The condensations of aldehydes with thioglycollic acid or α-mercaptopropionic acid were carried out; 2-substituted- or 2,4-disubstituted-1,3-oxathiolan-5-ones were thus obtained. The intermediate of the reaction was isolated only when phenylglyoxal and thioglycollic aicd were used.
Several halogenatedand other related derivatives of herbimycin A have been synthesized and evaluated in vivo for their activities against Ehrlich ascites carcinoma. Some of these derivatives show higher activities than herbimycin A. Among them the derivatives modified at the 4, 5, 6, and 7-positions of the ansa chain showed particularly high activities.Herbimycin A1), a new ansamycin antibiotic isolated from the culture broth of Streptomyces hygroscopicus AM-3672, shows herbicidal, anti-tobacco mosaic virus and antitumor activities2). The structure of herbimycin A has been confirmed as a benzoquinoid type ansamycin antibiotic3 4), which is similar to the other antitumor antibiotics, geldanamycin5,6), and macbecin7•8) In this paper, we wish to describe the synthesis of halogenated and other related derivatives of herbimycin A and their in vivo activities against Ehrlich ascites carcinoma.The hydrogen at the 19-position of herbimycin A is easily substituted by a nucleophile. For example, treatment of herbimycin A with pyridinium hydrobromide perbromide9) (also, pyridinium hydrobromide perbromide is an electrophilic reagent which attacks nucleophilic centers in molecules)in a mixture of chloroform and methanol at -35°C gave 19-bromoherbimycin A (1) and an unexpected product, 9,19-dibromo-7-decarbamoyl-7,8-O-carbonyl-8,9-dihydro-8-hydroxyherbimycin A (2) in 85 and 5 % yields, respectively. The yield of 2 was 15 % when the reaction was performed at -10°C.The structure of 1 was confirmed from a disappearance of the 19-proton signal observed in herbimycin A and a downfield shift (d 8.1 ppm) of the 19-carbon signal (6c 121.0) in the NMR spectrum, in addition to the indication of the substitution of a hydrogen atom by a bromine one in its mass spectrum. The structure of 2 was evidenced from the following data; the characteristic absorption of fivemembered cyclic carbonate at 1760 cm-1, in the IR spectrum, the disappearance of 19-proton signal in the 1H NMR and the existence of only one nitrogen atom in the elemental analysis. The 13C NMR spectrum showed the disappearance of olefinic carbon signals at 8 and 9-positions which were observed in the spectra of herbimycin A and 1. Further, two new carbon signals at S 85.9 (quarternary) and 67.8 (tertiary) were assigned to the carbons attached to oxygen and bromine, respectively. Treatment of 2 with tert-BuSnH10) in toluene at refluxing temperature afforded debrominated product (3).
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