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Synlett 2022; 33(04): 391-395
DOI: 10.1055/s-0041-1737803
DOI: 10.1055/s-0041-1737803
letter
Synthetic Approach toward (–)-Tetrodotoxin via Construction of the Bicyclo[2.2.2]octane Skeleton
This work was financially supported by Japan Society for the Promotion of Science (JSPS KAKENHI, Grant Number JP17H01523) and by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research: BINDS) from the Japan Agency for Medical Research and Development (AMED, Grant Number JP21am0101099). K.K. gratefully acknowledges the support of ‘Graduate Program of Transformative Chem-Bio Research (GTR)’ in Nagoya University, funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT, WISE Program).
Abstract
A synthetic approach toward (–)-tetrodotoxin (TTX) is described. Our approach features a stereoselective construction of the TTX core structure using the bicyclo[2.2.2]octane skeleton which was constructed via intramolecular Diels–Alder reaction of an o-quinone monoketal having the key functional groups. The robust asymmetric synthesis was achieved by an iridium-catalyzed dynamic kinetic resolution (DKR) of the aryl vinyl carbinol that could be easily prepared from a simple aromatic compound.
Key words
natural product - bicyclo[2.2.2]octane skeleton - oxidative cleavage - intramolecular Diels–Alder reaction - dynamic kinetic resolutionSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1737803.
- Supporting Information
Publication History
Received: 29 November 2021
Accepted after revision: 20 December 2021
Article published online:
28 January 2022
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- 27 (4aS,6aR,9S,9aR,9bS)-9a-Amino-9-(benzyloxy)-5-[(4-methoxyphenoxy)methyl]-3,3-dimethyl-6a,9,9a,9b-tetrahydro-1H-[1,3]dioxino[5,4-e]benzofuran-8(4aH)-one (2)To a stirred solution of 39 (28.8 mg, 56.5 μmol) in acetonitrile (2.0 mL) and water (2.0 mL) was added iodobenzene diacetate (54.6 mg, 170 μmol) at room temperature. After stirring for 1 h, sodium bicarbonate (47.5 mg, 566 μmol) was added to the mixture and the mixture was heated at 40–50 °C. After stirring for 90 min, the mixture was cooled to room temperature. A mixed solution of saturated aqueous sodium thiosulfate (3.0 mL) and saturated aqueous sodium bicarbonate (1.0 mL) was added to the mixture. After stirring for 20 min, brine (2.0 mL) was added to the mixture. The mixture was extracted with ethyl acetate (4.0 mL) five times. The combined organic layer was concentrated under reduced pressure to give a crude material, which was purified by neutral silica gel column chromatography (ethyl acetate/n-hexane, 1:1 to 3:2 to 2:1) to afford amine 2 (16.9 mg, 62%) as a colorless oil. [α]D 24 –31.3 (c 0.65, CHCl3). IR (neat): 3385, 3324, 3054, 2993, 2955, 2918, 2874, 2850, 2838, 1770, 1508, 1456, 1444, 1397, 1380, 1373, 1265, 1230, 1215, 1198, 1179, 1108, 1074, 1057, 1030, 980, 873, 826, 739, 703 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.32 (m, 5 H), 6.82 (s, 4 H), 5.91 (m, 1 H), 5.02 (d, J = 9.6 Hz, 1 H), 4.88 (d, J = 11.0 Hz, 1 H), 4.63 (m, 1 H), 4.55 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 14.2 Hz, 1 H), 4.41 (d, J = 14.6 Hz, 1 H), 3.97–3.86 (m, 2 H), 3.77 (s, 3 H), 3.61 (s, 1 H) 2.12 (m, 1 H), 1.42 (br s, 2 H), 1.33 (s, 3 H), 1.18 (s, 3 H). 13C NMR (CDCl3, 100 MHz): δ = 172.9, 154.2, 152.9, 139.9, 136.3, 129.0, 128.8, 128.6, 119.9, 116.0, 114.7, 100.0, 85.4, 80.7, 72.9, 68.0, 67.0, 60.1, 55.9, 48.5, 29.7, 19.5. HRMS (ESI+): m/z calcd for C27H31NNaO7 + [M + Na]+: 504.1993; found: 504.1993