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. 2020 Feb 21;22(4):1557-1562.
doi: 10.1021/acs.orglett.0c00154. Epub 2020 Feb 11.

Synthesis of Enantioenriched α-Deuterated α-Amino Acids Enabled by an Organophotocatalytic Radical Approach

Peng Ji  1 , Yueteng Zhang  1 , Yue Dong  1 , He Huang  1 , Yongyi Wei  1 , Wei Wang  1
Affiliations

Synthesis of Enantioenriched α-Deuterated α-Amino Acids Enabled by an Organophotocatalytic Radical Approach

Peng Ji et al. Org Lett. .

Abstract

A mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the well-established two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the long-standing challenge of the installation of sterically demanding side chains into α-amino acids.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Examples of α-deuterated amino acid therapeutics.
Scheme 1.
Scheme 1.
Synthesis of enantioenriched α-deuterated amino acids.
Scheme 2.
Scheme 2.
Scope of the organophotoredox-mediated asymmetric α-deuterated α-amino Acids synthesis with simple carboxylic acids[a] [a] Reaction conditions: unless specified, a mixture of 1 (0.3 mmol), 2 (0.2 mmol) and Mes-Acr-Me+•ClO4− (0.01 mmol) in anhydrous MeCN (2.0 mL) was irradiated with 40 W Kessil blue LEDs in N2 atmosphere at rt for specified time. [b] Yield of isolated products. [c] Deuteration and dr determined by 1H NMR. [d] No desired product was obtained under the standard reaction conditions. The reaction was carried out, as follows: a mixture of 1 (0.24 mmol), 2 (0.2 mmol) Cs2CO3 (0.24 mmol) and 4CzIPN (0.01 mmol) in anhydrous DMF (2.0 mL) was irradiated with 40 W Kessil blue LEDs in N2 atmosphere at rt for specified time.
Scheme 3.
Scheme 3.
Late-stage functionalization of pharmaceutics and natural products, conversion to amino acids and radical clock reaction. [a] Reaction conditions: unless specified, see footnote [a] in Scheme 2 and see SI. [b] Yield of isolated products. [c] Deuteration and dr determined by 1H NMR.
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References

    1. Furuta T; Takahashi H; Kasuya Y Evidence for a carbanion intermediate in the elimination of ammonia from L-histidine catalyzed by histidine ammonia-lyase. J. Am Chem. Soc 1990, 112, 3633; - PubMed
    2. Baldwin JE; Adlington RM; Marquess DG; Pitt AR; Porter MJ; Russell AT Evidence for an insertion-homolysis mechanism for carbon-sulphur bond formation in penicillin biosynthesis; 1. Synthesis of tripeptide probes. Tetrahedron, 1996, 52, 2515;
    3. Church NJ; Young DW Synthesis of the suicide substrate D-propargylglycine stereospecifically labelled with deuterium and investigation of its oxidation by D-amino acid oxidase. J. Chem. Soc. Perkin Trans. 1 1998, 52, 1475.
    1. Rose JE; Leeson PD; Gani D J Mechanisms and stereochemistry of the activation of (2S)- and (2R)-serine O-sulfate as suicide inhibitors for Escherichia coli glutamic acid decarboxylase. J. Chem. Soc. Chem. Commun 1992, 1784.
    1. Lian L-Y Middleton DA Labelling approaches for protein structural studies by solution-state and solid-state NMR. Prog. Nucl. Msgn. Reson. Spectrosc 2001, 39, 171;
    2. Sack I; Balazs YS; Rahimipour S; Vega S Solid-State NMR Determination of Peptide Torsion Angles: Applications of 2H-Dephased REDOR. J. Am. Chem. Soc 2000, 122, 12263;
    3. Gardner KH; Kay LE Production and Incorporation of 15N, 13C, 2H (1H-δ1 Methyl) Isoleucine into Proteins for Multidimensional NMR Studies. J. Am. Chem. Soc 1997, 119, 7599;
    4. Lastra E; Hegedus LS Synthesis of compounds containing two adjacent carbon-13 labels by photolytic reactions of chromium carbene complexes. J. Am. Chem. Soc 1993, 115, 87.

    1. For reviews of deuterium application in biomedical sciences and drug discovery, see:

    2. Atzrodt J; Derdau V; Kerr WJ; Reid M Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences. Angew. Chem. Int. Ed 2018, 57, 1758; - PubMed
    3. Yang J in Deuterium: Discovery and Applications in Organic Chemistry, Elsevier, Amsterdam, 2016, pp. 1;
    4. Gant TG Using Deuterium in Drug Discovery: Leaving the Label in the Drug. J. Med. Chem 2014, 57, 3595; - PubMed
    5. Pirali T; Serafini M; Cargnin S; Genazzani AA Applications of Deuterium in Medicinal Chemistry. J. Med. Chem 2019, 62, 5276; - PubMed
    6. Simmons EM; Hartwig JF On the interpretation of deuterium kinetic isotope effects in C-H bond functionalizations by transition-metal complexes. Angew. Chem., Int. Ed 2012, 51, 3066; - PubMed

    7. and selected examples of deuterated therapeutics:

    8. Pirali T; Serafini M; Cargnin S; Genazzani AA Applications of Deuterium in Medicinal Chemistry. J. Med. Chem 2019, 62, 5276; - PubMed
    9. Maltais F; Jung YC; Chen M; Tanoury J; Perni RB; Mani N; Laitinen L; Huang H; Liao S; Gao H; Tsao H; Block E; Ma C; Shawgo RS; Town C; Brummel CL; Howe D; Pazhanisamy S; Raybuck S; Namchuk M; Bennani YL In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats. J. Med. Chem 2009, 52, 7993; - PubMed
    10. Yamamoto T; Tokunaga E; Nakamura S; Shibata N; Toru T Synthesis and configurational stability of (S)- and (R)-deuteriothalidomides. Chem. Pharm. Bull 2010, 58, 110; - PubMed
    11. Jacques V; Czarnik AW; Judge TM; Van der Ploeg LH; DeWitt SH Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc. Natl. Acad. Sci. U.S.A 2015, 112, E1471. - PMC - PubMed

    1. For reviews of synthesis deuterated building blocks, see: 4e and

    2. Atzrodt J; Derdau V; Kerr WJ; Reid M C-H Functionalisation for Hydrogen Isotope Exchange. Angew. Chem., Int. Ed 2018, 57, 3022; - PubMed
    3. Sattler A Hydrogen/Deuterium (H/D) Exchange Catalysis in Alkanes. ACS Catal 2018, 8, 2296.

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