Asymmetric reductive amination

Despite its long history and common usage of the term, reductive amination has remained underdeveloped. Many studies are available regarding racemic reductive amination, but only Borner and Tararov have provided summaries of the asymmetric version [1], In this chapter we provide an overview of the available methods and achievements since the first demonstrated enantioselective reductive amination by Blaser in 1999 [2], 

Before discussing the relevant literature, a few qualifiers are mentioned and discussed. Reductive amination is sometimes incorrectly associated with the reduc tion of preformed imines and derivatives thereof. Reductive amination, by definition, is only the one pot conversion of a ketone to an amine in which a reductant coexists in the presence of a ketone starting material [4]. The term indirect reductive amination is occasionally used, but can be more tersely and accurately described as imine reduction [5]. The reader wUl note that depending on the perspective one takes for the transformation, the term reductive amination is applied when considering the reaction course of the ketone starting material, and the term reductive alkylation is applied when describing the starting amine s conversion to the product amine. 

Included in this section are procedures that are not classified as reductive amina 

Chiral Amine Synthesis Methods, Dei elopments and Applications. Edited by Thomas C, Nugent Copyright 2010 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3.527-32509-2 

The enantioselective reductive amination of ketoacid substrates has been dem onstrated and provides amino acids that are beyond the scope of this review [6]. Enzymatic based reductive amination is now possible and allows nonamino acid chiral amine synthesis, however, this field of study is also beyond the scope of this material [7]. Finally, much of the material discussed here also appeared in a recent review of ours on the general subject of chiral amine synthesis. 

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The List group came up with a novel concept for a catalytic asymmetric reductive amination, which involves enolizable aldehydes (Scheme 18) [33]. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

N. Mohr and H. Budzikiewicz 107) described another example of an asymmetric reductive amination using a (S)-proline moiety as chiral inductor. 

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

The previous examples are selected asymmetric reductive animations of ketones to give chiral, a-branched amines (Eq. 32) however, the corresponding reactions of aldehydes are unknown. We reasoned that such a process might be realized if enolizable, a-branched aldehydes are used. Their asymmetric reductive amination should give -branched amines via an enantiomer-differentiating kinetic resolution (Eq. 33). 

Scheme 14. Organocatalytic asymmetric reductive amination of ketones...

Scheme 15. Catalytic asymmetric reductive amination of aldehydes...

Dutheuil, G., Couve-Bonnaire, S. and Pannecoucke, X. (2007) Diastereomeric fluoroolefins as peptide bond mimics prepared by asymmetric reductive amination of a-fluoroenones. Angew. Chem. Int. Ed., 46, 1290-1292. 

Asymmetric reductive amination can be carried out on chiral ketones able to form an intermediate imine such as 3.231 or 3.232 [BWl, MN1, PP4] (Figure 3,92). According to the structure of the substrates, NaBH4, NaCNBHj, or Me4N(AcO)3BH are the reducing agents that give the best yields or selectivities. 

Similarly, direct asymmetric reductive amination is discouraged and should be replaced by the shorter and more accurate phrase asymmetric reductive amination or enantioselective reductive amination. 

The asymmetric reductive amination using ( + )-(/ )- or (—)-(S,)-l -phenylcthylamine as the chiral auxiliary has also been used in the synthesis of several cw-bicyclic lactams and amines32. 

Aspects featured in a review of asymmetric reductive aminations have included transition metal-mediated homogeneous-, enantioselective organocatalytic-. 

Asymmetric reductive amination of a dialkyl ketone by an alkylamine, catalysed by (193), formed the diazepane ring (194) with >97% yield and >94% ee. Purging of the by-product CO2 resulted in increased rate and almost quantitative yield of the product which otherwise formed carbamates with CO2 an adverse effect on the equilibrium between Ru-hydride and Ru-formate (catalyst forms) was thereby avoided. The rate could also be accelerated by trapping with nucleophilic secondary amines. ... 

The most efficient approach is probably the direct recycling of alanine from pymvate via NADH-dependent reduction in presence of ammonia catalyzed by alanine dehydrogenase. Overall, this sequence resembles a metal-fiee asymmetric reductive amination, which only requires ammonia and a low-cost reducing agent for NAD(P)H-recycling in molar amounts [1739]. 

Recently, Ru-JOSIPHOS complexes were found extraordinary effective for the enantioselective transfer hydrogenation of aryl ketones (168). A novel bidentate diphosphine with axial chirality (DM-SEGPHOS) was reported to form active catalyst with ruthenium for asymmetric reductive amination (169). 

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