Semi-Synthesis of (+)-Digitoxigenin from Androstenedione

Abstract

An efficient stereoselective semi-synthesis of (+)-digitoxigenin has been achieved by a nine-step sequence with a 20.4% overall yield. The key features of the synthesis include a Saegusa–Ito oxidation reaction, a direct C14β-hydroxylation, and a Stille cross-coupling.

Key words

cardiotonic steroids - digitoxigenin - androstenedione - Stille cross-coupling - hydroxylation - semi-synthesis

Publication History

Received: 29 April 2023

Accepted after revision: 21 June 2023

Accepted Manuscript online:
21 June 2023

Article published online:
24 August 2023

• References and Notes

• 1a Levi AJ, Boyett MR, Lee CO. Prog. Biophys. Mol. Biol. 1994; 62: 1
• 1b Schoner W, Scheiner-Bobis G. Am. J. Physiol.: Cell Physiol. 2007; 293: C509
• 1c Laursen M, Yatime L, Nissen P, Fedosova NU. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 10958
• 1d Horisberger J.-D. Physiology 2004; 19: 377
• 2a Babula P, Masarik M, Adam V, Provaznik I, Kizek R. Anti-Cancer Agents Med. Chem. 2013; 13: 1069
• 2b Schneider NF. Z, Cerella C, Simões CM. O, Diederich M. Molecules 2017; 22: 1932
• 3 Cai H, Wang H.-YL, Venkatadri R, Fu D.-X, Forman M, Bajaj SO, Li H, O’Doherty GA, Aravboger R. ACS Med. Chem. Lett. 2014; 5: 395
• 4 Orellana AM, Kinoshita PF, Leite JA, Kawamoto M, Scavone C. Front. Endocrinol. (Rome, Italy) 2016; 7: 10
• 5 Jacob PL, Leite JA, Alves AK. A, Rodrigues YK. S, Amorim FM, Néris PL, Oliveira MR, Mascarenhas RS. Parasitol. Res. 2013; 112: 1313
• 6 Harrison’s Principles of Internal Medicine, 14th ed. Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DS, Hauser SL, Longo DL. McGraw-Hill; New York: 1998
• 7 Schneider NF. Z, Geller FC, Persich L, Marostica LL, Pádua RM, Kreis W, Braga FC, Simões CM. O. Nat. Prod. Res. 2016; 30: 1327
• 8 Laphookhieo S, Cheenpracha S, Karalai C, Chantrapromma S, Rat-a-pa Y, Ponglimanont C, Chantrapromma K. Phytochemistry 2004; 65: 507
• 9 Ueda J.-y, Tezuka Y, Tezuka AH, Banskota AH, Tran QL, Tran QK, Saiki I, Kadota S. J. Nat. Prod. 2003; 66: 1427
• 10 Danieli N, Mazur Y, Sondheimer F. J. Am. Chem. Soc. 1962; 84: 875
• 11 Stork G, West F, Lee HY, Richard CA. I, Manabe S. J. Am. Chem. Soc. 1996; 118: 10660
• 12 Honma M, Nakada M. Tetrahedron Lett. 2007; 48: 1541
• 13 Kabat MM. J. Org. Chem. 1995; 60: 1823
• 14a Wiesner K, Tsai TY. R. Pure Appl. Chem. 1986; 58: 799
• 14b Wiesner K, Tsai TY. R, Minta A. Heterocycles 1979; 12: 1397
• 15 Koch V, Nieger M, Bräse S. Adv. Synth. Catal 2017; 359: 832
• 16 Bhattarai B, Nagorny P. Org. Lett. 2018; 20: 154
• 17a Barton DH. R, O’Brien RE. J. Chem. Soc. 1962; 470
• 17b Barton DH. R, Bashiardes G, Fourrey JL. Tetrahedron 1988; 44: 147
• 18 Shimizu S, Hagiwara K, Itoh H, Inoue M. Org. Lett. 2020; 22: 8652
• 19 Nicolaou KC, Zhong Y.-L, Baran PS. J. Am. Chem. Soc. 2000; 122: 7596
• 20a Ito Y, Hirao T, Saegusa T. J. Org. Chem. 1978; 43: 1011
• 20b Lu YD, Nguyen PL, Lévaray N, Lebel H. J. Org. Chem. 2013; 78: 776
• 21a Groszek G, Kurek-Tyrlik A, Wicha J. Tetrahedron 1989; 45: 2223
• 21b Hashimoto S, Katoh S.-i, Kato T, Urabe D, Inoue M. J. Am. Chem. Soc. 2017; 139: 16420
• 22a Mukai K, Kasuya S, Nakagava Y, Urabe D, Inoue M. Chem. Sci. 2015; 6: 3383
• 22b Khatri RH, Bhattarai B, Kaplan W, Li Z, Long MJ. C, Aye Y, Nagorny P. J. Am. Chem. Soc. 2019; 141: 4849
• 23 Digitoxigenin (1) TMSCl (314 mg, 2.9 mmol) was added to a solution of 10 (215 mg, 0.57 mmol), and imidazole (400 mg, 5.8 mmol) in DMF (10 mL) at rt, and the mixture was stirred at 70 °C for 15 h, then cooled to 0 °C. Sat. aq NaHCO₃ (10 mL) and H₂O (5 mL) were added, and the resultant mixture was extracted with Et₂O (4 × 10 mL). The combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), and concentrated under vacuum. The residue was added to a flask together with 10% Pd/C catalyst (123 mg) and EtOAc (8 mL). The flask was flushed with H₂ and attached to a H₂-filled balloon. The mixture was then stirred at rt for 1 h. 1 M aq HCl (2 mL) was added, and the mixture was stirred for 5 min. Sat. aq NaHCO₃ (10 mL) was added and the resultant mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), and concentrated under vacuum. The residue was purified by flash column chromatography [silica gel, PE–EtOAc (1:2)] to give a white solid; yield: 115 mg (70%); mp 253–254 °C. [α]_D ²⁰ +17.8 (c 0.4, MeOH), R_f = 0.3 (PE–EtOAc, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 5.88 (s, 1 H), 5.01 (dd, J = 18.1, 1.8 Hz, 1 H), 4.82 (dd, J = 18.1, 1.8 Hz, 1 H), 4.14 (t, J = 3.2 Hz, 1 H), 2.79 (dd, J = 8.8, 5.5 Hz, 1 H), 2.26–2.07 (m, 2 H), 1.90 (m, 3 H), 1.82–1.10 (m, 16 H), 0.97 (s, 3 H), 0.89 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃) δ = 174.70, 174.60, 117.65, 85.56, 73.49, 66.81, 50.93, 49.64, 41.80, 40.03, 35.98, 35.48, 35.40, 33.31, 33.14, 29.64, 27.90, 26.89, 26.48, 23.73, 21.36, 21.17, 15.79. HRMS (ESI): m/z [M + H]⁺ calcd. for C₂₃H₃₅O₄: 375.2530; found: 375.2529.