Direct Catalytic Asymmetric Aldol Reactions of Aldehydes with Unmodified Ketones

摘要

The aldol reaction is one of the most powerful of carbon-carbon bond-forming reactions, and the development of a range of catalytic asymmetric aldol-type reactions has thus proven to be a valuable contribution to asymmetric synthesis. In all of theseasymmetric aldol-type reactions, however, pre-conversion of the ketone moiety to a more reactive species such as an enol silyl ether, enol methyl ether, or ketene silyl acetal is an unavoidable necessity. Development of a direct catalytic asymmetric aldol reaction, starting from aldehydes and unmodified ketones is thus a worthwhile endeavor. Such reactions are known in enzyme chemistry: the fructose-1,6-bisphosphate and dihy-droxyacetone phosphate (DHAP) aldolases are characteristic examples. The mechanism of these is thought to involve cocatalysis by a Zn~(2+) ion and a basic functional group in the enzyme's active site; the latter abstracts a proton in proximity to a carbonyl compound while the former functions as a Lewis acid to activate the secondcarbonyl component. These aldolases can thus be thought of as multifunctional catalysts displaying both Lewis acidity and Bransted basicity, so making possible efficient catalytic asymmetric aldol reactions under typically mild in vivo conditions. An analogous cooperative mode of action can be seen in reactions mediated by any of several heterobimetallic asymmetric catalysts having both Lewis acidity and Brensted basicity, which have been developed by our research group.