Acetophenones asymmetric reduction

Kragl and Wandrey made a comparison for the asymmetric reduction of acetophenone between oxazaborolidine and alcohol dehydrogenase.[59] The oxazaborolidine catalyst was bound to a soluble polystyrene [58] and used borane as the hydrogen donor. The carbonyl reductase was combined with formate dehydrogenase to recycle the cofactor NADH which acts as the hydrogen donor. Both systems were run for a number of residence times in a continuously operated membrane reactor and were directly comparable. With the chemical system, a space-time yield of 1400 g L"1 d"1 and an ee of 94% were reached whereas for the enzymatic system the space-time yield was 88 g L 1 d"1 with an ee of >99%. The catalyst half-life times were... 

Boranes have opened the door to asymmetric reduction of carbonyl compounds. The first attempt at modifying borane with a chiral ligand was reported by Fiaud and Kagan,75 who used amphetamine borane and desoxyephedrine borane to reduce acetophenone. The ee of the 1-phenyl ethanol obtained was quite low (<5%). A more successful borane-derived reagent, oxazaborolidine, was introduced by Hirao et al.76 in 1981 and was further improved by Itsuno and Corey.77 Today, this system can provide high stereoselectivity in the asymmetric reduction of carbonyl compounds, including alkyl ketones. 

Asymmetric reduction of 2-bromo-(3-nitro-4-benzyloxy) acetophenone. . 157... 

ASYMMETRIC REDUCTION OF 2-BROMO-(3-NITRO-4-BENZYLOXY)ACETOPHENONE[161... 

The quininium and quinidinium fluoride catalysts, 10 (R=H etc., X=F) and 8 (R=H, X=F), were used for the asymmetric reduction of alkyl aryl ketones in conjunction with silanes.1751 One of the most efficient silanes proved to be tris(trimethylsiloxy)silane, which together with 8 (R=H, X=F) reduced acetophenone to give the alcohol 102 in almost quantitative yield with 78 % ee, as shown in Scheme 31. 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. 

Asymmetric reduction of acetophenone led to (/ )-( + )-1 -phenyl-1 -ethanol with 65 to 69, and with 72, whereas the (S)-( - )-alcohol was formed with 70 and 71. Again the optical yields were relatively low, with the highest 48%, obtained with 65. Asymmetric reductions in very low optical yields were observed with the simple alcohols (-)-l-phenyl-1-ethanol (73) and (-)-3,3-di-methyl-2-butanol (74) as chiral auxiliary reagents. 

The results on the asymmetric reduction of acetophenone discussed above are summarized in Table 2.1. The chiral catalyst systems described above have also been applied to a variety of ketones other than acetophenone. The results are summarized in Table 2.2. 

Chiral 1,2-aminodiols. Morrison el al.1 have prepared five chiral 1,2-aminodiols related to Darvon alcohol. The only useful one for asymmetric reduction of ketones in conjunction with LiAlH4 is 1, prepared from (S)-propylene oxide and (S)-ot-methylbenzylamine. Acetophenone and propiophenone are reduced by LiAlH4-l to the corresponding (R)-alcohols in 77-82% ee. In this case, the three (S)-centers reinforce one other. 

S. Rissom, J. Beliczey, G. Giffels, U. Kragl, and C. Wan drey, Asymmetric reduction of acetophenone in membrane reactors comparison of oxazaborolidine and alcohol dehydrogenase, Tetrahedron Asymm. 1999, 10, 923-928. 

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... 

The chiral BINAPHTHOL derivative (H)-ll and two equivalents of Zn(C2H5)2 produced an active catalyst for the asymmetric reduction of acetophenone with... 

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were first (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-0-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlHzt, the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantios-electivity in the reduction of acetophenone to 70% ee with an ethanol-modified lithium aluminum hydride-sugar complex.10... 

In 1987, Corey and co-workers proved that highly enantioselective reduction of ketones could be achieved by using stoichiometric borane in the presence of catalytic amounts of the oxazaborolidine 28a11 (Scheme 4.3j). Compound 28a, synthesized by heating (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine at reflux in THF with 3 equivalents of BH3 THF, shows excellent catalytic activity for the asymmetric reduction of acetophenone and other ketones. The B -methylated analog 28b was later synthesized to improve the air and moisture sensitivity associated with 28a. The third analog, 28c, with a 2-naphthyl substituent on the oxazaborolidine ring, has proven to be the best to afford the alcohol 29 with superb levels of enantioselectivity. 

Numerous theoretical treatments have been carried out to understand the mode of asymmetric induction of the Corey-Bakshi-Shibata (CBS) reduction, more thoroughly.12 Liotta et al. carried out computational studies to identify the transition states for CBS reductions of various ketones13 (Scheme 4.3k).In the asymmetric reduction of acetophenone with the catalyst (R)-28a, four transition states were found. Of the lowest energy is chairlike transition state A, which would lead to formation of the major enantiomer. In transition state A, the phenyl group of acetophenone occupies an equatorial position that is free from any steric interaction, as it is 5.5 A away from one of the two phenyl groups of the diphenylprolinol ring. On the other hand, transition state B, leading to the... 

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