Improved Route To Chiral Amines

A new reagent for ω-transaminase-catalyzed reactions could make it easier to convert ketones to chiral amines in research labs, and with additional development, the reaction might have commercial applications as well.

Many drugs and bioactive natural products feature chiral amines. One class of enzymes researchers use to synthesize them are the ω-transaminases, biocatalysts that convert prochiral ketones to corresponding optically pure amines. The reactions require an amine donor to contribute the amine group that appears in the product.

This kind of ω-transaminase-catalyzed chiral amine synthesis is already used in pharmaceutical manufacture. A few years ago, Merck & Co. in collaboration with biocatalyst maker Codexis developed a reaction catalyzed by an engineered ω-transaminase to replace a rhodium-catalyzed process for large-scale manufacturing of the commercial antidiabetes drug sitagliptin.

But ω-transaminase-catalyzed chiral amine synthesis reactions have drawbacks, including reaction inhibition by donor by-products and unfavorable equilibriums. So, to drive the reactions, large excesses of donor must be used and by-products removed.

To avoid these problems, Anthony P. Green and Nicholas J. Turner of the University of Manchester, in England, and Elaine O’Reilly of Manchester Metropolitan University now propose using o-xylylenediamine as the donor (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201406571). This donor doesn’t have to be used in excess because it is converted to an aromatic by-product that undergoes spontaneous polymerization to form a colored precipitate, which removes it from solution and appears to eliminate by-product inhibition.

The researchers used their reaction to aminate 4-fluorophenylacetone to a chiral amine with 93% yield and more than 99% enantiomeric excess.

Matthew D. Truppo, head of biocatalysis and continuous processing at Merck, in Rahway, N.J., says the new process “may help simplify some smaller-scale reactions that have particularly unfavorable equilibria.”

Biocatalysis specialist Wolfgang Kroutil of the University of Graz, in Austria, agrees. “Use of this amine donor is a rather clever idea” and will find use in lab-scale work, he says. But he predicts the reaction will not crack industrial drug production because the price of o-xylylenediamine is 600 times that of the currently favored donor, 2-propylamine.

O’Reilly says that the group’s “main goal now is to drive the cost of the process down further by using bulk-diamine donors that operate via similar mechanisms.”

Biocatalysis expert Uwe T. Bornscheuer of the University of Greifswald, in Germany, suggests another reason the donor might not be attractive for preparative-scale synthesis is that “at the end you have product and polymer sitting around in your flask or reactor,” which could make product isolation difficult.

But Kroutil notes that the reaction’s intensely colored precipitate will make it useful as a high-throughput screening tool. The colored precipitate can serve as an indicator for screening of libraries to identify ω-transaminase variants with desirable activity.