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.

Total Synthesis of (−)‐Alstofolinine A through a Furan Oxidation/Rearrangement and Indole Nucleophilic Cyclization Cascade

“…Next, several attempts to convert 10 into the bketoester using Mandersr eagent were unsuccessful, [16] and after screening as eries of different bases and keto-esterification reagents, [17] the desired b-ketoester indole ring was eventually obtained in quantitative yield by treatment with NaH and dimethyl carbonate.T hen, the crude product was treated with phenyl triflimide to provide the vinyl triflate 11 (76 %, two steps;Scheme 2). Next, several attempts to convert 10 into the bketoester using Mandersr eagent were unsuccessful, [16] and after screening as eries of different bases and keto-esterification reagents, [17] the desired b-ketoester indole ring was eventually obtained in quantitative yield by treatment with NaH and dimethyl carbonate.T hen, the crude product was treated with phenyl triflimide to provide the vinyl triflate 11 (76 %, two steps;Scheme 2).…”

“…Once the synthesis of 6gwas accomplished, we focused on the final stage of (À)-alstofolinine As ynthesis.T he indole ring 6g was converted to the N-methylindole ring with iodomethane,followed by reduction with Pd/C under ahydrogen balloon to provide the indole ring ketone 10 in ah igh yield. Next, several attempts to convert 10 into the bketoester using Mandersr eagent were unsuccessful, [16] and after screening as eries of different bases and keto-esterification reagents, [17] the desired b-ketoester indole ring was eventually obtained in quantitative yield by treatment with NaH and dimethyl carbonate.T hen, the crude product was treated with phenyl triflimide to provide the vinyl triflate 11 (76 %, two steps;Scheme 2).…”

Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J

“…The stereoconfigurations of 18a and 18b were assigned at later stage, according to a single-crystal X-ray diffraction (XRD) data of compound 22. Initially, we envisioned to subject both isomers of 18 to a Pd-catalyzed carbonylative cyclization 62,63 , however preparation of the corresponding enol triflate failed. Alternatively, the terminal alkene motif in 18b was regioselectively hydroformylated following Shi's protocol furnishing aldehyde 19 in 75% yield 64 .…”

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, [2] as well as the Maimone laboratorys radical cascade in the synthesis of berkeleyone A. [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.…”