Synthesis of Phenol Abietane Diterpenes Based on the Oxidative Radical Cyclization Utilizing the Mn(OAc)₃/Ac₂O System

Abstract

A new route to phenol abietane diterpenes from trans-communic acid is reported. The key step is the transformation of a β-ketoester into the corresponding O-acetylsalicilate, via a manganese(III)-based oxidative free-radical cyclization carried out in Ac₂O. Utilizing this, the first synthesis of (-)-sugikurojin A has been achieved. The immunosuppressor 19-hydroxyferruginol has also been synthesized.

Key words

enantiospecific synthesis - abietane diterpenoids - ­phenols

References and Notes

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24

Typical Procedure for Radical Cyclization
Strictly deoxygenated Ac₂O (20 mL) was added to a mixture of manganese(III) acetate dihydrate (3.21 g, 12 mmol) and LiCl (365 mg, 8.6 mmol) under argon atmosphere, and the resulting suspension was stirred at r.t. for 15 min. Then, a solution of β-ketoester (15, 1 g, 2.86 mmol) in deoxygenated Ac₂O (20 mL) was added, and the mixture was stirred at reflux for 9 h, at which time TLC showed no starting material. The reaction mixture was cooled to 0 °C, and then quenched with H₂O (10 mL). After stirring for 10 min, t-BuOMe (120 mL) was added and the reaction mixture was stirred for an additional 10 min. The mixture was washed with H₂O (10 × 30 mL) and brine (3 × 20 mL). The dried organic layer was evaporated and the residue was directly purified by flash chromatography (hexane-t-BuOMe, 7:3) to yield 22 (0.82 g, 74%) as a yellow syrup.

25

Spectroscopic properties of natural terpenoids (10 and 11) were identical to those reported in the literature. All new compounds were fully characterized spectroscopically and had satisfactory high-resolution mass spectroscopy data.
Selected Data
Compound 15: [a]_D ²⁵ +13.6 (c 0.9, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.52 (3 H, s), 1.05 (1 H, ddd, J = 13.4, 13.4, 4.1 Hz), 1.14 (1 H, ddd, J = 13.2, 13.2, 4.1 Hz), 1.19 (3 H, s), 1.41 (1 H, dd, J = 12.5, 2.7 Hz), 1.51 (1 H, dt, J = 14.1, 3.1 Hz), 1.59 (1 H, m), 1.77 (1 H, ddd, J = 17.6, 13.4, 4.2 Hz), 1.81 (1 H, dt, J = 13.8, 3,6 Hz), 1.95-2.10 (2 H, m), 2.17 (1 H, br d, J = 12.6 Hz), 2.36-2.44 (2 H, m), 2.61 (1 H, dd, J = 17.5, 3.3 Hz), 2.71 (1 H, dd, J = 17.5, 10.2 Hz), 3.43 (1 H, d, J = 15.4 Hz), 3.47 (1 H, d, J = 15.4 Hz), 3.61 (3 H, s), 3.72 (3 H, s), 4.34 (1 H, br s), 4.77 (1 H, br s). ¹³C NMR (125 MHz, CDCl₃): δ = 38.3 (C-1), 20.1 (C-2), 39.5 (C-3), 44.5 (C-4), 50.7 (C-5), 26.0 (C-6), 38.1 (C-7), 148.5 (C-8), 56.2 (C-9), 39.7 (C-10), 39.8 (C-11), 202.3 (C-12), 49.3 (C-13), 106.8 (C-14), 29.0 (C-15), 177.8 (C-16, COOCH₃), 13.1 (C-17), 167.9 (COOCH₃), 51.4 (COOCH₃), 52.5 (COOCH₃).
Compound 22: [a]_D ²⁵ +64.5 (c 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.01 (3 H, s), 1.07 (1 H, ddd, J = 13.6, 13.6, 4.1 Hz), 1.27 (3 H, s), 1.41 (1 H, ddd, J = 13.3, 13.3, 4.1 Hz), 1.51 (1 H, dd, J = 12.2, 1.4 Hz), 1.63 (1 H, m), 1.90-2.07 (2 H, m), 2.18 (1 H, m), 2.28 (1 H, br d, J = 13.7 Hz), 2.31 (3 H, s), 2.77 (1 H, ddd, J = 16.9, 12.7, 6.4 Hz), 2.94 (1 H, dd, J = 16.9, 4.5 Hz), 3.65 (3 H, s), 3.82 (3 H, s), 6.94 (1 H, s), 7.69 (1 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 37.7 (C-1), 20.0 (C-2), 39.1 (C-3), 44.2 (C-4), 51.5 (C-5), 20.9 (C-6), 31.5 (C-7), 133.6 (C-8), 148.8 (C-9), 39.2 (C-10), 120.8 (C-11), 154.9 (C-12), 120.2 (C-13), 132.7 (C-14), 170.1 (COOCH₃), 28.6 (C-16), 177.8 (COOCH₃), 23.0 (C-20), 52.2 (COOCH₃), 52.3 (COOCH₃), 21.2 (OCOCH₃), 165.2 (OCOCH₃).
Compound 23: [a]_D ²⁵ +48.4 (c 0.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.00 (3 H, s), 1.06 (1 H, ddd, J = 13.7, 13.7, 4.4 Hz), 1.26 (3 H, s), 1.37 (1 H, ddd, J = 13.2, 13.2, 3.8 Hz), 1.50 (1 H, d, J = 12.1 Hz), 1.63 (3 H, s), 1.66 (3 H, s), 1.86-2.04 (3 H, m), 2.09 (1 H, s), 2.12-2.23 (2 H, m), 2.27 (1 H, d, J = 13.4 Hz), 2.68 (1 H, ddd, J = 16.3, 12.7, 6.0 Hz), 2.79 (1 H, dd, J = 16.3, 4.9 Hz), 3.64 (3 H, s), 6.73 (1 H, s), 6.77 (1 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 37.9 (C-1), 20.2 (C-2), 39.5 (C-3), 44.2 (C-4), 51.5 (C-5), 21.4 (C-6), 31.6 (C-7), 126.4 (C-8), 149.2 (C-9), 38.5 (C-10), 114.4 (C-11), 153.7 (C-12), 129.0 (C-13), 125.9 (C-14), 75.9 (C-15), 30.5 (C-16), 30.6 (C-17), 28.3 (C-18), 178.2 (C-19), 23.0 (C-20), 53.1 (COOCH₃).
Compound 24: [a]_D ²⁵ +30.8 (c 0.8, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.77 (6 H, q, J = 7.9 Hz), 1.01 (9 H, t, J = 7.9 Hz), 1.02 (3 H, s), 1.08 (1 H, ddd, J = 14.0, 14.0, 4.1 Hz), 1.18 (3 H, d, J = 6.9 Hz), 1.19 (3 H, d, J = 6.9 Hz), 1.27 (3 H, s), 1.41 (1 H, ddd, J = 13.4, 13.4, 3.9 Hz), 1.54 (1 H, d, J = 12.0 Hz), 1.64 (1 H, br d, J = 14.0 Hz), 1.90-2.01 (2 H, m), 2.13 (1 H, br d, J = 14.1 Hz), 2.17 (1 H, dd, J = 13.6, 5.7 Hz), 2.28 (1 H, br d, J = 13.4 Hz), 2.73 (1 H, ddd, J = 16.3, 12.6, 5.9 Hz), 2.83 (1 H, dd, J = 16.3, 5.0 Hz), 3.21 (1 H, sept, J = 6.9 Hz), 3.66 (3 H, s), 6.65 (1 H, s), 6.82 (1 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 37.9 (C-1), 20.3 (C-2), 39.7 (C-3), 44.2 (C-4), 51.4 (C-5), 21.5 (C-6), 31.6 (C-7), 127.6 (C-8), 146.1 (C-9), 38.3 (C-10), 115.1 (C-11), 151.2 (C-12), 136.2 (C-13), 126.6 (C-14), 26.9 (C-15), 23.0 (C-16), 23.1 (C-17), 28.7 (C-18), 178.1 (C-19), 23.2 (C-20), 53.0 (COOCH₃), 5.7 (SiCH₂CH₃), 7.0 (SiCH₂CH₃).
Compound 25: [a]_D ²⁵ +72.6 (c 0.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.01 (3 H, s), 1.07 (1 H, ddd, J = 13.6, 13.6, 4.1 Hz), 1.22 (3 H, d, J = 6.9 Hz), 1.23 (3 H, d, J = 6.9 Hz), 1.26 (3 H, s), 1.39 (1 H, ddd, J = 13.3, 13.3, 4.1 Hz), 1.52 (1 H, d, J = 12.1 Hz), 1.61 (1 H, m), 1.80-2.05 (2 H, m), 2.16 (2 H, m), 2.27 (1 H, br d, J = 13.3 Hz), 2.71 (1 H, ddd, J = 16.4, 12.7, 5.9 Hz), 2.83 (1 H, dd, J = 16.4, 5.3 Hz), 3.11 (1 H, sept, J = 6.9 Hz), 3.65 (3 H, s), 4.54 (1 H, br s), 6.63 (1 H, s), 6.83 (1 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 37.9 (C-1), 20.2 (C-2), 39.6 (C-3), 44.2 (C-4), 51.4 (C-5), 21.4 (C-6), 31.6 (C-7), 127.7 (C-8), 146.7 (C-9), 38.4 (C-10), 112.2 (C-11), 151.1 (C-12), 132.0 (C-13), 126.9 (C-14), 27.0 (C-15), 22.7 (C-16), 22.9 (C-17), 28.9 (C-18), 178.2 (C-19), 23.1 (C-20), 53.0 (COOCH₃).
Compound 26: ¹H NMR (400 MHz, CDCl₃): δ = 0.80 (6 H, q, J = 7.9 Hz), 1.01 (9 H, t, J = 7.9 Hz), 1.08 (3 H, s), 1.13 (1 H, ddd, J = 13.6, 13.6, 4.1 Hz), 1.19 (3 H, d, J = 6.9 Hz), 1.21 (3 H, d, J = 6.9 Hz), 1.25 (3 H, s), 1.51 (1 H, ddd, J = 13.3, 13.3, 4.1 Hz), 1.60 (1 H, m), 1.70 (1 H, br d, J = 14.2 Hz), 2.03 (2 H, m), 2.20 (1 H, br d, J = 12.8 Hz), 2.31 (1 H, br d, J = 13.6 Hz), 2.92 (1 H, dd, J = 17.5, 2.1 Hz), 3.13 (1 H, dd, J = 17.5, 14.6 Hz), 3.21 (1 H, sept, J = 6.9 Hz), 3.69 (3 H, s), 6.72 (1 H, s), 7.91 (1 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 37.7 (C-1), 19.9 (C-2), 38.7 (C-3), 44.1 (C-4), 50.5 (C-5), 37.7 (C-6), 197.3 (C-7), 137.7 (C-8), 154.2 (C-9), 38.5 (C-10), 113.8 (C-11), 158.8 (C-12), 128.2 (C-13), 126.1 (C-14), 27.2 (C-15), 22.6 (C-16), 22.7 (C-17), 28.2 (C-18), 177.3 (C-19), 21.5 (C-20), 53.0 (COOCH₃), 5.6 (SiCH₂CH₃), 6.8 (SiCH₂CH₃).
Compound 28: [a]_D ²⁵ +36.0 (c 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.02 (3 H, s), 1.07 (1 H, ddd, J = 13.6, 13.6, 4.2 Hz), 1.18 (3 H, d, J = 6.9 Hz), 1.19 (3 H, d, J = 6.8 Hz), 1.27 (3 H, s), 1.39 (1 H, ddd, J = 13.4, 13.4, 3.8 Hz), 1.53 (1 H, d, J = 12.1 Hz), 1.60 (1 H, br d, J = 14.2 Hz), 1.90-2.05 (2 H, m), 2.13-2.21 (2 H, m), 2.28 (1 H, m), 2.29 (3 H, s), 2.77 (1 H, ddd, J = 16.7, 12.7, 6.2 Hz), 2.88 (1 H, dd, J = 16.7, 5.9 Hz), 2.91 (1 H, sept, J = 6.8 Hz), 3.65 (3 H, s), 6.65 (1 H, s), 6.84 (1 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 37.8 (C-1), 20.1 (C-2), 39.5 (C-3), 44.2 (C-4), 51.4 (C-5), 21.2 (C-6), 31.8 (C-7), 133.4 (C-8), 146.5 (C-9), 38.5 (C-10), 119.3 (C-11), 146.9 (C-12), 137.2 (C-13), 127.2 (C-14), 27.4 (C-15), 23.1 (C-16), 23.2 (C-17), 28.7 (C-18), 178.0 (C-19), 23.2 (C-20), 52.7 (COOCH₃), 21.1 (OCOCH₃), 170.1 (OCOCH₃).
Compound 29: [a]_D ²⁵ +53.3 (c 0.9, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.11 (3 H, s), 1.20 (3 H, d, J = 6.8 Hz), 1.22 (3 H, d, J = 6.8 Hz), 1.25 (3 H, s), 1.53 (1 H, ddd, J = 13.1, 13.1, 4.1 Hz), 1.68 (1 H, m), 1.98 (1 H, dt, J = 10.6, 3.6 Hz), 2.06 (1 H, dd, J = 14.5, 3.3 Hz), 2.26 (1 H, br d, J = 14.6 Hz), 2.33 (3 H, s), 2.98 (1 H, m), 2.97 (1 H, ddd, J = 17.9, 6.7, 3.3 Hz), 3.00 (1 H, sept, J = 6.8 Hz), 3.21 (1 H, dd, J = 17.9, 14.5 Hz), 3.69 (3 H, s), 7.02 (1 H, s), 8.01 (1 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 37.7 (C-1), 19.7 (C-2), 38.6 (C-3), 44.1 (C-4), 50.3 (C-5), 37.6 (C-6), 198.2 (C-7), 139.0 (C-8), 153.0 (C-9), 38.7 (C-10), 119.1 (C-11), 153.6 (C-12), 128.9 (C-13), 126.5 (C-14), 27.3 (C-15), 22.9 (C-16), 23.0 (C-17), 27.5 (C-18), 177.2 (C-19), 21.6 (C-20), 51.8 (COOCH₃), 177.2 (COOCH₃), 21.2 (OCOCH₃), 169.3 (OCOCH₃).