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The isotopic labelling of small molecules is integral to drug development and for understanding biochemical processes. The preparation of carbon-labelled α-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labelled products and presents a major challenge in 11 C applications ( 11 C t 1/2  = 20 min). Here we report that aldehydes catalyse the isotopic carboxylate exchange of native α-amino acids with *CO 2 (* = 14, 13, 11). Proteinogenic α-amino acids and many non-natural variants containing diverse functional groups undergo labelling. The reaction probably proceeds via the trapping of *CO 2 by imine-carboxylate intermediates to generate iminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage 11 C-radiolabelling of α-amino acids in the presence of [ 11 C]CO 2 . Carbon-labelled α-amino acids are valuable compounds in drug development and nuclear medicine, but are difficult and time consuming to prepare. Now, an aldehyde-catalysed method has been developed for the direct C1-labelling of α-amino acids using *CO 2 (* = 14, 13, 11), providing access to many proteinogenic and non-natural labelled α-amino acids.

Radical intermediates are key species in many chemical transformations. Recent advances have provided a new suite of selective radical alkylation reactions. This Comment highlights pioneering studies using alkyl amines that act as radical precursors in a number of catalytic processes by their conversion to alkylpyridinium salts.

Isotopically carbon-labeled α-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 α-amino acids using simple aldehyde catalysts in conjunction with [*C]CO 2 (* = 14, 13, 11). This late-stage labeling strategy is enabled by the one-pot carboxylate exchange of unprotected α-amino acids with [*C]CO 2 . The protocol consists of three separate procedures, describing the syntheses of (±)-[1- 13 C]phenylalanine, (±)-[1- 11 C]phenylalanine and (±)-[1- 14 C]phenylalanine from unlabeled phenylalanine. Although the delivery of [*C]CO 2 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 °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 α-amino acids and nonnatural derivatives, which is a breakthrough from existing methods. The synthesis of (±)-[1- 13 C]phenylalanine requires ~2 d, with product typically obtained in a 60–80% isolated yield ( n = 3, μ = 71, σ = 8.3) with an isotopic incorporation of 70–88% ( n = 18, μ = 72, σ = 9.0). Starting from the preformed imino acid (~3 h preparation time), rapid synthesis of (±)-[1- 11 C]phenylalanine can be completed in ~1 h with an isolated radiochemical yield of 13%. Finally, (±)-[1- 14 C]phenylalanine can be accessed in ~2 d with a 51% isolated yield and 11% radiochemical yield. Key points Amino acids can be labeled with carbon isotopes via carboxylate exchange using [*C]CO 2 where *C is either 13 C, 11 C or 14 C. Three procedures are described using phenylalanine as the example starting material; the main differences relate to the sources of [*C]CO 2 and how it is delivered. The products can be used immediately after a straightforward HPLC separation. Isotopically labeled amino acids are useful in pharmacology and for medical imaging. In this protocol, C1-labeled α-amino acids are prepared via late-stage carboxylate exchange of unprotected α-amino acids with [*C]CO 2 where *C is 13 C, 11 C or 14 C.

Preparing molecules with multiple 13C labels is difficult owing to the lack of available 13C-labelled reagents. Now, a hydroformylation approach to the synthesis of [13C3]propionaldehyde, using gas surrogates, provides a straightforward method to prepare bioactive molecules with three 13C labels.

Isotopically carbon-labeled α-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 α-amino acids using simple aldehyde catalysts in conjunction with [*C]CO (* = 14, 13, 11). This late-stage labeling strategy is enabled by the one-pot carboxylate exchange of unprotected α-amino acids with [*C]CO . The protocol consists of three separate procedures, describing the syntheses of (±)-[1- C]phenylalanine, (±)-[1- C]phenylalanine and (±)-[1- C]phenylalanine from unlabeled phenylalanine. Although the delivery of [*C]CO 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 °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 α-amino acids and nonnatural derivatives, which is a breakthrough from existing methods. The synthesis of (±)-[1- C]phenylalanine requires ~2 d, with product typically obtained in a 60-80% isolated yield (n = 3, μ = 71, σ = 8.3) with an isotopic incorporation of 70-88% (n = 18, μ = 72, σ = 9.0). Starting from the preformed imino acid (~3 h preparation time), rapid synthesis of (±)-[1- C]phenylalanine can be completed in ~1 h with an isolated radiochemical yield of 13%. Finally, (±)-[1- C]phenylalanine can be accessed in ~2 d with a 51% isolated yield and 11% radiochemical yield.

The isotopic labelling of small molecules is integral to drug development and for understanding biochemical processes. The preparation of carbon-labelled α-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labelled products and presents a major challenge in C applications ( C t  = 20 min). Here we report that aldehydes catalyse the isotopic carboxylate exchange of native α-amino acids with *CO (* = 14, 13, 11). Proteinogenic α-amino acids and many non-natural variants containing diverse functional groups undergo labelling. The reaction probably proceeds via the trapping of *CO by imine-carboxylate intermediates to generate iminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage C-radiolabelling of α-amino acids in the presence of [ C]CO .