Dominik Koszelewski

ω-Transaminases for the synthesis of non-racemic α-chiral primary amines

Optically pure amines are highly valuable products or key intermediates for a vast number of bioactive compounds; however, efficient methods for their preparation are rare. omega-Transaminases (TAs) can be applied either for the kinetic resolution of racemic amines or for the asymmetric synthesis of amines from the corresponding ketones. The latter process is more advantageous because it leads to 100% product, and is therefore a major focus of this review. This review summarizes various methodologies for transamination reactions, and provides an overview of omega-TAs that have the potential to be used for the preparation of a broad spectrum of alpha-chiral amines. Recent methodological developments as well as some recently identified novel omega-TAs warrant an update on this topic.

Formal Asymmetric Biocatalytic Reductive Amination

Asymmetric methods to prepare optically active a-chiral primary amines are highly demanded in asymmetric synthesis owing to the biological/pharmacological activity of many amines. Various techniques have been reported, such as asymmetric 1,2-addition to imines and asymmetric amination of a,a-disubstituted aldehydes, transformation of allylic alcohols into amines, (dynamic) kinetic resolution, and cyclic deracemization employing racemic amines as substrates. Asymmetric reductive amination of ketones has been investigated with transition-metal catalysts and organocatalysts, as well as via sulfinyl imine intermediates. Although tremendous progress in organo/metal catalysis has been achieved for the asymmetric reductive amination of ketones to access a-chiral amines, improved protocols are still required that are simple, green, and economically viable and that lead to high enantiomeric excesses. Biocatalytic reductive amination or transamination is well established for accessing a-amino acids from the corresponding a-keto carboxylic acids. However, the situation is different for primary amines that are not adjacent to a carbonic acid moiety. w-Transaminases have recently received attention for the preparation of such a-chiral unprotected amines. w-Transaminases are employed mainly in one way, namely for the kinetic resolution of racemic chiral amines; only a few reports deal with asymmetric synthesis by starting from a prochiral ketone, probably due to problems in shifting the equilibrium to the product side, as well as due to the moderate stereoselectivity of the employed w-transaminases. These asymmetric synthetic processes usually require at least stoichiometric amounts of an amine donor (for example, alanine). The latter leads to a side product (pyruvate), which has to be removed during the transformation by using, for instance, pyruvate decarboxylase or lactate dehydrogenase. Additionally, limitations due to inhibition by the product amine and by pyruvate have been reported. An ideal process would use ammonium as the amine donor, together with a cheap reducing agent (for example, formate, hydrogen, or glucose; see Scheme 1). Even

Synthesis of Optically Active Amines Employing Recombinant ω-Transaminases in E. coli Cells

Various recombinant ω‐transaminases, overexpressed in E. coli cells and employed as whole‐cell catalysts, are tested for the synthesis of enantiomerically pure amines from the corresponding prochiral ketones. Optically pure (S)‐amines are obtained by formal reductive amination, consuming just ammonia and a cheap reducing agent (formate) with up to 99 % ee and 97 % yield. The other enantiomer was accessible by employing the same ω‐transaminases in a kinetic resolution starting from racemic amines. A ω‐transaminase derived from an Arthrobacter species displayed the highest stereoselectivity for all substrates tested, both for the kinetic resolution of rac‐amines and for the amination of ketones.

Deracemization of Mexiletine Biocatalyzed by ω-Transaminases

(S)- as well as (R)-mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral orally effective antiarrhythmic agent, was prepared by deracemization starting from the commercially available racemic amine using omega-transaminases in up to >99% ee and conversion with 97% isolated yield by a one-pot two-step procedure. The absolute configuration could be easily switched to the other enantiomer, just by switching the order of the applied transaminases. The cosubstrate pyruvate needed in the first oxidative step was recycled by using an amino acid oxidase.

Artificial Multi‐Enzyme Networks for the Asymmetric Amination of sec‐Alcohols

Various artificial network designs that involve biocatalysts were tested for the asymmetric amination of sec-alcohols to the corresponding α-chiral primary amines. The artificial systems tested involved three to five redox enzymes and were exemplary of a range of different sec-alcohol substrates. Alcohols were oxidised to the corresponding ketone by an alcohol dehydrogenase. The ketones were subsequently aminated by employing a ω-transaminase. Of special interest were redox-neutral designs in which the hydride abstracted in the oxidation step was reused in the amination step of the cascade. Under optimised conditions up to 91 % conversion of an alcohol to the amine was achieved.

Regioselective Enzymatic Carboxylation of Phenols and Hydroxystyrene Derivatives

The enzymatic carboxylation of phenol and styrene derivatives using (de)carboxylases in carbonate buffer proceeded in a highly regioselective fashion: Benzoic acid (de)carboxylases selectively formed o-hydroxybenzoic acid derivatives, phenolic acid (de)carboxylases selectively acted at the β-carbon atom of styrenes forming (E)-cinnamic acids.

Enzymatic Racemization of Amines Catalyzed by Enantiocomplementary ω‐Transaminases

A strategy for the biocatalytic racemization of primary α-chiral amines was developed by employing a pair of stereocomplementary PLP-dependent ω-transaminases. The interconversion of amine enantiomers proceeded through reversible transamination by a prochiral ketone intermediate, either catalyzed by a pair of stereocomplementary ω-transaminases or by a single enzyme possessing low stereoselectivity. To tune the system, the type and concentration of a nonchiral amino acceptor proved to be crucial. Finally, racemization could be achieved by the cross-transamination of two different amines without a requirement for an external amino acceptor. Several synthetically and industrially important amines could be enzymatically racemized under mild reaction conditions.

Selective cycloaddition of tetracyanoethene (TCNE) and 7,7,8,8-tetracyano-p-quinodimethane (TCNQ) to afford meso-substituted phenylethynyl porphyrins.

π-Extended TCBD-porphyrins that contained a 1,1,4,4-tetracyanobuta-1,3-diene unit were prepared by a highly efficient [2+2] cycloaddition of tetracyanoethene (TCNE) or 7,7,8,8-tetracyano-p-quinodimethane (TCNQ) with meso-substituted trans-A(2)B(2)-porphyrins that contained two phenylethynyl groups, followed by a retro-electrocyclization reaction. Depending on the electronic properties of the arylethynyl groups, the cycloaddition reaction took place exclusively on either one or two ethynyl moieties with high yield. The addition of TCNQ proceeded with complete regioselectivity. The resulting π-expanded TCBD-porphyrins had a hypsochromically shifted Soret band and showed unique, broad absorption in the visible region.

Synthesis and linear and nonlinear optical properties of low-melting π-extended porphyrins

A large and diverse library of trans-A2B2 and A2BC-porphyrins possessing two arylethynyl substituents at the meso positions has been efficiently synthesized and tested for their two-photon absorption (2PA) behavior. All compounds fall into three general types A–π–A, D–π–D or D–π–A, where A is an electron-acceptor and D is an electron-donor moiety. These porphyrins contain two polyalkoxyaryl substituents, resulting in very low melting points (typically 110–125 °C) and superb solubility in non-polar solvents. Some of these porphyrins exhibit two different crystal phases in addition to an isotropic liquid state. Their linear and nonlinear optical properties were thoroughly elucidated and analyzed. π-Extended porphyrins emit light in the NIR and have moderate triplet state lifetimes. The increase of 2PA cross-section in the Soret region for porphyrins bearing strong electron-donating groups has been attributed to resonance enhancement (caused by intensification, redshift and broadening of the lowest Q-band) of gerade–gerade transition. The combination of high two-photon absorption cross-sections (>500 GM) and low melting points makes them perfect candidates for nonlinear optical materials in the 600–900 nm range.

Solvent-free Passerini reactions

Abstract The influence of the substrate structure and concentration on the yield of the Passerini reaction was studied. A new, solvent‐free methodology for a convenient preparation of α‐acyloxyamides 4 was established and compared to the classical methodology. A higher reaction yield was obtained in shorter time, especially in the case of aromatic aldehydes.