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Published November 14, 2012 | public
Book Section - Chapter

Catalytic Enantioselective Alkylation of Prochiral Ketone Enolates


The synthesis of stereogenic all-carbon quaternary centers remains a formidable challenge, notwithstanding the strides made by modem organic chemistry in this regard. Contemporary advances in enolate alkylation have made it a fundamental strategy for the construction of C-C bonds. Although methods for the reaction of a number of enolate types (e.g., ester, ketone, and propionimide) with a variety of alkylating agents exist, catalytic enantioselective variants of these transformations are relatively rare. Of the catalytic asymmetric methods available, there have been few examples of general techniques for the asymmetric alkylation of carbocyclic systems and still fewer examples that have the capacity to deliver all-carbon quaternary stereocenters. While the Merck phase transfer methylation and Koga alkylation of 2-alkyltetralone-derived silyl enol ethers represent notable exceptions, the breadth of application and utility of these reactions bas been limited. In fact, at the outset of our investigations in this area, there were no examples of catalytic enantioselective alkylations of monocyclic 2-substituted cycloalkanone enolates in the absence of either α'-blocking groups or α-enolate-stabilizing groups (e.g., R = aryl, ester, etc.; Figure 1). Concurrent to our work in this area, Trost and coworkers have published a series of papers that complement our studies. Jacobsen and coworkers, as well, have revealed a unique enantioselective method involving the chromium-catalyzed reaction of tin enolates with a variety of unactivated alkyl halides . Herein, we relate our development of Pd-catalyzed enantioselective functionalization reactions of prochiral enolates, specifically tetrasubstituted cyclic ketone enolates that give rise to quaternary stereogenicity. The synthetic utility of the building blocks derived from these reactions is demonstrated by application in a number of total syntheses.

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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. Published Online: 14 Jan 2013; Published Print: 14 Nov 2012

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