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Bulletin of the University of Osaka Prefecture. Ser. B, Agriculture and biology >
Vol.33 >

Please use this identifier to cite or link to this item: http://hdl.handle.net/10466/3155

Title: 生理活性アミノ酸の不斉合成
Other Titles: Asymmetric Syntheses of Biologically Active Amino Acids
Authors: 切畑, 光統
Author's alias: KIRIHATA, Mitsunori
Issue Date: 31-Mar-1981
Publisher: University of Osaka Prefecture
Citation: Bulletin of the University of Osaka Prefecture. Ser. B, Agriculture and biology. 1981, 33, p.135-171
Abstract: The asymmetric syntheses of biologically active hydroxy- and α-alkyl-amino acids were achieved by convenient and creative synthetic methods. The various optically active and stereoisomeric amino acids were isolated in high yields, and then the reaction mechanisms were discussed. An asymmetric synthesis of (4s, 3s)-4-amino-3-hydroxy-6-methylheptanoic acid (AHMHA), an amine moiety of pepstatines, from L-leucine has been studied, in charpter 1. The reaction of N-phthalyl-L-leucyl chloride (3) with ethyl tert-butyl malonate and (-)-menthyl tert-butyl malonate (4) afforded the corresponding condensation products (5b) and (5c), which were derived to β-ketoesters (7b) and (7c), respectively, by decarboxylation reaction under mild condition without racemization. Reduction of 7b with sodium borohydride gave the mixture of two diastereomers (8b_1) and (8b_2), which were hydrolyzed with 4N hydrochloric acid to afford the corresponding diastereomers (4s, 3s)AHMHA and (4s, 3R)-AHMHA, respectively. These compounds were separated by ion exchange resin chromatography. Similarly, the reaction of hydroxy diesters (6b) and (6c) to (8b) and (8c) , and subsequent hydrolysis afforded the diastereomeric mixture of 9 and 10. The extent of asymmetric reduction was examined by GLC analysis of the TMS derivatives of 8b and 8c. A new approach has been established for the stereoselective synthesis of β-hydroxy-α-amino acids (serine type amino acid) in charpter 2. β-C-Acylamino acid methyl esters (3) were prepared by the acid hydrolysis of oxazole-4-carboxylate derivatives (2), which were easily obtained by the reaction of methyl-2-isocyanoacetate (1) with acyl halides or acid chlorides in the presence of organic bases. The reduction of (2) to β-hydroxy-α-amino acid esters (6) was examined by the following two methods (A and B). Method A: Hydrogenation of β-C-oxo-α-amino acid esters (3) over PtO_2 or reduction with NaBH_4, LiBH_4 and Ca(BH_4)_2. By the method A, erythro-β-hydroxy-α-amino acids were obtained predominatly. The relative stereochemistry of the reaction products (erythro-(6) and threo-(6)) was also discussed. Hydrolysis of (6) with hydrochloric acid afforded β-hydroxy-α-amino acid (7). In charpter 3, optically active α-methylornithines were synthesized via sterically controlled Michael type addition of isocyanoacetic acid (+)- or (-)-menthylesters to acrylonitrile in the presence of sodium hydride. The isocyano group of γ-cyano-α-isocyano-α-methylpropionic acid esters (2) was converted stepwise to amino group of γ-cyano-α-amino-α-methylpropionic acid esters. Subsequently, after the protection of amino group by acetylation, N-acetyl cpmpounds (5) were hydrogenated in acetic anhydride to give di-N-acetylamide derivatives (6). Hydrolysis of 6 with hydrochloric acid gave optically active α-methylornithine (7), which was separated by ion exchange resin chromatography. Asymmetric synthesis of 7 from (+)-menthylester (la) gave (-)-7 (4.7 % e.e) and from (-)-menthylester (1b) gave (+)-7 (5.8 % e.e). The syntheses of α-alkylornithines, α-methyl, α-ethyl- and α-benzylornithines were achieved via alkylation of carbanion derived from α-isocyanoacetic acid ester (11). α, δ-N-Diacetyl (31), α-N,N-dimethyl (29) and δ-N-formyl-ornithines (33) and other various analogues were also synthesized by usual synthetic methods. These twelve structural analogues and derivatives of ornithine were evaluated as inhibitors of L-ornithine decarboxylase (ODC) obtained from rat liver, in chapters 3 and 4. From the degree of their inhibition on ODC, it has been possible to delineate some of the fundamental structures of ornithine which are required for inhibiting ODC. An affinity-gel for the effective purification of ODC has been prepared, in charpter 5; AH-Sepharose 4B was reacted succesively with α, δ-N-dinitrophenylsulfenyl-α-methylornithine succinimide ester (40). The nitrophenylsulfenyl group of the gel (41) was removed under mild conditions with aqueous sodium thiosulfate. The enzyme was bound selectively on the affinity-gel and could be eluted with 0.1~0.5 M NaCl solution. According to this method, ODC could be obtained in high yield.
URI: http://hdl.handle.net/10466/3155
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