Synthesis of C-13 Oxidised Cuparene and Herbertane Sesquiterpenes via a Paternò-Büchi Photocyclisation-Oxetane Fragmentation Strategy: Total Synthesis of 1,13-Herbertenediol

Abstract

The intramolecular Paternò-Büchi reaction of 5-aryl-4,4-dimethyl-hex-5-enals has been used to assemble the hindered cyclopentane skeleton of the cuparene and herbertane sesquiter­penes. Regioselective carbon-oxygen bond cleavage in the resulting oxetane is applied to the synthesis of 1,13-herbertane diol.

photochemistry - ring-opening - terpenoids - fused-ring systems - reduction

References

See the following recent examples, and references therein

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4 The combination of a Paternò-Büchi reaction and selective oxetane cleavage has found notable application in the synthesis of triquinane natural products. See: Reddy TJ. Rawal VH. Org. Lett.  2000,  2:  2711 ; and references therein

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10

Attempted preparation of the photochemical precursor 14 via an analogous sequence of reactions to that described in Scheme [1] was thwarted by the formation of 19 as the major product upon attempted Wittig olefination of 18. Alkene 19 is presumably formed by an initial retro-Michael addition under the reactions conditions to reform ketone 8, which subsequently undergoes Wittig olefination. The sluggish reactivity of hindered aryl ketones to the phosphorus ylide necessitates the high temperature employed, although the difference in reactivity of 2 and 18 under identical reaction conditions is notable. To date, we have been unable to achive methylation of 18 using other methods (Scheme [3] ).

Scheme 3

11

An oven dried Schlenk tube was equipped with a glass stirrer bar and charged with DBB (1.59 g, 5.97 mmol) and THF (10 mL). Lithium wire (83 mg, 11.90 mmol) was added in one portion and the mixture was sonicated for 5 min until a rich turquoise solution was achieved. The resulting solution was stirred for 5 h at r.t., cooled to -78 °C, and a solution of oxetane 15 (295 mg, 1.19 mmol) in THF (3 mL) added. The reaction mixture was then treated dropwise with a solution of diethylaluminium chloride in hexane (1 M, 5.97 mL, 5.97 mmol). Once addition was complete the reaction mixture was stirred at -78 °C for 1.5 h then quenched with 5% HCl (5 mL), and the resulting biphasic solution was allowed to warm to r.t. The aqueous layer was extracted with Et₂O (3 × 15 mL) and the combined organic phases were dried over MgSO₄, and concentrated in vacuo to furnish pale yellow oil. The crude product was purified by flash column chromatography (hexane-EtOAc 95:5) to afford first 2-(2′-methoxy-5′-methylphenyl)-2,3,3-trimethylcyclopentanol 17 as a transparent oil (67 mg, 22%); R_f = 0.30 (hexane-EtOAc 8:2). IR (CDCl₃): ν_max = 3412, 2945, 1498, 1465 and 1246 cm^-1. ¹H NMR (360 MHz, CDCl₃): δ = 7.18 (1 H, d, J = 1.9 Hz), 7.06-6.98 (1 H, m), 6.80 (1 H, d, J = 8.3 Hz), 5.15 (1 H, s), 3.79 (3 H, s), 2.47-2.32 (1 H, m), 2.29 (3 H, s), 2.09-2.01 (1 H, m), 1.72-1.66 (2 H, m), 1.49-1.44 (1 H, m), 1.29 (3 H, s), 1.16 (3 H, s), 0.64 (3 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 21.3 (q), 21.5 (q), 27.2 (q), 27.6 (t), 28.9 (q), 37.2 (t), 44.1 (s), 54.5 (s), 56.0 (q), 76.4 (d), 112.9 (d), 127.9 (d), 130.2 (s), 130.9 (d), 133.6 (s), 156.4 (s). ESI-MS: m/z = 271.1664 (C₁₆H₂₄O₂Na requires 271.1669). MS (EI): m/z (%) = 248 (98), 230 (50), 215 (63), 200 (15), 187 (72), 148 (100), 135 (57), 105 (29), 91 (25), 69 (15) and 41 (16). Followed by [1-(2′-methoxy-5′-methylphenyl)-2,2-dimethylcyclopentyl]-methanol 16 as a pale yellow oil (168 mg, 57%); R_f = 0.24 (hexane-EtOAc 8:2). IR (CDCl₃): ν_max = 3549, 3413, 2952, 1498, 1465, 1240 and 805 cm^-1. ¹H NMR (360 MHz, CDCl₃): δ = 7.08 (1 H, d, J = 1.9 Hz), 7.03-7.00 (1 H, m), 6.77 (1 H, d, J = 8.2 Hz), 4.60 (1 H, dd, J = 2.7 and 10.5 Hz), 3.77 (3 H, s), 3.49 (1 H, t, J = 10.2 Hz), 2.57-2.52 (1 H, m), 2.28 (3 H, s), 2.17-2.12 (1 H, m), 1.79-1.73 (2 H, m), 1.58-1.53 (2 H, m), 1.30 (1 H, d, J = 2.0 Hz), 1.10 (3 H, s), 0.67 (3 H, s). ¹³C NMR (90 MHz, CDCl₃): δ = 21.3 (q), 21.3 (t), 25.2 (q), 27.8 (q), 35.9 (t), 42.7 (t), 44.5 (s), 55.2 (q), 58.2 (s), 66.3 (t), 111.5 (d), 128.4 (d), 129.9 (s), 130.7 (s), 132.2 (d), 156.6 (s). ESI-MS: m/z = 271.1665 (C₁₆H₂₄O₂Na requires 271.1669). MS (EI): m/z (%) = 248 (54), 218 (20), 217 (95), 187 (44), 161 (42), 135 (100), 105 (19), 95 (17), 69 (29) and 41 (11).

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13 Aristoff PA. Johnson PD. Harrison AW. J. Am. Chem. Soc.  1985,  107:  7967 

14

A solution of HPPh₂ (0.182 mL, 1.05 mmol) in THF (3 mL) was cooled to 0 °C and a solution of n-BuLi in hexane (2.2 M, 0.47 mL, 1.04 mmol) was added dropwise. The orange solution was stirred at 0 °C for 5 min and then at r.t. for a further 30 min. A solution of alcohol 16 (40 mg, 0.16 mmol) in THF (2 mL) was added at r.t. and the resulting solution was refluxed for 45 min, cooled to 0 °C and quenched with 5% HCl (5 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic phases were dried over MgSO₄ and concentrated in vacuo to furnish a pale yellow oil. The crude product was purified by column chromatography (hexane-EtOAc 9:1) to afford 1,13-herbertenediol as a colourless oil (29 mg, 77%). Analytic data agree with those reported in the literature.²