Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Revised strategy and final stages.
A general and highly convergent synthetic route to the macrocyclic core structures of the antitumour agents amphidinolide N (1) and caribenolide I (2) has been developed, and the total synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures is described. Central to the revised strategy was the use of a Horner-Wadsworth-Emmons olefination between beta-ketophosphonate 51 and aldehyde 14 to construct the C1-C13 sector common to both 1 and 2. Stereoselective alkylation of hydrazone 11 with iodide 65 and then with bromide 56 allowed for the rapid assembly of the complete caribenolide I carbon skeleton. Key steps in the completion of the synthesis of des-epoxy-caribenolide I structure 78 included hydrolysis of a sensitive methyl ester using Me(3)SnOH, followed by regioselective macrolactonisation of the resulting diol seco-acid and global deprotection. Coupling of hydrazone 11, bromide 56 and iodide 64 was followed by an analogous sequence of late-stage manoeuvres to arrive at the fully deprotected des-epoxy-amphidinolide N framework, obtained as a mixture of hemiacetal and bicyclic acetal 84. Regio- and diastereo-selective epoxidation of the C6 methylene group in bicyclic acetal 84 provided access to iso-epoxy-amphidinolide N stereoisomer 89.
Nicolaou
K C
KC
Department of Chemistry and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California 92037, USA. kcn@scripps.edu
Bulger
Paul G
PG
Brenzovich
William E
WE
D000480:Alkynes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry
D000480:Alkynes; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D018942:Macrolides