Alcohol From ketone, enantioselective

Enantioselective organic synthesis using modified skeletal catalysts has wide application in areas such as pharmaceutical production for example, synthesis of chiral alcohols from ketones [90], which is described in detail elsewhere in this book. 

Microbial reduction has been recognized for decades as a laboratory method of preparing alcohols from ketones with exquisite enantioselectivity. The baker s yeast system represents one of the better known examples of biocatalysis, taught on many undergraduate chemistry courses. Numerous other microorganisms also produce the ADH enzymes (KREDs) responsible for asymmetric ketone reduction, and so suitable biocatalysts have traditionally been identified by extensive microbial screening. Homann et have... 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

The first report in this regard described a method for direct formation of the desired optically active (S)-alcohol 32a, via enantioselective reduction with a chiral amine complex of lithium aluminum hydride (Scheme 14.9). Therefore, the necessary chiral hydride complex 38 was preformed in toluene at low temperature from chiral amino alcohol 37. The resulting hydride solution was then immediately combined with ketone 31 to afford the desired (S)-alcohol 32a in excellent yield and enantiomeric excess. In addition to providing a more efficient route to the desired drug molecule, this work also led to the establishment of the absolute configuration of duloxetine (3) as S). 

The boron atom dominates the reactivity of the boracyclic compounds because of its inherent Lewis acidity. Consequently, there have been very few reports on the reactivity of substituents attached to the ring carbon atoms in the five-membered boronated cyclic systems. Singaram and co-workers developed a novel catalyst 31 based on dicarboxylic acid derivative of 1,3,2-dioxaborolane for the asymmetric reduction of prochiral ketones 32. This catalyst reduces a wide variety of ketones enantioselectively in the presence of a co-reductant such as LiBH4. The mechanism involves the coordination of ketone 32 with the chiral boronate 31 and the conjugation of borohydride with carboxylic acid to furnish the chiral borohydride complex 34. Subsequent transfer of hydride from the least hindered face of the ketone yields the corresponding alcohol 35 in high ee (Scheme 3) <20060PD949>. 

Enantioselective preparation of alcohols from the corresponding ketone by yeast reduction... 

The groups of Pete and Rau also employed chiral amino alcohols for the enantioselective protonation of simple enols 23a-c that were photochemically generated from 2-/-butyl indanones and tetralones 22a-c by a Norrish type II photoelimination (Scheme 9) [41,42]. Best enantioselectivities were obtained at — 40°C in acetonitrile with 0.1 equivalent of the chiral amino alcohol. In the case of indanone 22a, the selectivity reached 49% ee with (— )-ephedrine ent-18) and could not be further enhanced by the camphor derived inductor 20. With this amino alcohol, enantioselectivities over 80% ee were induced in the case of tetralone 22b. A benzyl substituent in place of the methyl group led to substantial decrease of the selectivity to 47% ee. Linear ketones gave low yields and enantioselectivities around 9% ee. 

Chiral Ligand of L1A1H4 for the Enantioselective Reduction of Alkyl Phenyl Ketones. Optically active alcohols are important synthetic intermediates. There are two major chemical methods for synthesizing optically active alcohols from carbonyl compounds. One is asymmetric (enantioselective) reduction of ketones. The other is asymmetric (enantioselective) alkylation of aldehydes. Extensive attempts have been reported to modify Lithium Aluminum Hydride with chiral ligands in order to achieve enantioselective reduction of ketones. However, most of the chiral ligands used for the modification of LiAlHq are unidentate or bidentate, such as alcohol, phenol, amino alcohol, or amine derivatives. 

In alcoholic medium, NaBH, converts a,P-unsaturated nitriles into cyanoethyl compounds under more severe conditions (refluxing alcohol for several hours). - i jpig enantioselective reduction of the double bond of each ( )- and (Z)-isomer of a,P-unsaturated nitriles derived from ketones has been evaluated using NaBH in EtOH/diglyme in the presence of semicorrin (/oCT catalyst the yields are good (about 75%), but the enantioselectivity remains modest (53-69%). - In contrast, it has been found that copper(l) hydride, a reagent that presumably operates by a mechanism akin to the Michael reaction, 754 cleanly and stereoselectively effects the reduction of a,P-iinsaturatcd to saturated nitriles in the presence of 2-butanol, as proton donnor, in THE. The use of LAH in THF at room temperature has also been reported in the stereoselective reduction of a,P-iinsaturatcd nitriles. 

Compared with well-established electrophilic it-allylpalladium chemisty, the catalytic asymmetric reaction via umpolung of jt-allylpalladium has received very limited exploration [93]. Zhou and co-workers investigated the Pd-catalyzed asymmetric umpolung allylation reactions of aldehydes [22a, 94], activated ketones [95], and imines [96] by using chiral spiro ligands (5)-18e, (S)-17c, and (5)-17a, respectively. One representative example is that of the Pd/(5)-18e-catalyzed umpolung allylation of aldehydes with allylic alcohols and their derivatives, which provided synthetically useful homoallylic alcohols from readily available allylic alcohols, with high yields and excellent enantioselectivities (Scheme 33). 

The spiroketal (+)-spiroxaliiie methyl ether 31 contains three secondary oxygenated ste-reogenic centers. In a showcase of current chiral technology, Barry M. Trost of Stanford University constructed (Angew. Chetn. Int. Ed. 2007, 46, 7664) the first two of the three alcohols by the enantioselective addition of an aUsyne to an aldehyde. The chiral catalyst 25 that directed the alkyne additions was derived from a commercial Hgand. The last alcohol center was derived from / -(+)-epoxypropane. Note that the spiroketal was not prepared in the usual way, by acid-catalyzed cyclization of a dihydroxy ketone, but by Pd-catalyzed cyclization of the alkyne diol 30. 

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