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Description

In medicinal chemistry, a bioisostere is a molecule derived by substituting an atom or functional group with another that shares similar structural or physicochemical characteristics. This strategy enables subtle modifications to the parent compound, aiming to reduce toxicity, optimize pharmacokinetic profiles, and enhance desired biological or physicochemical properties. Our research aims at installing deutero methyl isotopologues which are non-classical bioisosteres, using mechanochemical Mitsunobu reactions with greener solvents.

The method enables efficient incorporation of fully and partially deuterium-labelled methyl groups (CD3, CH2D, CHD2) on phenolic substrates. Using this strategy, we have prepared isotopologues suitable for ADME studies and isotopic tracing of drug candidates. Representative syntheses using phenolic substrates, analytical characterization, and a comparative green-chemistry assessment using 2-methyl-Tetrahydrofuran and ?-valerolactone (GVL) will be presented. Our research demonstrates that sonication combined with greener solvent systems provides an efficient and practical approach to phenolic ether synthesis and isotopic modification and can be applied to synthesis of deuterated drugs such as Deuterobenazine. Ongoing studies focus on expanding substrate scope, optimizing reaction conditions, improving yields, and evaluating regioselectivity across additional phenolic systems.

Publication Date

4-30-2026

Keywords

Mitsunobu Reaction, Methyl Isotopologue, Green Syntehsis

A Mechanochemical Mitsunobu Strategy for the Greener Synthesis of Methyl Isotopologues

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