The preparation and biological activity of the novel aza macrolides 6, 8, 11-13 and 15-20 are reported. These analogs display in vitro antibacterial properties that are superior to erythromycin A. The last few decades have seen many reports in the literature that deal with the systematic chemical and structural modification of the macrolide antibiotic erythromycin A (1), all aiming to improve its potency and spectrum, oral bioavailability, acid stability, and to eliminate gastrointestinal side effects. As a consequence of these studies, modified analogs such as clarithromycin (2) and azithromycin (3) have been recently marketed in the USA and Europe. Wilkening and coworkers recently reported the synthesis of the novel 15 membered aza macrolide 4 (L-701,677). Analog 4, a positional isomer of azithromycin, showed in vitro antibacterial properties similar to 3 and also displayed greater acid stability. Encouraged by these results, we now report on derivatives of 4 modified at the 4"-and 8a-positions. Specifically, we report here on the preparation and biological activities of the 4"-epi analog 6 and 4"-amino analogs 8 and 11-13. Further, we also report herein the efficient separation of the diastereomeric amines 15 and 16 and their subsequent derivatization.