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Abstract

The synthesis of (Z)-civetone (1) is described starting from oleic acid (5) via a series of reactions, intermolecular olefin self-metathesis, bromination/dehydrobromination into acetylene, semi-hydrogenation and intramolecular Dieckmann macrocyclization.

Keywords

Fragrance ingredient Olefin metathesis Oleic acid

References

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(a) Sack

(1915) Study of civet. Chemiker Zeitung, 39, 538. (b) Ruzicka L (1926) Carbon rings I. Constitution of civetone Helvetica Chimica Acta, 9, 230-248.

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N.J.

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C.W.

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(a) van Dam

P.B.

, Mittelmeijer

M.C.

, Boelhouwer

(1972) Metathesis of unsaturated fatty acids by a homogeneous tungsten hexachloride-tetramethyltin catalyst. Journal of the Chemical Society, Chemical Communications, 1221–1222; (b) Tsuji J. Hashiguchi S. (1980) Application of olefin metathesis to organic synthesis. Syntheses of civetone and macrolides. Tetrahedron Letters, 21, 2955–2958; (c) Tsuji J, Hashiguchi S. (1981) Metathesis reactions of unsaturated esters catalyzed by homogenous tungsten complexes. Syntheses of civetone and macrolides. Journal of Organometallic Chemistry, 218, 69–80; (d) Tsuji J, Mandai T. (1977), Synthesis of cis-civetone from a butadiene telomere. Tetrahedron Letters, 18, 3285–3286. (e) Choo Y -M, Ooi K -E, Ooi I -H, (1994) Synthesis of civetone from palm oil products. Journal of American Oil Chemists’ Society, 71, 911–913.

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M.F.C.

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J.C.

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, Seidel

(2000) Ring closing alkyne metathesis: stereoselective synthesis of civetone. Journal of Organometallic Chemistry, 606, 75–78.

(a) Hamasaki

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, Misaki

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(a) Mol

J.C.

(1994) Metathesis of unsaturated fatty acid esters and fatty oils. Journal of Molecular Catalysis, 90, 185–200;(b) Dinger MB, Mol JC. (2002) High turnover numbers with ruthenium-based metathesis catalysts. Advanced Synthesis & Catalysts, 344, 671–677; (c) Mol JC. (2002) Application of olefin metathesis in oleochemistry: an example of green chemistry. Green Chemistry, 4, 5–13; (d) Mol JC. (2004) Catalytic metathesis of unsaturated fatty acid esters and oils. Topics in Catalysis, 27, 97–104.

Ngo

H.L.

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T.A.

(2006) Metathesis of unsaturated fatty acids: synthesis of long-chain unsaturated-α,ω-dicarboxylic acids. Journal of American Oil Chemists’ Society, 83, 629–634.

10.

Dicarboxylic acid 6: ¹H NMR (400 MHz, TMS, CDCl₃) δ 5.36–5.32 (m, 2H), 2.35 (t, J = 6.8 Hz, 4H), 1.99–1.93 (m, 4H), 1.69–1.60 (m, 4H), 1.37–1.24 (m, 16H).

11.

Dibromodicarboxylic acid 8: ¹H NMR (400 MHz, TMS, CDCl₃) δ 4.19–4.15 (m, 2H), 2.37 (t, J = 6.8 Hz, 4H), 2.15–2.04 (m, 2H), 2.00–1.90 (m, 2H), 1.70–1.60 (m, 4H), 1.62–1.52 (m, 2H), 1.50–1.43 (m, 2H), 1.41–1.27 (m, 12H).

12.

A mixture of dibromide 8 (240 mg, 0.51 mmol) and potassium t-butoxide (464 mg, 4.14 mmol) in toluene (5 mL) was heated at reflux temperature for 12 h. After addition of aq. 1N hydrochloric acid, organic layer was extracted with ethyl acetate to provide a mixture of acetylene 9 and allene 10 (155 mg, 98%) in 90:10 ratio (NMR). Alkynyl diethylester 12a: ¹H NMR (400 MHz, TMS, CDCl₃) δ 4.15 (q, J = 7.2 Hz, 4H), 2.29 (t, J = 7.6 Hz, 4H), 2.13 (t, J = 7.6 Hz, 4H), 1.62 (tt, J = 7.6, 7.2 Hz, 4H), 1.50–1.42 (m, 4H), 1.41–1.28 (m, 12H), 1.25 (t, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, TMS, CDCl₃) δ 173.9, 80.2, 60.2, 34.4, 29.12, 29.10, 28.9, 28.7, 25.0, 18.8, 14.3.

13.

Diethylester of allene 10: 1H NMR (400 MHz, TMS, CDCl₃) δ 5.05 (quint, J = 4.8 Hz, 2H), 4.12 (q, J = 7.2 Hz, 4H), 2.29 (t, J = 7.2 Hz, 4H), 2.00–1.92 (m, 4H), 1.67–1.56 (m, 4H), 1.43–1.28 (m, 14H), 1.25 (t, J = 7.2 Hz, 6H) ¹³C NMR (100 MHz, TMS, CDCl₃) δ 203.8, 173.93, 173.90, 90.9, 90.8, 60.2, 34.4, 29.18, 29.17, 29.15, 29.03, 29.01, 28.9, 28.8, 25.01, 25.00, 18.79, 18.77, 14.3.

14.

Song

, Narine

S.S.

(2008) Synthesis and characterization of highly functionalized symmetric aromatic hexa-ol intermediates from oleic acid. Chemistry and Physics of Lipids, 155, 43–47.

15.

Ratio of acetylenic diester 12a and diethylester of allene 10 was determined to be 90:10 by the propargylic protons at δ 2.13 of 12a and olefinic protons at δ 5.05 of 10.

16.

(Z)-Diethylester 13a: ¹H NMR (400 MHz, TMS, CDCl₃) δ 5.34 (ddd, J = 5.6, 4.4, 0.8 Hz, 2H), 4.12 (q, J = 7.2 Hz, 4H), 2.28 (t, J = 7.2 Hz, 4H), 2.05–1.95 (m, 4H), 1.61 (tt, J = 7.6, 7.2 Hz, 4H), 1.37–1.26 (m, 16H), 1.25 (t, J = 7.2 Hz,6H). ¹³C NMR (100 MHz, TMS, CDCl₃) δ 173.9, 129.9, 60.2, 34.4, 29.7, 29.2, 29.18, 29.17, 27.2, 25.0, 14.3.

17.

Alkynyl di-t-butylester 12b was prepared by treatment with 2 equiv. of trifluoroacetic anhydride in THF at room temperature for 2 h and subsequent treatment of 5 eqiuv. t-butylalcohol for 4 h. Alkynyl di-t-butylester 12b: ¹H NMR (400 MHz, TMS, CDCl₃) δ 2.20 (t, J = 7.4 Hz, 4H), 2.13 (t, J = 7.0 Hz, 4H), 1.62–1.53 (m, 4H), 1.50–1.43 (m, 4H), 1.44 (s, 18H), 1.33–1.25 (m, 12H).

18.

(Z)- Di-t-butylester 13b:¹H NMR (400 MHz, TMS, CDCl₃) δ 5.34 (t, J = 4.4 Hz, 2H), 2.20 (t, J = 7.6 Hz, 4H), 2.04–1.97 (m, 4H), 1.63–1.53 (m, 4H), 1.44 (s, 18H), 1.38–1.25 (m, 16H).

19.

A solution of diethylester 13a in dry toluene was evaporated to dryness in vacuo beforehand. Potassium hydride (159 mg, min. 30% in mineral oil, 1.2 mmol) was washed with n-hexane 3 times. To a stirred suspension of potassium hydride in THF (9 mL) was added a solution of diethylester 13a (59 mg, 0.16 mmol) in THF (8 mL, 0.02M) under reflux for 6 h via a syringe pump. After being refluxed for 8 h, reaction was quenched by addition of 1 N hydrochloric acid. Extraction with ethyl acetate followed by column chromatography provided β-ketoester 14a (28 mg, 54%) along with dicarboxylic acid (25 mg, 45%). (Z)-β-Keto-diethylester 14a: ¹H NMR (400 MHz, TMS, CDCl₃) δ 5.34 (t, J = 4.8 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H),3.46 (dd, J = 9.2, 5.2 Hz, 1H), 2.52 (t, J = 6.8 Hz, 2H), 2.05–1.97 (m, 4H), 1.95–1.87 (m, 1H), 1.85–1.76 (m, 1H), 1.69–1.58 (m, 2H), 1.40–1.22 (m, 16H), 1.24 (t, J = 7.2 Hz, 3H). HRMS: m/z [M⁺] calcd for C₂₀H₃₄O3: 322.251; found: 322.2508.

20.

(Z)-Civetone (1): 1H NMR (400 MHz, TMS, CDCl₃) δ 5.34 (ddd, J = 5.6, 4.4, 1.2 Hz, 2H), 2.40 (t, J = 6.8 Hz, 4H), 2.06–1.97 (m, 4H), 1.67–1.58 (m, 4H), 1.39–1.23 (m, 16H). Ratio of (Z)-civetone (1) and other isomers was determined to be 90:10 by the peaks at δ 5.34 and 5.31.

Revisit to ( Z )-Civetone Synthesis

Abstract

Keywords

References