Primary amine-thioureas with improved catalytic properties for "difficult" Michael reactions: Efficient organocatalytic syntheses of (S)-baclofen, (R)-baclofen and (S)-phenibut

Article abstract of DOI:10.1002/adsc.201100636

Among the class of primary amine-thioureas based on tert-butyl esters of α-amino acids, the most efficient organocatalyst for "difficult" Michael reactions was identified. The derivative based on (S)-di-tert-butyl aspartate and (1R,2R)-diphenylethylenedia

Full text of DOI:10.1002/adsc.201100636

UPDATES
DOI: 10.1002/adsc.201100636
Primary Amine-Thioureas with Improved Catalytic Properties
for “Difficult” Michael Reactions: Efficient Organocatalytic
Syntheses of (S)-Baclofen, (R)-Baclofen and (S)-Phenibut
Michail Tsakos,a Christoforos G. Kokotos,a and George Kokotosa,*
a
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771,
Greece
Fax : (+30)-210-727-4761; phone: (+30)-210-727-4462; e-mail: gkokotos@chem.uoa.gr
Received: August 9, 2011; Revised: October 28, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100636.
Abstract: Among the class of primary amine-thiour-
eas based on tert-butyl esters of a-amino acids, the
most efficient organocatalyst for “difficult” Michael
reactions was identified. The derivative based on
(S)-di-tert-butyl aspartate and (1R,2R)-diphenyl-
ACHTUNGTRENNUNGethylenediamine provided the products of the reac-
tion between aryl methyl ketones and nitroolefins
in excellent yields and enantioselectivities. In addi-
tion, this new catalyst can be used at low catalyst
loading (5 mol%). The utility of this methodology
was highlighted by the efficient synthesis of (S)-ba-
clofen, (R)-baclofen and (S)-phenibut.
Figure 1. Efficient organocatalysts for “difficult” Michael re-
actions.
Keywords: amino acids; Michael addition; nitroole-
fins; organocatalysis; thioureas
reported to catalyze efficiently the Michael reaction
between aromatic ketones and nitroolefins. Jacobsenꢀs
thiourea 1 (Figure 1),[7] Tsogoevaꢀs thiourea 2,[8] Maꢀs
thiourea 3 based on sacharide[9] and thiourea 4 devel-
oped by Xu and co-workers[10] were among the most
succesful examples, along with thiourea 5 developed
by us (Figure 3).[11] In the present work, we would
Introduction
Organocatalysis now constitutes an established and like to present our recent findings on the study of the
powerful methodology in asymmetric organic synthe- structural features that are required in the catalystꢀs
sis.[1,2] Although a large number of organic transfor- structure in order to possess increased reactivity and
mations have been accomplished utilizing organoca- deliver increased selectivities.
talysis, there are only three most commonly used
modes of activation: enamine activation, iminium ion
activation and activation through hydrogen bonding.[3] Results and Discussion
Molecules that combine a primary amine with a thio-
urea functionality have emerged as very powerful or- The mode of dual activation by a thiourea organoca-
ganocatalysts.[4] One of the key organic transforma- talyst is illustrated in Figure 2. Based on our previous
tions that is catalyzed by this class of organocatalysts experience in organocatalysis,[12] we showed that two
is the “difficult” Michael reaction between aromatic chiral building units on a thiourea are necessary in
ketones and nitroolefins, since the asymmetric Mi- order that a catalyst can present high reactivity.[11,13]
chael reaction constitutes one of the most important In our earlier study,[11] the 1,2-diphenylethylene
À
À
processes for the synthesis of new C C and C X moiety and the bulky chiral backbone of an a-amino
bonds.[5,6] However, only few examples of chiral thio- acid were found to meet these criteria. However,
ureas containing a primary amino group have been when more than one asymmetric center coexists in
740
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 740 – 746

Primary Amine-Thioureas with Improved Catalytic Properties for “Difficult” Michael Reactions
Table 1. Michael reaction between acetophenone and trans-
b-nitrostyrene using various catalysts under the previously
optimized conditions.[a]
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
5[d]
6a[d]
6b[d]
6c[d]
6d[d]
7
8a
8b
9
68
32
51
27
37
100
98
22
–
À95
À77
À95
À96
À92
99
98
96
–
Figure 2. Dual activation of nucleophile and electrophile by
9
an organocatalyst.
10
11
10
7-ent
–
71
–
-99
[a]
Reaction conditions: catalyst (0.03 mmol), trans-b-nitro-
styrene (0.20 mmol) and acetophenone (2.00 mmol) in
CH2Cl2 (1.0 mL).
Isolated yield.
The enantiomeric excess (ee) was determined by chiral
[b]
[c]
HPLC.
[d]
Data from ref.[11]
diamine by (1R,2R)- diphenylethylenediamine, a quan-
titative yield and excellent selectivity were observed
(entry 6, Table 1). Directly attaching a phenyl group
instead of the aspartic acid side chain led to slightly
worse results (entry 7, Table 1). When the diphenyl-
ethylene moiety was replaced by the cyclohexyl
group, the ee remained high but the yield dropped sig-
nificantly (entry 8, Table 1). In order to prove that
both primary amine functionality and thiourea moiety
are required for the excellent catalytic reactivity, a ter-
tiary amine-thiourea 9 corresponding to the optimum
catalyst 7 as well as (1R,2R)-diphenylethylenediamine
10 were utilized as catalysts, however, no reaction
took place (entries 9 and 10, Table 1). The enantiomer
of 7 was also synthesized leading to the other enantio-
mer of the product in high yield and enantioselectivity
(entry 11, Table 1).
Figure 3. Organocatalysts utilized in this study.
the chiral units of the catalyst, a careful study of
Once the optimum catalyst was found, a screening
“match” and “mis-match” effects is necessary in order of the various reaction conditions took place
to identify the optimum combination of the configura- (Table 2). Chlorinated solvents and non-polar solvents
tion of stereogenic centers, which leads to optimum provided the best results (entries 1–8, Table 2). CHCl3
catalytic properties. Among the a-amino acids uti- afforded the product in quantitative yield and excel-
lized, (some of them, 5 and 6a–d are depicted in lent enantioselectivity (entry 2, Table 2), while the re-
Figure 3), catalyst 5 based on di-tert-butyl aspartate sults obtained in water are noteworthy (entry 8,
provided the best results (entry 1 vs. entries 2–5 in Table 2). Acid additives seem not to have an influ-
Table 1).[11] Although catalyst 5 provided the desired ence on the reaction outcome, although if water is
product in a good yield (68%) and the enantioselec- also added lower yields are obtained (entries 9–11,
tivity was high (95% ee), an improvement was still Table 2). The reaction can be performed at elevated
needed. Upon replacing the (1S,2S)-diphenylethylene- temperature and the ketone:nitrooelfin ratio can be
Adv. Synth. Catal. 2012, 354, 740 – 746
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
741

Michail Tsakos et al.
UPDATES
Table 2. Michael reaction between acetophenone and trans-
b-nitrostyrene using catalyst 7.[a]
Table 3. Michael reaction between aryl methyl ketones and
trans-b-nitrostyrene using catalyst 7.[a]
Entry Ketone
Reaction time Yield
[h]
ee
[%][b]
[%][c]
Entry
Conditions
Yield [%][b]
ee [%][c]
1
2
3
4
CH2Cl2
CHCl3
toluene
Et2O
100
100
98
>99
>99
>99
99
1
48
96
>99
>99
99
67
5
THF
–
–
6
7
EtOAc
DMSO
65
–
>99
–
2
72
72
72
96
72
80
89
73
74
82
8
9
H2O
85
>99
>99
>99
>99
>99
>99
99
CHCl3, PhCOOH
CHCl3, 4-NBA
CHCl3, PhCOOH, H2O
CHCl3
CHCl3
CHCl3
100
100
90
100
59[f]
100
98
10
11
12[d]
13[e]
14[d,g]
15[d,h]
16[d.i]
3
4[d]
>99
>99
99
CHCl3
CHCl3
>99
>99
96
[a]
Reaction conditions: catalyst (0.03 mmol), trans-b-nitro-
styrene (0.20 mmol) and acetophenone (2.00 mmol) in
CH2Cl2 (1.0 mL).
5
[b]
[c]
Isolated yield.
The enantiomeric excess (ee) was determined by chiral
HPLC.
Ketone:nitrostyrene 5:1.
6
[d]
[e]
[f]
Ketone:nitrostyrene 2:1.
7[d]
72
72
84
85
98
99
The reaction reaches completion after 96 h.
Reaction took place at 808C in a pressure vessel.
10 mol% catalyst was used.
[g]
[h]
[i]
5 mol% catalyst was used.
8
[a]
reduced with no significant loss in either the yield or
the selectivity (entries 12 and 14, Table 2). When the
ratio of ketone:nitrostyrene is reduced to 2:1, the re-
action is slower and needs prolonged reaction time to
reach completion (entry 13, Table 2). Furthermore,
the catalyst loading can be significantly reduced to
5 mol% (entry 16, Table 2). The scope and limitations
of the present methodology were also explored. A va-
riety of substituted aromatic methyl ketones was suc-
cessfully used under this protocol (Table 3). Electron-
Reaction conditions: catalyst (0.01 mmol), trans-b-nitro-
styrene (0.20 mmol) and acetophenone (1.00 mmol) in
CHCl3 (1.0 mL).
[b]
[c]
Isolated yield.
The enantiomeric excess (ee) was determined by chiral
HPLC.
10 mol% catalyst was used.
[d]
To further demonstrate the high enantiocontrol and
withdrawing groups, such as p-nitro and p-cyano, fur- reactivity that is provided by our new catalyst, a varie-
nished the desired product in high yields and excel- ty of substituted nitroolefins was used in the reaction
lent enantioselectivities (entries 2 and 3, Table 3). with either acetophenone or acetone (Table 4). It is
Halogen substituents such as p-fluoro and p-bromo, well established that such reactions suffer from de-
led also to high yields, although they required either creased yields in the case of acetophenone and low
higher catalyst loading (entry 4, Table 3), or longer re- enantioselectivities in the case of acetone.
action time (entry 5, Table 3). p-Acetoxyacetophe-
Like acetophenone, acetone afforded the product
none and p-hydroxyacetophenone were also well tol- in quantitative yield and excellent enantioselectivity
erated (entries 6 and 7, Table 3), while heterocyclic ar- (entries 1 and 2, Table 4). In some cases, when ace-
omatic moieties, like furyl, led to quantitative yield tone was employed, the yield was lower due to the
and high selectivity (entry 8, Table 3).
formation of the double Michael product. In order to
742
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 740 – 746

Primary Amine-Thioureas with Improved Catalytic Properties for “Difficult” Michael Reactions
Table 4. Michael reaction between ketones and nitroolefins
using catalyst 7.[a]
Entry R1 R2
Time [h] Yield [%][b] ee [%][c]
1
Ph Ph
Me Ph
Ph 4-MeOC6H4 72
Me 4-MeOC6H4 72
Ph 4-NO2C6H4 48
Me 4-NO2C6H4 48
Ph 4-FC6H4
Me 4-FC6H4
Ph 4-ClC6H4
48
48
96
96
98
91
96
85
99
91
99
92
87
99
82
94
79
76
96
>99
99
>99
99
99
94
>99
>99
>99
98
99
>99
99
2[d,e]
3
4[d,e]
5
6[d]
7
48
24
48
48
72
24
8
9
10[d,e] Me 4-ClC6H4
11
12
Ph 2-furyl
Me 2-furyl
13
Ph 3-NO2C6H4 96
Me 3-NO2C6H4 72
Ph 2-NO2C6H4 96
Ph 2-NO2C6H4 24
Me 2-NO2C6H4 72
14[d]
15
98
>99
99
Scheme 1. Organocatalyzted synthesis of (S)- and (R)-baclo-
fen.
16[f]
17[d]
99
injury or various neurological disorders.[14] The (R)-
enantiomer is an agonist of the GABAB receptor,
while the (S)-enantiomer is essentially inactive.[15]
Various syntheses starting from commercially avail-
able chiral materials or involving resolutions or syn-
theses based on biocatalytic transformations have
been reported.[16] The key-step involves the enantiose-
lective organocatalytic Michael addition between ace-
tophenone and nitroolefin 11. The use of primary
[a]
Reaction conditions: catalyst (0.01 mmol), nitroolefin
(0.20 mmol) and ketone (1.00 mmol) in CHCl3 (1.0 mL).
Isolated yield.
The enantiomeric excess (ee) was determined by chiral
HPLC.
10 mol% AcOH was used.
10 mol% catalyst was used.
The reaction took place at 808C in a pressure vessel.
[b]
[c]
[d]
[e]
[f]
avoid this side reaction, AcOH was added to the reac- amine thiourea 7 at 5 mol% catalyst loading delivered
tion mixture. When electron-donating substituents the Michael product in quantitative yield and excel-
were used, like p-methoxy, high yields can be ob- lent enantioselectivity. Using 7-ent the opposite enan-
tained in both the cases of acetophenone and acetone, tiomer was obtained in 71% yield and excellent enan-
accompanied by high enantioselectivities (entries 3 tioselectivity. Bayer–Villiger oxidation gave rise to
and 4, Table 4). The use of electron-withdrawing sub- a substituted g-nitro ester that can be transformed in
stituents on the nitroolefin afforded the desired prod- two steps into the desired (R)- or (S)-baclofen accord-
uct in good to high yields and always in high enantio- ing to published procedures.[16b] Another related
selectivities (entries 5–10, Table 4). Finally, nitroole- GABA-mimetic psychotropic drug, which is clinically
fins bearing heterocycles like furyl, were also well tol- used is phenibut.[17] Again, one of the two enantio-
erated (entries 11 and 12, Table 4). In order to expand mers is the biologically active one.[18] Using the model
the breadth of the substrate scope, meta- and ortho- reaction, the Michael product was delivered in excel-
substituted nitroolefins were employed (entries 13–17, lent yield and selectivity (Scheme 2). Bayer–Villiger
Table 4). Excellent yields and selectivities were ob- oxidation provided the corresponding g-nitro ester
tained, albeit in some cases prolonged reaction times that can furnish enantiopure phenibut by reported
were needed. It has to be highlighted that these pro- procedures.[19]
longed reaction times could be reduced, if the reac-
In order to account for the excellent stereoselectiv-
tion took place in a pressure vessel at 808C, without ity of the reaction, the following transition state is
any significant loss of the enantioselectivity (entry 16, proposed (Figure 4). The primary amine of the cata-
Table 4).
lyst activates the aromatic ketone through the forma-
The importance of this methodology is highlighted tion of an enamine. Unlike the enamine formed by
in the efficient synthesis of (S)- and (R)-baclofen a secondary amine, no secondary destabilizing inter-
(Scheme 1). Baclofen is an analogue of the neuro- actions are encountered.
transmitter g-aminobutyric acid which is used thera-
Simultaneously to the ketone activation, the hydro-
peutically to treat spasticity caused by spinal cord gen bonding between the thiourea moiety of the cata-
Adv. Synth. Catal. 2012, 354, 740 – 746
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
743

Michail Tsakos et al.
UPDATES
Figure 4. Proposed transition state of the Michael addition
of aryl methyl ketones to nitroolefins.
Scheme 2. Organocatalyzed synthesis of (S)-phenibut.
mation). The primary amine functionality of catalyst 5
is placed above the plane of the thiourea (Figure 5,
A), while the primary amine functionality of catalyst
lyst and the nitro group of the nitrostyrene is respon- 7 is placed below the plane of the thiourea (Figure 5,
sible for the electrophile activation, which guides the B). Thus, it is clear that the configuration of the di-
Michael addition just from the one face leading to
high enantiocontrol.
ACHTUNGTRENNUNG
The structures of catalysts 5 and 7 were minimized tiomer product and in the case of catalyst 7 to (S)-
using Maestro 9.1 Macromodel (see Supporting Infor- enantiomer. The minimized energy conformation of
Figure 5. Minimized energy conformations of: (A) catalyst 5, (B) catalyst 7, (C) intermediate enamine of catalyst 7 and (D)
superimposition of intermediate enamines of catalysts 5 and 7.
744
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 740 – 746

Primary Amine-Thioureas with Improved Catalytic Properties for “Difficult” Michael Reactions
2007, 46, 1570–1581; c) C. F. Barbas III, Angew. Chem.
the proposed intermediate enamine of catalyst 7 with
acetophenone as well as the superimposition of enam-
ines of catalysts 5 and 7 are illustrated in Figure 5, C
and D, respectively. In the case of enamine of catalyst
7, the phenyl ring of the (1R,2R)-diphenylethylenedi-
2008, 120, 44–50; Angew. Chem. Int. Ed. 2008, 47, 42–
47; d) A. Dondoni, A. Massi, Angew. Chem. 2008, 120,
4716–4739; Angew. Chem. Int. Ed. 2008, 47, 4638–4660;
e) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
Angew. Chem. 2008, 120, 6232–6265; Angew. Chem.
Int. Ed. 2008, 47, 6138–6171; f) X. Yu, W. Wang, Chem.
Asian J. 2008, 3, 516–532; g) A. Dondoni, A. Massi,
Angew. Chem. 2008, 120, 4716–4739; Angew. Chem.
Int. Ed. 2008, 47, 4638–4660; h) P. Melchiorre, M.
Marigo, A. Carlone, G. Bartoli, Angew. Chem. 2008,
120, 6232–6265; Angew. Chem. Int. Ed. 2008, 47, 6138–
6171; i) S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev.
2009, 38, 2178–2189; j) C. Zhong, X. Shi, Eur. J. Org.
Chem. 2010, 2999–3025; k) P. M. Pihko, I. Majander, A.
Erkkila, Top. Curr. Chem. 2009, 291, 29–75; l) J. B. Bra-
zier, N. C. O. Tomkinson, Top. Curr. Chem. 2009, 291,
281–347.
ACHTUNGTRENNUNGamine backbone seems to block efficiently the left
side of the thiourea moiety. It could be assumed that
this conformation locks the orientation of the nitroo-
lefin in such a way that the aryl group of the nitroole-
fin is away from the phenyl group of the diamine,
thus leading to higher levels of enantio-induction. In
the enamine of catalyst 5, the same phenyl group
from the catalystꢀs backbone seems to be far away,
thus not being able to produce such an efficient
blocking of the space, delivering lower levels of selec-
tivity.
[3] D. W. C. MacMillan, Nature 2008, 455, 304–308.
[4] For reviews on bifunctional organocatalysis, see:
a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743; b) P. S. Bhagury, B.-A. Song, S. Yang, D.-H.
Hu, W. Xue, Curr. Org. Synth. 2009, 6, 380–399; c) S. J.
Connon, Synlett 2009, 354–376; d) Z. Zhang, P. R.
Schreiner, Chem. Soc. Rev. 2009, 38, 1187–1198.
[5] For reviews on organocatalytic Michael reactions, see:
a) D. Almasi, D. A. Alonso, C. Najera, Tetrahedron:
Asymmetry 2007, 18, 299–365; b) S. B. Tsogoeva, Eur. J.
Org. Chem. 2007, 1701–1716; c) J. L. Vicario, D. Badia,
L. Carrillo, Synlett 2007, 2065–2092; d) S. Sulzer-Mosse,
A. Alexakis, Chem. Commun. 2007, 3123–3135.
[6] For selected examples of bifunctional thioureas catalyz-
ing asymmetric Michael reactions of ketones/aldehydes
with nitroolefins, see: a) M. P. Lalonde, Y. Chen, E. N.
Jacobsen, Angew. Chem. 2006, 118, 6514–6518; Angew.
Chem. Int. Ed. 2006, 45, 6366–6370; b) D. A. Yalalov,
S. B. Tsogoeva, S. Schwatz, Adv. Synth. Catal. 2006,
348, 826–832; c) T. Mandal, C.-G. Zhao, Angew. Chem.
2008, 120, 7828–7831; Angew. Chem. Int. Ed. 2008, 47,
7714–7717; d) H. Uehara, C. F. Barbas III, Angew.
Chem. 2009, 121, 10032–10036; Angew. Chem. Int. Ed.
2009, 48, 9848–9852; e) J.-R. Chen, Y.-J. Cao, Y.-Q.
Zhou, F. Tan, L. Fu, X.-Y. Zhu, W.-J. Xiao, Org.
Biomol. Chem. 2010, 8, 1275–1279; f) H. Uehara, R.
Imashiro, G. Hernandez-Torres, C. F. Barbas III, Proc.
Natl. Acad. Sci. USA 2010, 107, 20672–20677; g) D. B.
Ramachary, M. S. Prasad, R. Madhavachary, Org.
Biomol. Chem. 2011, 9, 2715–2721.
Conclusions
In conclusion, we have demonstrated that an easily
synthesized and low-cost primary amine-thiourea
based on (1R,2R)-1,2-diphenylethylenediamine and
(S)-di-tert-butyl aspartate is an excellent catalyst for
the “difficult” Michael reaction between aryl methyl
ketones and nitroolefins. The new catalyst may work
at low catalyst loading (5 mol%) providing the prod-
ucts in high to excellent yields and excellent enantio-
selectivities. The utility of this methodology was high-
lighted in the efficient synthesis of (S)- and (R)-baclo-
fen and (S)-phenibut.
Experimental Section
General Procedure for the Michael Reaction of
Ketones with Nitroolefins
A solution of catalyst 7 (5 mg, 0.01 mmol), nitroolefin
(0.2 mmol) and ketone (1 mmol) in chloroform (1 mL) was
stirred for the stated time. The solvent was evaporated and
the crude product was purified using flash column chroma-
tography eluting with the appropriate mixture of petroleum
ether (40–608C)/EtOAc to afford the desired product.
[7] H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128,
7170–7171.
[8] S. B. Tsogoeva, S. Wei, Chem. Commun. 2006, 1451–
1453.
[9] K. Liu, H.-F. Cui, J. Nie, K.-Y. Dong, X.-J. Li, J.-A. Ma,
Org. Lett. 2007, 9, 923–925.
[10] B.-L. Li, Y.-F. Wang, S.-P. Luo, A. G. Zhang, Z.-B. Li,
X.-H. Bu, D.-Q. Xu, Eur. J. Org. Chem. 2010, 656–662.
[11] C. G. Kokotos, G. Kokotos, Adv. Synth. Catal. 2009,
351, 1355–1362.
References
[1] For books, see: a) A. Berkessel, H. Grçger, in: Asym-
metric Organocatalysis – From Biomimetic Concepts to
Powerful Methods for Asymmetric Synthesis, (Ed.: A.
Berkessel) Wiley-VCH, Weinheim, 2005; b) P. I. Dalko,
in: Enantioselective Organocatalysis Reactions and Ex-
perimental Procedure, (Ed.: P. I. Dalko), Wiley-VCH,
Weinheim, 2007.
[12] a) E. Bellis, G. Kokotos, Tetrahedron 2005, 61, 8669–
8676; b) E. Bellis, G. Kokotos, J. Mol. Catal. A 2005,
241, 166–174; c) E. Bellis, K. Vasilatou, G. Kokotos,
Synthesis 2005, 2407–2413; d) E. Tsandi, C. G. Kokotos,
[2] For selected reviews, see: a) S. Mukherjee, J. W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569;
b) D. Enders, C. Grondal, M. R. M. Huttl, Angew.
Chem. 2007, 119, 1590–1601; Angew. Chem. Int. Ed.
Adv. Synth. Catal. 2012, 354, 740 – 746
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
745

Michail Tsakos et al.
UPDATES
S. Kousidou, V. Ragoussis, G. Kokotos, Tetrahedron
2009, 65, 1444–1449; e) E. Barbayianni, P. Bouzi, V.
Constantinou-Kokotou, V. Ragoussis, G. Kokotos, Het-
erocycles 2009, 78, 1243–1252.
[15] a) J. S. Kroin, Clin. Pharmacokinet. 1992, 22, 319–326;
b) J. Sawynok, C. Dickson, Prog. Neuro-Psychopharma-
col. Biol. Psychiatry 1984, 8, 729–731.
[16] For selected examples, see: a) O. Belda, S. Lundgren,
C. Moberg, Org. Lett. 2003, 5, 2275–2278; b) E. J.
Corey, F.-Y. Zhang, Org. Lett. 2000, 2, 4257–4259.
[17] I. Lapin, CNS Drug Rev. 2001, 7, 471–481.
[18] M. Dambrova, L. Zvejniece, E. Liepinsh, H. Cirule, O.
Zharkova, G. Veinberg, I. Kalvinsh, Eur. J. Pharmacol.
2008, 583, 128–134.
[13] a) S. Fotaras, C. G. Kokotos, E. Tsandi, G. Kokotos,
Eur. J. Org. Chem. 2011, 1310–1317; b) C. G. Kokotos,
D. Limnios, D. Triggidou, M. Trifonidou, G. Kokotos,
Org. Biomol. Chem. 2011, 9, 3386–3395.
[14] a) N. Bowery, Trends Pharmacol. Sci. 1989, 10, 401–
407; b) S. M. Hayek, P. N. Joseph, N. A. Mekhail,
Semin. Pain Med. 2003, 1, 238–253.
[19] F. Felluga, V. Gombac, G. Pitacco, E. Valentin, Tetrahe-
dron: Asymmetry 2005, 16, 1341–1345.
746
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 740 – 746