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DOI: 10.1055/s-0029-1217378
Total Synthesis of Valerenic Acid
Publication History
Publication Date:
16 June 2009 (online)
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
-
1a
European
Scientific Cooperative on Phytotherapy (ESCOP) Monographs
2nd
ed.:
Thieme;
Stuttgart/ New York:
2003.
p.539
-
1b
Kumar V. Phytother. Res. 2006, 20: 1023 -
2a
Ziegler G.Ploch M.Miettinen-Baumann A.Collet W. Eur. J. Med. Res. 2002, 7: 480 -
2b
Taibi DM.Petry H.Landis CA.Vitiello MV. Sleep Med. 2007, 11: 209 - 3
Schumacher B.Scholle S.Hölzl J.Khudeir N.Hess S.Müller CE. J. Nat. Prod. 2002, 65: 1479 - 4
Marder M.Viola H.Wasowski C.Fernandez S.Medina JH.Paladini AC. Pharmacol. Biochem. Behav. 2003, 75: 537 - 5
Stoll A.Seebeck E.Stauffacher D. Helv. Chim. Acta 1957, 40: 1205 - 6
Khom S.Baburin I.Timin E.Hohaus A.Trauner G.Kopp B.Hering S. Neuropharmacology 2007, 53: 178 - 7
Benke D.Barberis A.Kopp S.Altmann K.-H.Schubiger M.Vogt KE.Rudolph U.Möhler H. Neuropharmacology 2009, 56: 174 - 8
Dietz BM.Mahady GB.Pauli GF.Farnsworth NR. Mol. Brain Res. 2005, 138: 191 - 9
Ramharter J.Mulzer J. Org. Lett. 2009, 11: 1151 - 10
Bohlmann F.Lonitz M. Chem. Ber. 1980, 113: 2410 -
11a
Minami T.Usunomiya T.Nakamura S.Okubo M.Kitamura N.Okada Y.Ichikawa J. J. Org. Chem. 1994, 59: 6717 -
11b
Baudouy R.Sartoretti J. Tetrahedron 1983, 39: 3293 -
11c
Joseph KT.Krishna Rao GS. Tetrahedron 1967, 23: 3215 - 12
Ito Y.Hirao T.Saegusa T. J. Org. Chem. 1978, 43: 1011 - 13
Lee HW.Ji SK.Lee I.-YC.Lee JH. J. Org. Chem. 1996, 61: 2542 - 15 Chiral auxiliary:
Drewes SE.Malissar DGS.Roos GHP. Chem. Ber. 1993, 126: 2663 ; details for the synthesis of 10 will be published elsewhere -
16a
de Fátima A. Synlett 2005, 1805 -
16b
Brestensky DM.Huseland DE.McGettigan C.Stryker JM. Tetrahedron Lett. 1988, 29: 3749 - 17
Mahoney WS.Brestensky DM.Stryker JM. J. Am. Chem. Soc. 1988, 110: 291 - 22
Bal BS.Childers WE.Pinnick HW. Tetrahedron 1981, 37: 2091
References and Notes
The pulegone used in our experiments was purchased from ACROS ORGANICS and was 92% pure (pract. grade) according to the supplier.
18Racemic 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.
Natural valerenic acid was purchased from extrasynthèse (France).
21The structural data have been deposited with the Cambridge Crystallographic Data Centre. Deposition No. CCDC 719101.