Development of a Component-Based Synthesis for the Discovery of New Aminoglycoside Antibiotics and Diastereoselective Michael–Claisen Cyclizations en Route to 5-Oxatetracyclines

Abstract

This dissertation presents the development of a modular, fully synthetic approach to the aminoglycoside antibiotic family. The synthetic route features two convergent coupling reactions of three diversifiable components (2–4), where each component can be prepared by the union of two building blocks, which themselves are obtained in three or fewer steps from commercial chemicals. Illustration of the power of our approach has led to the preparation of three new aminoglycoside antibiotics from a common, late-stage intermediate, each of which contains novel structural modifications that are inaccessible through semisynthesis. Preliminary antimicrobial testing reveals that all of the newly synthesized analogs exhibit antibacterial activities against a panel of Gram-positive and Gram-negative strains. Methodological advances that permitted the syntheses of the individual components are also described in this dissertation. Specifically, efficient and large-sale preparations of the building blocks 6 and 7 facilitated the development of a highly stereoselective nitroaldol reaction, providing practical access to the garosamine thiophenyl glycosyl donor 2. Desymmetrization of the tartrate building block 8 and identification of a diastereoselective, intramolecular Mannich cyclization enabled the synthesis of the 2-deoxystreptamine derivative 4, where the amino groups are orthogonally protected to allow regioselective coupling of the fourth component, 5. In addition, an efficient preparation of the purpurosamine glycosyl donor 3, which proceeded in six steps from glutamic acid, will be discussed. Pertaining to a separate research program targeting novel tetracycline antibiotic derivatives, the last chapter of this dissertation details the anionic cyclizations of γ-oxa-α,β-unsaturated ketones with isoxazoles and o-toluate phenyl esters. The successful development of this methodology enabled the synthesis of 5-oxatetracyclines from D-arabinose using sequential, highly diastereoselective Michael–Claisen cyclization reactions via a 5-oxa-AB enone substrate.