Synthesis of α,δ-Disubstituted Tetraphosphates and Terminally-Functionalized Nucleoside Pentaphosphates
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nihms-1764155.pdf
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Accepted version
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Author(s)
Shepard, Scott M
Kim, Hyehwang
Bang, Qing Xin
Alhokbany, Norah
Cummins, Christopher C
Date Issued
December 29, 2020
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Synthesis of α,δ-Disubstituted Tetraphosphates and Terminally-Functionalized Nucleoside Pentaphosphates. Scott M. Shepard, Hyehwang Kim, Qing Xin Bang, Norah Alhokbany, and Christopher C. Cummins. Journal of the American Chemical Society 2021 143 (1), 463-470.
Version
Author's final manuscript
Abstract
The anion [P4O11]2–, employed as its bis(triphenylphosphine)iminium (PPN) salt, is shown herein to be a versatile reagent for nucleophile tetraphosphorylation. Treatment under anhydrous conditions with an alkylamine base and a nucleophile (HNuc1), such as an alcohol (neopentanol, cyclohexanol, 4-methylumbelliferone, and Boc-Tyr-OMe), an amine (propargylamine, diethylamine, morpholine, 3,5-dimethylaniline, and isopropylamine), dihydrogen phosphate, phenylphosphonate, azide ion, or methylidene triphenylphosphorane, results in nucleophile substituted tetrametaphosphates ([P4O11Nuc1]3–) as mixed PPN and alkylammonium salts in 59% to 99% yield. Treatment of the resulting functionalized tetrametaphosphates with a second nucleophile (HNuc2), such as hydroxide, a phenol (4-methylumbelliferone), an amine (propargylamine and ethanolamine), fluoride, or a nucleoside monophosphate (uridine monophosphate, deoxyadenosine monophosphate, and adenosine monophosphate), results in ring opening to linear tetraphosphates bearing one nucleophile on each end ([Nuc1(PO3)3PO2Nuc2]4–). When necessary, these linear tetraphosphates are purified by reverse phase or anion exchange HPLC, yielding triethylammonium or ammonium salts in 32% to 92% yield from [PPN]2[P4O11]. Phosphorylation of methylidene triphenylphosphorane as Nuc1 yields a new tetrametaphosphate-based ylide ([Ph3PCHP4O11]3–, 94% yield). Wittig olefination of 2′,3′-O-isopropylidene-5′-deoxy-5′-uridylaldehyde using this ylide results in a 3′-deoxy-3′,4′-didehydronucleotide derivative, isolated as the triethylammonium salt in 54% yield.
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DOI of Published Version
https://doi.org/10.1021/jacs.0c11884
