Total synthesis of (–)-tubingensin B enabled by the strategic use of an aryne cyclization


Tubingensin B is an indole diterpenoid that bears a daunting chemical structure featuring a disubstituted carbazole unit, five stereogenic centres—three of which are quaternary—and a decorated [3.2.2]-bridged bicycle. We describe our synthetic design toward a concise and enantiospecific total synthesis of tubingensin B, which hinges on the strategic use of a transient aryne intermediate. Although initial studies led to unexpected reaction outcomes, we ultimately implemented a sequence of carbazolyne cyclization followed by Rh-catalysed fragmentation to install the seven-membered ring and vicinal quaternary stereocentres of the natural product. Coupled with a late-stage radical cyclization to construct the [3.2.2]-bridged bicycle, these efforts have enabled the total synthesis of tubingensin B. The design and evolution of our succinct total synthesis underscores the utility of long-avoided aryne intermediates for the introduction of structural motifs that have conventionally been viewed as challenging.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The structures of tubingensins B and A.
Figure 2: Retrosynthetic analysis of tubingensin B.
Figure 3: Synthesis of coupling fragment 7 and assembly of tetrasubstituted alkene 13.
Figure 4: The key aryne cyclization forges the C20–C11 linkage.
Figure 5: Radical cyclization and first generation total synthesis of tubingensin B.
Figure 6: Concise total synthesis of tubingensin B.


  1. 1

    TePaske, M. R., Gloer, J. B., Wicklow, D. T. & Dowd, P. F. The structure of tubingensin B: a cytotoxic carbazole alkaloid from the sclerotia of Aspergillus tubingensis. Tetrahedron Lett. 30, 5965–5968 (1989).

    CAS  Article  Google Scholar 

  2. 2

    Swenson, D. C., TePaske, M. R., Baenziger, N. C. & Gloer, J. B. Tubingensin B, a cytotoxic carbazole alkaloid from the sclerotia of Aspergillus tubingensis. Acta Cryst. C 53, 1447–1449 (1997).

    Article  Google Scholar 

  3. 3

    Bian, M. et al. Total synthesis of anominine and tubingensin A. J. Am. Chem. Soc. 134, 8078–8081 (2012).

    CAS  Article  Google Scholar 

  4. 4

    Goetz, A. E., Silberstein, A. L., Corsello, M. A. & Garg, N. K. Concise enantiospecific total synthesis of tubingensin A. J. Am. Chem. Soc. 136, 3036–3039 (2014).

    CAS  Article  Google Scholar 

  5. 5

    Goetz, A. E., Shah, T. K. & Garg, N. K. Pyridynes and indolynes as building blocks for functionalized heterocycles and natural products. Chem. Commun. 51, 34–45 (2015).

    CAS  Article  Google Scholar 

  6. 6

    Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).

    CAS  Article  Google Scholar 

  7. 7

    Boente, J. M. et al. Oxocompostelline and oxocularine, structure and synthesis. Tetrahedron Lett. 24, 2295–2298 (1983).

    CAS  Article  Google Scholar 

  8. 8

    Huters, A. D., Quasdorf, K. W., Styduhar, E. D. & Garg, N. K. Total synthesis of (–)-N-methylwelwitindolinone C isothiocyanate. J. Am. Chem. Soc. 133, 15797–15799 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Skorobogatyi, M. V. et al. 5-Arylethynyl-2´-deoxyuridines, compounds active against HSV-1. Org. Biomol. Chem. 4, 1091–1096 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Tummatorn, J. & Dudley, G. B. Generation of medium-ring cycloalkynes by ring expansion of vinylogous acyl triflates. Org. Lett. 13, 1572–1575 (2011).

    CAS  Article  Google Scholar 

  11. 11

    Gulías, M., Durán, J., López, F., Castedo, L. & Mascareñas, J. L. Palladium-catalyzed [4+3] intramolecular cycloaddition of alkylidenecyclopropanes and dienes. J. Am. Chem. Soc. 129, 11026–11027 (2007).

    Article  Google Scholar 

  12. 12

    Freeman, F. & Robarge, K. D. Stereoselectivity in electrophile-mediated intramolecular cyclizations of hept-2-enitols. J. Org. Chem. 54, 346–359 (1989).

    CAS  Article  Google Scholar 

  13. 13

    White, J. D., Grether, U. M. & Lee, C.-S. (R)-(+)-3,4-Dimethylcyclohex-2-en-1-one. Org. Synth. 82, 108–114 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Kojima, A., Honzawa, S., Boden, C. D. J. & Shibasaki, M. Tandem Suzuki cross-coupling-Heck reactions. Tetrahedron Lett. 38, 3455–3458 (1997).

    CAS  Article  Google Scholar 

  15. 15

    Dudley, G. B., Tan, D. S., Kim, G., Tanski, J. M. & Danishefsky, S. J. Remarkable stereoselectivity in the alkylation of a hydroazulenone: progress towards the total synthesis of guanacastepene. Tetrahedron Lett. 42, 6789–6791 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Schwartz, B. D., Denton, J. R., Lian, Y., Davies, H. W. L. & Williams, C. M. Asymmetric [4+3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (−)-5-epi-vibsanin E. J. Am. Chem. Soc. 131, 8329–8332 (2009).

    CAS  Article  Google Scholar 

  17. 17

    Caubere, P. Applications of sodamide-containing complex bases in organic synthesis. Acc. Chem. Res. 7, 301–308 (1974).

    CAS  Article  Google Scholar 

  18. 18

    Gregoire, B., Carre, M.-C. & Caubere, P. Arynic condensation of ketone enolates. 17. New general access to benzocyclobutene derivatives. J. Org. Chem. 51, 1419–1427 (1986).

    CAS  Article  Google Scholar 

  19. 19

    Legault, C. Y. CYLview v. 1.0b (Université de Sherbrooke, 2009);

  20. 20

    Lipomi, D. J., Langille, M. F. & Panek, J. S. Total synthesis of basiliskamides A and B. Org. Lett. 6, 3533–3536 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Szpilman, A. M., Cereghetti, D. M., Wurtz, N. R., Manthorpe, J. M. & Carreira, E. M. Synthesis of 35-deoxy amphotericinB methyl ester: a strategy for molecular editing. Angew. Chem. Int. Ed. 47, 4335–4338 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Uyehara, T., Murayama, T., Sakai, K., Ueno, M. & Sato, T. Formal substitution at both bridgeheads of a bicyclo[2.2.2]oct-5-en-2-one and its application to a synthesis of (±)-modhephene. Tetrahedron Lett. 37, 7295–7298 (1996).

    CAS  Article  Google Scholar 

  23. 23

    Uyehara, T. et al. Rearrangement approaches to cyclic skeletons. XIII. Total synthesis of triquinane sesquiterpenes, (±)-modhephene and (±)-isocomene, on the basis of formal substitution at both bridgeheads of a bicyclo[2.2.2]-oct-5-en-2-one. Bull. Chem. Soc. Jpn 71, 231–242 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Tang, W. & Zhang, X. New chiral phosphorus ligands for enantioselective hydrogenation. Chem. Rev. 103, 3029–3069 (2003).

    CAS  Article  Google Scholar 

  25. 25

    Tranchier, J.-P., Ratovelomanana-Vidal, V., Genêt, J.-P., Tong, S. & Cohen, T. Asymmetric hydrogenation of phenylthio ketones with chiral Ru(II) catalysts. Tetrahedron Lett. 38, 2951–2954 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Reich, H. J., Chow, F. & Shah, S. K. Selenium stabilized carbanions. Preparation of α-lithio selenides and applications to the synthesis of olefins by reductive elimination of β-hydroxy selenides and selenoxide syn elimination. J. Am. Chem. Soc. 101, 6638–6648 (1979).

    CAS  Article  Google Scholar 

  27. 27

    Ishida, N., Sawano, S., Masuda, Y. & Murakami, M. Rhodium-catalyzed ring opening of benzocyclobutenols with site-selectivity complementary to thermal ring opening. J. Am. Chem. Soc. 134, 17502–17504 (2012).

    CAS  Article  Google Scholar 

  28. 28

    Clive, D. L. J., Cole, D. C. & Tao, Y. Formation of angularly-fused triquinanes by successive use of the Pauson–Khand reaction and radical closure. J. Org. Chem. 59, 1396–1406 (1994).

    CAS  Article  Google Scholar 

Download references


The authors are grateful to the NIH-NIGMS (R01 GM090007 to N.K.G.), the Dreyfus Foundation, the UCLA Gold Shield Alumnae, the National Science Foundation Graduate Research Fellowship Program (DGE-1144087 to M.A.C.) and the University of California, Los Angeles for financial support. We thank Y. Tang (University of California, Los Angeles) for an authentic sample of tubingensin B. These studies were also supported by shared instrumentation grants from the NSF (no. CHE-1048804) and the National Center for Research Resources (no. S10RR025631).

Author information




M.A.C. and J.K. designed and performed experiments and analysed experimental data. N.K.G. directed the investigations and prepared the manuscript with contributions from all authors; all authors contributed to discussions.

Corresponding author

Correspondence to Neil K. Garg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 2760 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Corsello, M., Kim, J. & Garg, N. Total synthesis of (–)-tubingensin B enabled by the strategic use of an aryne cyclization. Nature Chem 9, 944–949 (2017).

Download citation

Further reading