Aldehyde-Catalyzed Carboxylate Exchange in a-Amino Acids with Isotopically Labeled CO2

Abstract

a-Amino acids are among the essential chemical building blocks of life. These structures are embedded in many small molecule pharmaceuticals and are the primary components of peptide-based therapeutics and biologics. Isotopically labeled a-amino acids and their derivatives have widespread use in structural and mechanistic biochemistry, quantitative proteomics, absorption distribution metabolism and excretion (ADME) profiling, and as imaging agents in positron emission tomography (PET) techniques. The preparation of carbon-labeled a-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-labeled products and presents a major challenge in 11C applications (11C t1/2 = 20 min). Here we report that simple aldehydes catalyze the isotopic carboxylate exchange of native a-amino acids with *CO2 (* = 14, 13, 11). Proteinogenic a-amino acids and many non-natural variants containing diverse functional groups undergo labeling. The reaction likely proceeds via the trapping of *CO2 by imine-carboxylate intermediates to generate aminomalonates 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 11C-radiolabeling of a-amino acids in the presence of 11CO2.

Combining Umpolung and Carbon Isotope Exchange Strategies for Accessing Isotopically Labeled α-Keto Acids

“…In recent years, there have been rapid advancements in this field, 28,29 particularly concerning the isotope exchange of carboxylate groups in carboxylic acids. 30,31 In 2018, Gauthier and colleagues reported a groundbreaking method for the carbon isotope labeling of aromatic acids, involving a decarbonylation/ carbonylation process on aromatic acid chlorides within a dualchamber system (Figure 1Aa). 32 This innovative system allows for the efficient generation and exchange of labeled CO under a Pd-catalyzed mechanism, followed by a crucial hydrolysis step.…”

Enantioselective Carbon Isotope Exchange

“…30,31 We recently disclosed a racemic CIE method wherein α-amino acids are directly labeled from their native precursors by undergoing aldehyde-catalyzed carboxylation/decarboxylation in the presence of *CO 2 (Figure 1B). 23 Our earlier work was inspired by the function of pyridoxal phosphate (PLP) dependent enzymes, which perform various transformations of amino acids including decarboxylations, eliminations, and stereochemical inversions. Chin and Kim and co-workers have developed PLP-mimetic amino acid receptors such as (S)-1, which are designed to transform L-amino acids into D-amino acids via stoichiometric generation and equilibration of diastereomeric imine intermediates (Figure 1B).…”

Gold(I)-Mediated Radioiododecarboxylation of Arenes

“…An efficient decarboxylation/recarboxylation process catalyzed by CuBr has been described. 24 Additionally, metal-free processes 25,26 and photocatalytic strategies are available for carbon-14 labeling as well. 27,28 In all of these radiochemical processes, the decarboxylation and labeling reactions occur simultaneously within the same reaction mixture.…”