In the last decade, remarkable progress has been made toward direct catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products under operationally simple and environmentally friendly conditions. [1] In enamine catalysis, significant effort has focused on understanding the origin of diastereo-and enantioselectivity in organocatalysis. These studies have facilitated the design of syn-selective aldol and anti-selective Mannich reactions not originally addressed by organocatalytic methods. [2][3][4][5] The organocatalytic Michael reaction is often regarded as one of the most efficient and broadly applicable carbon-carbon bond-forming reactions known because a wide variety of acceptors can be employed and high stereoselectivity has been realized. [6] Although a large number of reports on the organocatalytic Michael reaction of aldehydes have been published, to the best of our knowledge, all of these reactions are syn selective. [7] Several studies, however, have reported success in the anti-selective organocatalytic Michael reaction of ketones. [8] Herein, we report the first highly anti-selective asymmetric Michael reactions of aldehydes and nitroolefins using a strategy designed to control the configuration of the reacting enamine.
The predominant stereochemical outcome of the enamine-based Michael reaction was first explained in the classic studies of Seebach and co-workers. [9] Seebach deduced that high syn selectivity can be explained by an acyclic synclinal transition-state model (Scheme 1 a). [9a] In this transition state, the thermodynamically stable E enamine reacts with E nitroolefins in a synclinal arrangement, in which the actual donor and acceptor atoms are situated close to each other (see NO 2 and NR'R'' in Scheme 1 a).
We have explored two routes for control of the overall diastereoselectivity of organocatalytic enamine reactions: 1) controlling the face selectivity of the reactive enamine to affect anti-Mannich reactions [2] and 2) controlling the E/Z configuration of the reactive enamine