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Synlett 2023; 34(17): 2034-2036
DOI: 10.1055/a-2114-8823
DOI: 10.1055/a-2114-8823
letter
Semi-Synthesis of (+)-Digitoxigenin from Androstenedione
We are grateful for the financial support from the National Natural Science Foundation of China (21772195) and the Fundamental Research Funds for the Central Universities (DUT22QN213).
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-synthesisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2114-8823.
- Supporting Information
Publication History
Received: 29 April 2023
Accepted after revision: 21 June 2023
Accepted Manuscript online:
21 June 2023
Article published online:
24 August 2023
© 2023. Thieme. All rights reserved
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- 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), Rf = 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.