Oxazaborolidine-borane complexes

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. 

During the addition, the oxazaborolidine-borane complex crystallizes. A slow addition of dry hexane favors the formation of larger crystals. 

The product is stored at room temperature protected from moisture. A nitrogen atmosphere is recommended for long term storage. Unlike the free oxazaborolidine that readily reacts with and is decomposed by atmospheric moisture, the oxazaborolidine-borane complex is significantly more stable, allowing it to be handled briefly in the open. 

The checkers observed gas evolution upon dissolution of the (S)-oxazaborolidine-borane complex in dichloromethane (CH2CI2) at room temperature. 

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... 

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. ... 

Diphenylprolinol (1) and borane-THF react in a multistep process to give the unsubstituted oxazaborolidine-borane complex (7) (eq 2). Formation of amine-borane complex (4) is exothermic, and this intermediate can be isolated as a stable crystalline solid. Subsequent conversion to oxazaborolidine (6) requires heating the THF solution under pressure (1.7 bar) at 70-75 °C for 48-72 h. Corey isolated and characterized free oxazaborolidine (6) as a solid (mp 107-124 °C), which was reported to be a mixture of monomer and dimer (NMR). Finally, addition of borane-THF to a solution of oxazaborolidine (6) affords oxazaborolidine-borane... 

A significantly more stable form of the catalyst is the crystalline oxazaborolidine-borane complex (ll). - This bo-rane complex is readily prepared from oxazaborolidine (9a) and Borane-Dimethyl Sulfide complex (BMS) (eq 9). 

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. 

Free oxazaborolidine (16), by itself, will not reduce ketones. Furthermore, (16) is not particularly stable, reacting with moisture (H2O), air (O2), unreacted amino alcohol, other alcohols, or, depending on the substituents, with itself to form various dimers. This instability is due to the strain of a partial double bond between nitrogen and boron (eq 4). Formation of the oxazaborolidine-borane complex (17) tends to release some of this strain. As such, (16) and (17) are generally prepared and used in situ without isolation in many cases, they have not been fully characterized. ... 

Substituted oxazaborolidines also react with borane (B2H6, H3B THF, or H3B SM62) to form an oxazaborolidine-borane complex (19) (eq 9). The oxazaborolidine-borane complex, by releasing the strain of the partial double bond between the ring boron and nitrogen, is more stable than the free oxazaborolidine, and in many cases exists as a stable crystalline solid. ... 

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-... 

These points will be further illustrated in three specific cases (1) reductions of carbonyl compounds by chiral oxazaborolidines-borane complexes ( 2.3), (2) reactions of carbonyl compounds with dialkylzinc reagents in the presence of chiral ligands ( 2.5.4), and (3) dihydroxylation of olefins by OSO4 in the presence of cinchona alkaloids ( 2.9). 

The oxazaborolidine-borane complexes reduce a wide variety of ketones (Table 1). Factors contributing to effective reduction have been delineated15,17. In particular, it is important that water be excluded from the reaction. The oxazaborolidine greatly accelerates the rate of reduction and it may be used in 5-10 mol% quantities. Below 4 mol% competing uncatalyzcd reduction begins to occur and the enantiomeric purity of the product decreases. 

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