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New biocatalytic approaches for lactonization and lactamization
Citation Link: https://doi.org/10.15480/882.1895
Publikationstyp
Doctoral Thesis
Date Issued
2018
Sprache
English
Author(s)
Advisor
Referee
Title Granting Institution
Technische Universität Hamburg
Place of Title Granting Institution
Hamburg
Examination Date
2018-11-12
Institut
TORE-DOI
Lactones and lactams are cyclic esters and amides, respectively. They are the monomers of polyesters and polyamides, such as polycaprolactone and polycaprolactam, which are the commonly used polymer materials in our daily life and in industry. Apart from that, lactones and lactams are also widely used as raw materials in the pharmaceutical industry and as flavors and fragrances or laundry detergents for bleaching. Up to date, the industrial synthesis of most of the lactones and lactams applies chemical synthesis methods established decades ago that need expensive metal catalysts, aggressive chemicals, high temperature, and depend on non-renewable resources. Thus, there is a necessity to develop more sustainable methods for the synthesis of lactones and lactams. In general, enzymatic reactions show high selectivity and can be conducted in mild conditions leading to environmentally benign approaches compared to chemical methods.
In the first part of the PhD study, a nicotinamide adenine dinucleotide (NADH)-dependent redox-neutral convergent cascade for lactonizations was developed. The redox-neutral convergent cascade is composed of a recently discovered type II flavin-containing monooxygenase from Rhodococcus jostii RHA1 (FMO-E) and the well-known horse liver alcohol dehydrogenase (HLADH). Two molar equivalents of ketone substrate converted by FMO-E and one molar equivalent of diol substrate converted by HLADH were converted into three molar equivalents of the single lactone product with high atom efficiency and self-sufficient cofactor regeneration. Two model cascade reactions were demonstrated for the synthesis of γ-butyrolactone and chiral bicyclic lactones. Biochemical characterization of FMO-E and HLADH was firstly done using the individual substrates of the enzymes in the evaluated cascades in order to find the optimal reaction conditions. Having identified the optimized conditions for the enzymatic cascade, achiral and chiral lactone products could be synthesized in high analytical yields (87%) and moderate to high enantioselectivities (up to 99%).
In the second part of the PhD study, a direct synthesis of lactams (5-, 6- and 7-membered) starting from amino alcohols in a parallel cascade was developed. HLADH together with the H2O forming NADH oxidase variant from Streptococcus mutans (SmNOX) made up the parallel cascade. First, crucial reaction parameters for the efficiency of this novel cascade reaction were elucidated. pH of the buffer, concentrations of HLADH and NAD+ were identified as the key parameters for the lactamization reaction. Under the optimized conditions, up to 95% analytical yields could be achieved in this newly developed cascade reaction in the case of γ-butyrolactam, whereby the yield decreased with increasing ring-size, as also known from the literature for ring-closure reactions.
Overall this PhD study dealt with new biocatalytic approaches for the synthesis of lactones and lactams. For lactone synthesis, NADH-dependent redox-neutral convergent cascade consisting of FMO-E and HLADH was developed for the synthesis of γ-butyrolactone and chiral bicyclic lactones with high atom efficiency in a self-sufficient cofactor regeneration fashion. For lactam synthesis, it was the first report on the direct synthesis of lactams from amino alcohols catalyzed by an alcohol dehydrogenase. The NAD+ regeneration was also achieved by coupling the SmNOX forming H2O as the sole by-product.
In the first part of the PhD study, a nicotinamide adenine dinucleotide (NADH)-dependent redox-neutral convergent cascade for lactonizations was developed. The redox-neutral convergent cascade is composed of a recently discovered type II flavin-containing monooxygenase from Rhodococcus jostii RHA1 (FMO-E) and the well-known horse liver alcohol dehydrogenase (HLADH). Two molar equivalents of ketone substrate converted by FMO-E and one molar equivalent of diol substrate converted by HLADH were converted into three molar equivalents of the single lactone product with high atom efficiency and self-sufficient cofactor regeneration. Two model cascade reactions were demonstrated for the synthesis of γ-butyrolactone and chiral bicyclic lactones. Biochemical characterization of FMO-E and HLADH was firstly done using the individual substrates of the enzymes in the evaluated cascades in order to find the optimal reaction conditions. Having identified the optimized conditions for the enzymatic cascade, achiral and chiral lactone products could be synthesized in high analytical yields (87%) and moderate to high enantioselectivities (up to 99%).
In the second part of the PhD study, a direct synthesis of lactams (5-, 6- and 7-membered) starting from amino alcohols in a parallel cascade was developed. HLADH together with the H2O forming NADH oxidase variant from Streptococcus mutans (SmNOX) made up the parallel cascade. First, crucial reaction parameters for the efficiency of this novel cascade reaction were elucidated. pH of the buffer, concentrations of HLADH and NAD+ were identified as the key parameters for the lactamization reaction. Under the optimized conditions, up to 95% analytical yields could be achieved in this newly developed cascade reaction in the case of γ-butyrolactam, whereby the yield decreased with increasing ring-size, as also known from the literature for ring-closure reactions.
Overall this PhD study dealt with new biocatalytic approaches for the synthesis of lactones and lactams. For lactone synthesis, NADH-dependent redox-neutral convergent cascade consisting of FMO-E and HLADH was developed for the synthesis of γ-butyrolactone and chiral bicyclic lactones with high atom efficiency in a self-sufficient cofactor regeneration fashion. For lactam synthesis, it was the first report on the direct synthesis of lactams from amino alcohols catalyzed by an alcohol dehydrogenase. The NAD+ regeneration was also achieved by coupling the SmNOX forming H2O as the sole by-product.
Subjects
Lactonsynthese
Lactamsynthese
Rhodococcus jostii RHA1
Pferdeleber-Alkoholdehydrogenase
Alkoholdehydrogenase
DDC Class
500: Naturwissenschaften
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