Biomimetic asymmetric reductions

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... 

Biomimetic oxidation and asymmetric reduction with coenzyme NAD analogs 99YGK512. 

Asymmetric reduction of ketones or aldehydes to chiral alcohols has received considerable attention. Methods to accomplish this include catalytic asymmetric hydrogenation, hydrosilylation, enzymatic reduction, reductions with biomimetic model systems, and chirally modified metal hydride and alkyl metal reagents. This chapter will be concerned with chiral aluminum-containing reducing re-... 

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. 

Asymmetric reduction of ketopantoyl lactone is an effective biomimetic route to R-(- )-pantolactone, an intermediate in the synthesis of the important d-( + )-pantothenic acid (a component of vitamins B and of coenzyme A) ... 

The approach using cyclodextrin as a binding site has also been developed. Cyclodextrins are widely utilized in biomimetic chemistry as simple models for an enzyme because they have the ability to form inclusion complexes with a variety of molecules and because they have catalytic activity toward some reactions. Kojima et al. (1980, 1981) reported the acceleration in the reduction of ninhydrin and some dyes by a 1,4-dihydronicotinamide attached to 3 Cyclodextrin. Saturation kinetics similar to enzymatic reactions were observed here, which indicates that the reduction proceeds through a complex. Since the cavity of the cyclodextrin molecule has a chiral environment due to the asymmetry of D-glucose units, these chiralities are expected to be effective for the induction of asymmetry into the substrate. Asymmetric reduction with NAD(P)H models of this type, however, has not been reported. Asymmetric reduction by a 1,4-dihydronicotinamide derivative took place in an aqueous solution of cyclodextrin (Baba et al. 1978), although the optical yield from the reduction was quite low. Trifluoromethyl aryl ketones were reduced by PNAH in 1.1 to 5.8 % e.e. in the presence of 3-cyclodextrin. Sodium borohydride works as well (Table 18). In addition to cyclodextrin, Baba et al. also found that the asymmetric reductions can be accomplished in the presence of bovine serum albumin (BSA) which is a carrier protein in plasma. 

Ohnishi Y, Numakunai T, Ohno A (1975b) Reduction by a model of NAD(P)H. Contribution of metal ion to asymmetric reduction of trifluoroacetophenone. Tetrahedron Lett 3813-3814 Ohnishi Y, Kagami M, Ohno A (1975c) Reduction by a model of NAD(P)H. Reduction of a-diketones and a-keto alcohols by 1-benzyl-1,4-dihydronicotinamide. Tetrahedron Lett 2437-2440 Ohnishi Y, Kagami M, Numakunai T, Ohno A (1976a) Reduction by a model of NAD(P)H. VIII. Effects of metal ion on the course and stereochemistry of the biomimetic reduction of olefin. Chem Lett 915-916... 

An oxidative cyclization has been exploited as the key step in the elegant asymmetric syntheses of both (+)- and (-)-galanthamine (291) (Scheme 29) (163). This biomimetic synthesis commenced with the secondary amine 311, which was readily prepared by the reductive amination of 3,5-dibenzyloxy-4-... 

Since CIgSiH is known to be activated by DMF and other Lewis bases to effect hydrosilylation of imines (Scheme 4.2) [8], it is hardly surprising that chiral formamides, derived from natural amino adds, emerged as prime candidates for the development of an asymmetric variant of this reaction [8]. It was assumed that, if successful, this approach could become an attractive altemative to the existing enzymatic methods for amine production [9] and to complement another organo catalytic protocol, based on the biomimetic reduction with Hantzsch ester, which is being developed in parallel [5]. 

D. B. Ramachary, M. Kishor, J. Org. Chem. 2007, 72, 5056-5068. Organocatalytic sequential one-pot double cascade asymmetric synthesis of Wieland-Miescher ketone analogues from a Knoevenagel/hydrogenation/Robinson annu-lation sequence scope and applications of organo-catalytic biomimetic reductions. 

D. B. Ramachary, M. Kishor, Org. Biomol. Chem. 2008, 6, 4176-4187. Direct amino acid-catalyzed cascade biomimetic reductive alkylations application to the asymmetric synthesis of Hajos-Parrish ketone analogues. 

In 2005, Huang et al. reported a tandem asymmetric conjugate reduction-fluorina-tion reaction by an efficient combination of iminium and enamine catalysis using two distinct secondary amine catalysts [16]. This method offered direct access to chiral multifunctionalized aldehydes from P-substituted enals and electrophilic florinated reagents in a biomimetic way (Schane 9.13). The diastereoselectivity of the products varied depending on the catalyst combination (Scheme 9.14). The chemistry presented here demonstrated for the first time the power of the multicatalysis process for control of the product diastereoselectivity based on the cycle-specific catalysis concept. 

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