An IMDA Approach to Tigliane and Daphnane Diterpenoids: Generation of Rings A, B and C Incorporating C-18

Abstract

A synthesis of the tricyclic ring system of the daphnane and tigliane diterpenes, incorporating C-18 and the C-13 oxygen functionality found in phorbol and related compounds is described. The convergent synthesis utilizes an intramolecular Diels-Alder reaction as the key stereocontrolling step.

Key words

phorbol - synthesis - tigliane - daphnane - IMDA

References

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1

Department of Chemistry, University of Cardiff, P.O. Box 912, Cardiff CF1 3TB, Wales.

15

(±)-(3a S ,6a S ,10a R ,10b S )-3-Oxo-8-triisopropylsilyloxy-1,2,3a,4,6,6a,9,10,10a,10b-decahydro-3 H -benzo[ e ]azulene-5,5,10-tricarboxylic Acid Diethyl Ester Methyl Ester (8a) and (±)-(3a S ,6a R ,10a R ,10b S )-3-Oxo-8-triisopropylsilyloxy-1,2,3a,4,6,6a,9,10,10a,10b-decahydro-3 H -benzo[ e ]azulene-5,5,10-tricarboxylic Acid Diethyl Ester Methyl Ester (8b) NB IUPAC-style numbering is used here for clarity. A screw-cap test-tube, rinsed sequentially with triethylamine and dry toluene, was charged with 16 (484 mg, 0.84 mmol), hydroquinone (4 mg, 0.04 mmol) and dry toluene (5 mL). The mixture was irradiated with ultrasound for 10 min while under a stream of nitrogen. The test-tube was sealed and heated at 160 °C for 72 h. The reaction mixture was cooled and concentrated and the crude product was purified by silica gel column chromatography [10% ethyl acetate/light petroleum (40-60 °C)] to afford a mixture of 8a and 8b (437 mg, 93%) as a colourless oil, ν_max/cm^-1(neat): 2945, 2866, 1730, 1683, 1464, 1251, 1206, 1162, 883, 806, 682. ¹H NMR (600 MHz, C₆D₆): δ = 0.84 (3 H, t, J = 7.1 Hz, CH ₃CH₂), 0.86-0.94 (4 H, m, 1 of 1-H_8b, CH ₃CH₂), 0.96 (3 H, t, J = 6.9 Hz, CH ₃CH₂), 1.00-1.21 (47 H, m, 1 × CH ₃CH₂, 1 of 1-H_8a, 10b-H_8a, 6 × CH(CH ₃)₂), 1.34 (1 H, dd, J = 11.8, 14.1 Hz, 1 of 4-H_8b), 1.53, (1 H, ddd, J = 9.1, 9.9, 10.8, 10a-H_8a), 1.58-1.71 (5 H, m, 1 of 1-H_8a, 1 of 2-H_8a, 1 of 1-H_8b, 1 of 2-H_8b, 10b-H_8b), 1.73 (1 H, dd, J = 10.2, 15.2, 4-H_8a), 1.78-1.82 (1 H, m, 10a-H_8b), 1.93-2.04 (3 H, m, 1 of 2-H_8b, 1 of 2-H_8a, 3a-H_8a), 2.07 (1 H, dd, J = 2.6, 10.2, 15.1 Hz, 1 of 6-H_8a), 2.13-2.24 (4 H, m, 3a-H_8b, 1 of 6-H_8b,1 of 9-H_8b, 6a-H_8a), 2.33 (1 H, ddd, J = 1.7, 5.0, 16.6 Hz, 1 of 9-H_8a), 2.43-2.48 (3 H, m, 1 of 6-H_8b, 6a-H_8b, 10-H_8a), 2.59 (1 H, ddd, J = 5.3, 10.1, 10.1 Hz, 10-H_8b), 2.64 (1 H, d, J = 15.1 Hz, 6-H_8a), 2.69 (1 H, dddd, J = 2.2, 3.7, 11.3, 16.6 Hz, 1 of 9-H_8a), 2.76 (1 H, dddd, J = 1.8, 1.8, 10.1, 17.0 Hz, 1 of 9-H_8b), 3.30, (3 H, s, CO₂CH ₃), 3.31, (3 H, s, CO₂CH ₃), 3.38 (1 H, d, J = 15.2 Hz, 1 of 4-H_8a), 3.45 (1 H, br ddd, J = 2.3, 2.3, 14.1 Hz, 1 of 4-H_8b), 3.81-4.01 (6 H, m, 6 of CH₃CH ₂), 4.09 (1 H, qd, J = 7.1, 10.9 Hz, 1 of CH₃CH ₂), 4.15 (1 H, qd, J = 7.0, 10.5 Hz, 1 of CH₃CH ₂), 5.03 (1 H, dd, J = 1.8, 5.2 Hz, 7-H_8b), 5.11 (1 H, dd, J = 2.2, 2.4 Hz, 7-H_8a); ¹³C NMR (150 MHz, C₆D₆): δ = 13.0 (CH(CH₃)₂, 13.9, 14.0, 14.1, 14.2 (4 × CH₂ CH₃), 18.2 (CH(CH₃)₂), 26.2 (1-C_8a), 28.6 (1-C_8b), 32.3 (4-C_8a), 33.4 (9-C_8b), 34.6 (9-C_8a), 34.8 (6a-C_8b), 36.7 (2-C_8a), 36.8 (6-C_8b), 37.0 (3a-C_8b), 37.2 (4-C_8b), 37.5 (2-C_8b), 42.5 (6-C_8a), 43.0 (10-C_8b), 44.8 (10a-C_8b), 45.6 (10b-C_8b), 47.2 (10-C_8a), 49.1 (10a-C_8a), 49.8 (6a-C_8a), 51.0 (10b-C_8a), 51.2, 51.3 (2 x CO₂ CH₃), 51.9 (3a-C_8a), 55.9 (5-C_8a), 57.1 (5-C_8b), 61.2, 61.3, 61.35, 61.44 (4 × CH₂CH₃), 107.7 (7-C_8b), 109.2
(7-C_8a), 148.3 (8-C_8a), 148.9 (8-C_8b), 170.9, 171.9, 172.2, 172.3 (4 × CO₂C₂H₅), 175.1, 175.6 (2 × CO₂CH₃), 214.2 (3-C_8a), 215.6 (3-C_8b). MS (EI): m/z = 578 (14) [M⁺], 535 (35), 519 (17), 324 (30), 256 (77), 69 (100). C₃₁H₅₀O₈Si requires 578.3275, found 578.3284.