Enzymatic cascade reactions experience tremendous attention by cutting short conventional step-by-step synthesis in a highly efficient and elegant fashion. Focusing on ω-transaminases, this review provides an overview of different biocatalytic strategies to afford a variety of (chiral) amines employing diverse cascade systems: Cascades to shift the reaction equilibrium as well as cascades for the amination of alcohols and nonactivated C−H bonds are discussed. Cascades enable the deracemization of rac-amines, other ones involve biocatalyzed C−C bond formation and C−C bond hydrolysis. Finally, the potential of spontaneous ring closure reactions initiated by ω-transaminases is illustrated.

Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4‐trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step‐efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3‐hydroxybenzaldehyde and pyruvate), and involves a carboligation step, a subsequent transamination, and finally a Pictet–Spengler reaction with a carbonyl cosubstrate. Appropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)‐metaraminol. Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo‐ and biocatalysts for optimal results.

Regioselective transformations are highly desirable in organic synthesis, since they allow for the differentiation between two or more (chemically identical) reactive centers, [1] which is otherwise only possible by employing sophisticated and laborious protection strategies. [2] However, protectinggroup-free strategies are superior and have received outstanding merits for their successes. [3,4] Although the regioselective amination of, for example, alkanes, [5] allylic systems, [6] or indoles, [7] has been recently described, the regioselective asymmetric bioamination of diketones has not yet been reported, to the best of our knowledge. For example, diketones, such as 1,5-diketo compounds, may serve as possible precursors for a chiral piperidine scaffold. [8] Consequently, we chose 2,6-diketones 1 as model substrates to investigate the possible asymmetric regioselective amination employing w-transaminases (w-TAs; Scheme 1). [9,10] Various (S)-and (R)-stereoselective w-transaminases were tested initially for the transformation of diketone 1 a at a substrate concentration of 50 mm (Table 1). Five w-TAs (Chromobacterium violaceum, [10i, 11] Bacillus megaterium, [10i, 12] (R)-Arthrobacter, [10b] Aspergillus terreus, and Hyphomonas neptunium [10b,h] ) out of six showed perfect regioselectivity for the differentiation between the two keto groups. Hence, the amination occurred exclusively at the sterically less demanding w-1 ketone moiety, leading to the amino ketone 2 a, while the w-3 position remained untouched. The intermediate amino ketone 2 a spontaneously cyclized, finally giving D1piperideine 4 a. Only the w-TA from Vibrio fluvialis [9h, 13] (entry 3) showed diminished regioselectivity, since regioisomer 5 a was formed in minor quantities (5-7 %) along with regioisomer 4 a at high conversion. Notably, the corresponding diamine was never detected in any experiment.Using alanine as amine donor led to the formation of pyruvate as a by-product, which was removed/recycled to alanine through the use of an alanine dehydrogenase (AlaDH) system. In all cases, perfect conversions were achieved for this system. When removing pyruvate by reduction to lactate through the use of a lactate dehydrogenase (LDH) system, the conversions varied from 56-98 %. The Scheme 1. Regioselective amination of various 1,5-diketones. Table 1: Asymmetric reductive amination of diketone 1 a. [a] AlaDH system LDH system Entry w-TA conv [%] 4 a [%] ee 4 a [%] 5 a [%] conv [%] 4 a [%] ee 4 a [%] 5 a [%] 1 C. violaceum > 99 > 99 > 99 (S) < 0.1 93 93 > 99 (S) < 0.1 2 B. megaterium > 99 83 [b] > 99 (S) < 0.1 98 98 > 99 (S) < 0.1 3 V. fluvialis > 99 93 > 99 (S) 7 98 92 > 99 (S) 6 4 (R)-Arthrobacter > 99 87 [b] > 99 (R) < 0.1 63 63 > 99 (R) < 0.1 5 A. terreus > 99 > 99 > 99 (R) < 0.1 56 56 > 99 (R) < 0.1 6 H. neptunium > 99 89 [b] > 99 (R) < 0.1 78 78 > 99 (R) < 0.1 [a] Conversions/compositions and ee values were determined by GC-FID analysis. Reaction conditions: diketone 1 a (50 mm), lyophilized E. coli cells containing the overexpressed w-T...

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