Short and convenient synthesis of two natural phthalides by a copper(I) catalysed Sonogashira/oxacyclisation copper(I) process

Article abstract of DOI:10.1016/j.tetlet.2013.12.032

Total synthesis of (±)-herbaric acid and (±)-(4- methoxybenzyl)-5,7-dimethoxyphthalide, two natural phthalide products, was achieved in 8 steps and 5 steps, respectively, starting from commercially available 3,5-dimethoxyaniline. The key step of the seque

Full text of DOI:10.1016/j.tetlet.2013.12.032

Tetrahedron Letters 55 (2014) 982–984
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Tetrahedron Letters
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Short and convenient synthesis of two natural phthalides
by a copper(I) catalysed Sonogashira/oxacyclisation copper(I) process
⇑
⇑
Julien Petrignet , Samuel Inack Ngi, Mohamed Abarbri, Jérôme Thibonnet
Laboratoire d’Infectiologie et Santé Publique (UMR Université François Rabelais/INRA 1282), Université François Rabelais, Faculté des Sciences, Parc de Grandmont,
32 Avenue Monge, 37200 Tours, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of ( )-herbaric acid and ( )-(4-methoxybenzyl)-5,7-dimethoxyphthalide, two natural
phthalide products, was achieved in 8 steps and 5 steps, respectively, starting from commercially avail-
able 3,5-dimethoxyaniline. The key step of the sequence included a copper-catalysed tandem cross-cou-
pling and oxacylisation reaction of terminal alkynes and 2-iodobenzoïc acid derivatives via 5-exo-dig
cyclisation with high stereo-, regio- and chemoselectivities. This straightforward method allows the
preparation of diverse phthalides, which belong to a group of pharmacologically important compounds.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 5 November 2013
Revised 3 December 2013
Accepted 9 December 2013
Available online 15 December 2013
Keywords:
Copper catalysis
Cyclisation
Phthalides
Total synthesis
Introduction
Results and discussion
Phthalides are known to be an important class of small oxygen-
ated heterocycles as they are widely represented in the area of nat-
ural compounds.1 Representative examples of such natural
products include typhaphthalide 1,2 paecilocin A 2 isolated from
a marine microorganism,3 herbaric acid 34 and the unnamed
phthalide 4 isolated from Australian liverwort Frullania falciloba
(Fig. 1).5
Because of their various biological properties, chemists have
developed many strategies to prepare this moiety.6 In the past dec-
ade, our group has developed a copper(I)-catalysed method which
provides five or six membered-ring lactones in one step starting
The non-commercial 2-iodo-4,6-dimethoxybenzoic acid 5 had
first to be synthesised in order to perform both total syntheses. It
was prepared on a multigram scale with a three step procedure
OH
OH
OH
O
O
O
O
O
O
HO
Ph
C7H15
CO2H
1
2
3
OMe
O
from 2-iodoacrylic acid derivatives and
a terminal alkyne
(Scheme 1).7 Indeed, this sequence consists of palladium free Sono-
gashira-like cross-coupling followed by 5-exo-dig or 6-endo-dig
oxacyclisation, according to the initial derivative. We demon-
strated that the nature of the 2-iodoacrylic acids influenced the
regioselectivity of the oxacyclisation.8 5-exo-dig was promoted in
the case of non-aromatic derivatives,9 6-endo-dig was the pre-
ferred cyclisation process in the case of heteroaromatic systems,10
and a mixture of phthalide and coumarin was obtained when
2-iodobenzoic acid was used as starting material.7 We present here
an application of our methodology for the total regioselective
synthesis of ( )-herbaric acid 3 and phthalide 4.
O
MeO
OMe
4
Figure 1. Examples of natural phthalides.
R
O
O
O
O
Cu(I), K2CO3
DMF, heat
OH
and/or
O
I
R
R
⇑
Corresponding authors. Tel.: +33 (2)47 36 73 59; fax: +33 (2)47 36 73 10.
E-mail addresses: julien.petrignet@univ-tours.fr (J. Petrignet), jerome.thibonnet@
5-exo-dig
6-endo-dig
univ-tours.fr (J. Thibonnet).
Scheme 1. Copper-catalysed one-pot process.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.032

J. Petrignet et al. / Tetrahedron Letters 55 (2014) 982–984
983
OEt
OEt
OMe
OMe
O
O
CuI (20 mol%)
H2 (1 atm)
Pd/C
K2CO3 (3 equiv)
PTSA
O
O
THF, H2O
RT, 2 h
EtOH
DMF, 80 °C, 16 h MeO
MeO
OEt
OEt
RT, 4 h
CHO
O
I
Path A
MeO
7
6
OMe
O
OH
(74%, two steps from 5)
O
MeO
MeO
OTHP
5
OMe
OMe
O
O
CuI (20 mol%)
H2 (1 atm)
Pd/C
EtOH, RT, 2 h
8
OH
K2CO3 (3 equiv)
PTSA
O
O
82%, from 7
90%, two steps from
DMF, 80 °C, 16 h
MeO
MeOH
MeO
9
RT, 16 h
Path B
10
OTHP
OTHP
9
(46%)
Scheme 2. Preparation of the key intermediate 8.
OMe
O
to yield 90% 8 over two steps. Total synthesis was achieved by
the oxidation of the alcohol 8 into dimethoxyherbaric acid 11 with
Jones reagent (Scheme 3). The transformation of 11 into herbaric
acid 3 can be performed in two steps, as already reported by
Brimble et al.12
As compound 5 seemed to promote oxacyclisation in favour of
the phthalide moieties whatever the terminal alkyne used, we
envisaged validating this with further total synthesis of the natural
product 4. A similar strategy was therefore used, but in this case 5
was treated with p-methoxyethynylbenzene in the presence of
copper iodide and potassium carbonate in DMF. This sequence
led to the exclusive formation of phthalide 12 at an acceptable
yield of 50%, and no trace of corresponding coumarin was ob-
served. Synthesis was easily completed by simple catalytic hydro-
genation of the alkene in the presence of Pd/C, which afforded the
natural compound 4 under its racemic form with an excellent 95%
yield (Scheme 4).13
CrO3, H2SO4
2 steps
8
( )-3
O
Ref 12
Acetone
MeO
O
0 °C to RT, 2 h
OH
11 (72%)
Scheme 3. Preparation of dimethoxyherbaric acid 11.
starting from 3,5-dimethoxyaniline, according to the literature.11
We then prepared the key intermediate 8 using two different strat-
egies (Scheme 2). Path A consisted of performing the copper-cata-
lysed key step between 5 and 3,3-diethoxypropyne as terminal
alkyne. The latter was chosen because we have previously demon-
strated that the oxacylisation step proceeds exclusively in favour of
the phthalide when o-iodobenzoic acid is used with such an
alkyne.7 In the present case, the reaction was performed in DMF
at 80 °C in the presence of CuI (20 mol %) and K2CO3 (3 equiv) to
yield phthalide 6 in a very regioselective manner (no trace of the
corresponding coumarin was detected in crude 1H NMR). The ace-
tal function was immediately hydrolysed in mild acid conditions
and aldehyde 7 was obtained as a single diastereoisomer, with a
good overall yield of 74% over two steps. The carbonyl and olefin
functions were then both hydrogenated in the presence of Pd/C
to provide the expected 8 with 82% yield.
In summary, we have developed a simple and useful method for
the synthesis of ( )-herbaric acid and ( )-(4-methoxybenzyl)-5,7-
dimethoxyphthalide starting from 3,5-dimethoxyaniline and ter-
minal alkynes. These reactions provide a rapid synthetic route for
the preparation of biologically interesting phthalide derivatives.
Acknowledgements
In path B, we undertook the key step Sonogashira/oxacyclisa-
tion with O-protected propargyl alcohol. As this alkyne is known
to promote 6-endo-dig cyclisation in the case of o-iodobenzoic
acid,7 we were pleased to note that only phthalide 9 was obtained,
with an acceptable yield of 46%. This unexpected regioselectivity
for the cyclisation step may be the consequence of the presence
of the electron-donating groups in the aromatic ring, which modify
the electronic distribution and therefore the cyclisation route for
this kind of molecule. Finally, phthalide 9 underwent catalytic
hydrogenation to afford 10, which was immediately hydrolysed
We thank the Departement d’Analyse Chimique Biologique et
Médicales for recording NMR, mass and HRMS analyses.
Supplementary data
Supplementary data (detailed experimental procedures and
copy of NMR data) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.12.032.
OMe
OMe
O
CuI (20 mol%)
H2 (1 atm)
Pd/C
K2CO3 (3 equiv)
O
4
( )- (95%)
5
MeO
EtOH, AcOEt
RT, 2 h
DMF
OMe
80 °C, 16 h
12 (50%)
Scheme 4. Total synthesis of natural phthalide 4.

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