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. 2021 Dec 17;23(24):9337-9342.
doi: 10.1021/acs.orglett.1c02736. Epub 2021 Sep 9.

Mild and Chemoselective Phosphorylation of Alcohols Using a Ψ-Reagent

Michał Ociepa  1 , Kyle W Knouse  1 , David He  1 , Julien C Vantourout  1 , Dillon T Flood  1 , Natalia M Padial  1 , Jason S Chen  2 , Brittany B Sanchez  2 , Emily J Sturgell  2 , Bin Zheng  3 , Shenjie Qiu  3 , Michael A Schmidt  3 , Martin D Eastgate  3 , Phil S Baran  1
Affiliations

Mild and Chemoselective Phosphorylation of Alcohols Using a Ψ-Reagent

Michał Ociepa et al. Org Lett. .

Abstract

An operationally simple, scalable, and chemoselective method for the direct phosphorylation of alcohols using a P(V)-approach based on the Ψ-reagent platform is disclosed. The method features a broad substrate scope of utility in both simple and complex settings and provides access to valuable phosphorylated alcohols that would be otherwise difficult to obtain.

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Figures

FIGURE 1.
FIGURE 1.
Alcohol phosphorylation: Literature precedent, limitations, and a mild solution using the ΨO reagent (1).
FIGURE 2.
FIGURE 2.
(A) Optimization of Ψ-based alcohol phosphorylation and (B) its use in the selective O-phosphorylation of aminoalcohol 4. aYields determined by quantitative 31P NMR (see SI). Isolated yields in brackets. DABCO – 1,4-diazabicyclo[2.2.2]octane; DIPEA – N,N-diisopropylethylamine; DBU – 1,8-diazabicyclo[5.4.0]undec-7-ene; DBN – 1,5-diazabicyclo[4.3.0]non-5-ene; TMG – 1,1,3,3-tetramethylguanidine.
FIGURE 3.
FIGURE 3.
Scope of the Ψ-based alcohol phosphorylation method. aIsolated as ammonium salt. bFrom N-Boc Serine. cReaction in DMF. dReaction in MeCN. eΨO (5.0 equiv.), DBU (5.0 equiv.), reaction in DMF on a 1.0 μmol scale. fDBU (2.5 equiv.), reaction in DMF, NMR yield.
FIGURE 4.
FIGURE 4.
(A) One-pot synthesis of dialkyl phosphate 28 and (B) scale up of Ψ-based phosphorylation of metronidazole.
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