Total synthesis and determination of the absolute configuration of frondosin B.
Two concise syntheses of (+/-)-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 --> 16 + 38) to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions. In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene to fix the double bond in its required position in the resultant dimethylcyclohexane ring. A third total synthesis was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in the enantiomerically enriched form. These studies establish the absolute configuration of the secondary methyl center in frondosin B to be R.
Inoue
M
M
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA.
Carson
M W
MW
Frontier
A J
AJ
Danishefsky
S J
SJ
D000447:Aldehydes / Q000138:chemical synthesis*; D001572:Benzofurans / Q000138:chemical synthesis*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology; D008968:Molecular Conformation; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
D000447:Aldehydes; D001572:Benzofurans; D006576:Heterocyclic Compounds, 4 or More Rings; D023062:Receptors, Interleukin-8A; C421322:frondosin B; C013243:salicylaldehyde; C105430:benzofuran