Total Synthesis of (-)-Stemoamide

Link: JOC Note ASAP

Staffan Torssell, Emil Wanngren, and Peter Somfai*

KTH Chemical Science and Engineering, Department of Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden

This is a rather short synthesis of (-)-stemoamide (1), the simplest member of various alkaloids present in Stemona tuberosa. Traditionally, the root extracts of this plant have been employed in Chinese and Japanese folk medicine for respiratory disorders and also as an antihelminthic.The synthesis started with lactam alcohol 4. Following routine reactions, beta,gamma-ester 2 was rapidly constructed. The reaction sequence featured N-alkylation of 6, one-carbon homologation from aldehyde to alkyne using Ohira-Bestmann diazophosphonate 8, iodoboration of 5 to give 3, Pd-catalyzed Negishi cross-coupling of 3 with Reformatsky reagent 9 which required DMPU a co-solvent, and finally RCM with Grubbs' 2nd generation catalyst.The installation of the lactone ring was first planned through hydroboration-oxidation followed by lactonization. However, several hydoration conditions tried either did not give any product or caused decomposition (9-BBN/THF or BH3-THF at both low and high temperatures). Thinking that failure was caused by the ester group, it was reduced to alcohol, but the reaction still failed.The lactonization was finally realized through lactonization-bromination of the carboxylic acid generated from ester 2, followed by in situ elimination of HBr to give 12. The synthesis was completed when 12 was subjected to 1,4-reduction to give 13 stereoselectively (NiCl2/NaBH4) via more accessible beta face, followed by a previously reported protocol of alpha-methylation. This also constituted an efficient strategy to install a C8-C9 trans-ring junction.The reaction was completed stereoselectively in only 12 steps from commercially available (S)-pyroglutaminol (4).