Utilization of tetrametaphosphate anhydride for the synthesis of disubstituted tetraphosphates, terminally modified nucleoside 5'-pentaphosphates, and beyond
Name
1192966259-MIT.pdf
Size
62.76 MB
Format
Adobe PDF
Checksum (MD5)
da13c4b32adb914c8cf3c712f59cbb7a
Author(s)
Kim, Hyehwang.
Advisor(s)
Christopher C. Cummins.
Date Issued
2020
Publisher
Massachusetts Institute of Technology
Abstract
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.
Description
Thesis: S.M., Massachusetts Institute of Technology, Department of Chemistry, May, 2020
Cataloged from the official PDF of thesis.
Includes bibliographical references (pages 111-114).
Subjects
Chemistry.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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