Divergent Stereoinduction Mechanisms in Urea-Catalyzed Additions to Imines

Abstract

Catalyst structure/enantioselectivity profiles for the asymmetric Strecker and Mannich reactions were obtained through systematic variation of each modular component of the catalyst. Althoug­h the thiourea derivative 1 afforded optimal results in both reactions (97-98% ee), the structural elements responsible for stereo­induction were found to be fundamentally different. Insights gleaned from these studies led to the development of a new generatio­n catalyst for the Mannich reaction that promotes the asymmetric silyl ketene acetal addition to N-Boc benzaldimine in 94% ee. The new catalyst is a simple amino acid derivative possesses­ing less than half the molecular weight and two fewer stereo­centers relative to 1.

asymmetric catalysis - organocatalysis - nucleophilic additions - imines - substituent effects

References

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The standard screening conditions are depicted in Scheme [1] . Benzaldimines were chosen as substrates for each reaction to maximize structural and electronic similarity. While aliphatic N-alkyl imines have been successfully employed in the Strecker reaction, aliphatic N-Boc aldimines have not been investigated in the Mannich reaction because no useful method has been identified for their synthesis.

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<A NAME="RY00903ST-12">12</A>

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Analogs of 24 derived from less sterically demanding amino acids (e.g. valine, alanine) also performed poorly as catalysts for the Mannich reaction. Catalyst 24 proved almost completely unreactive in the Strecker reaction.

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