Enantioselective hydrogenation reductive amination

An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359... 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

Iridium(III) hydride forms complexes with DIOP, BDPP (2,4-bis(diphenyl-phosphino)pentane), NORPHOS, and BINAP ligands to produce amines in 11 -80% ee.679 Similar modest results are obtained in the reduction of N-arylketimines with an iridium(HI) complex with (2S,3 S) -C HIRA PHOS as the chiral ligand.680 The indium complexes with chiral phosphinodihydrooxazoles catalyze the enantioselective hydrogenation of imines in supercritical carbon dioxide with up to 80% ee, but generally lower ee values are observed in... 

This chapter aims to provide an overview of the current state of the art in homogeneous catalytic hydrogenation of C=0 and C=N bonds. Diastereoselec-tive or enantioselective processes are discussed elsewhere. The chapter is divided into sections detailing the hydrogenation of aldehydes, the hydrogenation of ketones, domino-hydroformylation-reduction, reductive amination, domino hydroformylation-reductive amination, and ester, acid and anhydride hydrogenation. 

BINAP (40a) was first reported as a ligand in an enantioselective hydrogenation in 1980 [172], and provides good selectivity for the reductions of dehydroamino acid derivatives [173], enamides, allylic alcohols and amines, and a,p-unsaturated acids [4, 9, 11, 12, 174, 175]. The fame of the ligand system really came with the reduction of carbonyl groups with ruthenium as the metal [11, 176]. The Rh-BINAP systems is best known for the enantioselective isomerizations... 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Wilhams, G.D., Pike, R.A., Wade, C.E. and Wills, M. A One-pot Process for the Enantioselective S3mthesis of Amines via Reductive Amination under Transfer Hydrogenation Conditions. Org. Lett. 2003, 5, 4227 230. 

Kadyrov R, Riermeier TH (2003) Highly enantioselective hydrogen-transfer reductive amination catalytic asymmetric synthesis of primary amines. Angew Chem Int Ed Engl 42 5472-5474 Kang Q, Zhao ZA, You SL (2007) Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. J Am Chem Soc 129 1484-1485... 

The enantioselective reduction of a C=N double bond is an interesting alternative for the production of chiral amines by hydrogenation of enamides. Required imines or oximes can be prepared by reaction of ketones with amines or hydroxylamines. However, to date, trials to reduce these substrates with ethyl-DuPHOS catalysts gave no satisfying results. Therefore, transformation of ketones or a-keto acids into acylhydrazones and subsequent enantioselective hydrogenation has proven advantageous (eq 12, Table 5). ... 

Aqueous ammonia was found to increase the yield of the alcohol but not of the amine in the highly enantioselective hydrogen-transfer reductive amination of acetophenone, as recently described by Kadyrov et al. [18]. AU these reactions were performed in methanol/NHj with [((Kj-tol-binapjRuClJ as catalyst with a best asymmetric induction of 98% ee. 

A highly enantioselective hydrogenation of enamides (152) to afford amines (153), catalyzed by a dual chiral-achiral acid system has been developed by Antilla and Liu (Scheme 41). By employing a substoichio-metric amount of the chiral phosphoric acid (154) and acetic acid, the catalyst loading as low as 1 mol %, excellent chemical yields and enan-tioselectivities of the reduction products (153) were obtained. 

MK-1597. A similar procedure was used for the hydrogenation of a close analog for a related renin inhibitor (ee 99%, ton 100, tof 20 h ) [99] (Scheme 43). A catalyst prepared in situ from [Ru(cymene)Cl2]2 and-dm-segphos in presence of NH4OAC was used by Takasago [100] for the reductive amination of p-keto esters with very high enantioselectivities. The reaction shown in Scheme 44 was carried out on the 66-kg scale. 

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