Direct Transformation of N-Protected α,β-Unsaturated γ-Amino Amides into γ-Lactams through a Base-Mediated Molecular Rearrangement

J Org Chem. 2019 Dec 6;84(23):15145-15153. doi: 10.1021/acs.joc.9b01936. Epub 2019 Nov 11.

Abstract

Here, we are reporting a single-step transformation of N-protected α,β-unsaturated γ-amino amides into 5,5-disubstituted γ-lactams through a base-mediated new molecular rearrangement. In contrast to the known N- to C(O) cyclization of saturated γ-amino acids into corresponding γ-lactams, the new rearrangement involves the cyclization between N-terminal Cγ- to C-terminal amide N. The cyclization process was initiated by the migration of double bond from α,β → β,γ position. The enamine-imine tautomerization of the new β,γ-double bond and subsequent 5-exo-trig cyclization of terminal amide leads to the formation of N-protected 5,5-disubstituted γ-lactam. The structures of various γ-lactams obtained from the rearrangement were studied in single crystals. Overall, the results reported here demonstrate the facile and single-step transformation of N-protected α,β-unsaturated γ-amino amides into γ-lactams and provided an excellent opportunity to construct small-molecule peptidomimetics.

Publication types

  • Research Support, Non-U.S. Gov't