Total Syntheses of Amphidinolide T1 and T4 via Catalytic, Stereoselective Reductive Macrocyclizations

Journal of the American Chemical Society 127 (12), 4297-4307_, DOI: 10.1021/ja042733f

Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C−C bond, and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne−aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne−aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne−epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne−epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.