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.

Key words

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

References

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7

Kinetic studies carried out on both reactions are consistent with imine pre-association to catalyst followed by nucleophile addition to the catalyst-imine complex (ref. [5e] and Wenzel, A. G., unpublished results).

8

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.

9

Although negligible improvement in the Strecker reaction was observed with the N-allyl benzaldimine substrate screened in this study, pronounced improvement has been observed in cases of problematic substrates. (See ref. [5e] )

10

In general, conversion was found to correlate with enantioselectivity, with the more selective catalysts also proving to be the most reactive.

11

For a comprehensive description of the effect of varying the R³ substituent on the enantioselectivity of the Strecker reaction, see ref. [5a]

12

An optimization library performed during early-phase methodological development for the Mannich reaction revealed that variation of the R³ substituent of the salicylaldimine (R³ = t-Bu, Me, H, OTIPS, t-BuO, OMe, OCO-t-Bu, Br, Cl) has no effect on enantioselectivity or conversion (ref. [6] ).

13

The Strecker reactions were carried out at lower catalyst loadings and more dilute conditions {[20] = 0.98 mM in the Strecker vs. 42 mM in the Mannich}, thereby obviating the need for a solvent switch with sparingly soluble 20.

15

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.

16

The model Strecker reaction was catalyzed by 26 in 40% ee with the opposite sense of stereoinduction relative to 1.