A route for the total synthesis of enantiomerically enriched jasmonates 12-COOH-JA and 12-COOH-JA-Ile

Article abstract of DOI:10.1002/ejoc.201403347

Enantiomerically enriched oxidized conjugated or non-conjugated jasmonate derivatives were obtained through 3-alkynoates. Stereoselective reduction of the triple bond afforded exclusively the Z isomer. Protection of the amide function led to the non-conjugated derivatives, whereas the free amides provided the oxidized isoleucine derivatives of jasmonate.

Full text of DOI:10.1002/ejoc.201403347

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:05
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201403347
A Route for the Total Synthesis of Enantiomerically Enriched Jasmonates
12-COOH-JA and 12-COOH-JA-Ile
Clément F. Heinrich,[a] Emilie Widemann,[b] Jérémie Sanz,[a] Raphaël Lugan,[b]
Thierry Heitz,[b] Franck Pinot,[c] Michel Miesch,[a] and Laurence Miesch*[a]
Keywords: Synthetic methods / Natural products / Hormones / Diastereoselectivity
Enantiomerically enriched oxidized conjugated or non-con-
jugated jasmonate derivatives were obtained through 3-alk-
ynoates. Stereoselective reduction of the triple bond afforded
exclusively the Z isomer. Protection of the amide function led
to the non-conjugated derivatives, whereas the free amides
provided the oxidized isoleucine derivatives of jasmonate.
tional JAZ repressors.[2] To understand how JA metabolic
diversity is generated to orchestrate physiological adapta-
tions in plants, enantiomerically enriched oxidized JA con-
jugates are required. In particular, 12-COOH-JA-Ile, a
major catabolite of JA-Ile in planta, has been reported.[3]
The elucidation of two integrated catabolic pathways that
either oxidize or hydrolyze the JA-Ile conjugate in the
model plant Arabidopsis have been achieved recently.[4]
Introduction
Jasmonates (JAs) are a class of hormonal compounds
reminiscent of animal prostaglandins that orchestrate plant
defenses against herbivore or microbial attacks and assist
in important developmental processes (Figure 1).[1] Their
metabolic pathways are at the center of a paradigm of hor-
monal signaling that is unique to plants. To trigger most
known biological responses in plants, jasmonic acid (JA)
conjugation is needed to form jasmonoyl-isoleucine (JA-
Ile), which is the active hormonal compound that promotes
co-receptor assembly and proteolytic removal of transcrip-
Results and Discussion
Among the syntheses of 12-COOH JA-Ile reported, the
racemic carboxy derivative has been synthesized by oxid-
ation of the corresponding hydroxy derivative.[5] The 12-
hydroxylated derivative was synthesized through Wittig re-
action.[4b,6]
When we tried to obtain the 12 hydroxy derivatives, a
mixture of Z/E isomers (ratio 2.5:1) was always obtained,
Scheme 1.[7]
In addition, the yield of the oxidation step to provide the
target molecule was low.[5] To the best of our knowledge,
only diastereomeric mixtures of 12-COOH JA-Ile have been
reported.[5] For biological investigations, exclusively the en-
antiomerically enriched Z isomer is required, and to cir-
cumvent the low yield of the oxidation step we developed a
new route for the synthesis of enantiomerically enriched 12-
COOH JA-Ile.
Optical resolution as well as the synthesis of the conju-
gated amines were carried out by condensation of (Ϯ)-jas-
monic acid (3) with enantiomerically pure (l)-isoleucine
methyl ester hydrochloride in the presence of 1-[3-(di-
Figure 1. Jasmonoyl derivatives.
[a] Université de Strasbourg, Institut de Chimie, UMR 7177,
Laboratoire de Chimie Organique Synthétique,
1 rue Blaise Pascal, BP 296/R8, 67008 Strasbourg Cedex,
France
E-mail: lmiesch@unistra.fr
m.miesch@unistra.fr
http://www-chimie.u-strasbg.fr/~lcos/
[b] Université de Strasbourg, Institut de Biologie Moléculaire des
Plantes, Unité Propre de Recherche 2357 du Centre National
de la Recherche Scientifique, Université de Strasbourg,
12 rue du Général Zimmer, 67084 Strasbourg Cedex, France
[c] Institut de Biologie Moléculaire des Plantes, Unité Propre de
Recherche 2357 du Centre National de la Recherche
Scientifique, Université de Strasbourg,
methylamino)propyl]-3-ethylcarbodiimide
hydrochloride
(EDC·HCl) and 4-(dimethylamino)pyridine (DMAP) in
CH2Cl2 (Scheme 2).[8] Diastereomers 4a and 4b were ob-
tained in a ratio of 1:1 in good yields.
We first focused on the non-conjugated derivatives. Al-
though many classical methods exist for the hydrolysis of
12 rue du Général Zimmer, 67084 Strasbourg Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403347.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:05
Pages: 8
L. Miesch et al.
FULL PAPER
Scheme 1. Wittig reaction; KHMDS = potassium bis(trimethylsilyl)amide; TBS = tert-butyldimethylsilyl.
introduction of a triple bond and subsequent methanolysis
of the tertiary amide function to provide non-conjugated
alkyne 8a (Scheme 4).
The next step was to functionalize position 12. For this
reaction, 3-alkynoates seemed to be the best choice. Thus,
the metal-catalyzed intermolecular coupling reaction of ter-
minal alkyne 8a developed by Fu et al.[16] by using ethyl
diazoacetate in the presence of a catalytic amount of CuI
provided 3-alkynoate 9a in good yield (Scheme 5).
Scheme 2. Peptidic coupling.
primary and tertiary amides, the efficient hydrolysis of sec-
ondary amides has proven to be more problematic[9] and
requires special conditions. The cleavage of secondary
amides bonds requires harsh conditions, such as a strong
acidic medium,[10] which is not compatible with sensitive
functional groups. It is known that amides can be activated
towards hydrolysis by prior conversion into N-tert-butoxy-
carbonyl (Boc) amide derivatives.[11] To this end we con-
verted the ketal-protected derivative 5a[12] into correspond-
ing the Boc-amide 6a by treatment with Boc2O and DMAP
in accordance with Grieco’s procedure (Scheme 3).[13]
Scheme 5. Preparation of 3-alkynoate 9a.
Although Lindlar catalyst led only to 12% of the corre-
sponding alkenes, other catalysts, such as poisoned Lindlar
catalysts or Rosenmund catalyst, provided a mixture of Z
and E isomers (Table 1, Entries 1–5). P-2 Nickel catalyst
with ethylenediamine was very efficient in the reduction of
alkyne 9a to cis olefin 10a (Table 1, Entry 6).[17]
Saponification of diester 10a, followed by acidic treat-
ment afforded non-conjugated 12-COOH-JA (12a) in 61%
yield (19% overall yield over 9 steps; Scheme 6).
Conjugated derivatives were obtained by using a similar
procedure, although ketal derivative 5a was directly reduced
by ozonolysis reaction to provide conjugated aldehyde 13a.
Scheme 3. Synthesis of amide 6a; PTSA = p-toluenesulfonic acid.
Ozonolysis of the latter compound provided aldehyde A Bestmann–Ohira reaction carried out on non-protected
7a.[14] A Bestmann–Ohira[15] reaction with dimethyl 1-di- amide 13a afforded conjugated terminal alkyne 14a
azo-2-oxopropylphosphonate and aldehyde 7a allowed the (Scheme 7).
Scheme 4. Preparation of alkyne 8a.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:05
Pages: 8
Synthesis of Enantiomerically Enriched Jasmonates
Table 1. Reduction of 3-alkynoate 9a.
Conclusions
We have developed a convenient method to obtain enan-
tiomerically enriched oxidized conjugated or non-conju-
gated JA derivatives. The availability of these synthetic 12-
COOH-JA and 12-COOH-JA-Ile compounds will allow
deeper exploration of the complex regulation of JA-Ile hor-
mone homeostasis, and may help unravel the metabolic
steps that govern jasmonate hormone action and clearance.
This approach allows the preparation of both trans stereo-
isomers with respect to the stereochemistry of the five mem-
bered ring, which allows investigation of their putative in-
volvement in the biological process. Application of this in-
novative approach to other amino acids may provide access
to other conjugates prevalent in some plant sources and is
currently under investigation in our laboratory.
Entry Conditions
Z
E
Saturated
product 11 9a
3-alkynoate
product
10a
product
10aЈ
1
2
Pd/BaSO4
Pd/BaSO4 58%
+ quinoline
Pd/BaSO4
+ pyridine
Pd/CaCO3 10%
+ 2.5%
Pb(OAc)2
(KO2CN)2,
AcOH
Ni(OAc)2, 90%
NaBH4
(CH2NH2)2
–
–
15%
64%
23%
–
–
Experimental Section
3
4
–
–
94%
–
–
General: All reactions were performed in flame-dried glassware un-
der an Argon atmosphere. Commercial reagents were distilled prior
to use; CH2Cl2 and tetrahydrofuran (THF) were purified with a
Dry Solvent Station GT S100. Ozonolysis reactions were per-
formed with a Fischer 502 ozone generator and an ozone flow rate
of 0.1 mol/h. 1H NMR spectra were recorded at 300 and 500 MHz
by using the solvent residual peak as the internal standard. Split-
ting patterns were reported as s, singlet; d, doublet; t, triplet; q,
quartet; and m, multiplet. HRMS data were recorded with a micro-
TOF spectrometer equipped with an orthogonal electrospray (ESI)
interface. Thin layer chromatography was performed with silica gel
60 F254 glass plates. Merck Geduran® 40–63 μm silica gel was used
for column chromatography. Optical rotation was measured at
22 °C with a Perkin–Elmer 341 Polarimeter in a glass vessel with a
capacity of 1 mL with a continuous wave light to the sodium D line
(589 nm). The sample concentrations are expressed in g·100 mL–1.
Infrared spectra were recorded with a Bruker-ALPHA spectropho-
tometer.
2%
88%
5[a]
6
–
–
–
–
–
83%
–
[a] Entry 5 was performed under an argon atmosphere.
Resolution of 4a and 4b: At room temperature, to a solution of
jasmonic acid 3 (3.19 g, 15.2 mmol, 1 equiv.) in CH2Cl2 (50 mL)
was added l-isoleucine methyl ester hydrochloride (3.31 g,
18.2 mmol, 1.2 equiv.), DMAP (5.56 g, 45.5 mmol, 3 equiv.), and
EDC·HCl (3.49 g, 18.2 mmol, 1.2 equiv.). The reaction mixture was
stirred at room temperature for 1.5 h before being quenched with
an aqueous solution of HCl (1 n, 25 mL). The organic layer was
washed with a saturated aqueous solution of NaHCO3 (20 mL).
The aqueous layer was extracted with Et2O (3ϫ 40 mL). The com-
bined organic layer was washed with a saturated aqueous solution
of NaCl, dried with Na2SO4, filtered, and concentrated under re-
duced pressure (15 mbar, 25 °C) to obtain a yellowish oil. The
Scheme 6. Synthesis of 12-COOH-JA 12a.
3-Alkynoate 15a was obtained as previously described in
good yield. Hydrogenation, saponification and subsequent
acidic hydrolysis provided conjugated 12-COOH-JA-Ile
(17a) in 68% yield (32% overall yield over 8 steps;
Scheme 8).
Scheme 7. Preparation of terminal alkyne 14a.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:05
Pages: 8
L. Miesch et al.
FULL PAPER
Scheme 8. Reaction scheme for the synthesis of 17a.
crude mixture was purified by column chromatography (silica gel,
petroleum ether/EtOAc, 100:0 to 70:30) to afford compounds 4a
(2.34 g, 7.01 mmol, 46%) and 4b (2.55 g,7.59 mmol, 50%) as yel-
lowish oils (4.89 g,14.6 mmol, 96%, 4a:4b 1:1).
(d, J = 8.3 Hz, 1 H), 5.35–5.41 (m, 2 H), 4.6 (dd, J = 8.3, 4.8 Hz,
1 H), 3.84–3.92 (m, 4 H), 3.73 (s, 3 H), 2.52–2.58 (m, 1 H), 1.65–
2.38 (m, 10 H), 1.31–1.46 (m, 3 H), 1.15–1.21 (m, 1 H), 0.89–0.98
(m, 9 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 173.0, 172.1,
132.6, 128.2, 118.1, 65.1, 64.5, 56.5, 52.4, 51.8, 43.0, 40.4, 38.3,
(2S,3S)-Methyl 3-Methyl-2-(2-{(1R,2R)-3-oxo-2-[(Z)-pent-2-en-1-
yl]cyclopentyl}acetamido)pentanoate (4a): 1H NMR (CDCl3,
300 MHz): δ = 6.06 (d, J = 8.3 Hz, 1 H), 5.21–5.45 (m, 2 H), 4.57
(dd, J = 8.6, 4.9 Hz, 1 H), 3.70 (s, 3 H), 2.61 (dd, J = 14.0, 4.2 Hz,
1 H), 1.81–2.35 (m, 10 H), 1.33–1.55 (m, 2 H), 1.07–1.21 (m, 2 H),
0.86–0.94 (m, 9 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 219.5,
172.8, 171.3, 134.1, 125.5, 56.5, 54.4, 52.4, 41.3, 39.0, 38.1, 38.0,
35.5, 28.2, 27.0, 25.6, 21.0, 15.8, 14.6, 11.9 ppm. IR (neat): ν =
˜
3319, 1744, 1646, 1536, 1436, 1150, 948 cm–1. [α]2D2 +3.7 (c = 1.0,
MeOH). HRMS (m/z): calcd. for [M + Na]+ 404.2407; found
404.2372. Rf = 0.42 (petroleum ether/EtOAc, 60:40).
(2S,3S)-Methyl 2-(N-(tert-Butoxycarbonyl)-2-{(6R,7R)-6-[(Z)-pent-
2-en-1-yl]-1,4-dioxaspiro[4.4]nonan-7-yl}acetamido)-3-methylpent-
anoate (6a): At room temperature, to a solution of compound 5a
(1.28 g, 3.36 mmol, 1 equiv.) in THF (25 mL), was added Boc2O
(4.33 g, 20.1 mmol, 6 equiv.) and DMAP (2.46 g, 20.1 mmol,
6 equiv.), and the reaction mixture was heated to reflux tempera-
tures for 1.5 h. After cooling, the resulting mixture was concen-
trated under reduced pressure (15 mbar, 25 °C). Et2O was added
(20 mL), and the reaction mixture was washed with a saturated
solution of NaHCO3 (20 mL). The aqueous layer was extracted
with Et2O (3ϫ 50 mL). The combined organic phases were dried
with Na2SO4, filtered, and concentrated under reduced pressure
(15 mbar, 25 °C) to obtain a colorless oil. The crude mixture was
purified by column chromatography (silica gel, petroleum ether/
EtOAc, 100:0 to 85:15) to afford 6a as a colorless oil (1.61 g,
3.36 mmol, 100%). 1H NMR (CDCl3, 300 MHz): δ = 5.30–5.43
(m, 2 H), 4.93 (d, J = 9.2 Hz, 1 H), 3.82–3.92 (m, 4 H), 3.65 (s, 3
H), 3.20 (dd, J = 16.9, 3.7 Hz, 1 H), 2.76 (dd, J = 17.1, 10.0 Hz, 1
H), 1.92–2.29 (m, 8 H), 1.65–1.78 (m, 3 H), 1.46 (s, 9 H), 1.15–1.23
(m, 2 H), 1.10 (d, J = 6.4 Hz, 3 H), 0.93 (t, J = 7.6 Hz, 3 H), 0.83
(t, J = 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 175.0,
171.1, 152.4, 131.9, 128.1, 117.8, 83.7, 64.7, 64.1, 60.2, 51.9, 51.2,
44.0, 39.5, 35.3, 34.3, 28.2, 27.9, 26.6, 24.7, 20.6, 18.2, 14.2,
27.4, 25.9, 25.5, 20.6, 15.7, 14.4, 11.8 ppm. IR (neat): ν = 3309,
˜
1737, 1646, 1532, 1435, 1150 cm–1. [α]2D2 13.2 (c = 1.0, MeOH).
HRMS (m/z): calcd. for [M + Na]+ 360.2145; found 360.2119. Rf
= 0.43 (petroleum ether/EtOAc, 50:50).
(2S,3S)-Methyl
3-Methyl-2-(2-{(1S,2S)-3-oxo-2-[(Z)-pent-2-en-1-
yl]cyclopentyl}acetamido)pentanoate (4b): 1H NMR (CDCl3,
300 MHz): δ = 6.09 (d, J = 8.0 Hz, 1 H), 5.19–5.45 (m, 2 H), 4.59
(dd, J = 8.6, 4.7 Hz, 1 H), 3.70 (s, 3 H), 2.63 (dd, J = 14.1, 4.2 Hz,
1 H), 1.82–2.36 (m, 10 H), 1.33–1.54 (m, 2 H), 1.06–1.21 (m, 2 H),
0.86–0.94 (m, 9 H) ppm. 13C NMR (CDCl3, 300 MHz): δ = 219.4,
172.8, 171.2, 134.2, 125.4, 56.6, 54.4, 52.4, 41.5, 38.9, 38.2, 38.0,
27.4, 25.8, 25.5, 20.9, 15.8, 14.4, 11.8 ppm. IR (neat): ν = 3309,
˜
1738, 1646, 1531, 1435, 1150 cm–1. [α]2D2 +9.9 (c = 1.0, MeOH).
HRMS (m/z): calcd. for [M + Na]+ 360.2145; found 360.2119. Rf
= 0.52 (petroleum ether/EtOAc, 50:50).
(2S,3S)-Methyl 3-Methyl-2-(2-{(6R,7R)-6-[(Z)-pent-2-en-1-yl]-1,4-
dioxaspiro[4.4]nonan-7-yl}acetamido)pentanoate (5a): To a solution
of 4a (1.49 g, 4.41 mmol, 1 equiv.) in toluene was added ethylene
glycol (0.74 mL, 13.2 mmol, 3 equiv.) and PTSA (10 mg). The reac-
tion mixture was heated to reflux temperatures for 2.5 h with the
use of a Dean–Stark apparatus. After cooling to room temperature,
the resulting mixture was washed with an aqueous solution of satu-
rated NaHCO3 (20 mL). The aqueous phase was extracted with
CH2Cl2 (3ϫ 50 mL). The combined organic layer was dried with
Na2SO4, filtered, and concentrated under reduced pressure
(15 mbar, 25 °C) to obtain a yellowish oil. The crude reaction was
purified by column chromatography (silica gel, petroleum ether/
11.1 ppm. IR (neat): ν = 1740, 1697, 1458, 1148, 949 cm–1. [α]22-
˜
D
1.3 (c = 1.0, MeOH). HRMS (m/z): calcd. for [M + Na]+ 504.2932;
found 504.2906. Rf = 0.78 (petroleum ether/EtOAc, 70:30).
(2S,3S)-Methyl 2-{N-(tert-Butoxycarbonyl)-2-[(6R,7R)-6-(2-oxo-
ethyl)-1,4-dioxaspiro[4.4]nonan-7-yl]acetamido}-3-methylpentano-
ate (7a): At –78 °C, a solution of 6a (0.87 g, 1.81 mmol, 1 equiv.) in
EtOAc, 100:0 to 85:15) to afford product 5a as a yellowish oil MeOH (20 mL) was placed under ozonolysis conditions for 15 min,
1
(1.53 g, 4.01 mmol, 91%). H NMR (CDCl3, 300 MHz): δ = 5.90 before the addition of dimethyl sulfide (1.5 mL, 18.1 mmol,
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:05
Pages: 8
Synthesis of Enantiomerically Enriched Jasmonates
10 equiv.). After 5 min, the resulting mixture was warmed to room
temperature, stirred for 1 h, and concentrated under reduced pres-
sure (15 mbar, 25 °C) to obtain a yellowish oil. The crude mixture
was purified by column chromatography (silica gel, petroleum
ether/EtOAc = 100:0 to 85:15) to afford 7a as a colorless oil (0.51 g,
4 equiv.) was added dropwise. The mixture was stirred for a further
10 min, then a solution of alkyne 9a (110 mg, 0.34 mmol, 1 equiv.)
in dry ethanol (0.25 mmol/mL) was added dropwise. The reaction
mixture was stirred for 1 h, diluted with distilled water (20 mL)
and diethyl ether (20 mL), filtered through Celite®, washed with
dichloromethane, and concentrated under reduced pressure
1
1.12 mmol, 62%). H NMR (CDCl3, 300 MHz): δ = 9.69 (dd, J =
2.8, 1.6 Hz, 1 H), 4.89 (d, J = 9.3 Hz, 1 H), 3.72–3.91 (m, 4 H), (15 mbar, 25 °C). The aqueous layer was extracted with diethyl
3.62 (s, 3 H), 3.13 (dd, J = 16.7, 4.9 Hz, 1 H), 2.85 (dd, J = 16.8, ether (3ϫ 50 mL). The combined organic layers were dried with
8.2 Hz, 1 H), 2.10–2.57 (m, 5 H), 1.89–2.00 (m, 1 H), 1.64–1.80 (m, Na2SO4, filtered, and concentrated under reduced pressure to ob-
2 H), 1.43 (s, 9 H), 1.15–1.26 (m, 2 H), 1.06 (d, J = 6.4 Hz, 3 H), tain a yellowish oil. The crude mixture was purified by column
0.84–0.93 (m, 1 H), 0.78–0.82 (m, 3 H) ppm. 13C NMR (CDCl3, chromatography (silica gel, petroleum ether/EtOAc, 100:0 to 85:15)
300 MHz): δ = 202.5, 175.0, 171.2, 152.6, 117.4, 84.3, 64.8, 64.6,
to afford 10a as a colorless oil (100 mg, 0.31 mmol, 90%). 1H NMR
(CDCl3, 300 MHz): δ = 5.48–5.62 (m, 2 H), 4.09 (q, J = 7.1 Hz, 2
H), 3.78–3.87 (m, 4 H), 3.61 (s, 3 H), 3.06 (d, J = 5.1 Hz, 2 H),
2.52 (dd, J = 15.2, 4.5 Hz, 1 H), 2.15–2.27 (m, 2 H), 1.97–2.10 (m,
2 H), 1.83–1.91 (m, 1 H), 1.62–1.75 (m, 3 H), 1.27–1.33 (m, 1 H),
1.21 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
173.4, 172.2, 132.2, 121.7, 117.8, 64.9, 64.4, 60.8, 51.7, 51.3, 40.0,
60.5, 52.2, 47.3, 43.8, 43.3, 39.0, 35.1, 34.6, 28.6, 28.1, 25.0, 18.5,
11.4 ppm. IR (neat): ν = 2969, 1736, 1692, 1147, 948 cm–1. [α]22-
˜
D
5.0 (c = 0.5, MeOH). HRMS (m/z): calcd. for [M + K]+ 494.2151;
found 494.2316. Rf = 0.66 (petroleum ether/EtOAc, 60:40).
Methyl 2-[(6R,7R)-6-(Prop-2-yn-1-yl)-1,4-dioxaspiro[4.4]nonan-7-
yl]acetate (8a): At room temperature, to a solution of 7a (0.89 g,
1.95 mmol, 1 equiv.) in anhydrous MeOH (20 mL), Bestmann–
Ohira reagent (0.83 g, 4.30 mmol, 2.2 equiv.) and potassium carb-
onate (1.08 g, 7.82 mmol, 4 equiv.) was added. The resulting mix-
ture was stirred for 18 h and concentrated under reduced pressure
(15 mbar, 25 °C). Et2O (20 mL) was added, followed by a saturated
aqueous solution of NH4Cl (20 mL). The aqueous layer was ex-
tracted with Et2O (3ϫ 50 mL). The combined organic layer was
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure (15 mbar, 25 °C) to obtain a yellowish oil. The crude mixture
was purified by column chromatography (silica gel, petroleum
ether/EtOAc, 100:0 to 82:18) to afford 8a as a colorless oil (0.29 g,
39.6, 35.4, 33.3, 28.3, 27.0, 14.5 ppm. IR (neat): ν = 1732, 1150,
˜
947, 732 cm–1. [α]2D2 +9.6 (c = 1, MeOH). HRMS (m/z): calcd. for
[M + Na]+ 349.1622; found 349.1625. Rf = 0.51 (petroleum ether/
EtOAc, 70:30).
(Z)-5-[(1R,2R)-2-(Carboxymethyl)-5-oxocyclopent-yl]pent-3-enoic
Acid (12a): To a solution of compound 10a (100 mg, 0.31 mmol,
1 equiv.) in methanol (5 mL) was added an aqueous solution of
NaOH (1 n, 1.5 mL). The resulting mixture was heated to reflux
temperatures for 4 h and acidified to pH 1 with an aqueous solu-
tion of HCl (1 n). After 15 min, the mixture was cooled to room
temperature and was diluted with distilled water (20 mL), extracted
with CH2Cl2 (3ϫ 50 mL) and with Et2O (1ϫ 25 mL). The com-
bined organic layers were dried with Na2SO4, filtered, and concen-
trated under reduced pressure (15 mbar, 25 °C). The crude mixture
was purified by column chromatography (silica gel, CH2Cl2/
MeOH, 100:0 to 90:10) to afford 12a as a yellowish oil (46 mg,
1
1.21 mmol, 62%). H NMR (CDCl3, 300 MHz): δ = 3.79–3.91 (m,
4 H), 3.61 (s, 3 H), 2.69 (dd, J = 14.8, 4.5 Hz, 1 H), 1.99–2.20 (m,
4 H), 1.84 (t, J = 2.7 Hz, 1 H), 1.53–1.82 (m, 4 H), 1.10–1.23 (m,
1 H) ppm. 13C NMR (CDCl3, 300 MHz): δ = 173.2, 117.2, 83.6,
69.1, 65.2, 64.5, 51.6, 50.4, 40.0, 39.6, 35.3, 28.3, 18.2 ppm. IR
(neat): ν = 3279, 1732, 1150, 948 cm–1. [α]22 +18.9 (c = 1, MeOH).
˜
1
D
0.19 mmol, 61%). H NMR (CDCl3, 500 MHz): δ = 9.62 (br. s, 2
HRMS (m/z): calcd. for [M + Na]+ 261.1097; found 261.1093. Rf
H), 5.62–5.67 (m, 1 H), 5.48–5.54 (m, 1 H), 3.15 (d, J = 8.0 Hz, 2
H), 2.85 (d, J = 13.5 Hz, 1 H), 2.25–2.50 (m, 5 H), 2.08–2.17 (m,
1 H), 1.87–1.91 (m, 1 H), 1.58–1.64 (m, 1 H), 1.44–1.50 (m, 1
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 219.0, 179.4, 178.7,
130.6, 123.0, 53.7, 39.3, 38.1, 38.0, 33.2, 27.9, 26.0 ppm. IR (neat):
= 0.55 (petroleum ether/EtOAc, 80:20).
Ethyl 5-[(6R,7R)-7-(2-Methoxy-2-oxoethyl)-1,4-dioxaspiro[4.4]non-
an-6-yl]pent-3-ynoate (9a): To a solution of 8a (384 mg, 1.61 mmol,
1 equiv.) in anhydrous acetonitrile (7 mL) was added ethyl diazo-
acetate (255 μL, 2.42 mmol, 1.5 equiv.) and CuI (31 mg, 0.16 mmol,
10 mol-%). The resulting mixture was stirred for 4 h and concen-
trated under reduced pressure (15 mbar, 25 °C). The crude mixture
was purified by column chromatography (silica gel, petroleum
ether/EtOAc, 100:0 to 78:22) to afford 9a as a colorless oil
(4.98 mg, 1.53 mmol, 95%). 1H NMR (CDCl3, 300 MHz): δ = 4.01
(q, J = 7.2 Hz, 2 H), 3.69–3.81 (m, 4 H), 3.51 (s, 3 H), 3.08 (t, J =
2.5 Hz, 2 H), 2.64 (dd, J = 15.0, 4.5 Hz, 1 H), 1.97–2.27 (m, 5 H),
1.58–1.80 (m, 4 H), 1.12 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 173.1, 168.7, 117.0, 82.5, 72.1, 65.0, 64.3,
61.3, 51.3, 50.4, 39.8, 39.6, 35.1, 28.1, 26.1, 18.4, 14.1 ppm. IR
ν = 2925, 1702, 1406, 1278, 730 cm–1. [α]22-34.5 (c = 1, MeOH).
˜
D
HRMS (m/z): calcd. for [M + Na]+ 263.0890; found 263.0880. Rf
= 0.24 (CH2Cl2/MeOH, 90:10).
(2S,3S)-Methyl 3-Methyl-2-{2-[(6R,7R)-6-(2-oxoethyl)-1,4-dioxa-
spiro[4.4]nonan-7-yl]acetamido}pentanoate (13a): At –78 °C, a solu-
tion of 5a (1.05 g, 2.72 mmol, 1 equiv.) in MeOH (15 mL) was
placed under ozonolysis conditions for 15 min, before the addition
of dimethyl sulfide (2.00 mL, 27.2 mmol, 10 equiv.) at –78 °C. After
5 min, the resulting mixture was warmed to room temperature and
stirred for 1 h, then concentrated under reduced pressure (15 mbar,
25 °C) to obtain a yellowish oil. The crude mixture was purified by
column chromatography (silica gel, petroleum ether/EtOAc, 100:0
to 50:50) to afford 13a as a colorless oil (0.85 g, 2.39 mmol, 87%).
1H NMR (CDCl3, 300 MHz): δ = 9.55 (dd, J = 2.4, 1.3 Hz, 1 H),
(neat): ν = 1736, 1160, 949 cm–1. [α]22 +8.2 (c = 1, MeOH). HRMS
˜
D
(m/z): calcd. for [M + Na]+ 347.1465; found 347.1455. Rf = 0.50
(petroleum ether/EtOAc, 70:30).
(Z)-Ethyl 5-[(6R,7R)-7-(2-Methoxy-2-oxoethyl)-1,4-dioxaspi- 6.55 (d, J = 8.7 Hz, 1 H), 4.38 (dd, J = 8.4, 5.3 Hz, 1 H), 3.62–3.71
ro[4.4]nonan-6-yl]pent-3-enoate (10a): In a three-necked flask,
flame-dried under argon, was solubilized Ni(OAc)2 (60 mg,
0.34 mmol, 1 equiv.) in dry ethanol (15 mL), before the mixture was
degassed and placed under a hydrogen atmosphere. NaBH4 (13 mg,
0.34 mmol, 1 equiv.) in dry ethanol (0.25 mmol/mL) was added
dropwise. The resulting mixture was stirred for 30 min under a
hydrogen atmosphere. Then ethylenediamine (91 μL, 1.36 mmol,
(m, 4 H), 3.54 (s, 3 H), 2.42 (ddd, J = 16.8, 7.9, 2.5 Hz, 1 H), 2.25–
2.32 (m, 2 H), 1.94–2.21 (m, 3 H), 1.57–1.76 (m, 3 H), 1.18–1.31
(m, 2 H), 0.93–1.10 (m, 2 H), 0.70–0.75 (m, 6 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 202.3, 172.5, 171.7, 117.1, 64.4, 64.3, 56.4,
51.9, 46.6, 43.1, 41.2, 39.5, 37.5, 34.7, 28.0, 25.2, 15.4, 11.4 ppm.
IR (neat): ν = 3307, 2878, 1721, 1647, 1530, 1436, 1151, 950 cm–1.
˜
[α]2D2 +7.5 (c = 1.0, MeOH). HRMS (m/z): calcd. for [M + Na]+
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:05
Pages: 8
L. Miesch et al.
FULL PAPER
378.1887; found 378.1876. Rf = 0.40 (petroleum ether/EtOAc,
40:60).
ganic layer was dried with Na2SO4, filtered, and concentrated un-
der reduced pressure to obtain a yellowish oil. The crude mixture
was purified by column chromatography (silica gel, petroleum
ether/EtOAc, 100:0 to 50:50) to afford 16a as a colorless oil
(2S,3S)-Methyl 3-Methyl-2-{2-[(6R,7R)-6-(prop-2-yn-1-yl)-1,4-di-
oxaspiro[4.4]nonan-7-yl]acetamido}pentanoate (14a): At room tem-
perature, to a solution of 13a (0.85 g, 2.28 mmol, 1 equiv.) in
MeOH (20 mL), Bestmann–Ohira reagent (1.00 g, 5.24 mmol,
2.2 equiv.) and then potassium carbonate (0.82 g, 5.96 mmol,
2.5 equiv.) were added. The reaction mixture was stirred at room
temperature for 6 h before being concentrated under reduced pres-
sure (15 mbar, 25 °C). Saturated aqueous NH4Cl (25 mL) was
added, and the reaction mixture was extracted with diethyl ether
(3ϫ 50 mL). The combined organic layers were dried with Na2SO4,
filtered, and concentrated under reduced pressure (15 mbar, 25 °C)
to obtain a yellow oil. The crude mixture was purified by column
chromatography (silica gel, petroleum ether/EtOAc, 100:0 to 65:35)
to afford 14a as a colorless oil (0.70 g, 1.92 mmol, 84%). 1H NMR
(CDCl3, 300 MHz): δ = 6.00 (d, J = 8.3 Hz, 1 H), 4.60 (dd, J =
8.7, 4.8 Hz, 1 H), 3.83–3.96 (m, 4 H), 3.73 (s, 3 H), 2.66 (dd, J =
18.2, 9 Hz, 1 H), 2.35–2.44 (m, 1 H), 2.18–2.27 (m, 3 H), 1.96 (t, J
= 2.7 Hz, 1 H), 1.69–1.90 (m, 4 H), 1.33–1.47 (m, 2 H), 1.09–1.27
(m, 2 H), 0.89–0.94 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 172.5, 171.7, 116.3, 83.7, 68.8, 64.8, 64.2, 56.2, 51.8, 50.2, 41.9,
1
(101 mg, 0.23 mmol, 80%). H NMR (CDCl3, 300 MHz): δ = 6.18
(d, J = 8.6 Hz, 1 H), 5.44–5.60 (m, 2 H), 4.51 (dd, J = 8.6, 5.2 Hz,
1 H), 4.07 (q, J = 7.1 Hz, 2 H), 3.77–3.83 (m, 4 H), 3.65 (s, 3 H),
3.03–3.06 (m, 2 H), 2.46–2.55 (m, 1 H), 2.16–2.24 (m, 1 H), 1.96–
2.08 (m, 3 H), 1.62–1.89 (m, 5 H), 1.28–1.41 (m, 2 H), 1.19 (t, J =
7.1 Hz, 3 H), 1.08–1.13 (m, 1 H), 0.84 (t, J = 7.1 Hz, 6 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 172.8, 172.2, 172.1, 132.7, 121.5,
117.9, 64.9, 64.4, 60.9, 56.5, 52.2, 51.5, 42.6, 40.5, 38.0, 35.4, 33.2,
28.0, 27.0, 25.5, 15.7, 14.4, 11.8 ppm. IR (neat): ν = 3307, 1735,
˜
1647, 1436, 1152, 948 cm–1. [α]2D2-0.2 (c = 1.0, MeOH). HRMS
(m/z): calcd. for [M + Na]+ 462.2462; found 440.2589. Rf = 0.54
(petroleum ether/EtOAc, 50:50).
(Z)-5-[(1R,2R)-2-(2-{[(1S,2S)-1-Carboxy-2-methylbutyl]amino}-2-
oxoethyl)-5-oxocyclopentyl]pent-3-enoic Acid (17a): To a solution of
16a (55 mg, 0.12 mmol, 1 equiv.) in methanol (5 mL) was added an
aqueous solution of NaOH (1 n, 1.5 mL). The resulting mixture
was heated to reflux temperatures for 4 h and acidified to pH 1
with an aqueous solution of HCl (1 n). After 15 min, the mixture
was cooled to room temperature and was diluted with distilled
water (25 mL) then extracted with CH2Cl2 (3ϫ 50 mL) and Et2O
(25 mL). The combined organic phases were dried with Na2SO4,
filtered, and concentrated under reduced pressure (15 mbar, 25 °C).
The crude mixture was purified by column chromatography (silica
gel, CH2Cl2/MeOH, 100:0 to 90:10) to afford 17a as a yellowish oil
40.1, 37.6, 35.0, 27.8, 25.2, 17.9, 15.4, 11.4 ppm. IR (neat): ν =
˜
3290, 1741, 1646, 1435, 1153, 985 cm–1. [α]2D2 +7.6 (c = 1.0, MeOH).
HRMS (m/z): calcd. for [M + Na]+ 374.1938; found 374.1926. Rf
= 0.51 (petroleum ether/EtOAc, 50:50).
Ethyl 5-[(6R,7R)-7-(2-{[(2S,3S)-1-Methoxy-3-methyl-1-oxopentan-
2-yl]amino}-2-oxoethyl)-1,4-dioxaspiro[4.4]nonan-6-yl]pent-3-ynoate
(15a): At room temperature, to a solution of 14a (0.20 g,
0.57 mmol, 1 equiv.) in anhydrous acetonitrile (10 mL), was added
ethyl diazoacetate (90 μL, 0.85 mmol, 1.5 equiv.) and CuI (11 mg,
0.06 mmol, 10 mol-%). The reaction mixture was stirred for 4 h and
concentrated under reduced pressure (25 °C, 15 mbar). The crude
mixture was purified by column chromatography (silica gel, petro-
leum ether/EtOAc, 100:0 to 50:50) to afford pure 15a as a colorless
oil (0.24 g, 0.54 mmol, 94%). 1H NMR (CDCl3, 300 MHz): δ =
6.41 (d, J = 8.5 Hz, 1 H), 4.52 (dd, J = 8.5, 5.3 Hz, 1 H), 4.11 (q,
J = 7.1 Hz, 2 H), 3.78–3.89 (m, 4 H), 3.65 (s, 3 H), 3.20 (t, J =
2.5 Hz, 2 H), 2.75–2.81 (m, 1 H), 2.28–2.37 (m, 1 H), 2.10–2.22 (m,
3 H), 1.65–1.94 (m, 5 H), 1.32–1.49 (m, 2 H), 1.17–1.23 (m, 4 H),
0.82–0.87 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.8,
172.3, 169.4, 117.3, 83.1, 72.4, 65.1, 64.6, 61.7, 56.5, 52.1, 50.5,
42.3, 40.7, 37.9, 35.2, 28.1, 26.3, 25.5, 18.7, 15.7, 14.3, 11.7 ppm.
1
(30 mg, 0.09 mmol, 68%). H NMR (MeOD, 500 MHz): δ = 5.68
(dd, J = 17.9, 7.5 Hz, 1 H), 5.45 (dd, J = 17.9, 7.5 Hz, 1 H), 4.32
(dd, J = 17.1, 6.1 Hz, 1 H), 3.06–3.17 (m, 2 H), 2.80 (dd, J = 13.2,
4.3 Hz, 1 H), 2.42–2.46 (m, 2 H), 2.33–2.40 (m, 2 H), 2.14–2.20 (m,
3 H), 1.56–1.63 (m, 3 H), 1.20–1.29 (m, 2 H), 0.93–1.00 (m, 6
H) ppm. 13C NMR (MeOD, 125 MHz): δ = 222.4, 180.5, 178.6,
175.3, 130.5, 126.9, 60.8, 56.3, 42.9, 41.6, 39.4, 39.2, 36.5, 31.0,
28.9, 27.1, 17.1, 12.7 ppm. IR (neat): ν = 3342, 1702, 1644, 1558,
˜
1416 cm–1. [α]2D2–35.9 (c = 1, MeOH). HRMS (m/z): calcd. for [M
+ Na]+ 376.1731; found 376.1728. Rf = 0.42 (CH2Cl2/MeOH,
80:20).
Acknowledgments
Support for this work was provided by theCentre National de la
Recherche Scientifique (CNRS) and the Université de Strasbourg.
C. F. H. thanks MRT for a research fellowship. This project was
funded in part by the Agence Nationale de la Recherche (ANR)
contract ANR-12-BSV8-005.
IR (neat): ν = 3345, 1739, 1659, 1435, 1157, 949 cm–1. [α]22 = +1.3
˜
D
(c = 1.0, MeOH). HRMS (m/z): calcd. for [M + Na]+ 460.2306;
found 460.2305. Rf = 0.48 (petroleum ether/EtOAc, 50:50).
(Z)-Ethyl 5-[(6R,7R)-7-(2-{[(2S,3S)-1-Methoxy-3-methyl-1-oxopent-
an-2-yl]amino}-2-oxoethyl)-1,4-dioxaspiro[4.4]nonan-6-yl]pent-3-
enoate (16a): In a three-necked flask, flame-dried under argon, was
solubilized Ni(OAc)2 (52 mg, 0.29 mmol, 1.0 equiv.) in dry ethanol
(27 mL), then the mixture was degassed and placed under a
hydrogen atmosphere. NaBH4 (11 mg, 0.29 mmol, 1.0 equiv.) in dry
ethanol (0.25 mmol/mL) was added dropwise. The resulting mix-
ture was stirred for 30 min under a hydrogen atmosphere. Then
ethylenediamine (78 μL, 1.16 mmol, 4 equiv.) was added dropwise.
The mixture was stirred for another 10 min, before 15a (125 mg,
0.29 mmol, 1 equiv.) in a solution in dry ethanol (0.25 mmol/mL)
was added dropwise. The reaction mixture was stirred for 6 h and
diluted with distilled water (25 mL) and diethyl ether (25 mL), fil-
tered through Celite®, washed with dichloromethane, and concen-
trated under reduced pressure (15 mbar, 25 °C). The aqueous layer
was extracted with diethyl ether (3ϫ 50 mL). The combined or-
[1] a) J. Browse, Annu. Rev. Plant Biol. 2009, 60, 183–205; b) C.
Wasternack, B. Hause, Ann. Bot. 2013, 111, 1021–1058.
[2] a) A. Chini, S. Fonseca, G. Fernández, B. Adie, J. M. Chico, O.
Lorenzo, G. García-Casado, I. López-Vidriero, F. M. Lozano,
M. R. Ponce, J. L. Micol, R. Solano, Nature 2007, 448, 666–
671; b) B. Thines, L. Katsir, M. Melotto, Y. Niu, A. Mandao-
kar, G. Liu, K. Nomura, S. Y. He, G. A. Howe, J. Browse, Na-
ture 2007, 448, 661–665.
[3] Glauser, E. Grata, L. Dubugnon, S. Rudaz, E. E. Farmer, J.-
L. Wolfender, J. Biol. Chem. 2008, 283, 16400–16407.
[4] a) T. Heitz, E. Widemann, R. Lugan, L. Miesch, P. Ullmann,
L. Désaubry, E. Holder, B. Grausem, S. Kandel, M. Miesch,
D. Werck-Reichhart, F. Pinot, J. Biol. Chem. 2012, 287, 6296–
6306; b) N. Kitaoka, T. Matsubara, M. Sato, K. Takahashi, S.
Wakuta, H. Kawaide, H. Matsui, K. Nabeta, H. Matsuura,
Plant Cell Physiol. 2011, 52, 1757–1765; c) A. J. K. Koo, T. F.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:06
Pages: 8
Synthesis of Enantiomerically Enriched Jasmonates
Cooke, G. A. Howe, Proc. Natl. Acad. Sci. USA 2011, 108,
9298–9303; d) E. Widemann, L. Miesch, R. Lugan, E. Holder,
C. Heinrich, Y. Aubert, M. Miesch, F. Pinot, T. Heitz, J. Biol.
Chem. 2013, 288, 31701–31714.
diastereomer and the results are shown in the Supporting In-
formation. The percentages shown in brackets with a star ac-
count for the second diastereoisomer.
D. L. Flynn, R. E. Zelle, P. A. Grieco, J. Org. Chem. 1983, 48,
2424–2426.
M. Shoji, E. Kato, Y. Nakamura, T. Fujii, Y. Watanabe, M.
Ueda, Chem. Rec. 2006, 6, 344–355.
a) S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett
1996, 521–522; b) S. Ohira, Synth. Commun. 1989, 19, 561–
564.
[13]
[14]
[15]
[5] N. Kitaoka, H. Kawaide, N. Amano, T. Matsubara, K. Nabeta,
K. Takahashi, H. Matsuura, Phytochemistry 2014, 99, 6–13.
[6] H. Matsuura, F. Ohmori, M. Kobayashi, A. Sakurai, T. Yoshi-
hara, Biosci. Biotechnol. Biochem. 2000, 64, 2380–2387.
[7] The spectroscopic data mentioned in the Supporting Infor-
mation clearly show a mixture of compounds.
[8] a) J. C. Sheehan, S. L. Ledis, J. Am. Chem. Soc. 1973, 95, 875–
879; b) M. Schumacher, G. Coste, L. Miesch, Synthesis 2009,
1014–1020.
[16] A. Suárez, G. C. Fu, Angew. Chem. Int. Ed. 2004, 43, 3580–
3582; Angew. Chem. 2004, 116, 3664–3666.
[17] a) H. C. Brown, C. A. Brown, J. Am. Chem. Soc. 1963, 85,
1005–1006; b) C. A. Brown, V. K. Ahuja, J. Chem. Soc., Chem.
Commun. 1973, 553–554; c) C. A. Brown, V. K. Ahuja, J. Org.
Chem. 1973, 38, 2226–2230.
[9] J. C. Martin, J. A. Franz, J. Am. Chem. Soc. 1975, 97, 6137–
6144.
[10] G. A. Dilbeck, L. Field, A. A. Gallo, R. J. Gargiulo, J. Org.
Chem. 1978, 43, 4593–4596.
[11] M. J. Burk, J. G. Allen, J. Org. Chem. 1997, 62, 7054–7057.
[12] Only the biologically active diastereomer has been described
in the text. All reactions were also performed on the second
Received: October 14, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43347
/KAP1
Date: 20-12-14 11:59:06
Pages: 8
L. Miesch et al.
FULL PAPER
Synthetic Methodology
C. F. Heinrich, E. Widemann, J. Sanz,
R. Lugan, T. Heitz, F. Pinot, M. Miesch,
L. Miesch* ........................................ 1–8
A Route for the Total Synthesis of Enan-
tiomerically Enriched Jasmonates 12-
COOH-JA and 12-COOH-JA-Ile
Keywords: Synthetic methods / Natural
products / Hormones / Diastereoselectivity
A new synthetic route for enantiomerically
enriched 12-COOH-JA and 12-COOH-JA-
Ile from (+)-jasmonic acid is described.
Ozonolysis afforded corresponding alde-
hydes that could be converted into 3-
alkynoates. Z-Stereoselective reduction of
the triple bond gave the desired com-
pounds. N-tert-Butoxycarboxamide deriva-
tives led to non-conjugated 12-COOH-JA,
whereas free amides provided 12-COOH-
JA-Ile.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0