Stereoselective deoxygenation of erythromycin A at C-12: effect of structure and conformation on prokinetic activity.

the smooth muscle of the gastrointestinal (GI) tract of dog and is potentially useful as a GI prokinetic agent. In an effort to extend the SARof the motilides, we decided to determine the effect of C-12 deoxygenation of 2 on both antibacterial and prokinetic activities. The deoxy congener with the natural (R) configuration at C-12 4 is synthetically accessible3) from erythromycin B 3, but in order to obtain the (S')-epimer, we had to devise methodology for selective deoxygenation of 1. The 12-OH of 1 is hindered and inaccessible selectively, therefore our strategy was to take advantage of the reactivity and ^^-orientation of the vicinal ll-OH to prepare an 1 1,12-cyclic thionocarbonate. In accordance with Barton and McCombie,4) a tributylstannyl radical should attack the thiocarbonyl group to generate a radical intermediate which, in this case, could fragment to the secondary radical at C-ll or the tertiary radical at C-12. Since tertiary radicals are more stable than secondary radicals and react faster in both fragmentation and hydrogen abstraction reactions,5'6) we hoped that the Barton-McCombie deoxygenation would be selective for C-12, to give epimeric 12-deoxy congeners. Thus the 2'-OH and 4"-OH groups were sequentially and selectively protected with an acetyl and a benzyloxycarbonyl group respectively (Scheme 1) to provide 5. Treatment of 5 with thiophosgene gave the 1 1,12-cyclic thionocarbonyl-6,9-hemiacetal intermediate 6. Deoxy-