Online

Sadlowski, Corinne Marie

Chemistry

2015

PhD

Progress towards a concise total synthesis of subincanadine E is reported. This natural product was first isolated from the Picralima nitida cell suspension culture line in 1982 under the name pericine and later in 2002 from Aspidosperma subincanum as subincanadine E. It is the most potent compound of its class with in vitro cytotoxicity against both murine lymphoma L1210 and human epidermoid carcinoma KB cells (LD50, 0.3 ug/mL and 4.4 ug/mL, respectively) and was found to be six times more potent than codeine as an opiate agonist in a 3H-naloxone binding study (IC50, 0.6 umol/L). The first-generation synthesis produced an undesired internal olefin that, upon attempted isomerization, catalyzed an unusual intermolecular Diels-Alder reaction. A revised second-generation synthesis employed (±)-harmicine and showcased an intramolecular Pd-catalyzed cross-coupling reaction that furnished an unanticipated 5-membered ring instead of the predicted 6-membered ring via methylene linker activation. Further studies utilizing an amide intermediate and organocuprate chemistry produced no desired carbon-carbon bond formation. A third-generation synthesis was carried out from enantiopure (S)-carvone. This route explored regioselective oxime formation and protecting group manipulations for a subsequent Beckmann rearrangement, which provided the first access to 5-amino derivatives of carvone. An intramolecular Pd-catalyzed cross-coupling reaction was performed to construct the aza-bicycle prior to indole installation. Contingent on its success, indole introduction and a double alkylation would provide an akuammicine-like scaffold that can ring-open upon hydride exposure to afford (15S)-subincanadine E in 16 overall steps. This work accomplished 10 steps toward the first total asymmetric synthesis of (15S)-subincanadine E.