What Is Corey-Bakshi-Shibata Reduction?
The Corey-Bakshi-Shibata Reduction (abbreviated as CBS Reduction) refers to the enantioselective reduction of ketones to secondary alcohols catalyzed by chiral oxazaborolidines. Compared with the earliest reported "one-pot" system, the Corey group developed a more efficient catalytic system (high enantioselectivity, high yield, high reaction rate), and the catalyst precursor can be recycled. They also used various experimental methods to isolate the real catalyst for the reduction and determine its structure, and then gave a rational mechanism analysis to predict the absolute stereochemistry of the product, laying the foundation for the subsequent development of the reaction. CBS reduction is highly praised for its predictability, wide substrate range and excellent stereo control, and can usually achieve more than 95% enantiomeric excess (ee).
- Reagents: Chiral oxazaborolidine catalysts [typically synthesized from β-amino alcohols (e.g., derived from proline or diphenylprolinol)]; Borane reducing agents (e.g., BH3·THF, BH3·SMe2, catecholborane).
- Reactants: Ketones (prochiral).
- Products: Chiral secondary alcohols.
- Reaction type: Enantioselective reduction.
- Related reactions: Noyori reduction, Brown hydroboration.
Fig 1. Schematic diagram of Corey-Bakshi-Shibata reduction and catalyst. [1]
Mechanism of CBS Reduction
- The first step of the CBS reduction reaction is that BH coordinates to the α face of oxazaborolidine1 and the Lewis basic N atom to form a cis-fused complex 2, in which the B-Me-2 structure has been confirmed by X-ray single crystal diffraction.
- The coordination mode in 2 not only activates BH3 into a negative hydrogen donor but also greatly enhances the Lewis acidity of the B atom in the ring, so that it combines with the carbonyl oxygen atom from the side with less steric hindrance (a) and forms a cis relationship with BH3 to produce the transition state structure 3.
- Then the coordinated BH3 and the electron-deficient carbonyl carbon undergo stereoelectronically favorable and face-selective intramolecular hydrogen transfer in a six-membered ring transition state to obtain the reduction product 4.
- The high efficiency observed in the experiment is due to the presence of dual activation factors in 2 and 3. There are two possible ways to regenerate the catalyst: 1 and borate ester are obtained through ring elimination; another molecule of BH3 and 4 are added to obtain a transition state structure containing a BH3 bridge, which is then decomposed into 2 and borate ester. Finally, a disproportionation reaction occurs to obtain a dialkoxyborane, which is hydrolyzed with acid to obtain an optically active secondary alcohol.
Fig 2. Schematic diagram of Corey-Bakshi-Shibata reduction mechanism. [1]
Progress of CBS Reduction
Since the Corey group developed B-Me analogs that are insensitive to air and water and have better catalytic performance, the structural modification of oxazolidinone catalysts has continued, mainly focusing on the following five aspects: oxazolidinone ring system, geminal diphenyl group, geminal diboron group, borane reducing agent, and catalyst preparation method.
The scope of applicable substrates has also been greatly expanded: aromatic (hetero)ketones, α, β-unsaturated ketones, dialkyl ketones, ketones containing metallocene ligands, trihalomethyl ketones, etc.
The accumulation of the above achievements has accelerated the synthetic application of CBS reaction, such as the preparation of optically active ligands, chiral building blocks and the synthesis of biologically active substances. As for the field of total synthesis of natural products, it is frequently used.
Application Examples of CBS Reduction
The CBS reduction has found widespread use in the total synthesis of natural products, pharmaceuticals, and other complex molecules. Its ability to introduce chirality with high enantioselectivity makes it a valuable tool for constructing complex stereocenters. Examples include the synthesis of various biologically active compounds, such as prostaglandins, terpenes, and alkaloids.
- Example 1: Shubhangi P. Bhoite et al. used Keck allylation, CBS reduction and Wacker oxidation synthesis strategies to achieve the enantioselective synthesis of alkaloids (+)-hygroline and (+)-pseudohygroline with high optical purity (98% ee). [2]
- Example 2: Sonia De Angelis et al. achieved a convenient enantioselective CBS reduction of aromatic ketones in a flow microreactor system. [3]
Fig 3. Synthetic examples via CBS reduction reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 124-127.
- Bhoite, Shubhangi P., et al. Tetrahedron letters, 2015, 56(32), 4704-4705.
- De Angelis, Sonia, et al. Organic & Biomolecular Chemistry, 2016, 14(18), 4304-4311.
