Synthetic Approach toward (–)-Tetrodotoxin via Construction of the Bicyclo[2.2.2]octane Skeleton

Abstract

A synthetic approach toward (–)-tetrodotoxin (TTX) is described. Our approach features a stereoselective construction of the TTX core structure using the bicyclo[2.2.2]octane skeleton which was constructed via intramolecular Diels–Alder reaction of an o-quinone monoketal having the key functional groups. The robust asymmetric synthesis was achieved by an iridium-catalyzed dynamic kinetic resolution (DKR) of the aryl vinyl carbinol that could be easily prepared from a simple aromatic compound.

Key words

natural product - bicyclo[2.2.2]octane skeleton - oxidative cleavage - intramolecular Diels–Alder reaction - dynamic kinetic resolution

• References and Notes

• 1 Tahara Y. J. Pharm. Soc. Jpn. 1909; 587
• 2a Narahashi T, Deguchi T, Urakawa N, Ohkubo Y. Am. J. Physiol. 1960; 198: 934
• 2b Narahashi T, Moore JW, Scott WR. J. Gen. Physiol. 1964; 47: 965
• 3a de Lera Ruiz M, Kraus RL. J. Med. Chem. 2015; 58: 7093
• 3b Mulcahy JV, Pajouhesh H, Beckley JT, Delwig A, Du Bois J, Hunter JC. J. Med. Chem. 2019; 62: 8695
• 3c Zhao C, Liu A, Santamaria CM, Shomorony A, Ji T, Wei T, Gordon A, Elofsson H, Mehta M, Yang R, Kohane DS. Nat. Commun. 2019; 10: 2566
• 3d Kushnarev M, Pirvulescu IP, Candido KD, Knezevic NN. Expert Opin. Invest. Drugs 2020; 29: 259
• 4 Makarova M, Rycek L, Hajicek J, Baidilov D, Hudlicky T. Angew. Chem. Int. Ed. 2019; 58: 18338
• 5a Yoshida E, Nakayama H, Hatanaka Y, Kataoka Y. Chem. Pharm. Bull. 1990; 38: 982
• 5b Nakayama H, Hatanaka Y, Yoshida E, Oka K, Takanohashi M, Amano Y, Kanaoka Y. Biochem. Biophys. Res. Commun. 1992; 184: 900
• 5c Shen H, Li Z, Jiang Y, Pan X, Wu J, Cristofori-Armstrong B, Smith JJ, Chin YK. Y, Lei J, Zhou Q, King GF, Yan N. Science 2018; 362: eaau2596
• 5d Shen H, Liu D, Wu K, Lei J, Yan N. Science 2019; 363: 1303
• 5e Li Z, Jin X, Huang G, Wu K, Lei J, Pan X, Yan N. bioRxiv 2019; preprint; DOI
• 6a Nishikawa T, Urabe D, Yoshida K, Iwabuchi T, Asai M, Isobe M. Org. Lett. 2002; 4: 2679
• 6b Nishikawa T, Asai M, Isobe M. J. Am. Chem. Soc. 2002; 124: 7847
• 6c Nishikawa T, Urabe D, Yoshida K, Iwabuchi T, Asai M, Isobe M. Pure Appl. Chem. 2003; 75: 251
• 6d Nishikawa T, Urabe D, Yoshida K, Iwabuchi T, Asai M, Isobe M. Chem. Eur. J. 2004; 10: 452
• 6e Umezawa T, Hayashi T, Sakai H, Teramoto H, Yoshikawa T, Izumida M, Tamatani Y, Hirose T, Ohfune Y, Shinada T. Org. Lett. 2006; 8: 4971
• 6f Adachi M, Imazu T, Isobe M, Nishikawa T. J. Org. Chem. 2013; 78: 1699
• 6g Satake Y, Adachi M, Tokoro S, Yotsu-Yamashita M, Isobe M, Nishikawa T. Chem. Asian J. 2014; 9: 1922
• 6h Adachi M, Sakakibara R, Satake Y, Isobe M, Nishikawa T. Chem. Lett. 2014; 43: 1719
• 6i Adachi M, Miyasaka T, Kudo Y, Sugimoto K, Yotsu-Yamashita M, Nishikawa T. Org. Lett. 2019; 21: 780
• 6j Miyasaka T, Adachi M, Nishikawa T. Org. Lett. 2021; 23: 9232
• 7a Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T, Inoue S, Tanino H, Sugiura S, Kakoi H. J. Am. Chem. Soc. 1972; 94: 9217
• 7b Kishi Y, Fukuyama T, Aratani M, Nakatsubo F, Goto T, Inoue S, Tanino H, Sugiura S, Kakoi H. J. Am. Chem. Soc. 1972; 94: 9219
• 7c Ohyabu N, Nishikawa T, Isobe M. J. Am. Chem. Soc. 2003; 125: 8798
• 7d Hinman A, Du Bois J. J. Am. Chem. Soc. 2003; 125: 11510
• 7e Nishikawa T, Urabe D, Isobe M. Angew. Chem. Int. Ed. 2004; 43: 4782
• 7f Sato K, Akai S, Sugita N, Ohsawa T, Kogure T, Shoji H, Yoshimura J. J. Org. Chem. 2005; 70: 7496
• 7g Sato K, Akai S, Shoji H, Sugita N, Yoshida S, Nagai Y, Suzuki K, Nakamura Y, Kajihara Y, Funabashi M, Yoshimura J. J. Org. Chem. 2008; 73: 1234
• 7h Akai S, Seki H, Sugita N, Kogure T, Nishizawa N, Suzuki K, Nakamura Y, Kajihara Y, Yoshimura J, Sato K. Bull. Chem. Soc. Jpn. 2010; 83: 279
• 7i Maehara T, Motoyama K, Toma T, Yokoshima S, Fukuyama T. Angew. Chem. Int. Ed. 2017; 56: 1549
• 7j Murakami K, Toma T, Fukuyama T, Yokoshima S. Angew. Chem. Int. Ed. 2020; 59: 6253
• 7k Konrad DB, Rühmann K.-P, Ando H, Hetzler BE, Matsuura BS, Trauner D. ChemRxiv 2021; preprint; DOI
• 8 Biju PJ, Rao GS. R. S. Tetrahedron Lett. 1999; 40: 2405
• 9a Chen Y.-K, Peddinti RK, Liao C.-C. Chem. Commun. 2001; 1340
• 9b Krawczuk PJ, Schöne N, Baran PS. Org. Lett. 2009; 11: 4774
• 9c Leung GY. C, Li H, Toh Q.-Y, Ng AM.-Y, Sum RJ, Bandow JE, Chen DY.-K. Eur. J. Org. Chem. 2011; 183
• 9d Ogura A, Yamada K, Yokoshima S, Fukuyama T. Org. Lett. 2012; 14: 1632
• 9e Yang Q, Njardarson JT, Draghici C, Li F. Angew. Chem. Int. Ed. 2013; 52: 8648
• 10a Roggen M, Carreira EM. Angew. Chem. Int. Ed. 2011; 50: 5568
• 10b Schafroth MA, Sarlah D, Krautwald S, Carreira EM. J. Am. Chem. Soc. 2012; 134: 20276
• 11 Seidel JL, Epstein WW, Davidson DW. J. Chem. Ecol. 1990; 16: 1791
• 12 Nishiyama Y, Han-ya Y, Yokoshima S, Fukuyama T. J. Am. Chem. Soc. 2014; 136: 6598
• 13 Baldwin JE, Adlington RM, Ramcharitar SH. Tetrahedron 1992; 48: 2957
• 14 Hagiya K, Muramoto N, Misaki T, Sugimura T. Tetrahedron 2009; 65: 6109
• 15 Sakai N, Ohfune Y. Tetrahedron Lett. 1990; 31: 4151
• 16 Brown HC, Mead EJ. J. Am. Chem. Soc. 1953; 75: 6263
• 17 Otsubo K, Inanaga J, Yamaguchi M. Tetrahedron Lett. 1987; 28: 4437
• 18 Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Tetrahedron 1998; 54: 5635
• 19 Fukuyama T, Laird AA, Hotchkiss LM. Tetrahedron Lett. 1985; 26: 6291
• 20a Lindgren BO, Nilsson T. Acta Chem. Scand. 1973; 27: 888
• 20b Kraus GA, Taschner MJ. J. Org. Chem. 1980; 45: 1175
• 20c Kraus GA, Roth B. J. Org. Chem. 1980; 45: 4825
• 20d Bal BS, Childers WE, Pinnick HW. Tetrahedron 1981; 37: 2091
• 21a Soai K, Ookawa A, Hayashi H. J. Chem. Soc., Chem. Commun. 1983; 668
• 21b Krafft ME, Cheung YY, Abboud KA. J. Org. Chem. 2001; 66: 7443
• 22a De Mico A, Margarita R, Parlanti L, Vescovi A, Piancatelli G. J. Org. Chem. 1997; 62: 6974
• 22b Lee J.-H, Cho C.-G. Org. Lett. 2018; 20: 7312
• 23 Since the hydroxymethyl group connected to C9 is less hindered, the TEMPO oxidation first occurred at that hydroxy group.
• 24a Meerwein H, Schmidt R. Liebigs Ann. Chem. 1925; 444: 221
• 24b Verley A. Bull. Soc. Chim. Fr. 1925; 37: 537
• 24c Ponndorf W. Angew. Chem. 1926; 39: 138
• 25 Lee J, Kim M, Chang S, Lee H.-Y. Org. Lett. 2009; 11: 5598
• 26 Moriarty RM, Chany CJ, Vaid RK, Prakash O, Tuladhar SM. J. Org. Chem. 1993; 58: 2478
• 27 (4aS,6aR,9S,9aR,9bS)-9a-Amino-9-(benzyloxy)-5-[(4-methoxyphenoxy)methyl]-3,3-dimethyl-6a,9,9a,9b-tetrahydro-1H-[1,3]dioxino[5,4-e]benzofuran-8(4aH)-one (2)To a stirred solution of 39 (28.8 mg, 56.5 μmol) in acetonitrile (2.0 mL) and water (2.0 mL) was added iodobenzene diacetate (54.6 mg, 170 μmol) at room temperature. After stirring for 1 h, sodium bicarbonate (47.5 mg, 566 μmol) was added to the mixture and the mixture was heated at 40–50 °C. After stirring for 90 min, the mixture was cooled to room temperature. A mixed solution of saturated aqueous sodium thiosulfate (3.0 mL) and saturated aqueous sodium bicarbonate (1.0 mL) was added to the mixture. After stirring for 20 min, brine (2.0 mL) was added to the mixture. The mixture was extracted with ethyl acetate (4.0 mL) five times. The combined organic layer was concentrated under reduced pressure to give a crude material, which was purified by neutral silica gel column chromatography (ethyl acetate/n-hexane, 1:1 to 3:2 to 2:1) to afford amine 2 (16.9 mg, 62%) as a colorless oil. [α]_D ²⁴ –31.3 (c 0.65, CHCl₃). IR (neat): 3385, 3324, 3054, 2993, 2955, 2918, 2874, 2850, 2838, 1770, 1508, 1456, 1444, 1397, 1380, 1373, 1265, 1230, 1215, 1198, 1179, 1108, 1074, 1057, 1030, 980, 873, 826, 739, 703 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.32 (m, 5 H), 6.82 (s, 4 H), 5.91 (m, 1 H), 5.02 (d, J = 9.6 Hz, 1 H), 4.88 (d, J = 11.0 Hz, 1 H), 4.63 (m, 1 H), 4.55 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 14.2 Hz, 1 H), 4.41 (d, J = 14.6 Hz, 1 H), 3.97–3.86 (m, 2 H), 3.77 (s, 3 H), 3.61 (s, 1 H) 2.12 (m, 1 H), 1.42 (br s, 2 H), 1.33 (s, 3 H), 1.18 (s, 3 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 172.9, 154.2, 152.9, 139.9, 136.3, 129.0, 128.8, 128.6, 119.9, 116.0, 114.7, 100.0, 85.4, 80.7, 72.9, 68.0, 67.0, 60.1, 55.9, 48.5, 29.7, 19.5. HRMS (ESI+): m/z calcd for C₂₇H₃₁NNaO₇ ⁺ [M + Na]⁺: 504.1993; found: 504.1993