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Synlett 2021; 32(12): 1187-1191
DOI: 10.1055/a-1527-3781
DOI: 10.1055/a-1527-3781
letter
Synthetic Studies on the Viridin Skeleton through Regio- and Stereoselective Functionalization of the AE-Ring Moiety
This work was financially supported by the JSPS KAKENHI [18HO4411 (Middle Molecular Strategy) and 18H02556] and Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under Grant Number JP21am0101084.
Abstract
4,5,6,7-Tetrahydroisobenzofurans, corresponding to the AC(D)E ring structure of viridin and equipped with required substituents on the A-ring, were synthesized with high regio- and stereoselectivities via the Diels–Alder adduct of a furan derivative and maleic anhydride. The key steps of this work include the regioselective opening of a tetrahydrofuran ring, a stereoselective epoxidation, and an AlMe3-mediated regioselective epoxide opening followed by stereoselective C-methylation.
Key words
Diels–Alder reaction - regioselectivity - ring cleavage - tetrahydroisobenzofuran - viridin - furanosteroidsSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-1527-3781.
- Supporting Information
Publication History
Received: 01 April 2021
Accepted after revision: 11 June 2021
Accepted Manuscript online:
11 June 2021
Article published online:
30 June 2021
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References and Notes
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- 24 rac-(4R,5S,6R,7R)-3-{[(4-tert-Butylphenyl)sulfanyl]methyl}-7-(chloromethyl)-6-methoxy-4-methyl-4-phenyl-4,5,6,7-tetrahydro-2-benzofuran-5-ol (17a) and rac-(4S,6R,7R)-3-{[(4-tert-Butylphenyl)sulfanyl]methyl}-7-(chloromethyl)-6-methoxy-4-phenyl-6,7-dihydro-2-benzofuran-5(4H)-one (18a) A 1.0 M solution of DIBAL-H in hexane (0.97 mL, 1.0 mmol) was slowly added over 5 min to a solution of a 1:1 mixture of 15a and 15a′ (0.32 g, 0.66 mmol) in anhyd CH2Cl2 (6.6 mL) at –78 °C, and the mixture was stirred at –78 °C for 15 min. MeOH (0.4 mL) was added, and the mixture was stirred vigorously at –78 °C for 30 min then warmed to 0 °C. 2 N aq HCl was added at 0 °C, and the mixture was stirred vigorously at rt. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in anhyd CH2Cl2 (6.7 mL), and the solution was cooled to 0 °C. MsCl (0.079 mL, 1.01 mmol) and Et3N (0.28 mL, 2.0 mmol) were added, and the mixture was stirred at 0 °C for 10 min. Sat aq NaHCO3 was then added, and the mixture was vigorously stirred at 0 °C. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in 1:1 anhyd toluene–hexane (7.4 mL), and the mixture was cooled to –100 °C. A 2.0 M solution of AlMe3 in toluene (1.23 mL, 2.5 mmol) was added at –100 °C over 10 min, and the mixture was stirred at –100 °C for 2 h. 2 N aq HCl was added at 0 °C, and the mixture was vigorously stirred. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography [silica gel, hexane–EtOAc (12:1 to 10:1)] to afford 17a as a yellow oil [yield: 0.135 g (37%)] and 18a as a colorless oil [yield: 21 mg (6%)]. 17a IR (neat): 3480 cm–1. 1H NMR (500 MHz, acetone-d 6): δ = 7.53 (d, J = 1.5 Hz, 1 H), 7.31–7.29 (m, 2 H), 7.27–7.23 (m, 4 H), 7.19–7.13 (m, 3 H), 4.26 (d, J = 5.0 Hz, 1 H), 4.06 (dd, J = 5.0, 1.5 Hz, 1 H), 3.98 (dd, J = 10.5, 7.0 Hz, 1 H), 3.93 (dd, J = 10.5, 7.5 Hz, 1 H), 3.78 (dd, J = 4.5, 1.5 Hz, 1 H). 3.74 (d, J = 13.5 Hz, 1 H), 3.57 (d, J = 13.5 Hz, 1 H), 3.47 (s, 3 H), 3.36–3.29 (m, 1 H), 1.78 (s, 3 H), 1.27 (s, 9 H). 13C NMR (125 MHz, acetone-d 6): δ = 150.4, 149.0, 146.9, 138.0, 133.7, 130.9, 128.8, 128.2, 126.9, 126.8, 126.7, 123.5, 80.4, 80.0, 59.6, 45.4, 44.8, 40.3, 34.9, 32.0, 31.4, 22.5. HRMS (MALDI): m/z calcd [M + Na]+ for C28H33 35ClNaO3S: 507.1731; found: 507.1731. 18a IR (neat): 1732 cm–1. 1H NMR (500 MHz, acetone-d 6): δ = 7.60 (s, 1 H), 7.42–7.38 (m, 2 H), 7.31–7.22 (m, 3 H), 7.16–7.12 (m, 2 H), 7.04–7.00 (m, 2 H), 4.18 (d, J = 5.0 Hz, 1 H), 3.86 (dd, J = 11.0, 5.0 Hz, 1 H), 3.85 (s, 1 H), 3.70–3.64 (m, 1 H), 3.68 (d, J = 14.0 Hz, 1 H), 3.59 (dd, J = 11.0, 7.5 Hz, 1 H), 3.23 (s, 3 H), 3.22 (d, J = 14.0 Hz, 1 H), 1.32 (s, 9 H). 13C NMR (125 MHz, acetone-d 6): δ = 204.7, 152.1, 148.1, 139.1, 138.0, 133.9, 132.1, 130.3, 129.0, 127.9, 126.9, 122.0, 120.6, 83.0, 58.3, 52.3, 44.9, 41.2, 35.1, 32.1, 31.5. HRMS (MALDI): m/z [M + Na]+ calcd for C27H29 35ClNaO3S: 491.1420; found: 491.1418.
For total syntheses of 3, see:
For reviews, see: