Total Synthesis of (+)-Guaymasol

Abstract

The synthesis of (+)-guaymasol has been achieved from O-methyl chavicol by using a sequence combining a cross-metathesis and an asymmetric dihydroxylation of the newly created double bond. The first step using Grubbs type II catalyst delivered an inseparable 88:12 mixture of E and Z isomers. After treatment with AD-mix-β and deprotection of the benzyl ether by hydrogenolysis, (+)-guaymasol was finally isolated in 84% de and 90% ee.

Key words

natural products - total synthesis - cross-metathesis - dihydroxylation - phenols

• References and Notes

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• 27 Selected data: Compound 12a: Yield: 56% (104 mg from 500 mg of 5a over 3 steps); colourless oil. 1 H NMR (300 MHz, CDCl₃): δ = 0.89 (d, J = 6.6 Hz, 6 H), 1.54–1.75 (m, 1 H), 1.91 (t, J = 6.2 Hz, 2 H), 3.28 (d, J = 6.2 Hz, 2 H), 5.05 (s, 2 H), 5.38–5.62 (m, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.10 (d, J = 8.6 Hz, 2 H), 7.28–7.46 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.5, 28.6, 38.4, 42.0, 70.2, 114.9, 127.6, 128.0, 128.7, 129.5, 130.4, 130.6, 133.7, 137.4, 157.2. HRMS (CI): m/z [M + H]⁺ calcd for C₂₀H₂₄O: 281.1900; found: 281.1902. Compound 12b: Yield: 8% (14 mg from 500 mg of 5a); colourless oil. ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (d, J = 6.6 Hz, 6 H), 1.60–1.75 (m, 1 H), 2.04 (t, J = 6.7 Hz, 2 H), 3.34 (d, J = 6.7 Hz, 2 H), 5.05 (s, 2 H), 5.41–5.67 (m, 2 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.11 (d, J = 8.6 Hz, 2 H), 7.28–7.48 (m, 5 H). Compound (+)-13a: Yield: 85% (100 mg from 118 mg of 12a/12b); white solid; mp 81–83 °C; [α]_D +18.1 (c = 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 1.20–1.38 (m, 2 H), 1.40–1.59 (m, 1 H), 1.66–1.90 (m, 2 H, OH), 2.67 (dd, J = 13.8, 8.5 Hz, 1 H), 2.85 (dd, J = 13.8, 3.9 Hz, 1 H), 3.51–3.70 (m, 2 H), 5.05 (s, 2 H), 6.94 (d, J = 8.6 Hz, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 7.26–7.48 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.0, 23.8, 24.7, 39.5, 43.0, 70.2, 71.8, 75.6, 115.2, 127.6, 128.1, 128.7, 130.4, 130.5, 137.2, 157.7. HRMS (ESI): m/z [M + Na] calcd for C₂₀H₂₆NaO₃: 337.1774; found: 337.1769. Compound rac-13b: Yield: 6% (9 mg from 100 mg of 5b); white solid; mp 81–83 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (d, J = 6.5 Hz, 3 H), 0.99 (d, J = 6.7 Hz, 3 H), 1.14–1.38 (m, 2 H), 1.41–1.60 (m, 1 H), 1.66–1.96 (m, 2 H), 2.66 (dd, J = 13.9, 9.6 Hz, 1 H), 2.79 (dd, J = 3.5, 13.9 Hz, 1 H), 3.69–3.87 (m, 2 H), 5.05 (s, 2 H), 6.94 (d, J = 8.6 Hz, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 7.28–7.47 (m, 5 H). Guaymasol (+)-1: Yield: 78% (55 mg from 100 mg of 13a); colourless oil; [α]_D +23.5 (c = 0.4, CHCl₃) {see ref. 4: [α]_D +30.4 (c = 1.1, CHCl₃)}. ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (t, J = 6.9 Hz, 6 H), 1.20–1.37 (m, 1 H), 1.45–1.59 (m, 1 H), 1.74–1.91 (m, 1 H), 1.93 (s, 2 H), 2.66 (dd, J = 13.9, 8.5 Hz, 1 H), 2.83 (dd, J = 13.9, 3.9 Hz, 1 H), 3.52–3.64 (m, 2 H), 6.77 (d, J = 8.5 Hz, 2 H), 7.09 (d, J = 8.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.0, 23.8, 24.7, 39.4, 42.9, 71.8, 75.6, 115.7, 130.0, 130.7, 154.5. HRMS (ESI): m/z [M + Na] calcd for C₁₃H₂₀NaO₃: 247.1305; found: 247.1297.