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

Abstract

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity suggesting it plays an important role in antibiotic function.

Natural Products as Platforms To Overcome Antibiotic Resistance

“…Furthermore, the Andrade group designed syntheses to explore the effect of removing the methyl groups at C8 and C10, both of which flank the ketone at C9. 116–118 In the interest of brevity, we outline the culmination of their campaign with the synthesis of 4-desmethyl telithromycin ( 110 ) (Scheme 6). 119 …”

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.…”

“…42 This approach took advantage of γ-lactone intermediate 64, prepared in situ from the Sharpless asymmetric dihydroxylation of 16 used in the synthesis of 3; moreover, the cyclic and rigid nature of 64 was expected to be ideal in the kinetic protonation step (Scheme 14). 13 To test this hypothesis, we protected the C-5 hydroxyl as its TES ether to access 65. The stereochemical configuration of C-6 in 65 arguably plays the most important role in differentiating the diastereofaces upon generating the enolate …”

Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin

“…2 To address this, we initiated a structure-based drug design program wherein desmethyl analogues (i.e., CH 3 →H) of the third-generation macrolide antibiotic telithromycin (TEL, 2 ) 3 are prepared by total synthesis (Figure 1). To date, we have reported the total synthesis, molecular modeling and biological evaluation of 4,8,10-tridesmethyl TEL ( 3 ) 4a,b and 4,10-didesmethyl TEL ( 4 ) 4c against both wild-type and macrolide-resistant bacteria, which were found to be active ( vide infra ). Herein we extend our approach to 4,8-didesmethyl congener ( 5 ), our third desmethyl analogue of telithromycin ( 2 ).…”

“…4 Specifically, we found the ring-closing metathesis strategy was ideal for preparing 14-membered macroketolactones 8a and 8b in 60% isolated yields with Grubbs’ 2 nd generation catalyst (Scheme 1). 12 Application of this powerful method toward the synthesis of 9 , however, was ineffective in our hands despite the choice of catalyst (e.g., Grubbs’ 1 st generation catalyst and Hoveyda-Grubbs 2 nd generation catalyst).…”