Organic Chemistry Portal
Organic Chemistry Highlights

Monday, December 11, 2017
Douglass F. Taber
University of Delaware

Metal-mediated Ring Construction: The Herzon Synthesis of Pleuromutilin

John F. Hartwig of the University of California, Berkeley optimized (ACS Central Sci. 2017, 3, 302. DOI: 10.1021/acscentsci.6b00391) the sequence of a P450 enzyme, demonstrating that the Ir form then catalyzed the enantioselective cyclopropanation of 1 with 2 to give 3. Michael P. Doyle of the University of Texas at San Antonio prepared (Angew. Chem. Int. Ed. 2017, 56, 7479. DOI: 10.1002/anie.201704069) the protected cyclobutanone 6 by Cu-catalyzed addition of the sulfur yide 5 to 4.

Qingwei Meng of the Dalian University of Technology oxidized (Org. Lett. 2017, 19, 448. DOI: 10.1021/acs.orglett.6b03554) the ketone 7 to the alcohol 8. Wen-Jing Xiao of Central China Normal University reported (J. Am. Chem. Soc. 2017, 139, 63. DOI: 10.1021/jacs.6b11418) related results. Rai-Shung Liu of the National Tsing-Hua University demonstrated (Adv. Synth. Catal. 2017, 359, 402. DOI: 10.1002/adsc.201600980) that a Rh catalyst could promote the vinyl cyclopropane rearrangement of 9 to 10. Jian-Jun Feng and Junliang Zhang of East China Normal University devised (ACS Catal. 2017, 7, 1533. DOI: 10.1021/acscatal.6b03399) the Rh-catalyzed hetero-[5+2] cycloaddition of 11 to 12. Masahisa Nakada of Waseda University extended (Tetrahedron Lett. 2017, 58, 959. DOI: 10.1016/j.tetlet.2017.01.076) Cu-catalyzed enantioselective cyclization to the α-diazo β-ketoester 13, opening the doubly-activated cyclopropane product with thiophenoxide to give 14.

Massimo Bietti of Universita "Tor Vergata", Rome and Miquel Costas of the Universitat de Girona showed (ACS Central Sci. 2017, 3, 196. DOI: 10.1021/acscentsci.6b00368) that cyclopropanecarboxylic acid 16 was an effective adjuvant for the enantioselective oxidation of 15 to 17. Christophe Bour and Vincent Gandon of Université Paris-Sud established (Org. Biomol. Chem. 2017, 15, 584. DOI: 10.1039/C6OB02122K) that Bi(OTf)3 catalyzed the diastereoselective cyclization of 18 to 19. Rong-Jie Chein of the Institute of Chemistry, Academia Sinica, also observed (J. Org. Chem. 2017, 82, 1575. DOI: 10.1021/acs.joc.6b02766) high diastereoselectivity in the cyclization of 20 to 21. Ken Ishigami of the Tokyo University of Agriculture and Hidenori Watanabe of the University of Tokyo alkylated (Tetrahedron 2017, 73, 3271. DOI: 10.1016/j.tet.2017.04.061) the dianion of 22 with the iodide 23, leading after thermal elimination to the cyclohexenone 24.

Larry E. Overman of the University of California, Irvine assembled (J. Am. Chem. Soc. 2017, 139, 7192. DOI: 10.1021/jacs.7b04265) the bicyclic tertiary alcohol 26 by anionic cyclization of 25. Scott A. Snyder of the University of Chicago designed (J. Am. Chem. Soc. 2017, 139, 5007. DOI: 10.1021/jacs.7b01454) the cascade cyclization of 27 to 28.

(+)-Pleuromutilin (31), isolated from the fungus Clitopilus passeckerianus, binds to the highly-conserved peptidyl transferase center of the bacterial ribosome. En route to 31, Seth B. Herzon of Yale University developed (Science 2017, 356, 956, DOI: 10.1126/science.aan0003; Org. Lett. 2017, 19, 4980, DOI: 10.1021/acs.orglett.7b02476) the diastereoselective reductive cyclization of 29 to 30.

It is instructive to compare the Herzon route to the previous modern synthesis of pleuromutilin (31) described by Procter (The Procter Synthesis of (+)-Pleuromutilin 2013, November 13).

D. F. Taber, Org. Chem. Highlights 2017, December 11.