Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites

Abstract

Desymmetrization by phosphorylation represents a promising method with potential impact in many different areas of research. C2-Symmetric phosphoramidites have been used to desymmetrize myo-inosi- tol derivatives by functionalization at different positions. With this method, 1:1 mixtures of diastere- omers are obtained that can be separated subsequently. In this work, activation of a C2-symmetric phosphoramidite is achieved by addition of pentafluorophenol (PFP) and leads to a reactive PFP phos- phite, which can then be coupled to protected myo-inositol derivatives with reactive OH groups at the 1, 3, 4 and 6 positions. This strategy enhances the diastereoselectivity of the coupling reaction with a pre- ference towards phosphitylation at position 6 (up to 3:1) or position 3 (up to 2:1). The concept of atten- uative activation of phosphoramidites via in situ generated pentafluorophenol phosphite triesters is thus proven in these studies. It is further shown that Lewis–Acid catalysis enhances the rate of phosphite tri- ester coupling without affecting the diastereoselectivity. This novel strategy improves access to different phosphorylated myo-inositol derivatives and will thus enable further studies into the function of these important intracellular second messengers.