Asymmetric Synthesis of Chiral Halogenated Amines using Amine Transaminases

Abstract

Amine transaminases (ATAs) are versatile and industrially relevant biocatalysts that catalyze the transfer of an amine group from a donor to an acceptor molecule. Asymmetric synthesis from a prochiral ketone is the most preferred route to the desired amine product, as it is obtainable in a theoretical yield of 100 %. In addition to the requirement of active and enantioselective ATAs, the choice of a suitable amine donor is also important to save costs and to avoid additional enzymes to shift the equilibrium and/or to recycle the cofactors. In this work, we identified suitable (R)‐ and (S)‐ATAs from Aspergillus fumigatus and Silicibacter pomeroyi, respectively, to afford a set of halogen‐substituted derivatives of brominated or chlorinated 1‐phenyl‐2‐propanamine, 4‐phenylbutan‐2‐amine, and 1‐(3‐pyridinyl)ethanamine. Optimization of the donor–acceptor ratio enabled application of isopropylamine as an amine donor, which resulted in high conversions and amines with 73–99 % ee.

Biocatalytic Production of Amino Carbohydrates through Oxidoreductase and Transaminase Cascades

“…As imilar relative increasef rom sequential tos imultaneous reactionw as observed when l-alanine was used as the amine donor,b ut the yields obtained with l-alanine were roughlyt en times lower than those with 1-PEA as amine donor. [64] ActivityofCvi-w-TAtoward selectedoxidized6-aldo-d-galactosyl-containing carbohydrates [47,48,63] It is also notable that increasingt he concentration of the PLP cofactorf rom 20 mm to 1mm only moderately increased product yields in sequential reactions (Table 2) Because isopropylamine (IPA) is the preferred amined onor used by industry to push reaction equilibria towards the aminated product owing to its low cost and easyr emoval of the acetone byproduct, [63] IPAwas tested herein as ameanstofurther increase the formation of 2c from 2b.H owever,r eplacing 1-PEA by IPAr esulted in undetectable product formation (data not shown), consistent with the comparatively high sensitivity of Cvi-w-TAt o IPA.…”

“…in undetectable product formation (data not shown), consistent with the comparatively high sensitivity of Cvi-w-TAt o IPA. [64] ActivityofCvi-w-TAtoward selectedoxidized6-aldo-d-galactosyl-containing carbohydrates…”

Three‐liquid‐phase Spinning Reactor for the Transaminase‐catalyzed Synthesis and Recovery of a Chiral Amine

“…Transamination can be carried out either by direct amination of prochiral ketones (asymmetric synthesis mode) or by the thermodynamically favourable kinetic resolution of racemic amines. Due to a theoretical yield of 100 %, the asymmetric synthesis is often preferred . However, physical and chemical strategies for counteracting the unfavourable thermodynamic equilibrium and/ or product inhibition are needed .…”

“…Due to a theoretical yield of 100 %, the asymmetric synthesis is often preferred. [1][2][3] However, physical and chemical strategies for counteracting the unfavourable thermodynamic equilibrium and/ or product inhibition are needed. [4,5] Besides the use of an excess of amine donor (AD), methods such as coproduct or product cyclization [6][7][8] or polymerization, [9,10] evaporation of the volatile co-product [11,12] and enzymatic cascades [4,13] for co-product removal have been developed.…”

Combination of the Suzuki–Miyaura Cross‐Coupling Reaction with Engineered Transaminases

“…[16] DMF/water mixtures were a good startingp ointfor our claim of ATAs compatibility.R ecently,w er eported the successful production of chiral halogenated amines in DMF/water mixtures using the ATAf rom Aspergillus fumigatus (4CHI-TA) and Silicibacter pomeroyi. [27] We chose four biphenyl model compounds whichc over several aspects regardingp osition and substitution of the biphenyl moietya s well as the presence of heterocycles( Scheme1). Starting with the aryl bromides 5-bromo-3-acetyl-pyridine (1a)a sw ell as 4'bromoacetophenone (3a)a nd (fluoro-substituted) arylboronic acids we were ablet os ynthesize the desired biphenyl ketones 1b-4b with very good conversion according to the mentioned methodf rom Liu et al using sodium carbonate [14,19,28] as activating base and using free PdCl 2 as catalyst ( Table S1, Figure S2,Supporting Information).…”