Synthetic Studies towards the Africanane Sesquiterpenes via the Cope Rearrangement of gem-Dimethyl-Substituted Divinyl Cyclopropanes

To commemorate the 70^th birthday of Prof. Steven Ley, FRS; inspirational synthetic organic chemist, mentor and friend

Abstract

The Cope rearrangement of gem-dimethyl-substituted divinylcyclopropanes has been used to construct functionalised cycloheptadienes. These scaffolds have been further elaborated to furnish advanced intermediates en route to africanane sesquiterpene natural products, most notably pyxidatol C.

Key words

pericyclic reactions - cyclopropanes - natural products - pyxidatol C - africananes.

• References and Notes

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• 14 To a stirred solution of Et₂Zn (170 μL, 1 M in hexanes, 0.170 mmol) in CH₂Cl₂ (1 mL) at 0 °C was added CH₂I₂ (27 μL, 0.340 mmol). This was stirred for 10 min before the addition of 19 (25 mg, 0.0850 mmol) in CH₂Cl₂ (1 mL) via cannula. The reaction was stirred at 0 °C for 30 min before it was quenched by the addition of sat. aq NH₄Cl (5 mL). The organic layer was separated and the aqueous layer extracted with further portions of CH₂Cl₂ (2 × 10 mL). The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel, eluting with PE–Et₂O (15:1) to afford compound 20a as a colourless oil (8 mg, 32%) and 20b as a colourless oil (7 mg, 27%). Compound 20a: R_f = 0.21 (PE–Et₂O, 4:1). IR (thin film): ν_max = 3340, 2909, 2886, 2816 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.25–5.15 (2 H, m), 3.82–3.73 (3 H, m), 3.04 (1 H, d, J = 10.5 Hz), 2.37–2.31 (1 H, m), 1.80–1.74 (1 H, m), 1.57–1.43 (1 H, m), 1.06 (3 H, s), 0.98 (3 H, s), 0.92 (9 H, s), 0.90–0.88 (1 H, m), 0.82–0.77 (2 H, m), 0.10 (3 H, s), 0.10 (3 H, s). ¹³C NMR (101 MHz, CDCl₃): δ = 140.9, 125.0, 68.9, 65.3, 48.2, 42.7, 40.2, 39.0, 32.3, 30.7, 27.7, 25.9, 19.3, 18.3, –5.3, –5.3. ESI-MS: m/z = 333 [MNa⁺]. HRMS: m/z calcd for C₁₈H₃₄NaO₂Si [MNa⁺]: 333.2220; found: 333.2220. Compound 20b R_f = 0.16 (PE–Et₂O, 4:1). IR (thin film): ν_max = 3354, 2910, 2884, 2814 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.38–5.28 (2 H, m), 3.54–3.50 (2 H, m), 3.36 (1 H, dd, J = 10.0, 8.5 Hz), 3.06 (1 Hz H, d, J = 10.0 Hz), 2.93–2.88 (1 H, m), 1.84 (1 H, ddd, J = 14.0, 5.0, 2.0 Hz), 1.44–1.22 (2 H, m), 1.09 (3 H, s), 0.93 (3 H, s), 0.89 (9 H, s), 0.63–0.53 (2 H, m), 0.06 (6 H, s). ¹³C NMR (101 MHz, CDCl₃): δ = 142.5, 124.7, 77.4, 73.5, 66.5, 42.5, 41.4, 38.0, 32.7, 28.4, 27.0, 26.0, 18.3, 16.1, –5.2. ESI-MS: m/z = 333 [MNa⁺]. HRMS: m/z calcd for C₁₈H₃₄NaO₂Si [MNa⁺]: 333.2220; found: 333.2222.
• 15 Compound 27 exists as a mixture of diastereoisomers and keto–enol tautomers in solution in CDCl₃, complicating its NMR spectra such that it was not possible to determine its E/Z ratio; based on precedent for similar transformations (see ref. 10) and the stereochemical outcome of the subsequent step, it is likely that the E-isomer predominates.
• 16 A stirred solution of 27 (1.00 g, 2.74 mmol) in toluene (100 mL) was heated to 100 °C for 16 h. After being cooled to r.t. the solution was concentrated under reduced pressure. The resulting light yellow oil was dissolved in CH₂Cl₂ (50 mL) and stirred. TFA (2.8 mL) was then added, and the reaction mixture was refluxed for a further 16 h before concentrating under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel, eluting with PE–EtOAc (20:1) to afford compound 29 as a colourless oil (369 mg, 51%). R_f = 0.18 (PE–EtOAc = 20:1). IR (thin film): ν_max = 2954, 2930, 2858, 1745 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.83 (1 H, dd, J = 11.5, 6.0 Hz), 5.56 (1 H, dd, J = 12.0, 7.0 Hz), 5.50 (1 H, dt, J = 11.5, 2.0 Hz), 5.33 (1 H, d, J = 12.0 Hz), 4.15 (2 H, q, J = 7.0 Hz), 3.67–3.58 (1 H, m), 2.76–2.65 (1 H, m), 2.53–2.35 (2 H, m), 2.11 (3 H, s), 1.79–1.63 (2 H, m), 1.26 (3 H, t, J = 7.0 Hz), 1.13 (3 H, s, H-5), 1.10 (3 H, s, H-6). ¹³C NMR (101 MHz, CDCl₃): δ = 208.9, 173.2, 139.9, 139.2, 128.7, 123.2, 60.9, 47.4, 41.9, 39.4, 39.1, 32.5, 29.9, 29.5, 27.0, 14.4. ESI-MS: m/z = 287 [MNa⁺]. HRMS: m/z calcd for C₁₆H₂₄NaO₃ [MNa⁺]: 287.1618; found: 287.1610.
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• 19 The syntheses of cyclopropane intermediates similar to compound 32 were reported during Kerr’s synthesis of (+)-taylorione: Johnstone C, Kerr WJ, Lange U. J. Chem. Soc., Chem. Commun. 1995; 457