Highly Efficient Synthesis of Digoxin

Abstract

Taking advantage of the reliable stereocontrol capability of DMNPA group via long-distance-participation (LDP) effect as well as the mild and efficient deprotection conditions, the first and highly efficient synthesis of digoxin was achieved through a nine-step longest linear sequence with 41% overall yield.

Key words

digoxin - cardiac glycosides - synthesis - glycosylation - ­DMNPA

Publication History

Received: 23 November 2020

Accepted after revision: 05 January 2021

Accepted Manuscript online:
05 January 2021

Article published online:
27 January 2021

• References and Notes

• 1a Eichhorn EJ, Gheorghiade M. Prog. Cardiovasc. Dis. 2002; 44: 251
• 1b Fu J, Wu Z, Zhang L. Prog. Mol. Biol. Transl. Sci. 2019; 163: 487
• 2 Prassas I, Diamandis EP. Nat. Rev. Drug Discovery 2008; 7: 926
• 3 Cechova P, Berka K, Kubala M. J. Chem. Inf. Model. 2016; 56: 2434
• 4 Dostanic-Larson I, van Huysse JW, Lorenz JN, Lingrel JB. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 15845
• 5 Frese S, Frese-Schaper M, Andres A.-C, Miescher D, Zumkehr B, Schmid RA. Cancer Res. 2006; 66: 5867
• 6 Roberts DM, Gallapatthy G, Dunuwille A, Chan BS. Br. J. Clin. Pharmacol. 2016; 81: 488
• 7a Borovika A, Nagorny P. J. Carbohydr. Res. 2012; 31: 255
• 7b Bennett C, Galan MC. Chem. Rev. 2018; 118: 7931
• 8 Wiesner K, Tsai TY. R, Jin H. Helv. Chim. Acta 1985; 68: 300

For selected examples, see:
• 9a Tanaka H, Sakamoto H, Sano A, Nakamura S, Nakajima M, Hashimoto S. Chem. Commun. 1999; 1259
• 9b Wang H.-YL, Wu B, Zhang Q, Kang S.-W, Rojanasakul Y, O’Doherty GA. ACS Med. Chem. Lett. 2011; 2: 259
• 9c Wang H.-YL, Rojanasakul Y, O’Doherty GA. ACS Med. Chem. Lett. 2011; 2: 264
• 9d Hinds JW, McKenna SB, Sharif EU, Wang H.-YL, Akhmedov NG, O’Doherty GA. ChemMedChem 2013; 8: 63
• 9e Zeng J, Sun G, Wang R, Zhang S, Teng S, Liao Z, Meng L, Wan Q. Org. Chem. Front. 2017; 4: 2450
• 10a McDonald FE, Reddy KS. Angew. Chem. Int. Ed. 2001; 40: 3653
• 10b Zhou M, O’Doherty GA. Org. Lett. 2006; 8: 4339
• 10c Zhou M, O’Doherty GA. J. Org. Chem. 2007; 72: 2485
• 10d Ma Y, Li Z, Shi H, Zhang J, Yu B. J. Org. Chem. 2011; 76: 9748
• 11a Ma X, Yu B, Hui Y, Miao Z, Ding J. Carbohydr. Res. 2001; 334: 159
• 11b Zeng J, Wang R, Zhang S, Fang J, Liu S, Sun G, Xu B, Xiao Y, Fu D, Zhang W, Hu Y, Wan Q. J. Am. Chem. Soc. 2019; 141: 8509
• 11c Liu M, Liu K.-M, Xiong D.-C, Zhang H, Li T, Li B, Qin X, Bai J, Ye X.-S. Angew. Chem. Int. Ed. 2020; 59: 15204
• 12a Liu H, Zhou S.-Y, Wen G.-E, Liu X.-X, Liu D.-Y, Zhang Q.-J, Schmidt RR, Sun J.-S. Org. Lett. 2019; 21: 8049
• 12b Liu H, Hansen T, Zhou S.-Y, Wen G.-E, Liu X.-X, Zhang Q.-J, Codee JD. C, Schmidt RR, Sun J.-S. Org. Lett. 2019; 21: 8713
• 13 Zhang J, Shi H, Yu B. Chem. Commun. 2012; 48: 8679
• 14 Yu B. Acc. Chem. Res. 2018; 51: 507
• 15a Yu B, Sun J, Yang X. Acc. Chem. Res. 2012; 45: 1227
• 15b Zhu D, Yu B. Chin. J. Chem. 2018; 36: 681
• 16 Liu H, Liao J.-X, Hu Y, Tu Y.-H, Sun J.-S. Org. Lett. 2016; 18: 1294
• 17 van der Vorm S, van Hengst JM. A, Bakker M, Overkleeft HS, van der Marel GA, Codee JD. C. Angew. Chem. Int. Ed. 2018; 57: 8240
• 18 General Procedure for the Digitoxosylation To a solution of donor 2 (0.05 mmol) and digoxigenin (2.0 equiv) in dry CH₂Cl₂ (2.0 mL) was added freshly activated 4 Å MS or AW MS at room temperature under N₂ atmosphere. After being stirred at the same temperature for 30 min, Ph₃PAuOTf (0.2 equiv) was added at room temperature (or 0 °C and –10 °C) under N₂ atmosphere. The stirring was continued at room temperature (or at 0 °C) until TLC showed that all donor was consumed. Filtration was followed by concentration under reduced pressure to give a residue, which was further purified by silica gel column chromatography to provide the glycosylation products.
• 19 Analytic Data for Digoxin (1) White solid; [α]_D ²⁵ +3.0 (c 0.4, CHCl₃). ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.82 (t, J = 1.6 Hz, 1 H), 4.93 (AB, 2 H), 4.82 (dd, J = 2.0, 9.2 Hz, 2 H), 4.78 (dd, J = 2.0, 9.6 Hz, 1 H), 4.62–4.59 (m, 3 H), 4.25 (dd, J = 1.2, 3.2 Hz, 1 H), 4.19 (dd, J = 0.8, 2.8 Hz, 1 H), 4.10 (s, 1 H), 4.06–4.03 (m, 2 H), 3.89 (br s, 1 H), 3.86–3.83 (m, 1 H), 3.75–3.60 (m, 3 H), 3.26–3.20 (m, 2 H), 3.14 (dt, J = 2.0, 9.6 Hz, 2 H), 3.02 (ddd, J = 2.8, 6.8, 9.6 Hz, 1 H), 1.98–1.29 (m, 23 H), 1.17–1.02 (m, 3 H), 1.13 (d, J = 6.4 Hz, 3 H), 1.12 (d, J = 6.4 Hz, 3 H), 1.10 (d, J = 6.0 Hz, 3 H), 0.84 (s, 3 H), 0.65 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 176.9, 174.0, 115.8, 99.1, 99.0, 95.3, 84.3, 81.9, 81.6, 73.3, 73.0, 72.7, 72.1, 69.1, 67.6, 67.5, 67.0, 66.3, 66.1, 55.7, 45.2, 40.5, 38.4, 38.3, 37.9, 36.3, 34.7, 32.4, 31.6, 30.2, 29.7, 29.6, 26.8, 26.4, 26.0, 23.7, 21.3, 18.4, 18.0, 9.4. HRMS (ESI): m/z calcd for C₄₁H₆₄O₁₄Na [M + Na]⁺: 803.4188; found: 803.4184.