The Corey–Bakshi–Shibata reduction, commonly called the CBS reduction, is an enantioselective method for reducing prochiral ketones to chiral secondary alcohols. A prochiral ketone is an achiral ketone that becomes chiral when it is reduced. ^[1–4]

The main advantage of the CBS reduction is that it can produce one enantiomer of an alcohol preferentially over the other. Therefore, it is an important reaction in asymmetric synthesis, which aims to form one stereoisomer in greater amount than the others.

General Reaction

The reaction uses: ^[1,2]

• a chiral oxazaborolidine catalyst, known as a CBS catalyst; and
• a borane reducing agent, such as BH₃·THF or BH₃·SMe₂.

During the reaction, the C=O group of the ketone is reduced to a C–OH group, and the carbonyl carbon gains a hydrogen atom.

If the two groups attached to the carbonyl carbon, R¹ and R², are different, the carbon bearing the –OH group becomes a new stereogenic center. Therefore, two enantiomeric alcohols can, in principle, be formed. The chiral CBS catalyst makes the formation of one of these enantiomers more favorable.

Example

Consider the reduction of acetophenone. Acetophenone contains a planar carbonyl group. When the carbonyl group is reduced, its carbonyl carbon becomes attached to: ^[1,2]

• –OH
• H
• CH₃
• C₆H₅

Because these four groups are different, this carbon becomes a stereogenic center.

Reduction of acetophenone can therefore, in principle, produce either of the two enantiomers of 1-phenylethanol. However, in the CBS reduction, the chiral catalyst makes one reaction pathway more favorable than the other. As a result, one enantiomer is produced preferentially.

In the commonly illustrated reduction of acetophenone, an (S)-CBS catalyst system favors the formation of (R)-1-phenylethanol.

It is important not to interpret this example as a general rule that an (S)-CBS catalyst always produces an (R)-alcohol. The configuration of the major product depends on the substrate structure and its interaction with the chiral catalyst.

Mechanism

The CBS reduction is commonly explained using a simplified catalytic mechanism. ^[3,4]

The key role of the chiral CBS catalyst is to hold the ketone in a preferred orientation so that hydride is transferred more easily to one face of the carbonyl group than to the other.

Step 1: Coordination of Borane to the CBS Catalyst

The nitrogen atom of the CBS catalyst donates its lone pair to BH₃. This forms a catalyst–borane complex, thereby activating the borane for hydride transfer.

Step 2: Coordination of the Ketone

The oxygen atom of the ketone donates an electron pair to the boron atom within the oxazaborolidine ring of the CBS catalyst. The ketone is therefore held close to the coordinated borane. Because the CBS catalyst is chiral, the ketone can interact with it in different orientations. These orientations are not equally favorable.

One orientation is generally more favorable than the competing orientation, often because it experiences less steric hindrance. This preferred arrangement determines which face of the carbonyl group is more accessible to hydride transfer.

Step 3: Stereoselective Hydride Transfer

A hydride from a B–H bond of the coordinated borane is transferred to the carbonyl carbon. The transfer occurs through an organized cyclic arrangement, commonly represented as a six-membered transition state.

During this step:

• hydride is transferred to the carbonyl carbon;
• the C=O bond of the carbonyl group is converted into a C–O single bond in the resulting intermediate; and
• one face of the ketone is reduced preferentially.

Because the chiral catalyst favors one transition-state arrangement over the other, one alcohol configuration is ultimately formed in greater amount.

This is the origin of the enantioselectivity of the CBS reduction.

Step 4: Product Release and Catalyst Regeneration

Hydride transfer initially produces a boron-associated alkoxide or alkoxyborane species. The boron-containing product is released from the catalytic complex, and the CBS catalyst is regenerated to participate in another catalytic cycle. During the final hydrolytic workup, the boron-containing product is converted into the corresponding secondary alcohol.