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Japanese Chemists Achieve Enantioselective Phenoxylation of β-Keto Esters; Novel Method Allows Synthesis of α-Aryloxy-β-Keto Esters with High Enantioselectivity; Compounds Already Synthesized for Potential Treatment of 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 in Japan have now found that the SN2 reaction of α-chloro-β-keto esters with phenols proceeded smoothly, despite the fact that the reaction occurred at a tertiary carbon [1]. The scientists previously reported the highly enantioselective chlorination of β-keto esters with a chiral Lewis acid catalyst [2]. Thus, in the two investigations, the researchers have successfully demonstrated the enantioselective phenoxylation of β-keto esters. The novel presented method allows the synthesis of α-aryloxy-β-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 Associate Professor Kazutaka Shibatomi. “This is the first example of the enantioselective synthesis of α-aryloxy-β-keto esters, which would be useful synthetic intermediates for new drug candidates." Using this method, the researchers have already demonstrated the synthesis of some biologically active compounds, including a GPR119 agonist and a PPARγ (image) 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.

[English press release] [Japanese press release] [Chemistry-A European Journal abstract]

[1] Kazutaka Shibatomi, Manato Kotozaki, Nozomi Sasaki, Ikuhide Fujisawa, and Seiji Iwasa (2015). “Williamson ether synthesis with phenols at a tertiary stereogenic carbon: formal enantioselective phenoxylation of β-keto esters,” Chemistry - A European Journal, Article published online on August 18, 2015 before print, 10.1002/chem.201502042.
[2] Kazutaka Shibatomi, Yoshinori Soga, Akira Narayama, Ikuhide Fujisawa, and Seiji Iwasa (2012). “Highly enantioselective chlorination of β-keto esters and subsequent SN2 displacement of tertiary chlorides: a flexible method for the construction of quaternary stereogenic centers,” Journal of the American Chemical Society, 134(24): 9836-9839, 10.1021/ja304806j