A One-Pot Intramolecular Tandem Michael–Aldol Annulation Reaction for the Synthesis of Chiral Pentacyclic Terpenes

Abstract

A chiral tricyclic terpene possessing a 6,6,6-tricyclic framework and a 3,3-dimethyl-7-oxooctylidenyl side chain undergoes a double ring-closing reaction to give two chiral pentacyclic terpenes in a ratio of 4:3 via an intramolecular Michael addition followed by aldol condensation under basic conditions. Three new stereogenic centers are introduced in the initial Michael annulation reaction. Stereoselective installation of an ethoxycarbonyl group at C17 of the two pentacyclic terpenes separately gives the corresponding highly functionalized pentacyclic terpenoids with seven stereogenic centers. The structures and stereochemistry of key intermediates and products are established through X-ray crystallographic analysis. A mechanism is proposed for explaining the stereochemistry in the Michael annulation reaction.

Key words

1,4-addition - chiral synthesis - double ring-closing - pentacyclic triterpenes - tandem Michael–aldol annulation

• References

• 1 Catteai L, Zhu L, Van Bambeke F, Quetin-Leclercq J. Phytochem. Rev. 2018; 17: 1129
• 2 Sheng H, Sun H. Nat. Prod. Rep. 2011; 28: 543
• 3 Mallavadhani UV, Panda AK, Rao YR. Phytochem. 1998; 49: 901
• 4 Fernandes J, Castilho RO, Rangel da Costa M, Wagner-Souza K, Kaplan M, Auxiliadora C, Gattass CR. Cancer Lett. 2003; 190: 165
• 5 Hodges LD, Kweifio-Okai G, Macrides TA. Mol. Cell. Biochem. 2003; 252: 97
• 6 Katerere DR, Gray AI, Nash RJ, Waigh RD. Phytochem. 2003; 63: 81
• 7 Shinohara H, Shinohara G, Kuno N. PCT Int. Appl. (2003), WO 2003011267 A1 20030213, 2003
• 8 Park YS, Lee JH, Harvalkar JA, Bondar J, Safayhi H, Golubic M. Adv. Exp. Med. Biol. 2002; 507: 387
• 9 Sakurawi K, Yasuda F, Tozyo T, Nakamura M, Sato T, Kikuchi J, Terui Y, Ikenishi Y, Iwata T, Takahashi K, Konoike T, Mihara S, Fujimoto M. Chem. Pharm. Bull. 1996; 44: 343
• 10 Fujimoto M, Mihara S, Nakajima S, Ueda M, Nakamura M, Sakurai K. FEBS 1992; 305: 41
• 11 Mihara S, Sakurai K, Nakamura M, Konoike T, Fujimoto M. Eur. J. Pharmacol. 1993; 247: 219
• 12 Huang L, Chen CH. Curr. Drug Targets: Infect. Disord. 2002; 2: 33
• 13 Banno N, Akihisa T, Tokuda H, Yasukawa K, Taguchi Y, Akazawa H, Ukiya M, Kimura Y, Suzuki T, Nishino H. Biol. Pharm. Bull. 2005; 28: 1995
• 14 Chen D, Huang X, Zhou H, Luo H, Wang P, Chang Y, He X, Ni S, Shen Q, Cao G, Sun H, Wen X, Liu J. Eur. J. Med. Chem. 2017; 139: 201
• 15 Wang L, Wesemann S, Krenn L, Ladurner A, Heiss EH, Dirsch VM, Atanasov AG. Front. Pharmacol. 2017; 8: 375
• 16 Konoike T, Takahashi K, Araki Y, Horibe I. J. Org. Chem. 1997; 62: 960
• 17 Lu J, Aguilar A, Zou B, Bao W, Koldas S, Wangemann AP, Xie XS, Hua DH. Bioorg. Med. Chem. 2015; 23: 5985
• 18 Stelmakh A, Stellfeld T, Kalesse M. Org. Lett. 2006; 8: 3485
• 19 Kiyosei T, Misawa K, Ihara M. Tetrahedron Lett. 2001; 42: 8489
• 20 Tadano K, Nagashima K, Ueno Y, Ogawa S. J. Org. Chem. 1992; 57: 4496
• 21 Mischne M. Tetrahedron Lett. 2003; 44: 5823
• 22 Kametani T, Tsubuki M, Nemoto H. J. Org. Chem. 1980; 45: 4391
• 23 Surendra K, Corey EJ. J. Am. Chem. Soc. 2009; 131: 13928
• 24 Mukaiyama T, Shiina I, Iwadare H, Saitoh M, Nishimura T, Ohkawa N, Sakoh H, Nishimura K, Tani Y.-I, Hasegawa M, Yamada K, Saitoh K. Chem. Eur. J. 1999; 5: 121
• 25 CCDC 1922116 [(–)-6], CCDC 1922117 [(+)-11] and CCDC 1922118 [(+)-5] contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 26 Hall PL, Gilchrist JH, Collum DB. J. Am. Chem. Soc. 1991; 113: 9571
• 27 Magnus PD, Nobbs MS. Synth. Commun. 1980; 10: 273
• 28 Hill EA, Link DC, Donndelinger P. J. Org. Chem. 1981; 46: 1177
• 29 Bonnemann H, Bogdanovic B, Brinkmann R, He DW, Spliethoff B. Angew. Chem., Int. Ed. Engl. 1983; 9: 728