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Abstract

The first total synthesis of the complex glycolipid macroviracin D (BA-2836-4) (1) is described. This antivirally active metabolite isolated from the mycelium extracts of Streptomyces sp. BA-2836 incorporates a unique 46-membered macrodilactone motif decorated with glycosylated fatty acid appendices. Compound 1 consists of three identical subunits which are closely related to one of the segments found in cycloviracin B₁ (2), another antiviral glycoconjugate previously synthesized in our laboratory. Key steps of the synthesis route to 1 involve the stereoselective, ligand-controlled addition of the functionalized diorganozinc derivative 9 to aldehydes 8 a, b, a series of β-selective glycosidation reactions using appropriately protected trichloroacetimidate donors, and three esterifications via the Yamaguchi method; one of them is performed intramolecularly to forge the macrocyclic lactone ring of the target in 89 % isolated yield. This total synthesis also firmly establishes the absolute configuration of the subunits of compound 1 as 3R,17S,23R.