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 macro-lactone core imbedded in these natural products has inspired new synthetic methods for the construction of large ring lactones, beginning with the landmark synthesis of erythro-nolide 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-deoxyer-ythronolide 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.
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