Abstract
The erythromycins, discovered and isolated in the early 1950s, are the best-known members of the clinically important macrolide class of antibiotics. The 14-membered macrolactone core imbedded in these natural products has inspired new synthetic methods for the construction of large ring lactones, beginning with the landmark synthesis of erythronolide B by the Corey group in 1978. During these studies, a single acetonide protecting group was utilized at the C-3/C-5 position. Similarly, this protecting group was used by the Masamune group years later for the synthesis of 6-deoxyerythronolide B (6-dEB). While no rationale was given for the use of this acetonide at the time, its function was revealed during the historic synthesis of erythromycin A in 1981 by Woodward et al. In three consecutive reports, the Woodward group extensively explored the conformational requirements for efficient acylation-based macrolactonization of erythromycin A seco acid derivatives. In particular, cyclic protecting groups were placed at various positions to serve as biasing elements, that is, artificial structural features intended to aid macrocyclic ring closure through substrate preorganization. The results from this study led the Woodward group to conclude that “certain structural features such as ... cyclic protecting groups at C-3/C-5 and C-9/C-11 are required for efficient lactonization” and that “these structural requirements probably arise from conformation requirements for lactonization.” This conclusion—that preorganization is required for efficient cyclization—has become a wellaccepted doctrine that has influenced the planning of all ensuing erythromycin syntheses (see below). We now report for the first time that conformational restraining elements are in fact not required for attaining efficient lactonization of the erythromycin core structure, 6-deoxyerythronolide B (6dEB). Moreover, we demonstrate that the removal of biasing elements allows for more stereochemical flexibility in the cyclization of 6-dEB, thus enabling access to stereochemical analogues that are not readily accessible with the biasing elements in place. Overall these findings require revision of the 30-year-old dogma that preorganization is mandatory for achieving macrocyclization of the erythromycins. Inspired by the Woodward report, synthetic endeavors by the research groups of Stork, Nakata, Yonemitsu, Danishefsky, Kochetkov, Hoffmann, Evans, Woerpel, Nelson, and us have reduced the conformational space available to the seco acid backbones of the erythronolide series (that is, 6-dEB, erythronolide B, and erythronolide A) through the use of sixmembered-ring protecting groups on C-3/C-5 and C-9/C-11 (Scheme 1). In addition to scaffolds with cyclic protecting
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