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

Publikationsverlauf

Eingereicht: 23. November 2020

Angenommen nach Revision: 05. Januar 2021

Accepted Manuscript online:
05. Januar 2021

Artikel online veröffentlicht:
27. Januar 2021

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• 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.