Ketones asymmetric reductive amination, chiral

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). 

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. 

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). 

Chiral amines have been conveniently prepared also by asymmetric reductive amination of ketones using iridium catalysts and intriguing results with up to 96% ee have been obtained by Zhang and co-workers employing a catalytic system based on Ir./-binaphane in the presence of Ti(OPr )4 and iodine (Scheme 61). Water-soluble aquo complexes [Cp lr(H20)3](0Tf)2 494, [CpP Ir(H20)2](0Tf)2 504, and [Cp Ir(bpy)(H20)](0Tf)2 505 have been used to catalyze the reductive amination of hydrosoluble aldehydes and ketones as well as the dehalogenation of alkyl halides. The activity is markedly pH dependent and inactivation of the catalyst takes place reversibly on increasing the solution basicity due to Ir(H20), deprotonation and formation of mono- or dinuclear hydroxo complexes which are catalytically inactive. The structure of one of these compounds, [Cp Ir(bpy)(OH)]OTf 506, which reversibly forms from 494 around pH 6.6, is presented in Figure 42. 

A cooperative catalysis with the non-chiral Knolker iron complex (227) and a chiral Bronsted acid (223) has also been utilised for asymmetric reductive amination of ketones. Various ketones including aromatic, heteroaromatic and aliphatic ketones (228) have been transformed to the corresponding chiral amines (229) with high enantioselectivities up to 99% ee (Scheme 61). ... 

C2-symmetrical secondary amines by applying the stereoselective reductive amination protocol using chiral amines as the source of chirality. In 2005, Nugent et al. published a novel method for the asymmetric reductive amination of prochiral aliphatic ketones116 where the (/ )- or (5)-a-methylbenzylamine (MBA) were employed as the cheap chiral ammonia equivalent. Ti(0 Pr)4/Raney Ni/H2 were employed as the catalyst system for the one-pot conversion of the prochiral ketones 116a-e to the corresponding chiral amines 117a-e with excellent dia-stereoselectivity (Scheme 39.33). 

Stereoselective Reductive Amination Using Chiral Ketones as Auxiliary The first report of asymmetric reductive amination using chiral ketone was published by Nugent and co-workers in 2004. The current methodology includes dynamic kinetic resolution of a racemic ketone 128 producing a chiral ketone 129,... 

Kroutil and co-workers reported on a very efficient biocatalytic asymmetric reductive amination of ketones using co-transaminase as the enzyme for the synthesis of optically active a-chiral amines.Three enzyme systems were used for the successful operation of this methodology based on ... 

A more concise route to chiral amines would be direct synthesis from the ketone via direct asymmetric reductive amination. This has been developed successfully for the conversion of (3-ketoesters to chiral (3-amino acid esters and demonstrated in the manufacture of sitagliptin, a DPP-IV inhibitor for... 

The reductive amination of ketones with useful functional groups would be important in organic synthesis. In 2007, Kocovsky et al. proposed that the asymmetric reductive amination product of a-chloroketone 96 could be a precursor for preparing chiral aziridines 98 (Scheme 32.20). After optimizing the reaction conditions they found that sigamide 76 can catalyze the reductive amination reaction to afford corresponding chiral a-chloroamines 97 with up to 96% ee and 98% yield. A further cyclization under basic conditions yields chiral 1,2-diarylaziridines 98 in excellent yield without losing enantioselectivity [61]. 

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

The paramount significance of chiral amines in pharmaceutical and agrochemical substances drives the development of efficient catalytic asymmetric methods for their formation. In contrast to the high enantioselectivities observed in asymmetric reduction of both alkenes and ketones, only limited success has been achieved in the enantiose-lective hydrogenation of imines [118]. Currently, there are few efficient chiral catalytic systems available for the asymmetric hydrogenation of imines. 

In order to place later chapters in proper context, the first chapter offers a comprehensive overview of industrially important catalysts for oxidation and reduction reactions. Chapters 2 and 3 describe the preparation of chiral materials by way of the asymmetric reduction of alkenes and ketones respectively. These two areas have enjoyed a significant amount of attention in recent years. Optically active amines can be prepared by imine reduction using chiral catalysts, as featured in Chapter 4, which also discloses a novel reductive amination protocol. 

A review describing the major advances in the field of asymmetric reduction of achiral ketones using borohydrides, exemplified by oxazaborolidines and /9-chlorodiisopino- camphenylborane, has appeared. Use of sodium borohydride in combination with chiral Lewis acids has been discussed.298 The usefulness of sodium triacetoxyboro-hydride in the reductive amination of aldehydes and ketones has been reviewed. The wide scope of the reagent, its diverse and numerous applications, and high tolerance for many functional groups have been discussed.299 The preparation, properties, and synthetic application of lithium aminoborohydrides (LABs) have been reviewed. 

More successful asymmetric reductions have been based on amine (particularly alkaloid) complexes of bis(dimethylglyoximato) cobalt(II), also known as cobaloxime(II) and represented Co(dmg)2 (compound VII). Cobaloxime-chiral amine complexes have been used to catalyze the hydrogenation of both olefinic and ketonic substrates (Fig. 24). It has been determined that hydroxyamine modifiers, for example, alkaloids such as quinine, quinidine, and cinchonidine, are most effective. The highest optical purity obtained thus far has been 71%, observed for reduction of benzil in benzene solution at 10° using quinine as the... 

The enantioselective synthesis of optically active secondary amines via asymmetric reduction of prochiral ketimines was studied by screening various chiral hydrides. In this case, K-glucoride gave only disappointing results and was inferior to other reagents. Better results were obtained in the asymmetric reduction of prochiral Af-diphenylphosphinylimines to chiral N-(diphenylphosphinyl)amines (eq 1), which can then be readily converted into optically active primary amines. For this reaction the stereochemical course depends dramatically on the relative bulkiness of the groups R and R. The reaction conditions for reduction of C=N double bonds are the same as used for ketones, but the high reactivity of diphenylphosphinylimines dramatically reduces the reaction time. 

The modification of aluminum or boron hydrides with chiral protic substances, such as R OH or RR NH, generates useful reagents for the asymmetric reduction of prochiral ketones or imines leading to optically active secondary alcohols and amines, respectively. Some reviews have appearered in the literature. ... 

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