Erythronolide macrolactone

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

The first total synthesis of erythronolide B (1) by Corey stands as an event of great historical significance in synthetic chemistry it provides a powerful illustration of the utility of Corey s methods of macrolactonization and it demonstrates, in a particularly insightful way, the value of using readily accessible six-membered ring templates for the assembly of contiguous arrays of stereo-genic centers. 

In principle, all that remained to do to reach erythronolide (2) was to deprotect the Ci3 hydroxyl group of 62, conduct the macrolactonization, remove the acetonides, and carry out an oxidation state adjustment at C9. Of course this was easier said than done. The macrolactonization turned out to be very difficult. The Woodward group degraded Erythromycin A (1) to 17 thiopy-ridyl ester substrates, only three of which underwent lactonization under the Corey-Nicolaou conditions. Two of these derivatives gave low yields, but 63 cyclized to 64 in good yield. This effort established that (1) the 5-configuration was essential at C9 and (2) the C3-C5 and C9-C11 diol units had to be protected as cyclic acetals. Based on this information, carbamate-acetal 65 was eventually prepared Ifom the natural product and found to cyclize to 66 in 70% yield. Thus, to complete a total synthesis, it was necessary to convert w-acetorude 62 to 65, and move 66 forward to erythromycin A (1). 

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