Synthesis of α,δ-Disubstituted Tetraphosphates and Terminally-Functionalized Nucleoside Pentaphosphates

Journal Article

2021

Published in: Synthesis of α,δ-Disubstituted Tetraphosphates and Terminally-Functionalized Nu…

Cummins, Scott M. Shepard, Hyehwang Kim, Qing Xin Bang, Norah Alhokbany, and Christopher C. . 2021

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
(HNuc(1)), 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 ([P(4)O(11)Nuc(1)](3-)) as mixed PPN and alkylammonium salts in 59% to 99% yield. Treatment of the
resulting functionalized tetrametaphosphates with a second nucleophile (HNuc(2)), 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 ([Nuc(1)(PO3)(3)PO(2)Nuc(2-)](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 Nuc(1) 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.

• Publication Work Type: article
• Volume Number: 143
• Magazine \ Newspaper: Journal of the American Chemical Society (JACS)
• Pages: 463-470