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Synlett 2022; 33(04): 329-338
DOI: 10.1055/a-1354-0367
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Late-Stage Functionalization

Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization

Qi-Kai Kang
a   Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, P. R. of China
b   Institute of Natural Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, P. R. of China
,
Hang Shi∗
a   Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, P. R. of China
b   Institute of Natural Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, P. R. of China
› Author Affiliations

This project was supported by the National Natural Science Foundation of China (22071198) and the China Postdoctoral Science Foundation (2019M662118)
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Abstract

The introduction of deuterium and tritium into molecules is of great importance in drug discovery. Many attempts have been made to develop late-stage hydrogen isotope exchange (HIE) reactions to avoid multistep syntheses using commercially available labeled precursors. In this review, we summarize recent progress in catalytic HIE reactions, with our main focus on their applications in the late-stage labeling of bioactive complex molecules and pharmaceuticals1 Introduction

2 Non-Transition-Metal-Catalyzed Hydrogen Isotope Exchange

2.1 Organocatalysis

2.2 Photoredox Catalysis

3 Transition-Metal-Catalyzed Hydrogen Isotope Exchang

3.1 Palladium

3.2 Ruthenium

3.3 Iridium

3.4 Other Metals

4 Summary


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Key words

hydrogen isotope exchange reaction - late-stage functionalization - bioactive molecules - catalytic reaction - C–H functionalization - deuteration - tritiation
1

Introduction

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Qi-Kai Kang was born and grew up in Zhejiang, P. R. of China. He received his Ph.D. at Shanghai Institute of Organic Chemistry (SIOC) under the direction of Prof. Yong Tang in 2016. After graduation, he joined the group of Prof. Keiji Maruoka at Kyoto University (Japan) as a postdoctoral researcher. In 2019, he joined Hang Shi’s group at Westlake University (P. R. of China). His research interests focus on organometallic methodology and asymmetric catalysis.
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Hang Shi was born and grew up in Liaoning, P. R. of China. His graduate studies were carried out at Peking University under the direction of Prof. Zhen Yang, culminating in a Ph.D. degree in 2013. Then, he joined the group of Prof. Tobias Ritter at Harvard University (USA), as a postdoctoral researcher. During that period, he also performed part of the research at the Massachusetts General Hospital. At the end of 2015, he moved to the Scripps Research Institute and joined Prof. Jin-Quan Yu’s group. In 2018, he began his independent career at Westlake University (P. R. of China). His research interests focus on organometallic methodology and asymmetric catalysis.

Introducing functional groups during the very last steps of complex organic molecule syntheses, called late-stage functionalization (LSF),[1] has emerged in recent decades as a powerful tool for enabling new drugs to be discovered.[2] LSF has allowed a vast library of labeled target compounds to be established from advanced intermediates rather than requiring de novo synthesis. Given the large abundance of C–H bonds in molecules, developing C–H functionalization methods with high functional group compatibility as well as exclusive site-selectivity is of fundamental importance in LSF.[3] In this review, we provide a guide to employing catalytic hydrogen isotope exchange (HIE) reactions in late-stage labeling of bioactive complex molecules.

Deuterium and tritium play important roles in medicinal chemistry because of their different behaviors compared with protium (Scheme [1a]).[4] For instance, due to the deuterium kinetic isotope effect (DKIE), C–D bonds are, in general, more stable than C–H bonds in vivo. Introducing deuterium to a drug candidate could therefore alter absorption, distribution, metabolism, and excretion (ADME) of a drug candidate.[4a] [b] [5] As such, in 2017, deutetrabenazine, the first deuterium-labeled drug, was approved by the FDA for the treatment of chorea associated with Huntington’s disease and tardive dyskinesia.[6] In addition, deuterium and radioactive tritium-labeled compounds also serve as tracers in the study of drug metabolism.[4c] The above reasons have motivated efforts to develop efficient approaches for the direct incorporation of deuterium or tritium into molecules beside a multistep synthesis from commercially available labeled precursors. Here, we summarize recently developed catalytic HIE reactions categorized by catalyst type, and mainly focus on late-stage labeling of bioactive molecules.[7]

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Scheme 1 HIE reactions used to discover new drugs

# 2

Non-Transition-Metal-Catalyzed HIE

2.1

Organocatalysis

Base-catalyzed deuterations are among the oldest labeling methods. As an example, this protocol provides a facile way for H/D exchange of acidic hydrogen atoms in cortisone,[8] epitestosterone,[9] and androstendione,[10] which are stable to strong inorganic bases. The deuterated forms of these steroids have been used as internal standards for mass spectrometry analysis. Recently, milder conditions have been developed by using organic bases, such as pyrrolidine[11] and 1,8-diazabicyclo[5.4.0]undec-7-ene,[12] and successfully applied in labeling of bioactive molecules. Ondansetron (a drug approved by the US FDA to prevent nausea and vomiting caused by chemotherapy, radiation therapy, and surgery) as well as other bioactive molecules containing carbonyl motifs have been labeled with deuterium (Scheme [2]).

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Scheme 2 Organic-base-catalyzed deuteration

In complex molecules that cannot be readily deprotonated or that bear base-sensitive groups, acid-catalyzed HIE reactions provide an alternative way to introduce deuterium. In 2018, Yin’s group reported a benzoic acid-catalyzed deuteration at the methyl groups of N-heteroarylmethanes[13] (Scheme [3]). The H/D exchange proceeded via an enamie intermediate. Pharmaceutical compounds, including chloroxine, papverine, and tropicamide, are compatible under the acidic conditions. In addition, Heinrich’s group applied an inorganic acid perchloric acid in deuteration of electron-rich arenes, including glycosylated phytochemicals.[14]

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Scheme 3 Organic-acid-catalyzed deuteration
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Scheme 4 B(C6F5)3-catalyzed deuteration of pharmaceutical compounds

Recently, Wasa et al. found that N-alkylamine-based pharmaceutical compounds could be β-deuterated through a cooperative action of the catalyst B(C6F5)3 and the N-alkylamine substrate (Scheme [4a]).[15] B(C6F5)3, a sterically hindered strong Lewis acid, receives a hydride from an amine, generating the corresponding borohydride and an iminium ion. Subsequent deprotonation and deuteration through an enamine intermediate gives a β-deuterated product with high levels of deuterium incorporation. This regiospecific HIE reaction has been applied in the labeling of an array of bioactive tertiary amines, including both acyclic and cyclic ones. In addition, an α-deuteration protocol of carbonyl-based molecules was later developed by the same group (Scheme [4b]).[16] Enabled by the catalyst B(C6F5)3, deuterated pharmaceutical compounds pentoxifylline and donepezil were synthesized on gram scales.


# 2.2

Photoredox Catalysis

Visible-light induced photoredox catalysis has recently emerged as a powerful tool in the area of C–H functionalization.[17] In 2017, Macmillan’s group described deuteration and tritiation of N-alkylamines utilizing a photoredox-mediated hydrogen atom transfer (HAT) protocol (Scheme [5a]).[18] Enabled by a combination of photoredox catalyst and thiol hydrogen donor, the isotope exchange occurs specifically on a C(sp3)–H bond instead of a C(sp2)–H bond. Eighteen drug molecules, including both cyclic and acyclic amines, have been labeled with either deuterium or tritium at the α-position to nitrogen in high incorporation. More recently, Derdau’s group applied this protocol to the incorporation of deuterium and tritium in peptides (Scheme [5b]).[19]

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Scheme 5 Photoredox-catalyzed HIE of tertiary amines and peptides

In 2020, Wang reported a formyl-selective deuteration of aldehydes via a synergistic combination of light-driven, polyoxometalate-facilitated HAT and thiol catalysis.[20] Pregnenolone and ibuprofen derivatives were deuterated with high levels of incorporation (Scheme [6a]). In addition, deuteration of C(sp3)–H bonds was described by Wu’s group[21] (Scheme [6b]). Pharmaceutical molecules, including ammonaps, lidocaine, and (+)-griseofulvin, were successfully labeled.

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Scheme 6 Photoredox-catalyzed deuteration of formyl C–H bonds and C(sp3)–H bonds

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# 3

Transition-Metal-Catalyzed HIE

3.1

Palladium

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Figure 1 Pd/C-catalyzed deuteration of nucleosides and bioactive molecules

As one of the most widely used transition-metals for C–H functionalizations, palladium, particularly heterogeneous palladium, has proved useful for catalyzing late-stage HIE reactions. Pd/C under a H2 atmosphere and using D2O as a deuterium source has been used to catalyze the deuteration of purine nucleosides such as adenosine, guanosine and inosine[22] (Figure [1a]). A hydrogen atom on an sp2 carbon was selectively exchanged. The exact mechanism was not identified, but it was assumed that the palladium was activated by H2. Modified conditions using NaBD4 in place of H2 were developed to reduce hazards associated with the use of the gas[23] (Figure [1b]). Adding ethylenediamine to act as a ligand was shown to alter the catalyst reactivity and avoid debenzylation products generated under standard Pd/C-H2 conditions.[24]

Palladium on other inorganic carriers, such as CaCO3 or BaSO4, was also applied in late-stage HIE reactions. Myasoedov et al. developed a high-temperature solid-state catalytic isotope exchange (HSCIE).[25] This method is highly efficient in the selective, racemization-free deuteration/tritiation of amino acids, peptides and other bioactive molecules.[26] For example, insulin was labeled with a specific activity of 40 Ci/mmol and a total radioactivity amount of 3 mCi (Figure [2]).[27] Histidine (>45%) was identified as the amino acid with the highest tritium content.

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Figure 2 Tritiation of insulin through solid-state catalytic isotope exchange

# 3.2

Ruthenium

Heterogeneous-ruthenium-catalyzed HIE reactions have mainly been used to deuterate C–H bonds alpha to hydroxyl, thio, and amino groups in bioactive molecules. ­Sajiki et al. reported stereo- and regioselective deuterium labeling method for sugars (Scheme [7]).[28] The reaction was proposed to involve a direct C–H bond insertion mechanism by activated Ru catalyst, rather than proceeding via β-H elimination of a hydroxyl group. Deuteration of β-d-methylglucoside was found to be highly regioselective, and chirality was retained. Other substrates such as pyranosides (e.g., methyl-β-d-glucopyranoside), protected pyranosides (e.g., methyl 4,6-O-isopropylidene-β-d-glucopyranoside), and furanosides (e.g., ribose) were all compatible under the labeling conditions. In addition, deuterium and tritium labeling of thioether substructures in complex molecules was also achieved using the same catalyst (Scheme [8]).[29] The heterogeneous catalyst, Ru@PVP nanoparticle, was applied in the selective HIE reaction of bioactive aza-compounds, including chiral amines and peptides, with retention of chirality (Scheme [9]).[30] DFT calculations indicated that the selectivity for the α-position to nitrogen atom derived from a four-membered dimetallacycle as the key intermediate.

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Scheme 7 Ru/C-catalyzed deuteration of sugars
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Scheme 8 Ru/C-catalyzed deuteration and tritiation of thioethers
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Scheme 9 Ru-nanoparticle-catalyzed HIE of aza-compounds
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Scheme 10 Shvo-Ru-catalyzed α,β-deuteration of tertiary amines

In contrast with the α-position-selectivity presented in heterogeneous ruthenium catalyzed HIE reactions of tertiary amines, the homogeneous Shvo-Ru catalyst[31] was found by Beller and co-workers to execute deuteration at both the α- and β-positions[32] (Scheme [10]). The reaction proceeded via a hydrogen autotransfer mechanism (the ‘borrowing hydrogen’ strategy), with i-PrOH-d 8 acting as deuterium source. This allowed for the labeling of pharmaceuticals, such as Sunitinib (a multitargeted receptor tyrosine), Lidocaine (a commonly used local anesthetic), and Metoclopramide (antiemetic drug), with high degrees of deuterium incorporation.

Unlike tertiary amines, primary and secondary amines underwent α-deuteration exclusively in the HIE reaction catalyzed by a monohydrido-bridged ruthenium complex[33] (Scheme [11]). Instead of the direct C–H bond activation or hydrogen transfer mechanism mentioned above, this reaction might proceed via a β-H elimination process. The pharmaceuticals Sertraline (antidepressant) and Pregabalin (a medicine used for treating pain caused by nerve damage) were selectively deuterated.

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Scheme 11 Monohydrido-bridged-Ru-complex-catalyzed deuteration of primary and secondary amines

In 2020, Ackermann’s group reported a ruthenium(II) biscarboxylate-catalyzed ortho-deuteration and tritiation with carboxylic acid as directing group, providing a method for late-stage C–H deuteration and tritiation of complex molecules[34] (Scheme [12]). An ortho-metallated ruthenacycle, which was generated via a base-assisted internal electrophilic type substitution (BIES) C–H activation, was proposed as the key intermediate of the reaction.

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Scheme 12 ortho-Deuteration and tritiation enabled by a Ru(II) catalyst

# 3.3

Iridium

In the 1990s, Hesk et al.[35] and Heys’s group[36] reported late-stage HIE reactions of aromatics by the use of ­Crabtree’s catalyst (Figure [3]).[37] After that, an array of modified Ir(I) catalysts were developed and used to achieve HIE reactions of complex molecules (Figure [4]).[38] [39] [40]

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Figure 3 Crabtree’s Ir(I)-complex-catalyzed HIE
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Figure 4 Ir(I) catalysts for HIE

Kerr et al. found that a Ir-NHC-P complex exhibited good selectivity in ortho-directed deuteration or tritiation of aromatic C–H bonds in complex molecules.[39] Directing groups, such as amide, N-heterocycles, and sulfonamide, were well tolerated (Scheme [13a]).[39b] [c] Besides, for a substrate containing two distinct directing groups (sulfonamide and pyrazole), the site-selectivity of deuteration was dominated by iridium catalysts (Scheme [13b]).[39d,e] Other modified Ir(I) complexes such as Burgess’ catalyst,[40a] Tamm’s catalyst,[40b] [c] and Pieters’s nanoparticle catalyst[40d,e] were also applied in labeling of bioactive molecules and pharmaceuticals (Figure [5]).

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Scheme 13 Kerr’s Ir-catalyzed deuteration and tritiation of aryl C–H bonds
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Figure 5 Other Ir-catalyzed deuteration and tritiation of aryl C–H bonds
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Figure 6 Ir-catalyzed deuteration of C(sp3)–H bonds
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Figure 7 PCP-Ir-complex-catalyzed deuteration of alkenyl C–H bonds
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Scheme 14 Fe-catalyzed HIE

Ir(I) catalysts were also recognized as powerful tools in C(sp3)–H functionalizations, allowing tertiary amine pharmaceuticals[41a] (mirtazapine, azaperone, and caffeine) and peptides[41b] to be successfully labeled (Figure [6]). These reactions proceeded through a five-membered ring Ir intermediate, resulting in good deuterium incorporations at the α-position to nitrogen and the β-position to the carbonyl group.

In addition, a pincer-type iridium catalyst, described by Hartwig’s group, has been used to selectively label olefins in complex molecules (Figure [7]).[42] Since the H/D exchange occurred at a much faster rate for trans hydrogen atoms than for their cis counterparts, a selective deuteration in the complex molecules tiamulin and forskolin was achieved by terminating the reaction in 5–10 minutes. In contrast, a high degree of deuteration was obtained in altrenogest by prolonging the reaction time to 20 hours. No migration of double bonds occurred during the labeling.


# 3.4

Other Metals

Other metals, including manganese, iron, cobalt, nickel, and rhodium, have been found to catalyze HIE reactions;[7] however, applications of these catalysts in LSF are rare. In 2016, Chirik and co-workers reported an Fe-catalyzed C(sp2)–H labeling of pharmaceuticals (Scheme [14]).[43] In this methodology, directing groups are not necessary and the site selectivity is orthogonal to the Ir-catalyzed reaction. Deuteration and tritiation of various pharmaceuticals are demonstrated. The exact mechanism was not identified in their original publication, and in a following study it was found that FeD4(CNC–ligand) and FeD2N2(CNC–ligand) are active intermediates, which form through a facile oxidative addition of the initial catalyst to the D–D bond.[44]

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Scheme 15 Ni-catalyzed HIE

In 2018, the same group reported a Ni-catalyzed site-selective HIE reaction of C(sp2)–H bonds in nitrogen heteroarenes.[45a] An α-diamine nickel hydride complex offered a distinct site selectivity with other HIE metal catalysts, such as Crabtree’s and Kerr’s iridium species (Scheme [15a]). The Ni-catalyzed labeling occurs at the α-positions to N-heteroatoms and nitrogen-directed C–H bonds in an adjacent ring. Tritiation of a range of pharmaceuticals has been successfully conducted under a low pressure of T2 gas (0.15 atm). The specific activity was >15 Ci/mmol (>0.5 T/molecule) in most cases, which met the general specific activity requirements for use of tritium labeled drug candidates in ADME studies (Scheme [15b]). One year later, a second generation nickel hydride precatalyst bearing a more bulky and electron-releasing α-diimine was developed by the same group (Scheme [15c]).[45b] Compared with the previous Ni-precatalyst, this dimer is more labile and easily dissociates to monomeric nickel hydride, which is the catalytic-active species for C–H activation, resulting in an improvement of reactivity and a broader substrate scope.


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# 4

Summary

In recent years, hydrogen isotope exchange has emerged as an increasingly powerful tool for the isotopic labeling of complex molecules. Enabled by either non-transition-metal- or transition-metal-catalysts, an exclusive site-selectivity has been achieved in many elegant applications. These reactivities mainly occur at positions adjacent to carbonyl groups and heteroatoms (for C(sp3)–H bonds), or under the domination of directing groups (for C(sp2)–H bonds). For unbiased C–H bonds that are remote from a functional group, selective labeling methods are underdeveloped. To further expand the area of HIE reactions, and especially to widen applications in late-stage functionalization, exploration of new activation modes and catalysts is still required.


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Corresponding Author

Hang Shi
Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University
18 Shilongshan Road, Hangzhou 310024, Zhejiang Province
P. R. of China   

Publication History

Received: 16 November 2020

Accepted after revision: 14 January 2021

Accepted Manuscript online:
14 January 2021

Article published online:
08 February 2021

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Zoom Image
Qi-Kai Kang was born and grew up in Zhejiang, P. R. of China. He received his Ph.D. at Shanghai Institute of Organic Chemistry (SIOC) under the direction of Prof. Yong Tang in 2016. After graduation, he joined the group of Prof. Keiji Maruoka at Kyoto University (Japan) as a postdoctoral researcher. In 2019, he joined Hang Shi’s group at Westlake University (P. R. of China). His research interests focus on organometallic methodology and asymmetric catalysis.
Zoom Image
Hang Shi was born and grew up in Liaoning, P. R. of China. His graduate studies were carried out at Peking University under the direction of Prof. Zhen Yang, culminating in a Ph.D. degree in 2013. Then, he joined the group of Prof. Tobias Ritter at Harvard University (USA), as a postdoctoral researcher. During that period, he also performed part of the research at the Massachusetts General Hospital. At the end of 2015, he moved to the Scripps Research Institute and joined Prof. Jin-Quan Yu’s group. In 2018, he began his independent career at Westlake University (P. R. of China). His research interests focus on organometallic methodology and asymmetric catalysis.
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Scheme 1 HIE reactions used to discover new drugs
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Scheme 2 Organic-base-catalyzed deuteration
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Scheme 3 Organic-acid-catalyzed deuteration
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Scheme 4 B(C6F5)3-catalyzed deuteration of pharmaceutical compounds
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Scheme 5 Photoredox-catalyzed HIE of tertiary amines and peptides
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Scheme 6 Photoredox-catalyzed deuteration of formyl C–H bonds and C(sp3)–H bonds
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Figure 1 Pd/C-catalyzed deuteration of nucleosides and bioactive molecules
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Figure 2 Tritiation of insulin through solid-state catalytic isotope exchange
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Scheme 7 Ru/C-catalyzed deuteration of sugars
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Scheme 8 Ru/C-catalyzed deuteration and tritiation of thioethers
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Scheme 9 Ru-nanoparticle-catalyzed HIE of aza-compounds
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Scheme 10 Shvo-Ru-catalyzed α,β-deuteration of tertiary amines
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Scheme 11 Monohydrido-bridged-Ru-complex-catalyzed deuteration of primary and secondary amines
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Scheme 12 ortho-Deuteration and tritiation enabled by a Ru(II) catalyst
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Figure 3 Crabtree’s Ir(I)-complex-catalyzed HIE
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Figure 4 Ir(I) catalysts for HIE
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Scheme 13 Kerr’s Ir-catalyzed deuteration and tritiation of aryl C–H bonds
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Figure 5 Other Ir-catalyzed deuteration and tritiation of aryl C–H bonds
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Figure 6 Ir-catalyzed deuteration of C(sp3)–H bonds
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Figure 7 PCP-Ir-complex-catalyzed deuteration of alkenyl C–H bonds
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Scheme 14 Fe-catalyzed HIE
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Scheme 15 Ni-catalyzed HIE