α-Chymotrypsin andl-acylase aided synthesis of 5-hydroxypipecolic acid via Jacobsen's hydrolytic kinetic resolution of epoxy amino acids

Abstract

CO 2 Et N O CO 2 Et N O CO 2 Et N (RR)-Co-salen OH HO N CO 2 Et HO Boc N CO 2 Et HO Boc Boc H H Boc Boc H 5-hydroxypipecolic acid synthesis from intramolecular reaction of epoxy amino acids; enatiomers separated by hydrolase and diastereomeric epoxide separated by Jacobsen's hydrolytic kinetic resolution.ABSTRACT: Diethyl malonate derivatives were used to synthesize racemic 2-amino-5-hexenoic acid. This racemic 2-amino-5-hexenoic acid (homoallylyglycine) derivatives were efficiently resolved aided by chymotrypsin or L-acylase, giving rise to L-and D-enatiomers. These isolated enatiomerically pure amino acids with tert-butoxycarbonyl (Boc) protection were oxidised with 3-chloroperbenzoic acid. The oxidation gave rise to an inseparable diastereomeric epoxides due to newly generated chiral center at C 5 carbon. The isolation of one of the diastereomeric epoxide was possible by selectively converting the remaining diastereomer into a dihydroxyl compound catalysed by Jacobsen's hydrolytic kinetic resolution (HKR).The isolated epoxide was regioselectively attacked by LiBr to give vicinal halohydrin, with bromide attacking on terminal C 6 carbon.Upon (Boc) deprotection of the halohydrin, lead to intramolecular cyclization by attack of free amine at C 6 carbon, generating a single isomer of 5-hydroxypipecolic acid which was effortlessly recovered in good yield after re-protection of the amine with (Boc) group. Similarly the dihydroxyl compound isolated earlier was converted to an halohydrin with iodine at the C 6 carbon. This was feasible by efficient regioselective monotosylation with catalytic (Bu 2 SnO) followed by iodine substitution. This was utilized to synthesize the 5hydroxypipecolic acid derivative in the same described sequence consisting of Boc removal by acid treatment, cyclization, reprotection and purification. Finally the same sequence was repeated with D-isomer and two diastereomers were isolated.

A New Synthetic Route to Avibactam: Lipase Catalytic Resolution and the Simultaneous Debenzylation/Sulfation

“…Substantial effort has been devoted to the preparation of avibactam − (Scheme ). Initially, the Aventis infection division in Romainville (France) disclosed route A for its synthesis in the early stage of drug discovery. , In this process, double-chiral piperidine derivatives were used as starting material to provide avibactam via inversion of configuration, deprotection, urea-cyclization, deprotection, and sulfonation with about 9.0% total yields.…”

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

“…No nuclear Overhauser effect was observed between the two vinyl protons nor between the two sets of allylic protons. Previously, epoxidations of N-Boc and N-Cbz allyl-and homoallyl-glycine esters with m-chloroperbenzoic acid (m-CPBA) in dichloromethane had given 1:1 diastereomeric mixtures of the corresponding oxiranes, which were inseparable by chromatography [28][29][30]. The C3-protons of benzyl (2S,4RS)-2-(Boc)amino-3-(2-oxiranyl)propionate was reported to exhibit a doubling of signals in the 1 H NMR spectrum [28].…”

Use of Lipase Catalytic Resolution in the Preparation of Ethyl (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxylate, a Key Intermediate of the β-Lactamase Inhibitor Avibactam

“…In recent years, considerable research has focused on the synthesis of avibactam − (Scheme ), and in particular on the preparation of a key intermediate, ethyl (2 S ,5 R )-5-((benzyloxy)­amino)­piperidine-2-carboxylate − and its derivatives (Scheme ). In the early stages of β-lactamase inhibitor research, Sanofi-Aventis developed route A for the synthesis of avibactam. , In this process, piperidine derivatives with two chiral centers were used as starting materials to synthesize avibactam via inversion of configuration.…”