Total synthesis of avermectin B1a revisited

Total synthesis of avermectin B1a revisited was achieved by Masahiro Hirama and co-workers in Tohoku University in Japan.

Avermectins were isolated as compounds possessing anthelmintic activity from the culture broth of Streptomycesavermitilis by Ōmura and co-workers. Owing to their potent anthelmintic and insecticidal activities, as well as their unique pentacyclic architecture, the avermectin family attracted keen interest from synthetic organic chemists. We have recently completed a more efficient and straightforward total synthesis of avermectin B1a, as compared with previous syntheses.

In the 1970s, Ōmura’s group at the Kitasato Institute and researchers of Merck Sharp and Dohme Research Laboratories discovered potent antiparasitic agents, the avermectins, from the culture broth of Streptomyces avermitilis (S. avermectinius). Among this family, avermectin B1a (Figure 1) is the most potent anthelmintic congener. Ivermectin, a mixture of 22,23-dihydro-avermectins B1a and B1b, has been used as an important anthelmintic in veterinary fields and for the control of onchocerciasis and lymphatic filariasis in more than 200 million people worldwide.

Masahiro Hirama and coworkers achieved an efficient and straightforward total synthesis of avermectin B1a . The highlights of total synthesis include: (i) a vinylogous Mukaiyama aldol reaction to install the C1–C4 carbons; (ii) an intramolecular aldol reaction to form the octahydrobenzofuran; (iii) a formation of trityl oxetane acetal to protect a labile β-hydroxy aldehyde; (iv) a regioselective installation of C3–C4 double bond; (v) a highly diastereoselective construction of the north segment via coupling of the C22–C28 alkyne and the C15–C21 lactone; (vi) an E-selective Wittig reaction using trimethylphosphonium salt to connect the polyfunctionalized north and south segments; (vii) an efficient Shiina macrolactonization using a genuine seco acid; (viii) a modified synthesis of the disaccharide and improved glycosylation to afford avermectin B1a . In particular, we should emphasize that a unique and powerful ‘trityl oxetane acetal’ protecting group strategy worked well to prevent serious epimerization and double bond migration of the sensitive β-hydroxy carbonyl tetrahydrobenzofuran moiety of 1.


Figure 1

Journal of Antibiotics 2016, (69), 31-50.