Enantioselective Protonation

Abstract

Enantioselective protonation is a common process in biosynthetic sequences. The decarboxylase and esterase enzymes that effect this valuable transformation are able to control both the steric environment around the proton acceptor (typically an enolate) and the proton donor (typically a thiol). Recently, several chemical methods to achieve enantioselective protonation have been developed by exploiting various means of enantiocontrol in different mechanisms. These laboratory transformations have proven useful for the preparation of a number of valuable organic compounds.A fundamental method to generate a tertiary carbon stereocenter is to deliver a proton to a carbanion intermediate. However, enantioselective transfer of a proton presents unusual challenges, specifically, manipulating a very small atom and avoiding product racemization at a particularly labile stereocenter. As a result, the conditions for a successful enantioselective protonation protocol may be very specific to a certain substrate class. Tertiary carbon stereocenters are extremely common in valuable biologically active natural products, and thus the need for synthetically useful enantioselective methods to form these stereocenters is vital. 1In this review, we discuss several strategic approaches to enantioselective protonation. Emphasis has been placed on recently developed methods and their accompanying mechanisms in order to update the most recent prior reviews on this topic. 2,3,4,5,6,7,8 Each method relies on particular stereochemical control elements based on the mechanism of the protonation transformation. Appreciation of these controlling elements may lead to improved methods for preparing valuable chiral materials for a variety of synthetic applications. Important Factors in Achieving Enantioselective ProtonationSeveral of the most important practical features of enantioselective protonation were enumerated in Fehr's 1996 review. 2 Principal among these is the fact that enantioselective protonations are necessarily kinetic processes since under thermodynamic control racemate would be formed. Accordingly, it is often necessary to match the pK a of the proton donor and the product to prevent racemization before product isolation. It is unfortunate that the same anion stabilizing groups (e.g., ketones) that make protonations relatively easy to achieve also impart a degree of instability in the product. This has led some researchers to explore hydrogen atom transfer reactions in lieu of Brønsted acid-mediated protonations (see the subsection Enantioselective Hydrogen Atom Transfer below).Correspondence should be addressed to B.M.S. stoltz@caltech.edu. The authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Chem. Author manuscript; available in PMC 2010 April 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn addition to the obvious challenges of product stability under the reaction conditions, the rapid rate of proton exchange in solution often leads to significant l...