A Concise Synthesis of the Fully Functional Lactide Core of Cycloviracin B with Implications for the Structural Assignment of Related Glycolipids

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Abstract
The absolute stereochemistry at the site of attachment of the fatty acid residues to the lactide core of the glycolipids cycloviracin B1 (1) and glucolipsin A (13) has been elucidated as (3R,3‘R) by comparison of their 13C NMR data with those of the three possible, differently configured core structures 9, 12, and 14. Moreover, a careful analysis of this set of NMR data allows us to conclude that the structures previously proposed for a seemingly closely related class of antivirally active compounds, i.e., the fattiviracin family, need revision. The key step en route to the symmetrical dilactones 9 and 12 consists of a highly efficient cyclodimerization process which exploits the template effect exerted by potassium cations on the hydroxy acid cyclization precursor. The latter is obtained in excellent overall yield by a sequence involving ring-opening Claisen condensation of pentadecanolide to form the functionalized β-ketoester 4, asymmetric hydrogenation catalyzed by [(BINAP)RuCl2]2·NEt3, and a β-selective glycosylation reaction using trichloroacetimidate 6. The unsymmetrical dilactone 14, in contrast, is prepared by a stepwise approach based on a Yamaguchi lactonization as the means to close the macrocyclic ring.