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Synlett 2009(11): 1769-1772  
DOI: 10.1055/s-0029-1217378
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of Valerenic Acid

Sascha Koppa, W. Bernd Schweizerb, Karl-Heinz Altmann*a
a Institute of Pharmaceutical Sciences HCI H405, Swiss Federal Institute of Technology (ETH) Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland
b Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH) Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland
Fax: +41(44)6331369; e-Mail: karl-heinz.altmann@pharma.ethz.ch;
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Publication History

Received 10 March 2009
Publication Date:
16 June 2009 (online)

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Abstract

Valerenic acid is a major constituent of valerian root. It exhibits modulatory activity on the GABAA receptor and thus represents a potential new lead structure for the discovery of new an­xiolytics. Here we present the enantioselective total synthesis of valerenic acid, which departs from natural (R)-pulegone and proceeds through a bicyclic ketone as the central intermediate. Key transformations are the stereoselective reduction of a 3,4-disubstituted cyclohexenone and a microwave-assisted Wittig reaction.

Key words

total synthesis - natural product - valerenic acid - microwave-assisted Wittig reaction - GABAA receptor

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14

The pulegone used in our experiments was purchased from ACROS ORGANICS and was 92% pure (pract. grade) according to the supplier.

18

Racemic aldehyde 13 has been prepared previously by Bohlmann and Lonitz and found to be highly prone to epimerization on silica gel. [¹0]

19

Preparation and Analytical Data of Compound 1
To a solution of ethyl ester 14 (32 mg, 0.12 mmol) in 2-PrOH-H2O (5:1, 0.6 mL) was added LiOH (6 mg, 0.24 mmol), and the mixture was heated to 40 ˚C for 10 h. The solution was concentrated and the residue directly purified by FC (hexane-EtOAc = 5:1, 1% formic acid) to give 29 mg (97%) of valerenic acid (1) as a white solid. Crystals suitable for X-ray crystallography were obtained from hexane-MeOH-Et2O.
Mp 138.5-139.5 ˚C (lit.: 140-142 ˚C). [¹0] [α]D ²5 -13.0 (c 2.15, CHCl3); [α]D ²0 -119.8 (c 2.50, EtOH). {lit.: [α]D ²0
-120.0, EtOH}. [¹0] HRMS (EI): m/z calcd for C15H22O2: 234.1614; found [M]+: 234.1616. ¹H NMR (400 MHz, CDCl3, 25 ˚C): δ = 7.16 (d, J = 9.8 Hz, 1 H), 3.58-3.52 (m, 1 H), 3.00-2.92 (m, 1 H), 2.21 (br t, J = 7.5 Hz, 2 H), 2.05-1.96 (m, 1 H), 1.90 (s, 3 H), 1.89-1.73 (m, 3 H), 1.65 (br s, 3 H), 1.61-1.51 (m, 1 H), 1.47-1.39 (m, 2 H), 0.79 (d, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3, 25 ˚C): δ = 172.7, 146.2, 133.1, 131.2, 125.0, 47.4, 37.5, 34.6, 33.0, 28.8, 25.4, 24.5, 13.5, 12.1, 12.1. IR (neat): ν = 2932, 2856, 2834, 1675, 1632, 1422, 1299, 1255, 901 cm-¹.

20

Natural valerenic acid was purchased from extrasynthèse (France).

21

The structural data have been deposited with the Cambridge Crystallographic Data Centre. Deposition No. CCDC 719101.