C-5 Functionalization of (S)-Nicotine via 1-Acyl-1,4-dihydronicotine

Significance

A reasonably efficient deheteroaromatization-reheteroaromatization route to the anti-Parkinson agent SIB-1508Y is reported. Starting from readily available (S)-nicotine, reductive acylation via a disilylated intermediate, following chemistry previously developed in the Comins group (E. D. Smith, F. C. Février, D. L. Comins Org. Lett. 2006, 8, 179-182), leads to 1,4-tetrahydronicotine 1. Vielsmeier-Haack reaction followed by decarbomethoxylation affords aldehyde 2 in moderate overall yield. The rearomatization step to 5-formylnicotine (3) was achieved in a classical manner by heating with sulfur. Finally, a Seyferth-Gilbert homologation was used to form the alkyne moiety. SIB-1508Y is thus obtained in six steps and with an overall yield of 20%.