Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocenters

Abstract

Asymmetric transformationsi and transition metal-catalyzed cross-coupling reactionsii are critical components of modern organic synthesis. The impact of these reactions on synthetic chemistry and related fields can be measured in many ways. For example, in 2001 the Nobel Prize in chemistry was awarded to Dr. William Knowles, Professor Ryoji Noyori, and Professor K. Barry Sharpless for their contributions to catalytic asymmetric synthesis. Then, in 2010, Professors Richard Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the Nobel Prize for pioneering the development of catalytic cross-coupling reactions. The intersection of these two areas of research, the development of cross-coupling reactions that construct stereogenic centers though incorporation and control of secondary sp3 hybridized fragments, has emerged as an important frontier in reaction design.iii,iv The first stereochemical investigations of such cross-coupling reactions were primarily performed as part of stoichiometric mechanistic studies. The field has since evolved to encompass target-oriented endeavors and enable precise formation and manipulations of stereogenic centers. We now have a growing pool of cross-coupling reactions from which to construct tertiary stereogenic centers with excellent stereoselectivity. Stereochemical control in alkyl cross-coupling reactions can be accomplished in several ways. In a substrate-controlled stereoselective reaction, also referred to as a stereospecific reaction, stereochemical information is transferred from one of the starting materials to the product. For example, during a stereospecific cross-coupling reaction an enantioenriched electrophile will provide enantioenriched product in the presence of an achiral catalyst. Alternatively, an enantioenriched alkyl metal reagent can also be used to achieve a stereospecific cross-coupling. These two scenarios are illustrated in Scheme 1a. The success of the reaction can be determined by measuring enantiospecificity (es), which is calculated by dividing the enantiomeric excess (ee) of the product by the ee of the starting material.v In contrast, stereoselectivity can be controlled by chiral ligands on the metal in a catalyst-controlled stereoselective reaction. These reactions occur through a stereoconvergent process, utilizing racemic electrophiles or transmetalating agents (Scheme 1b). Scheme 1 General types of asymmetric cross-coupling reactions. This review will focus on the cross-coupling reactions of secondary alkyl reagents that afford enantioenriched tertiary carbon centers. The main sections will cover the two approaches outlined above; first, stereospecific reactions will be discussed, then stereoselective reactions that are controlled by chiral catalysts will be reviewed. Asymmetric substitution reactions of cuprates with alkyl halides and tosylates will also be presented to provide relevant context for subsequent development of catalytic methods. While there are many excellent diastereoselective cross-coupling reactions, we will focus on enantioselective variants that cannot be influenced by thermodynamic preference for formation of one diastereomer. Allylic displacement reactions,vi asymmetric Heck reactionsvii and cross-coupling reactions that result in products with axial chiralityviii will not be discussed in this review. Additionally, desymmetrization reactions of achiral compounds in cross-coupling reactions to construct tertiary and quaternary stereocenters are outside the scope of this review.ix We refer the reader to other recent reviews of asymmetric cross-coupling reactionsx and, for general discussions of cross-coupling reactions with alkyl partners, we refer the reader to recent reviews on cross-coupling reactions with alkyl halidesiii and alkyl metal complexes.iv