Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Abstract

Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017−2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.

Controlled Tetradeuteration of Straight‐Chain Fatty Acids: Synthesis, Application, and Insight into the Metabolism of Oxidized Linoleic Acid

“…For the development of a controlled and reliable HIE method for straight‐chain FAs, we focused on the following points: (i) the deuteration reaction should be based on the carboxyl functionality (or its derivatives) to achieve a site‐ and number‐selective deuteration process, which should enable broad generality, including applicability to rare and valuable FAs; (ii) low‐cost and user‐friendly deuterium sources, such as D 2 O and CH 3 OD, should be used; [7a] and (iii) an easy reaction setup using catalytic or inexpensive reagents without the need for strictly anhydrous or oxygen‐free conditions should be developed. The first point, i.e., the production of uniformly deuterated structures, can be expected to contribute to the production of common diagnostic product ions, which are advantageous for tracking PC species (see below).…”

“…After screening the reaction conditions for each step (for details, see the Supporting Information), we developed a concise sequential protocol for the controlled tetradeuteration of straight‐chain FAs (Scheme 2). Although aliphatic amides are challenging substrates, [7a, 13] the use of 8‐aminoquinoline amides [8a, 14] facilitates the catalytic β‐selective deuteration, followed by a K 2 CO 3 ‐mediated α‐selective deuteration, both of which are carried out with D 2 O or CH 3 OD as deuterium sources under atmospheric conditions . The two‐step tetradeuteration conditions were applied to a variety of 8‐aminoquinoline amides derived from a range of straight‐chain FAs (Table 1).…”

Base‐Mediated Remote Deuteration of N‐Heteroarenes – Broad Scope and Mechanism

“…Successfully employing this approach, the first deuterated drug, Austedo (deutetrabenazine), was launched in 2017 and currently more deuterated drug candidates are in clinic trials [2] . While this application requires chemical reactions that enable selective installation of deuterium atoms in drug scaffolds, methodologies that drive the incorporation of several deuterium atoms at once are highly sought after for the preparation of stable isotopically labeled internal standards for mass spectrometric bioanalytics [1e,2a,3] …”

“…However, the former reaction may suffer from less accessible substrates and selectivity problems in the prefunctionalization step, while the latter requires harsh reaction conditions, impeding the use for late stage deuteration of sensitive substrates. Therefore, methodologies allowing for the direct exchange of a hydrogen atom for a deuterium atom in one step (hydrogen isotope exchange, HIE) at a late stage are more desirable [1e,3] . While the moiety of pyridine has been famously used as a directing group for the iridium‐catalyzed HIE in the ortho positions of adjacent aromatic rings (Scheme 1) [12] and the increased reactivity of benzylic positions at pyridine rings can be exploited for acid‐catalyzed HIE, [13] more drastic conditions such as heating the substrate in a solution of NaOD in supercritical D 2 O can enable complete deuteration of all positions in a pyridine ring (Scheme 1).…”

Undirected, Pd-catalysed deuteration of indoles with programmable regioselectivity

“…Given the importance of deuterated indoles, a significant amount of work has gone into developing strategies for their deuteration (Scheme 1A): 8 Heterogeneous catalysis generally affords global deuteration of all free positions (2); [9][10][11][12] more recently a metal-free approach has also been reported. 13 Deuteration on the pyrrole moiety (C2 and C3, 3) has been achieved with ruthenium nanoparticles, 14 rhodium, 15 or under homogeneous Ag2CO3 catalysis.…”