Total Synthesis of Valerenic Acid

Abstract

Valerenic acid is a major constituent of valerian root. It exhibits modulatory activity on the GABA_A 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.

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

References and Notes

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<A NAME="RG08409ST-14">14</A>

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

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

<A NAME="RG08409ST-19">19</A>

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.

<A NAME="RG08409ST-20">20</A>

Natural valerenic acid was purchased from extrasynthèse (France).

<A NAME="RG08409ST-21">21</A>

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

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