Matematički model dinamičke kinetičke rezolucije katalizirane halogenhidrin-dehalogenazom

undergraduate thesis

• Title (english): Mathematical model of dynamic kinetic resolution catalyzed by halohydrin dehalogenase
• Author: Ana-Katarina Marić
• Mentor: Zvjezdana Findrik Blažević (mentor)
• Committee member: Zvjezdana Findrik Blažević (predsjednik povjerenstva)
• Committee member: Martina Sudar (član povjerenstva)
• Committee member: Marija Vuković Domanovac (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2020-09-10, Croatia
• Scientific / art field, discipline and subdiscipline: TECHNICAL SCIENCES; Chemical Engineering

Abstract

Optički čiste tvari imaju veliku važnost u farmaceutskoj industriji, a mogu se dobiti enantioselektivnom biokatalizom čije su dvije metode kinetička rezolucija i asimetrična sinteza. Konverzija početnih spojeva u optički čiste produkte pri kinetičkoj rezoluciji iznosi do 50 %. Ovaj nedostatak se rješava dinamičkom kinetičkom rezolucijom (DKR) koja se temelji na kinetičkoj rezoluciji kombiniranoj s in situ racemizacijom sporije reagirajućeg enantiomera. Pri odgovarajućim uvjetima dinamičkom kinetičkom rezolucijom se racemična smjesa može prevesti u jedan enantiomer. Efikasnost DKR ovisi o strukturnim parametrima supstrata i katalizatora te uvjetima in situ racemizacije. Matematički modeli se sastoje od kinetičkog i reaktorskog modela. U ovom radu je provedena validacija matematičkog modela dinamičke kinetičke rezolucije dobivanja (S)-5-bromometil-5-metiloksazolidin-2-ona iz
rac-2-bromometil-2-metil-oksirana katalizirana enzimom halogenhidrin-dehalogenazom HheC iz Agrobacterium radiobacter AD1. Reakcijska shema je podijeljena na tri reakcijska stupnja, pri čemu je prvi reakcija između (S)-epoksida i cijanatnih iona uz nastajanje
(S)-oksazolidinona. Istovremeno dolazi do reakcije (R)-epoksida i cijanatnih iona uz nastajanje (R)-oksazolidinona. Nadalje, drugi stupanj je nastajanje dibromoalkohola iz
(R)-epoksida i bromidnih iona te iz (S)-epoksida i bromidnih iona, dok je treći stupanj nastajanje rac-epoksida iz dibromoalkohola. Korišteni HheC enzim jedan je od nekolicine strukturno okarakteriziranih halogenhidrin-dehalogenaza. Kinetika ove reakcije određena je u ranijim radovima. Provođenjem eksperimenata validacije u kotlastom reaktoru uočeno je kako ovi enzimi imaju različit afinitet prema enantiomerima. Eksperimentalni podaci pokazali su zadovoljavajuće slaganje s ranije postavljenim modelom te su utvrđeni optimalni uvjeti pri kojima se dinamičkom kinetičkom rezolucijom može sintetizirati čisti
(S)-5-bromometil-5-metiloksazolidin-2-on.

Abstract (english)

Optically pure compounds are of great significance in the pharmaceutical industry and can be produced by enantioselective biocatalysis whose two methods are kinetic resolution and asymmetric synthesis. The conversion of the initial compounds to optically pure products by kinetic resolution does not exceed 50 %. This drawback is solved by dynamic kinetic resolution (DKR) which is based on kinetic resolution combined with in situ racemization of slower reacting enantiomer. Under adequate conditions, a racemic mixture can be transformed into one enantiomer by dynamic kinetic resolution. DKR efficiency depends on the structural parameters of substrates and catalysts as well as the conditions of in situ racemization. The mathematical model consists of the kinetic and the reactor model. In this paper, validation of the mathematical model of dynamic kinetic resolution for obtaining
(S)-5-bromomethyl-5-methyloxazolidin-2-one from rac-2-bromomethyl-2-methyl-oxirane catalyzed by HheC enzyme extracted from Agrobacterium radiobacter AD1 is conducted. The model is divided into three reaction steps, where the first one is the reaction of (S)-epoxide and cyanate ions with the formation of (S)-oxazolidinone. Simultaneously, the reaction with (R)-epoxide and cyanate ions forming (R)-oxazolidinone is happening. Furthermore, the second step is the formation of dibromoalcohol from (R)-epoxide and bromide ions as well as (S)-epoxide and bromide ions, while the third step is the formation of rac-epoxide from dibromoalcohol. HheC used in the experiment is one of the few structurally characterized halohydrin-dehalogenases. The kinetic of this reaction was determined in previous papers. While conducting validation experiments in the batch reactor it was recorded that these enzymes have a different enantiomeric affinity. Experimental data have shown a satisfactory match with the earlier developed model. Moreover, optimal conditions for dynamic kinetic resolution for obtaining optically pure (S)-5-bromomethyl-5-methyloxazolidin-2-one were stipulated.

• Keywords: halogenhidrin-dehalogenaza; epoksid; oksazolidinon; validacija; matematički model; dinamička kinetička rezolucija
• Keywords (english): halohydrin-dehalogenase; epoxide; oxazolidinone; validation; mathematical model; dynamic kynetic resolution
• Language: croatian
• URN:NBN: urn:nbn:hr:149:251651
• Study programme: Title: Applied Chemistry - Undergraduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Advanced materials and technologies; Study programme type: university; Study level: undergraduate; Academic / professional title: sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) primijenjene kemije (sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2021-09-11
• Created on: 2023-05-05 09:48:17