The labeling of unsaturated γ‐hydroxybutyric acid by heavy isotopes of hydrogen: iridium complex‐mediated H/D exchange by C─H bond activation vs reduction by boro‐deuterides/tritides

Abstract

3-Hydroxycyclopent-1-ene-1-carboxylic acid (HOCPCA (1)) is a potent ligand for high-affinity γ-hydroxybutyric acid binding sites in the central nervous system. Various approaches to the introduction of a hydrogen label onto the HOCPCA skeleton are reported. The outcomes of the feasible C─H activation of olefin carbon (C-2) by iridium catalyst are compared with the reduction of the carbonyl group (C-3) by freshly prepared borodeuterides. The most efficient iridium catalysts proved to be Kerr bulky phosphine N-heterocyclic species providing outstanding deuterium enrichment (up to 91%) in a short period of time. The highest deuterium enrichment (>99%) was achieved through the reduction of ketone precursor 2 by lithium trimethoxyborodeuteride. Hence, analogical conditions were used for the tritiation experiment. [ H]-HOCPCA selectively labeled on the position C-3 was synthetized with radiochemical purity >99%, an isolated yield of 637 mCi and specific activity = 28.9 Ci/mmol.

Frustrated Lewis pairs: A real alternative to deuteride/tritide reductions

“…This reactivity is in accordance with the data of FLP hydrogenations of polycyclic aromatic hydrocarbons (PAHs) reported in literature. 59 To investigate the affinity of 2 towards ketone functionalities, various substrates bearing a ketone moiety (31)(32)(33)(34)(35)(36)(37)(38) were used in the reduction with 2 under general conditions ( Table 2). The ketone moiety proved to be entirely unreactive under the general conditions, unless the ketone moiety was strongly activated by an electron withdrawing group ( Table 2, entries 1 and 2).…”

“…Commercially available tritides are unstable and possess low specific activity. A wide range of tritides can be freshly synthetized in house from carrier‐free tritium with treatment of n BuLi‐TMEDA system, producing LiT that can be used for a generation of variety of boro‐ and aluminium‐tritides, silanes, or stannanes . The synthesis of such tritides can be experimentally tricky and is always very sensitive to the quality of the reagents and the operator's skill.…”

“…2,3,[10][11][12][13] The current status of tritium chemistry methodologies comprises out of a portfolio of few fundamental synthetic approaches that radiochemist can chose from: metalcatalyzed exchange (hydrogen isotope exchange [HIE]), [14][15][16][17][18][19][20][21] tritiodehalogenation, [22][23][24][25][26][27][28] multiple bond reduction 27,[29][30][31] with T 2 , and tritides reduction ( Figure 1). 22,23,[32][33][34] The quite inert molecule of hydrogen always needs to be activated before any intended application. [35][36][37][38] The HIE approach has recently reached a significant improvement in terms of achieved specific activity (S.A.), 21,39,40 however, still suffers from low site-specificity label incorporation and the requirement of vast numbers of trials to develop workable reaction conditions, using up time and often the precious compound.…”

“…A wide range of tritides can be freshly synthetized in house from carrier-free tritium with treatment of nBuLi-TMEDA system, producing LiT that can be used for a generation of variety of boro-and aluminium-tritides, silanes, or stannanes. 13,22,23,[32][33][34]41 The synthesis of such tritides can be experimentally tricky and is always very sensitive to the quality of the reagents and the operator's skill. Inhouse-generated tritides possessing S.A. are generated in low yield and are subsequently used without isolation and purification in the complex mixture.…”

Tritiodefluorination of alkyl C–F groups

“…Tritium is the most versatile radioisotope used for identifying organic compounds in biochemical research. [1][2][3][4] Most frequently, tritiations are carried out using carrier-free tritium gas in the presence of a noble metal catalyst in order to reduce double or triple bonds, [5][6][7][8][9] tritiodehalogenation of appropriate synthetic precursors or to carry out 1 H/ 3 H exchanges on the desired molecule. [10][11][12][13][14] Catalytic dehalogenations of organic halides, using tritium gas, provide a state-of-the-art approach of site-selective labeling, while yielding high specific activity (SA) of the labeled material (Figure 1).…”