Ketone with chiral

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. 

Asymmetric Reduction of Ketones with Chiral Organoaluminum Reagents... 

Reduction of a, -acetylenic ketones with chiral borane NB-Enanthrane prepared by addition of 9-borabicyclo[3.3.1]nonane to the benzyl ether of nopol yielded optically active acetylenic alcohols in 74-84% yields and 91-96% enantiomeric excess [770]. Another way to optically active acetylenic alcohols is reduction with a reagent prepared from lithium aluminum hydride and (2S, 3R)-( -I- )-4-dimethylamino-3-methy 1-1,2-dipheny 1-2-butanol. At —78° mainly R alcohols were obtained in 62-99% yield and 34-90% enantiomeric excesses [893]. 

Tellers, D.M., Bio, M., Song, Z.J., McWilliams, J.C. and Sun, Y. Enantioselective Hydrogenation of an a-Alkoxy Substituted Ketone with Chiral Ruthenium (Phosphino-ferrocenyl)oxazohne Complexes. Tetrahedron Asymmetry 2006, 17, 550-553. 

Hamada, T., Torii, T, Onishi, T, Izawa, K. and Ikariya, T. Asymmetric Transfer Hydrogenation of a-Aminoalkyl-a -Chloromethyl Ketones with Chiral Rh Complexes. J. Org. Chem. 2004, 69, 7391-7394. 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

Reduction of perfluoroalkyl ketones with chiral lithium alkoxides gave chiral a-perfluoroalkyl alcohols in high enantiomeric excesses. The order of steric effects on this reaction is estimated as C7F15 > substituted phenyl > CF3.388... 

Chiral 1,3-diols. Coupling of diaryl ketones with chiral epoxides mediated by Yb (15, 366) provides chiral 1,3-diols in high optical yields. Generally two diols are formed by coupling at both carbon atoms, but coupling with styrene oxide occurs mainly at the more-substituted carbon. 

After early unsuccessful attempts to direct the photoreduction of ketones with chiral secondary alcohols [8-10]. Weiss et al. examined the sensitized cis-trans photoisomerization of 1,2-diphenylcyclopropane in chiral solvents but obtained the product without detectable optical rotation [11]. Seebach and coworkers were the first to achieve asymmetric induction for a photochemical reaction by a chiral solvent [12-15]. They examined the photopinacolization of aldehydes and ketones in the chiral solvent (S,S)-( + )-l,4-bis(dimethylamino)-2,3-dimethoxybutane (DDB, 4). Irradiation of acetophenone in the presence of 7.5 equiv. of DDB yielded a mixture of chiral d,/-pinacols 3/ent-3 and achiral meso-pinacol 2. At 25°C pinacol 3 was obtained with 8% ee, with the (R, / )-( + )-enantiomer prevailing. At lower temperatures the asymmetric induction was more effective, up to 23% ee at — 78°C in a 1 5 mixture of DDB and pentane (Scheme... 

The asymmetric sulfenylation of ketones with chiral sulfenamides is based on the direct reaction of 4-alkylcyclohexanones with optically active sulfenamides in the presence of a catalytic amount of triethylamine hydrochloride37. 

Stereoselective selenenylation of ketones with chiral selenamines has been utilized as a facile entry to optically active 4-substituted 2-cyclohexenones 9, but with low optical purity6. Thus, the reaction of 4-te/T-butyl- or 4-methylcyclohexanone with chiral selenamines in benzene or tetrahy-drofuran at various temperatures and/or times affords diastereomeric 2-arylseleno-4-/< /7-butyl-and 2-arylseleno-4-methylcyclohexanone (8). Oxidation of these selenides with hydrogen peroxide produces (S)-4-/erf-butyl- or (.S )-4-methyl-2-cyclohexenone (9) in quantitative yield6. 

Other selected examples are summarized in Table 2. In addition to aldehydes, both cyclic and acyclic ketones can be reduced equally well. sec-Phenethyl alcohol (11, R = Ph) as hydride source works more effectively than t-PrOH. On the basis of this finding, the asymmetric MPV reduction of unsymmetrical ketones with chiral alcohol in the presence of catalyst 10 was examined [30]. Treatment of 2-chloroacetophenone (12) with optically pure (R)-(+)-sec-phenethyl alcohol (1 equiv.) under the influence of catalytic 10 at 0 °C for 10 h afforded (5)-(+)-2-chloro-l-phenylethanol (13) with moderate asymmetric induction (82 %, 54 % enantiomeric excess, ee Sch. 8). Switch-... 

The earliest report of a reaction mediated by a chiral three coordinate aluminum species describes an asymmetric Meerwein-Poimdorf-Verley reduction of ketones with chiral aluminum alkoxides which resulted in low induction in the alcohol products [1]. Subsequent developments in the area were sparse until over a decade later when chiral aluminum Lewis acids began to be explored in polymerization reactions, with the first report describing the polymerization of benzofuran with catalysts prepared from and ethylaluminum dichloride and a variety of chiral compounds including /5-phenylalanine [2]. Curiously, these reports did not precipitate further studies at the time because the next development in the field did not occur until nearly two decades later when Hashimoto, Komeshima and Koga reported that a catalyst derived from ethylaluminum dichloride and menthol catalyzed the asymmetric Diels-Alder reaction shown in Sch. 1 [3,4]. This is especially curious because the discovery that a Diels-Alder reaction could be accelerated by aluminum chloride was known at the time the polymerization work appeared [5], Perhaps it was because of this long delay, that the report of this asymmetric catalytic Diels-Alder reaction was to become the inspiration for the dramatic increase in activity in this field that we have witnessed in the twenty years since its appearance. It is the intent of this review to present the development of the field of asymmetric catalytic synthesis with chiral aluminum Lewis acids that includes those reports that have appeared in the literature up to the end of 1998. This review will not cover polymerization reactions or supported reactions. The latter will appear in a separate chapter in this handbook. 

Asymmetric reduction of prochiral a,p-unsaturated ketones with chiral hydride reagents derived from LiAlH4 and (5)-4-anilino- and (S)-4-(2,6-xylidino)-3-methylamino-l-butanol gives (S)- and ( )-allylic alcohols, respectively, in high chemical and optical yields (Scheme 44).2° ... 

Hirao, A., Itsuno, S., Nakahama, S., Yamazaki, N. Asymmetric reduction of aromatic ketones with chiral alkoxyamine-borane complexes. J. Chem. Soc., Chem. Commun. 1981, 315-317. 

Table 1. Asymmetric hydrosUylation of ketones with chiral rhodium catalysts... 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

The reductive amination of prostereogenic ketones with chiral primary amines can be utilized for the preparation of secondary amines possessing two stereogenic centers. The reaction can formally be regarded as occurring in the following manner, which probably does correspond to the actual sequence of steps. 

Scheme 3.23. Enantioselective deprotonation of achiral ketones with chiral lithium amide...

Enantioselective Reductions. NaBH4 has been employed with less success than LiAULt or BH3 in enantioselective ketone reductions. Low to moderate ee values have been obtained in the asymmetric reduction of ketones with chiral phase-transfer catalysts, chiral crown ethers, -cyclodextrin, and bovine serum albumin. On the other hand, good results have been realized in the reduction of propiophenone with NaBH4 in the presence of isobutyric acid and of diisopropylidene-D-glucofuranose (ee = 85%), " or in the reduction of cr-keto esters and -keto esters with NaBHa-L-tartaric acid (ee >86%). ... 

Later, Ojlma reported on the hydrosilylation of a,/S-unsaturated ketones with chiral rhodium catalysts (Rh-BMPP and Rh-DIOP) and a-NpPhSiH2. As models, j8-lonone and 2-methylcyclohexenone were reduced to the corresponding alcohols with 33.5 and 43% optical selectivity. "" ... 

Nishiyama H, Kondo M, Nakamura T, Itoh K (1991) Highly enantioselective hydrosilylation of ketones with chiral and c2-symmetrical bis(oxazolmyl)pyridine-rhodium catalysts. Organometallics 10 500-508... 

Tian SK, Hong R, Deng L (2003) Catalytic Asymmetric Cyanosilylation of Ketones with Chiral Lewis Base. J Am Chem Soc 125 9900... 

Table 26.21 Reduction of representative ketones with chiral trialkylborohydride [ 1 ]...

Deprotonation of prochiral ketones with chiral amide bases such as (50), derived from the readily available enantiomerically pure 1-phenylethylamine, provides an efficient asymmetric synthesis of silyl enol ethers (51). 

Scheme 7 Earlier examples of hydrosilylation of ketones with chiral CuH complexes...

It was found that 4-substitnted a,a-diarylprolinol 162 catalyzed the asymmetric epoxidation of a, 3-enones to give the corresponding chiral epoxides in good yields and high enantioselectivities (np to 96%) nnder mild reaction conditions (Scheme 1.68) [109]. The extension of epoxidation to cyclic ot,P-unsaturated ketones with chiral primary salts was reported by Wang et al. in good yields and excellent enantioselectivities (up to 99%) [110]. 

SCHEME 32.11. Reduction of ketones with chiral ammonium salts. 

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