Ketimines asymmetric reduction

The first example of an asymmetric reduction of C=N bonds proceeding via DKR was reported in 2005 by Lassaletta et al. In this process, the transfer hydrogenation of 2-substituted bicyclic and monocyclic ketimines could be accomplished via DKR by using a HCO2H/TEA mixture as the hydrogen source and a chiral ruthenium complex including TsDPEN ligand,... 

More recently, an important chiral titanium catalyst for the asymmetric reduction with hydrogen of /V-substi luted dialkyl ketimines to enantioenriched amines has been... 

Coordination of the aluminum atom of the reducing complex was proposed to take place both to the oxygen atom of the hydroxy group and to the nitrogen atom of the amino group. The asymmetric reduction of enamine perchlorates and ketimines with menthol and bomeol chiral auxiliary reagents (50,51) presumably involves coordination of aluminum to the nitrogen atom of the substrate. 

A new, metal-free protocol involving (heteroaryl)oxazoline catalysts for the enantioselective reduction of aromatic ketones (up to 94% ee) and ketimines (up to 87% ee) with trichlorosilane has been developed. The reaction is characterized by an unusual, long-ranging chiral induction.The enantiodifferentiation is presumed to be aided by aromatic interactions between the catalyst and the substrate.360 Asymmetric reduction of A-arylketimines with trichlorosilane is catalysed by A-methyl-L-amino acid-derived Lewis-basic organocatalysts with high enantioselectivity (up to 92% ee) 61... 

Scheme 7.18 Asymmetric reduction of ketimines see Table 7.5 for R]-R3, and Figure 7.4 for catalysts.

B. T. Cho, Boron-Based Reducing Agents for the Asymmetrical Reduction of Functionalized Ketones and Ketimines, Aldrichim. Acta 2002, 35, 3-16. 

Scheme 19 Catalytic asymmetric reductive Mannich reaction of ketimines.

In addition, Ir-complexes of DIFLUORPHOS (81) have been used in the asymmetric hydrogenation of quinolines (07SL2743). Very recently, its Cu(I)-complex (as CuOAc-DIFLOURPHOS) was identified as the catalyst of choice for the asymmetric reductive Mannich reaction of ketimines (93a-c) with a broad substrate scope providing high enantio- and diastereoselectivities (Scheme 19, 08JA16146). 

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. 

All effective catalysts for the asymmetric reduction of prochiral C=N groups are based on complexes of rhodium, iridium, ruthenium, and titanium. Whereas in early investigations (before 1984) emphasis was on Rh and Ru catalysts, most recent efforts were devoted to Ir and Ti catalysts. In contrast to the noble metal catalysts which are classical coordination complexes, Buchwald s a sa-titanocene catalyst for the enantioselective hydrogenation of ketimines represents a new type of hydrogenation catalyst [6]. In this chapter important results and characteristics of effective enantioselective catalysts and are summarized. 

Asymmetric reduction of ketimines to sec-aminesf Of the various hydride reagents found to achieve high enantioselective reduction of ketones, the oxazaborolidine 1 of Itsuno, prepared from BH3 and (S)-(—)-2-amino-3-methyl-I,l-diphenylbutane-l-ol, derived from (S)-valine, (12,31), is the most effective in terms of asymmetric induction. Like Corey s oxazaborolidines derived from (S)-proline, 1 can also be used in catalytic amounts. The highest enantioselectivities obtain in reduction of N-phenylimines of aromatic ketones (as high as 88% ee). The enantioselectivities are lower in the case of N-t-butylimines of aryl ketones (80% ee). Reduction of N-phenylimines of prochiral dialkyl ketones with 1 results in 10-25% ees. 

The reduction of different carbon-carbon or carbon-heteroatom double bonds is an important transformation that generates in many cases new stereogenic centers. Particularly, the asymmetric reduction of prochiral ketimines represents one of the most important methods and straightforward procedures for preparing chiral amines. This approach is one of the key reactions and powerfiil tools in synthetic organic... 

Maikov, Kocovsky, and co-workers have developed different L-valine-based Lewis basic catalysts such as 81 [176, 177], for the efficient asymmetric reduction of ketimines 76 with trichlorosilane 2, or catalyst 82 [178] with a fluorous tag, which allows an easy isolation of the product and can be used in the next cycles, while preserving high enantioselectivity in the process. Sigamide catalyst 83 [179, 180] and Lewis base 84 [181] were employed in a low amount (5 mol%) affording final chiral amines 80 with high enantioselectivity (Scheme 30) [182]. Interestingly, 83 was used for the enantioselective preparation of vicinal a-chloroamines and the subsequent synthesis of chiral 1,2-diaryl aziridines. In these developed approaches the same absolute enantiomer was observed in the processes. 

Figure11.2 OAB-induced asymmetric reduction of ketimine derivatives.

In addition, the asymmetric reduction of A7-aryl ketimines with tri-chlorosilane could be achieved on polymer-supported organocatalysts by Kocovsky et alP Indeed, 7V-methylvaline-derived formamide anchored to a polymeric support, used at a catalyst loading of 15 mol %, allowed good enantioselectivities of up to 82% ee combined with good yields to be obtained for the formed chiral amines (Scheme 8.3). This novel methodology simplified the recovery of the catalyst, which could be reused at least five times without any loss of the activity. The best results were obtained with the catalysts directly attached to the polymer or via a suitable spacer. A strong influence of the solvents on the catalytic performance was observed with chloroform giving the... 

Figure 15.5 Formamides and related catalysts for asymmetric reduction of ketimines.

In 2009, the imidazole-derived Lewis base catalyst 92, which was prepared by Jones et al., was employed for the reduction of ketimines with trichlorosilane as the reducing agent Interestingly, low catalyst loading (as low as 1% mol) works well for this reduction (entry 13, Table 32.1) [57]. During their studies, the authors found that 92 is able to selectively reduce the imine while it is inactive for ketones. Therefore, in 2011, the same group developed an asymmetric reductive amination of ketones 16 catalyzed by 92 with trichlorosilane as the hydride donor (Scheme 32.19). However, the yields for the threealkyl ketimines, a two-step, one-pot procedure plus microwave irradiation is needed to secure a useful synthetic yield [60]. 

As mentioned, Matsumura published the first asymmetric reduction of ketimines with a proline formamide activator A 1 and trichlorosilane. The yield and selectivities were only moderate, but it paved the way for further developments. They showed that it was possible to reduce imines selectively in the presence of ketones without affecting the latter. Additionally, a transition state explaining the stereoinduction was hypothesized (Figure 32.6). Transition state TS 1 is preferred over TS 2 because of the steric phenyl-phenyl repulsion of the activator and the substrate. This explains the need of aryl imines for successfid stereoinduction. 

Gautier F-M, Jones S, Martin SJ. Asymmetric reduction of ketimines with trichlorosilane employing an imidazole derived organocatalyst. Org. BiomoL Chem. 2009 7 229-231. 

An example of Ellman s methodology as applied to a chiral reduction has been described in a drug discovery programme undertaken by Merck to develop selective non-steroidal glucocorticoid receptor agonists such as 243. Ketone 238 was converted to ketimine 239 by reaction with (i )-(-l-)-tert-butanesulfinamide and titanium tetraethoxide. Asymmetric reduction was effected by treatment with sodium borohydride followed by deprotection under acidic conditions to afford amine 242. The chiral product was subsequently converted to glucocorticoid receptor agonist 243 (Scheme 14.80). 

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