Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization

Kang, Qi‐Kai; Shi, Hang

doi:10.1055/a-1354-0367

Cited by 37 publications

(11 citation statements)

References 97 publications

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“…Deuterium is a stable and non-radioactive isotope of hydrogen and deuterium-labeled compounds are widely used in a broad range of disciplines [1][2][3][4][5][6] . While some applications need deuterated compounds with high overall deuterium content without considering site-and stereoselectivity, others require deuteration at a distinct position and/or in a stereoselective manner.…”

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confidence: 99%

“…Approval of the first deuterated drug, deutetrabenazine, by the US Food and Drug Administration in 2017 has further spurred the development of novel deuteration methods. While considerable progress has been made on regioselective nonasymmetric deuteration [2][3][4] , asymmetric deuteration remains underexplored. In this regard, protocols employing enantioenriched starting materials have emerged, allowing for stereoretentive hydrogen isotope exchange [7][8][9][10][11] and highly diastereoselective deuteration 12,13 .…”

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Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions

et al. 2022

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Site- and enantioselective incorporation of deuterium into organic compounds is of broad interest in organic synthesis, especially within the pharmaceutical industry. While catalytic approaches relying on two-electron reaction manifolds have allowed for stereoselective delivery of a formal deuteride (D–) or deuteron (D+) at benzylic positions, complementary strategies that make use of one-electron deuterium atom transfer and target non-benzylic positions remain elusive. Here we report a photochemical approach for asymmetric radical deuteration by utilizing readily available peptide- or sugar-derived thiols as the catalyst and inexpensive deuterium oxide as the deuterium source. This metal-free platform enables four types of deuterofunctionalization reactions of exocyclic olefins and allows deuteration at non-benzylic positions with high levels of enantioselectivity and deuterium incorporation. Computational studies reveal that attractive non-covalent interactions are responsible for stereocontrol. We anticipate that our findings will open up new avenues for asymmetric deuteration.

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Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions

et al. 2022

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“…Such traditional methods include the isotope exchange in acidic postions 8 , reductive methods using deuterium gas 9 or metalldeuterides 10 , or enolization followed by introduction of a deuterated methyl group. 11 However, these approaches are limited in their applicability to complex molecules such as pharmacophores. In this context, the latestage deuteration of bioactive molecules becomes highly attractive, since it inherently avoids the above-mentioned drawbacks (Figure 1A), which is for example evidenced by recent reports on photo-catalyzed deuterations based on HAT processes and transition metal-catalyzed protocols.…”

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“…Employing a substrate bearing two trifluoromethyl groups in 3,5-position 10 only aliphatic C-H deuteration was observed. Various other carboxylic acids bearing different aromatic EWG substituents (11)(12)(13)(14)(15) were well tolerated under the reaction conditions. We observed high levels of deuterium incorporation (up to Dtotal=8.5) for these substrates.…”

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Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids

Uttry¹,

Mal²,

Gemmeren

2021

Preprint

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Carboxylic acid moieties are highly abundant in bioactive molecules. In this study we describe the late-stage β C(sp3)–H deuteration of free carboxylic acids. Based on our finding that the C–H activation with our catalyst systems is reversible, the de-deuteration process was first optimized. The resulting conditions involve a novel type of ligands, which, amongst other positions, for the first time enables the functionalization of non-activated methylene β-C(sp3)–H bonds and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks.

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Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids

Uttry¹,

Mal²,

Gemmeren³

2021

Preprint

View full text Add to dashboard Cite

Carboxylic acid moieties are highly abundant in bioactive molecules. In this study we describe the late-stage β-C(sp3)–H deuteration of free carboxylic acids. Based on our finding that the C–H activation with our catalyst systems is reversible, the de-deuteration process was first optimized. The resulting conditions involve ethylenediamine-based ligands, which, amongst other positions, for the first time enables the functionalization of non-activated methylene β-C(sp3)–H bonds and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks.

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Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization

Cited by 37 publications

References 97 publications

Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions

Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions

Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids

Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids

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