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

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.