P-49 結核菌関連の細胞表層糖脂質TDCMの四立体異性体の合成(ポスター発表の部)

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Cell surface glycolipids of Mycobacterium were first purified in 1950 and called cord factor due to their characteristic cord forming growth. The structures have been probed to be trehalose-6,6'-dimycolate (TDM 1) in 1956, and has been accepting significant attention due to their various biological activities. Later on it became clear that these molecules are not directly correlated with the toxicity of Mycobacterium or its cord forming growth, and related Corynebacterium or Nocardia species also produce similar compounds such as trehalose 6,6'-dicorynomycolate [TDCM (2)] on their cell surface. TDM as well as a number of synthetic analogs with high molecular weight α-branched β-hydroxy fatty acids have been investigated dealing with the structure activity relationship, however every synthetic analog employed such purpose has been a mixture of enantiomers or diastereomers. We have been interested in this area from the standpoint on a relationship between biological activities and the absolute configurations of the α and β positions of the corynomycolic acid residue. Although the absolute structure of natural corynomycolic acid was established to be 2R3R based on the synthetic studies, pure TDCM has not yet been prepared. Thus, we would like to describe herein the syntheses and characterizations of four diastereomers of TDCM (2a-2d). Syntheses of four isomeric corynomycolic acids have first achieved by using Sharpless epoxidation product 3, however the regioselectivity of alkylative epoxide opening reaction was terrible to give desired 4a as a minor product. Thus we examined furthermore using Noyori's asymmetric hydrogenation reaction. (R)-BINAP-Ru catalyzed hydrogenation of racemic β-ketolactone (±)-10 provided optically active β-hydroxy ketolactone (2S, 3R)-11a in 84% yield, 98% de, and 98%ee. 11a was converted to RR and SR corynomycolic acid 18a and 18b, respectively. Coupling with trehalose derivative 19 afforded 2a and 2b, respectively. Isomeric 18c and 18d were derived f rom (S)-BINAP-Ru catalyzed hydrogenation product. TDCM 2a and three isomers 2b, 2c, and 2d were clearly distinguishable on the basis of 600MHz ^1H-NMR (Fig I). Isolation of TDCM from Corynebacterium matruchotii was reported recently, and the NMR spectrum was identical with our RR TDCM (2a). Thus the stereochemistry of natural TDCM was proved to be RR although [α]_D value is not identical due to impurity of natural product. Therefore, when some other trehalose ester of α-branched β-hydroxy fatty acids are isolated, one would easily determine the stereochemistry by comparing their NMR with our four isomers 2a-2d.
天然有機化合物討論会の論文
1995-09-01

P-49 結核菌関連の細胞表層糖脂質TDCMの四立体異性体の合成(ポスター発表の部)

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