Multiplicative Expansion of the Pool of Fully Synthetic Tetracycline Antibiotics

This thesis describes the development of chemical pathways for the preparation of more than 80 novel fully synthetic tetracyclines with structural variability at positions C5 and C5a. Progress toward the synthesis of 5-hetero-tetracyclines, another new class of tetracycline antibiotics, is also described. The results detailed herein - including successful C-ring-forming Michael-Claisen cyclizations of numerous modified AB precursors with just a few of the extraordinarily diverse D-ring precursors known to be effective nucleophiles in this key coupling reaction - represent the first steps toward a multiplicative expansion of the pool of fully synthetic tetracyclines.