Heteroaromatic Synthesis: The Tokuyama Synthesis of (-)-Rhazinilam

Mei-Huey Lin of the National Changhua University of Education rearranged (J. Org. Chem. 2014, 79, 2751. DOI: 10.1021/jo5001274) the initial allene derived from 1 to the γ-chloroenone. Displacement with acetate followed by hydrolysis led to the furan 2. A. Stephen K. Hashmi of Ruprecht-Karls-Universität Heidelberg showed (Angew. Chem. Int. Ed. 2014, 53, 3715. DOI: 10.1002/anie.201310146) that the Au-catalyzed conversion of the bis alkyne 3 proceeded selectively to give 5.

Tehshik P. Yoon of the University of Wisconsin used (Angew. Chem. Int. Ed. 2014, 53, 793. DOI: 10.1002/anie.201308820) visible light with a Ru catalyst to rearrange the azide 6 to the pyrrole 7. Cheol-Min Park, now at UNIST, found (Chem. Sci. 2014, 5, 2347. DOI: 10.1039/C4SC00125G) that a Ni catalyst reorganized the methoxime 8 to the pyrrole 9. A Rh catalyst converted 8 to the corresponding pyridine (not illustrated).

In the course of a synthesis of opioid ligands, Kenner C. Rice of the National Institute of Drug Abuse optimized (J. Org. Chem. 2014, 79, 5007. DOI: 10.1021/jo500568s) the preparation of the pyridine 11 from the alcohol 10. Vincent Tognetti and Cyrille Sabot of the University of Rouen heated (J. Org. Chem. 2014, 79, 1303. DOI: 10.1021/jo402729a) 12 and 13 under microwave irradiation to give the 3-hydroxy pyridine 14.

Tomislav Rovis of Colorado State University prepared (J. Am. Chem. Soc. 2014, 136, 2735. DOI: 10.1021/ja412444d) the pyridine 17 by the Rh-catalyzed combination of 15 with 16. Fabien Gagosz of the Ecole Polytechnique rearranged (Angew. Chem. Int. Ed. 2014, 53, 4959. DOI: 10.1002/anie.201402470) the azirine 18, readily available from the oxime of the β-keto ester, to the pyridine 19.

Matthias Beller of the Universität Rostock used (Chem. Eur. J. 2014, 20, 1818. DOI: 10.1002/chem.201304432) a Zn catalyst to mediate the opening of the epoxide 21 with the aniline 20. A Rh catalyst effected the oxidation and cylization of the product amino alcohol to the indole 22. Sreenivas Katukojvala of the Indian Institute of Science Education & Research showed (Angew. Chem. Int. Ed. 2014, 53, 4076. DOI: 10.1002/anie.201400161) that the diazo ketone 23 could be used to anneal a benzene ring onto the pyrrole 24, leading to the 2,7-disubstituted indole 25. Tomoya Miura and Masahiro Murakami of Kyoto University developed (J. Am. Chem. Soc. 2014, 136, 2272. DOI: 10.1021/ja412663a) the one-pot Cu-catalyzed dipolar cycloaddition of tosyl azide to the alkyne of 26, followed by Rh-mediated intramolecular addition to the benzene ring. That product could be oxidized directly to the indole 27. Edward A. Anderson of the University of Oxford observed (Chem. Commun. 2014, 50, 5187. DOI: 10.1039/C3CC45634J) that the sulfonamide 29, from Pd-catalyzed cyclization of 28, could also be desulfonylated and oxidized to the indole.

(-)-Rhazinilam (32), isolated from Rhazya stricta Decaisne, interferes with tubulin polymerization and dynamics. To assemble 32, Hidetoshi Tokuyama of Tohoku University devised (Angew. Chem. Int. Ed. 2013, 52, 7168. DOI: 10.1002/anie.201303067) the intramolecular cyclization of 30 to give the pyrrole 31.