Synthetic Studies toward Halichlorine: Complex Azaspirocycle Formation with Use of an NBS-Promoted Semipinacol Reaction

The investigations of a synthetic route incorporating a NBS-promoted semipinacol rearrangement to the 6-azaspiro[4.5]decane fragment within halichlorine (1) are presented. A convergent approach was pursued, utilizing two chiral, enantiomerically enriched building blocks, 2-trimethylstannyl piperidene 10 and substituted cyclobutanone 19. Noteworthy synthetic operations in this study include the following: (a) a highly diastereoselective NBS-promoted semipinacol reaction that established four stereogenic centers in ketone 25 and (b) the use of a N-p-toluenesulfonyl-2-iodo-2-piperidene as a precursor to a basic organometallic reagent, which was critical to the success of the coupling of fragments 10 and 19.