Towards the Total Synthesis of Jerangolids – Synthesis of an Advanced Intermediate for the Pharmacophore Substructure

Julian Lenhof,Johann Jauch,Volker Huch,Michael Hutter

doi:10.1002/ejoc.202000586

Abstract

The jerangolids are a class of natural products with a skipped diene substructure isolated from Sorangium cellulosum. Here, we present a new strategy for the total synthesis of these compounds based on a skipped diyne as central building block and a suitably substituted epoxy aldehyde as building block for the dihydropyran substructure. So far, we reached an advanced intermediate which is related to the pharmacophore subunit of the jerangolids as well as of the ambruticins. A key step is a Shi epoxidation with high e.r. to form the epoxy aldehyde. Both building blocks are coupled in a Carreira alkynylation, where additional mechanistic studies based on DFT calculation were realized. The alkynylation is followed by a nucleophilic 6‐endo‐tet epoxide opening to form the pyran structure and a Nicholas reduction to remove a propargylic OH group.

Highlights

The first jerangolids[1] were isolated by Gerth, Höfle and coworkers in 1995 from the myxobacterium Sorangium cellulosum So ce 307 (Figure 1).The jerangolids are structurally related to the ambruticins[2] (Figure 2) which were isolated from Polyangium cellulosum var. fulvum[2a,2b] and Sorangium cellulosum So ce 10.[2c,2d] Since both, the jerangolids and the ambruticins, show potent antifungal activity,[1,2] it was assumed[3] that the common substructure of both natural compounds (C6–C17 and C20–C22 jerangolide numbering) is the pharmacophore responsible for the fungicidal effect.[b] Dr M
Ring closure to the hydroxy-tetrahydropyran ring is effected through nucleophilic epoxide opening of the corresponding epoxy aldehyde 10 after Carreira alkynylation of the prochiral 3-methyl-1,4-pentadiyne 9
Starting from commercially available 5-trimethylsilyl-pent-4-yn-1-ol 12, hydroalumination with DIBALH and iodination with I2 led to vinyl iodide 18.[11]. Negishi coupling[12] with ethylzinc bromide gave unsaturated alcohol 11, which was converted to epoxy alcohol 19 through Shi epoxidation[13] with er = 98.5:1.5.[14]. Dess–Martin oxidation resulted in epoxy aldehyde 10 in 46 % yield over four steps

Summary

Introduction

The first jerangolids[1] were isolated by Gerth, Höfle and coworkers in 1995 from the myxobacterium Sorangium cellulosum So ce 307 (Figure 1).The jerangolids are structurally related to the ambruticins[2] (Figure 2) which were isolated from Polyangium cellulosum var. fulvum[2a,2b] and Sorangium cellulosum So ce 10.[2c,2d] Since both, the jerangolids and the ambruticins, show potent antifungal activity,[1,2] it was assumed[3] that the common substructure of both natural compounds (C6–C17 and C20–C22 jerangolide numbering) is the pharmacophore responsible for the fungicidal effect.[b] Dr M. After cooling to room temperature, dry CuCl (180 mg, 3.6 mmol) is added and the reaction mixture is heated to reflux for 1.5 hours. After cooling to room temperature, a solution of 15 (11.1 g, 50 mmol) in THF (8.5 mL) is added dropwise during 30 min.

Results

Conclusion