Oxazaborolidine, 5-methylated

The oxazaborolidines are easily prepared by heating ephedrine with borane dimethyl sulfide or the appropriate boronate ester. The aluminum reagent C is obtained by mixing ephedrine and trimethylaluminum. Borolidinc A is superior to its methyl derivative B and to the aluminum analog C. The diastereomeric borolidine obtained from borane and (S,S)-pseu-doephedrine failed to show any cnantioselectivity25. A variety of aromatic aldehydes can be enantioselectively alkylated in the presence of A, however, with heptanal the enantioselectivity is poor25. 

Another soluble polymer-enlarged catalyst was synthesized and tested by Wandrey et a/.[57] The catalyst was prepared by a coupling of an oxazaborolidine via a hydrosilylation reaction to a methyl hydrosiloxane-dimethylsiloxane copolymer (Figure 4.40). The catalyst was used in the enantioselective borane reduction of ketones. 

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%... 

CBS-catalyst1 01 B-methyl oxazaborolidine (prepared from (R)-2-(diphenyl-hydroxy-methyl)pyrrolidine and methyl boronic acid)[31], 1.85 g, 6.7mmol... 

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 CBS-catalyst [(S)-2-methyl-CBS-oxazaborolidine] (S)-5 (1.0 M in toluene) (The CBS catalyst is named after Corey, Bakshi, and Shibata) and the borane-THF complex (1.0 M in THF) were obtained from Aldrich Chemical Co., Inc. and used as received. THF was distilled from potassium directly before use. 

Triphenylphosphine Phosphine, triphenyl- (8,9) (603-35-0) (S)-2-Methyl-CBS-oxazaborolidine (CBS named after Corey, Bakshi, Shibata) ... 

The chiral reduction of phenacyl chloride (2) was run using either the methyl- or methoxy- oxazaborolidine (3) as the catalyst. After optimization of the reaction... 

S -Methyl lactate gives a poor ee in hydroboration of acetophenone, but ZnCl2 raises it.322 A molecular orbital method has looked at the enantioselectivities associated with four oxazaborolidine catalysts acting on phenyl methyl ketone.323 0>... 

Apart from the conventional transesterification and acid base reaction protocols mentioned above, oxazaborolidines could also be synthesized by a facile [3+2] cycloaddition of the Ar-oxidc 339 with 5-methyl methylidene borane 338 (Equation 15) <2004ZFA508>. 

The oxazaborolidine is finally made by heating diphenylprolinol (4) under reflux with a suitable alkyl(aryl)boronic acid or, better, with the corresponding boroxine in toluene in the presence of molecular sieves—the water can also be removed by azeotropic distillation. According to the literature, methyl-oxazaborolidine (Me-CBS) can be either distilled or recrystallized. The key point is that the catalyst must be free from any trace of water or alkyl(aryl)boronic acid because those impurities decrease enantioselection. 

Oxazaborolidines were developed for reduction of carbonyls and were shown to be of value in the reduction of imines. 8 5-Hydrogen oxazaborolidines were prepared in situ from 1 and BH3 THF (tetrahydrofuran), whereas stock solutions of 5-methyl oxazaborolidines were obtained by reaction with trimethylboroxinc. ... 

Researchers at Sepracor later disclosed the use of a new class of chiral oxazaborolidines derived from r/. v-aminoindanol in the enantioselective borane reduction of a-haloketones.6,7 The 5-hydrogen oxazaborolidine ligand 10 was prepared in situ from d,v-aminoindanol 1 and BH3 THF.8 Stock solutions of 5-methyl oxazaborolidine 11-16 were obtained by reaction of the corresponding N-alkyl aminoindanol with trimethyl boroxine.6,7 5-Methyl catalyst 11 was found to be more selective (94% ee at 0°C) than the 5-hydrogen catalyst 10 (89% ee at 0°C), and enantioselectivities with 11 increased at lower temperatures (96% ee at -20°C). The catalyst structure was modified by introduction of A-a I kyI substituents. As a general trend, reactivities and selectivities decreased as the steric bulk or the chelating ability of the A -alkyl substituent increased (Scheme 17.4). 

In 1987, Corey and co-workers proved that highly enantioselective reduction of ketones could be achieved by using stoichiometric borane in the presence of catalytic amounts of the oxazaborolidine 28a11 (Scheme 4.3j). Compound 28a, synthesized by heating (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine at reflux in THF with 3 equivalents of BH3 THF, shows excellent catalytic activity for the asymmetric reduction of acetophenone and other ketones. The B -methylated analog 28b was later synthesized to improve the air and moisture sensitivity associated with 28a. The third analog, 28c, with a 2-naphthyl substituent on the oxazaborolidine ring, has proven to be the best to afford the alcohol 29 with superb levels of enantioselectivity. 

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... 

Starting with quinone 180, which was obtained by methylation of hydroxyqui-none 169, the oxazaborolidine-catalyzed intermolecular Diels-Alder reaction with butadiene was conducted at —50°C in toluene. Within 48 hours, 99% of the starting material was converted into adduct 171 in 99% optical purity (Scheme 18). 

For example, (S)-2-methyl-CBS-oxazaborolidine binds reversibly with diborane to form the reactive reducing species 1.64. Coordination of the ketone oxygen with the Lewis acidic boron orients and activates the carbonyl group for hydride transfer to its si face. The... 

Enantioselective reduction of ketones by boranes and an enantiomeric catalyst oxazaboro-lidine (the CBS catalyst) is known as the Corey, Bakshi and Shibata method . Both enantiomers of 2-methyl-CBS-oxazaborolidine (6.52 and 6.53) are used for the reduction of prochiral ketones, imines and oximes to produce chiral alcohols, amines and amino alcohols in excellent yields and enantiomeric excesses. 

Ac = Acetyl acac = Acetylacetonate bda = Benzylidene-acetone BINOL = l,l -bi-2-naphthol Bn = Benzyl brsm = Yield based on recovered starting material Bu = Bntyl CAN = Ceric anunonium nitrate CBS = Corey/Bakshi/Shibata catalyst [(+) or (—)-(S)-2-methyl-oxazaborolidine] COD = Cyclo-l,5-octadiene COT = Cyclooctatetraene Cp = Cyclopentadienyl Cp = Penta-methylcyclopentadienyl Cy = Cyclohexyl DCC = Dicy-clohexylcarbodiimde DMF = Ai,A-dimethylformainide DMPU = l,3-dunethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidin-one DMSO = Dimethylsnlfoxide dppe = Diphenylphosp-hinoethane dr = Diastereomer ratio dppm = Diphenylphos-phinomethane E = Electrophile ee = Enantiomeric excess EHMO = Extended htickel molecular orbital Et =... 

Asymmetric Borane Reduction. The reaction of ATBH with trimethylboroxine by refluxing in toluene affords the chiral B-methyl oxazaborolidine in high yield (eq 2) This oxaz-aborolidine can serve as an efficient catalyst for the asymmetric borane reduction ofprochiral ketones (eq 3). The corresponding chiral secondary alcohols are obtained in high yields with good enantioselectivities. 

Problems with the preparation and stability of oxazaborolidine (6) led to the development of a series of B-substituted ox-azaborolidines derived from diphenylprolinol. The B-methyl substituted oxazaborolidine (9a) was first prepared (eq 5) by reaction of diphenylprolinol (1) with methylboronic acid under dehydrating conditions (toluene at 23 °C in the presence of 4 X molecular sieves or toluene at reflux using a Dean-Stark trap) followed by vacuum distillation (0.1 mmHg, 170°C). Based on NMR evidence, the product (mp 74-87 °C) was reported to be a mixture of monomer and dimer. The corresponding B-butyloxazaborolidine (9c), prepared in a similar manner from n-butylboronic acid, was also reported to be a mixture of monomer and dimer. Subsequent investigations demonstrated that the reported dimers were in fact the intermediate (8) and the more stable disproportionation product (10) (eq 6). Furthermore, the presence of (8) or (10) was demonstrated to be deleterious to the enantioselectivity of the catalyst. ... 

Enantioselective Reduction ofa,P-Ynones. Oxazaborolidine ligands 1 are among the most effective catalysts for the enantioselective reduction of ketones to secondary alcohols. Substitution of the methyl or butyl group on boron by a trimethylsilylmethyl group led to a much improved catalyst for the catecholborane mediated reduction of a, 3-ynones. For example, the enantioselectiv-ities for the reduction of an a, 3-ynone was improved from 60% to 98.5% when the nature of the R group was modified (eq 1). ... 

As far as the stereochemical course of the reaction is concerned, the configuration of the emergent stereocenter may be explained in terms of the mechanism proposed by Corey et al. for similar oxazaborolidine mediated reactions. Thus, the transition state operates such that the bigger group (Rl) is located remotely from the methyl group on the boron atom (eq 2). 

Oxazaborolidines derived from proline (3) (see a,a-Diphenyl-2-pyrrolidinemetha not) and valine (1 R = i-Pr) (see 2-Amino-3-methyl-1,1-diphenyl-1-butanol) have received the most attention. 

Enantioselective Reduction of Imines and Ketoxime O-Ethers. In addition to the reduction of prochiral ketones, chiral oxazaborolidines have been employed as enantioselective reagents and catalysts for the reduction of imines (eq 11) and ketoxime O-ethers (eq 12) - to give chiral amines. It is interesting to note that the enantioselectivity for the reduction of ketoxime O-ethers is opposite that of ketones and imines. For more information, see 2-Amino-3-methyl-l,l-diphenyl-I-butanol. 

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