Synlett 2016; 27(08): 1145-1164
DOI: 10.1055/s-0035-1561329
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© Georg Thieme Verlag Stuttgart · New York

Conjuring a Supernatural Product – DelMarine

Kanny K. Wan
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pine Rd, La Jolla, CA 92037, USA   eMail: rshenvi@scripps.edu
,
Ryan A. Shenvi*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pine Rd, La Jolla, CA 92037, USA   eMail: rshenvi@scripps.edu
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Publikationsverlauf

Received: 22. September 2015

Accepted after revision: 21. Dezember 2015

Publikationsdatum:
19. Februar 2016 (online)


Abstract

The asmarine alkaloids constitute a small family of terpene-nucleobase marine metabolites defined by a unique N-hydroxy-diazepine pharmacophore that effects moderate to potent cytotoxicity against several cancer cell lines. Isolation of the metabolites from an unidentified producer organism provided enough material for initial assay, but this material was soon exhausted, impeding further study. Procurement of material through synthesis is the obvious solution. Here we chronicle our discovery of simple but potent asmarine analogues that solve the material supply problem.

1 Introduction

2 Project Selection

3 Project Design

3.1 The Big Picture

3.2 Synthetic Strategy

3.3 Challenges in the Design

4 The Quest to Find Bioactive Asmarines

4.1 Model Systems as Proof of Concepts

4.2 Stereoselectivity Investigation with Clerodane-Appended Cyclization Precursors

4.2.1 Obtaining the Cyclization Precursor

4.2.2 Results from Cyclization Screening

4.3 Toward the Synthesis of Asmarine A

4.4 A Turning Point: Screening Forward

5 Biological Investigation of the Asmarine Scaffold

5.1 Cytotoxicity Assays of our Synthetic Intermediates and their Enantiomers

5.2 Synthesis of Analogues for a More In-Depth Biological Investigation

6 Synthesis of Simple Asmarine Analogues and their Cytotoxicity

7 Conclusion

 
  • References

  • 1 Pronin SV, Shenvi RA. J. Am. Chem. Soc. 2012; 134: 19604
  • 2 Jansen DJ, Shenvi RA. J. Am. Chem. Soc. 2013; 135: 1209
  • 3 Lu H.-H, Martinez MD, Shenvi RA. Nat. Chem. 2015; 7: 604
  • 4 Wan KK, Iwasaki K, Umotoy JC, Wolan DW, Shenvi RA. Angew. Chem. Int. Ed. 2015; 54: 2410
  • 5 Wan KK. Ph.D. Dissertation. The Scripps Research Institute; USA: 2015
  • 6 Yosief T, Rudi A, Stein Z, Goldberg I, Gravalos GM. D, Schleyer M, Kashman Y. Tetrahedron Lett. 1998; 39: 3323
  • 7 Yosief T, Rudi A, Kashman Y. J. Nat. Prod. 2000; 63: 299
  • 8 Rudi A, Aknin M, Gaydou E, Kashman Y. J. Nat. Prod. 2004; 67: 1932
  • 9 Rudi A, Shalom H, Schleyer M, Benayahu Y, Kashman Y. J. Nat. Prod. 2004; 67: 106
  • 10 Pronin SV, Shenvi RA. Nat. Chem. 2012; 4: 915
  • 11 Pappo D, Kashman Y. Tetrahedron 2003; 59: 6493
  • 12 Pappo D, Shimony S, Kashman Y. J. Org. Chem. 2005; 70: 199
  • 13 Pappo D, Rudi A, Kashman Y. Tetrahedron Lett. 2001; 42: 5941
  • 14 Ohba M, Tashiro T. Heterocycles 2002; 57: 1235
  • 15 Vik A, Gundersen L.-L. Tetrahedron Lett. 2007; 48: 1931
  • 16 Rodgen SA, Schaus SE. Angew. Chem. Int. Ed. 2006; 45: 4929
  • 17 Haesslein J, Jullian N. Curr. Top. Med. Chem. 2002; 2: 1037
  • 18 Sharma S, Mehndiratta S, Kumar S, Singh J, Bedi PM. S, Nepali K. Recent Pat. Anti-Cancer Drug Discovery 2015; 10: 308
  • 19 Suy S, Mitchell JB, Samuni A, Mueller S, Kasid U. Cancer 2005; 103: 1302
  • 20 Bobbitt JM, Flores MC. L. Heterocycles 1988; 27: 509
  • 21 Vik A, Hedner E, Charnock C, Samuelsen Ø, Larsson R, Gundersen L.-L, Bohlin L. J. Nat. Prod. 2006; 69: 381
  • 22 Kürti L, Chein R.-J, Corey EJ. J. Am. Chem. Soc. 2008; 130: 9031
  • 23 Sarma AS, Chattopadhyay P. J. Org. Chem. 1982; 47: 1727
  • 24 Giner-Sorolla A. J. Heterocycl. Chem. 1970; 7: 75
  • 25 Tokoroyama T. Synthesis 2000; 611
  • 26 Montgomery JA, Hewson K. J. Org. Chem. 1961; 26: 4469
  • 27 Adam W, Krebs O. Chem. Rev. 2003; 103: 4131
  • 28 Keck GE, Webb RR, Yates JB. Tetrahedron 1981; 37: 4007
  • 29 Schmidt VA, Alexanian EJ. Angew. Chem. Int. Ed. 2010; 49: 4491
  • 30 Okukado N, Negishi E.-i. Tetrahedron Lett. 1978; 19: 2357
  • 31 Negishi E.-i, Hu Q, Huang Z, Qian M, Wang G. Aldrichim. Acta 2005; 38: 71
  • 32 Garegg PJ, Regberg T, Stawinski J, Stromberg R. J. Chem. Soc., Perkin Trans. 2 1987; 271
  • 33 Giner-Sorolla A, Bendich A. J. Am. Chem. Soc. 1958; 80: 3932
  • 34 Wipf P, Lim S. Angew. Chem., Int. Ed. Engl. 1993; 32: 1068
  • 35 Chen J, Ma S. J. Org. Chem. 2009; 74: 5595
  • 36 Tintillier P, Dupas G, Bourguignon J, Queguiner G. Tetrahedron Lett. 1986; 27: 2357
  • 37 Ling T, Xu J, Smith R, Ali A, Cantrell CL, Theodorakis EA. Tetrahedron 2011; 67: 3023
  • 38 Donohoe TJ, Guyo PM, Helliwell M. Tetrahedron Lett. 1999; 40: 435
  • 39 Duthaler RO, Roberts JD. J. Am. Chem. Soc. 1978; 100: 4969
  • 40 Leach AG, Houk KN. J. Am. Chem. Soc. 2002; 124: 14820
  • 41 Adam W, Bottke N, Engels B, Krebs O. J. Am. Chem. Soc. 2001; 123: 5542
  • 42 Whitesides GM, Ehmann WJ. J. Org. Chem. 1970; 35: 3565
  • 43 Pasto DJ, Taylor RT. Org. React. 2004; 40: 91
  • 44 Iwasaki K, Wan KK, Oppedisano A, Crossley SW. M, Shenvi RA. J. Am. Chem. Soc. 2014; 136: 1300
  • 45 Lo JC, Yabe Y, Baran PS. J. Am. Chem. Soc. 2014; 136: 1304
  • 46 Wood K, Hannah R, Moravec RA (Promega Corp) CA2437253 A1, 2002
  • 47 Kangas L, Grönroos M, Nieminen A. Med. Biol. 1983; 62: 338
  • 48 Crouch SP. M, Kozlowski R, Slater KJ, Fletcher J. J. Immunol. Methods 1993; 160: 81
  • 49 Farfan A, Yeager T, Moravec R, Niles A. Cell Notes 2004; 10: 2
  • 50 Riss T, Moravec R, Niles A. Cell Notes 2005; 13: 16
  • 51 Gundersen LL. Phytochem. Rev. 2013; 12: 467
  • 52 Phillips AJ. Nat. Chem. 2011; 3: 575