Total synthesis of (+)-scholarisine A

A total synthesis of (+)-scholarisine A, a monoterpenoid indole alkaloid belonging to the akuammiline family of alkaloids, was undertaken due to the inherent synthetic challenge as well as the possibility of discovering a route to access the akuammiline alkaloid family. An effective total synthesis of (+)-scholarisine A was planned after an extensive literature search elucidated successful synthetic tactics and strategic pitfalls discovered by others during earlier efforts. An enantiospecific synthesis of (+)-scholarisine A was next implemented employing a 25-step sequence. Highlights of the synthesis include a reductive cyclization, involving a nitrile and an epoxide; a modified Fischer indole protocol; a late stage oxidative-lactonization; and an intramolecular cyclization leading to the indolenine ring system of (+)-scholarisine A. Finally, a retrobiosynthetic fragmentation of scholarisine A has been demonstrated. Exploitation of this fragmentation is expected to provide synthetic access to the entire akuammiline alkaloid family