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Synthesis of Densely Phosphorylated Bis‐1,5‐Diphospho‐ myo ‐Inositol Tetrakisphosphate and its Enantiomer by Bidirectional P‐Anhydride Formation
Author(s) -
Capolicchio Samanta,
Wang Huanchen,
Thakor Divyeshsinh T.,
Shears Stephen B.,
Jessen Henning J.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201404398
Subject(s) - enantiomer , chemistry , inositol , phosphorylation , sugar phosphates , kinase , stereochemistry , atropisomer , chemical synthesis , inositol phosphate , enantiopure drug , glycosylation , molecule , phosphate , biochemistry , organic chemistry , in vitro , enantioselective synthesis , receptor , catalysis
The ubiquitous mammalian signaling molecule bis‐diphosphoinositol tetrakisphosphate (1,5‐(PP) 2 ‐myo‐InsP 4 , or InsP 8 ) displays the most congested three‐dimensional array of phosphate groups found in nature. The high charge density, the accumulation of unstable P‐anhydrides and P‐esters, the lack of UV absorbance, and low levels of optical rotation constitute severe obstacles to its synthesis, characterization, and purification. Herein, we describe the first procedure for the synthesis of enantiopure 1,5‐(PP) 2 ‐myo‐InsP 4 and 3,5‐(PP) 2 ‐myo‐InsP 4 utilizing a C 2 ‐symmetric P‐amidite for desymmetrization and concomitant phosphitylation followed by a one‐pot bidirectional P‐anhydride‐forming reaction that combines sixteen chemical transformations with high efficiency. The configuration of these materials is unambiguously shown by subsequent X‐ray analyses of both enantiomers after being individually soaked into crystals of the kinase domain of human diphosphoinositol pentakisphosphate kinase 2.