Towards synthesis of kavalactone derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.07.102

Kavalactone derivatives were synthesized using a Heck reaction of the 4-methoxy-6-vinyl-5,6-dihydropyran-2-one with aryl iodides. The Suzuki-Miyaura reaction of an aryl boronic acid and (Z)-4-methoxy-6-(2-iodovinyl)-5,6-dihydropyran-2-one has also been successfully used to produce both Z and E isomers of lactones.

Full text of DOI:10.1016/j.tetlet.2008.07.102

Tetrahedron Letters 49 (2008) 6607–6609
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Towards synthesis of kavalactone derivatives
Patrícia A. Amaral a,b, Nicolas Gouault a, Myriam Le Roch a, Vera L. Eifler-Lima b, Michèle David a,
*
a EA 4090 Substances lichéniques et photoprotection, Université Européenne de Bretagne, Université de Rennes1, 2 Av. du Pr L. Bernard, 35043 Rennes, France
b Laboratório de Síntese Orgânica Medicinal, University Federal of Rio Grande of Sul, Av. Ipiranga, 2752, Porto Alegre/RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Kavalactone derivatives were synthesized using a Heck reaction of the 4-methoxy-6-vinyl-5,6-dihydro-
pyran-2-one with aryl iodides. The Suzuki–Miyaura reaction of an aryl boronic acid and (Z)-4-meth-
oxy-6-(2-iodovinyl)-5,6-dihydropyran-2-one has also been successfully used to produce both Z and E
isomers of lactones.
Received 21 May 2008
Revised 17 July 2008
Accepted 18 July 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Kavalactones
Heck reaction
Suzuki–Miyaura reaction
Yangonin
Piper methysticum (kava-kava) is a plant native to the oceanic
Islands of the South Pacific, which has been used as a folklore med-
icine and in the preparation of a traditional ceremonial beverage
for thousands of years.1 Modern use of kava root as a natural anx-
iolytic in several studies showed favourable results compared to a
number prescription medications including benzodiazepines. In
fact, kavalactones comprise 15% of the dried rootstock and display
various and important biological properties such as sedative, anx-
iolytic, anti-inflammatory and analgesic effects.2 The psychoactive
ingredients consist of a group of structurally related lipophilic lac-
ties.6 Various synthetic pathways, aiming to racemic7 or enantio-
pure compounds,8 have been studied to access kavalactones via
standard aldol-based strategies involving the corresponding elec-
tron-rich cinnamaldehydes but none of them are generally applica-
ble to the synthesis of oxygen-substituted kavalactone derivatives
such as yangonin and methysticin.
In connection with a programme devoted to the synthesis of
4-oxo valerolactones derivatives and the evaluation of their in vivo
analgesic effect,9 we present in this work two approaches to the
tones derivatives with an arylethylene-a-pyrone core known as
kavalactones (Fig. 1). Among these compounds, yangonin 1 is one
of the major components of kava extract and it has been reported
to be responsible for the pharmacological activity.3 It has shown a
promising TNF-a
release inhibitory activity.4
The pharmacological actions found for the kavalactones justify
their synthesis and the preparation of original analogues. The lack
of systematic studies of the pharmacological activities for the iso-
lated kavalactones5 motivates their production in sufficient quan-
tities for further structure–activity relationship investigations. In
addition, it is still unknown which compound is responsible for
the pharmacological effects observed for the vegetal extracts or
even whether these actions are due to one or more of these
compounds.
The synthesis of six-membered unsaturated d-lactones has gen-
erated a widespread interest, due to their occurrence in a large
number of natural products possessing potent biological activi-
* Corresponding author. Tel.: +33 0223234860; fax: +33 0223234425.
E-mail address: michele.david@univ-rennes1.fr (M. David).
Figure 1. Kavalactones isolated from Piper methysticum.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.102

6608
P. A. Amaral et al. / Tetrahedron Letters 49 (2008) 6607–6609
synthesis of yangonin 1, desmethoxyyangonin 2 and structural
analogues.
This prompted us to run the reaction under controlled microwave
irradiation.
In order to devise a synthesis that would provide rapid access to
novel compound libraries for biological evaluation, we first
planned a strategy based on the Heck10 cross-coupling reaction
between the pyrone 3 and various aryl iodides (Fig. 2).
The precursor for the Heck reaction was successfully prepared
by aldol condensation of ethyl acetoacetate with acrolein and sub-
sequent lactonization according to a reported method.9 Although it
was possible to isolate and purify the b-ketone-intermediate, we
decided to carry out the methylation with dimethyl sulfate in ace-
tone at room temperature8e to afford 3 in a 52% yield overall
(Scheme 1).
We then focused on the palladium-catalyzed cross coupling of 3
with some aryl iodides. To the best of our knowledge, no example
related to the transformation of 3 to 4 has been reported in the
literature.
First, reactions were carried out using various substituted iodo-
benzenes as the coupling partners, 5 or 10 mol % of tetrakis(tri-
phenylphosphine) palladium(0) in the presence of Hünig’s base
in DMF for 16 h at 80 °C (Table 1).
Microwave-promoted palladium-catalyzed coupling reaction is
known to reduce reaction times. In addition, the microwave irradi-
ation procedures have received great attention due to their effi-
cient and environmentally benign conditions.11,12 The reaction
conditions were optimized using 4-iodoanisole as substrate over
a wide temperature range: 25–150 °C. After some experimenta-
tion, we found it essential to employ a moderate microwave power
(300 W) to avoid decomposition of lactone 3 as observed by HPLC
monitoring. The best result, 47% isolated yield of 4a, was obtained
in 5.5 min (Table 2, entry 1). If prolonged irradiation or higher tem-
peratures were used, more side products resulting from total
decomposition of the pyrone moiety were observed by 1H NMR.
It has been noticed that the decomposition pathway might involve
a ‘ring-opening-decarboxylation’ sequence. No improvement was
observed by increasing the amounts of Pd catalyst or change the
source of Pd. Employing this protocol to other aryl iodides afforded
the compounds 4b, 4c and 4d within 5.5 min (entries 2–5), but the
yields were only slightly improved. Less-activated aryl iodide (p-
nitro-iodobenzene), which failed to afford the corresponding
cross-coupling product regardless of heating procedure, is used
(Table 1, entry 5 and Table 2, entry 5).
Under these conventional thermal heating conditions, we
observed that reactions did not proceed satisfactorily due to the
heat-induced decomposition of the pyrone 3. In addition, we
noticed that increasing the reaction temperature to 180 °C or
longer reaction time led to total pyrone moiety decomposition.
According to the disappointing results, we decided to investi-
gate the Suzuki–Miyaura cross-coupling reaction of various aryl
boronic acids with (Z)-6-(2-iodovinyl)-4-methoxy-5,6-dihydro-
2H-pyran-2-one 5. Therefore, the pyrone 5 was prepared following
our optimized reaction conditions for the synthesis of the pyrone 3
(Scheme 1). Aldol condensation of ethyl acetoacetate with (Z)-iod-
oacrolein,13 subsequent lactonization and then methylation affor-
ded Z isomer in 46% yield overall.
In order to optimize the yield of cross-coupled products 4, we
focused on the employment of efficient catalyst system with
Pd(OAc)2 and 2-(2,6-dimethoxybiphenyl)dicyclo-hexyl-phosphine
(S-Phos)14,15 as ligand. Thus, treatment of pyrone 5 with boronic
acids in toluene at 80 °C for 20 h in the presence of K3PO4 as base
afforded the required kavalactone derivatives 4a, 4b and 4e in sat-
isfactory yields (Scheme 2). However, we were surprised to obtain
Figure 2. Retrosynthetic analysis.
Table 2
Fast palladium-catalyzed coupling reactions under microwave irradiation (300 W,
5.5 min)
Entrya
Aryl iodide
Catalyst
Product/yield (%)
Scheme 1. Reagents and conditions: (a) LDA, THF 0 °C, acrolein; (b) dimethyl
R1
R2
sulfate, K2CO3, dry acetone, rt.
1
2
3
4
5
OCH3
H
F
O–CH2–O
NO2
H
H
H
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
4a
4b
4d
4c
46
42
40
42
H
nrb
Table 1
Heck cross-coupling reactions under thermal heating conditions
a
Initial microwave irradiation of 300 W was used, the temperature being ramped
from rt to 150 °C.
b
No reaction.
Entry
Aryl iodide
Mol %/catalyst
Product/yield (%)
R1
R2
1
2
3
4
5
OCH3
H
O–CH2–O
F
NO2
H
H
5% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
4a
4b
4c
4d
35
40
40
H
H
40
nra
a
No reaction.
Scheme 2. Suzuki cross-coupling reaction.

P. A. Amaral et al. / Tetrahedron Letters 49 (2008) 6607–6609
6609
In summary, we have devised two approaches for the prepara-
tion of kavalactone derivatives, a class of compounds with interest-
ing biological activities. The potential of yangonin to inhibit the
LPS-stimulated TNF-a production in human whole blood is cur-
rently in progress. Further work to extend the Suzuki–Miyaura
cross coupling to a diverse range of easily available boronic acids
with Z and E iodoacrolein is underway in our laboratory.
Acknowledgements
This work was supported by CAPES/COFECUB project 418/03.
The authors thank Pr. P. van de Weghe, for helpful discussion,
one of reviewers for his comments and Centre Régional de Mesures
Physiques de L’Ouest (CRMPO) in Rennes (France) for performing
HRMS analyses.
Scheme 3.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.102.
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a stereoselective cross-coupling reaction.16,17 1H NMR analysis of
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to partial isomerization (Z/E = 100/0–73/27) after 20 h at 80 °C in
toluene (Scheme 3). This could be explained by possible formation
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and desmethoxyyangonin 2, refluxing benzene with DDQ for 2 h4
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