Total syntheses of amphidinolides T1 and T4 via catalytic, stereoselective, reductive macrocyclizations.
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.
Colby
Elizabeth A
EA
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
O'Brien
Karen C
KC
Jamison
Timothy F
TF
D000480:Alkynes / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis*; D002384:Catalysis; D003500:Cyclization; D004852:Epoxy Compounds / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis*; D018942:Macrolides; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D000097442:Amphidinolides
D000480:Alkynes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004852:Epoxy Compounds; D007783:Lactones; D018942:Macrolides; C414522:amphidinolide T; D000097442:Amphidinolides; C472184:amphidinolide T4