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.
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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.
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.
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.
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.
Hinterding K, Alonso-Díaz D, Waldmann H. Organic synthesis and biological signal transduction. Angew Chem Int Ed. 1998;37:688–749.
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.
Okamoto R, Takeda K, Tokuyama H, Ihara M, Toyota M. Toward the total synthesis of (±)-Andrastin C. J Org Chem. 2013;78:93–103.
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.
Yin S, Sugimoto K, Nemoto H, Matsuya Y. Synthetic study towards construction of potential scaffold of antitumor agents andrastins. Heterocycles. 2017;95:187–99.
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.
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.
Clarke ML, France MB. The carbonyl ene reaction. Tetrahedron. 2008;64:9003–31.
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.
Shimizu H, Murakami M. Reaction of 2-alkynylbenzoyl cyanides with carboxylic acids producing functionalized indenones. Synlett 2008;1817–20.
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.
Gasper B, Carreira EM. Mild Cobalt-Catalyzed Hydrocyanation of Olefins with Tosyl Cyanide. Angew Chem Int Ed. 2007;46:4519–22.
Ley SV, Norman J, Griffith WP, Marsden SP. Tetrapropylammonium perruthenate, Pr4N+RuO4 −, TPAP: a catalytic oxidant for organic synthesis. Synthesis. 1994;639–66.
Hill RK, Conley RT. Abnormal Beckmann rearrangement of spiroketoximes in polyphosphoric acid. J Am Chem Soc. 1960;82:645–52.
Smith AB III, Leenay TL, Liu H-J, Nelson LAK, Ball RG. A caveat on the swern oxidation. Tetrahedron Lett. 1988;29:49–52.
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.
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The authors declare that they have no conflict of interest.
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Dedication: Dedicated with respect to Professor Samuel J. Danishefsky for his outstanding contributions to natural products synthesis.
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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). https://doi.org/10.1038/s41429-018-0136-x