Enantioselective reductive amination

By analogy with the enantioselective reduction of prochiral ketones to chiral alcohols an attractive method for producing enantiomerically pure amines would be enantioselective reductive amination of a ketone via enzymatic reduction of an imine intermediate (Scheme 6.11). Unfortunately the required enzymes-amine... 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

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],... 

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. 

The first reported example of enantioselective reductive amination was that of Blaser et al. at Solvias (Scheme 7.7) [2]. At the time, 1999, they were still tweaking the industrial process for metolachlor, the active ingredient of the herbicide Dual , and examined its synthesis via the reductive amination of methoxyacetone with 2 methyl 5 ethyl aniline (MEA, limiting reagent). Working at the 100 mmol scale, they showed that a very low loading of an Ir xyhphos complex, under 80 bar (1160 psi) H2, neat, 50 °C, and 14 h, were optimal. By doing so, a 76% ee with full conversion was achieved. 

Scheme 7.1 The first enantioselective reductive amination synthesis of metolachlor.

Although this was an outstanding first example of enantioselective reductive amination that achieved the project s ee target, the final industrial process actually employed the corresponding preformed and isolated imine because ofthe advantage of reducing by one hundredth the catalyst loading compared to the reductive amination process outlined here [8]. 

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. 

An efficient enantioselective reductive amination of a-branched aldehydes (90) via d5namic kinetic resolution catalyzed by (89) has been described (Scheme 26). Reductive coupling of 1,3-enynes to heterocyclic aromatic aldehydes use an achiral rhodium-catalyst with a chiral Bronsted acid (89) as co-catalyst (Scheme 27). A highly efficient enantioselective aza-ene-type reaction of N-benzoylimines (91) with enecarbamates (92) has been achieved. The reaction can be performed at extremely low loading of the catalyst (93) without notable loss of enantioselectivity of P-aminoimines obtained (Scheme 28). ... 

Other combinations of two dehydrogenases, such as amino acid dehydrogenases and formate dehydrogenase, were described by several groups to achieve the reductive amination of a-keto acids into chiral amino acids in high yields and enantioselectivities. Formate dehydrogenase has also been combined by Bolte and co-workers with an amino acid aminotransferase to achieve enantioselective reductive amination of a-keto acids with small amino acids as the amination agent. ... 

Scheme 2.7 Industrial process for the enantioselective reductive amination of a-keto acids to afford optically active natural and nonnatural a-amino acids [1,2].

Scheme 11.11 Enantioselective reductive amination with Hantzsch ester 39.

The group of Benaglia reported a sequential reduction of ketimines that worked with trichlorosilane (169) as the reducing agent (Scheme 42.38). Furthermore, picolinamides of ephedrine 108a,b turned out to be viable catalysts for the direct enantioselective reductive amination starting from ketone 167 and anihne (168) [87]. 

Another relevant example is provided by the enzymatic s)mthesis of the antidiabetic, sitagliptin, which was codeveloped by Merck and Codexis workers [67] to replace a rhodium-catalyzed, high-pressure, as5mimetric hydrogenation of an enamine. If involves an overall enantioselective reductive amination of a ketone using an (R)-transaminase-catalyzed reaction with isopropylamine (Figure 1.5). The starting point was an (R)-selective transaminase, which showed no activity with the ketone substrate. In silico studies were employed to identify whaf was needed to be able to fif fhe... 

Synthesis of Chiral a-Amino Acids by Asymmetric Reductive Amination of Keto Acid Substrates In 2003, Rh-Deguphos catalyzed enantioselective reductive amination of a-keto acids 106 with benzylamine (BnNH2)... 

Tararov VI, Bomer A. Approaching highly enantioselective reductive amination. Synlett 2005 2005(2) 203 211. 

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