Concise Syntheses of Cystothiazoles A, C, D, and Melithiazol B

Abstract

Several antifungal substances, cystothiazoles A (2), C (1), D (3), 1,2) and melithiazol B (4) 3) were isolated from different strains of the myxobacterium Cystobacter fuscus and Archangium gephyra, respectively. These antifungal substances possessing a bithiazole skeleton as well as a bmethoxyacrylate moiety, and 2 have shown potent antifungal activity against the phytopathogenic fungus Phytophthora capsici (2 mg/disk), and have also shown activity against a broad range of additional fungi with no effect on bacterial growth. 1) Furthermore, when 2 was examined for in vitro cytotoxicity using human colon carcinoma HCT-116 and human leukemia K562 cells, the resulting IC 50 values were 110-130 ng/ml, which were significantly higher than those of myxothiazol A. [4][5][6] The fungicidal activity of these bmethoxyacrylate (MOA) inhibitors has been shown to be due to their ability to inhibit mitochondrial respiration by blocking electron transfer between cytochrome b and cytochrome c.7) The absolute structure of 2 was established by a combination of spectroscopic analysis and chemical degradation of the natural product.1) The left-side structure of 2 has been reported to be responsible for its antifungal activity. 8) For the purpose of studying the structure-biological activity relationships of cystothiazole A congeners, efficient synthesis of the left-side aldehyde 5a is considered to be highly important.The first enantiocontrolled synthesis of 2 was achieved based on the preparation of a bis-thiazole core and application of an asymmetric Evans aldol methodology for development of the C(4)/C(5) vicinal stereochemistry. 9) After our syntheses of cystothiazoles A (2) 10,11) and B 12) were reported, further syntheses of cystothiazoles A 2, 8,[13][14][15][16] and B, 16) as well as syntheses of the C 9,14) and E 17,18) types, were reported. In this paper, we describe a concise chiral synthesis of cystothiazoles A (2) and C (1) and melithiazol B (4) for the purpose of improving the overall yield and the (E)-selectivity at the C(6)/C(7) double bond. Moreover, the first chiral synthesis of cystothiazole D (3) is described. Our retrosynthetic strategy for these natural products is illustrated in Chart 1. It can be seen that these compounds can be synthesized by modified Julia coupling 19) between the left-side aldehyde 5b and the right-side sulfone 6 or 7. The synthesis of the leftside aldehyde 5b is shown in Chart 2.The starting (2R,3S)-diol 10 was obtained from (2R,3S)-epoxy butanoate 8 20-23) via (2R,3S)-2-hydroxy ester 9 using a previously reported procedure.11) Bis-silylation (11, quantitative yield) of 10 followed by consecutive treatment with nBuLi and methyl chloroformate gave acetylenecarboxylate 12 in 93% overall yield. It was previously reported that conjugate addition of MeOH to a 3-substituted prop-2-ynoate congener in the presence of Bu 3 P selectively gave a (2E)-3-methoxy-acrylate congener. 24) Applying this procedure, conjugate addition of MeOH to acetylenecarboxylate 12 in the presence of a catalytic amount o...

Muscarine, imidazole, oxazole, and thiazole alkaloids

“…Moreover, cystothiazoles A 431, C 432, D 433, and melithiazol B 434 have been concisely synthesized using the same strategy. 377 Synthesis of 14-hydroxycystothiazole C 435, (14,15)-dihydroxycystothiazole A 436, and (14,15)-dihydroxycystothiazole C 437 has been also completed and, therefore, the absolute configurations of 435-437 were unambiguously assigned as 4R,5S,14S. 378 Through a microwaveassisted olefin cross-metathesis reaction, an alternative total synthesis of cystothiazole A 431 was achieved.…”

Thiazoles in Peptides and Peptidomimetics

“…13). [77,78] Bi-thiazoles occur in other natural products such as micrococcinic acid (89) and macrocyclic peptides (see section below). …”