Utilization of tetrametaphosphate anhydride for the synthesis of disubstituted tetraphosphates, terminally modified nucleoside 5'-pentaphosphates, and beyond
Massachusetts Institute of Technology. Department of Chemistry.
Christopher C. Cummins.
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In this thesis, the use of tetrametaphosphate anhydride ([PPN]₂[P₄O₁₁]) for the synthesis of substituted tetrametaphosphates, disubstituted tetraphosphates, and [epsilon]-labelled nucleoside 5'-pentaphosphates was explored. Treatment of anion [P4₄O₁₁]²⁻ with phenol derivatives, primary and secondary amines, and phosphorus ylides under anhydrous conditions results in the corresponding substituted tetrametaphosphates. Further treatment of the resulting tetrametaphosphates with a second nucleophile such as hydroxide, amines, and nucleoside monophosphates results in ring opening to a linear tetraphosphate derivative bearing the two nucleophiles on each terminal end. This method was used for the synthesis of [epsilon]-fluorophore labelled nucleoside 5'-pentaphosphates, an important class of reagents for high-throughput DNA sequencing. The reaction between anion [P₄O₁₁]²⁻ and methylidene triphenylphosphorane yields a new tetrametaphosphate based ylide, which was shown to undergo the Wittig reaction with suitable aldehydes. One interesting example of such a Wittig reaction was between 2',3'-O-isopropylidene-5'-uridylaldehyde and the tetrametaphosphate ylide which led to a 3'-deoxy-3',4'-didehydronucleoside derivative. For the penta- and hexaphosphorylation of nucleosides, two new bicyclic phosphate anhydride compounds, [PPN]₃[P₅O₁₄] and [PPN]₄[P₆O₁₇], were synthesized. Although conditions for ring-opening anion [P₆O₁₇]²⁻ could not be found, it was found that anion [P₅O₁₄]³⁻ undergoes ring-opening with 4-methylumbelliferone in the presence of ZnCl₂ as a Lewis acid additive. The fluorophore-substituted pentametaphosphate intermediate was found to undergo further ring-opening with primary amines and nucleoside monophosphates to result in disubstituted pentaphosphates and [zeta]-fluorophore labelled nucleoside hexaphosphates, respectively.
Thesis: S.M., Massachusetts Institute of Technology, Department of Chemistry, May, 2020Cataloged from the official PDF of thesis.Includes bibliographical references (pages 111-114).
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology