It is known that the reveromycin A ( 1)-type 6,6-spiroketal core I can undergo acid-catalyzed isomerization to afford the spiroisomer II as the result of an unfavorable steric interaction involving the axial C19 side chain in I that is alleviated in II , albeit at the cost of an anomeric effect (Figure 1). Thus, the energy difference between the 6,6-spiroketals I and II is small. In addition, when the C18 alcohol is free, acid-induced isomerization provides the more stable reveromycin B (2) 5,6-spiroketal coreIII exclusively. This energy profile has been observed in the reported thermodynamic approaches (i.e., cyclization of a “dihydroxy-ketone” precursor) to the 6,6-spiroketal of 1, which providedmixtures of spiroisomers,and degradative and synthetic
studies have demonstrated the strong preference for the reveromycin B-type 5,6-spiroketal III.
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