A Single-Step Asymmetric Phosphodiester Synthesis from Alcohols with Phosphoenolpyruvate Phosphodiester

Abstract

Phosphodiesters are important structural motifs observed in a diverse field of molecular science. It is, thus, important to develop a simple and robust way to synthesize them from corresponding alcohols. Here we report a single-step asymmetric phosphodiester synthesis from alcohols with phosphoenolpyruvate phosphodiesters as phosphoryl donors. This transformation allows for the use of various functionalized alcohols as substrates and would be useful for diverse fields including biology and medicine.

Key words

phosphorylation - alcohol - phosphodiester - phosphoenolpyruvate - pentacoordinate phosphorus

Publication History

Received: 05 May 2021

Accepted after revision: 17 May 2021

Accepted Manuscript online:
17 May 2021

Article published online:
08 June 2021

• References and Notes

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• 20 Standard Procedures for Phosphorylation of Alcohols: Methyl 4-(3-{[hydroxy(methoxy)phosphoryl]oxy}propoxy) Benzoate (23) A heat-gun-dried and argon-flushed test tube equipped with a magnetic stirrer bar was charged with 3-bromopyruvic acid (50.1 mg, 300 μmol, 1.0 equiv.) and diethyl ether (180 μL, 1.66 M). Then, a solution of trimethyl phosphite (37.2 mg, 300 μmol, 1.0 equiv.) in diethyl ether (180 μL, 1.66 M) was added dropwise at a gently reflux rate, and the reaction mixture was stirred at r.t. After 1 h, the solvent was removed under high vacuum, and the resulting dimethyl phosphoenolpyruvate was used without further purification. To the freshly-prepared dimethyl phosphoenolpyruvate (58.5 mg, 300 μmol, 3.0 equiv.) were added sequentially acetonitrile (1.0 mL, 0.10 M), substrate methyl 4-(3-hydroxypropoxy)benzene (21.0 mg, 100 μmol, 1.0 equiv.), and methyl nicotinate (13.7 mg, 100 μmol, 1.0 equiv.). The mixture was warmed to 60 °C and stirred for 6 h. Then the reaction mixture was cooled to r.t. and concentrated. After adding saturated aq. Na₂CO₃, the mixture was washed three times with diethyl ether. The aqueous layer was acidified with concentrated HCl to pH 1 and extracted five times with dichloromethane. The combined organic layers were dried over with Na₂SO₄, filtered, and concentrated to afford crude product, which was purified by preparative HPLC to afford the corresponding phosphorylated product 23 in 52% yield. ¹H NMR (CDCl₃, 400 MHz): δ = 7.95 ­(d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 4.21 (dt, J = 6.4, 6.4 Hz, 2 H), 4.10 (t, J = 6.4 Hz, 2 H), 3.86 (s, 3 H), 3.68 (d, J = 11.4 Hz, 3 H), 2.17–2.11 (m, 2 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 166.9, 162.4, 131.6, 122.7, 114.0, 64.1 (d, J = 4.8 Hz), 63.7, 54.0 (d, J = 5.7 Hz), 51.9, 29.9 (d, J = 6.7 Hz). ³¹P NMR (CDCl₃, 159 MHz): δ = 1.6. ESI-MS: m/z = 303.1 [M – H]^–. HRMS: m/z calcd for [C₁₂H₁₆O₇P]^–: 303.0639; found: 303.0639.
• 21 This manuscript was posted on ChemRxiv: Fujiyoshi K, Kawashima S, Yamatsugu K, Kanai M. ChemRxiv 2021; reprint