5-(Pyrrolidine-2-yl)tetrazole: Rationale for the increased reactivity of the tetrazole analogue of proline in organocatalyzed aldol reactions

5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1), i.e. the tetrazolic acid analogue of proline, has been found to be significant more reactive than L-proline (2) in various organocatalyzed reactions. In the organocatalyzed direct asymmetric aldol reaction, acetone was reacted with aromatic and aliphatic aldehydes to afford the resulting beta-hydroxy ketones in good yields and moderate to high enantiomeric excesses. The increased reactivity of 1, as compared to 2, has been rationalized through a combined computational and NMR spectroscopic study. It was found that catalyst 2 was almost completely engaged in oxazolidinone formation with the aldehyde whereas 1 did not take part in such parasitic equilibrium. This finding, together with the improved solubility of the tetrazole analogue, is proposed to account for the observed reactivity. (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim., Germany, 2005.