Oxa-Michael-based divergent synthesis of artificial glutamate analogs

Herein we report stereoselective generation of two skeletons, 1,3-dioxane and tetrahydropyranol, by oxa-Michael reaction as the key reaction from delta-hydroxyenone. The construction of the 1,3-dioxane skeleton, achieved through hemiacetal formation followed by oxa-Michael reaction from delta-hydroxyenone, was exploited to access structurally diverse heterotricyclic artificial glutamate analogs. On the other hand, formation of a novel tetrahydro-2H-pyranol skeleton was accomplished by the inverse reaction order: oxa-Michael reaction followed by hemiacetal formation. Thus, this study succeeded in showing that structural diversity in a compound collection can be acquired by interchanging the order of just two reactions. Among the skeletally diverse, heterotricyclic artificial glutamate analogs synthesized in this study, a neuronally active compound named TKM-50 was discovered in the mice in vivo assay.