Synthesis 2020; 52(15): 2185-2189
DOI: 10.1055/s-0040-1707390
psp
© Georg Thieme Verlag Stuttgart · New York

A Concise and Modular Three-Step Synthesis of (S)-Verapamil using an Enantioselective Rhodium-Catalyzed Allylic Alkylation Reaction

Mai-Jan Tom
a  Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada   Email: Andrew.Evans@chem.queensu.ca
,
Ben W. H. Turnbull
a  Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada   Email: Andrew.Evans@chem.queensu.ca
,
a  Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada   Email: Andrew.Evans@chem.queensu.ca
b  Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, P. R. of China
› Author Affiliations
We sincerely thank the National Sciences and Engineering Research Council (NSERC) for a Discovery Grant and Queen’s University for generous financial support.
Further Information

Publication History

Received: 04 February 2020

Accepted after revision: 11 April 2020

Publication Date:
05 June 2020 (online)


§ Undergraduate researcher.

Abstract

A concise and modular asymmetric synthesis of the calcium channel blocker (S)-verapamil is described. This approach employs an enantioselective rhodium-catalyzed allylic alkylation reaction between an α-isopropyl-substituted benzylic nitrile and allyl benzoate to construct the challenging acyclic quaternary stereocenter. The terminal olefin then serves as a convenient synthetic handle for a hydroamination to introduce the phenethylamine moiety, furnishing (S)-verapamil in three steps and 55% overall yield, thus providing the most efficient synthesis of this important pharmaceutical reported to date. Furthermore, given the modular nature of the synthesis, it can be readily modified to prepare structurally related bioactive agents.

Supporting Information

 
  • References


    • For select publications on medicinal drug candidates escaping from flatland, see:
    • 1a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
    • 1b Ritchie TJ, Macdonald SJ. F. Drug Discov. Today 2009; 14: 1011
    • 1c Lovering F. Med. Chem. Commun. 2013; 4: 515

      For select reviews on the enantioselective construction of quaternary carbon stereogenic centers, see:
    • 2a Corey EJ, Guzman-Perez A. Angew. Chem. Int. Ed. 1998; 37: 388
    • 2b Christoffers J, Mann A. Angew. Chem. Int. Ed. 2001; 40: 4591
    • 2c Denissova I, Barriault L. Tetrahedron 2003; 59: 10105
    • 2d Trost BM, Jiang C. Synthesis 2006; 369
    • 2e Quasdorf KW, Overman LE. Nature 2014; 516: 181 ; and pertinent references cited therein

      For recent reviews on the enantioselective construction of acyclic quaternary carbon stereogenic centers, see:
    • 3a Das JP, Marek I. Chem. Commun. 2011; 47: 4593
    • 3b Feng J, Holmes M, Krische MJ. Chem. Rev. 2017; 117: 12564
    • 5a Ramuz H. Helv. Chim. Acta 1975; 58: 2050
    • 5b Theodore LJ, Nelson WL. J. Org. Chem. 1987; 52: 1309
    • 5c Brenna E, Caraccia N, Fogliato G, Fronza G, Fuganti C. Tetrahedron 1997; 53: 10555
    • 5d Im DS, Cheong CS, Lee SH, Park H, Youn BH. Tetrahedron: Asymmetry 1999; 10: 3759
    • 5e Bannister RM, Brookes MH, Evans GR, Katz RB, Tyrrell ND. Org. Process. Res. Dev. 2000; 4: 467
    • 5f Brenna E, Fuganti C, Grasselli P, Serra S. Eur. J. Org. Chem. 2001; 1349
    • 5g Im DS, Cheong CS, Lee SH. J. Mol. Catal. B: Enzym. 2003; 26: 131
  • 6 Mermerian AH, Fu GC. Angew. Chem. Int. Ed. 2005; 44: 949
  • 7 Oliveira CC, Pfaltz A, Correia CR. D. Angew. Chem. Int. Ed. 2015; 54: 14036
  • 8 For an example of the formal asymmetric synthesis of verapamil, which utilizes a stereospecific copper-catalyzed allylic arylation, see: Kobayashi Y, Saeki R, Nanba Y, Suganuma Y, Morita M, Nishimura K. Synlett 2017; 28: 2655

    • For recent reviews on the rhodium-catalyzed allylic substitution reaction, see:
    • 9a Evans PA, Leahy DK. In Modern Rhodium-Catalyzed Organic Reactions . Evans PA. Wiley-VCH; Weinheim: 2005. Chap. 10, 191-214
    • 9b Turnbull BW. H, Evans PA. J. Org. Chem. 2018; 83: 11463
  • 10 For mechanistic studies, see: Evans PA, Nelson JD. J. Am. Chem. Soc. 1998; 120: 5581

    • For related examples of enantioselective rhodium-catalyzed allylic substitution reactions, see:
    • 11a Evans PA, Clizbe EA, Lawler MJ, Oliver S. Chem. Sci. 2012; 3: 1835
    • 11b Wright TB, Evans PA. J. Am. Chem. Soc. 2016; 138: 15303
    • 11c Wright TB, Turnbull BW. H, Evans PA. Angew. Chem. Int. Ed. 2019; 58: 9886
  • 12 Turnbull BW. H, Evans PA. J. Am. Chem. Soc. 2015; 137: 6156
  • 13 For the α-arylation of alkyl nitriles, see: Jiao Z, Chee KW, Zhou JS. J. Am. Chem. Soc. 2016; 138: 16240
  • 14 Carlier PR, Madura JD. J. Org. Chem. 2002; 67: 3832
  • 15 Langlotz I, Marsch M, Harms K, Boche G. Z. Kristallogr. New. Cryst. Struct. 1999; 214: 509
  • 16 Rucker RP, Whittaker AM, Dang H, Lalic G. J. Am. Chem. Soc. 2012; 134: 6571
  • 17 Laguerre M, Boyer C, Carpy A, Panconi E, Cognic F, Vaugien B. Eur. J. Med. Chem. 1990; 25: 351
  • 18 Chen G, Wang Z, Wu J, Ding K. Org. Lett. 2008; 10: 4573
  • 19 Theodore LJ, Nelson WL. J. Labelled Compd. Radiopharm. 1987; 24: 1195
  • 20 The spectral data were obtained in CD3OD rather than CDCl3 because of the difficulties in observing one of the quaternary atoms; more details are given in the SI.