The Shindo Synthesis of Stemonamine

Stemonamine (3), isolated from the Chinese medicinal shrub Stemona sessilifolia, shows significant antitussive activity. Mitsuru Shindo of Kyushu University envisioned that the cyclopentenone of 3 could be installed by the cyclization of 1 to 2 (Chem. Eur. J. 2018, 24, 1539. DOI: 10.1002/chem.201706057).

For the assembly of 1, the authors combined two enantiomerically pure starting materials. Following the procedure of Denmark, they prepared the lactone 7 from L-malic acid (4).

The pyrrolidine of 1 was sourced from L-proline (8). As developed by Williams, condensation with the hemiacetal 9 led to 10, that was alkylated with allyl bromide, leading to 11. Reductive deprotection followed by reprotection then completed the preparation of 12.

Coupling of 7 with 13 gave 14, that on hydrolysis led to 15. Transmetalation of the derived iodide gave an intermediate organolithium, that cyclized to 16. On exposure to Ph₃P/I₂, the bridging oxygen was converted to the secondary iodide, that was reduced with zinc to give 1. On exposure to 17, the keto ester cyclized to a β-lactone, that lost CO₂ by chelotropic elimination to complete the assembly of 2.

Condensation of 2 with propionaldehyde followed by oxygenation gave the β-diketone. Oxygenation proceeded with significant diastereoselectivity, leading to the alcohol 19. Cyclization of the derived carbonate followed by O-methylation led to 20, that was selectively deoxygenated to stemonamine (3).

Natural products are usually isolated in enantiomerically pure form, but stemonamine (3) as isolated was racemic. The synthetic stemonamine prepared in enantiomerically enriched form readily racemized, and also epimerized to 21. Remarkably, the racemization proceeded more rapidly than did the epimerization.