Oxone®-KI Induced Lactonization and Etherification of Unsaturated Acids and Alcohols: A Formal Synthesis of Mintlactone

Massimo Curini; Francesco Epifano; M. Carla Marcotullio; Francesca Montanari

doi:10.1055/s-2003-45009

LETTER

Oxone^®-KI Induced Lactonization and Etherification of Unsaturated Acids and Alcohols: A Formal Synthesis of Mintlactone

Massimo Curini, Francesco Epifano, M. Carla Marcotullio*, Francesca Montanari
Dipartimento di Chimica e Tecnologia del Farmaco-Sez. Di Chimica Organica, Università degli Studi, via del Liceo 1, 06123 Perugia, Italy
Fax: +39(075)5855116; e-Mail: marcotu@unipg.it;

Abstract

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Abstract

Unsaturated acids and alcohols interact with Oxone^® and KI in acetonitrile-H₂O and undergo iodolactonization and iodoetherification in short times with good yields. The reaction has been used for the formal synthesis of mintlactone starting from isopulegol.

Key words

Oxone^® - cyclizations - iodolactonizations - iodoetherifications - mintlactone

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References

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General Procedure for the Iolactonization and the Iodoetherification: To a stirred solution of 2 mmol of Oxone^® in 5 mL of a 4:1 H₂O-CH₃CN mixture, 4 mmol of KI were added. After 10 min to the deep purple solution 1 mmol of the alkenoic acid (or the alkenol) in 2 mL of CH₃CN was added. The reaction was followed by TLC. After the appropriate time (see Table [1] and Table [2] ) the reaction mixture was diluted with H₂O (10 mL), washed with a sat. solution of Na₂S₂O₃ and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried and evaporated at reduced pressure. All the products resulted pure by ¹H and ¹³C NMR.

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To a stirred solution of 6-methyl-5-hepten-2-one (Aldrich) (2 mmol) in 21 mL EtOH a solution of 40 mg (1 mmol) of NaBH₄ in 2 mL of H₂O was added. The reaction was monitored by TLC. At the end 10 mL of acetone were added and the mixture was evaporated at reduced pressure. The crude product was diluted with H₂O (20 mL), acidified to pH 4 with a 4% solution of HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried and evaporated. The residue was purified by column chromatography. Elution with CH₂C1₂-MeOH 5% gave 210 mg (93%) of alcohol 17. Oil. ¹H NMR (200 MHz, CDCl₃): δ = 1.23 (d, 3 H, J = 6 Hz), 1.40-1.60 (m, 2 H), 1.66 (s, 3 H), 1.73 (s, 3 H), 2.11 (m, 2 H), 3.84 (m, 1 H), 5.17 (m, 1 H). ¹³C NMR (50.1 MHz, CDCl₃): δ = 17.7, 23.4, 24.5, 25.7, 39.1, 67.9, 124.0, 132.4.

Yellow oil. ¹H NMR: δ = 1.10 (d, 3 H, J = 6.0 Hz), 1.30-1.50 (m, 2 H), 1.41 (s, 3 H), 1.50 (s, 3 H), 2.31 (m, 2 H), 3.82 (m, 1 H), 4.12 (dd, 1 H, J = 5.0, 12.0 Hz). ¹³C NMR: δ = 19.5, 22.2, 3 1.2, 34.5, 37.3, 38.5, 66.3.

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<A NAME="RG30603ST-26">26</A> Compound 25 has been already reported as an intermediate in a short synthesis of (-)-mintlactone by thallium(III)-mediated cyclization of (-)-isopulegol: Ferraz HMC. Grazini MVA. Ribeiro CMR. Brocksom U. Brocksom TJ. J. Org. Chem. 2000, 65: 2606

3,6-Dimethyl-octahydro-1-benzofuran-3-ol(25). Oil. 1:1 Mixture of diastereoisomers. Yield 80%. ¹H NMR: δ = 0.90-2.10 (m, 6 H), 0.97 (d, 3 H, J = 6.5 Hz), 1.25 (s, 3 H), 1.34 (s, 3 H), 3.20 (dd, 1 H, J = 4.0, 10.0 Hz), 3.26 (dd, 1 H, J = 4.0, 10.0 Hz), 3.67 (d, 1 H, J = 9.0 Hz), 3.79 (d, 1 H, J = 10.0 Hz), 3.86 (d, 1 H, J = 10.0 Hz), 3.87 (d, 1 H, J = 9.0 Hz). ¹³C NMR: δ = 21.4, 22.0, 22.0, 22.7, 22.8, 24.0, 31.0, 31.0, 34.2, 34.3, 40.2, 40.3, 54.8, 56.4, 77.4, 77.8, 81.2, 81.2, 82.3, 82.3.