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.

Synthesis of functionalized 1-azaspirocyclic cyclopentanones using bronsted acid or N-bromosuccinimide promoted ring expansions.

Azaspirocyclic ring systems are present in a variety of alkaloids. Functionalized 1-azaspirocyclopentanones (6, 7, 11, 12) can be efficiently constructed through semipinacol ring expansion reactions of 2-(1-hydroxycyclobutyl)-p-toluenesulfonylenamides (4) promoted by either a Bronsted acid ((S)-(+)-10-camphorsulfonic acid or HCl) or N-bromosuccinimide, an electrophilic bromine source. Reactions promoted by N-bromosuccinimide tend to proceed in higher yields (80-95%) and with greater diastereoselectivity (3:1-1:0) compared to those reactions promoted by a Bronsted acid. In addition, N-bromosuccinimide promoted reactions can produce a complementary stereochemical outcome compared to the reactions using Bronsted acid.