Vicinal Diamines as Smart Cosubstrates in the Transaminase‐Catalyzed Asymmetric Amination of Ketones

Abstract

Transaminases (TAs) have recently been established as catalysts for the asymmetric, reductive amination of prochiral ketones. Depending on the ketone substrate and the amine donor (the cosubstrate), equilibrium constants may limit high conversions; thus, methods to overcome this limitation are required. Removal of the co‐product from the reaction equilibrium through spontaneous, intramolecular reactions has provided a successful solution to this problem; therefore, these amine donors have been named “smart cosubstrates”. Here, we present a comparison of various bifunctional amine donors including vicinal diamines as potential structural cosubstrate motifs. Upon TA‐catalyzed deamination of 1,2‐diamines, spontaneous dimerization of the resulting α‐aminoketones and oxidation gave heteroaromatic pyrazines.

Isopropylamine as Amine Donor in Transaminase‐Catalyzed Reactions: Better Acceptance through Reaction and Enzyme Engineering

“…The downside of this strategy is a very often unfavorable reaction equilibrium, which makes strategies for equilibrium shifting necessary. Therefore several equilibrium displacement techniques were established, for instance involving enzymatic cascades in order to remove co‐products,, utilization of ‘smart‐donors’ which are converted into sacrificial co‐substrates after transamination or application of the amine donor in large excess . In fact, IPA is the industrially favored amine donor for asymmetric syntheses since it is cheap, achiral – so the enantioselectivity of the ATA has not to be considered – and the by‐product acetone is supposed to have a drastic lower reactivity in the back reaction .…”

Asymmetric Synthesis of Chiral Halogenated Amines using Amine Transaminases

“…For this purpose, pyruvate decarboxylase, alanine dehydrogenase, or, most commonly, a combination of lactate dehydrogenase and glucose dehydrogenase (LDH/GDH system) are applied to drive the desired transamination reaction to completeness. More recently, aliphatic diamines were reported as effective amine donors …”

Development of Biotransamination Reactions towards the 3,4-Dihydro-2H-1,5-benzoxathiepin-3-amine Enantiomers

“…Three different types of enzymes were Due to the amine transaminases catalytic mechanism, which involves two pairs of ketones and amines in equilibrium, the reductive amination of the substrate must be thermodynamically favoured in order to obtain high yields of the desired product [45,46]. In order to displace the equilibrium towards amine formation, the removal of the generated co-products by coupling different multienzyme networks is often required [20], but also worth noting is the use of sacrificial substrates, which normally range from the use of a large excess of a commercially available amine donor, typically isopropylamine [47], to "smart cosubstrates", mainly diamines, in a stoichiometric amount that are able to drive equilibrium by spontaneous cyclisation or aromatisation reactions [31,[48][49][50]. Promisingly, we have found a favourable ∆G of -31.0 kJ/mol (calculated at M06-2X/6-311++G(3df,2p) level; see Section 3.8) for the transamination of 6 to 9 when using isopropylamine and acetone is formed as a by-product, probably due to ring strain instability.…”