分子内環化反応を利用した非天然アミノ酸及びプロリン誘導体の効率的合成法に関する研究

Abstract

Cyclic amino acids (imino acids) were synthesized from intramolecular cyclization of aminoacids functionalized with side chain epoxides; The allyl glycine and homo allyl glycinederivatives were obtained from the diethyl 2-aminomalonate derivatives, in a series ofreaction which finally gave a racemic mixture of allyl glycine/homo allyl glycine. Theseracemic mixture were well resolved and separated by one of these commercially availableenzymes, L-acylase, ?-chymotrypsin and subtilisin Carlsberg. The epoxides were obtained byepoxidation of the side chain of enatiomerically pure 2-amino-4-pentenoic acid and its higher homologue 2-amino-5-hexenoic acid (homo allyl glycine). The epoxides were thenintramolecularly cyclized to form 4-hydroxyproline from epoxide of allyl glycine or5-hydroxypipecolic acid from epoxide of homo allyl glycine.The enatiomers of allyl glycine were separated by effective resolution aided bysubtilisin Carlsberg or L-acylase. The enatiomerically pure allyl glycine derivatives with(Boc) protection were epoxidized with m-CPBA which generated the inseparablediastereomeric epoxide. Upon removal of the Boc protection generated highly nucleophilicamine which attacked the side-chain epoxide intramolecularly at the C5 carbon generating 4-hydroxyproline derivatives. Due to presence of 2 chiral centers formed during theepoxidation trans- and cis- isomers of 4-hydroxyprolines are formed. Fortunately the cisisomer was transformed to a lactone with the removal of alcohol. The cis-conformation of the hydroxyl and ester was necessary for the intramolecular reaction; the trans- isomer remained as such without lactone formation. Due to the selective intramolecular lactonization of the cis- isomer into an hydrophobic lactone, the separation of the lactone from the hydrophilic trans- isomer was facile and easy. Similarly starting from the D- isomers two diastereomers 6 of 4-hydroxyproline were synthesized.Similarly racemic mixture of 2-amino-5-hexenoic acid were synthesized from diethylmalonate derivatives. This racemic mixture of 2-amino-5-hexenoic acid was separated byresolution aided by L-acylase or ?-chymotrypsin. The separated enatiomerically pure aminoacids with tert-butoxycarbonyl (Boc) protection were oxidized with excess amount of 3-chloroperbenzoic acid (m-CPBA). The oxidation by m-CPBA generates two inseparablediastereomeric epoxides which are formed due to new chiral center at C5 carbon. One of thediastereomeric epoxide in the inseparable mixture was selectively converted to a dihydroxylcompound catalyzed by Jacobsen\u27s hydrolytic kinetic resolution (HKR) which was easilyseparated from the remaining diastereomeric epoxide. The epoxide was converted to a vicinalhalohydrin, with bromide attacking on terminal C6 carbon. Upon (Boc) deprotection of thehalohydrin, the free amine attacked the C6 carbon, generating 5-hydroxypipecolic acid whichwas isolated in good yield after protection of the amine with (Boc) group. In a similar manner the dihydroxyl component which was converted to an halohydrin by efficient regioselective mono-tosylation with catalytic (Bu2SnO) followed tosyl replacment by iodine substitution.The halohydrin was used to synthesize 5-hydroxypipecolic acid derivative by Boc removalwith acid treatment, intramolecular cyclization, N- reprotection and isolation. The samesequence was repeated for D- isomers.Finally racemic mixture of 2-amino-5-hexenoic acid were prepared by the samesequence described above. This racemates were subjected to subtilisin carlsberg basedresolution, which gave chiraly pure 2-amino-5-hexenoic acid. The alkene side chain of thefully protected amino acids were oxidized with m-CPBA, which gave the diastereomers,which were not separable. On treating the epoxide with acid led to the removal of N-Bocgroup and formation of the free amine. This amine was allowed to attack the epoxide, bytreating the amine with base, which led to the neutralization of the acid. The amine7 regioselective attacked the C6 carbon to generate the 5-hydroxypipecolic acid derivatives.The amine was again reprotected with Boc2O to generate the fully protected 5-hydroxypipecolic acid derivatives Due to the diastereomeric nature of the starting material, twoproduct were formed (cis-) and (trans)-5-hydroxypipecolic acid. But in our reactionconditions the cis- isomer due to the close proximity of the hydroxyl and ester groupunderwent in-situ lactonization to form the hydrophobic lactone. The lactone was easilyisolated from the trans- ester. Similarly starting from the L- isomer two isomers of 5-hydroxypipecolic acid were obtained.九州工業大学博士学位論文 学位記番号:工博甲第401号 学位授与年月日:平成27年9月25日1. Introduction|2. Instrumentation|3. Intramolecular cyclization of epoxy amino acids produced from allylglycines to prepare four stereoisomers of 4-hydroxyproline derivatives|4. Chemoenzymatic synthesis of 5-hydroxy pipecolic acid via Jacobsen\u27s hydrolytic kinetic resolution of epoxy amino acids|5 Regioselective cyclization and facile separation of 5-hydroxypipecolic acid|6. General Conclusion九州工業大学平成27年