Development of a Modular Synthetic Route to (+)-Pleuromutilin, (+)-12-epi-Mutilins, and Related Structures

Abstract

We describe the development of an enantioselective synthetic route to (+)-pleuromutilin (1), (+)-12-epi-mutilin, and related derivatives. A key hydrindanone was prepared in three steps and 48% overall yield from cyclohex-2-en-1-one. 1,4-Hydrocyanation provided a nitrile (53%, or 85% based on recovered starting material) that was converted to the eneimide 57 in 80% yield by the 1,2-addition of methyllithium to the nitrile function, cyclization, and in situ acylation with di-tert-butyldicarbonate. The eneimide 57 was employed in a 2-fold neopentylic coupling reaction with an organolithium reagent derived from the alkyl iodides (R)- or (S)-30, which contain the C11-C13 atoms of the target, to provide diastereomeric diketones in 60% or 48% yield (for coupling with (R)- or (S)-30, respectively). The diketone derived from (S)-30 contains the (S)-C12 stereochemistry found in pleuromutilin and was elaborated to an alkynylaldehyde. Nickel-catalyzed reductive cyclization of this alkynylaldehyde, to construct the eight-membered ring of the target, unexpectedly provided a cyclopentene (67%), which arises from participation of the C12-α-olefin in the transformation. The diketone derived from the enantiomeric C12-fragment (R)-30 underwent reductive cyclization to provide the desired product in 60% yield. This was elaborated to 12-epi-mutilin by a four-step sequence (39% overall). Installation of the glycolic acid residue followed by C12 epimerization (Berner et al. Monatsh. Chem. 1986, 117, 1073) generated (+)-pleuromutilin (1). (+)-12-epi-Pleuromutilin and (+)-11,12-di-epi-pleuromutilin were prepared by related sequences. This work establishes a convergent entry to the pleuromutilins and provides a foundation for the production of novel antibiotics to treat drug-resistant and Gram-negative infections.

Figure 1.

Structures of natural (+)-pleuromutilin (1) and the deacylated derivative (+)-mutilin (2), structures of the semisynthetic C14 derivatives tiamulin (3), retapamulin (4), and lefamulin (5), and the structure of a representative 12-epi-mutilin derivative 6. Natural (+)-pleuromutilin (1) and the semisynthetic C14 derivatives 3─5 are active primarily against Gram-positive pathogens. 12-epi-Mutilin derivatives such as 6 possess extended spectrum activity against Gram-negative and drug-resistant pathogens.

Scheme 1.

Key Steps in the Gibbons (A), Boeckman (B), and Procter (C) Syntheses of Pleuromutilin (1)

Scheme 2.

(A) Outlines of Our Strategy To Access (+)-Mutilin (2). (B) Cyclization Substrate 16 Targeted. (C) Destabilizing syn-Pentane and Transannular Interactions Arising from a More Flexible and Saturated Cyclization Precursor

Scheme 3.

Stereoselective Synthesis of the Hydrindanone 14

Scheme 4.

(A) Attempted Synthesis of the Diketone 25 via the Acid Chloride 23 or the Lactone 27. (B) Synthesis of the Alkyl Iodide (S)-30

Scheme 5.

Attempted Synthesis of the Hydrindanone 33

Scheme 6.

(A) Synthesis of the C11─C14 Aldehyde 37. (B) Synthesis of the Hydrindanone 42

Scheme 7.

(A) 1,4-Addition of Lithium Divinylcuprate and Hydrogen Cyanide to the Hydrindanone 14. (B) Improved Procedure for the 1,4-Hydrocyanation of 14 Involving Recycling of the Undesired Diastereomer 50

Scheme 8.

Synthesis of the Cyclopentene 53 from the Enone 42

Scheme 9.

Synthesis of the Alkynylaldehyde 62 from the Hydrocyanation Product 49

Scheme 10.

Divergent Cyclization Pathways of the Alkynyl Aldehyde 62

Scheme 11.

C12 Epimerization of Pleuromutilin 22-O-Tosylate (69) Reported by Berner

Scheme 12.

Synthesis of the Tetracycle 79

Scheme 13.

(A) Attempted Nozaki–Hiyama–Kishi Cyclization of the Vinyl Triflate 80 and Attempted Reductive Cyclization of the Alkenyl Aldehyde 81. (B) Attempted Aldol–Dehydration Ring Closure of the Dialdehyde 84. (C) Attempted Ring-Closing Metathesis of the Diene 86. (D) Proposed Mechanism for the Reductive Cleavage of 81

Scheme 14.

Synthesis of (+)-Pleuromutilin (1), (+)-12-epi-Pleuromutilin (97), and (+)-11,12-Di-epi-Pleuromutilin (93)