Catalytic asymmetric reduction of ketones

One of the simplest transformations you could imagine of a prochiral unit into a chiral one is the reduction of a ketone. Although chiral auxiliary strategies have been used to make this type of reaction asymmetric, conceptually the simplest way of getting the product as a single enantiomer would be to use a chiral reducing agent—in other words, to attach the chiral influence not to the substrate (as we did with chiral auxiliaries) but to the reagent. We need an asymmetric version of NaBH₄.

One of the more widely used solutions to this challenge is the chiral borohydride analogue invented by Itsuno in Japan and developed by Corey, Bakshi, and Shibata. It is based on a stable boron heterocycle made from an amino alcohol derived from proline (see the box below for the synthesis), and is known as the CBS catalyst after its developers. The active reducing agent is generated when the heterocycle forms a complex with borane. Only catalytic amounts (usually about 10%) of the boron heterocycle are needed because borane is sufficiently reactive to reduce ketones only when complexed with the nitrogen atom. The rest of the borane just waits until a molecule of catalyst becomes free.

CBS reductions are best when the ketone’s two substituents are well-differentiated sterically—just as Ph and Me are in the example above. The reaction works because the heterocyclic catalyst brings together the borane (which complexes to its basic nitrogen atom) and the carbonyl compound (which complexes to its Lewis-acidic boron atom). Complexation activates both partners towards reaction: donating electron density to the borane is essential to persuade it to transfer hydride, and withdrawing electron density from the carbonyl group makes it electrophilic enough to react with a weak hydride source. The hydride is delivered via a six-membered cyclic transition state, with the enantioselectivity arising from the preference of the larger of the ketone’s two substituents (RL) for the pseudoequatorial position on this ring.

Until recently, the CBS reagent was one of the most commonly used asymmetric reducing agents for ketones. But in the early years of the 21st century a new reaction has taken over that role—one in which the job of bringing together the ketone and the reducing agent is taken by an atom of ruthenium. The ruthenium is added as Ru(II) in a 16-electron complex (see p. 1116) with an aromatic compound such as 1,3,5-trimethylbenzene (known as mesitylene). A chiral ligand is needed—the diamine derivative shown here is best. Only very small amounts (often << 1%) of the catalyst and ligand are required, which is a good thing as both are much more expensive than the reagents in the CBS reduction. The reducing agent itself can be hydrogen or, more conveniently, a more easily handled source of hydrogen atoms such as isopropanol (which gets oxidized to acetone) or formic acid (which gets oxidized to carbon dioxide). Here’s a typical example; we will explain how it works shortly.

Ruthenium is one of a select group of transition metals (Pd, Ru, Rh, Cu, Os, and Ti being the others) which play an important role in asymmetric catalysis. The key to their success is the transition metal coordination chemistry we looked at in the last chapter: the metals can act as coordination sites for substrates, and by using other ligands which are chiral and enantiomerically pure, the reactions they catalyse can be made to take place in an asymmetric environment. The ruthenium-catalysed reduction of ketones starts with coordination of the tosyl-diamine ligand ((S,S)-N-toluenesulfonyl 1,2-phenylenediamine, or ‘TsDPEN’) to the ruthenium metal. This is a 16-electron complex, and can be reduced by formic acid to an 18-electron ruthenium hydride.

Now comes the reduction. Provided the ketone approaches the ruthenium complex in the right orientation, with the smaller methyl group tucked in under the ruthenium and the larger aryl group pointing away from the bulky ligands, the 18e complex can transfer to the carbonyl group simultaneously H− from Ru and H+ from the protonated nitrogen. The chiral ligand means that the alcohol is formed as a single enantiomer, and the ruthenium catalyst is regenerated.

The reduction shown below is particularly important because it generates a late inter mediate in the industrial synthesis of the anti-asthma drug montelukast (Singulair). Several methods have been used, but in 2008 chemists at the Croatian pharmaceutical company Pliva patented a method using the ruthenium catalyst with a derivative of TsDPEN as a ligand to gives the product in 83% yield and 99.8% ee on a scale of several kilograms.

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المزيد

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المزيد

مواضيع ذات صلة

Chiral reagents

Enantiomeric excess

Alkylation of enolates

Resolution can be used to separate enantiomers

Nature is asymmetric

Palladium catalysis in the total synthesis of a natural alkaloid

Alcohols and amines as intramolecular nucleophiles

Oxypalladation and the Wacker oxidation

Alkenes coordinated to palladium (II) are attacked by nucleophiles

Palladium-catalysed amination of aromatic rings

Intramolecular alkylations make rings

Vinyl epoxides provide their own alkoxide base