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

The anion [P 4 O 11 ] 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 (PO 3 ) 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 [P 4 O 11 ]. Phosphorylation of methylidene triphenylphosphorane as Nuc 1 yields a new tetrametaphosphate-based ylide ([Ph 3 PCHP 4 O 11 ] 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.