This paper describes the successful implementation of a stereocontrolled strategy for the total chemical synthesis of the pyrrolidine-based alkaloid (--)-kaitocephalin. This scalable synthetic route profits from the strategic utilization of substrate-controlled manipulations for the iterative installation of the requisite stereogenic centers. The key transformations include a diastereoselective modified Claisen condensation, a chemo- and diastereoselective reduction of a beta-keto ester, and the substrate-directed hydrogenation of a dehydroamino ester derivative. During the course of our investigations, an interesting stereoconvergent cyclization reaction was discovered for the efficient assembly of the kaitocephalin 2,2,5-trisubstituted pyrrolidine core.
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