Ketones borane reduction

The aziridine carbinols are also effective ligands in the preparation of oxazaborolidine catalysts for the asymmetric ketone reduction with borane (Fig. 4) [551. 

L-699,392, Merck s drug for the treatment of chronic asthma, is an example of asymmetric amplification on an industrial scale (see Figure 13.19). The ketone reduction can be carried out stoichiometrically with a borane-(-)-a-pinene reagent. The terpene natural products are often mixtures of isomers and enantiomers. A reagent prepared from 98% optically pure (-)-a-pinene gives a product e.e. of 97%, but a reagent prepared from less expensive 70% optically pure (-)-a-pinene yields a product e.e. of 95%, which can be pushed to >99.5% by using an excess [30]. 

Selective reduction of ot,a-dihalo ketones." Reduction of a,a-dihalo ketones can he effected without hydrogenolysis of the halo groups with either DIBAH or borane dimethyl sulfide. Reactions with the former reagent are generally faster but work-up can be complicated by gelatinous aluminum salts. In general, the yields are roughly comparable. 

Alcohols are converted to alkyl iodides by reaction with A A-diethyl-aniline/borane/iodine. Reductive iodination is observed when this system reacts with ketones or with carboxylic acids934,935. Direct reduction of aromatic aldehydes to benzyl bromide is reported by Le Corre and coworkers, who have brominated benzaldehydes and acetophenones in presence of a trimethylamine/borane complex and have obtained benzyl bromides and a-bromoethylbenzenes, respectively936. See also Reference937. 

Enantioselective Reduction of Oxime 0-Ethers. In addition to the reduction of prochiral ketones, oxazaborolidine (3) has been used (both stoichiometrically and catalytically with borane-THF) to catalyze the enantioselective reduction of prochiral ketoxime O-ethers to the corresponding amine (eq Unlike the ketone reduction described above, the... 

Enantioselective Ketone Reduction. Following Itsuno s lead for enantioselective reductions using diphenylvalinol, Kraatz was the first to describe the use of a 1 2 mixture of (5)-diphenylprolinol (1) and Borane-Tetrahydrofuran for the stoichiometric enantioselective reduction of ketone (2) to obtain the plant growth regulator triapenthenol (3) (eq 1). Although not characterized at the time, the species responsible for the enantiose-lectivity observed was presumed to be an oxazaborolidine-borane complex. ... 

Several other 1,3,2-oxazaborolidines have been successfully used as chiral catalysts or reagents in borane-promoted reduction of ketones, imines and oxime ethers, and lactones as well as in aldol condensations, Diels-Aldercycloadditions, and ally Imetal additions to aldehydes. ... 

Enantioselective Ketone Reduction. After the pioneering work of Itsuno et al., Corey s group isolated the 1,3,2-oxazaborolidine derived from chiral a,a-diphenyl-2-pyrrolidinemethanol (2) and applied it (and also other related B-alkyl compounds) to the stereoselective reduction of ketones with borane-tetrahydrofuran, borane-dimethyl sulfide (BMS) or catecholborane.It was named the CBS method (after Corey, Bakshi, and Shibata). Since then, the CBS method has become a standard and has been extensively used, specially for aromatic and a,p-unsaturated ketones, not only in academic laboratories but also in industrial processes. ... 

Enantioselective Ketone Reduction. The major application of chiral oxazaborolidines has been the stoichiometric (as the oxazaborolidine-borane complex) (eq 1) and catalytic (in the presence of a stoichiometric borane source) (eq 2) enantioselective reduction of prochiral ketones. These asymmetric catalysts work best for the reduction of aryl alkyl ketones, often providing very high (>95% ee) levels of enantioselectivity. 

Linney, L. P., Self, C. R., Williams, I. H. Computational elucidation of the catalytic mechanism for ketone reduction by an oxazaborolidine-borane adduct. J. Chem. Soc., Chem. Commun. 1994,1651-1652. 

Li, M., Tian, A. Enantioselective reduction of 3,3-dimethyl-butanone-2 with borane catalyzed by oxazaborolidine. Part 1. Quantum chemical computations on the structures and properties of catalyst and catalyst-borane-ketone adducts. THEOCHEM 2001, 544, 25-35. 

Keywords Hydroboration, Ketone, Reduction, Oxazaborolidine, Oxazaphospholidine, Borane, Borohydride... 

The borane complex 1, as an important intermediate responsible for the enan-tioselectivity of ketone reductions, is a remarkably stable sohd. An alternative... 

The structurally more rigid (S)-prolinol-based amino alcohol was introduced early in the study of borane reductions [18]. Sterically more hindered ox-azaborolidines 4 (Fig. 1) based on (S)-(-)-diphenylhydroxymethylpyrrolidine have been prepared by Corey [23,25]. These catalysts have been widely used for the borane reduction of various kinds of ketones. After these successful results had appeared for asymmetric ketone reduction, several oxazaborohdines (Fig. 1) were prepared. Many of them were successfully used in the reduction of aromatic ketones. Selected results of enantioselective borane reduction using various oxazaborohdines are shown in Scheme 4. The table to this scheme shows only the data obtained from the reduction of acetophenone as a representative aromatic ketone. In most cases, high enantioselectivity is obtained in the nearly quantitative yield. 

Instead of amino alcohols, enantiopure P-hydroxysulfoximines are also efficient chiral auxiliaries for the ketone reduction with borane [110]. Treatment of P-hydroxysulfoximine 72 with borane would form a boron-containing six-mem-bered heterocycle as a catalyst as shown in Scheme 16. The mechanism may be analogous to that for the oxazaborolidine reduction. a-Haloacetophenone and... 

Another chirally modified Lewis acid catalyst used in the borane reduction is the chiral lanthanum alkoxide [114]. The reaction of lanthanum triisopropoxide with enantiopure binaphthol gave a catalyst system for the borane reduction of ketones. Reduction of 6 -methoxy-2 -acetonaphtone gave the corresponding secondary alcohol in 100% yield with 61.8% ee (S) [114]. 

Table 7.2. Examples of ketone reductions mediated by oxazaborolidines. The Cat. column refers to the catalysts in Figure 7.2. The reductant is borane, unless otherwise noted. For entries 3 and 9, the product may spontaneously cyclize. The products of entries 16 and 17 are primary amines.

Scheme 7.5. Alpine-borane method of asymmetric reduction, (a) Preparation of Alpine-Borane . (b) Reduction of deuterio benzaldehyde [52], (c) Reduction of propargyl ketones...

The origin of the enantioselectivity has been examined using semiempirical (AMI) computations. " The main differences in stability arise at the stage of formation of the borane-ketone complex, where the boron changes from sp to sp hybridization. The boron substituents introduce additional steric compressions. Table 2.6 gives some typical results for enantioselective reduction of ketones. 

Poly-L-leucine and a polymeric BINOL the epoxidation of enones. Poly-L-leucine imni An air- and moisture-stable ionic liquid in. hiral (salen)Mn(III) complexes that are used i Ketone reductions. Corey s oxazaboroh virane reduction. A cheap borane source for tl. ilso modifications, for example, using alunui jerivative 85." ... 

Long-range mediation by achiral boronate (IJ-asymmetric induction) in ketone reduction by borane is feasible. Enantioselective reduction of imines with stoichiometric quantities of a cyclic dialkoxyborane prepared from tartaric acid has been reported. 

Reduction of aldehydes and ketones is possible with borane. Stereoselective reduction of ketones is possible when a heteroatom is located a- or p- to the carbonyl group. Treatment of a (3-hydroxy-ketone with catecholborane results in the selective formation of the syn 1,3-diol product (7.94). The borane reacts preferentially with the alcohol to release hydrogen gas and to form the boronic ester 107. A second equivalent of the borane then effects the reduction to give the syn diastereomer. For the preparation of the anti diastereomer, triacetoxyborohydride can be used (see Scheme 7.86). 

The intermediate formed in the borane (B2H6) reduction of aldehydes and ketones. Hydrolysis produces the corresponding alcohol. See this Chapter (Reduction). 

Midland and coworkers [13,14] achieved the reduction of sterically less congested propargyl ketones with AIpine-Borane. The reduction is accomplished using 2 equiv of 0.5-M solutions of AIpine-Borane (Table 26.11) [14]. Terminal acetylenic ketones and acetylenic ketoesters are completely reduced after 8 h at room temperature. Internal acetylenic ketones require 1-4 days at room temperature for complete reductions. The optically active chromanyl substrates (entries 7, 8) yield diastereomeric alcohols with (R,R) R,S) ratios of 85 15 for internal and 91 9 for the terminal acetylenes with the AIpine-Borane derived from (-i-)-a-pinene of 100% ee. The reagent obtained from pure (-)-a-pinene affords 18 82 ratio of the two diastereomeric internal propargylic alcohols. 

---