The development of robust and efficient synthetic methods towards isotopically enriched molecules is an ongoing challenge within the field of synthetic organic chemistry. Isotopically enriched molecules are useful as tools to study mechanisms of synthetic reactions and biosynthetic pathways. Furthermore, deuterium and carbon-13 enriched pharmaceutical molecules are often used in absorption, distribution, metabolism and excretion (ADME) studies, as internal standards for mass spectrometry-based analysis. The synthesis of oxygen-18 alcohols however, is challenging and as such, they are underutilised for the aforementioned applications. Here we present a novel method of accessing oxygen-18 alcohols, by means of a Mitsunobu esterification reaction using an oxygen-18 enriched carboxylic acid (1), to access an oxygen-18 enriched ester. Hydrolysis of this ester intermediate affords the desired oxygen-18 enriched alcohol. Using this method, oxygen-18 enriched primary and secondary alcohols have been synthesised with excellent isotopic purity. Current work is focussed on accessing oxygen-18 enriched pharmaceuticals directly from the unlabelled molecule. These isotopically enriched molecules will serve as internal standards for mass-spectrometry based analysis during ADME studies. This method provides an alternative means of enriching pharmaceutical molecules with heavy isotopes, thus giving an alternative to traditional deuterium and carbon-13 enriched pharmaceuticals.

Oxygen-18 enrichment of alcohols by a modified Mitsunobu esterification reaction

2019 Spring National Meeting

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