Enantioselective imine reductions

In a very recent paper, this group has extended this strategy, developing chiral borane catalysts for the enantioselective imine reduction with enantioselectivities as high as 84% [20]. 

The first enantioselective imine reduction using Hantzsch esters as hydride donor was carried our by Singh and Batra in Using cysteine-derived catalysts, only moderate,... 

The first catalytic asymmetric reduction of imines, as summarized in Equation 14, was achieved by Kagan in 1973 [135]. Since then a number of catalytic enantioselective imine reductions involving hydrogenations or hydrosilylations have been developed [20, 33, 36, 37]. 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

A recent development is the transfer hydrogenation of heterocyclic systems such as pyrrole, pyridinium and quinoline systems. Whilst at present the yields and enantioselectivities are modest, further development may improve this situation. For example, 1-methyl-isoquinoline has been reduced to the tetrahydro species and 1-picoline has been reduced to 1-methylpiperidine [86]. Interestingly, these reductions involve alkene as well as imine reduction. 

Asymmetric variants of imine reduction have also been developed towards enantiopure aziridines. Reduction of chiral /V-tert-butanesulfinyl a-halo imines afforded enantiopure aziridines in good to excellent yields <07JOC3211>. Enantioselective catalytic reduction of a-chloroimines utilizing metal-free L-valine-derived formamide 45 followed by base-mediated ring closure provided aziridines with preserved enantiopurity <07AG(I)3722>. 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

In 1996, the enantioselective borane reduction of imines catalyzed by an oxazaphospholidine-borane complex in refluxing toluene has been described. Thus, optically active amines have been obtained with enantioselectivities up to 63% [33]. 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

The highly enantioselective hydride reduction of the di-imine of entry 2.6 was accomplished with sodium borohydride and sub-stoichiometric amounts of a chiral amino alcohol as catalyst [24]. 

The diastereoselective and enantioselective synthesis of optically active 2-amino-3,3-dimethylbutanes was achieved as follows pinacolone was reacted individually with ( + )-(/ )-and ( —)-(S)-phenylethylamine to afford the corresponding chiral ( )-imines. Reduction of the imines with borane-tetrahydrofuran complex resulted in addition of hydride to the less hindered face of the azomethine to give (R,R)- and (S. -benzylamine, respectively, which, on hydrogenolysis (10% Pd/C), afforded (7 )- and (5 )-2-amino-3,3-dimethyl butane, respectively, with high enantiomeric purity (ee >99.5%)3. 

Refers to the enantioselective step (reduction of the phosphinoyl imine), requires 24 equiv of Et3N/HC02H (2 5 ratio), reactions performed at room temperature. 

The titanocene catalyzed asymmetric imine reduction may be used in kinetic resolutions of racemic pyrrolines [96]. The most efficient kinetic resolution was observed for 5-substituted pyrrolines, and the mechanistic postulate outlined above readily accomodates the experimental results, as shown by the matched pair transition structure in Scheme 7.12 [96]. Pyrrolines substituted at the 3- and 4-positions were reduced with excellent enantioselectivity, but kinetic resolution of the starting material was only modest [96]. 

In contrast, the enantioselectivity of cyclic imine reduction is independent of hydrogen pressure. 

Group 4 metallocene complexes can also be used as catalysts in the reduction of C=N bonds. Willoughby and Buchwald employed the titanium-based Brintzinger catalyst (3.54) for the asymmetric reduction of imines. The catalyst is activated by reduction to what is assumed to be the titanium(III) hydride species (3.55). The best substrates for this catalyst are cyclic imines, which afford products with 95-98% ee. Various functional groups including alkenes, vinyl silanes, acetals and alcohols were not affected under the reaction conditions. For example, the imine (3.56) was reduced with excellent enantioselectivity, without reduction of the alkene moiety. 

Later improvements addressing both problems of limited solubility and hydrolytic stability came with the development of water-soluble ligands having the notable DuPHOS skeleton, for which excellent enantioselectivity in ketone, olefin and imine reductions have been reported. Zhang and RajanBabu groups independently pursued the synthesis... 

Later, DeVries, Bakos, and their coworkers confirmed that the enantioselective catalyst for imine reduction is actually monosidfonated ligand 4a prepared via RP-HPLC separation of mixtures of ligands 4a-c. By using monosulfonated ligand 4a as an inseparable mixture of diastereomers (chirahty on phosphorus) under otherwise the same condition,... 

P-Borylation of a,P-Unsaturated imines. Fernandez and coworkers have also developed a route to y-ainino alcohols via a tandem sequence of enantioselective -borylation of a,p-unsaturated imines, followed by iterative imine reduction and boronic ester oxidation. In the presence of B2pin2, CuOTf and a binapthol-derived phosphoramidite ligand, asymmetric conjugate addition of (V-protected Q ,/3-unsaturated imines occurred in high yield and with excellent enantioselectivity. Diasteroselective reduction of the imine to the corresponding jyn-y-amino alcohol was achieved with BH3 THF (eq 56). The authors postulated that... 

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