Asymmetric reduction conditions

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. 

The results cited in this section indeed appear very promising and encouraging, but there are still many problems to solve. Chemical and optical yields are extremely sensitive to experimental conditions such as current density and electrolyte composition Some experimental details in the asymmetric reduction of citraconic acid are indeed puzzling, such as a temperature maximum of the optical yield, and the fact the same product enantiomer is formed regardless if D or l polyvaline was used... 

Resting cell of G. candidum, as well as dried cell, has been shown to be an effective catalyst for the asymmetric reduction. Both enantiomers of secondary alcohols were prepared by reduction of the corresponding ketones with a single microbe [23]. Reduction of aromatic ketones with G. candidum IFO 5 767 afforded the corresponding (S)-alcohols in an excellent enantioselectivity when amberlite XAD-7, a hydro-phobic polymer, was added to the reaction system, and the reduction with the same microbe afforded (R)-alcohols, also in an excellent enantioselectivity, when the reaction was conducted under aerobic conditions (Figure 8.31). 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

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). 

The asymmetric reduction of the benzoxathiin is very appealing because of its simplicity (Scheme 5.3). It was envisioned that intermediate 16 could be prepared from thiol-phenol 7 and bro moke tone 17. Scheme 5.8 summarized the synthesis for 16. The l,3-benzoxathiol-2-one 35 was prepared from 1,4-benzoquinone and thiourea following a literature procedure with minor modifications. Benzylation of 35 with benzyl bromide in the presence of KI gave benzyl ether 36 as a crystalline solid. It was observed that the benzylation gave better results when the reaction was run under anaerobic conditions. Hydrolysis of thiocarbonate 36 gave free thiophenol 7 which was used directly in the next reaction. 

The asymmetric reduction of enamides using hydrogenation conditions is a well documented reaction with a number of groups reporting excellent results [14]. Syn delivery of hydrogen from the same face of the molecule ensures that the enamide geometry defines the relative stereochemistry obtained, and a range of chiral catalysts have been developed to control the absolute stereochemistry. However, a... 

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],... 

Enantioselectivities in the asymmetric reduction under phase transfer catalyzed conditions reported till now are still moderate, and should be improved further in future. 

Early studies of the asymmetric reduction of prochiral ketones by chiral aluminum alkoxides have been reviewed by Morrison and Mosher (1). Doering and Young (123) reported the reduction of methyl cyclohexyl ketone with chiral 3-methyl-2-butanol in the presence of a catalytic amount of aluminum alkoxide to give the (S)-( + )-carbinol in a 22% optical yield. Jackman and co-workers (124) similarly reduced methyl n-hexyl ketone with chiral 3,3-dimethyl-2-butanol to the (S)-( - )-carbinol in a 6% optical yield. Other attempts resulted in similar low optical yields or gave only racemic products. Since the reductions were carried out under equilibrium conditions, racemization could have accounted for the low optical yields. 

A range of chiral alkaloids have been screened for the asymmetric reduction of 2- and 4-acetyl pyridine [41] and results are given in Table 10.5. Brucine and strychnine give the highest enantiomeric excess in the pyridinylethanols produced. Reduction of 3-acetylpyridine however affords no optically active alcohol under all conditions employed. A further effect of the added alkaloid is to raise the yield of secondary alcohol at the expense of the pinacols relative to reactions where no alkaloid is present. The high enantiomeric excess found during reduction of 4 ... 

Asymmetric reduction of the double bond of the dehydroamino acid residue in 522 can be effected in different ways since the peptide moiety can act as a chiral auxiliary. Heterogeneous hydrogenations using a Pd/C catalyst are the most frequently used conditions. Among the different amino acids evaluated as chiral auxiliaries, proline is the auxiliary of choice and has led to the best diastereodiffer-... 

Asymmetric reduction of a,fi-enon s. This combination of reagents (1 1) in conjunction with N-cthylaniline (2 equivalents) reduces alkyl aryl ketones to alcohols with high stereoselectivity.1 Under these conditions 2,/1-unsaturated ketones arc reduced to optically active (S)-allylic alcohols. Optical yields of 80 98% have been reported for open-chain enones. Reduction of cyclic enones is somewhat less efficient. The method was used to reduce 1 to 2, which has been used as an intermediate in an anthracyclinone synthesis.2... 

Kagan and Schiffers carefully studied the effect of the lithium salts of BINOL (17) and related axially chiral binaphthols on the reduction of a variety of ketones with trialkoxysilanes [24]. They found that diethyl ether, with TMEDA as an additive, was the best solvent for asymmetric reduction of ketones. In the presence of 5 mol% of the monolithium salt of BINOL (17), acetophenone (1) could be reduced with trimethoxysilane in 80% yield and with 61% ee. Enantiomeric excesses > 90% were achieved under the same conditions with 2, 4, 6 -trimethyl-acetophenone (18) or a-tetralone (19) as substrates. Aliphatic ketones such as... 

While chiral catalysts containing N-P=0 moieties have been increasingly studied in borane-mediated asymmetric reduction of ketones, a study of a range of such species (e.g. 81) indicates that the configuration at phosphorus plays little or no role in determining enantioselectivity, and indeed the stereochemistry at the phosphorus centre may be scrambled under the reaction conditions.304... 

Free-radical reductions mediated by chiral stannanes, germanes, and silanes may occur with enantioselectivities in excess of 99% ee. Owing to the involvement of radical intermediates and the mild reaction conditions, this process is applicable for a large variety of simple or even complex target molecules that are incompatible to asymmetric reductions that require ionic reaction conditions. 

The CBS reduction has also proven to be an efficient method for asymmetric reduction of a,ft-unsaturated enones14 and ynones15 (Scheme 4.31). The asymmetric reduction of alkynyl ketones affords propargylic alcohols 30 with high levels of enantioselectivity and in moderate to good yields. Optimized reaction conditions for the reduction are the use of THF at — 30° C, 2 equivalents of chiral oxazaborolidine 28b, and 5 equivalents of borane methyl sulfide complex. 

Hermitage S, Howard JAK, Jay D, Pritchard RG, Probert MR, Whiting A (2004) Mechanistic studies on the formal aza-Diels-Alder reactions of N-aryl imines evidence for the non-concertedness under Lewis-acid catalysed conditions. Org Biomol Chem 2 2451-2460 Hoffmann S, Nicoletti M, List B (2006) Catalytic asymmetric reductive ami-nation of aldehydes via dynamic kinetic resolution. J Am Chem Soc 128 13074-13075... 

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