Synthesis 2023; 55(11): 1700-1705
DOI: 10.1055/a-1948-3335
paper
Special Issue dedicated to Prof. Cristina Nevado, recipient of the 2021 Dr. Margaret Faul Women in Chemistry Award

A Seven-Step Total Synthesis of (–)-Thebaine

Shen Tan
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Yu-Tao He
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Ping Lan
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
b   Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, P. R. of China
,
Lorenzo V. White
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
› Institutsangaben
We thank the National Natural Science Foundation of China (Grant No. 22250410258) and the Ministry of Science and Technology of the People's Republic of China for financial support.


This paper is dedicated to Professor Cristina Nevado, University of Zürich, in recognition of her receipt of the 2021 Dr. Margaret Faul Women in Chemistry Award

Abstract

The morphinan alkaloid (–)-thebaine is an industrially important chemical intermediate deployed in the semi-synthesis of various opioid medicines. Here, a seven-step total synthesis of this natural product is reported from simple, commercially available starting materials. The pivotal aryl allyl ether substrate, which is obtained through successive Suzuki-Miyaura cross-coupling and Mitsunobu substitution reactions, was engaged in a double-Heck cyclization sequence. The tetracyclic product of these processes was subjected to a photochemical hydroamination reaction that generated a N-Boc piperidine derivative embodying the full pentacyclic morphinan framework. Over a further three simple steps, this last compound was converted into (–)-thebaine.

Supporting Information



Publikationsverlauf

Eingereicht: 05. August 2022

Angenommen: 21. September 2022

Accepted Manuscript online:
21. September 2022

Artikel online veröffentlicht:
08. November 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

    • 1a Berényi S, Csutorás C, Sipos A. Curr. Med. Chem. 2009; 16: 3215
    • 1b Hudlicky T. Can. J. Chem. 2015; 93: 492 ; and references cited therein
    • 2a Fossati E, Narcross L, Ekins A, Falgueyret J.-P, Martin VJ. J. PLoS One 2015; 10: e0124459
    • 2b Li X, Krysiak-Baltyn K, Richards L, Jarrold A, Stevens GW, Bowser T, Speight RE, Gras SL. ACS Omega 2020; 5: 9339 ; and references cited therein

      For various perspectives on supply chain matters, see:
    • 3a Thangavel T, Wilson CR, Jones S, Scott JB, Voglmayr H. Plant Dis. 2017; 101: 392
    • 3b Thangavel T, Jones S, Scott JB. Plant Dis. 2018; 102: 2277
    • 3c Smolke C.; STAT, 2020; https://www.statnews.com/2020/07/16/synthetic-biology-yeast-help-fix-broken-drug-supply-chain/ (accessed May 24, 2022)
    • 3d Sousa JP. M, Ramos MJ, Fernandes PA. ChemBioChem 2022; 23: e202100623
  • 4 Lipp A, Ferenc D, Gütz C, Geffe M, Vierengel N, Schollmeyer D, Schäfer HJ, Waldvogel SR, Opatz T. Angew. Chem. Int. Ed. 2018; 57: 11055 ; and references cited therein
  • 5 Reed JW, Hudlicky T. Acc. Chem. Res. 2015; 48: 674
  • 6 White LV, Hu N, He Y.-T, Banwell MG, Lan P. Angew. Chem. Int. Ed. 2022; e202203186
  • 7 Zhan K, Li Y. Catalysts 2017; 7: 337 ; and references cited therein
  • 8 Eagon S, Delieto C, McDonald WJ, Haddenham D, Saavedra J, Kim J, Singaram B. J. Org. Chem. 2010; 75: 7717
  • 9 Dounay AB, Overman LE, Wrobleski AD. J. Am. Chem. Soc. 2005; 127: 10186
  • 10 Bach T, Schröder J. J. Org. Chem. 1999; 64: 1265
  • 11 Brice JL, Meerdink JE, Stahl SS. Org. Lett. 2004; 6: 1845
  • 12 For a recent review covering intramolecular double Heck reactions, see: Ju B, Kong W. Asian J. Org. Chem. 2020; 9: 1154
  • 13 Nguyen TM, Nicewicz DA. J. Am. Chem. Soc. 2013; 135: 9588
  • 14 Trost BM, Tang W, Toste FD. J. Am. Chem. Soc. 2005; 127: 14785
  • 15 Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T. Synlett 2007; 2859
  • 16 Srimurugan S, Su C.-J, Shu H.-C, Murugan K, Chen C. Monatsh. Chem. 2012; 143: 171
  • 17 Barton DH. R, Crich D. Tetrahedron 1985; 41: 4359
    • 18a Coop A, Rice KC. Heterocycles 1998; 49: 43
    • 18b Huang X.-R, Srimurugan S, Lee G.-H, Chen C. J. Chin. Chem. Soc. 2011; 58: 101
  • 19 Sandulenko IV, Semenova DV, Zelentsova MV, Moiseev SK, Koldobskii AB, Peregudov AS, Bushmarinov IS, Kalinin VN. J. Fluorine Chem. 2016; 189: 7
  • 20 Caldwell GW, Gauthier AD, Mills JE. Mag. Res. Chem. 1996; 34: 505
  • 21 For a previous single-crystal X-ray analysis of compound 1, see: Mahler CH, Stevens ED, Trudell ML, Nolan SP. Acta Crystallogr., Sect. C 1996; 52: 3193
  • 22 Kok GB, Scammells PJ. RSC Adv. 2012; 2: 11318
  • 23 Najmi AA, Bhat MF, Bischoff R, Poelarends GJ, Permentier HP. ChemElectroChem 2021; 8: 2590
  • 24 Liu X, Jiang S, Kong L, Ye R, Xiao L, Xu X, He Q, Wei Y, Li Z, Sun H, Xie Q, Xu X, Lu Y, Wang Y, Li W, Fu W, Qiu Z, Liu J, Shao L. ACS Chem. Neurosci. 2021; 12: 1018 ; and references cited therein
  • 25 Still WC, Kahn M, Mitra A. J. Org. Chem. 1978; 43: 2923
  • 26 Amos SG. E, Nicolai S, Waser J. Chem. Sci. 2020; 11: 11274
  • 27 Soldatova N, Postnikov P, Troyan AA, Yoshimura A, Yusubov MS, Zhdankin VV. Tetrahedron Lett. 2016; 57: 4254
  • 28 Bhasin KK, Singh J. J. Organomet. Chem. 2002; 658: 71
    • 29a Mudryk B, Sapino C, Dung JS, Sebastian A. US Patent 6365742 B2, 2002
    • 29b Lin Z, Francis CA, Kaldahl CA, Antczak KG, Kumar V. US Patent 6790959 B1, 2004
  • 30 Bartels-Keith JR. J. Chem. Soc. C 1966; 617
  • 31 CCDC 2176231 (1) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 32 Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JA. K, Puschmann H. J. Appl. Crystallogr. 2009; 42: 339
  • 33 Sheldrick GM. Acta Crystallogr., Sect. A 2015; 71: 3
  • 34 Sheldrick GM. Acta Crystallogr., Sect. C 2015; 71: 3