Oxazaborolidine catalyzed reduction

Treatment of 9 with 3-lithiofuran (3-bromofuran, nBuLi) affords a 1 1 mixture of diastereomeric carbinols, which are readily separated by silica gel chromatography. However, the undesired C-2 -epimer of 28 is efficiently converted to the other diastereomer by oxidation of the alcohol with Dess-Martin periodinane and subsequent stereoselective oxazaborolidine-catalyzed reduction to give the desired 2 -(/ )-carbinol exclusively. This recycling of the undesired 2 -(S)-epimer allows for the transformation of 9 to 28 in 95 % yield overall. 

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... 

In particular, reduction of unsymmetric ketones to alcohols has become one of the more useful reactions. To achieve the selective preparation of one enantiomer of the alcohol, chemists first modified the classical reagents with optically active ligands this led to modified hydrides. The second method consisted of reaction of the ketone with a classical reducing agent in the presence of a chiral catalyst. The aim of this chapter is to highlight one of the best practical methods that could be used on an industrial scale the oxazaborolidine catalyzed reduction.1 1 This chapter gives an introductory overview of oxazaborolidine reductions and covers those of proline derivatives in-depth. For the oxazaborolidine derivatives of l-amino-2-indanol for ketone reductions see Chapter 17. 

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. 

Oxazaborolidine-Catalyzed Reduction with Boron Hydride... 

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-... 

Table 1 Chiral Oxazaborolidine Catalyzed Reduction of Acetophenone and 1-Tetralone ...

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. 

Alagona, G., Ohio, C., Persico, M., Tomasi, S. Quantum Mechanical Study of Stereoselectivity in the Oxazaborolidine-Catalyzed Reduction of Acetophenone. J. Am. Chem. Soc. 2003, 125, 10027-10039. 

Reduction using boranes. A practical modification of the oxazaborolidine-catalyzed reduction of ketones with borane is to replace the trialkylborane component with trimethyl borate. For the reduction of (3-silyl and ( -stannyl enones the use of 80 is advocated. ... 

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... 

Barco, A., Benetti, S., Bergamini, P, De Risi, C., Marchetti, P, Pollini, G.P, and Zanirato, V., Diastereoselective synthesis of (l-arnino-a-hydroxy phosphonates via oxazaborolidine catalyzed reduction of P-phthahmido-a-keto phosphonates. Tetrahedron Lett., 40, 7705, 1999. 

Because of their biological activity, optically active a-hydroxyphosphonates have received increasing interest. Enantio-enriched dialkyl a-hydroxyphosphonates were obtained by the oxazaborolidine catalyzed reduction of a-ketophospho-nates with catecholborane (Scheme 11) [96]. 

An optimized procedure (in situ) for the oxazaborolidine-catalyzed reduction is disclosed. Several papers describe the access to propargylic alcohols,and it is interesting to note that strong remote steric effects are transmitted across the triple bond. ... 

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