Oxazaborolidine borane reduction

Other S/N ligands have been investigated in the enantioselective catalytic reduction of ketones with borane. Thus, Mehler and Martens have reported the synthesis of sulfur-containing ligands based on the L-methionine skeleton and their subsequent application as new chiral catalysts for the borane reduction of ketones." The in situ formed chiral oxazaborolidine catalyst has been used in the reduction of aryl ketones, providing the corresponding alcohols in nearly quantitative yields and high enantioselectivities of up to 99% ee, as shown in Scheme 10.60. 

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. 

One common approach incorporates an oxazaborolidine-mediated catechol-borane reduction starting from a-ketophosphonates (146).155 The reaction proceeds with good yield and gives excellent ee (up to 99%). 

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). 

The reduction using oxazaborolidine borane needs to be done in anhydrous... 

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). 

Enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. 

Borane reduction catalyzed by chiral oxazaborolidines (CBS reduction, CBS = Corey, Bakshi, and Shibata) exhibits excellent enantio- and chemoselectiv-ity for a wide variety of ketonic substrates (Figure 1.27). This reaction was originally developed as a stoichiometric system consisting of diphenylvalinol and borane, ° but was later extended to a useful catalytic method. Because of the high efficiency of this reaction, many chiral oxazaborolidines have been synthesized from p-amino alcohols.Among them the prolinol-derived oxazaboro-lidine is one of the most widely used catalysts. ... 

Corey extended the utility of this catalytic hydroboration chemistry remarkably (38). Scheme 15 shows some examples of the highly en-antioselective asymmetric borane reduction of ketones. The well-designed chiral oxazaborolidines, which act as catalyst precursors, have... 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

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. 

A polymer-bound oxazaborolidine catalyst enantioselective borane reductions of ketones, Tetrahedron Asymm. 1995, 6, 2755-2766. 

Borane Reduction Catalyzed by Oxazaborolidines and Phosphorus-based Catalysts... 

Scheme 11.1 also summarizes other impressive examples of the performance of the CBS method [1-8]. Several excellent reviews on the CBS method have appeared recently [1, 2], and no detailed discussion of the development of the process or substrate scope shall be presented in this review. Please note, however, that the oxazaborolidine-catalyzed borane reduction of ketones is a prime example of bi-functional catalysis [2, 9] - as shown in Scheme 11.2, the current mechanistic picture involves simultaneous binding of both the ketone and the borane to the Lewis-acidic (boron) and Lewis-basic (nitrogen) sites of the catalyst A. In the resulting ternary complex B, the reaction partners are synergistically activated toward hydride transfer. 

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). 

After the identification of aprepitant as a clinical candidate, Merck invested considerable process research toward an improved synthesis of aprepitant, which culminated in the elegant manufacturing process shown in Scheme 6.21,22 The key step relies on displacement of a trifluoroacetate from intermediate 48 by the optically active alcohol intermediate 49. The synthesis of 49 was accomplished via an oxazaborolidine-catalyzed borane reduction of the corresponding acetophenone. Although the displacement resulted in an almost equal mixture of the two diastereomers 50 and 51, the desired diastereomer 50 could be recovered in high yield by base-catalyzed equilibration of the mixture and crystallization. Addition of p-fluorophenyl magnesium bromide followed by hydrogenolysis afforded the key intermediate 40, which can be readily converted to 1 as detailed in the previous synthesis. 

The oxazaborolidine-catalyzed borane reduction to prepare (R)-1 is an improvement over existing methods such as the p-chlorodiisopinocampheylborane reduction,6 and enzymatic resolution14 for several reasons. First, the reaction uses an easily obtained catalytic reducing agent that provides the chiral alcohol in 92% ee. Secondly, the reaction proceeds at a reasonable rate (6-8 hr) and affords the chiral alcohol (92% ee) In nearly quantitative yield (97%). Finally, the work-up, isolation and purification of the product is straightforward and requires no column chromatography, only bulb-to-bulb distillation and recrystallization, affording (R)-1 in 75% yield with 97% ee. In addition, the catalyst precursor, (S)-a,a-diphenylpyrrolidinemethanol. can be easily recovered in excellent yield. 

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... 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

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. 

Reaction of ATBH with trimethyl borate in THF presumably affords the B-methoxy oxazaborolidine, which effectively catalyzes asymmetric borane reduction of prochi-ral ketones. Thus the borane reduction of acetophenone with the reagent prepared in situ from 0.1 equiv of ATBH and 0.12 equiv of trimethyl borate provides... 

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. ... 

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. 

Oxazaborolidine catalyzed reductions are generally performed in an aprotic solvent, such as dichloromethane, THF, or toluene. When the reactions are run in a Lewis basic solvent, such as THF, the solvent competes with the oxazaborolidine to complex with the borane, which can have an effect on the enantioselectivity and/or rate of the reaction. The solubility of the oxazaborolidine-borane complex can be the limiting factor for reactions run in toluene, although this problem has been circumvented by using oxazaborolidines with more lipophilic... 

The mode of addition and the reaction temperature both affect the enantioselectivity of the reaction. The best results are obtained when the ketone is added slowly to a solution of the oxazaborolidine (or oxazaborolidine-borane complex) and the borane source, at as low a temperature that provides a reasonable reaction rate. This is in contrast to a previous report that indicated that oxazaborolidine-catalyzed reductions lose stereoselectivity at lower temperatures . With unsubstituted (R = H) oxazaboro-... 

COREY Enalioseleclive borane reduction Enanlioseleclive reduction o( ketones by borane or catecholborane catalyzed by oxazaborolidine 3... 

Oxazaborolidines have been found to be a unique catalyst for asymmetric borane reduction of ketones and imines [35,36]. Coordination of BH3 to the nitrogen atom of 24 serves to activate BH3 as a hydride donor and to increase the Lewis acidity of the boron atom (Eq. 9). The Lewis acidity of the boron atom in the oxazaborolidine plays an important role in the reduction. Several types of polymer-supported oxazaborolidine have been reported and are considered to be polymer-supported boron-based Lewis acids. 

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