Total synthesis of structurally diverse pleuromutilin antibiotics

Abstract

The emergence of drug-resistant bacterial pathogens has placed renewed emphasis on the total chemical synthesis of novel antibacterials. Tetracyclines, macrolides, streptogramins and lincosamides are now accessible through flexible and general synthetic routes. Pleuromutilins (antibiotics based on the fungal metabolite pleuromutilin) have remained resistant to this approach, in large part due to the difficulties encountered in the de novo construction of the decahydro-3a,9-propanocyclopenta[8]annulene skeleton. Here we present a platform for the total synthesis of pleuromutilins that provides access to diverse derivatives bearing alterations at previously inaccessible skeletal and peripheral positions. The synthesis is enabled by the serendipitous discovery of a vinylogous Wolff rearrangement, which serves to establish the C9 quaternary centre in the targets, and the development of a highly diastereoselective butynylation of an α-quaternary aldehyde, which forms the C14 secondary alcohol. The versatility of the route is demonstrated through the synthesis of seventeen structurally distinct derivatives, with many possessing potent antibacterial activity.

Fig. 1.. The structures of (+) pleuromutilin (1), clinically relevant derivatives, and prior synthetic art.

a. Structures of (+)-pleuromutilin (1), 12-epi-pleuromutilin (2), retapamulin (3), lefamulin (4), and extended spectrum pleuromutilins (ESPs, 5). b. Overview of the prior synthetic route to (+)-pleuromutilin (1) by Murphy et al.

Fig. 2.. An unexpected vinylogous Wolff rearrangement provided access to the C9 quaternary stereocenter and formed the basis for a synthetic route to C12 normethyl pleuromutilins.

a. Arndt–Eistert homologation of the α-diazoketone 11 provided the homologation product 12 and the rearrangement product 13. b. Potential mechanistic pathways for the rearrangement may involve a concerted 2,3-rearrangement of the α-diazoketone 14 or rearrangement of the ketocarbene 16. c. Synthesis of the C12 normethyl pleuromutilin derivative 24. d. Proposed orientation of the (Z)-enolate 25. e. X-ray structure of the mutilin derivative 26. f. MMFF (Merck molecular force field) overlay of 1 and 24.

Fig. 3.. Scope of the butynylation reaction, competition of a fully derivatized analog and synthesis of a C7-substitued pleuromutilin.

a. Products synthesized by addition to 20. Isolated yields and diastereoselectivity are reported. b. Synthesis of the C12 normethyl lefamulin derivative 37. c. Synthesis of the C7-substituted derivative 45.

Fig. 4.. Preparation of pleuromutilin derivatives, including ring contractions in the six- and eight-membered rings.

a. Synthesis of the ring-contracted derivatives 51, 55 and 56; NOE enhancements supporting the relative stereochemistry of 48, 50, 52, 53, and 54 are indicated by arrows. b. Synthesis of the derivative 59, which contains a seven-membered ring. NOE enhancements supporting the relative stereochemistry of 58 are indicated by arrows.

Fig. 5.. Seventeen structurally-distinct derivatives were prepared and evaluated against a panel of Gram-positive and Gram-negative bacteria.

Fully synthetic pleuromutilins prepared using the synthetic platform that feature different core modifications (24, 37, 45, 63–72), ring sizes (51, 55, 56, 59) and C14 glycolic ester derivatives (R¹–R³). The compounds were compared to semisynthetic controls (lefamulin (4), 60–62; shown in the gray box) against a panel of Gram-positive and Gram-negative bacteria. Minimum Inhibitory Concentrations (μg/mL) are reported. MSSA: methicillin-susceptible S. aureus; MRSA: methicillin-resistant S. aureus; MRSE: methicillin-resistant S. epidermidis; MSSE: methicillin-susceptible S. epidermidis; VSE: vancomycin-susceptible Enterococcus; VRE: vancomycin-resistant Enterococcus; PISP: penicillin-intermediate S. pneumoniae; PRSP: penicillin-resistant S. pneumoniae.