Exceptionally Mild and High-Yielding Synthesis of Vinyl Esters of Alpha-Ketocarboxylic Acids, Including Vinyl Pyruvate, for Parahydrogen-Enhanced Metabolic Spectroscopy and Imaging.

Metabolic changes often occur long before pathologies manifest and treatment becomes challenging. As key elements of energy metabolism, α-ketocarboxylic acids (α-KCA) are particularly interesting, e.g., as the upregulation of pyruvate to lactate conversion is a hallmark of cancer (Warburg effect). Magnetic resonance imaging with hyperpolarized metabolites has enabled imaging of this effect non-invasively and in vivo, allowing the early detection of cancerous tissue and its treatment. Hyperpolarization by means of dynamic nuclear polarization, however, is complex, slow, and expensive, while available precursors often limit parahydrogen-based alternatives. Here, we report the synthesis for novel C, deuterated ketocarboxylic acids, and a much-improved synthesis of 1-C-vinyl pruvate-d6, arguably the most promising tracer for hyperpolarizing pyruvate using parahydrogen-induced hyperpolarization by side arm hydrogenation. The new synthesis is scalable and provides a high yield of 52%. We elucidated the mechanism of our Pd-catalyzed trans-vinylation reaction. Hydrogenation with parahydrogen allowed us to monitor the addition, which was found to depend on the electron demand of the vinyl ester. Electron-poor α-keto vinyl esters react slower than "normal" alkyl vinyl esters. This synthesis of C, deuterated α-ketocarboxylic acids opens up an entirely new class of biomolecules for fast and cost-efficient hyperpolarization with parahydrogen and their use for metabolic imaging.