Synthetic Studies on the Viridin Skeleton through Regio- and Stereoselective Functionalization of the AE-Ring Moiety

Shuhei Hori; Sho Ishida; Go Itoh; Koji Sugiyama; Chiharu Yuki; Masahiro Egi; Kenzo Yahata; Takashi Ikawa; Shuji Akai

doi:10.1055/a-1527-3781

Synlett, Table of Contents

Synlett 2021; 32(12): 1187-1191
DOI: 10.1055/a-1527-3781

letter

Synthetic Studies on the Viridin Skeleton through Regio- and Stereoselective Functionalization of the AE-Ring Moiety

Shuhei Hori

^aGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, Japan

,

Sho Ishida

^bSchool of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan

,

Go Itoh

^bSchool of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan

,

Koji Sugiyama

^aGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, Japan

,

Chiharu Yuki

^aGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, Japan

,

Masahiro Egi

^cGraduate Division of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan

,

Kenzo Yahata

^aGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, Japan

,

Takashi Ikawa

^aGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, Japan

,

Shuji Akai ∗

^aGraduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka 1-6, Suita, Osaka 565-0871, Japan

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Abstract

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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 - furanosteroids

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References

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 recent examples of domino dynamic kinetic resolution/IMDA reactions, see:

25a Tsuchimochi I, Hori S, Takeuchi Y, Egi M, Satoh T, Kanomata K, Ikawa T, Akai S. Synlett 2021; 32: 822
25b Sugiyama K, Kawanishi S, Oki Y, Kamiya M, Hanada R, Egi M, Akai S. Bioorg. Med. Chem. 2018; 26: 1378

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