Imines, asymmetric reduction

As with hydrogenation, hydrogen transfer of imines is a poorly developed field.126-130 However, recent arene-Ru11 systems bearing chiral 1,2-diamine co-ligands have been found to be excellent catalysts for asymmetric reduction of imines with formic acid as donor.31,131-134... 

Asymmetric reductions. The reagent can effect asymmetric reduction of alkyl aryl ketones and unhindered dialkyl ketones in high optical yield.1 It is the most useful reagent known to date for asymmetric reduction of even hindered a-keto esters to (S)-a-hydroxy esters in >90% ee.2 It is also effective for asymmetric reduction of phosphinyl imines of dialkyl ketones, RlR2C=NP(0)(C6H5)2 (50-84% ee).3... 

In an attempt to prepare alkylamines by asymmetric reduction of imines with chiral hydride reagents, diphenylphosphinyl imines (38), prepared by reaction of ketoximes (39) with chlorodiphenylphosphine [(Cg 115)2 PCI], were reduced in the presence of a variety of chiral aluminum and boron hydride reagents43. Among the most promising reagents was BINAHL-H44 (40), a chiral hydride compound prepared by the modification of lithium... 

Cervinka has employed these reagents in the asymmetric reduction of im-monium salts (49,50) and imines (51). The reduction of 2-substituted jV-methyl-A -tetrahydropyridinium perchlorates (10) with (— )-menthol-LAH in ether or THF led to optically active piperidine derivatives (eq. [10]). The optical purity obtained for the Pr" derivative was 12%. In the case of R = Me and Pr" the configuration of the predominant enantiomer was shown to be S. The (-)-menthol-LAH reagent was similarly shown to reduce l-methyl-2-alkyl-A -di-hydropyrrolinium perchlorates (11) to optically active pyrrolidine derivatives (eq. [11]). The optical yield could be calculated only for R = CH2Ph, and was only 6% (/ enantiomer) obtained with a 1 1 (— )-menthoi-LAH reagent. With 2 1 or 3 1 molar ratios of menthol LAH, the optical yield decreased. The... 

Scheme 16 Asymmetric reduction of imines with iridium catalysts...

Catalytic asymmetric reduction of unsaturated compounds is one of the most reliable methods used to synthsize the corresponding chiral saturated products. Chiral transition metal complexes repeatedly activate an organic or inorganic hydride source, and transfer the hydride to olefins, ketones, or imines from one... 

Next, a few examples of asymmetric reductions with trichlorosilane are presented. An asymmetric reduction of ketones and imines was reported by Matsumura and coworkers by using trichlorosilane as reductant and A-formyl pyrrolidine derivative 36 as ligand (Scheme 28) [101, 102]. 

Later, Maikov and Kocovsky reported the asymmetric reduction of imines with A -methyl L-valine derivative 37 with high yield and enantioselectivity (Scheme 29) [103]. 

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. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

While nonracemic trifluoroalanines can easily undergo racemization or dehydro-fluorination, many asymmetric syntheses oftrifluoroalanines have been proposed. These syntheses generally involve an asymmetric reduction step of an imine or an enamine. This step can be performed by utilizing either chiral catalysts or chiral auxiliaries. 

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. 

In the 1990s, no improvement has been reported for the asymmetric hydrosily lation of imines (Scheme 2.3) by using chiral Rh-catalysts. Imines 59 and 60 were reduced with 2 by using DIOP-Rh catalysts to the corresponding secondary amines 61 and 62 with 65% ee and 66% ee, respectively [43], Chiral Ru-catalyst, however, achieved higher enantioselectivity in the asymmetric reduction of a particular imine (see below). 

TABLE 6. Asymmetric reduction of prochiral imines via hydrosilylation catalyzed by (S,S)-(EBTHI)Ti complex" in THF... 

Iridium complexes appear to be more suited to the control of asymmetric reductions of simple imines than those of rhodium or ruthenium268,269. The use of ligand BDPP (P12)... 

Asymmetric reduction of imines. Japanese chemists2 have prepared a number of chiral sodium triacyloxyborohydrides from N-acyl derivatives of natural a-amino acids. The most effective are derived from (S)-proline. A particularly useful reducing agent is 1, derived from N-benzyloxycarbonyl-(S)-proline (equation I). 

ASYMMETRIC PROTONATION (S)-2-Aminopropyl benzyl ether. ASYMMETRIC REDUCTION, OF IMINES ... 

Catalytic asymmetric synthesis of enantiopure diaryl-methanols and -methylamines (important pharmaceutical intermediates) has been reviewed (76 references), focusing on (i) aryl transfers on to aryl-aldehydes and -imines and (ii) asymmetric reductions of diaryl-ketones and -ketoimines.284... 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

Novartis (Ciba Geigy) has developed ferrocenyldiphosphines, 4, for the asymmetric hydrogenation of sterically hindered /V-aryl imines, specifically for the industrial manufacture of Meto-lachlor (52), a pesticide sold since March 1997 as the enantiomerically enriched form under the trade name DUAL MAGNUM and, more recently, Dual Gol (see Chapters 15 and 31).73 76 The synthesis of 52 involves the asymmetric reduction by a catalyst formed in situ from [Ir(COD)Cl]2 and 4h to give 53 and subsequently 52 in 80% ee (Scheme 12.15).74... 

Sertraline (16) is an antidepressant that inhibits the uptake of serotonin in the central nervous system.148 It is marketed by Pfizer under the name Zoloft.149 One methodology that can be used relies on an asymmetric reduction (see also Chapter 16) (Scheme 31.11).150-156 The lactone can be used as a chiral starting material for the Friedel-Crafts reaction. The established stereogenic center in the tetralone controls the reduction of the imine.157 The alternative is a resolution approach (Scheme 31.12).148-153-158-161... 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

Table 7.7 Asymmetric reduction of imines 80 with trichlorosilanes catalyzed by chiral amides (10 mol%) derived from cyclic amino acids in CH2CI2 (Scheme 7.18 and Fig. 7.4) [3c, 79, 81, 82],...

The organocatalytic enantioselective reduction of C=C, C=0, and C=N double bonds is a relatively young area for which many new and exciting developments can be expected in the near future. Hantzsch esters are useful organic hydrides, and a recent review has summarized the results obtained to date in organocataly-sis [27]. The case of silicon hydrides is convenient for imine or ketone reductions, as a chiral base can act as an organic catalyst. The asymmetric reductions of ketones catalyzed by oxazaborolidines and pioneered by Itsuno [28] and Corey [29] could not be included in this chapter. 

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