Formal Total Synthesis of (±)-Herbertene-1,13-diol and (±)-α-Herbertenol via Ireland Ester Claisen Rearrangement and RCM Reaction Sequence

Abstract

A combination of Ireland ester Claisen rearrangement and ring-closing metathesis (RCM) reactions has been employed for efficient formal total syntheses of herbertene-1,13-diol and α-herbertenol, sesquiterpenes containing two vicinal quaternary carbon atoms on a cyclopentane ring.

Key words

(±)-herbertene-1,13-diol - (±)-α-herbertenol - Ireland ester Claisen rearrangement

References

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9

Yields refer to isolated and chromatographically pure compounds. All the compounds exhibited spectral data (IR, ¹H NMR and ¹³C NMR and MS) consistent with their structures.
Selected Spectral Data.
3-Methylbut-2-enyl 2-(2-methoxy-5-methylphenyl)pent-4-enoate (9): IR (neat): ν_max = 1733 cm^-1. ¹H NMR (300 MHz, CDCl₃ + CCl₄): δ = 6.99 (1 H, s), 6.95 (1 H, d, J = 8.2 Hz), 6.69 (1 H, d, J = 8.2 Hz), 5.71 (1 H, ddt, J = 17.1, 10.2, 6.7 Hz), 5.26 (1 H, br t, J = 7.2 Hz), 5.01 (1 H, d, J = 17.1 Hz), 4.93 (1 H, d, J = 10.2 Hz), 4.55 (1 H, dd, J = 12.4, 6.9 Hz), 4.49 (1 H, dd, J = 12.4, 7.2 Hz), 3.97 (1 H, t, J = 8.1 Hz), 3.77 (3 H, s), 2.71 (1 H, dt, J = 14.1, 8.1 Hz), 2.40 (1 H, dt, J = 14.1, 6.7 Hz), 2.27 (3 H, s), 1.72 (3 H, s), 1.66 (3 H, s). ¹³C NMR (75 MHz, CDCl₃ + CCl₄): δ = 173.4 (C), 154.6 (C), 137.9 (C), 136.1 (CH), 129.5 (C), 129.1 (CH), 128.3 (CH), 127.3 (C), 119.3 (CH), 116.4 (CH₂), 110.6 (CH), 61.3 (CH₂), 55.5 (CH₃), 44.1 (CH), 36.8 (CH₂), 25.8 (CH₃), 20.7 (CH₃), 18.1 (CH₃). MS: m/z (%) = 288 (17) [M⁺], 220 (36), 179 (28), 175 (100), 160 (28), 145 (16), 128 (15), 121 (23), 105 (28). HRMS: m/z calcd for C₁₈H₂₄O₃Na [M + Na]: 311.1623; found: 311.1630.
Methyl 2-allyl-3,3-dimethyl-2-(2-methoxy-5-methyl-phenyl)pent-4-enoate (12): IR (neat): ν_max = 1738, 1198, 911 cm^-1. ¹H NMR (300 MHz, CDCl₃ + CCl₄): δ = 7.00 (1 H, dd, J = 8.4, 1.5 Hz), 6.92 (1 H, d, J = 1.5 Hz), 6.73 (1 H, d, J = 8.4 Hz), 6.25 (1 H, dd, J = 17.4, 10.8 Hz), 5.84 (1 H, ddt, J = 17.4, 10.2, 7.2 Hz), 5.03-4.85 (4 H, m), 3.70 (3 H, s), 3.55 (3 H, s), 2.88 (1 H, dd, J = 15.0, 6.6 Hz), 2.81 (1 H, dd, J = 15.0, 7.2 Hz), 2.31 (3 H, s), 1.22 (3 H, s), 1.06 (3 H, s). ¹³C NMR (75 MHz, CDCl₃ + CCl₄): δ = 174.1 (C, C=O), 155.3 (C), 146.7 (CH), 136.7 (CH), 131.4 (CH), 129.3 (C), 128.2 (C), 128.1 (CH), 116.2 (CH₂), 111.4 (CH₂), 111.2 (CH), 56.1 (C), 55.1 (CH₃), 50.5 (CH₃), 43.8 (C), 39.9 (CH₂), 24.7 (CH₃), 24.1 (CH₃), 21.0 (CH₃). MS: m/z (%) = 302 (2) [M⁺], 233 (43), 201 (98), 173 (100), 158 (47), 145 (26), 128 (20), 115 (19). HRMS: m/z calcd for C₁₉H₂₆O₃Na [M + Na]: 325.1780; found: 325.1783.
Methyl 2,2-dimethyl-1-(2-methoxy-5-methylphenyl)cyclo-pent-3-enecarboxylate (13): mp 62-65 °C. IR (neat): ν_max = 1741, 1252, 1235 cm^-1. ¹H NMR (300 MHz, CDCl₃ + CCl₄): δ = 7.24 (1 H, s), 6.96 (1 H, d, J = 8.4 Hz), 6.70 (1 H, d, J = 8.4 Hz), 5.61 (1 H, d, J = 6.0 Hz), 5.55 (1 H, d, J = 6.0 Hz), 3.70 (3 H, s), 3.58 (3 H, s), 3.04 (1 H, d, J = 16.5 Hz), 2.80 (1 H, d, J = 16.5 Hz), 2.27 (3 H, s), 1.23 (3 H, s), 0.93 (3 H, s). ¹³C NMR (75 MHz, CDCl₃ + CCl₄): δ = 175.2 (C), 155.0 (C), 142.1 (CH), 130.7 (C), 129.6 (CH), 128.6 (C), 128.0 (CH), 124.6 (CH), 111.1 (CH), 61.1 (C), 55.3 (CH₃), 51.2 (CH₃), 50.2 (C), 42.3 (CH₂), 25.8 (CH₃), 24.2 (CH₃), 21.1 (CH₃). MS: (%) = 274 (47) [M⁺], 243 (16), 242 (100), 227 (27), 215 (62), 199 (32), 173 (11), 159 (20), 145 (19), 135 (21). HRMS: m/z calcd for C₁₇H₂₂O₃Na [M + Na]: 297.1467; found: 297.1462.

10

Generation of the lithium enolate of the ester 6 with LDA and warming up the reaction (or refluxing), or quenching with t-butyldimethylsilyl chloride and heating the resultant TBDMS enol ether, however, failed to generate the Ireland ester Claisen rearrangement product.^4d