Reductions also with oxazaborolidines

The reduction of dialkylketones and alkylaryl ketones is also conveniently accomplished using chiral oxazaborolidines, a methodology which emerged from relative obscurity in the late 1980s. The type of borane complex (based on (,V)-diphenyl prolinol)[39] responsible for the reductions is depicted below (10). Reduction of acetophenone with this complex gives (/ )-1 -phenylethanol in 90-95% yield (95-99% ee) [40]. Whilst previously used modified hydrides such as BiNAL-H (11), which were used in stoichiometric quantities, are generally unsatisfactory for the reduction of dialkylketones, oxazaborolidines... 

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

Addition of triethylamine to the oxazaborolidine reaction system can significantly increase the enantioselectivity, especially in dialkyl ketone reductions.79 In 1987, Corey et al.80 reported that the diphenyl derivatives of 79a afford excellent enantioselectivity (>95%) in the asymmetric catalytic reduction of various ketones. This oxazaborolidine-type catalyst was named the CBS system based on the authors names (Corey, Bakshi, and Shibata). Soon after, Corey s group81 reported that another fi-methyl oxazaborolidine 79b (Fig. 6-6) was easier to prepare and to handle. The enantioselectivity of the 79b-catalyzed reaction is comparable with that of the reaction mediated by 79a (Scheme 6-36).81 The -naphthyl derivative 82 also affords high enantioselectivity.78 As a general procedure, oxazaborolidine catalysts may be used in 5-10 mol%... 

New chiral oxazaborolidines that have been prepared from both enantiomers of optically active inexpensive a-pinene have also given quite good results in the asymmetric borane reduction of prochiral ketones.92 Borane and aromatic ketone coordinate to this structurally rigid oxazaborolidine (+)- or (—)-94, forming a six-membered cyclic chair-like transition state (Scheme 6-41). Following the mechanism shown in Scheme 6-37, intramolecular hydride transfer occurs to yield the product with high enantioselectivity. With aliphatic ketones, poor ee is normally obtained (see Table 6-9). 

An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most promising is the oxazaborolidine I, which is ultimately derived from the amino acid proline.96 The enantiomer is also available. A catalytic amount (5— 20 mol %) of this reagent along with BH3 as the reductant can reduce ketones such as acetophone and pinacolone in >95% e.e. An adduct of borane and I is the active reductant. 

Chromans with defined stereochemistry are accessible by manipulation of dihydrochromeno[3,2-b]azete-2,8-diones 26 which result from the cyclisation of azetidine-2-carboxylic chlorides 25 <99T5567> and also from chroman-4-ones via an initial enantioselective reduction by BHj in the presence of Coreyls oxazaborolidine <99T7555>. 

The use of oxazaborolidines as asymmetric reduction catalysts257 and the enantioselectivity of diphcnyloxazaborolidinc reduction of ketones have been reviewed.258 Large-scale practical enantioselective reduction of prochiral ketones has been reviewed with particular emphasis on the Itsuno-Corey oxazaborolidinc and Brown s 5-chlorodiisopinocampheylborane (Ipc2BCl) as reagents.259 Brown himself has also reviewed the use of Ipc2BCl.260 Indolinoalkylboranes in the form of dimers have been confirmed by 11B NMR as the products of the reduction of trifluoroacetylindoles by diborane.261... 

The oxazaborolidine-catalyzed reduction of 1,2-diketones (Equation (258)),1116-1120 1,2-keto-imines (Equation (259)),1121-1123 and 1,2-diimines (Equation (260))1124 provided optically active 1,2-diols, amino alcohols, and 1,2-diamines with both high enantiomeric and diastereomeric excess. The method can be also effective for (3- and y-analogs. 

The CBS reduction has also proven to be an efficient method for asymmetric reduction of a,ft-unsaturated enones14 and ynones15 (Scheme 4.31). The asymmetric reduction of alkynyl ketones affords propargylic alcohols 30 with high levels of enantioselectivity and in moderate to good yields. Optimized reaction conditions for the reduction are the use of THF at — 30° C, 2 equivalents of chiral oxazaborolidine 28b, and 5 equivalents of borane methyl sulfide complex. 

C. The reported procedure provides a practical preparation of (S)-tetrahydro-i-methyl-3,3-diphenyl-lH,3H-pyrrolo[i,2-c][l,3,2]oxazaboroie and conversion to its more stable borane complex.13 The oxazaborolidine-borane complex has also been prepared by treatment of a toluene solution of the free oxazaborolidine with gaseous fiborane followed by recrystallization from a dichloromethane-hexane bilayer.14 This nd other chiral oxazaborolidines have been used to catalyze the enantioselective eduction of prochiral ketones.15 The yield and enantioselectivity of reductions using catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13... 

For aryl ketones the Corey-Bakshi-Shibata (CBS) reduction using oxazaborolidines as catalysts for the boron hydride mediated hydrogenation is particularly useful, with maximum selectivities up to 99 % ee (see Scheme 4) [34]. The excellent review by Corey et al. [35] also shows clearly the power for chemo- and enantioselective reduction of purely aliphatic a,//-enones and -ynones only on the carbonyl group. In the re-... 

Several novel catalysts in which borohydride is complexed with a difiinctional chiral ligand have been developed and used for the enantioselective reduction of prochiral ketones to chiral alcohols. Corey-Bakshi-Shibatareduction (CBS reduction) is an organic reaction which reduces ketones enantioselectively into alcohols by using chiral oxazaborolidines and BHs-THF or catecholborane as stoichiometric reductants (CBS reagent, 1.64) (also see Chapter 6, section 6.4.2). 

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. ... 

However, also in this case enantio-selectivities never exceeded the values obtained with the oxazaborolidine in solution, probably because of diffusional limitations within the polymer support, which enhanced the contribution of the non-selective, direct borane reduction of the ketone. In spite of the rather low imprinting effects obtained in these initial attempts, we feel that this approach still represents a most interesting application of molecularly imprinted polymers in catalysis and deserves further attention in the near future. 

Chiral oxazaborolidine salts are useful catalysts not only for enantioselective reductions (i.e., CBS reduction), but also for promoting enantioselective D-A reactions. The cationic Lewis acids formed by reaction of chiral oxazaborolidines with triflic acid [TfOH] or trifluoromethanesulfonimide [(Tf)2NH] coordinate to dienophiles to direct subsequent cycloadditions in a highly controlled fashion. The D-A reactions using these chiral salts proceed in CH2CI2 under very mild conditions at temperatures as low as -95 °C (Table 9.4). ... 

The use of membrane reactors is favorable not only with respect to an increase in the total turnover number. In certain cases the selectivity can also be increased by applying high concentrations of the soluble catalyst together with making use of the behavior of a continuously operated stirred-tank reactor. Basically, this is also possible with a catalyst coupled to an insoluble support, but here the maximum volumetric activity is limited by the number of active sites per mass unit of the catalyst. This has been shown for the enantioselective reduction of ketones (eq. (2)) such as acetophenone 5 with borane 6 in the presence of polymer-enlarged oxazaborolidines 8 and 9 [65-67]. 

Some amino alcohols react with borane to generate oxazaborolidines, which have been mainly used in asymmetric reduction of ketones (Section 3.2.3) and imines (Section 3.3.1) [NNl, S3]. In addition, they can also perform some chemoselective reductions [IWl]. 

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... 

A study comparing asymmetric borane reductions of kctoxime ethers and /V-substituted ketimines mediated by selected chiral oxazaborolidines 8-14 has been carried out. The corresponding amines were obtained with up to 99% ee50-52. The enantioselective reduction of imines using chiral dialkoxyboranes has also been the subject of a study60. 

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