyrrolines have been synthesized by highly enantioselective Fesulphos-Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl ethylene, followed by reductive sulfonyl elimination. High levels of reactivity, exoselectivity, and enantioselectivity have been accomplished for a variety of substituted azomethine ylides. This cycloaddition-desulfonylation strategy has been applied as a key step in the enantioselective synthesis of a biologically active C-azanucleoside.

Palladium-Catalyzed Cross-Coupling Reaction of Secondary Benzylic Bromides with Grignard Reagents

A mild palladium-catalyzed Kumada-Corriu reaction of secondary benzylic bromides with aryl and alkenyl Grignard reagents has been developed. In the presence of the Xantphos ligand, the undesired beta-elimination pathway is minimized, affording the corresponding cross-coupling products in acceptable to good yields. The reaction proceeds with inversion of the configuration.

Pauson−Khand Reactions of Electron-Deficient Alkenes

Despite the common perception that alkenes possessing electron-withdrawing groups are not adequate substrates for Pauson−Khand (PK) reactions, a number of successful examples of this reaction involving electron-deficient alkenes, such as α,β-unsaturated ketones, esters, nitriles, sulfoxides and sulfones, have been reported in recent years. In the case of the intramolecular PK reaction of 1-sulfinyl-1,6-enynes and 1-sulfonyl-3-oxygenated-1,6-enynes these processes have been applied in asymmetric synthesis. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Catalytic Asymmetric Synthesis of α‐Quaternary Proline Derivatives by 1,3‐Dipolar Cycloaddition of α‐Silylimines

Pyrrolidines and derivatives are privileged scaffolds in synthetic and medicinal chemistry, and are present in a myriad of natural products and biologically active compounds. In particular, modified proline derivatives have been extensively used as conformationally rigid cores in peptidomimetics. In this area, a-quaternary amino acids have received great attention since this type of unit improves the lipophilicity and restricts the conformational flexibility of the peptidic chain, and therefore has a great impact in the biological activity. Furthermore, a-quaternary prolines have found wide application as chiral synthons and organocatalysts in organic synthesis. As a consequence, a variety of strategies for their enantioselective preparation, mainly based on the funtionalization of l-proline, have been reported. Despite this progress, the development of efficient asymmetric methodologies to access densely substituted aquaternary prolines are still in high demand. The catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with activated olefins is one of the most reliable and straightforward approaches to the preparation of optically active highly substituted 2-carboxylate pyrrolidine derivatives. Since the seminal contributions of Zhang and coworkers and Jørgensen and co-workers in the metalcatalyzed enantioselective preparation of 2,5-disubstituted pyrrolidine derivatives using Schiff bases of amino acid esters as azomethine precursors, outstanding progress has been achieved in this research area. 9] In this context, and because of its high reactivity, glycinate imines are the most frequently employed azomethine ylide precursors in this reaction. a-Silylimines constitute a different and much less studied type of azomethine ylide precursor, which leads to 5unsubstituted pyrrolidines, a substitution pattern not accessible by the typical process from Schiff bases of amino acid esters (Scheme 1a). However, despite this structural interest, as far as we are aware, their use in catalytic asymmetric processes remains undocumented.

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of α‐Iminonitriles

The 1,3-dipolar cycloaddition of azomethine ylides with alkenes is one of the most powerful and convergent methods for the stereoselective synthesis of pyrrolidines, a heterocyclic moiety widely present in the structure of natural products, pharmaceuticals and chiral ligands. Improving the overall chemical and stereochemical efficiency of this reaction, pioneered by Grigg with stoichiometric metal chiral complexes, a great effort has been devoted in recent years in the development of catalytic asymmetric protocols. In this field a wide variety of outstanding chiral complex catalysts have been reported, mainly Ag, Cu and Cu catalysts, but also Zn, Ni and Ca complexes. In addition, several organocatalytic asymmetric methods have been also developed in the last few years. Concerning the scope of the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides, although there is an ample tolerance with regard to the nature of the dipolarophile (i.e., a,b-unsaturated esters, maleimides, a,b-unsaturated nitriles, enones, enals, nitroalkenes, vinyl sulfones and fullerene), the structural variety at the azomethine dipole is much more limited. By far most catalytic asymmetric versions reported to date are based on the use of a-iminocarbonyl substrates, specifically a-iminoesters. The great effectiveness of a-iminoesters as dipole precursors relies on the enhanced acidity of the a-position and the formation of a robust five-membered, N,O-bidentate-metalated, azomethine ylide, which facilitates the asymmetric induction from the chiral ligand. The inherent limitation of this strategy is the restricted structural versatility with regard to the substitution at C2, always providing pyrrolidines with a C2 carboxylate ester substitution. To access other types of substituted pyrrolidines, a-iminonitrile precursors are very appealing, since in the resulting 2-cyanopyrrolidines the cyano group could further act as leaving group allowing its formal substitution by hydrogen or by a carbon nucleophile, and thus leading to a wider variety of substituted pyrrolidines. Two decades ago KaneACHTUNGTRENNUNGmasa, Tsuge et al. reported the non-enantioselective thermal and LDA-promoted (LDA= lithium diisopropylACHTUNGTRENNUNGamide)[10] cycloaddition of alkyl-substituted a-iminonitriles with electron-deficient dipolarophiles, but the catalytic asymmetric version of this process remained to be developed. We describe herein the first catalytic asymmetric procedure for the 1,3-dipolar cycloaddition of a-iminonitriles, as well as some synthetic applications and a DFT theoretical study on the presumed nature of the metalated 1,3-dipole. To evaluate the viability of a-iminonitriles as dipole precursors in catalytic asymmetric 1,3-dipolar cycloadditions, we first studied the reaction of N-benzylidenaminoacetonitrile (1) with methyl acrylate in the presence of ligand Fesulphos (2, 10 mol %). This ligand had proved to be very efficient in the 1,3-dipolar cycloadditions of a-iminoesters with a wide variety of dipolarophiles (acrylates, maleates, fumarates, maleimides, enones, bissulfonylethylenes and fullerene), providing the pyrrolidines usually with high control of the endo/exo selectivity and enantioselectivity. However, a very poor reactivity and stereoselectivity was obtained in the reaction of methyl acrylate with a-iminonitrile 1 a in the presence of a variety of copper and silver salts (11% yield and 22 % ee for the major adduct as the best results, Scheme 1). In an attempt to find a more efficient catalyst system for this reaction we next tested a variety of ligands, albeit with moderate success. A promising enantioselectivity was found with AgOAc/Taniaphos (3) as catalyst system (30 % yield, 68 % ee for endo-4). To improve the efficiency of the process we next applied this catalyst system to a more reactive dipolarophile, such as dimethyl fumarate (Table 1). Interestingly, unlike the previously reported thermal or LDA-mediated reactions, which give rise to C2/C5 cis/trans mixtures of isomers, this catalytic asymmetric reaction provided exclusively the C2/C5 [a] R. Robles-Mach n, Dr. I. Alonso, Dr. J. Adrio, Prof. Dr. J. C. Carretero Departamento de Qu mica Org nica, Facultad de Ciencias Universidad Aut noma de Madrid Cantoblanco 28049 Madrid (Spain) Fax: (+34) 914973966 E-mail : javier.adrio@uam.es juancarlos.carretero@uam.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200903443.

Cu-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides with β-Phenylsulfonyl Enones. Ligand Controlled Diastereoselectivity Reversal

A catalytic asymmetric procedure for the 1,3-dipolar cycloaddition of (E)-beta-phenylsulfonyl enones with azomethine ylides to provide highly functionalized pyrrolidine derivatives is described. In the presence of chiral Cu(I)-Segphos catalysts the adducts were obtained with high regio-, diastereo-, and enantioselectivity. Interestingly, a switch from endo to exo selectivity was observed when Segphos or DTBM-Segphos ligand was used.

Au-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with maleimides.

An efficient protocol for the Au(I)-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with phenylmaleimide has been developed. In the presence of cationic Au(I)/DTBM-segphos complex, excellent diastereoselectivity and high levels of enantioselectivity (up to 97% ee) have been attained with a variety of α-substituted isocyanoacetates. The synthetic potential of the resulting enantioenriched 1-pyrrolines has been demonstrated by the preparation of highly substituted pyrrolidines bearing a quaternary stereocenter.

Pyrrole and Oligopyrrole Synthesis by 1,3-Dipolar Cycloaddition of Azomethine Ylides with Sulfonyl Dipolarophiles

A procedure for the synthesis of functionalized, substituted pyrroles by 1,3-dipolar cycloaddition of azomethine ylides has been developed. This protocol is based on the metal-catalyzed cycloaddition of alpha-iminoesters with sulfonyl dipolarophiles, followed by the base-promoted elimination of the sulfonyl groups. A wide variety of 2,5-disubstituted and 2,3,5- and 2,4,5-trisubstituted pyrroles have been prepared in satisfactory yields from 1,2-bis(sulfonyl ethylene), beta-sulfonylenones, and beta-sulfonylacrylates. This method can be applied in an iterative and straightforward manner to the construction of oligopyrroles, from bipyrroles to pentapyrroles. Iterative [n+1] and [n+2] approaches have been devised, the latter involves double 1,3-dipolar cycloaddition from pyrrolyl-based bis(iminoesters).

N-(2-pyridylmethyl)imines as azomethine precursors in catalytic asymmetric [3 + 2] cycloadditions.

An efficient Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition of N-(2-pyridylmethyl) imines has been developed. In the presence of a Cu(CH(3)CN)(4)PF(6)/bisoxazoline catalyst system, high levels of enantioselectivity (up to 97% ee) and moderate to high exo selectivity were achieved with a wide variety of substituted dipolarophiles, including maleimides, fumarates, fumarodinitrile, enones, and nitroalkenes. The reaction with unsymmetrically substituted dipolarophiles is completely regioselective.