Harnden M R, Bailey S, Boyd M R, Taylor D R, Wright N D
J Med Chem. 1978 Jan;21(1):82-7. doi: 10.1021/jm00199a015.
Total synthesis of a series of thiazolinone and thiazolidinone analogues of the antibacterial oxazolinone antibiotic indolmycin is described. The synthetic route involves nucleophilic displacement of mesyloxy and chloro groups from methyl 2-substituted-3-(indol-3-yl)propionates 3 and 4 and butyrate 19 with N-substituted thioureas. The formation of the rearranged chloro esters 29, 43, and 44 from beta(RS,RS)-methyl indolmycenate (27), alpha(RS,SR)-methyl 2-hydroxy-3-(2-methylindol-3-yl)butyrate (39), and alpha-methyl 2-hydroxy-3-(indol-3-yl)valerate (41) supports a reaction mechanism involving neighboring group participation by the indole C-3 carbon during nucleophilic displacement on the beta-carbon of a C-3 substituent. Structure-activity relationships are discussed. Although neither indolmycin nor its diastereoisomer isoindolmycin is antiviral, 2-monoalkylaminothiazolinone analogues have in vitro activity against both RNA viruses and bacteria. The most active compound is the sulfur isostere of indolmycin, and only the levorotatory enantiomer 46, with the same absolute stereochemistry as natural indolmycin, has antimicrobial activity.
描述了抗菌恶唑啉酮抗生素吲哚霉素的一系列噻唑啉酮和噻唑烷酮类似物的全合成。合成路线包括用N-取代硫脲从2-取代-3-(吲哚-3-基)丙酸甲酯3和4以及丁酸酯19中亲核取代甲磺氧基和氯基团。由β-(RS,RS)-甲基吲哚霉素酯(27)、α-(RS,SR)-甲基2-羟基-3-(2-甲基吲哚-3-基)丁酸酯(39)和α-甲基2-羟基-3-(吲哚-3-基)戊酸酯(41)形成重排氯酯29、43和44，支持了一种反应机理，即在C-3取代基的β-碳上进行亲核取代时，吲哚C-3碳参与邻基参与。讨论了构效关系。尽管吲哚霉素及其非对映异构体异吲哚霉素都没有抗病毒活性，但2-单烷基氨基噻唑啉酮类似物对RNA病毒和细菌都有体外活性。最具活性的化合物是吲哚霉素的硫等排体，只有与天然吲哚霉素具有相同绝对立体化学的左旋对映体46具有抗菌活性。
