Copper-catalyzed Enantioselective Conjugate Addition Reactions of Organozinc Reagents

Conjugate addition (1,4-addition) of carbon nucleophiles to a; b-unsaturated compounds is one of the most important carbon–carbon bond-forming strategies in synthetic organic chemistry [1]. The versatility of the conjugate addition is mainly due to the large variety of nucleophiles (organometallic reagents, Michael donors, other carbanions) and acceptors (a; b-unsaturated aldehydes, ketones, nitriles, phosphates, esters, and sulfones, as well as nitroalkenes) that can be used [2]. Recent progress in the development of highly enantioselective Michael additions has been reviewed [3]. The most frequently employed organometallic reagents in conjugate addition reactions are organocuprates derived from organolithium or Grignard reagents [4– 12]. A number of other transition metal catalysts (Ni, Co, Pd, Ti) and organometallic reagents (R2Zn, R3Al, RBX2) have been shown to provide valuable alternatives to organocopper chemistry for achieving this transformation [5, 12]. In particular, the exploitation of dialkylzinc reagents has been extremely successful in the development of highly enantioselective catalytic 1,4-additions in recent years [6, 9, 11, 12]. These efforts are summarized in this chapter. The conjugate addition of organometallic reagents RnM to an electron-deficient alkene under, for instance, copper catalysis conditions results in a stabilized carbanion that, upon protonation, affords the chiral b-substituted product (Scheme 7.1, path a). Quenching of the anionic intermediate with an electrophile creates a disubstituted product with two new stereocenters (Scheme 1, path b). With a prochiral electrophile, such as an aldehyde, three new stereocenters can be formed in a tandem 1,4-addition-aldol process (Scheme 1, path c). A number of conjugate additions delivering excellent enantioselectivities through the use of organocuprates in the presence of stoichiometric amounts of chiral (nontransferable) ligands are known today [7–9]. A major challenge has been the development of enantioselective 1,4-additions of Modern Organocopper Chemistry. Edited by Norbert Krause Copyright > 2002 Wiley-VCH Verlag GmbH ISBNs: 3-527-29773-1 (Hardcover); 3-527-60008-6 (Electronic)