The objective of this research is to devise and develop novel and efficient pathways for the total synthesis of certain macrolide antibiotics. The strategy to be employed involves stereocontrolled elaboration of specific subunits of these structures in optically pure form, followed by linkage of these segments in a convergence upon the target molecule. Exemplifying this approach, the broad spectrum anthelmintic agent, avermectin B1a is to be constructed from segments representing the hexahydrobenzofuranone nucleus, the spiro ketal moiety, and a linear insert between these units. Final closure of the macrolide is envisioned by translactonization employing a Beta-lactone. The dimeric macrolide ionophores boromycin and aplasmomycin will be assembled from their half structures which have already been completed. Improved methods are proposed for synthesis of the pyran and tetrahydrofuran components of these structures and for installation of the glycollate at the terminus of the half structures. New variations are set forth for the synthesis of verrucarol, the trichothecanoid nucleus of the cytotoxic antibiotic verrucarin A, and for elaboration of the related T2 toxin. The key to establishing the functionalized C ring of verrucarol will be an intramolecular photochemical cycloaddition of a vinyl ester, followed by ring expansion of a cyclobutyl carbinol. The pyran ring of latruculin B, and unusual cysteine-containing macrolide from a marine source and a potent cholinesterase inhibitor, is to be synthesized by means of a hetero Diels-Alder reaction, for which the diene component will be derived from segments connected via Wittig reactions. The synthesis of pseudomonic acid C, a broad-spectrum antibacterial agent which is strongly bound to human serum, focuses on the central tetrahydropyran nucleus. This is to be constructed in an entiospecific manner employing borneol as chiral auxiliary.
| Avery, Mitchell A; Choudhry, Satish C; Dhingra, Om Prakash et al. (2014) Total synthesis of macrodiolide ionophores aplasmomycin A and boromycin via double ring contraction. Org Biomol Chem 12:9116-32 |
| White, J D; Hanselmann, R; Jackson, R W et al. (2001) Total synthesis of rutamycin B, a macrolide antibiotic from Streptomyces aureofaciens. J Org Chem 66:5217-31 |
