The use of enzyme-catalyzed chemical reactions for the synthesis of polymers and the preparation of high-grade, enantiomerically pure chemical intermediates has received considerable attention in academia and industry over the past decades. These enzyme-catalyzed reactions on non-natural substrates generally proceed under mild conditions and with an excellent degree of selectivity. In this thesis, the suitability of Candida antarctica Lipase B (CALB) as catalyst in the preparation of optically pure small organic molecules, functional polymer architectures and amino acid based supramolecular building blocks is explored. Additionally, we are eager to gain a better theoretical insight in the use of CALB for the enzymatic ring opening polymerization (eROP) of lactones. Finally, the aggregation behavior of the supramolecular benzene-1,3,5-tricarboxamide (BTA) building blocks described in this thesis has been investigated in detail. In Chapter 2, the Bäckvall system for the dynamic kinetic resolution (DKR) of 1-phenylethylamine was optimized for use with a single equivalent of acyl donor and shorter reaction times. The aim was to develop a dynamic kinetic resolution polymerization (DKRP) system for the preparation of chiral polyamides. By the use of a single equivalent of isopropyl methoxyacetate as acyl donor, the reaction time was decreased from 72 to 26 h, without having a negative influence on the chemo- or enantioselectivity (90 and 97%, respectively) of the DKR process. The wider applicability of the modified DKR procedure was demonstrated for 7 other (di)amine substrates. Polymerization of the two diamine substrates with an activated diacyl donor showed conversion of both the amine and the acyl donor, but suffered from the poor solubility of the reaction products. The direct synthesis of polyesters with pendant functional groups by chemo- and regioselective polymerization is described in Chapter 3. Novozym 435, a commercially available and immobilized form of CALB, was used as catalyst. First, an epoxide functionalized polymer with a Mn of 9.7 kg/mol and a PDI of 1.9 was prepared by the enzymatic ring-opening polymerization of ambrettolide epoxide. In addition, isopropyl aleuritate, a monomer comprising two secondary and one primary hydroxy group, was synthesized. The Novozym 435-catalyzed acylation of this monomer appeared to be highly selective towards the primary hydroxy group. Enzyme-catalyzed homopolymerization gave well-defined polymers with a reasonable molecular weight (Mn: 5.6 kg/mol, PDI: 3.2). In contrast, the chemically catalyzed polymerization resulted in the formation of cross-linked polymers. Co-polymers of ¿-caprolactone and isopropyl aleuritate of varying composition were prepared via enzyme-catalyzed polymerization and the possibility of post-modification of these polymers was shown. In Chapter 4, theoretical molecular dynamics and docking studies were performed to gain insight into the relationship between the lactone ring size and eROP rate. The docking studies directly showed the importance of a transoid ester bond for good substrate recognition by the enzyme catalyst, thereby giving an explanation for the seemingly low eROP rates of the small, purely cisoid lactones. The possibility of enzyme-catalyzed peptide bond formation for the synthesis of BTAs comprising amino acid derived substituents was explored in Chapter 5. Both the Thermolysin-based peptide bond formation and the Novozym 435-catalyzed DKR of oxazol-5(4H)-ones with alcohol nucleophiles were investigated. Reactions on model compounds that required the transformation of a single functional group proceeded readily in both approaches, while similar transformations on a triply substituted central benzene core were less successful. The influence of the increased steric demands and the altered equilibrium by introduction of the tri-substitution pattern were directly noticeable. Moreover, stability problems were unexpectedly encountered for a phenylalanine derived tris(oxazol-5(4H)-one). On the other hand, structurally more simple BTA precursors comprising a single 5-oxo-4,5-dihydrooxazolin-2-yl substituent did show a slow, CALB-catalyzed ring opening process. In Chapter 6, N',N''-bis(octyl)-N-(¿-hydroxyalkyl) BTAs with an ethylene, butylene, and hexylene spacer were synthesized and their solid state and self-assembly behavior were studied. The introduction of a single hydroxy group in the BTA structure had a distinct influence on the solid state properties. The temperatures for the transition to the isotropic state were significantly lower compared to nonfunctionalized BTAs. In addition, in dilute methylcyclohexane solution the hydroxy functional BTAs showed a stronger tendency to aggregate than the (octyl)3 BTA. Moreover, the three hydroxy functional BTAs turned out to be excellent organogelators for apolar cyclic and branched organic solvents at a concentration of 1 wt%. Novozym 435-catalyzed acylation of the primary hydroxy groups of these BTAs was applied to control the organogelation behavior. Chapter 7 discusses the influence of the sterically demanding phenylalanineoctyl ester (PheOct) moiety on the supramolecular self-assembly behavior of BTAs in dilute solution. These BTAs with one or three PheOct moieties were the target compounds for the DKR of oxazol-5(4H)-ones described in Chapter 5. Introduction of the PheOct moiety led to an isodesmic classification of the aggregation behavior. A weak majority rules effect was observed for the mono PheOct substituted BTA, whereas no effect was found for (PheOct)3 BTA. Mixing experiments with (octyl)3 BTA revealed a strong induction of a preferred helicity for the mono PheOct BTA, while (PheOct)3 BTA preferentially gave a more stable 1:1 heterocomplex.
|Qualification||Doctor of Philosophy|
|Award date||14 Jan 2010|
|Place of Publication||Eindhoven|
|Publication status||Published - 2010|