Stereodivergent Direct Catalytic Asymmetric Mannich-Type Reactions of α-Isothiocyanato Ester with Ketimines

摘要

Chiral α,β-diamino acids are key structural motifs in many biologically active compounds. Catalytic asymmetric direct Mannich-type reactions of aldimines and nucleophiles, which contain an α-amino equivalent unit, provide straightforward access to chiral α,β-diamino acids. Unnatural amino acids that contain tetrasubstituted carbon centers are useful chiral building blocks for the synthesis of pharmaceuticals, and artificial peptides with distinctive chemical and biological properties Several research groups including ours, have reported Mannich-type reactions of aldimines with α-substituted donors, such as an alanine methyl ester Schiff base, α-substituted nitroacetates, and α-substituted oxazolones, for the synthesis of α,β-diamino acid surrogates bearing an α-tetrasubstituted carbon center.A In contrast, there are no reports of the catalytic asymmetric synthesis of β-tetrasub-stituted chiral α,β-diammo acids, which require the reaction of much less reactive ketimines. Thus, there is a high demand for the development of a new method for the synthesis of α-tetrasubstituted α,β-diamino acid surrogates. To address this issue, we herein report the utility of group 2 metal/Schiff base 1 complexes (Figure 1). The Sr/1 and Mg/1 catalysts promoted a direct Mannich-type reaction of α-methyl-α-isothiocyanato ester 2 with ketimines 3 (see Table 1), thus providing stereo-divergent access to α,β-diamino esters with vicinal tetrasubstituted carbon stereocenters.