Asymmetric synthesis and applications of β-amino Weinreb amides: Asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-a-methylbenzylamide to a range of α,β-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The β-amino Weinreb amide products may be transformed into β-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes β-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral δ-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.