Racemization, reductive

Reduction. Kornbium found that reduction of (—)-2-nitrooctane to the amine by iron and acetic acid proceeds with at least 82% retention of optical purity. Platinum hydrogenation in acetic acid was somewhat less satisfactory, and platinum hydrogenation in absolute ethanol led to 90% racemization. Reduction with L1AIH4 was attended with complete racemization. 

Despite its long history and common usage of the term, reductive amination has remained underdeveloped. Many studies are available regarding racemic reductive amination, but only Borner and Tararov have provided summaries of the asymmetric version [1], In this chapter we provide an overview of the available methods and achievements since the first demonstrated enantioselective reductive amination by Blaser in 1999 [2],... 

A more cost-effective and reliable route to 464 uses lactamides 465 or 467 as the precursor [95,117] (Scheme 67). These are readily available from lactamides 6c and 466 by standard inexpensive benzylation conditions (benzyl chloride, sodium hydride) or phase-transfer conditions (benzyl chloride, sodium hydroxide, tricaprylmethylammonium chloride, 92% yield). These alkylations, which have also been performed with / -chlorobenzyl chloride and / -methoxybenzyl chloride, proceed with no racemization. Reduction of lactamides 465 or 467 with sodium bis(2-methoxyethoxy)aluminum hydride (Vitride) furnishes (/S)-2-benzyl-oxypropanal (464) in high yield. The aldehyde itself is not very stable, and has a propensity to hydrate, so it should be used immediately after preparation. 

Compound 396 was obtained as an inseparable mixture of two racemates. Reduction of this mixture, followed by acetylation of the alcohol group, resulted in 397. Subsequent Wittig reaction converted ketone 397 into methylene 398. Deprotection of the alcohol group facilitated regio- and stereoselective epoxidation with wt-CPBA and final acetylation of the alcohol group afforded the racemic natural product trichodermin (375) (Scheme 8.2). 

Borneol and isoboineol are respectively the endo and exo forms of the alcohol. Borneol can be prepared by reduction of camphor inactive borneol is also obtained by the acid hydration of pinene or camphene. Borneol has a smell like camphor. The m.p. of the optically active forms is 208-5 C but the racemic form has m.p. 210-5 C. Oxidized to camphor, dehydrated to camphene. 

Piperitone is of considerable technical im portance. It is a colourless oil of a pleasant peppermint-like smell. (-)-Piperilone has b.p. 109-5-110-5 C/I5mm. Piperitone yields thymol on oxidation with FeCl. On reduction with hydrogen in presence of a nickel catalyst it yields menthone. On reduction with sodium in alcoholic solution all forms of piperitone yield racemic menthols and womenthols together with some racemic a-phel)andrene. 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

The enzyme is a single enantiomer of a chiral molecule and binds the coenzyme and substrate m such a way that hydride is transferred exclusively to the face of the carbonyl group that leads to (5) (+) lactic acid Reduction of pyruvic acid m the absence of an enzyme however say with sodium borohydride also gives lactic acid but as a racemic mixture containing equal quantities of the R and S enantiomers... 

In a first step, JS ocardia asteroides selectively oxidizes only (3)-pantolactone to ketopantolactone (19), whereas the (R)-pantolactone remains unaffected (47). The accumulated ketopantolactone is stereospecificaHy reduced to (R)-pantolactone in a second step with Candidaparapsilosis (product concentration 72 g/L, 90% molar yield and 100% ee) (48). Racemic pantolactone can also be converted to (R)-pantolactone by one single microbe, ie, Jiodococcus erythropolis by enantioselective oxidation to (3)-pantolactone and subsequent stereospecific reduction in 90% yield and 94% ee (product concentration 18 g/L) (40). 

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiendy reduces all simple four- to nine-membered cycHc ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aUphatic acycHc ketones (C-4—C-10) (103,104) can be efficiendy achieved by alcohol dehydrogenase isolated from Thermoanaerohium hrockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse Hver and T. hrockii... 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

The enantiosclective synthesis of (-)-bilobalide was achieved based on successful synthesis of the chiral enone A and the highly stereoselective reduction of enone A to the desired a-alcohol B. Further transformation to (-)-bilobalide was accomplished following the route used for racemic bilobalide (Ref. 2). 

On treatment of N-methylpapaverine, formed by the lithium aluminum hydride reduction of papaverine methiodide with phosphoric acid, N-methylpavine is formed which is identical with the racemic alkaloid argemonine. This reaction was used for the synthesis of the alkaloid (-h)-coreximine (268) (174) and similar compounds containing the proto-berberine grouping in the molecule (269,270). 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Racemic or optically active perhydropyrido[l,2-a]pyrazines were obtained by reduction of 9a5-perhydropyrido[l,2-u]pyrazin-4-one with LAH in Et20 at room temperature (99H(51)2065) and by reduction of perhydropyr-ido[l,2-u]pyrazine-l,4-diones with LAH in boiling THF (97USP5703072, 00JAP(K)00/86659). Treatment of (9uS)-2-(fcrf-butoxycarbonyl)perhydro-pyrido[l,2-u]pyrazin-4-one with LAH in Lt20 afforded (9uS)-2-fcrf-butox-ycarbonyl-l,6,7,8,9,9a-hexahydro-2//-pyrido[l,2-a]pyrazine (99H(51)2065). 

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