leahciM! The N‐heterocyclic carbene catalyzed umpolung of Michael acceptors proceeds through the formation of a deoxy‐Breslow intermediate (see scheme; EWG=electron‐withdrawing group). This nucleophilic species can react with other Michael acceptors in an intermolecular fashion, thereby resulting in the formation of homo‐ or heterodimeric olefins. This “Michael umpolung” should become a valuable method for the formation of densely functionalized olefins.

Dedicated to Professor Ronald Breslow on the occasion of his 80th birthday a-Amino acids are one of the most important classes of compounds in nature and synthetic chemistry, and, consequently, many approaches have been developed for the synthesis of enantioenriched a-amino acids.[1] Among these synthetic routes, a particularly versatile and challenging method to set up the chirality at the a position of a-amino acids is the formation of a transient enolate through a Michael addition followed by a stereoselective protonation. Enantioselective protonation is important in many biosynthetic sequences, and the development of powerful catalytic processes remains an ongoing challenge. [2,3] Many different approaches for catalyzed enantioselective protonations have been realized; however, the combination of a conjugate addition with the asymmetric protonation of a transiently formed enolate stands out as being especially efficient and atom economic. [4][5][6] In the context of a-amino acid synthesis, this strategy was first explored by Pracejus et al. in 1977 for the synthesis of cysteine derivatives with moderate enantioselectivities (up to 54 % ee) by using methyl 2-phthalimidoacrylate as the Michael acceptor and cinchona alkaloids as the chiral catalysts. [7] More recently, asymmetric approaches based on the use of organocatalysts [4c] or metal-based catalysts [6] have shown improved selectivities, but the scope has remained limited.The cyanide or N-heterocyclic carbene (NHC) catalyzed [8] addition of an aldehyde to a Michael acceptor, the Stetter reaction, [8,9] is a versatile synthetic transformation. Whereas the intramolecular asymmetric Stetter reaction has been investigated extensively by the research groups of Enders, Rovis, and others, [8,10] the more versatile intermolecular asymmetric version has proven to be much more challenging. In the last two years, the first moderately to highly enantioselective intermolecular Stetter reactions were reported by the research groups of Enders [11] and Rovis, [12] and very recently an enzyme-catalyzed variant was reported by Müller and co-workers [13] (Scheme 1). However, selectivities are not yet optimal and the substrate scope seems to be very limited-a general system remains to be found. In addition, a stereocenter is formed in the b position in each of these cases. An asymmetric Stetter reaction that builds up only a stereocenters seems to be even more challenging. The key to success might be a highly stereoselective intramolecular proton transfer that relays the stereochemical information after the initial enantioselective attack of the Breslow intermediate on the Michael acceptor (Scheme 2). Herein we report a highly asymmetric intermolecular Stetter reacScheme 1. Chiral NHC- [11,12] or enzyme-catalyzed [13] intermolecular asymmetric Stetter reactions. EWG = electron-withdrawing group, Ar = aromatic group, Het = heteroaromatic group, R = rest.Scheme 2. Proposed reaction pathway for an intermolecular enantioselective Stetter reaction.

The N-heterocyclic carbene (NHC)-catalyzed hydroacylation of unactivated alkynes to provide alpha,beta-unsaturated ketones is reported. In addition, a rare case of an efficient and selective dually NHC-catalyzed cascade reaction involving the hydroacylation of alkynes and a subsequent intermolecular Stetter reaction allows the formation of chromanones containing a 1,4-diketone moiety.

Scheme 1. Metal-free asymmetric halocyclization with a C nucleophile. Tf = trifluoromethanesulfonyl.

Simple Stetter: A novel N-heterocyclic carbene (NHC) was designed by combining an electron-rich 2,6-dimethoxy substituent and an underestimated yet promising chiral motif. With this NHC in hand, a highly enantioselective intermolecular Stetter reaction of simple acrylates was developed, yielding versatile α-chiral γ-ketoesters. This represents the first catalytic asymmetric route towards these valuable compounds (see scheme).