Phosphorylation with Pyrophosphoric Acid

Abstract

Dihydrogenphosphates of primary and secondary aliphatic alcohols as well as phenol were prepared by a very simple procedure with pyrophosphoric acid. t-Butyl and benzyl dihydrogenphosphates could be obtained by a slight modification of the reaction conditions. For the purpose of phosphorylation pyrophosphoric acid was more reactive than orthophosphoric acid.

Mild and Chemoselective Phosphorylation of Alcohols Using a PSI-Reagent

“…As indicated in Table 2A, simple amines are tolerated in this reaction (5, 14, 15) as well as basic heterocycles (16,19). Alkynes (7), azides (8), thiophenes (9), aryl iodides (10), olefins (11), alkyl halides (12, 13), nitro arenes (17,19), and indoline (18) were unscathed upon P-O bond formation. Finally, four medicinally relevant substrates were phosphorylated (Table 2B): metronidazole (19), AZT (20), cholesterol (21), and a tyrosine-containing peptide bearing histidine, aspartamide, and glutamide side-chains.…”

“…5 Current purely chemical alcohol phosphorylation methods all suffer from various limitations and/or multistep processes (Figure 1). [6][7][8][9][10] For example, the use of P(III)-based phosphoramidites require a three step process for installation including protecting group removal and oxidation. 7 P(V)based strategies such as the use of POCl3 and derivatives thereof can be problematic due to over reactivity (often producing mixtures of mono-, di-, and tri-alkylphosphates) and protecting group manipulations.…”

“…8 The direct use of phosphoric acid requires high temperatures and exhibits limited scope due to the high acidity and harsh conditions. 9 Activation methods used in concert with phosphoric acid or its salts have been employed with limited scope. 10 The recently reported bioinspired method based on an enzymatically produced P(V)-reagent (PEP-K) solves many of these problems despite requiring its use in excess at 100 °C.…”

Mild and Chemoselective Phosphorylation of Alcohols Using a PSI-Reagent

“…As indicated in Table 2A, simple amines are tolerated in this reaction (5, 14, 15) as well as basic heterocycles (16,19). Alkynes (7), azides (8), thiophenes (9), aryl iodides (10), olefins (11), alkyl halides (12, 13), nitro arenes (17,19), and indoline (18) were unscathed upon P-O bond formation. Finally, four medicinally relevant substrates were phosphorylated (Table 2B): metronidazole (19), AZT (20), cholesterol (21), and a tyrosine-containing peptide bearing histidine, aspartamide, and glutamide side-chains.…”

“…5 Current purely chemical alcohol phosphorylation methods all suffer from various limitations and/or multistep processes (Figure 1). [6][7][8][9][10] For example, the use of P(III)-based phosphoramidites require a three step process for installation including protecting group removal and oxidation. 7 P(V)based strategies such as the use of POCl3 and derivatives thereof can be problematic due to over reactivity (often producing mixtures of mono-, di-, and tri-alkylphosphates) and protecting group manipulations.…”