A modular and enantioselective synthesis of the pleuromutilin antibiotics

Abstract

The tricyclic diterpene fungal metabolite (+)-pleuromutilin has served as a starting point for antibiotic development. Semisynthetic modification of its glycolic acid subunit at C14 provided the first analogs fit for human use, and derivatization at C12 led to 12--pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given the inherent limitations of semisynthesis, however, accessing derivatives of (+)-pleuromutilin with full control over their structure presents an opportunity to develop derivatives with improved antibacterial activities. Here we disclose a modular synthesis of pleuromutilins by the convergent union of an enimide with a bifunctional iodoether. We illustrate our approach through synthesis of (+)-12--mutilin, (+)-11,12-di--mutilin, (+)-12--pleuromutilin, (+)-11,12-di--pleuromutilin, and (+)-pleuromutilin itself in 17 to 20 steps.

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

“…Several semisynthetic derivatives of P are used to treat Gram-positive pathogens in humans (retapamulin) and in veterinary medicine (tiamulin, valnemulin), 18 and recently epi-mutilin derivatives have been developed as antibiotics with activity against some Gram-negative bacteria. 19–22 Investigation of the antibacterial activity of P and its derivatives has inspired several total synthesis efforts 20,21,23–25 that, combined with previous work on structure elucidation 26,27 and structure–activity relationship studies, 18,28,29 provide a wealth of synthetic information about the chemical reactivity of the pleuromutilin ring system. Structural transformations of the P ring system identified through these efforts afford several good starting points for novel diversification reactions.…”

Directed evolution of the rRNA methylating enzyme Cfr reveals molecular basis of antibiotic resistance

“…5D). Given recent synthetic advances that enable more extensive modification of the pleuromutilin scaffold ( 56, 57 ), these results will inform design of next-generation antibiotics that can overcome Cfr-mediated resistance.…”

“…The pleuromutilin class of antibiotics have recently regained interest for their applications as antimicrobial agents in humans but existing molecules remain ineffective against pathogens with Cfr ( Goethe et al, 2019) . Given recent synthetic advances that enable more extensive modification of the pleuromutilin scaffold (Farney et al, 2018;Murphy et al, 2017) , the structural insights we obtained will inform the design of next-generation antibiotics that can overcome Cfr-mediated resistance.…”

Total synthesis of complex terpenoids employing radical cascade processes

“…47 Asymmetric routes to pleuromutilin have been slower to transpire, the first being Procter’s 2013 synthesis, 48 and very recently, Herzon’s 2017 report. 49,50 In addition, a number of approaches to the nucleus of 21 have been documented. 51–54 Herein we discuss Procter’s 2013 synthesis which utilized an impressive SmI 2 -mediated radical cascade to construct two of the three rings found in the target in a single step (Scheme 1).…”