Activated asymmetric reduction

Optically Active PO. The synthesis of optically pure PO has been accompHshed by microbial asymmetric reduction of chloroacetone [78-95-5] (90). (3)-2-Meth5loxirane [16088-62-3] (PO) can be prepared in 90% optical purity from ethyl (3)-lactate in 44% overall yield (91). This method gives good optical purity from inexpensive reagents without the need for chromatography or a fermentation step. (3)-PO is available from Aldrich Chemical Company, having a specific rotation [0 ] ° 7.2 (c = 1, CHCl ). 

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. 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

Optically active 1-alkoxyallylstannanes are more readily available by asymmetric reduction of acylstannanes using either ( + )-(/J)-BINAL-Il105 106 or LiAlH4-Darvon alcohol [(2S,3/ )-4-dimethylamino-3-mcthy]-1,2-diphenyl-2-butanol] 06 followed by O-alkylation. The stereoselectivity of the BINAL-H reductions differs from that usually observed, and has been attributed to a tin-oxygen hypervalent interaction107, l08. 

A very interesting approach to optically active sulphoxides, based on a kinetic resolution in a Pummerer-type reaction with optically active a-phenylbutyric acid chloride 269 in the presence of /V,A -dimethyIaniline, was reported by Juge and Kagan332 (equation 149). In contrast to the asymmetric reductions discussed above, this procedure afforded the recovered sulphoxides in optical yields up to 70%. Chiral a, /1-unsaturated sulphoxides 270 were prepared via a kinetic resolution elaborated by Marchese and coworkers333. They found that elimination of HX from racemic /i-halogenosulphoxides 271 in the presence of chiral tertiary amines takes place in an asymmetric way leading to both sulphoxides 270 and 271, which are optically active (optical yields up to 20%) with opposite configurations at sulphur (equation 150). 

Asymmetric reduction with very high ee values has also been achieved with achiral reducing agents and optically active catalysts. The two most important... 

In the above cases, an optically active reducing agent or catalyst interacts with a prochiral substrate. Asymmetric reduction of ketones has also been achieved with an achiral reducing agent, if the ketone is complexed to an optically active transition metal Lewis acid. ... 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

To date, synthetically useful enantioselective hydroalumination is limited to the asymmetric reductive ring-opening reaction of bicycHc ethers. In spite of the fact that further studies are necessary to get a detailed understanding of the reaction mechanism, this reaction provides a new route to various cycloalkenol derivatives, which are useful intermediates in the preparation of biologically active compounds. 

In 1999, this methodology was applied to the synthesis of unnatural biologically active ( + )-5-epi-nojirimycin-5-lactam, a potent and selective glycosidase inhibitor.The key step of this synthesis was the asymmetric reduction of a cyclic triacetyloxy meso imide under the same conditions to those described above, which resulted in the formation of the corresponding hydroxy 5-lactam in good yield and enantioselectivity of 85% ee (Scheme 10.59). 

In 2000, Woodward et al. reported that LiGaH4, in combination with the S/ 0-chelate, 2-hydroxy-2 -mercapto-1,1 -binaphthyl (MTBH2), formed an active catalyst for the asymmetric reduction of prochiral ketones with catecholborane as the hydride source (Scheme 10.65). The enantioface differentiation was on the basis of the steric requirements of the ketone substituents. Aryl w-alkyl ketones were reduced in enantioselectivities of 90-93% ee, whereas alkyl methyl ketones e.g. i-Pr, Cy, t-Bu) gave lower enantioselectivities of 60-72% ee. 

Manufacture of ruthenium precatalysts for asymmetric hydrogenation. The technology in-licensed from the JST for the asymmetric reduction of ketones originally employed BINAP as the diphosphine and an expensive diamine, DAIPEN." Owing to the presence of several patents surrounding ruthenium complexes of BINAP and Xylyl-BINAP, [HexaPHEMP-RuCl2-diamine] and [PhanePHOS-RuCl2-diamine] were introduced as alternative catalyst systems in which a cheaper diamine is used. Compared to the BINAP-based systems both of these can offer superior performance in terms of activity and selectivity and have been used in commercial manufacture of chiral alcohols on multi-100 Kg scales. 

The optically active glycols are a convenient starting material for the preparation of optically active carbinols, hydroxy-acids, etc. The biological method of asymmetric reduction is perhaps the only convenient method for the preparation of these glycols. The steps in the preparation of other optically active glycols arc identical with those of /-propylene glycol. In some cases it is found convenient to oxidize the chlorohydrin to the... 

Enoate reductase reduces a,/3-unsaturated carboxylate ions in an NADPH-dependent reaction to saturated carboxylated anions. Useful chiral synthons can be conveniently prepared by the asymmetric reduction of a triply substituted C—C bond by the action of enoate reductase, when the double bond is activated with strongly polarizing groups [22]. Enoate reductases are not commercially available as isolated enzymes therefore, microorganisms such as baker s yeast or Clostridium sp. containing enoate reductase are used to carry out the reduction reaction. 

Octonol is an intermediate for the production of several optically active pharmaceuticals, such as steroids and vitamins. The asymmetric reduction of 2-octanone to (5)-2-octonol by baker s yeast was inhibited severely by substrate and product concentration of 10 him and 6 mM respectively. Whole-cell biotransformation of 2-octanone in a water-ra-dodecane biphasic system yielded a high product concentration of 106him with 89% ee in 96h [37],... 

The use of optically active amines in bis(dimethylglyoximato)co-baltate(Il)amine systems (Section II,C) has led to asymmetric reduction... 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

Asymmetric reduction of oxime ethers,2 The complex (1) of (- )-norephedrine with BH3 (2 equiv.) reduces prochiral oxime ethers to optically active amines the... 

In the later work, low optical activity (<30% ee) was observed for the products [e.g. 5] and the high asymmetric induction of the earlier work was attributed to carry over of the catalyst or chiral degradation derivatives (oxiranes) of the catalysts. Although the reported stereoselective reduction of acetophenone has been discredited, it has been suggested that the use of a chiral solvent, such as menthyl methyl ether, enhances the asymmetric reduction [7], The veracity of this claim has not been proven. 

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... 

The 36d-LAH complex was applied to the reduction of ketone oximes and their O-tetrahydropyranyl and O-methyl derivatives to optically active amines (69). Results for a variety of phenyl alkyl and dialkyl ketones are shown in Table 4. The predominant amines formed all were of the S absolute configuration with optical purities up to 56%. The oxime hydroxy group presumably reacts with the less hindered H2 in the 36d-LAH complex (cf. Scheme 6) to form an oxime complex (45), which probably undergoes infermolecular hydride transfert of H2 from a second molecule of the 36d-LAH complex (Scheme 8). Asymmetric reduction with the ethanol-modified 36d-LAH reagent gave amines of R con-... 

The asymmetric reduction of C=N double bonds in prochiral oximes afforded a maximum of 18% ee [380, 384, 385]. Prochiral azomethines were reduced to the corresponding 1,2-diamines and secondary amines using 36 optically active supporting electrolytes. The dimers were optically inactive, while the monomers showed low optical inductions (<11% ee). The effect of electrolyte, substrate concentration, temperature, pH, and cathode potential on the induction was studied. It was proposed that the enantioselectivity... 

The asymmetric reduction of prochiral ketones to their corresponding enantiomerically enriched alcohols is one of the most important molecular transformations in synthetic chemistry (20,21). The products are versatile intermediates for the synthesis of pharmaceuticals, biologically active compounds and fine chemicals (22,23). The racemic reversible reduction of carbonyls to carbinols with superstoichiometric amounts of aluminium alkoxides in alcohols was independently discovered by Meerwein, Ponndorf and Verley (MPV) in 1925 (21—26). Only in the early 1990s, first successful versions of catalytic... 

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