Oxazaborolidine-catalyzed enantioselective reduction

The oxazaborolidine-catalyzed enantioselective reduction of aryl alkyl ketones was used in the asymmetric synthesis of the naturally occurring molecule (15 )-(—)-salsolidine 4119 (Scheme 4.3o). The ketone 42 underwent oxazaboroli-dine-mediated reduction to furnish the alcohol 43 in excellent yield and greater than 95% ee. The alcohol 43 was then coupled with the reagent 44 under Mit-sunobu conditions to produce the aminoacetal 45. 

In many stereoselective reactions, the effect of temperature on the selectivity is as expected, with better results being obtained at lower temperature. A lower tempertaure is often required to increase the selectivitty. From the practical point of view, one of the most attractive feature of this enantioselective reduction is that excellent enantioselectivity is obtained at a relatively high temperature such as room temperature. In some cases, the selectivity of the oxazaborolidine catalyzed borane reduction increases with increasing temperature until an optimal range is reached (30-50 °C) where the selectivity then begins to decrease [76]. Interpretation of this phenomena is not so easy. The amount of catalyst dimer that exists in a temperature-dependent equiUbrium with the monomeric form, might have an effect on the selectivity. 

In the oxazaborolidine-catalyzed borane reduction of ketones, the effect of additives has been investigated. For example, addition of triethylamine was found to improve the enantioselectivity in the stoichiometric reduction [77]. Some alcohols, e.g., f-PrOH, also efficiently enhanced the enantioselectivity of the reduction [78]. When the stoichiometric amount of the oxazaborolidine was used. 

The term CBS-reduction refers to the enantioselective, oxazaborolidine-catalyzed borane reduction for a review, see Corey EJ, Helal C (1998) Angew Chem 110 2093 Angew Chem Int Ed Engl 37 1986... 

The enantioselective reduction of ketones has become a key reaction not only for the production of chiral alcohols, but for the production of fimctionalized compounds in general, thanks to the versatility of the hydroxyl fimctionality. The oxazaborolidine-catalyzed borane reduction of ketones [2] has become an important reaction due to the fact that the stereochemistry of the alcohols can be predicted and because of the wide substrate acceptance of this catalytic system (it works with aromatic as well as with aliphatic ketones). Among all the known oxazaboroUdine catalysts, the proline-based one is very interesting not only because it is one of the most selective catalysts, but also because another related reagent, the 4-hydroproline, is commercially available and possesses a functional group which could be used for the linkage to a polymer. 

Gajda T (1994) Enantioselective synthesis of diethyl 1-hydroxyalkylphosphonates via oxazaborolidine catalyzed borane reduction of diethyl a-ketophosphonates. Tetrahedron Asym 5 1965-1972... 

A modified oxazaborolidine 2 catalyzing the enantioselective reduction of acetophenone or tetralone with borane proved to give ttn values in the same order of magnitude [10, 11]. Using a special hydroxyproUne-based polymer-enlarged oxazaborolidine 3, a ttn of 1400 for the reduction of tetralone was achieved (Fig. 3.1.3, 3) [5, 12]. 

Reduction of ketones. Merck chemists3 have used oxazaborolidine-catalyzed reduction of a ketone for introduction of chirality in a synthesis of MK-927 (4), a carbonic anhydrase inhibitor. They found that even traces of water decreases the enantioselectivity in reductions of 2. Highest enantioselectivity (98 2) is obtained by... 

The organocatalytic enantioselective reduction of C=C, C=0, and C=N double bonds is a relatively young area for which many new and exciting developments can be expected in the near future. Hantzsch esters are useful organic hydrides, and a recent review has summarized the results obtained to date in organocataly-sis [27]. The case of silicon hydrides is convenient for imine or ketone reductions, as a chiral base can act as an organic catalyst. The asymmetric reductions of ketones catalyzed by oxazaborolidines and pioneered by Itsuno [28] and Corey [29] could not be included in this chapter. 

Recently, Katz employed oxazaborolidine (2) to catalyze the enantioselective reduction of ketone (7) (eq 6). The resultant carbinol was used for the synthesis of optically active helical metallocene oligimers. ... 

Enantioselective Reduction of Oxime 0-Ethers. In addition to the reduction of prochiral ketones, oxazaborolidine (3) has been used (both stoichiometrically and catalytically with borane-THF) to catalyze the enantioselective reduction of prochiral ketoxime O-ethers to the corresponding amine (eq Unlike the ketone reduction described above, the... 

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-... 

Oxazaborolldines have emerged as important reagents for the enantioselective reduction of a variety of prochiral ketones. CBS reduction (chiral oxazaborolidine-catalyzed reduction)of unsymmetrical ketones with diphenyl oxazaborolidine in the presence of BH3 proceeds catalytically to provide alcohols of predicable absolute stereochemistry in high enantiomeric excess. 

E.J. Corey and co-workers synthesized the cdc25A protein phosphatase inhibitor dysidiolide enantioselectively. In the last phase of the total synthesis, the secondary alcohol functionality of the side-chain was established with a highly diastereoselective oxazaborolidine-catalyzed reduction using borane-dimethylsulfide complex in the presence of the (S)-6-methyl CBS catalyst. Finally, a photochemical oxidation generated the y-hydroxybutenolide functionality. This total synthesis confirmed the absolute stereochemistry of dysidiolide. 

Li, M., Tian, A. Enantioselective reduction of 3,3-dimethyl-butanone-2 with borane catalyzed by oxazaborolidine. Part 1. Quantum chemical computations on the structures and properties of catalyst and catalyst-borane-ketone adducts. THEOCHEM 2001, 544, 25-35. 

The third approach to obtain diarylmethylpiperazine derivatives uses the highly stereospecific chiral oxazaborolidine-catalyzed reduction, using catecholborane as the reductant of the 4-bromobenzophenone chromium tricarbonyl complex, as described by Corey and Helal [59], followed by the stereospecific displacement of the hydroxyl benzyl group by the /V-substituted-piperazine [44]. As outlined in Scheme 2, Delorme et al. [44] used this approach for the enantioselective synthesis of compound 31, (+)-4-[ (aS)-a-(4-benzyl-l-piperazinyl)benzyl]-lV,lV-diethylben-zamide. Lithiation of the readily available benzene chromium tricarbonyl with n-BuLi in the presence of TMEDA in THF at —78 °C, followed by addition of... 

Enantioselective reduction of ketones by borane or catecholborane catalyzed by oxazaborolidine 3 (see 1st edition). 

Liao and Li enantioselectively synthesized and studied the antifungal activity of optically active miconazole and econazole. The key step was the enan-tioselective reduction of 2-chloro-l-(2,4-dichlorophenyl)ethanone catalyzed by chiral oxazaborolidine [10]. 

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%... 

Oxazaborolidine lb was used in an enantioselective route to (rans-2,5-diaryl-tetrahydrofurans.2 Reduction of the keto ester 3 with BH, catalyzed by lb furnishes... 

Enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. 

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... 

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