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


Duss, Michael; Capolicchio, Samanta; Linden, Anthony; Ahmed, Nisar; Jessen, Henning J (2015). Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites. Bioorganic & Medicinal Chemistry, 23(12):2854-2861.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2015
Deposited On:12 Nov 2015 09:21
Last Modified:05 Apr 2016 19:30
Publisher:Elsevier
ISSN:0968-0896
Funders:Swiss National Science Foundation (Ambizione Grant PZ00P2_136816, Novartis (Postgraduate Fellowship
Publisher DOI:https://doi.org/10.1016/j.bmc.2015.03.023

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