Pushing the Limits of Aminocatalysis: Enantioselective Transformations of α-Branched β-Ketocarbonyls and Vinyl Ketones by Chiral Primary Amines

Enantioselective α-functionalizations of carbonyl compounds are fundamental transformations for the asymmetric synthesis of organic compounds. One of the more recent developments along this line is in aminocatalysis, which leads to the direct α-functionalization of simple aldehydes and ketones. However, most of the advances have been achieved with linear aldehydes and ketones as substrates. Effective aminocatalysis with α-branched carbonyls, particularly α-branched ketones, has remained elusive. The primary difficulty arises from the space-demanding α-substituent, which impedes iminium/enamine formation. In 2005, synthetic organic chemists revived catalysis using primary amines, which brought new attention to these challenges, because of the conformational flexibility of primary amines. On the basis of early biomimetic studies by Hine, in 2007 we developed the bioinspired chiral primary amine catalysts featuring primary-tertiary diamines. This type of catalyst involves enamine/iminium catalysis, and we could apply this chemistry to all of the major types of ketones and aldehydes. In this Account, we present research from our laboratory that significantly expands aminocatalysis to include α-branched ketones such as β-ketocarbonyls and α-substituted vinyl ketones. Our primary amine catalysis methodology, when used alone or in conjunction with metal catalysts, provides convenient access to both enantiopure α-tertiary and quaternary ketones, structures that are not available via other approaches. Our mechanistic studies showed that acidic additives play the critical role in facilitating catalytic turnover, most likely by shuttling protons during the enamine/iminium tautomerizations. These additives are also critical to induce the desired stereochemistry via ammonium N-H hydrogen bonding. Proton transfer by shuttling is also stereoselective, resulting in enantioselective enamine protonation as observed in the reactions of α-substituted vinyl ketones. In addition, we have carried out density functional theory studies that help to delineate the origins of the stereoselectivity in these reactions.