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. 2021 Nov 10;12(46):15291-15297.
doi: 10.1039/d1sc04980a. eCollection 2021 Dec 1.

Asymmetric synthesis of dibenzo[ b, d]azepines by Cu-catalyzed reductive or borylative cyclization

Patricia Rodríguez-Salamanca  1 , Rocío Martín-de la Calle  1 , Verónica Rodríguez  2 , Pedro Merino  3 , Rosario Fernández  2 , José M Lassaletta  1 , Valentín Hornillos  1   2
Affiliations

Asymmetric synthesis of dibenzo[ b, d]azepines by Cu-catalyzed reductive or borylative cyclization

Patricia Rodríguez-Salamanca et al. Chem Sci. .

Abstract

A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d]azepines is described. Use of 2'-vinyl-biaryl-2-imines as substrates and in situ formed [CuI/(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereo- and enantioselectivities (>20 : 1 d.r., up to 99% ee). Moreover, the same catalyst was found to facilitate a related borylative cyclization to afford versatile boronic ester derivatives. Both reactions proceed under mild conditions (rt) and are applicable to a variety of substituted aromatic and heterocyclic derivatives.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Configurational stability of acyclic and bridged biaryls.
Fig. 2
Fig. 2. Selected bioactive dibenzoazepines and related analogues.
Scheme 1
Scheme 1. Catalytic asymmetric synthesis of axially chiral 7-membered cyclic bridged biaryl amines.
Scheme 2
Scheme 2. Substrate scope. Reactions performed on 0.2 mmol scale for a 36 h period at rt. Yields of isolated product after chromatography. A single diastereomer was observed by 1H NMR in the crude reaction mixtures. Ee's were determined by HPLC on chiral stationary phases. aReaction performed on 2 mmol (566 mg) scale.
Scheme 3
Scheme 3. Kinetic resolution of rac-1Fa. Reaction performed on 0.2 mmol scale for a 36 h period at rt. Yields of isolated product after chromatography. Ee's were determined by HPLC on chiral stationary phases.
Scheme 4
Scheme 4. Copper-catalyzed borylative cyclization. Reactions performed on 0.2 mmol scale. Yields of isolated product after chromatography. A single diastereomer (>20 : 1 d.r.) was observed as determined by 1H NMR in the crude reaction mixtures. Ee's were determined by HPLC analysis.
Scheme 5
Scheme 5. Derivatization reactions.
Scheme 6
Scheme 6. Computational analysis for the axial epimerization for dibenzoazepines 2A (wb97xd/def2tzvp//wb97xd/def2svp/cpcm = diisopropylether). Relative free energies are given in brackets in kcal mol−1. Data for R = Ph in plain text, data for R = tBu in italics. For details see the ESI.
Scheme 7
Scheme 7. Synthesis of tert-butyl-substituted dibenzoazepine 2Aw.
Scheme 8
Scheme 8. Catalytic cycle and stereochemical model.
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References

    1. Bringmann G. Gulder T. Gulder T. A. M. Breuning M. Chem. Rev. 2011;111:563–639. doi: 10.1021/cr100155e. - DOI - PubMed
    2. Smyth J. E. Butler N. M. Keller P. A. Nat. Prod. Rep. 2015;32:1562–1583. doi: 10.1039/C4NP00121D. - DOI - PubMed
    3. Wencel-Delord J. Panossian A. Leroux F. R. Colobert F. Chem. Soc. Rev. 2015;44:3418–3430. doi: 10.1039/C5CS00012B. - DOI - PubMed
    4. Wang Y.-B. Tan B. Acc. Chem. Res. 2018;51:534–547. doi: 10.1021/acs.accounts.7b00602. - DOI - PubMed
    5. Cheng J. K. Xiang S.-H. Li S. Ye L. Tan B. Chem. Rev. 2021;121:4805–4902. doi: 10.1021/acs.chemrev.0c01306. - DOI - PubMed
    6. Lassaletta J. M., Atropisomerism and Axial Chirality, World Scientific, New Jersey, 2019
    1. Bringmann G. Mortimer A. J. P. Keller P. A. Gresser M. J. Garner J. Breuning M. Angew. Chem., Int. Ed. 2005;44:5384–5427. doi: 10.1002/anie.200462661. - DOI - PubMed
    1. Pira S. L. Wallace T. W. Graham J. P. Org. Lett. 2009;11:1663–1666. doi: 10.1021/ol900333c. - DOI - PubMed
    1. Superchi S. Casarini D. Laurita A. Bavoso A. Rosini C. Angew. Chem., Int. Ed. 2001;40:451–454. doi: 10.1002/1521-3773(20010119)40:2<451::AID-ANIE451>3.0.CO;2-2. - DOI - PubMed
    2. Zhang Y. Liu Y.-Q. Hu L. Zhang X. Yin Q. Org. Lett. 2020;22:6479–6483. doi: 10.1021/acs.orglett.0c02282. - DOI - PubMed
    3. Guo Y. Liu M.-M. Zhu X. Zhu L. He C. Angew. Chem., Int. Ed. 2021;60:13887–13891. doi: 10.1002/anie.202103748. - DOI - PubMed
    1. Zhang Y. Chang Z. Zhao H. Crespi S. Feringa B. L. Zhao D. Chem. 2020;6:2420–2429.

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