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

• References and Notes

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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), 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.