Formation of Bicyclic Cyclopentenone Derivatives by Robinson-Type Annulation of Cyclic β-Oxoesters Containing a 1,4-Diketone Moiety

Abstract

Robinson-type cyclopentannulations of cyclic β-oxoesters possessing a 1,4-diketone moiety are accomplished under four different Brønsted basic reaction conditions. Using pyrrolidine/acetic acid in DMSO, an oxohexahydrocyclopenta[a]indene (42%) and an N-Boc-protected oxohexahydrocyclopenta[c]pyridine derivative (62%) are obtained with retention of the ester moieties. The latter compound defines an interesting new scaffold for medicinal chemistry with three positions allowing further derivatizations. The use of KOtBu in DMSO or NaH in toluene leads to cyclopentene derivatives with either partial ester saponification and decarboxylation or displacement of the ester moiety within the carbon skeleton. With aqueous KOH, the cyclopentannulations are successful in almost all cases, but with the ester moieties cleaved off. The respective bicyclic and tricyclic products are obtained in good to excellent yields. The 1,4-diketone starting materials are prepared by cerium-catalyzed oxidative coupling of β-oxoesters with isopropenyl acetate. Alternatively, a two-step sequence consisting of α-propargylation followed by palladium-catalyzed alkyne hydration is used.

Keywords

heterocyclic compounds - piperidine derivatives - cyclopentenone - Robinson annulation - ketones - diketones - alicyclic compounds - bicyclic compounds - alkyne hydration

• References

• 1a Rapson WS. Robinson R. J. Chem. Soc. 1935; 1285
• 1b Du Feu EC. McQuillin FJ. Robinson R. J. Chem. Soc. 1937; 53

Reviews:
• 2a Gawley RE. Synthesis 1976; 777
• 2b Jung ME. Tetrahedron 1976; 32: 3
• 2c Varner MA. Grossman RB. Tetrahedron 1999; 55: 13867
• 3 Christoffers J. Scharl H. Eur. J. Org. Chem. 2002; 1505
• 4 Clark RD. Ray NC. Williams K. Blaney P. Ward S. Crackett PH. Hurley C. Dyke HJ. Clark DE. Lockey P. Devos R. Wong M. Porres SS. Bright CP. Jenkins RE. Belanoff JK. Bioorg. Med. Chem. Lett. 2008; 18: 1312
• 5a Asagami T. Belanoff JK. Azuma J. Blasey CM. Clark RD. Tsao PS. J. Nutr. Metabol. 2011; 235389
• 5b Solomon MB. Wulsin AC. Rice T. Wick D. Myers B. McKlveen J. Flak JN. Ulrich-Lai Y. Herman JP. Horm. Behav. 2014; 65: 363
• 5c Zalachoras I. Houtman R. Atucha E. Devos R. Tijssen AM. I. Hu P. Lockey PM. Datson NA. Belanoff JK. Lucassen PJ. Joëls M. de Kloet ER. Roozendaal B. Hunt H. Meijer OC. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 7910
• 6 Christoffers J. Sluiter J. Schmidt J. Synthesis 2011; 895
• 7a Sandham DA. Meyers AI. J. Chem. Soc., Chem. Commun. 1995; 2511
• 7b Ward DE. Shen J. Org. Lett. 2007; 9: 2843
• 7c Hiroya Y. Suwa Y. Ichihashi Y. Inamoto K. Doi T. J. Org. Chem. 2011; 76: 4522
• 7d Lei S. RSC Adv. 2013; 3: 11014
• 7e Behenna DC. Stoltz BM. J. Am. Chem. Soc. 2004; 126: 15044
• 8a Welch SC. Assercq J.-M. Loh J.-P. Glase SA. J. Org. Chem. 1987; 52: 1440
• 8b Corey EJ. Ghosh AK. Tetrahedron Lett. 1987; 28: 175
• 9 Xie Z.-F. Suemune H. Sakai K. J. Chem. Soc., Chem. Commun. 1988; 612
• 10a Snyder L. Meyers AI. J. Org. Chem. 1993; 58: 7507
• 10b Clive DL. J. Wang J. J. Org. Chem. 2004; 69: 2773
• 10c Clift MD. Taylor CN. Thomson RJ. Org. Lett. 2007; 9: 4667
• 11 Geibel I. Christoffers J. Eur. J. Org. Chem. 2016; 918
• 12 Barco A. Benetti S. Pollini GP. Synthesis 1973; 316
• 13a Fukuda Y. Utimoto K. J. Org. Chem. 1991; 56: 3729
• 13b Mizushima E. Sato K. Hayashi T. Tanaka M. Angew. Chem. Int. Ed. 2002; 41: 4563 ; Angew. Chem. 2002, 114, 4745
• 13c Toullec PY. Genin E. Antoniotto S. Genet J.-P. Michelet V. Synlett 2008; 707
• 14 Chang M.-Y. Cheng Y.-C. Synlett 2016; 27: 1931
• 15 Li X. Hu G. Luo P. Tang G. Gao Y. Xu P. Zhao Y. Adv. Synth. Catal. 2012; 354: 2427
• 16 Palomo C. Oiarbide M. Garcia JM. Bañuelos P. Odriozola JM. Razkin J. Linden A. Org. Lett. 2008; 10: 2637
• 17 Grigg R. Sakee U. Sridharan V. Sukirthalingam S. Thangavelauthum R. Tetrahedron 2006; 62: 9523
• 18 Englert L. Silber K. Steuber H. Brass S. Over B. Gerber H.-D. Heine A. Diederich WE. Klebe G. ChemMedChem 2010; 5: 930
• 19 Beth A. Pelletier J. Russo R. Soucy M. Burnell RH. Can. J. Chem. 1975; 53: 1504
• 20 Shook CA. Romberger ML. Jung S.-H. Xiao M. Sherbine JP. Zhang B. Lin F.-T. Cohen T. J. Am. Chem. Soc. 1993; 115: 10754
• 21 Brown SW. Pauson PL. J. Chem. Soc., Perkin Trans. 1 1990; 1205
• 22 Bannett F. Fenton G. Knight DW. Tetrahedron 1994; 50: 5147
• 23 Pérez-Serrano L. Blanco-Urgoiti J. Casarrubios L. Domínguez G. Pérez-Castells J. J. Org. Chem. 2000; 65: 3513
• 24 McHugh M. Proctor GR. J. Chem. Res., Miniprint 1984; 2230