Sulfanyl Radical-Induced Cyclization of Linalyl Acetate to the Iridane Skeleton: A Short Synthesis of (±)-Dehydroiridomyrmecin

Abstract

Sulfanyl radicals promote radical cyclization both in linalyl acetate (2) and its derivative 3, leading highly selectively to monoterpenoids with an iridane skeleton. We have investigated the addition of different sulfanyl radicals such as PhS^• , 4-NO₂C₆H₄S^• and PhCH₂CH₂S^• and found that the latter radical produces the best ­results (87-93%). Natural iridoid dehydroiridomyrmecin (1) at an overall yield of 28% was synthesized in four steps using this method.

sulfanyl radical - iridane skeleton - addition-cyclization reaction - polyprenes - dehydroiridomyrmecin

References

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General Procedure for Radical Cyclization (4, 5, 6, 9, 10, 11). A solution of thiophenol (0.18 mL, 1.66 mmol) and AIBN (136 mg, 0.83 mmol) in benzene (16 mL) was added dropwise (8 mL/h) under an argon atmosphere to a boiling solution of 3 (200 mg, 0.83 mmol) in benzene (8 mL). The solvent was evaporated under reduced pressure. Purification of the residue by column chromatography (hexane-t-BuOMe, 20:1) afforded 9, 262 mg (90%, see Table [1] ).

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Compound 12: ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (3 H, d, J = 7.1 Hz), 1.50 (3 H, br s), 1.69-1.81 (1 H, m), 1.90-2.04 (1 H, m), 2.13-2.25 (2 H, m), 2.82 (1 H, dq, J = 4.0, 7.0 Hz), 3.15-3.23 (1 H, m), 3.51 (1 H, br d, J = 12.9 Hz), 3.62 (3 H, s), 3.89 (1 H, br d, J = 12.9 Hz), 7.18-7.40 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 15.0, 24.4, 31.8, 36.9, 41.0, 50.0, 51.6, 126.5, 128.3 (2 C), 130.9 (3 C), 136.7, 138.9, 175.9. IR (film): 2946, 2844, 1731, 1583, 1479, 1437, 1378, 1197, 1170, 1088, 1024, 741, 691 cm^-1. HRMS-FAB: m/z calcd for C₁₇H₂₂O₂SNa [M + Na]⁺: 313.1238; found: 313.1239.

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5% of sulfone was obtained.

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30

Preparation of Dehydroiridomyrmecin ( 1).
Trifluoroacetic anhydride (1.02 mL, 7.32 mmol) was added to a stirred solution of sulfoxide 13 (560 mg, 1.83 mmol) in CH₂Cl₂ (73 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C and then 1 N aq NaOH (18 mL) and THF (60 mL) were added and stirring continued for 4 h at r.t. The reaction mixture was extracted with Et₂O and the combined organic layer was washed with aq NH₄Cl and brine. Evaporation of the solvent followed by column chromatography (petroleum ether-Et₂O, 5:1) furnished 60 mg (11%) of methyl 7-trifluoroacetoxy irid-1-ene-9-oate (14) and 140 mg (46%) of dehydroiridomyrmecin (1).
Compound 14: ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (3 H, d, J = 7.0 Hz), 1.74 (3 H, s), 1.74-1.82 (1 H, m), 1.97-2.05 (1 H, m), 2.15-2.35 (2 H, m), 2.75 (1 H, dq, J = 3.9, 7.0 Hz), 3.03 (1 H, br s), 3.56 (3 H, s), 4.88 (1 H, d, J = 12.2 Hz), 4.97 (1 H, d, J = 12.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 14.4, 24.6, 37.3, 41.2, 50.1, 51.5, 63.4, 124.6, 128.4, 144.9, 175.6 (2 C). IR (film): 2952, 1783, 1734, 1457, 1348, 1220, 1164 cm ^{- 1}.
Dehydroiridomyrmecin ( 1): ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 1.01 (3 H, d, J = 7.2 Hz), 1.40-1.51 (1 H, m), 1.70 (3 H, s), 1.85-1.97 (1 H, m), 2.20-2.30 (1 H, m), 2.35-2.45 (1 H, m), 2.90 (1 H, quint., J = 7.2 Hz), 3.15-3.25 (1 H, m), 4.77 (1 H, d, J = 13.1 Hz), 4.87 (1 H, d, J = 13.1, Hz). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 11.6, 13.6, 27.1, 38.3, 40.3, 46.9, 65.8, 130.0, 137.0, 174.9. IR (film): 2948, 1733, 1437, 1376, 1206, 1156 cm ^{- 1}. HRMS (CI): m/z calcd for C₁₀H₁₅O₂ [M + H]⁺: 167.1072; found: 167.1070.