94(P-51) 海洋産微生物由来抗炎症活性環状ペプチド、サイクロマリンAの合成研究(ポスター発表の部)
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Cyclomarin A (1) was isolated from the marine baterium Streptomyces sp. by Fenical and co-workers. The structure of cyclomarin A (1) was determined using 1D and 2D NMR methods, and the stereochemistry was determined from an X-ray crystal structure of its diacetate derivative. Cyclomarin A contains three common amino acids (alanine, valine, N-methylleucine), and four unusual amino acids (β-methoxyphenylalanine (2), 2-amino-3,5-dimethylhex-4-enoic acid (3), N-methyl-δ-hydroxyleucine (4), N-(1,1-dimethy1-2,3-epoxypropyl)-β-hydroxytryptophan (5)). Cyclomarin A is currently undergoing preclinical trials as an antiinflammatory and antiviral agent by Phytera, Inc. The intriguing biological activities of cyclomarin A coupled with its structural curiosities have led us to investigate the total synthesis of cyclomarin A. We now wish to report the stereoselective synthesis of the four unusual amino acids. The stereoselective synthesis of the β-methoxyphenylalanine derivative 12 was achieved by the Schollkopfs syn-selective aldol reaction between benzaldehyde (8) and the titanium derivative 7 of chiral bislactim ether 6, followed by O-methylation. The synthesis of the 2-amino-3,5-dimethylhex-4-enoic acid derivative 19 involves stereoselective methylation of the γ-lactone 14 derived from aspartic acid, and Wittig olefination of the lactol 16. N-Methyl-δ-hydroxyleucine was synthesized by the Evans' asymmetric azido transfer reaction of the chiral imide 22, which was prepared by the Horner-Emmons reaction using phenylglycine derived chiral imide phosphonate. For the synthesis of the hydroxytryptophan derivative, the efficient method for the synthesis of N-reverse prenyl indole (27) was initially developed by the N-propargylation of the indoline (28), partial hydrogenation of the terminal alkyne, and oxidation to the indole using chemical manganese dioxide (CMD). This method was also used for the synthesis of the antifungal indole alkaloids 31 and (S)-32. We next applied N-reverse prenyl indole (27) for the synthesis of the hydroxytryptophan derivative. Vilsmeier's formylation and (DHQD)_2-PYR mediated asymmetric dihydroxylation afforded the diol 34, which was converted to the epoxide 35 via the corresponding mono-tosylate. Horner-Emmons olefination followed by Sharpless' asymmetric aminohydroxylation provided the hydroxytryptophan derivative 37. Further approach to the total synthesis of cyclomarin A is currently underway in our laboratory and will be reported in the symposium.
- 天然有機化合物討論会の論文
- 2001-09-01
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