A Platform for the Discovery of New Lincosamide Antibiotics

This dissertation presents a flexible synthetic approach to the lincosamide antibiotics, developed with the aim of rejuvenating an underexploited class to combat multidrug-resistant bacterial pathogens. The only clinically relevant lincosamide, clindamycin (1.3), has been in continuous clinical use for nearly half a century, though its utility is limited by a narrow spectrum of action and a liability to promote life-threatening C. difficile infections. Prior campaigns to address these concerns have relied largely upon semi-synthetic approaches, owing in part to the lack of practical synthetic routes to the two molecular hemispheres – a “northern” aminooctose and a “southern” cyclic amino acid – that constitute the class. Exploiting the lincosamides’ natural modularity, I developed synthetic routes to both moieties, enabling diversification at strategic sites identified by analysis of X-ray crystal structures of canonical lincosamides bound to the bacterial ribosome, as well as by existing structure–activity relationship (SAR) data. Three synthetic routes are exhibited in this dissertation, beginning with the preparation of β-oxygenated prolines as rationally designed variants of clindamycin’s southern half. In this work, a novel annulation of pseudoephenamine glycinamide (2.3) is described, marrying prior methods developed in the Myers laboratory for C,N-bis-alkylation and aldolization of chiral glycine equivalents. This chemical innovation led to the discovery of a bicyclic southern-half scaffold amenable to further optimization, displaying particular promise in our search for candidates with improved in vitro antimicrobial activity and diminished risk for colitis relative to clindamycin. Also presented are two independent routes to the northern-half component. In the first, a pivotal nitroaldol coupling enabled the component-based synthesis of methylthiolincosamine (1.11) from non-carbohydrate building blocks 3.28 and 3.29. Adaptation of this route permitted the synthesis and evaluation of 41 lincosamides bearing modifications to the strategic positions C1 and C6, offering actionable insights into the SAR of this residue. Consequently, a second- generation synthesis to northern-half variants was developed, enabling more expedient exploration of this hemisphere, and facilitating the synthesis of clindamycin (1.3) in 4 steps from the versatile N-tert-butanesulfinimine intermediate 4.10. Through building-block exchange and adaptation of the routes described