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Synlett 2021; 32(08): 810-813
DOI: 10.1055/a-1346-5650
DOI: 10.1055/a-1346-5650
letter
Highly Efficient Synthesis of Digoxin
This work was financially supported by the National Natural Science Foundation of China (21867012, 21877055, and 21762024) and the Natural Science Foundation of Jiangxi Province (20161ACB20005, 20171BCB23036, and 20171BAB203008).
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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-1346-5650.
- Supporting Information
- CIF File
Publication History
Received: 23 November 2020
Accepted after revision: 05 January 2021
Accepted Manuscript online:
05 January 2021
Article published online:
27 January 2021
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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.
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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.
For selected examples, see: