Efficient Aldol-Type Reaction of O-Protected α-Hydroxy Aldehydes and N-Trimethylsilyl Ketene Imines: Synthesis of β,γ-Dihydroxy-Nitriles

An uncatalyzed aldol-type reaction of aromatic N-trimethylsilyl ketene imines with O-protected α-trialkylsilyloxy or α-benzyloxy aldehydes is reported. It is shown that N-trimethylsilyl ketene imines (SKIs) are essential for the success of this aldol-type reaction, and that almost complete control of stereochemistry in the formation of the stereocentre vicinal to the stereogenic centre present in the starting aldehyde is seen when these compounds are used. A very high syn stereoselectivity was observed at room temperature, and a reversal of stereoselectivity to favour the formation of the anti product may be achieved at low temperature. Preliminary theoretical calculations support the hypothesis that the aldol-type reaction is facilitated by the formation of a cyclic transition state, with concomitant silatropic migration from the ketene imine-nitrogen to the aldehyde oxygen. The catalyst-free aldol reaction has been applied to aromatic N-trimethylsilyl ketene imines bearing two different aromatic groups. In these reactions, the diastereoselectivity for the stereocentre arising from aldehyde sp2 carbon remained extremely high, but the stereoselectivity for the formation of the new quaternary stereocentre was unsatisfactory.