Total Synthesis of (−)-4,8,10-Tridesmethyl Telithromycin

Abstract

Novel sources of antibiotics are required to address the serious problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we report the details of our efforts that ultimately led to the total synthesis of (−)-4,8,10-tridesmethyl telithromycin (3) wherein methyl groups have been replaced with hydrogens. The synthesis of desmethyl macrolides has emerged as a novel strategy for preparing bioactive antibiotics.

Total Synthesis of Desmethyl Macrolide Antibiotics

“…To simplify the chemical synthesis, we also targeted desmethyl analogues at the C-8 and C-10 positions (i.e., 3-5) to probe the roles of those methyl groups in terms of bioactivity. [11][12][13][14][15] The retrosynthesis of the simplest congener, 4,8,10-tridesmethyl telithromycin (3), is shown in Scheme 1 and is exemplary for the remaining analogues. 11,12 Inspection of 3 and an advanced protected intermediate 7 reveals three topological subgoals: (1) installation of the C-11-C-12 oxazolidinone bearing the butyl-biaryl side chain 9, (2) stereoand site-selective glycosylation at the C-5 hydroxyl position with known D-desosamine donor 10, 16 and (3) preparation of the 14-membered macrolactone ring 11.…”

Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin

“…Experience obtained from the total syntheses of 4,8,10-tridesmethyl TEL ( 3) iv proved extremely useful in the preparation of CET counterpart 7 . The total synthesis outlined in Scheme 1 began with diol 8 , which was used in the synthesis of 3 .…”

“…v To access 14 , we employed the venerable Evans aldol reaction xviii to establish the requisite stereochemistry at C2 and C3. This tactic was successfully employed in the preparation of all desmethyl analogues 3–5 .…”

“…This tactic was successfully employed in the preparation of all desmethyl analogues 3–5 . iv, vi, vii To this end, DIBAL-mediated regioselective ring opening of PMP-acetal 10 furnished primary alcohol 11 in 60% yield. xix Swern oxidation of 11 gave an intermediary aldehyde, which was subjected to standard Evans aldol reaction conditions with propionimide 12 to secure 13 in 78% over two steps (dr>20:1).…”

Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin

“…2 Sharpless dihydroxylation (AD mix-β) of 5 furnished γ-lactone 6 by in situ lactonization of the newly formed C-6 hydroxyl in 85% yield (er>20:1). 11 Protection of the C-5 alcohol as its triethylsilyl (TES) ether was accomplished with TESCl and imidazole.…”