Total Synthesis of (+)-Pleuromutilin

Abstract

An 18-step synthesis of the antibiotic (+)-pleuromutilin is disclosed. The key steps of the synthesis include a highly stereoselective SmI2-mediated cyclization to establish the eight-membered ring, and a stereospecific transannular [1,5]-hydrogen atom transfer to set the C10 stereocenter. This strategy was also used to prepare (+)-12-epi-pleuromutilin. The chemistry described here will enable efforts to prepare new mutilin antibiotics.

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.…”

Taxane Meets Propellane: First Chemical Synthesis of Highly Complex Diterpene Canataxpropellane

“…To name just a few, the radical retrosynthesis approach by the Baran group as exemplified for pyrone diterpenes comes to mind, as well as the Maimone laboratory's radical cascade in the synthesis of berkeleyone A . Classical synthetic targets as pleuromutilin have recently been reinvestigated and shown to be accessible by much shorter and more efficient routes, as demonstrated by Herzon and Reisman …”

“…[3] Classical synthetic targets as pleuromutilin have recently been reinvestigated and shown to be accessible by much shorter and more efficient routes, as demonstrated by Herzon [4] and Reisman. [5] Terpenoid natural products containing propellane motifs present considerable challenges owing to their typically dense array of quaternary stereogenic carbons at their ring junctions. As recent contributions have showcased, ingenious routes have to be developed to make these structures accessible.…”

Taxan trifft Propellan: Erste Totalsynthese des hochkomplexen Diterpens Canataxpropellan

“…Die radikalischen retrosynthetischen Schnitte von Baran, veranschaulicht an der Synthese von Pyron-Diterpenen, [2] und die Radikalkaskade auf dem Weg zu Berkeleyon A von Maimone sind hierfür nur zwei Beispiele. [3] Klassische Ziele wie Pleuromutilin wurden kürzlich wieder untersucht, und es konnte zum Beispiel von Herzon [4] und Reisman [5] gezeigt werden, dass viel kürzere und effizientere Synthesewege mçglich sind.…”