A Flexible Asymmetric Approach to Methyl 5-Alkyltetramates and Its Application in the Synthesis of Cytotoxic Marine Natural Product Belamide A

By using a methyl tetramate derivative (R)‐ or (S)‐9 as a novel chiral building block, a direct, flexible, and highly enantioselective approach to methyl (R)‐ or (S)‐5‐alkyltetramates (2) is disclosed. Among the synthesized methyl 5‐alkyltetramates 2, methyl 5‐methyltetramate (2 a) is found in cytotoxic mirabimide E (4) and dysideapyrrolidone (5), and methyl 5‐benzyltetramate (2 g) is a substructure in the potent antineoplastic dolastatin 15 (3). On the basis of this method, the first asymmetric synthesis of the antimitotic tetrapeptide belamide A (7) has been achieved in seven steps from (S)‐9, with an overall yield of 23.8 %. Not only have the structure and absolute configuration of (+)‐belamide A (7) been confirmed, but also the solvent used for recording the 13C NMR spectrum, the 13C NMR spectrum data correlation, and optical rotation data of natural belamide A (7) have been revised. A versatile chiral building block: A direct and flexible asymmetric approach to either methyl (R)‐ or (S)‐5‐alkyltetramates has been developed by using methyl (R)‐ or (S)‐tetramate derivative 1 as a chiral building block (see scheme; HMPA=hexamethylphosphoramide, CAN=cerium(IV) ammonium nitrate, Bn=benzyl). By using this method, the first asymmetric synthesis of the antimitotic marine natural product belamide A has been accomplished.