Total Synthesis of (R)-(+)-Kavain via (MeCN)₂PdCl₂-Catalyzed Isomerization of a cis Double Bond and Sonochemical Blaise Reaction

Abstract

From the chiral source 2,3-O-isopropylidene-d-glyceraldehyde 2, the natural product (R)-(+)-kavain 1a was efficiently synthesized in a total yield of 25% via (MeCN)₂PdCl₂-catalyzed isomerization of the cis double bond of an olefin as the key step and sonochemical Blaise reaction. The chiral center adjacent to the cis double bond was retained without protection of the free allylic hydroxy during the isomerization process.

kavain - total synthesis - (MeCN)₂PdCl₂-catalyzed - isomerization - cis double bond - sonochemical Blaise reaction

References

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12

Isomerization of the cis double bond: A solution of nitriles 5 (145 mg, 0.84 mmol) and bis(acetonitrile)palladium(II) chlorine (17.5 mg, 0.07 mmol) in benzene (5 mL) was stirred at reflux for ca. 5 h until the cis form of 5 was fully consumed (monitored by TLC). After removal of the solvent in vacuo, the residue was dissolved in EtOAc (50 mL) and filtered to remove the insoluble solid. The EtOAc soluble fraction was then purified by flash column chromatography on silica gel (EtOAc-petroleum ether, 1:4) to afford the desired pure trans form of 5 (132 mg, 91%) as a colorless oil. ¹H NMR (400MHz, CDCl₃): δ = 2.25 (br, 1 H), 2.63-2.69 (dd, J = 6.2, 16.7 Hz, 1 H), 2.69-2.75 (dd, J = 5.5, 16.7 Hz, 1 H), 4.652 (m, 1 H), 6.25 (dd, J = 6.7, 15.9 Hz, 1 H), 6.74 (d, J = 15.9 Hz, 1 H), 7.27-7.40 (m, 5 H); EI-MS: m/z =173 (M⁺).

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Sonochemical reactions: A mixture of the trans form of 5 (205 mg, 1.18 mmol) and activated Zn (0.80 g, 12.3 mmol) in anhyd THF (10 mL) was subjected to ultrasonic irradiation at 50 °C for 10 min and then methyl bromoacetate (0.70 ml, 5.86 mmol) was added dropwise under a nitrogen atmosphere. The resultant mixture was irradiated under the same conditions for another 5 h, then acidified with 2 M HCl (to pH 3), stirred at r.t. for 10 min, and diluted with EtOAc (60 mL). The organic phase was washed with sat. NaHCO₃ (20 mL), brine (20 mL), and then dried over anhyd Na₂SO₄. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel (petroleum ether-EtOAc, 10:3) to afford the desired product 6 (206 mg, 70%), as a pale yellow oil. [α]_D ²⁰ +19.4 (c 1.15, CHCl₃), {lit.¹⁵ [α]_D ²⁵ +20.2 (c 1.0, CHCl₃)}. ¹H NMR (400MHz, CDCl₃): δ = 2.88 (d, J = 6.1 Hz, 2 H), 3.53 (s, 2 H), 3.75 (s, 3 H), 4.79 (m, 1 H), 6.22 (dd, J = 6.2, 15.9 Hz, 1 H), 6.67 (dd, J = 1.1, 15.9 Hz, 1 H), 7.25-7.39 (m, 5 H). EIMS: m/z = 248 (M⁺).

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16 (R)-(+)-Kavain 1a: white crystals; mp 115-116 °C (lit.¹⁸ 105-106 °C); [α]_D ²⁰ +110.2 (c 1.1, EtOH), {lit.¹⁸ [α]_D ²⁰ +105 (c 1, EtOH)}. IR (KBr): 1704.8, 1623.8, 1392.4, 1247.7, 1230.4 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.58-2.53 (dd, J = 4.4, 16.9 Hz), 2.71-2.64 (dd, J = 10.7, 16.9 Hz), 3.77 (s, 3 H), 5.07 (m, 1 H), 5.20 (s, 1 H), 6.29-6.24 (dd, J = 6.2, 16.1 Hz), 6.76 (d, J = 16.1 Hz), 7.41-7.26 (m, 5 H). EI-MS: m/z = 230 (M⁺). Anal. Calcd for C₁₄H₁₄O₃: C, 73.03; H, 6.13. Found: C, 73.33; H, 6.12.

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