The first enantioselective synthesis of cytotoxic natural products rigidiusculamides A (ent-21) and B (8) has been achieved by two synthetic routes. The first one is convergent based on the common intermediate 11, obtained through a high yielding SmI2-mediated Reformatsky-type reaction. A highly diastereoselective one-pot DessMartin periodinane-mediated bis-oxidation allowed the direct conversion of the diastereomeric mixture of 11 into rigidiusculamide B (8). Isolation of minor diastereomer 21, in combination with computational work, allowed us to suggest the structure of the natural rigidiusculamide A to be ent-21, as synthesized by the second route. Four diastereomers (7, ent-7, 22?a, and 22?b) and an enantiomer (21) of rigidiusculamide A (ent-21) have been synthesized. On the basis of literature precedents and computational work, a biosynthetic pathway for rigidiusculamides A and B was proposed to account for the opposite configuration at C-5 of those two congeners. ; National Basic Research Program (973 Program) of China [2010CB833200]; NSF of China [20832005, 21072160]; NFFTBS [J1030415]; NSF of Fujian Province of China [2011J01056]