C o n s t r u c t i o n o f Q u a t e r n a r y S t e r e o g e n i c C a r b o n C e n t e r s Abstract: Highly site-selective Mukaiyama-Michael additions of silyl ketene imines to a,b-unsaturated aldehydes and ketones are described. The combination of silicon tetrachloride and a chiral bisphosphoramide provides an effective catalyst system for promoting the addition of silyl ketene imines to a variety of aromatic enals with high site selectivity and moderate to good diastereo-and enantioselectivity.The catalytic, enantioselective synthesis of compounds containing quaternary stereogenic carbon centers continues to provide organic chemists with challenges for catalyst design and reaction development. 1 The key issue in the construction of these centers is to identify catalyst systems that can overcome the substantial steric encumbrance encountered in the carbon-carbon bond-forming event, while still providing an effective environment for obtaining high asymmetric induction. Although a number of elegant solutions have recently been devised for achieving this goal, certain types of reaction frameworks still present significant obstacles and provide platforms for novel catalyst design and innovation in synthetic methods.An important transformation that presents promising opportunities for setting quaternary stereogenic centers is the Michael reaction. 2 This venerable process has long been recognized as one the most reliable methods for carbon-carbon bond formation as it allows for the preparation of the synthetically useful class of 1,5-dicarbonyl compounds. Moreover, the high exothermicity of the catalytic Michael reaction provides the energy needed to overcome the steric strain of setting a quaternary center. The successful implementation of a catalytic, enantioselective variant of this reaction 3 requires a catalyst that can control the relative and absolute topicity for the combination of two fully substituted sp 2 centers. For activation of the nucleophile, the catalyst has to control the configuration of a disubstituted enolate. On the other hand, activation of the electrophile requires the catalyst to be coordinated selectively at one of the binding sites of the Lewis basic oxygen (anti vs. syn, Scheme 1) and also control the conformation of the conjugated double bonds in the acceptor (s-cis vs. s-trans, Scheme 1). 4 In recent years, creative solutions to these challenges have appeared that provide Michael addition products containing quaternary stereogenic carbons in good yield and high selectivity. 1,2
Scheme 1Despite these achievements some limitations still exist for certain combinations of donors and acceptors. For example, existing methods are limited to readily enolizable carbonyl compounds, such as b-keto esters, a-cyano ketones, and b-diketones in combination with acyclic and cyclic ketones. The addition of simple ketones, esters or nitriles to a,b-unsaturated aldehydes or ketones finds no general solution for the synthesis of quaternary stereogenic carbon centers because of the problem of controlli...