Reduction of ketones, enantioselective

Trialkylboranes and dialkylchloroboranes are also useful for reduction of aldehydes and ketones.These reactions involve the coordination of the carbonyl oxygen to boron and transfer of a (3-hydrogen through a cyclic TS. 

Alpine-Hydride and NB-Enanatride are trade names of the Sigma Aldrich Corporation. M. M. Midland, A. Kazubski, and R. E. Woodling, J. Org. Chem., 56, 1068 (1991). 

In most cases, the enantioselectivity can be predicted by a model that places the smaller carbonyl substituent toward the isopinocampheyl methyl group.  

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. 

An even more efficient approach to enantioselective reduction of ketones is to use a chiral catalyst. One of the most successful is the oxazaborolidine D, which is 

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Table 5.5 gives some typical results for enantioselective reduction of ketones by alkylborohydrides and chloroboranes. 

Scheme 5.6. Enantioselective Reduction of Ketones Using CBS-Oxazaborolidine... 

The following reducing agents effect enantioselective reduction of ketones. Propose a transition structure that is in accord with the observed enantioselec-tivity. 

Groeger, H., Chamouleau, F., Orologas, N. et al. (2006) Enantioselective reduction of ketones with designer cells at high substrate concentrations highly efficient access to functionalized optically active alcohols. Angewandte Chemie-Intemational Edition, 45 (34), 5677-5681. 

Ferrocene-based complexes have some potential for the enantioselective reduction of ketones, but compared to other ligand classes this is relatively limited [3]. Rh complexes of bppfa, bophoz and josiphos are among the most selective catalysts for the hydrogenation of a-functionalized ketones (Table 25.9 Fig. 25.18, 30-32). Ru complexes of walphos and ferrotane are quite effective for... 

In summary, many attempts have been made at achieving enantioselective reduction of ketones. Modified lithium aluminum hydride as well as the ox-azaborolidine approach have proved to be very successful. Asymmetric hydrogenation catalyzed by a chiral ligand-coordinated transition metal complex also gives good results. Figure 6-7 lists some of the most useful chiral compounds relevant to the enantioselective reduction of prochiral ketones, and interested readers may find the corresponding applications in a number of review articles.77,96,97... 

Enantioselective reduction of ketones using n-arylsulfonyl oxazaborolidines... 

ENANTIOSELECTIVE REDUCTION OF KETONES USING N-ARYLSULFONYL OXAZABOROLIDINES... 

Chiral oxazaborolidines. Enantioselective reduction of ketones with a reagent prepared from BH, and the chiral vic-amino alcohol 1 (12,31) is now known to involve an oxazaborolidine. Thus BH3 and (S)-l, derived from valine, react rapidly in THF to form 2, m.p. 105-110°, which can serve as an efficient catalyst... 

Enantioselective reduction of ketones.1 The ability of diborane in combination with the vic-amino alcohol (S)-2-amino-3-methyl-l,l-diphenyl-l-butanol (12, 31) to effect enantioselective reduction of alkyl aryl ketones involves formation of an intermediate chiral oxazaborolidine, which can be isolated and used as a catalyst for enantioselective borane reductions (equation I). 

The enantioselective reduction of ketones has been reviewed (317 references). 

The applications of sodium acyloxyborohydrides, formed from sodium borohydrides in carboxylic acid media, are reviewed. ° Useful reviews of the stereoselective reduction of endocyclic C=N compounds and of the enantioselective reduction of ketones have appeared. ... 

The reduction of an unsymmetrical ketone creates a new stereo center. Because of the importance of hydroxy groups both in synthesis and in relation to the properties of molecules, including biological activity, there has been a great deal of effort directed toward enantioselective reduction of ketones. One approach is to use chiral borohydride reagents.92 Boranes derived from chiral alkenes can be converted to borohydrides, and there has been much study of the enantioselectivity of these reagents. Several of the reagents are commercially available. 

Scheme 5.4 shows some examples of enantioselective reduction of ketones using I. Adducts of borane with several other chiral /i-aminoalcohols are being explored as chiral catalyst for reduction of ketones.102 Table 5.6 shows the enantioselectivity of several of these catalysts toward acetophenone. 

The control of reactivity to achieve specific syntheses is one of the overarching goals of organic chemistry. In the decade since the publication of the third edition, major advances have been made in the development of efficient new methods, particularly catalytic processes, and in means for control of reaction stereochemistry. For example, the scope and efficiency of palladium- catalyzed cross coupling have been greatly improved by optimization of catalysts by ligand modification. Among the developments in stereocontrol are catalysts for enantioselective reduction of ketones, improved methods for control of the... 

Asymmetric addition of a dialkylzinc reagent to an aldehyde, catalyzed by a Lewis base or a Lewis acid, is a viable alternative to enantioselective reduction of ketones as means to prepare enantiomerically enriched alcohols like 605 and... 

IN SITU FORMATION OF LIGAND AND CATALYST APPLICATION IN RUTHENIUM-CATALYZED ENANTIOSELECTIVE REDUCTION OF KETONES... 

The complex of Me2Zn with (5, 5 )-ebpe, 107, has been applied successfully as catalyst in the enantioselective reduction of ketones by polymethylhydrosiloxane and combines excellent product yields with high ee values . Its structure comprises the iV,iV-chelate coordination of the ebpe ligand to the MeiZn unit (Figure 51). It is remarkable that in this case the two secondary amine functionalities are coordinated to zinc and leave the Zn—C bonds unaffected. Indeed, usually secondary amines undergo a fast deprotonation reaction with dialkylzinc compounds. 

Letondor, C., Humbert, N. and Ward, TR. (2005) Artificial metaUoenzymes based on biotin-avidin technology for the enantioselective reduction of ketones by transfer hydrogenation. Proc. Natl. Acad. Sci. U.S.A., 102, 4683-4687 Letondor, C., Pordea, A., Humbert, N., Ivanova, A., Mazurek, S., Novic, M. and Ward, TR. (2006) Artificial transfer hydrogenases based on the biotin-(strept)avidin technology Fine tuning the selectivity by saturation mutagenesis of the host protein. J. Am. Chem. Soc., 128, 8320-8328. 

The enantioselective reduction of ketones using oxazaborolidine-borane complexes is a useful synthetic route to chiral alcohols (equation 63). Additives such as simple alcohols have been found to enhance the enantioselectivity of the process, and the reaction has been used in the large-scale synthesis of an important drug with anti arrhythmic properties249. 

Reaction of achiral and chiral bis(oxazolines) (BOX) with catecholborane (CATBH) provides boron-BOXate complexes that can be used as catalysts in the enantioselective reduction of ketones. It has been shown that asymmetric transfer of the hydride ion from the boron atom of CATBH to the prochiral carbonyl is the rate-determining step of the catalytic reaction.314... 

The enantioselective reduction of ketones using borane and a chiral oxazaborolidine as catalyst (CBS Catalyst). Usually, MeCBS... 

Menthol catalyses the enantioselective reduction of ketones by NaBH4 in diglyme proton- and auto-catalytic possibilities are investigated, and trialkyl borate species generated during the reaction may also play a role in catalysis.302... 

A recoverable fluorous prolinol catalyst has been developed for enantioselective reduction of ketones. 309 ... 

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