A general approach to medium ring azabicycles, total synthesis of cremastrine, and total synthesis of grandisine D

Abstract

The azabicyclic ring system is a common structural subunit present in numerous alkaloid natural products and serves as an important scaffold in biologically active and pharmaceutically significant compounds. Pyrrolizidine, indolizidine, pyrrolo[1,2-a]azepine, and pyrrolo[1,2-a]azocine are common examples of the azabicyclic ring system that have received much attention from the synthetic community. Due to the prevalence and importance of this scaffold, we have developed a robust, enantioselective, and functionally flexible methodology to rapidly access these diverse azabicyclic ring systems. To demonstrate the utility of our technology, we synthesized the azabicyclic alkaloids cremastrine and grandisine D. Cremastrine was reported to display selective inhibition of the muscarinic acetylcholine subtype 3 receptor and its synthesis marks the first to date. Grandisine D has been shown to selectively activate the human δ-opioid receptor and our synthesis was accomplished in the most efficient total synthesis to date.