Synthetic Studies on Thiostrepton Family of Peptide Antibiotics: Synthesis of the Tetrasubstituted Dihydroquinoline Portion of Siomycin D1

The tetrasubstituted dihydroquinoline portion of siomycin D 1 , a member of the thiostrepton family of peptide antibiotics, was synthesized from 5,6,7,8-tetrahydroquinoline featuring the modified Reissert-Henze reaction, the homolytic aromatic substitution reaction, the modified Boekelheide rearrangement, and the Jacobsen asymmetric epoxidation.In 1961, siomycin A was isolated from the culture broth of Streptomyces sioyaensis by the Shionogi group. 1 In 1969, siomycin B was recognized as an artifact of siomycin A, and siomycin C was isolated from the same culture broth. 2 Siomycin D 1 was also isolated from the same culture broth in 1980 as a minor component of the siomycins. 3Their structures were elucidated by chemical degradation studies 4 and NMR spectral studies 3,5 by comparison with those of thiostrepton, which is a representative compound of this class of peptide antibiotics and whose structure had been confirmed by X-Ray crystallographic analysis. 6The characteristic structure of the thiostrepton family of peptide antibiotics is the bicyclic structure containing a tetrasubstituted dehydropiperidine moiety, a tetrasubstituted dihydroquinoline moiety, four thiazole moieties, a thiazoline moiety, dehydroamino acid moieties, and a dihydroxyisoleucine moiety (Figure 1).Because of these complex structural features, synthetic studies on the thiostrepton family of antibiotics have scarcely been attempted. 7Most efforts have focused on the syntheses of the much simpler thiopeptide antibiotics: the berninamycins, 8 the micrococcins, 9 nosiheptide, 10 sulfomycin I, 11 cyclothiazomycin, 12 A10255, 13 GE 2270 A, 14 and promothiocin A. 15 These antibiotics show high activities against Gram-positive bacteria and mycobacteria, 1,2,3 and their mode of action has been described.9i,15b,16 In this paper, we describe the enantioselective synthesis of the tetrasubstituted dihydroquinoline portions (1) and (2) of siomycin D 1 .It has been proposed by Floss and his co-workers 16b that the 4-(1-hydroxyethyl)quinoline derivatives of 1 would be intermediates of the thiostrepton biosynthesis.We were interested in the Floss synthesis of 4-(hydroxymethyl)quinoline-2-carboxylic acid, which was used in the studies of the biosynthesis of thiostrepton, from quinoline.16b This synthetic process was applied to the early stage of our synthesis of 1 and 2 with slight modifications.