New synthetic path to potential diabetes drug

A new study has revealed a new synthetic route to potential medicines for type 2 diabetes.

Aryl alkyl ethers are important structural motifs found in many biologically active compounds. Therefore, stereoselective etherification is a highly important synthetic operation in the preparation of drug candidates. However, very few enantioselective methods have been described for the synthesis of chiral tertiary aryl ethers.

Researchers at Toyohashi Tech have found that the SN2 reaction of alpha-chloro-beta-keto esters with phenols proceeded smoothly despite the fact that the reaction occurred at a tertiary carbon.

They previously reported the highly enantioselective chlorination of beta-keto esters with a chiral Lewis acid catalyst. Thus, in the two investigations, they have successfully demonstrated the enantioselective phenoxylation of beta-keto esters. The novel presented method allows the synthesis of alpha-aryloxy-beta-keto esters with high enantioselectivity.

Etherification by the SN2 reaction is an older synthetic method called Williamson ether synthesis, but very few researchers have succeeded in conducting this reaction with tertiary halides, said researcher Kazutaka Shibatomi, adding that this is the first example of the enantioselective synthesis of alpha-aryloxy-beta-keto esters that would be useful synthetic intermediates for new drug candidates.

Using this method, the researchers demonstrated the synthesis of some biologically active compounds, such as a GPR119 agonist and a PPAR modulator, for the potential treatment of type 2 diabetes. The researchers expect that the present method will also be helpful in preparing other types of synthetic drugs.

The study appears in Chemistry - A European Journal.