Mild and Chemoselective Phosphorylation of Alcohols Using a Ψ-Reagent
Michał Ociepa, Kyle W. Knouse, David He, Julien C. Vantourout, Dillon T. Flood, Natalia M. Padial, Jason S. Chen, Brittany B. Sanchez, Emily J. Sturgell, Bin Zheng, Shenjie Qiu, Michael A. Schmidt, Martin D. Eastgate and Phil S. Baran*
*Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States,
Email: pbaran
scripps.edu
M. Ociepa, K. W. Knouse, D. He, J. C. Vantourout, D. T. Flood, N. M. Padial, J. S. Chen, B. B. Sanchez, E. J. Sturgell, B. Zheng, S. Qiu, M. A. Schmidt, M. D. Eastgate, P. S. Baran, Org. Lett., 2021, 23, 9337-9342.
DOI: 10.1021/acs.orglett.1c02736
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Abstract
The use of a P(V)-based Ψ-reagent enables an operationally simple, scalable, and chemoselective method for the direct phosphorylation of alcohols. The method provides access to valuable phosphorylated alcohols that would be otherwise difficult to obtain.
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General procedure for the Ψ-based phosphorylation of alcohols
For solid alcohols:
A 4-dram vial equipped with a stir bar was charged with an alcohol (0.1 mmol,
1.0 equiv.) and Ψ0 reagent (64 mg, 0.15 mmol, 1.5 equiv.). The vial
was closed with a Teflon septum screw cap, evacuated and backfilled with argon
(two cycles). Subsequently, the reagents were dissolved in anhydrous DCM (1 mL),
followed by dropwise addition of DBU (23 無, 0.15 mmol, 1.5 equiv.). The
resulting solution was stirred at ambient temperature for 1 h. After that time,
premixed solution of H2O (50 無) in MeCN (1 mL) was added, followed
by another portion of DBU (45 無, 0.3 mmol, 3.0 equiv.), and the reaction was
stirred at ambient temperature for 15 min. Upon completion the resulting mixture
was transferred to a round-bottom flask using MeOH and concentrated in vacuo.
The crude material was purified by preparative HPLC or HILIC silica gel
chromatography. To remove residual water isolated monoalkyl dihydrophospahates
were dried in vacuo at 50蚓 or lyophilized.
For liquid alcohols:
A 4-dram vial equipped with a stir bar was charged with Ψ0 reagent
(64 mg, 0.15 mmol, 1.5 equiv.). The vial was closed with a Teflon septum screw
cap, evacuated and backfilled with argon (two cycles). Subsequently, Ψ0 was
dissolved in anhydrous DCM (1 mL), followed by addition of alcohol (0.1 mmol,
1.0 equiv.). The resulting mixture was stirred for 2 min, after which DBU (23
無, 0.15 mmol, 1.5 equiv.) was added dropwise and the reaction was stirred at
ambient temperature for 1 h. After that time, premixed solution of H2O
(50 無) in MeCN (1 mL) was added, followed by another portion of DBU (45 無, 0.3
mmol, 3.0 equiv.), and the resulting solution was stirred at ambient temperature
for 15 min. Upon completion the reaction mixture was transferred to a
round-bottom flask using MeOH and concentrated in vacuo. The crude material was
purified by preparative HPLC or HILIC chromatography on silica gel. To remove
residual water isolated monoalkyl dihydrophospahates were dried in vacuo at 50蚓
or lyophilized.
Note: In case of alcohols insoluble in DCM, anhydrous MeCN or DMF can be used as a solvent in the first step of the reaction.
Key Words
ID: J54-Y2021
