Catalytic Chemoselective O-Phosphorylation of Alcohols

Abstract

Phosphorylation of alcohols is a fundamentally important reaction in both life science and physical science. Product phosphate monoesters play key roles in living organisms, natural products, pharmaceuticals, and organic materials. Most of the chemical methods to date for synthesizing phosphate monoesters, however, require multistep sequences or are limited to specific types of substrates possibly due to harsh conditions. An alternative way to enable the simple production of phosphate monoesters from highly functionalized precursor alcohols is, thus, highly desired. We report herein a catalytic phosphorylation of alcohols with high functional group tolerance using tetrabutylammonium hydrogen sulfate (TBAHS) and phosphoenolpyruvic acid monopotassium salt (PEP-K) as the catalyst and phosphoryl donor, respectively. This method enables the direct introduction of a nonprotected phosphate group to the hydroxy group of a diverse menu of alcohol substrates, including functionalized small molecules, carbohydrates, and unprotected peptides. Nuclear magnetic resonance, mass spectrometric, and density functional theory analyses suggest that an unprecedented mixed anhydride species, generated from PEP-K and TBAHS, acts as an active phosphoryl donor in this reaction. This operationally simple and chemoselective catalytic phosphorylation allows for the efficient production of densely functionalized O-phosphorylated compounds, which are useful in diverse fields including biology and medicine.

Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies

“…Recent studies in this area clearly demonstrate the need for such chemistry, but both methods enable access to a wide range of phosphorylated substrates but require either multiple steps or harsh conditions. 75 , 76 …”

Poly(ADP-ribose): the structure and the synthesis

“…82 To date, many approaches of converting alcohols into their phosphate esters have been fabricated by exerting inorganic phosphorylation reagents, such as white phosphorus, 83 phosphoric acid 83 and POCl3. 84,85 These reactions need amines as organic bases or organic ammonium salts as catalysts, and some reactions even take place under hostile conditions, such as rather high temperature. On the other hand, yields of these reactions are always undesired.…”

Key advances in biocatalytic phosphorylations in the last two decades: Biocatalytic syntheses in vitro and biotransformations in vivo (in humans)

“…For moving towards more sustainable phosphorylation reactions, the use of highly selective catalysts is of great interest. [ 31 ] The development of highly selective chemical catalysts for the transfer of the donors with the protected phosphorus‐containing groups, either via the oxidation state 5 or 3 of the phosphorus atom, can however take a substantial effort and still requires at least two reaction steps. Nature on the other hand offers access to phosphorus‐transferring enzymes from 14 enzyme sub‐subclasses.…”