Synthesis of (-)-halichonic acid and (-)-halichonic acid B.

Abstract

The first syntheses of the amino acids (-)-halichonic acid and (-)-halichonic acid B have been achieved in ten steps starting from commercially available (-)-α-bisabolol. The optimized synthetic route includes a new purification method for isolating (-)-7-amino-7,8-dihydrobisabolene in enantiomerically pure form via recrystallization of its benzamide derivative. The key intramolecular aza-Prins reaction forms the characteristic 3-azabicyclo[3.3.1]nonane ring system of halichonic acid along with the lactonized form of halichonic acid B in an 8:1 ratio. Optical rotation measurements confirmed that these synthetic compounds were in fact the enantiomers of the natural products, establishing both the relative and absolute configurations of the halichonic acids.