An Enantioselective Total Synthetic Approach to (+)-Heptemerone G and (+)-Guanacastepene A from 2-Furyl Methyl Carbinol

Abstract

An enantioselective synthesis of the key bicyclic building block for (+)-heptemerone G and (+)-guanacastepene A construction has been accomplished. 2-Furyl methyl carbinol was used as the starting material and (S)-4-hydroxy-2-methylcyclopent-2-en-1-one as the primal optically active intermediate.

Key words

total synthesis - tandem Michael additions - kinetic resolution - rearrangement - tantalum

• References and Notes

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Synthesis of 10 from 6:
• 42a Allylmagnesium bromide (1.30 M in Et₂O, 42.0 mL, 55.9 mmol) was added dropwise to a stirred solution of anhyd LiBr (5.69 g, 65.5 mmol) and CuI (12.48 g, 65.5 mmol) in THF (70 mL) at –78 °C. After 0.5 h, TMSCl (7.0 mL, 55.9 mmol) and 6 (2.75 g, 21.8 mmol) were added. The suspension was stirred at –78 °C for additional 1 h, allowed to warm to r.t. (in ca. 20 min), briefly stirred at that temperature (ca. 10 min) and cooled to 0 °C. Et₃N (20 mL), and hexanes (200 mL) were added and the slurry was set aside for ca. 15 min. The liquid layer was decanted from a semisolid mass into brine and sat. aq NaHCO₃ (1:1, 50 mL). The organic layer was separated, washed with brine and dried. The solvent was evaporated and the residue was distilled using a Kügelrohr apparatus (120 °C/1.5 mmHg) to give a mixture of 7 and 8 (oil, 4.39 g, 84% yield, 90:10 by ¹H NMR). Compound 7: ¹H NMR (400 MHz): δ = 5.68–5.82 (m, 1 H), 4.96–5.08 (m, 2 H), 3.59 (ddd, J = 7.2, 3.2, 3.2 Hz, 1 H), 3.27 (s, 3 H), 2.44–2.58 (m, 2 H), 2.18–2.36 (m, 2 H), 2.03 (ddd, J = 14.0, 7.2, 7.2 Hz, 1 H), 1.50 (br s, 3 H), 0.17 (s, 9 H). ¹³C NMR (100 MHz): 144.0, 136.4, 116.2, 113.8, 81.6, 56.1, 50.9, 39.1, 36.2, 10.1, 0.5. cis-Isomer, 8: ¹H NMR (400 MHz): δ = 3.90 (ddd, J = 6.8, 6.8, 6.8 Hz, 1 H).
• 42b To a solution of 7/8 (90:10, 240 mg, 1 mmol) and 9 (170 mg, 1 mmol) in CH₂Cl₂ (2 mL), stirred at –45 °C to –40 °C, TrSbCl₆ (28 mg, 0.05 mmol, 5 mol%) in CH₂Cl₂ (1 mL) was added. The mixture was stirred at –45 °C to –40 °C for 4 h and then the reaction was quenched with H₂O (0.1 mL). The mixture was allowed to warm to r.t. Anhyd Na₂SO₄ was added to bind H₂O, the solid was filtered off and washed with hexanes–CH₂Cl₂ (1:1, 3 × 3 mL). The filtrates were combined and the solvent was evaporated. The residue was chromatographed on silica gel (12 g) using EtOAc–hexanes (15:85, ca. 300 mL) to give 10 as an oil; yield: 229 mg (68%); [α]_D ¹⁸ +67.9 (c = 1.34, CHCl₃). ¹H NMR (400 MHz): δ = 5.83 (dddd, J = 6.8, 8.0, 10.2, 16.8 Hz, 1 H), 5.07 (ddd, J = 16.8, 4.8, 1.6 Hz, 1 H), 5.01 (ddd, J = 10.2, 1.6, 0.8 Hz, 1 H), 4.59 (d, J = 1.2 Hz, 2 H), 3.66 (ddd, J = 7.6, 7.6, 7.6 Hz, 1 H), 3.32 (s, 3 H), 2.75 (dd, J = 18.4, 7.2 Hz, 1 H), 2.47 (ddd, J = 17.2, 10.8, 5.2 Hz, 1 H), 2.10–2.35 (m, 4 H), 1.97 (ddd, J = 7.6, 7.6, 7.6 Hz, 1 H), 1.88 (ddd, J = 14.4, 10.8, 5.2 Hz, 1 H), 1.77 (ddd, J = 14.4, 10.8, 5.2 Hz, 1 H), 1.24 (s, 9 H), 0.91 (s, 3 H). ¹³C NMR (100 MHz): δ = 218.7, 203.4, 177.8, 136.6, 116.3, 80.2, 67.7, 57.5, 51.8, 48.9, 43.2, 38.7, 33.7, 33.1, 29.5, 27.1, 18.3. HRMS: m/z [M⁺] calcd for C₁₉H₃₀O₅: 338.20932; found: 338.20989.
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• 47 Transformation of 10 into 12 was carried out essentially as described earlier for a similar compound.²⁰ Compound 11: oil, yield: 451 mg (85%); [α]_D ¹⁹ +81.3 (c = 1.24, CHCl₃). ¹H NMR (400 MHz): δ = 5.83 (dddd, J = 6.8, 8.0, 10.2, 16.8 Hz, 1 H), 5.07 (ddd, J = 16.8, 4.8, 1.6 Hz, 1 H), 5.01 (ddd, J = 10.2, 1.6, 0.8 Hz, 1 H), 4.96 (d, J = 1.2 Hz, 1 H), 4.89 (s, 1 H), 4.45 (d, J = 0.4 Hz, 2 H), 3.66 (ddd, J = 7.6, 7.6, 7.6 Hz, 1 H), 3.32 (s, 3h), 2.75 (dd, J = 18.8, 7.2 Hz, 1 H), 2.30–2.38 (m, 1 H), 2.00–2.25 (m, 4 H), 1.74–1.84 (m, 2 H), 1.48–1.59 (m, 1 H), 1.19 (s, 9 H), 0.90 (s, 3 H). ¹³C NMR (100 MHz): δ = 218.6, 178.0, 143.7, 136.8, 116.1, 112.0, 80.3, 66.3, 57.5, 52.8, 47.5, 43.4, 38.7, 34.4, 33.15, 28.0, 27.1, 18.9. HRMS: m/z [M + Na]⁺ calcd for C₂₀H₃₂O₄: 359.21928; found: 359.21968. Compound 12: oil; yield: 307 mg (94%); [α]_D ¹⁷ +129.5 (c = 1.17, CHCl₃). ¹H NMR (400 MHz): δ = 5.78 (dd, J = 7.6, 1.2 Hz, 1 H), 4.36 (s, 2 H), 3.64 (ddd, J = 10.0, 7.6, 7.6 Hz, 1 H), 3.33 (s, 3 H), 2.84 (dd, J = 18.8, 7.2 Hz, 1 H), 2.52 (ddd, J = 16.4, 8.0, 2.8 Hz, 1 H), 2.02–2.20 (m, 4 H), 1.92 (ddd, J = 14.0, 4.4 Hz, 1 H), 1.78–1.88 (m, 1 H), 1.29–1.38 (m, 1 H), 1.16 (s, 9 H), 0.88 (s, 3 H). ¹³C NMR (100 MHz): δ = 217.6, 178.2, 136.9, 127.8, 79.2, 70.8, 58.0, 52.5, 51.5, 42.2, 38.8, 32.9, 27.1, 25.5, 24.6, 14.4. HRMS: m/z [M⁺] calcd for C₁₈H₂₈O₄: 308.19876; found: 308.19741. Preparation of the ‘Basic tert-Butanol’ Reagent: KOH (200 mg) and H₂O (0.4 mL) were added to t-BuOH (20 mL) and the mixture was vigorously stirred for 1 h at r.t. The mixture was set aside for 16 h. The upper layer was used for the elimination reaction. ‘Basic tert-butanol’ (7 mL) was added to 12 (106 mg), the mixture was stirred at r.t. for 20 min and then partitioned between hexanes (60 mL) and H₂O (50 mL). The aqueous layer was separated and extracted with hexanes (20 mL). The combined organic extract was washed with brine, dried and the solvent was evaporated. The residue was chromatographed on silica gel (yield: 3 g, hexanes–EtOAc, 9:1) to give 3 (oil, 86 mg, 91%); [α]_D ¹⁹ +24.2 (c = 2.03, CHCl₃). ¹H NMR (400 MHz): δ = 7.34 (dd, J = 5.6, 1.6 Hz, 1 H), 6.08 (dd, J = 6.0, 2.8 Hz, 1 H), 5.77 (br d, J = 5.6 Hz, 1 H), 4.40 (s, 2 H), 2.86 (ddd, J = 15.2, 2.0, 3.2 Hz, 1 H), 2.47 (ddd, J = 17.2, 5.6, 2.4 Hz, 1 H), 2.37 (dt, J = 17.6, 4.4 Hz, 1 H), 2.14–2.29 (m, 2 H), 2.01 (ddd, J = 14.0, 6.0, 4.4 Hz, 1 H), 1.53 (ddd, J = 16.0, 10.4, 5.6 Hz, 1 H), 1.18 (s, 9 H), 1.00 (s, 3 H). ¹³C NMR (100 MHz): δ = 213.6, 178.2, 162.9, 135.3, 131.2, 127.2, 71.7, 51.4, 51.0, 38.8, 30.9, 28.5, 27.1, 26.6, 18.4; in agreement with the spectra of racemic material (ref. 20).