Diastereospecific synthesis of new 4-substituted l-theanine derivatives

Article abstract of DOI:10.1016/j.tetasy.2014.03.016

Considering the biological activity of l-theanine as a potent agonist of NMDA receptors, impacting on glutamatergic synapse activity, we have developed an asymmetric synthesis of new enantiomerically pure 4-substituted l-theanine derivatives. The key step is a stereospecific alkylation on a previously synthesized and correctly protected (S)-pyroglutamate.

Full text of DOI:10.1016/j.tetasy.2014.03.016

Tetrahedron: Asymmetry 25 (2014) 690–696
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereospecific synthesis of new 4-substituted L-theanine
derivatives
Fatiha Sebih a,b, Salima Bellahouel b, Marc Rolland c, Aicha Derdour b, Jean Martinez a, Valérie Rolland a,
⇑
a IBMM-UMR 5247, CNRS, UM2, UM1, Place E. Bataillon, 34095 Montpellier Cédex 5, France
b Laboratoire de Synthèse Organique Appliquée LSOA, Université d’Oran, Département de Chimie, Bp 1524 El M’Naouer, Oran 31000, Algeria
c IEM-UMR5635, CNRS-UM2-ENSCM, Place E. Bataillon, 34095 Montpellier Cédex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 March 2014
Accepted 25 March 2014
Considering the biological activity of
L
-theanine as a potent agonist of NMDA receptors, impacting on
glutamatergic synapse activity, we have developed an asymmetric synthesis of new enantiomerically
pure 4-substituted -theanine derivatives. The key step is a stereospecific alkylation on a previously syn-
thesized and correctly protected (S)-pyroglutamate.
L
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
During the search for new molecules capable of activating,
blocking or modulating Glu receptor subtypes, such as ionotropic
glutamate receptors (i-Glu Rs) according to the selective agonists,
NMDA, AMPA and KA and the G-protein coupled metabotropic
glutamate receptors (m-Glu Rs) and (or) excitatory aminoacid
transporters (EAATs), we considered the synthesis of various 3 or
4-substituted glutamate analogues and various 3-substituted
aspartate analogues (Fig. 2) and their biological activity evaluation.
L
-Theanine (5-N-ethylglutamine) is a non-proteinogenic amino
acid1 present in the range of 1–2.5% of green tea leaves essentially
in Camellia sinensis and is the major flavour component of tea, that
is, the ‘umami taste’.2
In addition to its flavouring, L-theanine can modulate peripheral
physiological parameters such as reducing blood pressure3 and
helping to manage allergic disorders.4 Moreover, thanks to its great
ability to cross the blood–brain barrier (BBB), L-theanine also dis-
plays a wide array of CNS actions resulting in beneficial behav-
ioural effects such as anxiolytic and pro-mnesiant actions, likely
via the acute modulation of neurotransmitter levels such as dopa-
mine5 and amino acids.6 In addition, the long-term effects of
Bn
R
HO
R
O
HOOC
HOOC
HOOC
COOH
COOH
COOH
NH2
NH2
R: -OH, -Bn8
NH2
L
-theanine results in protective action against glutamate neurotox-
icity while prevention of synaptic plasticity deficits under patho-
logical conditions has also been identified. -Theanine could
5
R: -CH3, -iPr, -CH2-CH2Ph,6
D,L
-TBOA
-CH2-Ph 7
L
therefore be an interesting structure to develop new agents that
interact with the glutamatergic system, bearing in mind that it
binds glutamatergic ionotropic receptors,7 especially NMDA recep-
tors, and that it crosses the BBB easily (Fig. 1).
Figure 2. b-Substituted aspartate derivatives: inhibitors of EAATs.
DL-threo-b-Benzyloxyaspartate (DL-TBOA) is the most potent
blocker for the human EAAT1 and EAAT2.5 Recently we reported
on a concise, asymmetric synthesis of enantiomerically pure
b-substituted b-hydroxy aspartates via an aldol reaction between
a glycine enolate derived from an oxazinone intermediate (used
H
N
C
as facial discriminator) and various
a-keto esters with excellent
O
COOH
diastereoisomeric excess.6 Enantiomerically pure b-methyl-b-
hydroxyaspartates, b-isopropyl-b-hydroxyaspartates and b-phen-
ylethyl-b-hydroxyaspartates were prepared and characterized.
These derivatives exhibited moderate inhibitory effects on gluta-
mate transport as evaluated by electrophysiological measurements
on cultured hippocampal neurons. Mekki et al. proposed two years
H2N
Figure 1. Structure of
L
-theanine (5-N-ethylglutamine).
⇑
Corresponding author. Tel.: +33 04 67 14 49 36; fax: +33 04 67 14 48 66.
E-mail address: Valerie.rolland@univ-montp2.fr (V. Rolland).
http://dx.doi.org/10.1016/j.tetasy.2014.03.016
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

F. Sebih et al. / Tetrahedron: Asymmetry 25 (2014) 690–696
691
O
P
R
R
OH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
H2N
H2N
H2N
R: COOH, NH2
H2N
R: H, Ph, Bn11
(2S,3S)- and (2S,3R)-
(2S,4R)-4-
11
3-methylglu 9
methylglu11
Figure 3. Some glutamic acid derivatives exhibiting biological activity on glutamatergic synapses.
ago a short, regiospecific and stereoselective synthesis of a new
-b-threo-benzyl-b-hydroxyaspartate (Fig. 2).7 This new target
mimics both the inhibitory EAATs effect of both -b-threo-OH-Asp
and of -b-threo-benzyl-Asp which are the most potent synthetic
2. Results and discussion
L
L
The direct C4 alkylation of glutamines has not been described in
the literature and alkylation with different alkylating reagents on
L
EAATs blockers known to date.8 The key step is a regiospecific
and stereoselective Sharpless asymmetric aminohydroxylation
(SAA) reaction on previously synthesized benzyl fumarate.7
The C3 or C4 alkylated glutamate analogue derivatives were also
studied as EAAT blockers. Wehbe et al.9 described a short four-step
synthesis of (2S,3R)- and (2S,3S)-3-methyl glutamic acids: the
Schiff base of tert-butyl glycinate and the inexpensive chiral auxil-
iary (2R,3R,4R)-2-hydroxypinan-3-one (HP) reacted with ethylcrot-
onate via an asymmetric Michael addition and led to both
diastereoisomers (dr 56:44), which were easily separated by pre-
parative HPLC. The biological activity of the glutamate transport
blocker was evaluated by recording spontaneous excitatory trans-
missions, which showed that (2S,3R)-3-methyl glutamic acid
exhibited important inhibitory effects on the glutamate transport
(Fig. 3).9
correctly protected L
-theanine did not succeed. Del Bosco et al.12
described a C4 alkylation using (S) protected glutamate as starting
material. The alkylation reaction of the lithium enolate of Z-Glu(O-
Me)OtBu with methyl iodide led to two diastereoisomers with a
3:1 ratio and 21% yield. Alkylation of the lithium enolate of
Z-Glu(OMe)OtBu with benzyl bromide led to a single stereoisomer
but in only 28% yield.
Considering that for the synthesis of theanine derivatives the
last step is an amidification reaction on the lateral chain under
basic conditions, the N and C protecting groups have to be stable.
Alkylation of the lithium enolate of Z-Glu(OtBu)OBn with benzyl
bromide or methyl bromide using Bosco’s experimental conditions
was unsuccessful because of the high steric hindrance of the tert-
butyl protecting group compared to the methyl group, which led
to Z-Glu(OtBu)OBn being completely recovered.
One of the most studied inhibitors of glutamate transport is
(2S,4R)-4-methylglutamic acid. Vandenberg et al. proved the real
influence of the nature of the chemical group at the C4 position.10
Ten years ago Wehbe et al. described the enantioselective synthe-
sis of new 4-substituted glutamic acid derivatives with an acidic
(carboxylic or phosphinic acid) or basic (amine) function. Some
of them have moderate activity on glutamate transport.11
In continuation of our interests to find new tools for glutama-
tergic synapse studies, especially with regards to the positive mod-
As described by Taver et al.,
chosen as the starting product.13 The C-protecting group was first
a benzyl ester ( -Pyr-OBn). The stereoselective methylation using
L-pyroglutamic acid (L-Pyr-OH) was
L
LiHMDS and methyl triflate proceeded with a cis–trans ratio of
1:4 in 34% yield over two steps. However, the lithium hydroxide
ring opening did not proceed as well as planned and the benzyl
ester was hydrolysed. A modification of the protecting group
scheme was required and in our approach for the synthesis of thea-
nine derivatives (Scheme 1), we investigated the use of a tert-butyl
group instead of a benzyl moiety and we realized protection of
commercially available (S)-pyroglutamate in (S)-N-Boc-Pyr-OtBu 1.
The key step was the alkylation reaction with methyl bromide,
the alkylation step was carried out with a yield of 52% and led to
dialkylation on C2 and C4 (Y = 15%) and a diastereomeric mixture
(dr = 59:41) with C4 alkylation (Y = 37%), evaluated by LCMS anal-
ysis and 1H NMR characterization of the crude mixture. The low
steric hindrance of methylbromide had an impact on the regiose-
lectivity and stereoselectivity. The overall yield of the alkylation
was higher than those reported by Del Bosco et al. due to the addi-
tion of HMPA (hexamethylphosphoramide) forming favourable
aggregates.
ulator effects of
apply our expertise in stereoselective syntheses to obtain C4 alkyl-
ated -theanine derivatives. Synthetic - and -theanine and - and
-5-N-propylglutamine have been previously synthesized by
L-theanine on NMDA receptors, we decided to
L
L
D
L
D
MAOS in an inexpensive and environmentally friendly method
and these synthetic compounds were tested for their potential bio-
logical activity on cultured brain cells. The agonistic effect of syn-
thetic
L-theanine on NMDA receptors has been verified and
confirmed on cultured hippocampal neurons by measuring the
intracellular calcium changes with fura 2. The preliminary results
indicate that enantiomerically pure
and -theanine displayed greater positive modulator effects on
NMDA-mediated responses than -theanine and were not blockers
L- and D-5-N-propylglutamine
D
L
With benzyl bromide, the alkylation step of the corresponding
of glutamate transport transport (Fig. 4).
protected compound
1 led to C4-benzyl derivatives (2S,4R)-
4-benzyl-di-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate 2a,
(2S,4R)-4-(4-isopropylbenzyl)-di-tert-butyl 5-oxopyrrolidine-1,2-
dicarboxylate 2b and (2S,4R)-4-(4-tert-butylbenzyl)-di-tert-butyl
5-oxopyrrolidine-1,2-dicarboxylate 2c with total stereospecificity
(de >99%): in each case only one stereoisomer was isolated. The
moderate yields (44–58%) were evaluated after separation by
silica gel column chromatography. Even if moderate yields were
observed, (S)-N-Boc-Pyr-OtBu 1 was easily recovered without
any degradation or other protecting group hydrolysis.
R
H
N
H
N
C
C
O
O
H2N
COOH
H2N
COOH
L-5-N-propylglutamine
C4-sustituted L-theanine
derivatives
The (2S,4R)-configuration of compound 2a was confirmed by
X-ray structure determination (Fig. 5) after recrystallization from
an AcOEt/cyclohexane solvent system.
Figure 4. New derivatives of L-theanine: potential NMDA receptors agonist or co-
agonist.

692
F. Sebih et al. / Tetrahedron: Asymmetry 25 (2014) 690–696
R
R
c
2
a, b
O
O
4
COOH
2
4
N
N
tBu
Boc
CO2
(2S,4R)
BocHN
Boc
CO2tBu
CO2tBu
(2R,4S)
1
2
2a:
2b:
2c:
3
(S)-N-Boc-Pyr-OtBu
R = H Y = 58%
R = iPr Y = 52%
R = tBu Y = 44%
3a:
3b:
3c:
R = H Y = 98%
R = iPr Y = 96%
R = tBu Y = 94%
d
R
R
e
4
4
NH
NH
2
2
O
O
H2N
BocHN
CO2tBu
CO2H
4
(2S,4R)
5
(2S,4R)
4a: R = H Y = 98%
4b: R = iPr Y = 96%
4c: R = tBu Y = 94%
5a: R = H Y = 99%
5b: R = iPr Y = 99%
5c: R = tBu Y = 99%
Scheme 1. General plan for the synthesis of enantiomerically pure C4-benzyl
L-theanine derivatives from (S)-N-Boc-Pyr-OtBu, 1. Reagent and conditions: (a) LiHMDS, HMPA,
THF, ꢀ78 °C, 45 min then (b) 4-RBnBr, THF, ꢀ78 °C, 1 h ; (c) LiOH/THF/H2O, ꢀ10 °C, 1 h; (d) EtNH2, BOP, TEA, THF, rt, 1 h; (e) TFA, DCM, rt, 90 min.
The following step was the ring opening. In the literature, when
a pyrrolidone carboxylic acid or pyroglutamic acid is treated with
10 equiv of 33% aqueous solution of ethylamine EtNH2 for 20 days
at 37 °C in a sealed glass tube, the L-theanine is obtained in only 9%
yield.14 Yan et al. described lactam ring opening directly by EtNH2
applying an enzymatic method with theanine synthetase. An equi-
librium between
did not exceed 20% of
L
-Glu and
L-theanine was observed and the yield
L
-theanine after 7 days.15
In order to increase the yield and decrease the reaction time, we
carried out the ring opening under basic conditions (NaOH or LiOH)
while taking care of protecting group preservation, which was then
followed by amide bond formation with EtNH2 (Scheme 1). After
ring opening according to IUPAC rules, C4-benzylated pyrogluta-
mates starting compounds became C2-benzylated-5-oxopentanoic
acids 3a, 3b and 3c.
With NaOH or LiOH at RT, the tert-butyl ester was partially
hydrolysed. The ring opening was optimized by separately stirring
compounds 2a, 2b and, 2c at ꢀ10 °C over 10 min with an aqueous
solution of LiOH (2 equiv) and THF and by increasing the
temperature to ꢀ5 °C. The ring opening was followed by HPLC
analysis and CCM. Compounds (2R,4S)-2-benzyl-5-(tert-butoxy)-4-
((tert-butoxycarbonyl)amino)-5-oxopentanoic acid 3a, (2R,4S)-2-(4-
isopropylbenzyl)-5-tert-butoxy-4-((tert-butoxycarbonyl)amino)-
5-oxopentanoic acid 3b, and (2R,4S)-2-(4-tert-butylbenzyl)-
5-tert-butoxy-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid
3c were obtained in 94–98% yield as colourless oils.
The amide bond formation was carried out in THF with a
commercially available anhydrous solution of ethylamine in THF,
using classic activation by BOP reagent [(benzotriazol-1-yloxy)tris
(dimethylamino)phosphonium hexafluorophosphate] and triethyl-
amine as the base. Compounds 4a, 4b and 4c were obtained
quantitatively after 1 h of stirring at rt. Finally, the N-Boc and OtBu
protecting groups were removed by TFA in THF; the C4 benzylated
Figure 5. Ortep diagram of compound (2S,4R)-2a. Thermal ellipsoïds are shown at
50% probability level.
The specific rotation measurements of enantiomerically pure
2a, 2b and 2c were calculated as references. High resolution
NMR spectral analyses (600 MHz) were compared with those in
the literature for similar compounds (Table 1).11
For H6a and H6b, the dihedral angle was determined exactly
from X-ray analysis but in solution this value was not significant
because of possible rotational conformations.
The enantiomeric excess of 2a, 2b and 2c were was confirmed
by chiral HPLC on two different columns: Chiralcel OD-RH column
in water/acetonitrile as the solvent system and on a Chiralpak AD-
H column in hexane/isopropanol as the solvent system.
The regiospecificity and stereospecificity at C4 were induced by
the (S)-configuration of C2, while the high steric hindrance of
different benzyl bromide alkylating reagents helped the N-Boc
and OtBu protecting groups to behave as facial discriminators as
shown in Scheme 2.
L-theanine derivatives 5a, 5b and 5c were obtained as white solids
in very good yields.
As described in the introduction, preliminary results indicated
that enantiomerically pure
-theanine displayed greater positive modulator effects on
NMDA-mediated responses than -theanine and interestingly were
L- and D-c-N-propylglutamine and
Compounds 2b and 2c did not crystallize but by using high res-
olution 1H NMR analyses (600 MHz), we were able to confirm an
(R)-absolute configuration for C4.
D
L

F. Sebih et al. / Tetrahedron: Asymmetry 25 (2014) 690–696
693
Table 1
Chemical shifts (ppm/TMS) and coupling constants (Hz) of compounds 2a (2S,4R) compared with those of 17b11
Ha Hb
O
Ha
Hb
O
H
O
H
6
4
3
H2N
N
4
3
Ha
Hb
Ha
2
NH
2
O
O
Hb
O
H
H
O
HO
17b11
(2S,4R)-2a
ppm (CD3OD) 17b11
(2S,4S)-
2a
ppm (CDCl3) 2a
coupling constants (Hz)
17b11
Dihedral angle 2a
Dihedral angle 17b11
d (H2)
d (H3a
d (H3b
4.27
2.01
1.96
4.257
2.282
2.534
3J (H2-H3a
)
)
2.1
9.2
—
13.2
11.2
8.9
9,3
4.3
14
1.7
9.5
<0.5
13.3
10.5
8.6
24.06
96.72
19.0
101.0
)
)
3J (H2-H3b
4J (H2-H4)
2J (H3a-H3b
3J (H3a-H4)
3J (H3b-H4)
)
d (H4)
2.91
2.872
149.22
28.42
169.54
63.0
145.0
24.0
d (H6a
)
3.26
2.68
3.233
3.135
3J (H4-H6a
)
8.3
6.9
d (H6b
)
3J (H4-H6b
)
2J (H6a-H6b
)
R
Br
O
R
H
H
O
O
O
O
, Li
O
N
N
O
O
O
O
Scheme 2. Stereospecific alkylation of the lithium enolate of (S)-N-Boc-Pyr-OtBu, 1.
not blockers of glutamate transport. The evaluation of the potential
biological activity of C4-benzylated -theanine derivatives 5a, 5b
and 5c is currently underway by measuring spontaneous synaptic
transmissions on the intracellular calcium concentration ([Ca2+]i)
of cultured hippocampal neurons with fura-2.16
and other major peaks being reported. LC–MS identification was
by electrospray on HPLC Waters Alliance 2690. Flash chromatogra-
phy was carried out using E-Merck Silica Gel (Kieselgel 60, 230–
400 mesh) as the stationary phase. Thin layer chromatography
was carried out on aluminium plates pre-coated with Merck Silica-
gel 60F254 and were visualized by quenching of Ultra-Violet fluo-
rescence, or by staining with a 10% methanol phosphomolybdic
acid solution followed by heating. Analytic HPLC were was
performed on a Waters apparatus 717 plus autosampler with Mil-
L
3. Conclusion
A
concise, asymmetric synthesis of enantiomerically pure
C4-alkylated -theanine derivatives as new co-agonists of NMDA
receptors has been discussed. The key step is a stereospecific alkyl-
ation on a protected -pyroglutamate. The lactam ring opening pro-
lenium32 program on SymmetryShield™ RP18 3.5
l
m 2.1 ꢁ 20 mm
L
column and using linear gradient of ACN in H2O with 0.1% TFA in
5 min with 3 mL/min flow. Analytical chiral HPLC experiments
were performed on a unit composed of a Merck D-7000 system
manager, Merck-Lachrom L-7100 pump, Merck-Lachrom L-7360
oven, Merck-Lachrom L-7400 UV-detector and Jasco OR-1590
polarimeter using Beckman Coulter System Gold 126 Solvent Mod-
ule HPLC machine with column Chiralcel OD-RH (250 ꢁ 4.6 mm)
and water/acetonitrile solvent system or with Chiralpak AD-H
(250 ꢁ 4.6 mm) and hexane/isopropanol solvent system. Both col-
umns are from Chiral Technologies Europe (Illkirch, France). Opti-
cal rotations were determined on a Perkin–Elmer 341 polarimeter
in an appropriate solvent (20 °C, sodium ray). THF was distilled
from sodium/benzophenone ketyl. Reagents were supplied from
commercial sources (ALDRICH, FLUKA).
L
cedure has also been optimized. We have confirmed the
stereochemistry of C4 by X ray analysis, 1H NMR (600 MHz) and
chiral HPLC data. This approach may be considered as a promising,
short and efficient strategy to develop new tools, and to evaluate
their impact on glutamatergic transmission in the central nervous
system.
4. Experimental
4.1. General
Melting points were obtained using a Büchi 510 capillary appa-
ratus and are uncorrected. 1H NMR spectra were recorded at
300 MHz and 75 MHz using a Brüker AC300 instruments, at 600
MHz using a Brüker AC600 instrument. Chemical shifts are quoted
in parts per million and are referenced to the residual solvent peak.
The following abbreviations are used: s, singlet; d, doublet; t, trip-
let; q, quartet; m, multiplet. Coupling constants are reported in
Hertz (Hz). High resolution mass spectra (HRMS) were recorded
on micromass electrospray instruments with only molecular ion
4.2. Synthesis of (2S,4R)-4-benzyl-di-tert-butyl-5-oxopyrro
lidine-1,2-dicarboxylate 2: general procedure for the alkylation
of (S)-N-Boc-Pyr-OtBu
A mixture of (S)-di-tert-butyl-5-oxopyrrolidine-1,2-dicarboxyl-
ate [(S)-N-Boc-Pyr-OtBu] 1 (1.2 g, 4.2 mmol) in anhydrous THF
(15 mL) was stirred under argon and cooled to ꢀ78 °C. A solution

694
F. Sebih et al. / Tetrahedron: Asymmetry 25 (2014) 690–696
of LiHMDS 1 M in anhydrous THF (3.6 mL, 5 mmol, 1.2 equiv) was
added dropwise under argon with a syringe, followed by HMPA
(1.28 mL, 5 mmol, 1.2 equiv). After 45 min of stirring, aryl bromide
(4.2 mmol, 1 equiv) was added dropwise with a syringe. After 1 h
at ꢀ78 °C, the reaction was quenched by the slow addition of sat-
urated NH4Cl at rt. The solution was extracted 3 times with AcOEt.
The combined organic layers were washed with water and brine,
dried over MgSO4 and concentrated under reduced pressure. The
crude products were purified by chromatography (silica gel,
EtOAc/cyclohexane, 1:4) and led to products 2a, 2b and 2c
(Scheme 1). The separated starting compound 1, (S) N-Boc-Pyr-
OtBu, as also recovered.
Rf = 0.58 (AcOEt/cyclohexane, 1:4). tR = 3.13 mn. ½a D20
¼ ꢀ2:9 (c
ꢂ
1.0 in CH2Cl2). MS (ES+) m/z 432.3 (M+H)+, 454.2 (M+Na)+, 332.3
(MH-Boc)+. 1H NMR (600 MHz, CDCl3) d (ppm) 4.34 (dd, 1H, H2,
3J(H2-H3a) = 2.1 Hz, 3J (H2-H3b) = 9.4 Hz), 3.22 (dd, 1H, H6a 3J (H4-
,
H
H
H
H
H
H
6a) = 9.1 Hz, 2J (H6a-H6b) = 14.2 Hz), 2.9 (dtd, 1H, H4, 3J (H4-
6b) = 4.3 Hz, 3J (H4-H6a) = 9.1 Hz, 3J(H4-H3b) = 8.8 Hz, 3J (H4-
3a) = 11.1 Hz), 2.65 (dd, 1H, H6b
3J (H4-H6b) = 4.3 Hz, 2J (H6b
6a) = 14.2 Hz), 2.04 (ddd, 1H, H3a
3J (H2-H3a) = 2.1 Hz, 3J (H4-
3a) = 11.1 Hz, 2J (H3a-H3b) = 13.3 Hz), 1.98 (ddd, 1H, H3b 3J (H2-
3b) = 9.4 Hz, 3J (H4-H3b) 8.8 Hz, 2J (H3a-H3b) = 13.3 Hz), 1.50 (s,
,
-
,
,
9H, NCO2C(CH3)3), 1.43 (s, 9H, CO2C(CH3)3), 1.3 (s, 9H, Ph-
C(CH3)3) 7.1–7.3 (2d, 4H, ArH, 3J= 8.2 Hz). 13C NMR (75 MHz, CDCl3)
dc (ppm) 27.91, 28.00, 31.32, 34.37, 35.79, 43.23, 57.72, 82.22,
83.22, 125.47, 128.62, 135.15, 149.40, 170.30, 174.60.
Chiralcel-OD-RH column; H2O/ACN (65:35), 1 mL/min, 30 min,
214 nm, tR = 12.43 min.
4.2.1. (2S,4R)-4-Benzyl-di-tert-butyl 5-oxopyrrolidine-1,2-dicar-
boxylate 2a
This compound was obtained as a white solid in 58% yield after
purification on silica gel chromatography. Compound 2a was
recrystallized from an AcOEt/cyclohexane mixture as the solvent
system (X-ray analysis: deposition numbers 984,810). De >99%.
Mp 75–79 °C; Rf = 0.3 (AcOEt/cyclohexane, 1:4). tR = 2.64 min.
Chiralpak AD-H column; hexane/isopropanol (95:5), 1 mL/min,
45 min, 214 nm, tR = 35.41 min.
4.3. Synthesis of C4-benzylated glutamate derivatives: general
procedure for the pyroglutamate ring opening
½
a 2D0
ꢂ
¼ ꢀ4:0 (c 1.0, CH2Cl2). MS (ES+) m/z 376.4 (M+H)+, 398.3
(M+Na)+, 276.3 (MH-Boc)+. 1H NMR (600 MHz, CDCl3): d (ppm)
4.27 (dd, 1H, H2, 3J (H2-H3a) = 2.1 Hz, 3J (H2-H3b) = 9.2 Hz), 3.26
Pure 2a, 2b and 2c (1 mmol, 1 equiv) were dissolved in an aque-
ous solution of LiOH (84 mg, 2 mmol, 2 equiv) with the minimum
amount of THF and were stirred at ꢀ10 °C for 10 min and then
for 1 h at ꢀ5 °C. The reaction was followed by HPLC until the dis-
appearance of compounds 2a, 2b or 2c. Compounds 3a, 3b or 3c
were extracted with AcOEt; the organic layers were washed 3
times with aq. citric acid, then with water. The organic layers were
dried over MgSO4 and concentrated under reduced pressure; com-
pounds 3a, 3b and 3c were obtained in 94–98% yields as colourless
oils.
(dd, 1H, H6a,
3J (H4-H6a) = 9.3 Hz, 2J (H6a-H6b) = 14.0 Hz), 2.91
(dtd, 1H, H4, 3J (H4-H6a) = 9.3 Hz, 3J (H4-H6b) = 4.3 Hz, 3J (H4-
H
H
H
3a) = 11.2 Hz, 3J (H4-H3b) = 8.9 Hz), 2.68 (dd, 1H, H6b
6b) = 4.3 Hz, 2J (H6a-H6b) = 14.0 Hz), 2.01 (ddd, 1H, H3a
,
3J (H4-
3J (H2-
,
3a) = 2.1 Hz, 3J (H3a-H4) = 11.2 Hz, 2J (H3a-H3b) = 13.2 Hz), 1.96
(ddd, 1H, H3b
,
3J (H3b-H2) = 9.2 Hz, 3J (H3b-H4) = 8.9 Hz, 2J (H3a
-
H
3b) = 13.2 Hz), 1.51 (s, 1H, NCO2C(CH3)3), 1.44 (s, 9H, CO2C(CH3)3),
7.17–7.29 (m, 5H, ArH). 13C NMR (75 MHz, CDCl3) dc (ppm) 27.57,
36.17, 43.26, 57.66, 82.10, 83.26, 126.38, 128.65, 129.03, 138.35,
149.35, 170.21, 174.43.
Chiralcel-OD-RH column; isocratic H2O/ACN (80:20), 1 mL/min,
30 min, 214 nm, tR = 21.18 min.
Chiralpak AD-H column; isocratic hexane/isopropanol (75:25),
1 mL/min, 45 min, 214 nm, tR = 32.67 min.
4.3.1. (2R,4S)-2-Benzyl-5-(tert-butoxy)-4-((tert-butoxy-carbonyl)-
amino)-5-oxopentanoic acid 3a
tR = 2.37 min. Rf = 0.43 (DCM/EtOH, 96:4). ½a D20
¼ ꢀ0:4 (c 1.0,
ꢂ
MeOH). MS (ES+) m/z 394.4 (M+H)+, 406.4 (M+Na)+, 294.4 (MH-
Boc)+. 1H NMR (300 MHz, MeOD) d (ppm) 4.0 (m, 1H, H4), 2.91
(m, 1H, H2), 2.79 (m, 2H, CH2-Ph), 2.10 (m, 1H, H3), 1.71 (m, 1H,
H3), 1.42 (s, 18H, NCO2C(CH3)3, CO2C(CH3)3). 7.16–7.25 (m, 5H,
ArH). 13C NMR (75 MHz, CDCl3) dc (ppm) 28.26, 28.77, 34.51,
39.79, 45.47, 54.33, 80.53, 82.74, 127.55, 129.47, 130.12, 140.24,
158.02, 173.35, 178.23.
4.2.2. (2S,4R)-4-(4-Isopropylbenzyl)-di-tert-butyl 5-oxopyrrol-
idine-1,2-dicarboxylate 2b
This compound was obtained as a white solid in 52% yield after
purification by silica gel chromatography. de>99%. Mp 62-65 °C.
Rf = 0.52 (AcOEt/cyclohexane, 1:4). tR = 3.02mn. ½a D20
¼ ꢀ3:4 (c
ꢂ
1.0, CH2Cl2). MS (ES+) m/z 418.3 (M+H)+, 440.3 (M+Na)+, 318.3
(MH-Boc)+. 1H NMR (600 MHz, CDCl3): d (ppm) 4.34 (dd, 1H, H2,
4.3.2. (2R,4S)-2-(4-Isopropylbenzyl)-5-tert-butoxy-4-((tert-but
3J (H2-H3a) = 2.1 Hz, 3J (H2-H3b) = 9.3 Hz), 3.22 (dd, 1H, H6a
,
3J (H4-
oxycarbonyl)amino)-5-oxopentanoic acid 3b
H
6a) = 9.4 Hz, 2J (H6a-H6b) = 14.1 Hz), 2.9 (m, 1H, (CH3)2-CH-Ph,
3J = 6.9 Hz), 2.87 (dtd, 1H, H4, 3J (H4-H6b) = 4.3 Hz, 3J (H4-
6a) = 9.4 Hz, 3J (H4-H3b) = 8.8 Hz, 3J (H4-H3a) = 11.1 Hz), 2.65 (dd,
1H, H6b
3J (H4-H6b) = 4.3 Hz, 2J (H6b-H6a) = 14.0 Hz), 2.03 (ddd,
1H, H3a
3J (H2-H3a) = 2.1 Hz, 3J (H4-H3a) = 11.1 Hz, 2J (H3a
3b) = 13.3 Hz), 1.97 (ddd, 1H, H3b
3J (H2-H3b) = 9.3 Hz, 3J (H4-
3b) = 8.8 Hz, 2J(H3a-H3b) = 13.3 Hz), 1.51 (s, 9H, NCO2C(CH3)3),
tR = 2.72 min. Rf = 0.29 (DCM/EtOH, 98:2). ½a D20
¼ ꢀ0:3 (c 1.0,
ꢂ
MeOH). MS (ES+) m/z 436.4 (M+H)+, 458.3 (M+Na)+, 336.2 (MH-
Boc)+. 1H NMR (300 MHz, MeOD) d (ppm) 4.03 (m, 1H, H4), 2.85
(m, 2H, H2 and CH(CH3)2), 2.75 (m, 2H, CH2-Ph), 2.11 (m, 1H,
H
,
,
-
H3a), 1.73 (m, 1H, H3b), 1.42 (s, 18H, NCO2C(CH3)3, CO2C(CH3)3),
H
H
,
1.22 (d, 6H, CH(CH3)2, 3J = 6.9 Hz), 7.17–7.21 (2d, 4H, ArH,
3J = 7.9 Hz). 13C NMR (75 MHz, CDCl3) dc (ppm) 24.60, 28.34,
28.84, 34.39, 35.05, 39.42, 45.47, 54.34, 80.54, 82.24, 127.49,
130.14, 137.54, 148.24, 157.96, 173.32, 178.41.
1.44 (s, 9H, CO2C(CH3)3), 1.23 (d, 6H, (CH3)2-CH-Ph, 3J = 6.9 Hz),
7.09-7.15 (2d, 4H, ArH, 3J = 8.1 Hz). 13C NMR (75 MHz, CDCl3) dc
(ppm) 23.99, 27.94, 33.68, 35.64, 43.32, 57.76, 82.25, 83.25,
126.66, 128.93, 135.55, 147.14, 149.43, 170.34, 174.64.
Chiralcel-OD-RH column; H2O/ACN (65:35), 1 mL/min, 30 min,
214 nm, tR = 14.87 min.
4.3.3. (2R,4S)-2-(4-tert-Butylbenzyl)-5-tert-butoxy-4-((tert-but
oxycarbonyl)amino)-5-oxopentanoic acid 3c
tR = 2.82 min. Rf = 0.35 (DCM/EtOH, 98:2). ½a D20
¼ ꢀ0:3 (c 1.0,
ꢂ
Chiralpak AD-H column; hexane/isopropanol (90:10), 1 mL/
min, 30 min, 214 nm, tR = 23.54 min.
MeOH). MS (ES+) m/z 450.4 (M+H)+, 472.3 (M+Na)+, 350.4
(MHꢀBoc)+. 1H NMR (300 MHz, MeOD) d (ppm) 4.02 (m, 1H, H4),
2.95 (m, 1H, H2), 2.75 (m, 2H, CH2-Ph), 2.10 (m, 1H, H3a), 1.90
(m, 1H, H3b), 1.43 (s, 18H, NCO2C(CH3)3, CO2C(CH3)3), 1.29 (s, 9H,
C(CH3)3), 7.13–7.36 (2d, H, ArH, 3J = 7.9 Hz). 13C NMR (75 MHz,
CDCl3) dc (ppm) 28.25, 28.64, 31.84, 34.29, 35.20, 45.35, 54.28,
80.01, 82.81, 126.33, 129.48, 136.71, 149.93, 173.10, 178.06.
4.2.3. (2S,4R)-4-(4-tert-Butylbenzyl)-di-tert-butyl 5-oxopyrrol-
idine-1,2-dicarboxylate 2c
This compound was obtained as a white solid in 44% yield after
purification by silica gel chromatography. de>99%. Mp 54–60 °C.

F. Sebih et al. / Tetrahedron: Asymmetry 25 (2014) 690–696
695
4.4. Synthesis of protected C4-benzylated
L
-theanine derivatives:
4.5. Synthesis of C4-benzylated
L-theanine derivatives: general
general procedure for the amide bond formation on N5
procedure for protecting group hydrolysis
Products 3a–c (200 mg, 1 equiv) were suspended in dry THF
(6 mL) under argon and stirred magnetically, after which the BOP
reagent (1.2 equiv), triethylamine TEA (3 equiv) and ethylamine
solution in anhydrous THF 2 M (1 equiv) were added. After 1 h at
room temperature, the THF was evaporated under vacuum and
the oily residue was dissolved in AcOEt, washed 3 times with aque-
ous citric acid solution (10%), 3 times with 1 M aqueous NaHCO3
solution, saturated NH4Cl solution and finally with water. The or-
ganic layer was dried over MgSO4, filtered and concentrated under
vacuum. Products 4a–c were obtained in quantitative yields as
white solids.
The enantiomerically pure N- and C-protected 4a–c (60 mg)
were added to a solution of TFA/DCM (4 mL, 2 M). Reactions were
stirred at room temperature. The protecting group hydrolysis was
followed by CCM and analytical HPLC. After 2 h, the reaction mix-
tures were concentrated under reduced pressure. The residues
were then washed with Et2O to afford products 5a–c as white sol-
ids in quantitative yields.
4.5.1. (2S,4R)-4-Benzyl-2-amino-5-(ethylamino)-5-oxopentanoic
acid or (2S,4R)-4-benzyl-theanine 5a
tR = 1.08 min. Rf = 0.16 (Et2O/AcOEt, 4/6). Mp 97–101 °C.
½
a 2D0
ꢂ
¼ þ1:3 (c 1.0, CD3OD). MS (ES+) m/z 265.3 (M+H)+, 287.3
(M+Na)+, 220.2 (M-CO2)+. 1H NMR (300 MHz, CD3OD) d (ppm);
3.9 (m, 1H, H2), 3.10 (m, 2H, CH2-Ph), 2.92 (m, 3H, CH3CH2NH,
H4), 2.33 (m, 1H, H3a), 1.96 (m, 1H, H3b), 0.97 (t, 3H, CH3CH2NH,
3J = 7.3 Hz) 7.26 (m, 5H, ArH). 13C NMR (75 MHz, CD3OD) dc
(ppm) 14.39, 33.68, 35.05, 39.24, 46.49, 52.48, 127.50, 129.34,
130.00, 139.73, 172.33, 175.73. HRMS calculated for C14H21N2O3
m/z (M+H)+ 265,1552; found 265.1548.
4.4.1. (2S,4R)-tert-Butyl-4-benzyl-2-((tert-butoxycarbonyl)
amino)-5-(ethylamino)-5-oxopentanoate or (2S,4R)-4-benzyl-
N-Boc-theanine tert-butyl ester 4a
tR = 2.32 min. Rf = 0.48 (cyclohexane/AcOEt, 6:4). Mp 75–79 °C.
½
a 2D0
ꢂ
¼ þ2:4 (c 1.0, CHCl3). MS (ES+) m/z 421.3 (M+H)+, 443.4
(M+Na)+, 321.3 (MH-Boc)+. 1H NMR (300 MHz, CDCl3) d (ppm);
6.63 (s, 1H, NHBoc), 5.12 (s, 1H, NH, CH3CH2NH), 4.12 (m, 1H,
H2), 3.22 (q, 2H, CH3CH2NH, 3J = 7.28 Hz), 3.00 (dd, 1H, CHaHb-Ph,
3J (H4-Ha) = 7.9 Hz, 2J (Ha-Hb) = 4.3 Hz), 2.60 (dd, 1H, CHaHb-Ph, 3J
(H4-Hb) = 13.48 Hz, 2J (Ha-Hb) = 4.3 Hz), 2.41 (m, 1H, H4), 2.17 (m,
1H, H3a), 1.59 (m, 1H, H3b), 1.42 (s, 18H, NCO2C(CH3)3, CO2C(CH3)3),
1.04 (d, 3H, CH3CH2NH, 3J = 7.2 Hz), 7.20 (m, 5H, ArH); 13C NMR
(75 MHz, CDCl3) dc (ppm) 14.63, 27.95, 28.28, 29.57, 34.24, 37.28,
38.52, 44.89, 52.59, 80.11, 82.10, 126.23, 128.36, 128.93, 139.63,
156.62, 171.46, 173.62.
4.5.2. (2S,4R)-4-(4-Iso-propylbenzyl)-2-amino-5-(ethylamino)-
5-oxopentanoic acid or (2S,4R)-4-(4-iso-propylbenzyl)-theanine
5b
tR = 1.58 min. Rf = 0.24 (Et2O/AcOEt, 4:6). Mp 82–87 °C
½
a 2D0
ꢂ
¼ þ1:1 (c 1.0, MeOH). MS (ES+) m/z 307.3 (M+H)+, 329.4
(M+Na)+, 262.3 (M-CO2)+. 1H NMR (300 MHz, MeOD) d (ppm)
3.76 (m, 1H, H2), 3.17 (m, 1H, CHaHb-Ph), 3.04 (m, 1H, CHaHb-Ph),
2.9 (m, 4H, CH3CH2NH, CH–(CH3)2, H4), 2.24 (m, 1H, H3a), 1.97
(m, 1H, H3b), 1.20 (d, 6H, CH–(CH3)2, 3J = 6.9 Hz), 0.89 (t, 3H CH3-
CH2NH, 3J = 7.25 Hz), 7.12–7.18 (m, 4H, ArH). 13C NMR (75 MHz,
CDCl3) dc (ppm) 13.87, 23.79, 33.68, 34.35, 34.43, 38.21, 46.22,
53.05, 126.67, 129.44, 136.78, 147.59, 173.12, 175.98. HRMS calcu-
lated for C17H27N2O3 m/z (M+H)+ 307,2022; found 307.2025.
4.4.2. (2S,4R)-tert-Butyl 4-(4-iso-propylbenzyl)-2-((tert-butoxy-
carbonyl)amino)-5-(ethylamino)-5-oxopentanoate or (2R,4S)-4-
(4-isopropylbenzyl)-N-Boc-theanine tert-butyl ester 4b
tR = 2.69 min. Rf = 0.61 (cyclohexane/AcOEt, 6:4). Mp 68–72 °C.
½
a 2D0
ꢂ
¼ þ2:3 (c 1.0, CHCl3). MS (ES+) m/z 463.5 (M+H)+, 485.4
(M+Na)+, 363.4 (MH-Boc)+. 1H NMR (300 MHz, CDCl3) d (ppm)
6.52 (m, 1H, NHBoc), 5.12 (m, 1H, CH3CH2NH), 4.13 (m, 1H, H2),
3.21 (q, 2H, CH3CH2NH, 3J = 7.28 Hz), 2.95 (dd, 1H, CHaHb-Ph, 3J
(H4-Ha) = 15.53 Hz, 2J (Ha-Hb) = 6.8 Hz), 2.84 (m, 1H, –CH–(CH3)2),
2.58 (dd, 1H, CHaHb-Ph, 3J (H4-Hb) = 13.37 Hz, 2J (Ha-Hb) = 6.8 Hz),
2.3 (m, 1H, H4), 2.17 (m, 1H, H3a), 1.59 (m, 1H, H3b), 1.42 (s, 18H,
NCO2C(CH3)3, CO2C(CH3)3), 1.22 (d, 6H, 3J = 6.9 Hz), 1.02 (t, 3H, CH3-
CH2NH, 3J = 7.28 Hz), 7.17–7.21 (2d, 4H, ArH, 3J = 7.9 Hz). 13C NMR
(75 MHz, CDCl3) dc (ppm) 14.63, 23.98, 24.05, 27.96, 33.7, 34.22,
45.18, 52.65, 80.06, 82.34 126.40, 128.82, 136.83, 146.77, 156.23,
171.54, 173.76.
4.5.3. (2S,4R)-4-(4-tert-Butylbenzyl)-2-amino-5-(ethylamino)-5-
oxopentanoic acid or (2S,4R)-4-(4-tert-butylbenzyl) theanine 5c
tR = 1.71 min. Rf = 0.27 (Et2O/AcOEt, 4/6). Mp 74–79 °C
½
a 2D0
ꢂ
¼ þ0:9 (c 1.0, CD3OD). MS (ES+) m/z 321.3 (M+H)+, 343.5
+
(M+Na)+, 276.3 (MH-CO2)
.
1H NMR (300 MHz, CDCl3) d (ppm)
3.75 (m, 1H, H2), 3.12 (m, 1H, CHaHb-Ph), 2.98 (m, 1H, CHaHb-Ph),
2.81 (m, 3H, CH3CH2NH, H4), 2.25 (m, 1H, H3a), 1.92 (m, 1H, H3b),
1.26 (s, 9H, C–(CH3)3), 0.87 (t, 3H, CH3CH2NH, 3J = 7.25 Hz), 7.10–
7.28 (2d, 4H, ArH, 3J = 8.17 Hz). 13C NMR (75 MHz, CDCl3) dc
(ppm) 14.66, 14.71, 31.87, 33.88, 35.21, 35.25, 39.28, 46.58,
52.57, 126.38, 129.89, 136.77, 150.60, 172.22, 175.94. HRMS calcu-
lated for C18H29N2O3 m/z (M+H)+ 321,2178; found 321.2174.
4.4.3. (2S,4R)-tert-Butyl 4-(4-tert-butylbenzyl)-2-((tert-butoxy-
carbonyl)amino)-5-(ethylamino)-5-oxopentanoate or (2R,4S)-4-
(4-tert-butylbenzyl)-N-Boc-theanine tert-butyl ester 4c
tR = 2.77 min. Rf = 0.67 (cyclohexane/AcOEt, 6:4). Mp 60–68 °C.
4.6. X-ray crystal-structure determination of 2a
Suitable crystals of 2a for X-ray diffraction studies were grown
in AcOEt/cyclohexane as a colourless prism. The crystals of 1
(C21H29NO5) are monoclinic. At 187 K, a = 9.30881(19) Å,
b = 10.5384(2) Å, c = 10.8965(2) Å, b = 104.491 (2)°, V = 1034.93
(4) Å3, Mr = 375.45, Z = 2, Space group P21, dcalcd = 1.205 g/cm3,
½
a 2D0
ꢂ
¼ þ2:2 (c 1.0, CHCl3). MS (ES+) m/z 477.5 (M+H)+, 499.5
(M+Na)+, 377.3 (MH-Boc)+. 1H NMR (300 MHz, CDCl3) d (ppm)
6.50 (m, 1H, NHBoc), 5.09 (m, 1H, CH3CH2NH), 4.09 (m, 1H, H2),
3.22 (q, 2H, CH3CH2NH, 3J = 7.24 Hz), 2.96 (dd, 1H, CHaHb-Ph,
3J(H4–Ha) = 15.58 Hz, 2J (Ha-Hb) = 7.9 Hz), 2.59 (dd, 1H, CHaHb-Ph,
3J (H4-Hb) = 13.74 Hz, 2J (Ha-Hb) = 7.9 Hz), 2.37 (m, 1H, H4), 2.20
(m, 1H, H3a), 1.57 (m, 1H, H3b), 1.43 (s, 9H, NCO2C(CH3)3), 1.41 (s,
9H, CO2C(CH3)3), 1.27 (s, 9H, C–(CH3)3), 1.02 (t, 3H CH3CH2NH,
3J = 7.24 Hz), 7.05–7.26 (2d, 4H, ArH, 3J = 8.18 Hz). 13C NMR
(75 MHz, CDCl3) dc (ppm) 14.63, 27.96, 28.30, 31.37, 34.21, 34.36,
36.89, 38.14, 45.29, 51.28, 80.05, 82.31, 125.26, 128.55, 136.33,
149.01, 156.98, 171.56, 173.75.
l
(Cu Ka
) = 0.70 mmꢀ1, F(000) = 404. Intensities of 19,131 reflec-
tions of which 3686 were unique (Rint = 0.052) were measured
with an Xcalibur, Sapphire 3, Gemini diffractometer (graphite
monochromated CuK
a radiation (k = 1.54184 Å), CCD-detector, x
scanning, 2Hmax = 67.8°).17 Data reduction was performed with
CrysAlisPro and an empirical absorption correction was applied.17
Equivalent reflections, other than Friedel pairs (1716, 97% cover-
age), were merged.

696
F. Sebih et al. / Tetrahedron: Asymmetry 25 (2014) 690–696
3. Yokogoshi, H.; Kato, Y.; Sagesaka, Y.; Matsuura, T.; Kakuda, T.; Takeuchi, N.
The structures were solved by ab initio (charge-flipping) meth-
Biosci., Biotechnol., Biochem. 1995, 59, 615–618.
ods using SUPERFLIP18 and refined using SHELXL.19 H atoms were
treated by a mixture of independent and constrained refinement.
The carbon of the phenyl from the benzyl residue was disordered
over two positions, which were used during the refinement. A view
of the molecule is shown in Figure 5. Full-matrix least-squares
refinement against F2 in anisotropic approximation for non-hydro-
gen atoms was converged to wR2 = 0.112 for 3686 reflections
4. Kim, N. H.; Jeong, H. J.; Kim, H. M. Amino Acids 2012, 42, 1609–1618.
5. Yamada, T.; Terashima, T.; Kawano, S.; Furuno, R.; Okubo, T.; Juneja, L. R.;
Yokogoshi, H. Amino Acids 2009, 36, 21–27.
6. Wehbe, J.; Kassem, T.; Rolland, V.; Rolland, M.; Tabcheh, M.; Roumestant, M. L.;
Martinez, J. Org. Biomol. Chem. 2003, 1, 1938–1942.
7. a Mekki, S.; Bellahouel, S.; Vanthuyne, N.; Rolland, M.; Derdour, A.; Martinez, J.;
Rolland, V. Tetrahedron: Asymmetry 2012, 23, 94–99; b Mekki, S.; Rolland, V.;
Bellahouel, S.; Van der Lee, A.; Rolland, M. Acta Crystallogr. 2011, C67, o301–
o305.
8. Esslinger, C. S.; Agarwal, S.; Gerdes, J.; Wilson, P. A.; Davis, E. S.; Awes, A. N.;
O’Brien, E.; Mavencamp, T.; Koch, H. P.; Poulsen, D. J.; Rhoderick, J. F.;
Chamberlin, A. R.; Kavanaugh, M. P.; Bridges, R. J. Neuropharmacology 2005, 49,
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9. Wehbe, J.; Rolland, V.; Roumestant, M. L.; Martinez, J. Tetrahedron: Asymmetry
2003, 14, 1123–1126.
10. Vandenberg, R. J.; Mitrovic, A. D.; Chebib, M.; Balcar, V. J.; Johnston, G. A. R. Mol.
Pharmacol. 1997, 51, 809.
11. Wehbe, J.; Rolland, V.; Fruchier, A.; Roumestant, M. L.; Martinez, J. Tetrahedron:
Asymmetry 2004, 15, 851–858.
12. Del Bosco, M.; Johnstone, A. N. C.; Bazza, G.; Lopatriello, S.; North, M.
Tetrahedron 1995, 51, 8545–8554.
(R1 = 0.043 for 3529 reflections with F2 > 2 (F2), S = 1.05). Refine-
r
ment of the absolute structure Flack parameter yielded a value of
ꢀ0.04(13),20 while the Hooft analysis21 gave the absolute parame-
ter y = 0.07(9), P2(true) = 1.000 and P3(true) = 1.000, which con-
firmed that the refined coordinates represent the true
enantiomorph as the Parson parameter z = 0.08(8). Final atomic
coordinates, geometrical parameters and crystallographic data
have been deposited with the Cambridge Crystallographic Data
Centre, 11 Union Road, Cambridge CB2 1EZ, UK (E-mail: depos-
it@ccdc.cam.ac.uk; fax: +44 1223 336033) and are available upon
request by quoting the deposition numbers 984,810 for 2a.
13. Tarver, J. E., Jr.; Terranova, K. M.; Joullie, M. M. Tetrahedron 2004, 60, 10277–
10284.
14. Lichtenstein, N. J. Am. Chem. Soc. 1942, 64, 1021–1022.
15. Yan, S. H.; Dufour, J. P.; Meurens, M. J. Tea Sci. 2003, 23, 99–104.
16. Crouzin, N.; de Jesus Ferreira, M. C.; Cohen-Solal, C.; Aimar, R. F.; Vignes, M.;
Guiramand, J. Free Radical Biol. Med. 2007, 42(9), 1326–1337.
17. CrysAlisPro, Version 1.171.35.21; Agilent Technologies: Yarnton, Oxfordshire,
England, 2012.
18. a Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786–790; b Palatinus, L.;
Van der Lee, A. J. Appl. Crystallogr. 2008, 41, 975–984; c Palatinus, L.; Prathapa,
S. J.; van Smaalen, S. J. Appl. Crystallogr. 2012, 45, 575–580.
19. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
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Acknowledgments
This work was supported by Erasmus Mundus Averroes pro-
gram fellowship and international convention between CNRS and
Algerian’DGRFP.
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