A synthetic route to the hexahydrobenzofuran nucleus of avermectins via diazoketone cyclization

✍ Scribed by James D. White; Anura P. Dantanarayana

• Publisher: Elsevier Science
• Year: 1987
• Tongue: French
• Weight: 211 KB
• Volume: 28
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)96876-x

✦ Synopsis

A hexahydrobenzoIABlfuran characteristic of the avermectins and certain milbemycins was synthesized via acid-catalyzed intramolecular addition of a diazoketone to a r-lactone; subsequent transformations led to structures containing much of the functionality and stereochemistry present in the corresponding segments of these macrolides. The broad-spectrum anthelmintic activity associated with avermectins and milbemycinsl has stimulated intense interest in the synthesis of these StreptomYces metabolites.' The hexahydrobenzofuran subunit cornnon to the avermectins, such as BIa (11, and to the o series of milbemycins presents an especially challenging objective and, although several routes to this system have been reported,3 there remains a need for efficient, stereoselective pathways to this nucleus. As implied by the schematic trisection of 1, our plan for its total synthesis envisions convergence of a hexahydrobenzofuran, an octadienyl chain, and a spiroketal moiety. A target representing the first of these segments is identified as 2. We describe in this Letter a synthesis of 3 that is fundamentally different from existing routes to this substructure of the avermectins and which sets in place the crucial stereochemistry and double bond of the cyclohexene ring of 1. The key step in the sequence is acid-catalyzed cyclization of a diazoketone, a strategy that was suggested by earlier approaches of Elderfield and Yates' to furan-3-ones.