Total synthesis and revision of C6 stereochemistry of (+)-amphidinolide W.
An enantioselective first total synthesis and structural revision of the cytotoxic natural product amphidinolide W is described. We initially investigated a ring-closing metathesis based synthetic strategy to form the 12-membered macrocycle. This strategy was unsuccessful as it led to formation of a 17-membered macrocycle. Subsequently, we explored an alternative strategy that involved cross-metathesis followed by a Yamaguchi macrolactonization reaction sequence utilizing the same key intermediates. This strategy led to the synthesis of amphidinolide W. The synthesis was carried out in a convergent manner, and four of the five stereogenic centers in amphidinolide W were set by asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross-metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W has now been revised through our synthesis.
Ghosh
Arun K
AK
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu
Gong
Gangli
G
D002087:Butyrates / Q000737:chemistry; D007783:Lactones / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009574:Nitro Compounds / Q000737:chemistry; D013237:Stereoisomerism; D000097442:Amphidinolides
D002087:Butyrates; D007783:Lactones; D018942:Macrolides; D009574:Nitro Compounds; C508635:6-(nitrooxy)hexyl-(2z)-4-(acetyloxy)-3-(4-(methylsulfonyl)phenyl)-2-phenylbut-2-enoate; C449925:amphidinolide W; D000097442:Amphidinolides