Total Synthesis of the Post-translationally Modified Polyazole Peptide Antibiotic Goadsporin.

Hannah L Dexter,Huw E L Williams,Christopher J Moody,William Lewis

doi:10.1002/anie.201612103

Hannah L Dexter, Huw E L Williams + Show 2 more

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https://doi.org/10.1002/anie.201612103

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Abstract

The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is reported in which the key steps are the use of rhodium(II)-catalyzed reactions of diazocarbonyl compounds to generate the four oxazole rings, which demonstrates the power of rhodium carbene chemistry in organic chemical synthesis.

Highlights

Retrosynthetic analysis of goadsporin 1 via protected form 2, which is split into the left- and right-hand fragments 3 and 4
Some of the building blocks required for the synthesis of goadsporin are readily available proteinogenic L-amino acids, the heterocyclic components need to be accessed
Whilst the two thiazoles should be approachable through the well-established Hantzsch reaction, we elected to synthesize the four oxazoles by using rhodium carbene chemistry, a mild and versatile method used previously in the synthesis of azolecontaining natural products.[5-7]

Summary

Introduction

Retrosynthetic analysis of goadsporin 1 via protected form 2, which is split into the left- and right-hand fragments 3 and 4. Ester hydrolysis and amide coupling with valine methyl ester hydrochloride gave compound 8. Cleavage of the ester using the known mild hydrolysis reagent trimethyltin hydroxide in 1,2-dichloroethane[11] gave the bis-oxazole carboxylic acid 12 (Scheme 3).

Results

Conclusion