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Jihed Brahmi

Kaïss Aouadi

Moncef Msaddek

Jean-Pierre Praly

Sébastien Vidal

lable at ScienceDirect
C. R. Chimie 19 (2016) 933e935Contents lists avaiComptes Rendus Chimie
www.sciencedirect.comFull paper/MemoireA stereoselective method for the synthesis of enantiopure
3-substituted 4-hydroxyproline derivatives via 1,3-dipolar
cycloadditions
Jihed Brahmi a, Kaïss Aouadi a, *, Moncef Msaddek a, Jean-Pierre Praly b,
Sebastien Vidal b
a Universite de Monastir, Laboratoire de Synthese Heterocyclique, Produits Naturels et Reactivites, Faculte des Sciences de Monastir,
Avenue de l’Environnement, 5000 Monastir, Tunisia
b Universite de Lyon, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, UMR CNRS 5246, Laboratoire de Chimie
Organique 2eGlycochimie, Bâtiment Curien, 43, boulevard du 11-Novembre-1918, 69622 Villeurbanne, Francea r t i c l e i n f o
Article history:
Received 4 February 2016
Accepted 7 March 2016
Available online 7 April 2016
Keywords:
Chiral nitrone
1,3-Dipolar cycloaddition
1,2,3-Triazole
4-Hydroxyproline
Click chemistry* Corresponding author.
http://dx.doi.org/10.1016/j.crci.2016.03.003
1631-0748/© 2016 Académie des sciences. Publishea b s t r a c t
The stereoselective 1,3-dipolar cycloaddition between (Z)-1,4-dichloro-2-butene and a
menthone-derived nitrone led to the corresponding isoxazolidine. Regioselective azidation
of a single chlorine atom followed by another Cu(I)-catalyzed azideealkyne 1,3-dipolar
cycloaddition (CuAAC) induced enantiopure 1,2,3-triazolyl-functionalized isoxazolidines.
The subsequent acidic cleavage of the menthone chiral auxiliary and reductive cleavage of
the isoxazolidine NeO bond triggered an intramolecular cyclization through the
displacement of the second chlorine. This rapid and stereoselective synthetic strategy
provided reliable access to a series of enantiopure 3-substituted 4-hydroxyproline
derivatives.
© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.1. Introduction
Hydroxy-L-proline (HP) represents an excellent molec-
ular scaffold for the synthesis of diverse multi-
functionalized unnatural amino acids. Such pyrrolidines
are challenging targets from a synthetic point of view and
have a high potential as biologically active molecules [1].
The introduction of a hydroxyl group at the 3- or 4-position
of L-proline could lead to helical oligopeptides displaying
on their outer surface the hydroxyl functionality available
for further potential conjugation [2]. The present study
reports on the stereoselective synthesis of 3-substituted 4-
hydroxyproline derivatives via 1,3-dipolar cycloadditions.
The obtained scaffolds, therefore, present the hydroxyl
group at the 4-position, and a 1,2,3-triazole connected tod by Elsevier Masson SAS. Athe pyrrolidine scaffold through a carbonecarbon bond, at
the 3-position.
Menthone-derived nitrones incorporating a glycine
equivalent [3] have now demonstrated the potential of 1,3-
dipolar cycloadditions with alkenes to create in a single
step three contiguous stereogenic centers with strict ster-
eocontrol [4e9]. Various alkenes have been used for the
synthesis of diastereoisomers of 4-hydroxyisoleucine [5].
This is a molecule found in fenugreek (Trigonellafoenum-
graecum), a plant traditionally used as an antidiabetic
remedy thanks to its insulinotropic properties. An efficient
synthesis of (aS,3R,4S)-3-glycinyl-4-hydroxypyrrolidine
and 3-substituted 4-hydroxyproline derivatives was also
reported with a total control of the stereochemistry (Fig. 1)
[6,7]. This strategy is based on a cascade of cyclo-
additionecyclization using (E)- or (Z)-1,4-dichlorobut-2-
ene and chiral nitrones as glycine equivalents [6,7].
Another approach in which the nitrone cycloaddition isll rights reserved.
Fig. 1. Selected scaffolds obtained from a common menthone-based nitrone
precursor.
Scheme 1. Synthesis of enantiopure 3-substituted 4-hydroxyproline de-
rivatives. Reagents and conditions: (a) iPr2NEt, CuI, mW, DMF, 110 C, 15 min;
(b) AcOH, Ac2O, cat. H2SO4, 50 C, 6.5 h; (c) H2 (1 atm), Pd(OH)2, MeOH, rt, 4
days.
J. Brahmi et al. / C. R. Chimie 19 (2016) 933e935934followed by a Cu(I)-catalyzed azideealkyne cycloaddition
(CuAAC) provides rapid access to enantiopure 1,2,3-
triazolylisoxazolidine derivatives [8]. A recent strategy to-
wards cycloalkylglycines has been demonstrated [9].
The general strategy towards unnatural amino acids
originating from menthone-based nitrones as chiral auxil-
iaries for a glycine derivative can now be applied to the
stereoselective synthesis of unprecedented 4-hydroxy-3-
substituted proline derivatives in only 6 steps at a high
overall yield (Fig. 1). The synthesis proceeds through 1,3-
dipolar cycloaddition of the menthone-based nitrone and
(Z)-1,4-dichloro-2-butene, followed by a regioselective
azidation of a chlorine atom and the subsequent installa-
tion of a 1,2,3-triazole moiety by microwave-assisted
CuAAC. Hydrolytic cleavage of the menthone chiral auxil-
iary followed by catalytic reduction of the NeO bond led to
an amine intermediate that readily cyclized intramolecu-
larly through nucleophilic displacement of the remaining
chlorine atom [6,7].Fig. 2. ORTEP representation of the crystal structure of 3a.2. Results and discussion
The synthesis of the mono-azido-mono-chlorinated
scaffold 1 [6] has been reported. Discussion on the regio-
selectivity of mono-azidation is provided [6,7]. Copper-
catalyzed 1,3-dipolar cycloaddition under microwave irra-
diation of azide 1 with various functionalized alkynes gave
the corresponding 1,2,3-triazolyl-functionalized iso-
xazolidines 2aef with high yields (Scheme 1). Acidic
cleavage of the chiral auxiliary in 2aef under the action of a
mixture of acetic acid, acetic anhydride and a catalytic
amount of sulfuric acid brought about methylamides3aed,fwith good yields. In the case of isoxazolidine 2e, the
same reaction was attempted but without success. The
structure of isoxazolidine 3a was unambiguously deter-
mined by a single crystal X-ray diffraction analysis [10]
(Fig. 2). It provided reliable data for the structural charac-
terization of this series of intermediates.
4-Chloromethyl isoxazolidines 3aef can be readily
converted to the corresponding pyrrolidines 4 upon
reduction of the NeO bond and subsequent nucleophilic
J. Brahmi et al. / C. R. Chimie 19 (2016) 933e935 935displacement of the chlorine atom by the generated amine
functionality [6]. Indeed, reductive cleavage under hydro-
genolysis conditions of the NeO bond of the 4-
chloromethyl isoxazolidine 3a led to the enantiopure
methylamide 4a in an almost quantitative yield. Mean-
while, catalytic hydrogenolysis applied to compounds
3ced led to a separable mixture of 4ced (27 and 15%) and
4′ced (70 and 84%). In the case of compounds 3b,f, the
reaction led to a complex mixture of inseparable products.
For compound 3b, the opening of the NeO bond by cata-
lytic hydrogenation (H2, Pd/C) induced an inseparable
mixture of products. The NO2 group was most probably
reduced to NH2 and further unexpected reactivities may be
observed. In the case of compound 3f, the acetate might be
cleaved by intra- or intermolecular reaction with the
generated amine leading to an inseparable mixture of
products. Two other conditions for the cleavage of the NeO
bond were then applied [Mo(CO)6, CH3CNeH2O [11]; Zn,
AcOH [3b]] for these compounds but without success.
The obtained N-methylated products 4′ced were re-
ported in the N-alkylations of amines carried out using
different alcohols as the solvent and with 10% Pd/C or 20%
Pd(OH)2/C as the catalyst at room temperature [12].
3. Conclusion
In conclusion, 1,3-dipolar cycloaddition of a menthone-
based nitrone to (Z)-1,4-dichloro-2-butene occurred with
the simultaneous creation of three contiguous stereogenic
centers to afford a dichlorinated isoxazolidine-based cyclo-
adduct. Regioselective substitution of the chlorine atom by
an azide group, followed by another azideealkyne 1,3-
dipolar cycloaddition (CuAAC) induced enantiopure 1,2,3-
triazolyl-functionalized isoxazolidines. Acidic cleavage of
the chiral auxiliary led directly to the 3-methylamide iso-
xazolidines. An amino group was then generated by
reductive cleavage of the isoxazolidine NeO bond which
triggered an intramolecular cyclization. This rapid and
stereoselective synthetic strategy provides reliable access
to a series of enantiopure 3-substituted 4-hydroxyproline
derivatives.
Acknowledgements
Financial support from the University of Monastir, Uni-
versity of Lyon and Centre national de la recherche scien-
tifique (CNRS) are gratefully acknowledged. The authors
thank Dr. F. Albrieux, C. Duchamp and N. Henriques from
the Centre Commun de Spectrometrie de Masse (ICBMS
UMR-5246) for their assistance and access to mass spec-
trometry facilities.Appendix A. Supplementary data
Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.crci.2016.03.003.References
[1] (a) P. Wilhelm, B. Lewandowski, N. Trapp, H. Wennemers, J. Am.
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A stereoselective method for the synthesis of enantiopure 3-substituted 4-hydroxyproline derivatives via 1,3-dipolar cycloadditions

Mojgan Hashemzehi

Naser Saghatoleslami

Hamed Nayebzadeh

A study on the structure and catalytic performance of ZnxCu1−xAl2O4 catalysts synthesized by the solution combustion method for the esterification reaction

Anthony Quéro

Roland Molinié

Déborah Brancourt

Minasoa Johanne Rémy

François Mesnard

lable at ScienceDirect
C. R. Chimie 19 (2016) 1056e1061Contents lists avaiComptes Rendus Chimie
www.sciencedirect.comAccount/RevueSesquiterpene composition of Cinnamosma fragrans: A
Malagasy endemic plant used in traditional medicine
Composition en sesquiterpenes de Cinnamosma fragrans, une plante
malgache endemique utilisee en medecine traditionnelle
Anthony Quero, Roland Molinie, Deborah Brancourt, Minasoa Johanne Remy,
François Mesnard*
Universite de Picardie Jules-Verne, EA 3900-BIOPI Biologie des Plantes et Innovation, IUT d'Amiens, Departement Genie Biologique,
avenue des Facultes, Le Bailly et Faculte de Pharmacie, 1, rue des Louvels, 80025 Amiens cedex, Francea r t i c l e i n f o
Article history:
Received 1 March 2016
Accepted 5 April 2016
Available online 17 May 2016
Keywords:
Cinnamosma fragrans
Phytochemistry
Sesquiterpenes
Traditional use
Madagascar
Motscles:
Cinnamosma fragrans
Phytochimie
Sesquiterpenes
Utilisation traditionnelle
Madagascar* Corresponding author.
E-mail address: francois.mesnard@u-picardie.fr (
http://dx.doi.org/10.1016/j.crci.2016.04.006
1631-0748/© 2016 Published by Elsevier Masson SA
(http://creativecommons.org/licenses/by-nc-nd/4.0/a b s t r a c t
Cinnamosma fragrans is an endemic plant used in traditional medicine. The geographical
distribution of this Canellaceae is limited to Madagascar. Few phytochemical investigations
performed on this plant have described atypical sesquiterpenes including drimane-type
sesquiterpenes, drimane-type sesquiterpene lactones, sesquiterpene lactams and colo-
ratane sesquiterpenes. These original sesquiterpenes are associated with pharmaceutical
activities.
© 2016 Published by Elsevier Masson SAS on behalf of Académie des sciences. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).F.
S
).r é s u m é
Cinnamosma fragrans est une plante endemique utilisee en medecine traditionnelle. La
repartition geographique de cette Canellacee est limitee a Madagascar. Les rares in-
vestigations phytochimiques realisees sur cette plante ont permis de decrire des
sesquiterpenes atypiques, dont des sesquiterpenes de type drimane, des lactones ses-
quiterpeniques de type drimane, des lactames sesquiterpeniques et des sesqui-
terpeniques de type coloratane. Ces sesquiterpenes originaux sont associes a des activites
pharmacologiques.
© 2016 Published by Elsevier Masson SAS on behalf of Académie des sciences. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).1. Introduction
Cinnamosma fragrans is an endemic medicinal plant
used for decades in the Malagasy territory. This species of
the family Canellaceae is better known under theMesnard).
on behalf of Académie devernacular names of Mandravasarotra, Saro, or Sakar-
ivohazo. This plant native to the northern and eastern part
of the island is traditionally used in the treatment of
several types of pathologies. C. fragrans is used to treat
respiratory problems and limits the presence of parasites
and gastrointestinal infections [1]. Decoctions of the bark
are also used against muscular aches, fatigue or malarial
symptoms [2]. The traditional use of this plant attracts
interest.s sciences. This is an open access article under the CC BY-NC-ND license
A. Quero et al. / C. R. Chimie 19 (2016) 1056e1061 1057Few phytochemical investigations performed on this
plant have revealed the presence of original sesquiter-
penes including drimane-type sesquiterpenes, drimane-
type sesquiterpene lactones, sesquiterpene lactams and
coloratane sesquiterpenes. To date, 18 sesquiterpenes
have been described in the bark or leaves of C. fragrans.
These compounds are currently not well known and
described.
C. fragrans is also known for its commercial essential
oil. The essential oil has strong antimicrobial activities and
is described in many applications for the treatment of
infectious diseases in otorhinolaryngology. Consequently,
some products based on this essential oil are also mar-
keted for cosmetic use. For a review of the biological ac-
tivities associated with the phytochemical composition of
the Saro essential oil, see the article by Randrianarivelo
et al [1].
After a botanical description of the plant, the objective
of this review is to describe all sesquiterpenes present in C.
fragrans. The biological activities associated with these
secondary metabolites are also briefly described.Fig. 1. Drimane (1) and coloratane (2) skeleton.2. History, geographical distribution and botanical
description of C. fragrans
The genus Cinnamosma was established by Henri Bail-
lon in 1867 from a Madagascar tree, even though thirty
years before him, Richard (director of the botanical garden
of Bourbon at this period) had collected samples of the
same plant in north of Madagascar at Diego Suarez. Henri
Baillon also established a species and gave it the name C.
fragrans due to its intense fragrance. Baillon read a
description of this plant on 8 June 1867 in front of the
Linnean Society of Paris and the identity of this plant was
recognized [3].
C. fragrans belongs to the family of Canellaceae which is
constituted by five genera (Capsicodendron, Canella, Cin-
namosma, Pleodendron, and Warburgia) [2]. It is a family
rather limited today, but once it counted many more spe-
cies and had a more uniform geographical distribution in
the world. C. fragrans like all species of the genus is
endemic to Madagascar. It is distributed mainly in the
northern and eastern part of the island [1]. It grows in
dense and dry forests or in tropophytic forests on sedi-
mentary, crystalline, calcareous or siliceous soils at low
altitudes (between 0 and 800 meters). It is often near
running waters, among shady stony ground or at the bot-
tom of the gorge [4].
C. fragrans is a shrub or a small aromatic tree that has a
pleasant smell and is always green. The bark, leaves and
fruits have a burning and spicy taste. Its branches are cy-
lindrical, slightly angular on younger stems and irregularly
wrinkled longitudinally. The branches are sometimes
marked by large lenticels. Its bark is light colored,
yellowish-white and sometimes gray [3e5].
The flower of C. fragrans is sessile or subsessile, axillary
and almost always solitary. It is small (circa 5 mm), acti-
nomorphic, hermaphrodite and hypogynous. At the top of
the peduncle, the flower has 3 to 7 bracts. These latter are
large, of unequal size and deciduous. The lower bracts aresmaller and scaly to become increasingly large up towards
the apex of the flower [3e5].
3. Sesquiterpenes of C. fragrans
Sesquiterpenes are secondary metabolites formed from
three isoprene units where a further molecule IPP reacts
with GPP to form farnesyl pyrophosphate (FPP). FPP is
further converted to linear or cyclic products to obtain a
sesquiterpene with a 15 carbon skeleton. Sesquiterpenes
have a broad structural diversity but the majority and the
most functional forms are cyclic. In C. fragrans, all sesqui-
terpenes described so far are cyclic (bicyclofarnesane)
[6e8].3.1. Drimane-type sesquiterpenes
The name drimane designates a structure derived from
drimenol. Drimenol is the first drimane sesquiterpene
discovered. It was isolated from the bark of Drimys winterri
Forst a species belonging to the Canellaceae. This family is a
rich source of drimanes and these particular sesquiterpenes
are scarcely isolated from other trees. Drimane-type ses-
quiterpenes have a structure with the absolute configura-
tion depicted in Fig. 1 [9,10]. In C. fragrans, the first
drimane-type sesquiterpenes was identified in 1967 from
an acetone extract of the bark. This sesquiterpene, called
cinnamodial (C17H24O5) (compound 1 in Fig. 2), is one of
the compounds responsible for its pungent taste. This
majority sesquiterpene is found not only in other species of
Cinnamosma but also in other genera and species of the
family Canellaceae [2,11,12]. The phytochemical in-
vestigations performed later have identified another ma-
jority compound in methanol extract: capsicodendrin
(compound 2 in Fig. 2) [2]. The capsicodendrin with a
molecular formula of C34H48O10 was first discovered in
another species of the family Canellaceae: Capsicodendron
dinisii [12]. It is a pseudo-disesquiterpene since it corre-
sponds to two sesquiterpene units connected by an ether
bond [13]. Two other drimane-type sesquiterpenes were
identified in this extract: cinnafragrin A (C34H48O10)
(compound 3 in Fig. 2) and cinnafragrin B (C35H50O10)
(compound 4 in Fig. 2). Both these compounds are also
pseudo-disesquiterpenes. Cinnafragrin A is an epimer of
capsicodendrin and cinnafragrin B is a methylated deriva-
tive of capsicodendrin [2]. Recently, another drimane-type
sesquiterpene with a molecular formula of C19H28O7 was
discovered (compound 5 in Fig. 2) [14].
Fig. 2. Drimane-type sesquiterpenes.
A. Quero et al. / C. R. Chimie 19 (2016) 1056e106110583.2. Drimane-type sesquiterpene lactones
Sesquiterpene lactones are derivates from sesquiter-
pene in which one of the methyl groups of the isopropyl
group is oxidized to the lactone group [15]. These second-
ary metabolites are widely represented in the plant
kingdom. They attract interest for their high biological ac-
tivity due to their potential in the treatment of cancer and
cardiovascular disease [7]. In C. fragrans, phytochemical
explorations until today have been able to detect 7
drimane-type sesquiterpene lactones. Cinnamolide
(C15H22O2) (compound 6 in Fig. 3) and cinnamosmolide
(C17H24O5) (compound 7 in Fig. 3) were identified at the
same time as cinnamodial from an acetone extract of the
bark [16,17]. In parallel, the same research team has iden-
tified the same year three other minority compounds:
bemarivolide (C17H24O4) (compound 8 in Fig. 3),bemadienolide (C15H20O2) (compound 9 in Fig. 3) and fra-
grolide (C15H20O3) (compound 10 in Fig. 3) [18]. Cinnafra-
grin C (C51H70O14) (compound 11 in Fig. 3) a trimeric
drimane-type sesquiterpene lactone has been identified
[2]. The unit C of this trimeric compound corresponds to
ugandensolide, a sesquiterpene found in Warburgia ugan-
densis [19]. Recently, another drimane-type sesquiterpene
lactone with a molecular formula of C20H28O8 was discov-
ered (compound 12 in Fig. 3) [14].
3.3. Sesquiterpene lactams
Sesquiterpene lactams have rarely been found in nature.
In C. fragrans, 4 of them were discovered recently by ethyl
acetate soluble extraction of a methanol extract of leaves
[14]. Their molecular formula are C26H35O5N (compound 13
in Fig. 4), C26H35O6N (compound 14 in Fig. 4), C27H35O7N
Fig. 3. Drimane-type sesquiterpene lactones.
Fig. 4. Sesquiterpene lactams.
A. Quero et al. / C. R. Chimie 19 (2016) 1056e10611060(compound 15 in Fig. 4), C28H37O7N (compound 16 in
Fig. 4). Compound 14 is a hydroxy derivative of compound
13 in the C-12 position and compound 16 is a methylated
derivative of compound 15 in the C-7 position. Compound
16 differs from compound 13 by the presence of a OAC
group in the C-3 position. The authors suggest some acet-
ylated compounds may be formed during extraction
isolation procedures. The classification of these compounds
is still a subject of debate. The presence of a nitrogen atom
in a heterocyclic ring in these compounds can be used to
classify these compounds in alkaloids also [14].3.4. Coloratane sesquiterpenes
The coloratane structure corresponds to drimane where
one of the methyl groups at position 4 is shifted to position
3 while leaving an exocyclic methylene group as depicted
in Fig. 1 [20,21]. In C. fragrans, 2 coloratane sesquiterpenes
were discovered in water soluble extraction of a methanol
extract of leaves [22]. The molecular formulas of these two
glycosyl compounds are C21H32O10 (compound 17 in Fig. 5)
and C22H34O10 (compound 18 in Fig. 5). Compound 18 dif-
fers from compound 17 by the presence of a methyl group
in the hydroxy group linked to C-11 position. The presence
of this methyl group could be attributed to an artifact ob-
tained during extraction and isolation procedures.
4. Biological activity associated to sesquiterpenes of C.
fragrans
In 2006, Harinantenaina and Asakawa studied the
ability of some sesquiterpenes of C. fragrans to inhibit the
activity of alpha-glucosidase. This enzyme hydrolyses di-
saccharides into monosaccharides to be absorbed throughFig. 5. Coloratane sesquiterpenes.the intestinal mucosa. Such inhibitors are used in the
treatment of type-2 diabetes. The results showed that
capsicodendrin (compound 2) and cinnamodial (com-
pound 1) induce a strong inhibition of the alpha-
glucosidase activity. Cinnafragrin A (compound 3)
(epimer of capsicodendrin) showed no inhibitory activity
and for cinnafragrin B (compound 4), the methylated de-
rivative of capsicodendrin, its inhibitory activity is low. The
results highlight the importance of the structural configu-
ration in the inhibitory activity [12].
In 2014, Nomoto and his collaborators studied the
cytotoxicity activity toward lung adenocarcinoma A549
cells. In parallel, they studied anti-Leishmania major activ-
ity. Their results show that cinnamolide (compound 6), the
drimane-type sesquiterpene lactone with a molecular for-
mula of C20H28O8 (compound 12) and the sesquiterpene
lactam with the molecular formula C26H35O5N (compound
13) have a moderate cytotoxic activity and a moderate anti-
Leishmania major activity [14]. The presence of these
cytotoxic compounds does not appear to be an obstacle for
the cosmetic application of C. fragrans as so far they have
not been found in the essential oil of Saro [23].
5. Conclusion
C. fragrans has original sesquiterpenes. So far, phyto-
chemical analyzes have identified 18 sesquiterpenes which
can be grouped into four broad categories: drimane-type
sesquiterpenes, drimane-type sesquiterpene lactones,
sesquiterpene lactams and coloratane sesquiterpenes.
These sesquiterpenes have interesting biological activities.
C. fragrans is a traditional use plant still under-exploited.
Phytochemical investigations must continue to explore in
depth the sesquiterpene contents of this plant and bio-
logical activity tests must be multiplied to better under-
stand the medicinal properties associated with this
endemic Malagasy plant.References
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