Double Bond Isomerization/Enantioselective Aza-Petasis-Ferrier Rearrangement Sequence as an Efficient Entry to Anti- and Enantioenriched β-Amino Aldehydes

摘要

Considerable efforts have been devoted to the development of syn-or anti-selective synthesis of β-amino aldehydes in an optically active form, which are versatile synthetic precursors of amino alcohols, amino acids, β-lactams, and amino sugars, among others. Organocatalysis in direct Mannich reactions of aldehydes with aldimines using chiral secondary amine catalysts has emerged as a powerful method to provide β-amino aldehydes in high diastereo- and enantioselectivities. However, one critical drawback inherent in the methodologies reported to date is that aromatic or glyoxylate-derived aldimines are employed as adaptive substrates in most cases. The enantioselective direct Mannich reaction of aliphatic aldimines has largely been unexploited because these aldimines are readily isomerized to their enamine form. To overcome this intrinsic problem, we envisioned an alternative strategy to furnish optically active β-amino aldehydes having an aliphatic substituent (R~1) at the β-position by a combination of two catalytic reactions (Scheme 1).