NADH model reduction

The Zincke reaction has also been adapted for the solid phase. Dupas et al. prepared NADH-model precursors 58, immobilized on silica, by reaction of bound amino functions 57 with Zincke salt 8 (Scheme 8.4.19) for subsequent reduction to the 1,4-dihydropyridines with sodium dithionite. Earlier, Ise and co-workers utilized the Zincke reaction to prepare catalytic polyelectrolytes, starting from poly(4-vinylpyridine). Formation of Zincke salts at pyridine positions within the polymer was achieved by reaction with 2,4-dinitrochlorobenzene, and these sites were then functionalized with various amines. The resulting polymers showed catalytic activity in ester hydrolysis. ... 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

The reduction of 5-nitrouracil derivatives 381 has been performed using l-benzyl-l,4-dihydronicotinamide 382 as a reduced nicotinamide adenine dinucleotide (NADH) model <1998H(49)475>, although the same products can also be obtained with sodium borohydride <1976JME1072>. 

Pyrrolopyridine derivatives, such as compound 144, in the presence of Mg salts such as magnesium perchlorate, serve as chiral and nonchiral NADH models in the reduction of organic nitro compounds <1996JHC1211>. Similar derivatives, such as compound 145, serve as NADH models in the asymmetric reduction of methyl benzoylformate and A -acetyl enamines <1997TA3309>. 

Recently, Inouye et al. 92) reported that NADH model compounds (59,60,61) carrying one or two (S)-prolinamite moieties as the asymmetric center showed virtually complete stereoselectivity in the asymmetric reduction of several ketones. 

Ascorbate, cysteine, hydroquinone, and NADH are capable of acting as re-ductants for NOMb formation in model systems containing sodium nitrite and Mb (Fox and Ackerman, 1968). Ascorbate, cysteine, and hydroquinone all form nitroso-reductant intermediates which released NO, forming a NO-MMb complex which was then reduced to NOMb. Release of NO from the reductant-NO complex was rate limiting in production of NOMb. For NADH as reductant, reduction of NOMMb to NOMb was the rate limiting step. In summary, two reduction steps were required, the reduction of nitrite (as nitrous acid or its anhydride, N2O3) to NO, and reduction of NOMMb to NOMb. 

The catalytic effect of metal ions such as Mg2+ and Zn2+ on the reduction of carbonyl compounds has extensively been studied in connection with the involvement of metal ions in the oxidation-reduction reactions of nicotinamide coenzymes [144-149]. Acceleration effects of Mg2+ on hydride transfer from NADH model compounds to carbonyl compounds have been shown to be ascribed to the catalysis on the initial electron transfer process, which is the rate-determining step of the overall hydride transfer reactions [16,87,149]. The Mg2+ ion has also been shown to accelerate electron transfer from cis-dialkylcobalt(III) complexes to p-ben-zoquinone derivatives [150,151]. In this context, a remarkable catalytic effect of Mg2+ was also found on photoinduced electron transfer reactions from various electron donors to flavin analogs in 1984 [152], The Mg2+ (or Zn2+) ion forms complexes with a flavin analog la and 5-deazaflavins 2a-c with a 1 1 stoichiometry in dry MeCN at 298 K [153] ... 

The prepared compounds systematically differed in the distance of the dihydropyridine and the flavin recognition part. Binding between flavin and the NADH model systems was proved by potentiometric pH titrations. Redox reaction between the NADH model systems and flavin was monitored by UV - VIS spectroscopy. The intensity of the long-wave absorption of flavin at 456 nm significantly decreased during the reaction and the decrease was attributed to the reduction of flavin to the fully reduced flavohydroquinone. At the same time, the intensity of the peak around 360 nm decreased as well, because of the reduction of flavin and the concerted oxidation of the 1,4-dihydronicotinamide to the corresponding pyridinium species. Kinetics of the electron transfer was studied and two reasonable kinetic models were proposed. 

Irradiation of NADH model compounds in the presence of benzyl bromide or p-cyanobenzyl bromide in acetonitrile brings about reduction of the benzyl halides to the corresponding toluene compounds114. Like the S l substitution reaction, this photoreduction also occurs via an electron-transfer chain mechanism. Unlike in that case, though, here an electron transfer from the excited state of the NADH compound is solely responsible for the initiation step. In the propagation, the benzyl radical produced by C—Br bond cleavage in the radical anion abstracts hydrogen from the NADH compound. This yields a radical intermediate, from which electron transfer to benzyl bromide occurs readily (equations 39-42). 

Another use of compound (1) involves synthesis of NADH models incorporating chiral and nonchiral l/f-pyrrolo[2,3-6]pyridine derivatives. In this latter application, the products derived from compound (1) have been useful for the study of systems that were unreactive with similar reagents. By the appropriate manipulation of reaction conditions, products derived from compound (1) selectively form either (but only one) enantiomer in reduction of a prochiral ketone. Finally, the products derived from compound (1) are useful reagents in the preparation of chiral precursors of target molecules <91T429>. 

Many achiral or chiral substituted382 and bridged 1,4-dihydropyridines383 have been prepared by a reduction of quaternary pyridium salts with sodium hydrosulphite as NADH models for enantioselective reduction of some prochiral substrates. A lithium aluminium hydride reduction of Af-acylenamines has also been observed384-386. 

An autorecycling system for the specific 1,4-reduction of a,p-unsaturated ketones and aldehydes was based on 1,5-dihydro-5-deazaflavin, which can be regarded as an NADH model. The reaction occurs on heating the substrate with catalytic amounts of 5-deazaflavin in 98% formic acid, typically at 120 "C for 24 h (Scheme 80). 

LnCpa and Cp2LnCl complexes initiate the dehalogenation of aiyl and vinyl halides by NaH. Chemoselectivity is observed in the reduction of m-bromochloro-benzene and p-iodochlorobenzene to chlorobenzene [192], The asymmetric reduction of methylphenyl glyoxylate to methyl mandelate by NADH models is catalyzed by chiral lanthanide )6-diketonates [193],... 

An interesting amine oxide (78) finds utility in the ketone synthesis. Good enantioselectivity for reduction of ketones by A-benzyl-3-p-toluenesulfinyl-1,4-dihydropyridine ° and a 2,5-pyridinophane 79, NADH models, in the presence of Mg(C10 )2 has been observed. 

Asymmetric Reduction with Chiral NADH Model Compounds... 

Progress in coenzyme NADH model compounds and as3Tnmetric reduction of benzoylformate 07SL2785. 

Pierre, J.-L. Gagnaire, G. Chautemps, P. An artificial allosteric system Regulation of a biomimetic reduction (NADH model) by potassium ions. Tetrahedron Lett. 1992, 33 (2), 217-220. 

Table 28. Reduction of 48 or 49 with NADH model compounds. ...

Baba N, Matsumura Y, Sugimoto T (1978) Asymmetric reduction of aryl trifluoromethyl ketones with an achiral NADH model compound in a chiral hydrophobic binding site of sodium cholate micelle,... 

Baba N, Oda J, Inouye Y (1982) Abhangigkeit der Enantioselektivitat von der relativen Konzentration des Substrats bei einer NADH--Modellreaktion. Angew Chem 94 465-466 Baba N, Oda J, Inouye Y (1983) Addition effect of some macrocyclic polyethers on the asymmetric reduction with chiral NADH model compounds. Bull Inst Chem Res Kyoto Univ 61 113-116 Baba N, Amano M, Oda J, Inouye Y (1984) Asymmetric reduction with chiral NADH model compounds A dynamic aspect of product stereochemistry. J Am Chem Soc 106 1481-1486 Bally C, Leuthardt F (1970) Die Stereospezifitat der Alkoholdehydro-... 

Fukuzumi S, Tanaka T (1982a) A charge-transfer complex as an intermediate in the reduction of chloranil by a NADH model compound. Chem Lett 1513-1516... 

Fukuzumi S, Kondo Y, Tanaka T (1982c) Electron transfer reactions of an NADH model with iron(lll) complexes. A two-step electron transfer mechanism. Chem Lett 1591-1594 Fukuzumi S, Hironaka K, Tanaka T (1983a) halides by an NADH model compound. An mechanism. J Am Chem Soc 105 4722-4727 Fukuzumi S, Kondo Y, Tanaka T (1 983b) An inhibitory effect of Mg " ion by the complex formation with 1-benzyl-1,4-dihydronicotinamide on the reduction of 7,7,8,8-tetracyano-p-quinodimethane. Chem Lett 485-488... 

Fukuzumi S, Kondo Y, Tanaka T (1983c) Evidence for a single electron transfer activation in the hydride transfer from an NADH model compound to tetracyanoethylene. Chem Lett 751-754 Fushimi M, Baba N, Oda J, Inouye Y (1980) Asymmetric reduction of a-keto-esters and trifluoroacetophenone with N-anionized Hantzsch ester. Bull Inst Chem Res Kyoto Univ 58 357-365 Gase RA, Boxhoorn G, Pandit UK (1976) Metal-complex mediated catalysis of reduction of 2-benzoylpyridine by an NADH-model. 

Holbrook JJ, Stinson RA (1973) The use of ternary complexes to study ionizations and isomerizations during catalysis by lactate dehydrogenase. Biochem J 131 739-748 Hoshide F, Ohi S, Baba N, Oda J, Inouye Y (1982) Asymmetric reduction with bis(NADH) model compounds. Agric Biol Chem 46 2173-2175 Hoshide F, Baba N, Oda J, Inouye Y (1983) Asymmetric reduction by an NADH model compound with L-prolinamide in the N1 substituent. Agric Biol Chem 47 2141-2143... 

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