Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Synthetic study of andrastins: stereoselective construction of the BCD-ring system


Andrastins are meroterpenes isolated from Penicillium sp. FO-3929 that display highly potent inhibitory activities toward protein farnesyltransferase. Structurally, they possess a unique steroidal tetracyclic skeleton (the ABCD-ring) with three contiguous quaternary stereocenters on the C-ring. Herein, we describe our nitrile cyclization-based approach to the stereoselective construction of the BCD-ring system of andrastins, which contains three contiguous quaternary stereocenters on the C-ring and the correct oxidation states of the D-ring.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5


  1. 1.

    Shiomi K, Uchida R, Inokoshi J, Tanaka H, Iwai Y, Ōmura S. Andrastins A~C, new protein farnesyltransferase inhibitors, produced by Penicillium sp. FO-3929. Tetrahedron Lett. 1996;37:1265–8.

    CAS  Article  Google Scholar 

  2. 2.

    Ōmura S, Inokoshi J, Uchida R, Shiomi K, Masuma R, Kawakubo T, et al. Andrastins A-C, new protein farnesyltransferase inhibitors produced by Penicillium sp. FO-3929. I. Producing strain, fermentation, isolation, and biological activities. J Antibiot. 1996;49:414–7.

    Article  Google Scholar 

  3. 3.

    Uchida R, Shiomi K, Inokoshi J, Sunazuka T, Tanaka H, Iwai Y, et al. Andrastin A-C, new protein farnesyltransferase inhibitors produced by Penicillium sp. FO-3929. II. Structure elucidation and biosynthesis. J Antibiot. 1996;49:418–24.

    CAS  Article  Google Scholar 

  4. 4.

    Uchida R, Shiomi K, Inokoshi J, Tanaka H, Iwai Y, Ōmura S. Andrastin D, novel protein farnesyltransferase inhibitor produced by Penicillium sp. FO-3929. J Antibiot. 1996;49:1278–80.

    CAS  Article  Google Scholar 

  5. 5.

    Hinterding K, Alonso-Díaz D, Waldmann H. Organic synthesis and biological signal transduction. Angew Chem Int Ed. 1998;37:688–749.

    CAS  Article  Google Scholar 

  6. 6.

    Xu G, Elkin M, Tantillo DJ, Newhouse TR, Maimone TJ. Traversing biosynthetic carbocation landscapes in the total synthesis of andrastin and terretonin meroterpenes. Angew Chem Int Ed. 2017;56:12498–502.

    CAS  Article  Google Scholar 

  7. 7.

    Okamoto R, Takeda K, Tokuyama H, Ihara M, Toyota M. Toward the total synthesis of (±)-Andrastin C. J Org Chem. 2013;78:93–103.

    CAS  Article  Google Scholar 

  8. 8.

    Toyota M, Okamoto R, Ogata T, Ihara M. Ti(III)-induced radical cyclization. A stereoseletive entry to the perhydrobenzo[e]indene unit of new protein farnesyltransferase inhibitors, andrastins A–D. Tetrahedron Lett. 2004;45:9203–5.

    CAS  Article  Google Scholar 

  9. 9.

    Yin S, Sugimoto K, Nemoto H, Matsuya Y. Synthetic study towards construction of potential scaffold of antitumor agents andrastins. Heterocycles. 2017;95:187–99.

    CAS  Article  Google Scholar 

  10. 10.

    Yin S, Takai K, Minato D, Sugimoto K, Ohtsu H, Tsuge K, et al. Construction of cis-fused hydrindane skeleton with a lactone tether utilizing intramolecular Diels–Alder reaction. Heterocycles. 2016;93:783–91.

    CAS  Article  Google Scholar 

  11. 11.

    Yoshimura F, Torizuka M, Mori G, Tanino K. Intramolecular conjugate addition of α,β-unsaturated lactones having an alkanenitrile side chain: stereocontrolled construction of carbocycles with quaternary carbon atoms. Synlett. 2012;23:251–4.

    Article  Google Scholar 

  12. 12.

    Clarke ML, France MB. The carbonyl ene reaction. Tetrahedron. 2008;64:9003–31.

    CAS  Article  Google Scholar 

  13. 13.

    Hamana H, Sugasawa T. The ene reaction of trisubstituted alkenes with electron-deficient nitriles in the presence of boron trichloride. Chem Lett. 1985;14:575–8.

    Article  Google Scholar 

  14. 14.

    Shimizu H, Murakami M. Reaction of 2-alkynylbenzoyl cyanides with carboxylic acids producing functionalized indenones. Synlett 2008;1817–20.

  15. 15.

    Sakai T, Danheiser RL. Cyano Diels–Alder and cyano ene reactions. Applications in a formal [2+2+2] cycloaddition strategy for the synthesis of pyridines. J Am Chem Soc. 2010;132:13203–5.

    CAS  Article  Google Scholar 

  16. 16.

    Gasper B, Carreira EM. Mild Cobalt-Catalyzed Hydrocyanation of Olefins with Tosyl Cyanide. Angew Chem Int Ed. 2007;46:4519–22.

    Article  Google Scholar 

  17. 17.

    Ley SV, Norman J, Griffith WP, Marsden SP. Tetrapropylammonium perruthenate, Pr4N+RuO4 , TPAP: a catalytic oxidant for organic synthesis. Synthesis. 1994;639–66.

  18. 18.

    Hill RK, Conley RT. Abnormal Beckmann rearrangement of spiroketoximes in polyphosphoric acid. J Am Chem Soc. 1960;82:645–52.

    CAS  Article  Google Scholar 

  19. 19.

    Smith AB III, Leenay TL, Liu H-J, Nelson LAK, Ball RG. A caveat on the swern oxidation. Tetrahedron Lett. 1988;29:49–52.

    CAS  Article  Google Scholar 

Download references


We acknowledge Dr. Eri Fukushi and Mr. Yusuke Takata (GC-MS & NMR Laboratory, Faculty of Agriculture, Hokkaido University) for their mass spectral measurements. TA is a Research Fellow of the Japan Society for the Promotion of Science (JSPS). This work was supported by JSPS KAKENHI Grant Numbers JP15K01795, JP18K05339, JP18H01970, and JP15H05842 in Middle Molecular Strategy.

Author information



Corresponding authors

Correspondence to Fumihiko Yoshimura or Keiji Tanino.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dedication: Dedicated with respect to Professor Samuel J. Danishefsky for his outstanding contributions to natural products synthesis.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yoshimura, F., Abe, T., Ishioka, Y. et al. Synthetic study of andrastins: stereoselective construction of the BCD-ring system. J Antibiot 72, 384–388 (2019).

Download citation


Quick links