Melithiazol I

A convergent synthesis of cystothiazoles C 1 and D 3 was achieved based on Julia coupling between the functionalized aldehyde 5b, corresponding to left half of the final molecule, and aryl sulfone 6 or 7, bearing a bithiazole moiety, corresponding to right half. Methylation of 1 and 3 gave cystothiazole A 2 and melithiazol B 4, respectively. The overall yield (5 steps from (2R,3S)-3-methylpent-4-yne-1,2-diol 10; 57%) of 5b via the present route was improved in comparison to that of the previously reported functionalized aldehyde 5a (7 steps from 10; 13%). By applying the modified Julia coupling method, selectivity (6E/6Z=20 : 1-26 : 1) toward the (6E)-form of the coupled products (15 or 19) against the corresponding (6Z)-form was improved in comparison to the Wittig method (6E/6Z=4 : 1-6.9 : 1).

A short and convergent synthesis of the myxobacterial antibiotic melithiazole C is described featuring a highly E-selective cross-metathesis as the key step.

This study reports the uncovering of new myxobacterial natural products through comprehensive analysis of the Myxococcus fulvus secondary metabolome. Statistics-based mining of mass spectrometry data paved the way for full structure elucidation of two new secondary metabolites named fulvuthiacene A and B, and investigation of the underlying biosynthetic pathway revealed an evolutionary link between the fulvuthiacene hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) gene cluster and the related myxothiazol and melithiazol assembly lines. Detailed characterization of the post-PKS modification enzyme cascade responsible for the fulvuthiacenes' terminal β-methoxy-methyl acrylate moiety was pursued by heterologous expression of these enzymes in the myxothiazol producer Stigmatella aurantiaca DW4/3-1. The discovery of fulvuthiacenes provides new insights into the overall structure-activity relationship picture for the β-methoxyacrylate class of respiratory chain inhibitors and might thus serve as starting point for the development of next-generation β-methoxymethacrylate fungicides.