A practical guide for the preparation of C1-labeled -amino acids using aldehyde catalysis with isotopically labeled CO2

NATURE PROTOCOLS(2024)

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Abstract
Isotopically carbon-labeled alpha-amino acids are valuable synthetic targets that are increasingly needed in pharmacology and medical imaging. Existing preparations rely on early stage introduction of the isotopic label, which leads to prohibitive synthetic costs and time-intensive preparations. Here we describe a protocol for the preparation of C1-labeled alpha-amino acids using simple aldehyde catalysts in conjunction with [*C]CO2 (* = 14, 13, 11). This late-stage labeling strategy is enabled by the one-pot carboxylate exchange of unprotected alpha-amino acids with [*C]CO2. The protocol consists of three separate procedures, describing the syntheses of (+/-)-[1-C-13]phenylalanine, (+/-)-[1-C-11]phenylalanine and (+/-)-[1-C-14]phenylalanine from unlabeled phenylalanine. Although the delivery of [*C]CO2 is operationally distinct for each experiment, each procedure relies on the same fundamental chemistry and can be executed by heating the reaction components at 50-90 degrees C under basic conditions in dimethylsulfoxide. Performed on scales of up to 0.5 mmol, this methodology is amenable to C1-labeling of many proteinogenic alpha-amino acids and nonnatural derivatives, which is a breakthrough from existing methods. The synthesis of (+/-)-[1-C-13]phenylalanine requires similar to 2 d, with product typically obtained in a 60-80% isolated yield (n = 3, mu = 71, sigma = 8.3) with an isotopic incorporation of 70-88% (n = 18, mu = 72, sigma = 9.0). Starting from the preformed imino acid (similar to 3 h preparation time), rapid synthesis of (+/-)-[1-C-11]phenylalanine can be completed in similar to 1 h with an isolated radiochemical yield of 13%. Finally, (+/-)-[1-C-14]phenylalanine can be accessed in similar to 2 d with a 51% isolated yield and 11% radiochemical yield.
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