Croomine is a representative member of the Stemona class of alkaloids. These novel polycyclic natural products were isolated from medicinal plants used extensively in traditional East Asian medicine as antitussive and antituburcular agents. In addition to their medicinal uses, the Stemona alkaloids have recently attracted attention for their potent insecticidal activity. Notably, the structures of most members of this class of natural products are characterized by a common pyrrolidinyl butyrolactone core. An enantioselective method of accessing this structural motif via a catalytic vinylogous Mannich reaction has been proposed. This research plan relies on the ability of Jacobsen's recently developed non-metal catalyst for the Strecker reaction to activate imines towards nucleophilic attack. The addition of electron-rich 2-silyloxyfurans to the imine-catalyst complex is expected to occur with high levels of enantio- and diastereoselectivity. Optimization of the catalyst structure for this transformation will be performed by combinatorial synthesis of a small, """"""""focused"""""""" library of catalyst analogs. After exploring the substrate scope of this new reaction, the synthetic utility of the enantioselective vinylogous Mannich will be demonstrated in a concise total synthesis of (+)-croomine (7 steps, best case).
