Synthese von Stickstoff-Heterozyklen unter Einsatz von Enzymen und Metallkatalysatoren

Zumbrägel N. Synthese von Stickstoff-Heterozyklen unter Einsatz von Enzymen und Metallkatalysatoren. Bielefeld: Universität Bielefeld; 2019

Lipase-catalyzed chemoselective ester hydrolysis of biomimetically coupled aryls for the synthesis of unsymmetric biphenyl esters

Lipases are among the most frequently used biocatalysts in organic synthesis, allowing numerous environmentally friendly and inexpensive chemical transformations. Here, we present a biomimetic strategy based on iron(III)-catalyzed oxidative coupling and selective ester monohydrolysis using lipases for the synthesis of unsymmetric biphenyl-based esters under mild conditions. The diverse class of biphenyl esters is of pharmaceutical and technical relevance. We explored the potency of a series of nine different lipases of bacterial, fungal, and mammalian origin on their catalytic activities to cleave biphenyl esters, and optimized the reaction conditions, in terms of reaction time, temperature, pH, organic solvent, and water-organic solvent ratios, to improve the chemoselectivity, and hence control the ratio of unsymmetric versus symmetric products. Elevated temperature and increased DMSO content led to an almost exclusive monohydrolysis by the four lipases Candida rugosa lipase (CRL), Mucor miehei lipase (MML), Rhizopus niveus lipase (RNL), and Pseudomonas fluorescens lipase (PFL). The study was complemented by in silico binding predictions to rationalize the observed differences in effcacies of the lipases to convert biphenyl esters. The optimized reaction conditions were transferred to the preparative scale with high yields, underlining the potential of the presented biomimetic approach as an alternative strategy to the commonly used transition metal-based strategies for the synthesis of diverse biphenyl esters

Merging Heterocyclic Chemistry and Biocatalysis in One-Pot Processes through Compartmentalization of the Reaction Steps

Zumbrägel N, Gröger H. Merging Heterocyclic Chemistry and Biocatalysis in One-Pot Processes through Compartmentalization of the Reaction Steps. Bioengineering. 2018;5(3): 60.A proof of concept for a one-pot process merging a heterocycle formation by a classical chemical approach at basic conditions with a biocatalytic reduction, running at neutral pH conditions, is reported. A crucial component for this process is the compartmentalization of the single reactions by the use of polydimethylsiloxane thimbles. This process was applied successfully towards an asymmetric synthesis of (S)-2,2,3-trimethyl-1-thia-4-azaspiro[4.4]nonane, leading to excellent enantioselectivities of 99% enantiomeric excess (ee)

Enantioselective reduction of sulfur-containing cyclic imines through biocatalysis

Zumbrägel N, Merten C, Huber SM, Gröger H. Enantioselective reduction of sulfur-containing cyclic imines through biocatalysis. Nature Communications. 2018;9(1): 1949

Structural Characterization of an S-enantioselective Imine Reductase from Mycobacterium Smegmatis

Meyer T, Zumbrägel N, Geerds C, Gröger H, Niemann H. Structural Characterization of an S-enantioselective Imine Reductase from Mycobacterium Smegmatis. Biomolecules. 2020;10(8): 1130.NADPH-dependent imine reductases (IREDs) are enzymes capable of enantioselectively reducing imines to chiral secondary amines, which represent important building blocks in the chemical and pharmaceutical industry. Since their discovery in 2011, many previously unknown IREDs have been identified, biochemically and structurally characterized and categorized into families. However, the catalytic mechanism and guiding principles for substrate specificity and stereoselectivity remain disputed. Herein, we describe the crystal structure of S-IRED-Ms from Mycobacterium smegmatis together with its cofactor NADPH. S-IRED-Ms belongs to the S-enantioselective superfamily 3 (SFam3) and is the first IRED from SFam3 to be structurally described. The data presented provide further evidence for the overall high degree of structural conservation between different IREDs of various superfamilies. We discuss the role of Asp170 in catalysis and the importance of hydrophobic amino acids in the active site for stereospecificity. Moreover, a separate entrance to the active site, potentially functioning according to a gatekeeping mechanism regulating access and, therefore, substrate specificity is described

Expanding the Scope of Asinger Chemistry towards Enantiomerically Pure Secondary Amines and β-Aminothiols through Chemoenzymatic Derivatization of 3-Thiazolines

Hyseni M, Zumbrägel N, Offermanns H, Gröger H. Expanding the Scope of Asinger Chemistry towards Enantiomerically Pure Secondary Amines and β-Aminothiols through Chemoenzymatic Derivatization of 3-Thiazolines. Chemistry. 2019;2019(1):180-191.A proof of concept for a novel approach towards enantiomerically highly enriched acyclic secondary amines and β-aminothiols as non-cyclic target molecules when starting from 3-thiazolines as heterocycles is presented. Starting from 2,2,4,5,5-pentamethyl-3-thiazoline, we demonstrated this chemoenzymatic pathway to both of these types of amine molecules, which were isolated as urea derivatives with a non-optimized yield of up to 20%. As a substrate, 2,2,4,5,5-pentamethyl-3-thiazolidine, which was obtained with an enantiomeric excess (ee) of 99% in a biotransformation from the corresponding 3-thiazoline according to a recently developed protocol, was used. For the reductive desulfurization of this substrate leading to a sulfur-free secondary amine, in situ formed Ni2B turned out to be a suitable reducing reagent. However, when using lithium aluminum hydride as a reducing agent, β-aminothiol was obtaine

One-pot synthesis of a 3-thiazolidine through combination of an Asinger-type multi-component-condensation reaction with an enzymatic imine reduction

Zumbrägel N, Gröger H. One-pot synthesis of a 3-thiazolidine through combination of an Asinger-type multi-component-condensation reaction with an enzymatic imine reduction. Journal of Biotechnology. 2018;291:35-40

Lipase-Catalyzed Chemoselective Ester Hydrolysis of Biomimetically Coupled Aryls for the Synthesis of Unsymmetric Biphenyl Esters

Lipases are among the most frequently used biocatalysts in organic synthesis, allowing numerous environmentally friendly and inexpensive chemical transformations. Here, we present a biomimetic strategy based on iron(III)-catalyzed oxidative coupling and selective ester monohydrolysis using lipases for the synthesis of unsymmetric biphenyl-based esters under mild conditions. The diverse class of biphenyl esters is of pharmaceutical and technical relevance. We explored the potency of a series of nine different lipases of bacterial, fungal, and mammalian origin on their catalytic activities to cleave biphenyl esters, and optimized the reaction conditions, in terms of reaction time, temperature, pH, organic solvent, and water–organic solvent ratios, to improve the chemoselectivity, and hence control the ratio of unsymmetric versus symmetric products. Elevated temperature and increased DMSO content led to an almost exclusive monohydrolysis by the four lipases Candida rugosa lipase (CRL), Mucor miehei lipase (MML), Rhizopus niveus lipase (RNL), and Pseudomonas fluorescens lipase (PFL). The study was complemented by in silico binding predictions to rationalize the observed differences in efficacies of the lipases to convert biphenyl esters. The optimized reaction conditions were transferred to the preparative scale with high yields, underlining the potential of the presented biomimetic approach as an alternative strategy to the commonly used transition metal-based strategies for the synthesis of diverse biphenyl esters

Enantioselective Biocatalytic Reduction of 2H-1,4-Benzoxazines Using Imine Reductases

Zumbrägel N, Machui P, Nonnhoff J, Gröger H. Enantioselective Biocatalytic Reduction of 2H-1,4-Benzoxazines Using Imine Reductases. The Journal of Organic Chemistry. 2018;84(3):1440-1447

Biocatalytic Reduction of 2-Monosubstituted 3-Thiazolines Using Imine Reductases

Zumbrägel N, Wagner K, Weißing N, Gröger H. Biocatalytic Reduction of 2-Monosubstituted 3-Thiazolines Using Imine Reductases. Journal of Heterocyclic Chemistry. 2019;56(3):788-794