Asymmetric Reduction of Imines

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... 

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... 

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

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]. 

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 ... 

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],...

In 1993, Bolm reported that these reactions could be performed using catalytic quantities (10 mol%) of the chiral P-hydroxy sulfoximine.132 The enantiomeric purities of the product alcohols ranged from 52% (1-indanone) to 93% (PhCOCHjOSiRj). In many cases the enantiomeric purities were enhanced using sodium borohydride as reductant in the presence of chlorotrimethylsilane.133 These methods have been extended to the asymmetric reductions of imines.134 /V-SPh-substituted imines gave the highest enantioselectivities and these reductions proceeded in the same stereochemical sense as the reductions of ketones. 

Preparative Methods both enantiomers of the a-methyl sultam may be prepared on a multigram scale in optically pure form by asymmetric hydrogenation of imine (2a) followed by simple crystallization (eq 1). The (7 )-enantiomer of the a-f-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization. However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivati-zation of the racemic auxiliary (obtained in 98% yield from reaction of (2b) with Sodium Borohydride in MeOH) with 10-Camphorsulfonyl Chloride, separation of the resulting diastere-omers by fractional crystallization, and acidolysis. Prochi-ral imines (2a) and (2b) are readily prepared from inexpensive Saccharine by treatment with Methyllithium (73%) and t-Butyllithium (66%), respectively. 

A disulfide-linked bis(aminoethanol) 82 prepared from L-cystine also catalyzes the borane reduction of ketones. Other oxazaborolidine derivatives are obtained from 83, 84, " and 85, " and polymer-bound species. Those derived from the ephedra bases find use in the asymmetric reduction of imines. bicyclic oxazaborolidine generated... 

Scheme 4.1 Preparation of amines by asymmetric reduction of imines generated from prochiral ketones.

Scheme 4.2 Preparation of amines by asymmetric reduction of imines generated from prochiral ketones. For R R, and R , see Tables 4.1 4.11.

Figure4.1 Formamides derived from cyclic amino acids as catalysts forthe asymmetric reduction of imines.

Scheme 4.4 Preparation of a substituted 3 amino acids by asymmetric reduction of imines involving dynamic kinetic resolution. For R, see Table 4.7 Ar p MeOC6H4.

Figure 4.3 a Picolinic amides as catalysts for the asymmetric reduction of imines. 

The asymmetric reduction of imines represents a potentially very attractive route to chiral amines and has been studied by two groups (Figure 14.50). Vaijayanthi and Chadha examined the reduction of a series of aryl imines 79 using Candida parapsilosis ATCC 7330. A range of different aryl substituents were found to be tolerated yielding (R) secondary amines 80 in good yields (55 80%) and high ee (95 99%) [70]. 

Scheme 7.10. Titanocene catalyzed asymmetric reduction of imines [85], In the accompanying discussion, the catalyst shown is designated the S,S enantiomer, in accord with the CIP rules for describing metal arenes [88]. This is a different designation than that used by Buchwald, however. ...

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. 

The asymmetric reduction of imines and iminium species can be achieved using organocatalysts. The transfer hydrogenation of imines is catalysed by acids and this has led to the development of biomimetic asymmetric reductions using enan-tioselective Bronsted acids in combination with Hantzsch esters as a hydride... 

More recently, in organocatalysis, Kocovsky [69] has reported asymmetric reduction of imine with trichlorosilane catalyzed by an (A-methylvaline)-derived formamide anchored to a polymer. Under the best conditions, with 15 mol% of the catalyst enantiomeric excesses were about 85% and the catalyst could be reuse. 

Scheme 7.11 Asymmetric reduction of imines using titanocene hydride complex 16.

Reduction of Schiff bases to secondary amines has been accomplished for some years both by catalytic hydrogenation and by chemical reduction. Especially, the heterogeneous catalytic hydrogenation of the Schiff bases of chiral a-keto esters has been extensively studied, while LiAlH3(OR ), RjBH, and Li[R2( -Bu)BH] have been used for the asymmetric reduction of imines [la],... 

Asymmetric hydrosilylation of ketones and ketoimines has been demonstrated in the absence of transition metal catalysts. Using catalytic amounts of chiral-alkoxide Lewis bases such as binaphthol (BINOL), Kagan was able to facilitate the asymmetric reduction of ketones (eq 19). This process is believed to arise from activation of the triethoxysilane by mono-alkoxide addition to give an activated pentavalent intermediate, which can undergo coordination of an aldehyde. This highly ordered hexacoordinate transition state directs reduction in an asymmetric manner, with subsequent catalyst regeneration. Brook was able to facilitate a similar tactic for asymmetric reduction by employing histidine as a bi-dentate Lewis base activator of triethoxysilane. A similar chiral lithium-alkoxide-catalyzed asymmetric reduction of imines was demonstrated by Hosomi with the di-lithio salt of BINOL and trimethoxysilane. ... 

Figure 1.6 Selected biocatalytic asymmetric reductions of imines to amines.

Table 15.8 Asymmetric reduction of imines 106 derived from aromatic amines with trichlorosilanes catalyzed by chiral Lewis bases 110,112-115,118, and 120-124 (Scheme 15.25 and Figures 15.5 and 15.6).

After the methodology for asymmetric reduction of imines with trichlorosilane employing model substrates had been firmly estabhshed, the focus of research in the field gradually shifted towards the synthesis of functionahzed chiral amines, which represent important building blocks for pharmaceutical, agricultural, and fine chemical industries. 

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