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Identifier

000406662

Title

α) Εφαρμογές ενζυμικών αναγωγών στην σύνθεση γ-βουτυρολακτονών και του φυσικού προϊόντος Stereocalpin A β) Απομόνωση συνθετικών Κετορεδουκτασών

Alternative Title

a) Application of enzymatic reductions in the synthesis of γ-butyrolactones and the natural product Stereocalpin Α b) Isolation of synthetic ketoreductases

Author

Τζανακάκη, Αγγελική Γ.

Thesis advisor

Σμόνου, Ιουλία

Reviewer

Βασιλικογιαννάκης, Γεώργιος
Στρατάκης, Εμμανουήλ

Abstract

The subject of the present thesis is the study of stereoselective enzymatic reductions with ketoreductases for the synthesis of optically active intermediates of natural products and the development of new synthetic ketoreductases. In the first part, the chemoenzymatic approach for the synthesis of aldol subunit 5-hydroxy-2,4-dimethyl-3-oxo-octanoic acid (HDMOO) of Stereocalpin A is presented, in order to investigate the right structure assignment of this natural product. The attempted synthesis of the referred subunit, with the key step to be an enzymatic reduction, gave the resulted 5-hydroxy-4-methyl-3-oxooctanoic tert-butylester after screening of a series of ketoreductases with adequate stereoselectivity and good enantiomeric excess in favor of Β stereoisomer. In the second part, the stereoselective synthesis of disubstituted γ-butyrolactones, starting from three different ketodiesters via enzymatic reduction with ketoreductases is described. The enzymatic reduction resulted exclusively to the γ-butyrolactones synthesis under the reaction conditions, without any isolation of the hydroxy diester intermediate. Different KREDs were utilized in each case, which led to excellent reactions rates in most of the cases, high diastereoselectivity and very good enantioselectivity at specific examples. The last chapter includes the production of new ketoreductases and the determination of enzymatic activity, having as substrate ethyl 2-methyl acetoacetate. Enzyme production proceeds with cloning of appropriate strains which express the desired protein-ketoreductase in bacterial host E.coli cells, and different modes of the produced enzymes were used for the study of enzymatic activity.

Language

Greek

Subject

2-Μέθυλο οξικός αιθυλεστέρας

Biocatalysis

Biotechnology

Ethyl 2-methyl acetoacetate

Microbial enzymes

NADPH

Stereocalpin A

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