Enhanced gelation property due to intra-molecular hydrogen bonding in a new series of bis(amino acid)-functionalized pyridine-2,6-dicarboxamide organogelators

Article abstract of DOI:10.1016/j.tet.2007.02.037

A series of pyridine-2,6-dicarboxamide derivatives containing two α-amino acid pendant groups was prepared and characterized. Three of the synthesized compounds obtained from this series, all having aromatic amino acid side chains, were found to be excell

Full text of DOI:10.1016/j.tet.2007.02.037

Tetrahedron 63 (2007) 7407–7418
Enhanced gelation property due to intra-molecular hydrogen
bonding in a new series of bis(amino acid)-functionalized
pyridine-2,6-dicarboxamide organogelators
a
Hak-Fun Chowa,b, and Guo-Xin Wang
*
aDepartment of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
bThe Center of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
Received 16 November 2006; revised 5 January 2007; accepted 1 February 2007
Available online 14 February 2007
Abstract—A series of pyridine-2,6-dicarboxamide derivatives containing two a-amino acid pendant groups was prepared and characterized.
Three of the synthesized compounds obtained from this series, all having aromatic amino acid side chains, were found to be excellent organo-
gelators toward aromatic solvents (mgcw10–20 mg/mL), alcoholic solvents (mgcw4–15 mg/mL), and CCl4 (mgcw4–10 mg/mL). It was
found that the intra-molecular hydrogen bonds between the pyridine dicarboxamide N–Hs and the pyridine N atom were the key structural
elements for gel formation. This series of compounds represented one of the rare examples where both inter- and intra-molecular hydrogen
bonds were needed for effective gel formation. FTIR, 1H NMR, and CD spectroscopy revealed that both hydrogen bonding and p–p aromatic
stacking were the driving forces for gelation.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
generally used to create disorder in the crystal packing and
to prevent the gelator from precipitation in the gelled state.
It is therefore not surprising to find that many strong organo-
gelators are found to possess branching or non-branching
long chain alkyl groups (ꢀ8 carbon atoms) in part of their
structures.2,3
The gelation of organic solvents by low molecular weight or-
ganic compounds is one of the most intriguing self assembly
processes in chemistry.1 Gelation is typified by the formation
of a stable three dimensional, non-covalent network struc-
ture through the intricate interactions (e.g., ionic, hydrogen
bonding, p–p stacking and/or the hydrophobic effect)
between the gelator–gelator, gelator–solvent, and solvent–
solvent molecules. To a certain extent, the gelation power
of a gelator depends mainly on gelator–gelator and gelator–
solvent interactions. While the gelator–solvent interaction is
sometimes difficult to assess or quantify, gelator–gelator in-
teractions have been frequently and successfully used as the
principal driving force to explain the gelation mechanism.1a
It has been rationalized that the inter-molecular interactions
between the many gelator molecules have to be delicately
balanced in such a way that their crystallization/precipita-
tion as a result of exceedingly strong inter-molecular interac-
tion, or dissolution because of extremely weak interaction,
can be prevented. The other major factor that controls the
crystallization process, in addition to inter-molecular inter-
actions, is the crystal packing of the gelator molecules. In
order to avoid crystallization, structurally flexible units are
Among the various driving forces for gelation, inter-mole-
cular hydrogen bonding is highly directional and ener-
getically stronger than p–p stacking and hydrophobic
interactions. It is actually one of the major driving forces
in the gelation of carbohydrate-,4 nucleic acid-,1f and amino
acid-based gelators.1e What is not often observed, however,
is the presence of intra-molecular hydrogen bonding in a
gelator molecule. As anticipated, the presence of intra-
molecular hydrogen bonding in a gelator molecule would in-
variably lead to greater structural rigidity, and consequently
better crystallinity, and a higher tendency toward precipita-
tion. Here we wish to report an unusual finding that intra-
molecular hydrogen bonding can actually be a pre-requisite
structural element for effective gel formation in a series
of bis(amino acid)-functionalized3,5 pyridine-2,6-dicarb-
oxamide organogelator molecules 1.
The amino acid gelator molecules 1 were accidentally found
during our ongoing investigative work on the structural di-
versity and conformational property of amino acid-based
dendrons. Our group recently reported a library of a-amino
acid-based dendrons 26 and b-alanine-based dendrimers7
(e.g., 3) and showed that they self-assembled to form
Keywords: Self-assembly; Amino acids; Organogelators; Inter-molecular
hydrogen bonding; Intra-molecular hydrogen bonding; p–p; Aromatic
stacking.
* Corresponding author. Tel.: +86 852 26096341; fax: +86 852 26035057;
e-mail: hfchow@cuhk.edu.hk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.037

7408
H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
BocHN
O
NHBoc
O
R5
R6
BocHN
R4
NHBoc
R7
O
O
NH
HN
HN
NH
ArHN
R
O
N
O
N
NHAr
R
H
H
NH
R2
HN
R3
O
O
O
O
N
O
O
HN
NH
1
CO2R1
2
BocHN
O
O
NHBoc
NH
HN
HN
O
NH
O
BocHN
NH
O
O
HN
NHBoc
NHBoc
NH
NH
O
O
O
O
O
HN
HN
NH
O
O
O
HN
BocHN
O
NH
HN
O
HN
NH
NH
HN
BocHN
O
O
NHBoc
3
aggregates in many organic solvents. Furthermore, the
a-amino acid-based dendrons 2, bearing different amino
acid moieties within the dendritic skeleton, were found to
be powerful organogelators with minimum gelation concen-
tration (mgc) as low as 2 mg/mL. We also demonstrated that
their gelation strength was strongly dependent on the nature
of the focal point functionality (i.e., R1) and the amino acid
side chain residues (i.e., R2–R7). Despite the presence of
many hydrogen bonding amide functionalities, these com-
pounds were shown to be devoid of higher order secondary
structure in polar solvents. Inspired by the work of Par-
quette,8 we decided to introduce conformational rigidity
into our a-amino acid-based dendrons 2 by replacing the
3,5-diaminobenzamide branching unit with a 4-aminopyri-
dine-2,6-dicarboxamide unit (Scheme 1). The latter func-
tional moiety was known to exist predominantly in the
syn–syn conformation due to the formation of two intra-
molecular hydrogen bonds of the carboxamide N–Hs with
the pyridine N atom. In a pilot study, a series of G1 a-amino
acid-based pyridine-2,6-dicarboxamides 1 was prepared as
model compounds to examine their conformational behav-
ior.9 As expected, the conformational rigidity of the two
carboxamide groups was instilled into the system and was
confirmed by spectroscopic studies. However, as reported
in this paper, to our surprise, these derivatives 1 still main-
tained their powerful gelation ability in many organic sol-
vents. Furthermore, it was found that the gelation ability
disappeared if the two intra-molecular hydrogen bonds
were removed from the system. Hence, the target bis(amino
acid) functionalized pyridine-2,6-dicarboxamides 1 consti-
tute a rare class of organogelator, which requires both intra-
and inter-molecular hydrogen bonding for effective gel for-
mation.10 The gelation mechanism, as well as the morphol-
ogy of the resulting organogels was examined by various
spectroscopic techniques.
ArHN
R
O
N
O
N
NHAr
R
BocHN
R
NHBoc
R
O
O
H
H
HN
NH
N
O
O
CO2R
Scheme 1. Modification of central core.
NH2
2. Results and discussion
2.1. Synthesis
The general synthetic route to the target compounds 1-aa bear-
ing different amino acid pendant chains (Table 1) was shown
in Scheme 2. Boc-protected or Cbz-protected amino acids
4-aa were coupled to 3,5-dimethylaniline in the presence of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) to
give the corresponding protected amino amides 5-aa in 65–
92% yield. The Boc- and Cbz-protecting groups were then
removed by trifluoroacetic acid (TFA), or catalytic hydro-
genolysis, respectively, to furnish the diamino esters 6-aa.
Finally, coupling of 6-aa with pyridine-2,6-dicarboxylic acid
in the presence of EEDQ gave the target compounds 1-aa in
yields ranging from 58 to 79% (overall yield from amino

H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
7409
Table 1. List of target organogelators
2.2. Characterization
Compound
R
2.2.1. NMR spectroscopy. The structural identities of all
intermediates and target compounds were characterized
by 1H and 13C NMR spectroscopy. Due to the poor solubil-
ity of some of the target compounds, their NMR spectra
were recorded in DMSO-d6 solution. The 1H NMR spectra
of the organogelators were found to possess three charac-
teristic features. One was a set of invariable C–H signals
originating from the common pyridine-2,6-dicarboxamide
central core and two anilide functionalities at the amino
acid carboxyl end (Fig. 1). The second was the signals
due to the N–H protons of the pyridine-2,6-dicarboxamide
and the anilide functionalities, which varied slightly in
chemical shift values according to the nature of the amino
acid side chain. While the anilide N–H signals were lo-
cated at the expected chemical shift region (d 8.4–8.6 in
CDCl3; d 10.0–10.1 in DMSO-d6), the amide N–H signals
were significantly downfield shifted (d 8.3–8.7 in CDCl3;
d 9.0–9.8 in DMSO-d6), indicating that they were hydrogen
bonded to the pyridine N atom. This finding was consistent
with data reported in the literature.8,9 Finally, the third
characteristic feature was a set of variable ‘fingerprint’ sig-
nals due to the protons originating from the different amino
acid side chains. For example, the 1H NMR spectrum
of compound 1-Val showed the presence of the isopropyl
side chain as a doublet at d 1.17 and a multiplet at
d 2.40–2.49. Likewise, the ‘feature’ signals of 1-Asn
were found at d 2.82 (CH2), 4.94 (CH), 7.07 (CONH2),
and 7.60 (CONH2). Compound 1-Pro, due to the absence
of the carboxamide N–Hs and hence the removal of con-
formational locking by intra-molecular hydrogen bonds,
1-Gly
1-Ala
1-Val
1-Leu
1-Phe
1-Asp b-benzyl ester
1-Tyr
1-Ser
1-Asn
1-Pro
H
Me
i-Pr
CH2(i-Pr)
Bn
CH2CO2Bn
CH2C6H4OH
CH2OH
CH2CONH2
a
—
a
For structure see Scheme 2.
amide 5-aa). The proline derived compound 1-Pro, having
a backbone structure that was very different from the other
amino acid derived target compounds, was synthesized in
a similar manner in overall 39% yield from Cbz-proline.
We also prepared three phenylalanine derived structural
analogues 7–9 in order to investigate the structural require-
ments for optimal gelation. Compound 7 has the central
pyridine ring replaced by a phenyl ring. For compound 8,
the linkages between the amino acid pendant groups and
the pyridine ring are replaced by an ester instead of an amide
functionality. We also prepared compound 9 in order to ex-
amine the effect of the amide functionality at the amino acid
carboxyl end on gelation by replacing the N-(3,5-dimethyl-
phenyl) groups with N-butyl groups. The synthetic routes
for these compounds were very similar to those described
for compounds 1 except that the more reactive 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide methiodide (EDCI) was
used as the coupling reagent for the synthesis of compound
8. The synthetic details are given in Section 4.
1
existed as a mixture of rotamers as shown by H NMR
study.
NH2
O
O
O
NH2
P = Cbz, H2, 10% Pd-C
P = Boc, TFA
NHP
NHPro
ArHN
ArHN
HO
EEDQ
R
R
R
4-aa
5-aa (65–92%)
6-aa
ArHN
O
N
O
N
NHAr
HO2C
N
CO2H
O
O
H
H
N
N
R
R
NHAr
ArHN
N
N
EEDQ
O
O
O
O
1-Pro
1-aa (58–79% from5-aa)
Ar = 3,5-dimethylphenyl
Scheme 2. General synthetic routes to target organogelators 1.
ArHN
Bn
O
N
O
N
NHAr
Bn
ArHN
Bn
O
O
O
O
NHAr
Bn
H3C(H2C)3HN
Bn
O
N
O
N
NH(CH2)3CH3
Bn
H
H
H
H
N
N
O
O
O
O
O
O
8
9
7
Ar = 3,5-dimethylphenyl

7410
H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
6.7
6.7
carbon nuclei due to the common backbone skeleton were
nearly the same. Hence, the carbon signals of the pyridine
ring were found to be situated between d 124 and
149 ppm, while the aromatic carbon signals of the 3,5-
dimethylanilide moiety were found between d 116 and
139 ppm. Two sets of C]O signals, located at w d 164
2.2
2.3
7.2
8.4–8.6
7.3
10.0–10.1
8.3–8.7
9.0–9.8
O
N
NH
R
O
N
NH
R
1
H
H
and 170 were found. Similar to the H NMR spectroscopic
analysis, the chemical identities of the amino acid side
chains could also be ascertained by their respective ‘finger-
print’ 13C NMR signals.
N
N
O
O
8.4
8.3
8.0
CDCl3
8.2
d -DMSO
2.2.2. Mass spectrometric analysis. The structures of the
gelators were characterized by fast atom bombardment
(FAB) mass spectroscopy or secondary ion mass spectro-
metry (L-SIMS). In addition to molecular ions in the form
of M+ or (M+H)+, dimeric M2+ or (M2+H)+ ions were also
found (Fig. 3), suggesting the presence of molecular aggre-
gates in the solution state. The exact mass of the molecular
ion peak matched well with the theoretical value.
6
Figure 1. 1H NMR spectral features of the target organogelators.
1
The H NMR spectrum of 1-Asp b-benzyl ester deserves
additional comments, as the carboxamide N–H signal was
even further downfield shifted to d 9.47 (CDCl3) due to the
presence of extra intra-molecular hydrogen bonding inter-
actions with the carboxyl oxygen atoms of the b-benzyl
esters (Fig. 2). Furthermore, this doublet signal remained
at the same position (d 9.47) over a concentration range of
0.7–44.6 mM in CDCl3. On the other hand, the chemical
shift value of the corresponding amide N–Hs of the benz-
ene-1,3-dicarboxamide analogue 7, due to an absence of
intra-molecular hydrogen bonding, was upfield shifted to
2.3. Gelation properties
As described earlier, the target compounds were prepared to
investigate their conformational behavior. It was therefore
unexpected to find them capable of forming gels with
organic solvents, particularly in view of their relatively rigid
structures as compared to the 3,5-diaminobenzoic acid
derived organogelators.5e,6 Nonetheless, their gelation prop-
erties were subsequently revealed and therefore examined in
various solvents (Table 2). Among the many amino acid
derivatives, those containing aromatic side chain such as
1-Phe and 1-Asp b-benzyl ester were the best organogela-
tors. The remaining compounds were either too soluble or
too insoluble in the solvent system and some of them precip-
itated from solution after cooling. In particular, those carry-
ing highly hydrophilic side chains, such as 1-Asn and 1-Ser
were poorly soluble. It was of interest to note that 1-Tyr, even
though it possessed two aromatic side chains, was a poor
organogelator. This was probably due to the two extra phe-
nolic groups that increased its tendency to precipitate from
solution. Similar to the 3,5-diaminobenzoic acid dendritic
organogelators, strong gels were formed from 1-Phe and
1-Asp b-benzyl ester in aromatic solvents (Fig. 4). Although
1
d 8.89 (DMSO-d6). H NMR titration study of a CDCl3
solution of 1-Asp b-benzyl ester with DMSO-d6 revealed
the presence of two N–Hs of different microenvironments.
The carboxamides N–Hs (Ha) that were hydrogen bonded
to the pyridine N experienced little change of chemical shift
(Dd<0.05) upon addition of the hydrogen bond acceptor
solvent DMSO-d6, indicating that they formed very stable
intra-molecular hydrogen bonds. However, the chemical
shift values of the anilide N–Hs (Hb) showed significant
downfield shifts upon addition of DMSO-d6, suggesting
that the initially non-hydrogen bonded Hbs began to form
intermolecular hydrogen bonds in the presence of acceptor
solvent molecules.
The 13C NMR spectra of the target compounds also shared
a common spectral feature; the chemical shift values of the
9.6
9.5
8.66
9.4
9.3
9.2
9.1
9.0
8.9
8.8
8.7
8.6
OCH2Ph
N
9.47
O
Ha
Hb
N
Ar
N
O
O
1-Asp -benzyl ester (CDCl3)
Ha
Hb
0.00
0.05
0.10
0.15
0.20
6
Ratio of d -DMSO/CDCl3 (v/v)
Figure 2. (Left) 1H NMR data of the N–Hs in 1-Asp b-benzyl ester. (Right) DMSO-d6 1H NMR titration study of 1-Asp b-benzyl ester (c¼32 mM) in CDCl3
at 25 ꢁC.

H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
7411
55
100
90
80
70
60
50
40
30
20
10
0
69
154
668 (M + H)+
370
307
519
1336 (M2 + H)+
1400
200
400
600
800
m/z
1000
1200
1600
Figure 3. FAB mass spectrum of compound 1-Phe.
Table 2. Gelation properties of organogelators in various solventsa
Solvent
1-Gly
1-Ala
1-Val
1-Leu
1-Phe
1-Asp b-benzyl ester
1-Tyr
1-Ser
1-Asn
1-Pro
7
8
9
Hexane
MeOH
EtOH
i-PrOH
CCl4
CHCl3
I
P
I
I
I
P
I
P
I
I
I
I
I
P
I
P
I
I
P
P
P
P
S
I
S
S
P
P
P
P
P
I
I
P
I
P
I
I
I
I
I
I
I
I
P
I
I
I
I
I
P
P
P
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
P
I
I
I
I
P
P
P
P
P
P
I
S
S
P
P
P
P
P
P
P
P
P
P
P
P
I
S
P
P
P
P
P
P
P
P
P
P
P
P
I
P
S
S
P
S
I
S
S
P
P
P
P
S
S
S
P
P
P
P
P
I
S
S
P
P
P
P
P
P
P
P
P
P
P
P
I
S
P
P
P
P
P
P
P
S
G (15)
G (15)
G (10)
S
I
S
G (4)
G (8)
G (4)
S
I
S
G (15)
G (15)
G (10)
S
I
S
Et2O
THF
I
P
P
P
P
P
P
P
P
P
Acetone
Benzene
Toluene
m-Xylene
p-Xylene
Anisole
o-DCBb
C6H5NO2
S
S
S
G (10)
G (10)
G (10)
G (10)
G (20)
G (20)
P
G (10)
G (10)
G (10)
G (10)
G (20)
G (20)
P
G (15)
G (15)
G (15)
G (15)
G (20)
G (20)
P
G (20)
P
a
G¼transparent gel; I¼insoluble; P¼precipitation; S¼soluble. The values given in parentheses are the minimum concentration (mg/mL) to achieve gelation
at 25 ꢁC.
o-Dichlorobenzene.
b
Figure 4. (Left) Transparent gels of 1-Phe at 20 mg/mL in various solvents (from left to right): p-xylene, m-xylene, toluene, anisole, o-dichlorobenzene, ethanol,
and 2-propanol. (Right) Transparent gels of 1-Asp b-benzyl ester at 20 mg/mL in various solvents (from left to right): ethanol, 2-propanol, CCl4, toluene,
m-xylene, and p-xylene.

7412
H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
their mgc values were slightly inferior (w10–20 mg/mL)
as compared to the 3,5-diaminobenzoic analogues, they
exhibited a wider gelation solvent spectrum, as very strong
gels (mgc¼4–10 mg/mL) were also formed in CCl4 and
alcoholic solvents such as ethanol and 2-propanol.
ring, were both poor organogelators. Both of these com-
pounds still contained the phenylalanine side chain, but
were devoid of gelating power. It was therefore concluded
that the intra-molecular hydrogen bonds between the
carboxamide N–Hs and the pyridine N were extremely
important in conferring the gelation power. In other words,
an increase in structural rigidity actually enhanced the gela-
tion property of this class of bis(amino acid)-functionalized
organogelators.
It was interesting to note that, compound 7, having the
carboxamide linkages replaced by ester linkages, and
compound 8, having the pyridine ring replaced by a phenyl
Table 3. FTIR data of 1-Phe in CHCl3 solution, p-xylene gels, and KBr disca
Replacing the 3,5-dimethylanilide aromatic rings at the
carboxyl termini, however, did not seem to have any
apparent effect on the gelation behavior. Compound 9,
containing simple N-butyl pendant groups at the amino
acid carboxyl ends, also formed transparent gels with com-
parable mgc values and similar solvent specificities. Appar-
ently this is a structural motif where wider structural
varieties could be accommodated without hampering the
gelating ability.
Physical
states
Absorption (cmꢂ1 b
nanilide N–H ncarboxamide N–H nanilide C]O ncarboxamide C]O
)
CHCl3
3412
3305
1686
1666
solution
(15 mM)
p-Xylene gel 3406
3275
3308
1669
1662
(20 mg/mL)
Solid
(KBr disc)
3390
a
All spectra were recorded at 25 ꢁC.
Peak assignments were made based on the IR spectral data of compound 8
and N2,N6-dibenzylpyridine-2,6-dicarboxamide.
2.4. Gelation mechanism
b
2.4.1. Infra-red spectroscopy. The gelation mechanism of
the organogelators was investigated by infra-red (FTIR),
NMR, and circular dichroism (CD) spectroscopy. The solu-
tion FTIR spectrum of 1-Phe exhibited two N–H and two
C]O peaks (Table 3 and Fig. 5). Upon gelation in p-xylene
(20 mg/mL), the two N–H peaks were red-shifted by about 6
and 30 cmꢂ1. Incidentally, the two C]O peaks merged into
one single broader peak at 1669 cmꢂ1. This value repre-
sented a red shift of 17 cmꢂ1 with respect to the anilide
C]O signal. Similar findings were also noted for the solid
state KBr sample of compound 1-Phe. Hence, there was
strong evidence that hydrogen bonding was involved in gel
formation.
100
80
60
CHCl3 solution
40
p-xylene gel
KBr disc
2.4.2. NMR spectroscopy. Monitoring the change of
chemical shift values by variation of the temperature could
provide valuable information on the organization of the
gelators in the gel network. Hence, the H NMR spectra of
1-Phe in toluene-d8 (c¼20 mg/mL) at different temperatures
20
3600 3500 3400 3300 32001800
wavelength (cm-1
1700
1600
)
1
Figure 5. FTIR spectra of 1-Phe in different physical states (peaks with an
asterisk are due to p-xylene absorption).
O
NHbAr
Hc
Ha
N
Bn
N
O
Ha Hb
Hc
i
ii
iii
iv
v
vi
11
10
9
8
7
6
5
4
3
2
1
Figure 6. 1H NMR (toluene-d8) stacked spectra of 1-Phe (c¼20 mg/mL) at different temperature and physical states: (i) 25 ꢁC, gel, (ii) 30 ꢁC, gel, (iii) 40 ꢁC,
solution–gel, (iv) 50 ꢁC, solution–gel, (v) 75 ꢁC, solution–gel, (vi) 100 ꢁC, solution state.

H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
7413
20 ꢁC (Fig. 7). Increasing the temperature of the gel sample
did not lead to any noticeable changes of both the intensity
and position of the CD band. Finally, when the gel sample
was forced to dissolution by heating, the original CD band
was slightly shifted to 308.5 nm. From these experiments,
it could be concluded that the chiroptical properties of the
organogelator in the gel state were similar to those in the
solution state. In other words, there was little chiroptical
amplification during gel formation and this also suggested
that the chiral organogelators were not organized in a syner-
gistic and orderly manner in the gel state. This also implied
that the molecules had a high degree of orientational free-
dom and were possibly tumbling in the gel state, which
was consistent with the results obtained from NMR study.
The relatively small blue shift (2 nm) of the CD signal
upon gelation also indicated that the energy gap of the
electronic transition was widened upon gelation. This can
be assigned to a change of p–p interactions between the
organogelator and the aromatic solvent (i.e., p-xylene) on
going from the solution to the gel state.
20 °C gel
28 °C gel
36 °C gel
45 °C gel
52 °C gel
60 °C gel
Hot solution
1400
1200
1000
800
600
400
200
0
290
300
310
320
330
wavelength (nm)
Figure 7. Temperature dependent CD spectra of 1-Phe in p-xylene
(15 mg/mL).
were recorded (Fig. 6). At 25 ꢁC in the gel state, the chemical
shift values of the carboxamide N–Hs (Ha) and anilide N–Hs
(Hb) in toluene gel were located at dw9.6 andw9.1, respec-
tively. At elevated temperatures (30–75 ꢁC), these two N–H
signals shifted upfield due to partial melting of the gel and
hence a gradual breakdown of the inter-molecular hydrogen
bonding network. Finally, at 100 ꢁC where the gel turned
into a solution, the chemical shift values of two relevant
N–Hs appeared at dw8.4 and w7.9, respectively. These
results also demonstrate that inter-molecular hydrogen
bonding is the main driving force for gel formation.
2.5. Electron microscopy
The morphology of the gel structure was examined by
scanning electron microscopy (SEM). Figure 8 showed the
electron micrographs of xerogels from 1-Phe and 1-Asp
b-benzyl ester in different solvents. The micromorphology
of the gels was found to be independent of the gelating sol-
vent. Thexerogelsappeared aslongthinfiberswith a diameter
range of 50–70 nm. This value was much larger than the
figure expected from a single molecular chain and suggested
that the xerogels were actually super-bundles resulting from
2.4.3. CD spectroscopy. The CD spectrum of 1-Phe in p-xy-
lene gels (15 mg/mL) displayed one CD band at 306.5 nm at
Figure 8. SEM images of xerogels of (top left) 1-Phe in CCl4, (top right) 1-Phe in p-xylene, (bottom left) 1-Asp b-benzyl ester in CCl4, and (bottom right) 1-Asp
b-benzyl ester in p-xylene.

7414
H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
the intertwining of several molecular chains. Such super-
bundles were further extended to form a large three-dimen-
sional fibrillar network. Although these bis(amino acid)-
based pyridine-2,6-dicarboxamides were optically active,
we were unable to identify any chiral microstructures such
as helical architecture in their SEM images.
4.2. General procedure for the synthesis of N-protected
amino amides 5
A solution of the 3,5-dimethylaniline (1.1 equiv) and EEDQ
(1.1 equiv) in THF was added to a solution of CbzNH- or
BocNH-protected amino acid (1.0 equiv) at 20 ꢁC. The mix-
ture was stirred at 20 ꢁC for 24 h. The solvent was removed
under reduced pressure and the product was isolated accord-
ing to the following procedure.
3. Conclusions
4.2.1. 5-Gly (P¼Boc). Starting from Boc-alanine (3.85 g,
22.0 mmol), 3,5-dimethylaniline (2.93 g, 24.2 mol), and
EEDQ (5.98 g, 24.2 mmol), the title compound (4.80 g,
78%) was obtained as a white solid by precipitation from
By replacing the central 3,5-diaminobenzoic acid ring with
pyridine-2,6-dicarboxylic acid, a new series of bis(amino
acid)-containing pyridine-2,6-dicarboxamide derivatives 1
was prepared. Three of the synthesized compounds (1-Phe,
1-Asp b-benzyl ester, and 9), all bearing aromatic amino
acid side chains, were found to be excellent organogelators
toward aromatic solvents (mgcw10–20 mg/mL). In contrast
to the 3,5-diaminobenzoic acid derived organogelators, the
pyridine-2,6-dicarboxamide derivatives have an expanded
range of gelating solvents. In addition to aromatic solvents,
they are also efficient organogelators for alcohols (mgcw4–
15 mg/mL) and CCl4 (mgcw4–10 mg/mL). It was found that
the intra-molecular hydrogen bonds between the carbox-
amide N–Hs and the pyridine N atom were the key structural
elements for gel formation. This series of compounds thus
represents one of the rare examples where both inter- and
intra-molecular hydrogen bondings are needed for gel
1
acetone/Et2O. Mp: 160–162 ꢁC; H NMR (CDCl3): d 8.30
(1H, br s), 7.14 (2H, s), 6.75 (1H, s), 5.47 (1H, br s), 3.93
(2H, d, J¼5.4), 2.27 (6H, s), 1.47 (9H, s); 13C NMR
(CDCl3): d 167.7, 156.4, 138.7, 137.3, 126.2, 117.7, 80.5,
45.4, 28.3, 21.3; MS (FAB): m/z 279 [(M+H)+, 80%];
HRMS (L-SIMS): calcd for C15H23N2O3 (M+H)+:
279.1703, found 279.1698; Anal. Calcd for C15H22N2O3:
C, 64.73, H, 7.97, N, 10.06. Found: C, 64.59, H, 8.02, N, 9.92.
4.2.2. 5-Ala (P¼Boc). Starting from Boc-alanine (3.80 g,
20.1 mmol), 3,5-dimethylaniline (2.68 g, 22.1 mmol), and
EEDQ (5.46 g, 22.1 mmol), the title compound (5.40 g,
92%) was obtained as a white solid by precipitation from
acetone/Et2O. Mp: 145–146 ꢁC; [a]D ꢂ91.5 (c 0.75,
1
formation. FTIR, H NMR, and CD spectroscopy revealed
that both H-bonding and p–p aromatic stacking were the
driving forces for gelation.
1
CHCl3); H NMR (CDCl3): d 8.21 (1H, br s), 7.14 (2H, s),
6.74 (1H, s), 5.00 (1H, br s), 4.38–4.20 (1H, m), 2.28 (6H,
s), 1.49 (9H, s), 1.42 (3H, d, J¼6.0); 13C NMR (CDCl3):
d 171.1, 156.0, 138.4, 137.6, 125.9, 117.6, 80.4, 50.7,
28.3, 21.2, 18.1; MS (FAB): m/z 293 [(M+H)+, 100%];
HRMS (L-SIMS): calcd for C16H25N2O3 (M+H)+:
293.1860, found 293.1855; Anal. Calcd for C16H24N2O3:
C, 65.73, H, 8.27, N, 9.58. Found: C, 65.79, H, 8.33, N, 9.55.
4. Experimental
4.1. General
THF was distilled from sodium benzophenone ketyl and
CH2Cl2 from CaH2 prior to use. Silica gel for flash chroma-
tography is Macherey Nagel 60M (230–400 mesh) silica gel.
Cbz-protected or Boc-protected L-amino acids and other
reagents were used as supplied from Aldrich or Sigma. All
reactions were conducted under dry N2 unless otherwise
stated. All NMR spectra were recorded in DMSO-d6 (dried
4.2.3. 5-Val (P¼Boc). Starting from Boc-valine (4.35 g,
20.0 mmol), 3,5-dimethylaniline (2.67 g, 22.0 mmol), and
EEDQ (5.45 g, 22.0 mmol), the target compound (4.90 g,
76%) was obtained as a white solid by precipitation from
acetone/Et2O. Mp: 140–141 ꢁC; [a]D ꢂ29.9 (c 0.55,
1
CHCl3); H NMR (CDCl3): d 7.84 (1H, br s), 7.14 (2H, s),
6.74 (1H, s), 5.10 (1H, br s), 3.99 (1H, dd, J¼9 and 6),
2.27 (6H, s), 2.24–2.17 (1H, m), 1.46 (9H, s), 1.02 (3H, d,
J¼6.0), 0.98 (3H, d, J¼6.0); 13C NMR (CDCl3): d 169.9,
156.0, 138.7, 137.3, 126.2, 117.7, 61.0, 30.6, 28.3, 21.3,
19.4, 18.0; MS (FAB): m/z 321 [(M+H)+, 80%]; HRMS
(L-SIMS): calcd for C18H29N2O3 (M+H)+: 321.2173, found
321.2171; Anal. Calcd for C18H28N2O3: C, 67.47, H, 8.81,
N, 8.74. Found: C, 67.68, H, 9.35, N, 8.29.
˚
€
over molecular sieves 4 A) on a Bruker DPX300 Spectro-
1
meter at 300 MHz for H and 75.5 MHz for 13C nucleus at
25 ꢁC unless otherwise stated. The residual proton or carbon
signals of DMSO-d6 (dH¼2.50; dC¼39.52) were used as
internal references. All chemical shifts are reported in ppm
(d) and coupling constants in Hz. FAB and L-SIMS spectra
were carried out on a Thermo Finnigan MAT 95XL Mass
Spectrometer. Melting points were measured on an Electro-
thermal IA9100 Digital Melting Point Apparatus and are
4.2.4. 5-Leu (P¼Cbz). Starting from Cbz-leucine (5.30 g,
20.0 mmol), 3,5-dimethylaniline (2.66 g, 22.0 mmol), and
EEDQ (5.43 g, 22.0 mmol), the title compound (5.70 g,
77%) was obtained as a white solid by precipitation from ace-
€
uncorrected. IR spectra were recorded on a Bruker Vertex
70 FTIR Spectrophotometer. Optical rotations were taken
on a Perkin Elmer 341 Polarimeter at 589 nm and at
20 ꢁC. CD spectra were recorded on a JASCO J-715 Spectro-
polarimeter connected to a NESLAB RTE-211 Temperature
Controller. All SEM images were taken on a Leo 1450 VP
Scanning Electron Microscope. Elemental analyses were
performed at MEDAC LTD, Brunel Science Center,
Cooper’s Hill Lane, Englefield Green, Egham, Surrey
TW20 0JZ, UK.
1
tone/Et2O. Mp: 138–140 ꢁC; [a]D +8.0 (c 0.95, DMF); H
NMR (CDCl3): d 8.32 (1H, br s), 7.38–7.27 (5H, m), 7.12
(2H, s), 6.73 (1H, s), 5.46 (1H, br s), 5.12 (1H, d, J¼12),
5.08 (1H, d, J¼12), 4.42–4.30 (1H, m), 2.24 (6H, s), 1.77–
1.68 (2H, m), 1.62–1.56 (1H, m), 0.95 (3H, d, J¼6), 0.94
(3H, d, J¼6); 13C NMR (CDCl3): d 170.5, 156.6, 138.6,
137.4, 135.9, 128.5, 128.2, 128.0, 126.1, 117.7, 67.3, 54.3,

H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
7415
41.0, 24.7, 22.8, 22.1, 21.3; MS (FAB): m/z 369 [(M+H)+,
94%]; HRMS (L-SIMS): calcd for C22H29N2O3 (M+H)+:
369.2173, found 369.2178; Anal. Calcd for C22H28N2O3:
C, 71.71, H, 7.66, N, 7.60. Found: C, 71.56, H, 7.72, N, 7.61.
55.6, 21.3; MS (FAB): m/z 343 [(M+H)+, 54%]; HRMS
(L-SIMS): calcd for C19H23N2O4 (M+H)+: 343.1652, found
343.1655; Anal. Calcd for C19H22N2O4: C, 66.65, H, 6.48,
N, 8.18. Found: C, 66.34, H, 6.47, N, 8.03.
4.2.5. 5-Phe (P¼Boc). Starting from Boc-phenylalanine
(26.5 g, 100 mmol), 3,5-dimethylaniline (13.3 g, 110 mmol),
and EEDQ (27.2 g, 110 mmol), the title compound (31.3 g,
85%) was obtained as a white solid by precipitation from
acetone/Et2O. Mp: 143–144 ꢁC. [a]D ꢂ15.4 (c 1.0,
4.2.9. 5-Asn (P¼Cbz). Starting from Cbz-asparagine (5.30 g,
19.9 mmol), 3,5-dimethylaniline (2.65 g, 21.9 mmol), and
EEDQ (5.41 g, 21.9 mmol), the target product (5.00 g,
68%) was obtained as a white solid by precipitation from
acetone/Et2O. Mp: 156–158 ꢁC; [a]D ꢂ2.3 (c 0.90, DMF);
1H NMR: d 9.89 (1H, s), 7.58 (1H, d, J¼7.8), 7.41–7.30
(6H, m), 7.27 (2H, s), 6.99 (1H, s), 6.73 (1H, s), 5.07 (2H,
s), 4.51 (1H, q, J¼7.8), 2.59–2.45 (2H, m), 2.26 (6H, s);
13C NMR: d 171.0, 169.9, 155.7, 138.7, 137.5, 136.8,
128.3, 127.7, 124.7, 117.0, 65.4, 52.3, 37.1, 21.0; MS
(FAB): m/z 370 [(M+H)+, 68%]; HRMS (L-SIMS): calcd
for C20H23N3O4 (M+H)+: 370.1761, found 370.1756;
Anal. Calcd for C20H23N3O4: C, 65.03, H, 6.28, N, 11.37.
Found: C, 65.01, H, 6.27, N, 11.35.
1
CHCl3); H NMR (CDCl3): d 7.67 (1H, br s), 7.35–7.23
(5H, m), 7.00 (2H, s), 6.73 (1H, s), 5.16 (1H, br s), 4.46–
4.35 (1H, m), 3.13 (2H, d, J¼6.9), 2.26 (6H, s), 1.42 (9H,
s); 13C NMR (CDCl3): d 169.4, 155.7, 138.6, 137.1, 136.7,
129.3, 128.8, 127.0, 126.2, 117.8, 80.5, 56.7, 38.5,
28.3, 21.3; MS (FAB): m/z 369 [(M+H)+, 30%]; HRMS
(L-SIMS): calcd for C22H29N2O3 (M+H)+: 369.2173, found
369.2179; Anal. Calcd for C22H28N2O3: C, 71.71, H, 7.66,
N, 7.60. Found: C, 71.69, H, 7.71, N, 7.51.
4.2.6. 5-Asp b-benzyl ester (P¼Boc). Starting from
Boc-aspartic acid b-benzyl ester (16.2 g, 50.1 mmol), 3,5-
dimethylaniline (6.68 g, 55.1 mmol), and EEDQ (13.6 g,
55.1 mmol), the target compound (16.1 g, 75%) was ob-
tained as a white solid by precipitation from acetone/Et2O.
4.2.10. 5-Pro (P¼Cbz). Starting from Cbz-proline (5.00 g,
20.1 mmol), 3,5-dimethylaniline (2.67 g, 22.1 mmol), and
EEDQ (5.46 g, 22.1 mmol), the target compound (4.60 g,
65%) was obtained as a white solid by precipitation from
acetone/Et2O. Mp: 124–126 ꢁC; [a]D ꢂ129.1 (c 0.65,
1
1
Mp: 133–135 ꢁC; [a]D ꢂ25.8 (c 0.55, CHCl3); H NMR
CHCl3); H NMR: d 9.92 and 9.90 (total 1H, s), 7.45–7.35
(CDCl3): d 8.42 (1H, br s), 7.32–7.28 (5H, m), 7.12 (2H,
s), 6.75 (1H, s), 5.82 (1H, br s), 5.16 (1H, d, J¼12.3), 5.13
(1H, d, J¼12.3), 4.70–4.59 (1H, m), 3.06 (1H, dd, J¼17.1
and 4.2), 2.79 (1H, dd, J¼17.1 and 6.3), 2.28 (6H, s), 1.47
(9H, s); 13C NMR (CDCl3): d 171.8, 168.7, 155.8, 138.6,
137.3, 135.2, 128.6, 128.4, 128.2, 126.2, 117.6, 80.8, 66.9,
51.3, 35.8, 28.2, 21.3; MS (FAB): m/z 427 [(M+H)+,
57%); HRMS (L-SIMS): calcd for C24H31N2O5 (M+H)+:
427.2227, found 427.2230; Anal. Calcd for C24H30N2O5:
C, 67.59, H, 7.09, N, 6.57. Found: C, 67.59, H, 7.15, N, 6.52.
(2H, m), 7.35–7.14 (5H, m), 6.74 (1H, s), 5.15–4.95 (2H,
m), 4.42–4.32 (1H, m), 3.60–3.40 (2H, m), 2.27 (6H, s),
2.27–2.23 (1H, m), 2.00–1.82 (3H, m); 13C NMR: d 170.8,
170.5, 153.9, 153.6, 138.7, 138.6, 137.4, 136.9, 136.7,
128.3, 127.9, 127.7, 127.4, 126.8, 124.7, 124.6, 117.1,
116.9, 65.8, 65.7, 60.4, 59.8, 47.1, 46.5, 31.2, 30.1, 23.8,
23.0, 21.0; MS (FAB): m/z 353 [(M+H)+, 93%]; HRMS
(L-SIMS): calcd for C21H25N2O3 (M+H)+: 353.1860, found
353.1861; Anal. Calcd for C21H24N2O3: C, 71.75, H, 6.86,
N, 7.95. Found: C, 71.36, H, 6.83, N, 7.93.
4.2.7. 5-Tyr (P¼Cbz). Starting from Cbz-tyrosine (6.30 g,
20.0 mmol), 3,5-dimethylaniline (2.66 g, 22.0 mmol), and
EEDQ (5.43 g, 22.0 mmol), the target compound (6.70 g,
80%) was obtained as a white solid by precipitation from ace-
tone/Et2O. Mp: 153–155 ꢁC; [a]D +38.3 (c 0.65, DMF); 1H
NMR: d 9.94 (1H, s), 9.24 (1H, s), 7.63 (1H, d, J¼8.1),
7.41–7.20 (7H, m), 7.15 (2H, d, J¼8.1), 6.75–6.60 (3H, m),
5.01 (2H, s), 4.38–4.28 (1H, m), 2.93 (1H, dd, J¼13.5 and
4.5), 2.75 (1H, dd, J¼13.5 and 10.2), 2.27 (6H, s); 13C
NMR: d 170.5, 155.8, 155.7, 138.6, 137.5, 136.9, 130.1,
128.2, 127.8, 127.6, 127.4, 124.8, 117.0, 114.8, 65.2, 57.2,
36.7, 21.0; MS (FAB): m/z 419 [(M+H)+, 24%]; HRMS
(L-SIMS): calcd for C25H26N2O4 (M+H)+: 419.1965, found
419.1974; Anal. Calcd for C25H26N2O4: C, 71.75, H, 6.26,
N, 6.69. Found: C, 71.67, H, 6.29, N, 6.53.
4.3. (S)-N-Butyl-2-benzyloxycarbonylamino-3-phenyl-
propamide
A solution of Cbz-phenylalanine (6.00 g, 20.0 mmol),
n-butylamine (1.61 g, 22.0 mmol), and EEDQ (5.45 g,
22.0 mmol) was stirred in THF at 20 ꢁC for 24 h. The solvent
was removed under reduced pressure and the residue was
chromatographed on silica gel (eluent: hexane/EtOAc¼1/1)
to give the target product (5.70 g, 80%) as a white solid. Rf:
0.66 (hexane/EtOAc¼1/1); Mp: 127–130 ꢁC; [a]D +12.3 (c
1
0.50, CHCl3); H NMR (CDCl3): d 7.29–7.05 (10H, m),
5.73 (1H, br s), 5.50–5.40 (1H, m), 4.98 (2H, s), 4.29 (1H,
q, J¼7.2), 3.15–2.90 (4H, m), 1.30–1.17 (2H, m), 1.17–
1.03 (2H, m), 0.77 (3H, d, J¼7.2); 13C NMR (CDCl3):
d 170.6, 155.9, 136.6, 136.1, 129.2, 128.6, 128.5, 128.1,
127.9, 126.9, 66.9, 56.4, 39.1, 38.9, 31.2, 19.8, 13.6; MS
(FAB): m/z 355 [(M+H)+, 28%]; HRMS (L-SIMS): calcd
for C21H27N2O3 (M+H)+: 355.2016, found 355.2019;
Anal. Calcd for C21H26N2O3: C, 71.16, H, 7.39, N, 7.90.
Found: C, 71.06, H, 7.51, N, 7.76.
4.2.8. 5-Ser (P¼Cbz). Starting from Cbz-serine (4.80 g,
20.1 mmol), 3,5-dimethylaniline (2.67 g, 22.1 mmol), and
EEDQ (5.46 g, 22.1 mmol), the title compound (4.80 g,
70%) was obtained as a white solid by precipitation from ace-
tone/Et2O. Mp: 150–152 ꢁC; [a]D ꢂ10.7 (c 0.65, DMF); 1H
NMR (CDCl3): d 8.48 (1H, br s), 7.38–7.32 (5H, m), 7.10
(2H, s), 6.77 (1H, s), 5.95–5.88 (1H, m), 5.17 (2H, s),
4.34–4.20 (2H, m), 3.78–3.65 (1H, m), 3.00–2.90 (1H, m),
2.29 (6H, s); 13C NMR (CDCl3): d 169.1, 157.2, 138.8,
137.0, 135.8, 128.6, 128.4, 128.1, 126.5, 117.9, 67.6, 62.5,
4.4. (S)-N-(3,5-Dimethylphenyl)-2-hydroxy-3-phenyl-
propamide
A mixture of (S)-2-hydroxy-3-phenylpropionic acid11 (3.30 g,
19.9 mmol), 3,5-dimethylaniline (2.65 g, 21.8 mmol), and

7416
H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
EEDQ (5.40 g, 21.8 mmol) was stirred in THF at 20 ꢁC for
24 h. The solvent was removed under reduced pressure
and the residue was chromatographed on silica gel (eluent:
hexane/EtOAc¼2/1) to afford the target compound
(4.00 g, 75%) as a white solid. Rf : 0.42 (hexane/EtOAc¼
4.6.2. 1-Ala. Starting from 6-Ala [obtained from deprotec-
tion of 5-Ala (P¼Boc) (5.60 g, 19.2 mmol)], pyridine-2,6-
dicarboxylic acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g,
21.1 mmol), the titled compound (3.50 g, 71%) was obtained
as a white solid by precipitation from acetone/Et2O. Mp:
238–239 ꢁC; [a]D +206.9 (c 0.65, DMF); 1H NMR: d 10.02
(2H, s), 9.34 (2H, d, J¼9.0), 8.29–8.18 (3H, m), 7.29 (4H,
s), 6.74 (2H, s), 4.77–4.60 (2H, m), 2.27 (12H, s), 1.58
(6H, d, J¼9.0); 13C NMR: d 170.9, 163.4, 148.8, 139.4,
138.8, 137.7, 124.9, 117.2, 49.8, 21.1, 17.9; MS (FAB):
m/z 516 [(M+H)+, 55%], 1031 [(M2+H)+, 8%]; HRMS
(L-SIMS): calcd for C29H34N5O4 (M+H)+: 516.2605, found
516.2609; Anal. Calcd for C29H33N5O4: C, 67.55, H, 6.45,
N, 13.58. Found: C, 67.41, H, 6.66, N, 13.46.
1
2/1); Mp: 127–129 ꢁC; [a]D ꢂ150.7 (c 0.65, CHCl3); H
NMR (CDCl3): d 8.22 (1H, s), 7.38–7.24 (5H, m), 7.16
(2H, s), 6.78 (1H, s), 4.45–4.35 (1H, m), 3.33 (1H, dd,
J¼14.1 and 4.2), 2.96 (1H, dd, J¼14.0 and 8.7), 2.61 (1H,
d, J¼4.5), 2.30 (6H, s); 13C NMR (CDCl3): d 170.7,
138.7, 136.8, 136.7, 129.5, 128.8, 127.0, 126.3, 117.6,
73.1, 40.8, 21.3; MS (FAB): m/z 270 [(M+H)+, 100%];
HRMS (L-SIMS): calcd for C17H20NO2 (M+H)+:
270.1489, found 270.1494; Anal. Calcd for C17H19NO2: C,
75.81, H, 7.11, N, 5.20. Found: C, 75.68, H, 7.11, N, 5.15.
4.6.3. 1-Val. Starting from 6-Val [prepared from the depro-
tection of 5-Val (P¼Boc) (6.14, 19.1 mmol)], pyridine-2,6-
dicarboxylic acid (1.60 g, 9.6 mol), and EEDQ (5.21 g,
21.1 mmol), the target product (4.30 g, 79%) was obtained
as a white solid by precipitation from acetone/Et2O. Mp:
231–232 ꢁC; [a]D +195.2 (c 0.50, DMF); 1H NMR
(CDCl3): d 8.70 (2H, d, J¼8.7), 8.63 (2H, s), 8.37 (2H, d,
J¼7.5), 8.03 (1H, t, J¼7.5), 7.19 (4H, s), 6.73 (2H, s),
4.73 (2H, dd, J¼8.7 and 7.5), 2.49–2.40 (2H, m), 2.23
(12H, s), 1.17 (12H, d, J¼6.9); 13C NMR (CDCl3):
d 169.3, 163.9, 148.6, 139.1, 138.6, 137.5, 126.1, 125.4,
117.8, 60.0, 31.2, 21.3, 19.5, 18.5; MS (FAB): m/z 572
[(M+H)+, 93%], 1143 [(M2+H)+, 14%]; HRMS (L-SIMS):
calcd for C33H42N5O4 (M+H)+: 572.3231, found 572.3229;
Anal. Calcd for C33H41N5O4: C, 69.33, H, 7.23, N, 12.25.
Found: C, 69.14, H, 7.65, N, 12.18.
4.5. General procedure for the deprotection of the
N-protecting groups
(a) Deprotection of Cbz group: A solution of Cbz-protected
amino compound 5 (P¼Cbz) and 10% Pd/C in THF/
EtOH (v/v¼1/1) was stirred under H2 (1 atm) at 20 ꢁC
and the reaction was monitored by TLC until the starting
material disappeared. The reaction mixture was filtered
through Celite and washed with THF. The combined
filtrates were concentrated under reduced pressure to
give the crude product 6 that was directly used in the
next reaction without characterization.
(b) Deprotection of Boc group: A solution of Boc-protected
amino compound 5 (P¼Boc) in TFA/CH2Cl2 (v/v¼1/1)
was stirred at 20 ꢁC and the reaction was monitored by
TLC until the starting material disappeared. The excess
TFA was removed under reduced pressure and the resi-
due neutralized with NaHCO3 solution. The residue
was then extracted with EtOAc and the combined
extracts were washed with saturated NaCl solutions.
The organic phase was dried (MgSO4), filtered, and
evaporated under reduced pressure to give the crude
product 6 that was directly used in the next step without
characterization.
4.6.4. 1-Leu. Starting from 6-Leu (prepared from 5-Leu
(P¼Cbz) (7.06 g, 19.1 mmol), pyridine-2,6-dicarboxylic
acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g, 21.1 mmol),
the target product (4.20 g, 73%) was obtained as a white solid
by precipitation from acetone/Et2O. Mp: 162–163 ꢁC; [a]D
1
+151.9 (c 1.15, DMF); H NMR (CDCl3): d 8.58 (2H, d,
J¼7.8), 8.41 (2H, s), 8.35 (2H, d, J¼7.8), 8.02 (1H, t,
J¼7.8), 7.16 (4H, s), 6.72 (2H, s), 4.90–4.75 (2H, m), 2.23
(12H, s), 2.00–1.70 (6H, m), 1.01–0.88 (12H, m); 13C
NMR (CDCl3): d 169.8, 164.0, 148.4, 139.1, 138.7, 137.5,
126.2, 125.5, 117.7, 53.0, 40.2, 25.0, 22.9, 22.3, 21.3; MS
(FAB): m/z 600 [(M+H)+, 30%]; HRMS (L-SIMS): calcd
for C35H46N5O4 (M+H)+: 600.3544, found 600.3538.
4.6. General procedure for the bis(amino acid)-
functionalized pyridine-2,6-dicarboxamides 1
A mixture of the deprotected, free amino carboxamide 6
(2.0 equiv), pyridine-2,6-dicarboxylic acid (1.0 equiv), and
EEDQ (2.2 equiv) in THF was stirred at 20 ꢁC for 24 h under
N2. The solvent was then removed under reduced pressure
and the residue was purified according to the following
methods.
4.6.5. 1-Phe. Starting from 6-Phe (prepared from 5-Phe
(P¼Boc) (7.06 g, 19.1 mmol), pyridine-2,6-dicarboxylic
acid (1.60 g, 9.6 mol), and EEDQ (5.21 g, 21.1 mmol), the
target compound (4.80 g, 75%) was obtained as a white solid
by flash chromatography (eluent: hexane/acetone¼1:1). Rf:
0.35 (hexane/acetone¼2/1); Mp: 170–171 ꢁC; [a]D ꢂ13.7
4.6.1. 1-Gly. Starting from 6-Gly [obtained from deprotec-
tion of 5-Gly (P¼Boc) (5.33 g, 19.2 mmol)], pyridine-2,6-
dicarboxylic acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g,
21.1 mmol), the target compound (2.70 g, 58%) was ob-
tained as a white solid by precipitation from acetone/Et2O.
Mp: >300 ꢁC (dec); 1H NMR: d 10.05 (2H, s), 9.81 (2H, t,
J¼6.0), 8.30–8.22 (3H, m), 7.28 (4H, s), 6.73 (2H, s), 4.21
(4H, d, J¼9.0), 2.26 (12H, s); 13C NMR: d 167.3, 163.7,
148.4, 139.5, 138.7, 137.6, 124.8, 124.3, 116.9, 42.9, 21.0;
MS (FAB): m/z 488 [(M+H)+, 20%], 975 [(M2+H)+, 2%];
HRMS (L-SIMS): calcd for C27H30N5O4 (M+H)+:
488.2292, found 488.2292.
1
(c 0.75, CHCl3); H NMR: d 10.14 (2H, s), 9.31 (2H, d,
J¼7.8), 8.18 (3H, s), 7.48 (4H, d, J¼6), 7.40–7.15 (10H,
m), 6.75 (2H, s), 4.95 (2H, q, J¼7), 3.35–3.21 (4H, m),
2.27 (12H, s); 13C NMR: d 169.4, 163.2, 148.4, 139.3,
138.5, 137.5, 129.2, 128.1, 126.3, 124.9, 124.7, 117.1,
55.7, 37.4, 21.0; MS (FAB): m/z 668 [(M+H)+, 43%], 1335
[(M2+H)+, 7%]; HRMS (L-SIMS): calcd for C41H42N5O4
(M+H)+: 668.3231, found 668.3231.
4.6.6. 1-Asp b-benzyl ester. Starting from 6-Asp b-benzyl
ester [prepared from 5-Asp b-benzyl ester (P¼Boc)

H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
7417
(8.17 g, 19.1 mol)], pyridine-2,6-dicarboxylic acid (1.60 g,
9.6 mmol), and EEDQ (5.21 g, 21.1 mmol), the target com-
pound (5.28 g, 70%) was obtained as a white solid by precip-
itation from acetone/Et2O. Mp: 175–176 ꢁC; [a]D +21.4
solid by precipitation from acetone/Et2O. Mp: >200 ꢁC
1
(dec); [a]D ꢂ185.8 (c 0.55, CHCl3); H NMR: d 10.04,
9.91, 9.62, 9.60 (total 2H, 4 s), 8.15–7.50 (total 3H, m),
7.31, 7.27, 7.13, 6.97 (total 4H, 4 s), 6.73–6.63 (total 2H,
m), 5.00–4.33 (total 2H, m), 3.90–3.40 (total 4H, m),
2.38–1.55 (total 20H, m); 13C NMR: d 170.7, 170.3, 170.0,
165.4, 165.2, 165.0, 152.3, 152.1, 152.0, 138.9, 138.7,
138.3, 138.1, 137.55, 137.48, 137.4, 124.7, 124.6, 124.4,
117.7, 117.1, 116.8, 62.1, 61.0, 60.9, 49.4, 48.9, 47.7,
32.2, 29.5, 29.3, 28.8, 25.0, 24.5, 21.7, 21.0, 20.9; MS
(FAB): m/z 568 [(M+H)+, 88%]; HRMS (L-SIMS): calcd
for C33H38N5O4 (M+H)+: 568.2918, found 568.2907.
1
(c 0.80, CHCl3); H NMR (CDCl3): d 9.47 (2H, d, J¼8.1),
8.70 (2H, s), 8.34 (2H, d, J¼7.8), 8.05 (1H, t, J¼7.8),
7.30–7.22 (10H, m), 7.15 (4H, s), 6.71 (2H, s), 5.20–5.09
(6H, m), 3.15–3.00 (4H, m), 2.24 (12H, s); 13C NMR
(CDCl3): d 172.0, 167.8, 163.9, 147.6, 139.4, 138.6, 137.4,
135.2, 128.4, 128.2, 126.1, 125.2, 117.5, 67.2, 50.6,
34.4, 21.3; MS (FAB): m/z 784 [(M+H)+, 6%]; HRMS
(L-SIMS): calcd for C45H46N5O8 (M+H)+: 784.3341, found
784.3347; Anal. Calcd for C45H45N5O8: C, 68.95, H, 5.79,
N, 8.93. Found: C, 69.10, H, 5.92, N, 8.54.
4.7. Compound 7
4.6.7. 1-Tyr. Starting from 6-Tyr [prepared from 5-Tyr
(P¼Cbz) (8.01 g, 19.1 mmol)], pyridine-2,6-dicarboxylic
acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g, 21.1 mmol),
the title compound (4.80 g, 72%) was obtained as a white
solid by precipitation from acetone/Et2O. Mp: 148–
150 ꢁC; [a]D +63.5 (c 0.40, DMF); 1H NMR (CDCl3):
d 8.49 (2H, s), 8.27 (2H, d, J¼7.8), 8.00–7.90 (3H, m),
7.17 (4H, s), 6.92 (4H, d, J¼8.4), 6.76 (2H, s), 6.69 (4H,
d, J¼8.4), 6.61 (2H, br s), 5.05–4.93 (2H, m), 3.25 (2H,
dd, J¼14.1 and 6.6), 3.09 (2H, dd, J¼14.1 and 6.0), 2.27
(12H, s); 13C NMR (CDCl3): d 169.0, 163.8, 155.4, 147.8,
139.4, 139.3, 137.2, 131.0, 127.0, 126.6, 125.7, 117.8,
116.1, 54.4, 35.2, 21.3; MS (FAB): m/z 700 [(M+H)+,
26%]; HRMS (L-SIMS): calcd for C41H42N5O6 (M+H)+:
700.3130, found 700.3145.
A mixture of 6-Phe [obtained from 5-Phe (P¼Boc) (7.10 g,
19.3 mmol)], benzene-1,3-dicarboxylic acid (1.60 g,
9.6 mmol), and EEDQ (5.24 g, 21.2 mmol) in THF was
stirred at 20 ꢁC for 24 h under N2. The target compound 7
(4.50 g, 70%) was obtained as a white solid by precipitation
from acetone/Et2O. Mp: 255–256 ꢁC; [a]D +44.8 (c 0.85,
1
DMF); H NMR: d 10.11 (2H, s), 8.89 (2H, d, J¼9.0),
8.29 (1H, s), 7.98 (2H, dd, J¼9.0 and 3.0), 7.58 (1H, t,
J¼9.0), 7.48–7.15 (14H, m), 6.74 (2H, s), 4.95–4.82 (2H,
m), 3.20–3.05 (4H, m), 2.27 (12H, s); 13C NMR: d 170.1,
166.1, 138.7, 138.1, 137.7, 134.1, 130.1, 129.2, 128.1,
126.9, 126.3, 124.9, 117.1, 55.9, 37.2, 21.1; MS (FAB):
m/z 667 [(M+H)+, 38%], 1334 [(M2+H)+, 7%]; HRMS
(ESI): calcd for C42H42N4O4Na (M+Na)+: 689.3098, found
689.3094.
4.6.8. 1-Ser. Starting from 6-Ser [prepared from 5-Ser
(P¼Cbz) (6.56 g, 19.1 mmol)], pyridine-2,6-dicarboxylic
acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g, 21.1 mmol),
the title compound (3.42 g, 65%) was obtained as a white
solid by precipitation from acetone/Et2O. Mp: 250–
4.8. Compound 8
A mixture of (S)-N-(3,5-dimethylphenyl)-2-hydroxy-3-
phenylpropamide (5.43 g, 19.1 mmol), pyridine-2,6-dicarb-
oxylic acid (1.60 g, 9.6 mmol), and EDCI (6.26 g,
21.1 mmol) in THF was stirred at 20 ꢁC for 24 h. The target
compound (4.83 g, 75%) was obtained as a white solid by
precipitation from acetone/Et2O. Mp: 140–141 ꢁC; [a]D
1
251 ꢁC; [a]D +156.2 (c 0.60, DMF); H NMR: d 10.05
(2H, s), 9.01 (2H, d, J¼7.8), 8.31–8.20 (3H, m), 7.31 (4H,
s), 6.75 (2H, s), 5.25 (2H, br s), 4.80–4.70 (2H, m), 3.98–
3.88 (4H, m), 2.27 (12H, s); 13C NMR: d 168.4, 163.4,
148.8, 139.5, 138.7, 137.6, 124.9, 117.2, 61.6, 56.4, 21.1;
MS (FAB): m/z 548 [(M+H)+, 36%], 1095 [(M2+H)+, 2%];
HRMS (L-SIMS): calcd for C29H33N5O6 (M+H)+:
548.2504, found 548.2502.
1
+6.1 (c 0.50, DMF); H NMR: d 10.21 (2H, s), 8.32–8.21
(3H, m), 7.50 (4H, d, J¼9.0), 7.35 (4H, t, J¼9.0), 7.30–
7.20 (6H, m), 6.77 (2H, s), 5.51 (2H, dd, J¼6.0 and 3.3),
3.43–3.30 (4H, m), 2.27 (12H, s); 13C NMR: d 166.7,
163.1, 147.2, 139.4, 138.1, 137.7, 136.4, 129.5, 128.2,
126.6, 125.2, 117.3, 75.7, 37.3, 20.9; MS (FAB): m/z 670
[(M+H)+, 26%]; HRMS (L-SIMS): calcd for C41H40N3O6
(M+H)+: 670.2912, found 670.2921; Anal. Calcd for
C41H39N3O6: C, 73.52, H, 5.87, N, 6.27. Found: C, 73.31,
H, 5.93, N, 6.20.
4.6.9. 1-Asn. Starting from 6-Asn [prepared from 5-Asn
(P¼Cbz) (7.07 g, 19.1 mmol)], pyridine-2,6-dicarboxylic
acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g, 21.1 mmol),
the target compound (3.51 g, 61%) was obtained as a white
solid by precipitation from acetone/Et2O. Mp: >243 ꢁC
1
(dec); [a]D +122.8 (c 0.65, DMF); H NMR: d 10.03 (2H,
4.9. Compound 9
s), 9.52 (2H, d, J¼9.0), 8.30–8.27 (3H, m), 7.60 (2H, s),
7.29 (4H, s), 7.07 (2H, s), 6.74 (2H, s), 4.94 (2H, q,
J¼7.8), 2.82 (4H, d, J¼7.8), 2.26 (12H, s); 13C NMR:
d 171.8, 169.2, 163.0, 148.3, 139.8, 138.7, 137.6, 124.9,
124.5, 117.3, 51.2, 36.8, 21.1; MS (FAB): m/z 602
[(M+H)+, 10%]; HRMS (L-SIMS): calcd for C31H36N7O6
(M+H)+: 602.2722, found 602.2724.
The Cbz protecting group in (S)-N-butyl-2-benzyloxycar-
bonylamino-3-phenylpropamide (6.79 g, 19.1 mmol) was
removed according to Section 4.5 to give the corresponding
free amino compound. The crude product was stirred with
pyridine-2,6-dicarboxylic acid (1.60 g, 9.6 mmol) and
EEDQ (5.21 g, 21.1 mmol) in THF at 20 ꢁC for 24 h. The
solvent was evaporated under reduced pressure and the
target compound (3.85 g, 70%) was obtained as a white solid
by flash chromatography (eluent: hexane/acetone¼1/1). Rf:
0.69 (hexane/acetone¼1/1); Mp: 165–166 ꢁC; [a]D ꢂ35.8
4.6.10. 1-Pro. Starting from 6-Pro [prepared from 5-Pro
(P¼Cbz) (6.75 g, 19.1 mmol)], pyridine-2,6-dicarboxylic
acid (1.60 g, 9.6 mmol), and EEDQ (5.21 g, 21.1 mmol),
the target compound (3.28 g, 60%) was obtained as a white
1
(c 0.50, CHCl3); H NMR (CDCl3): d 8.48 (2H, d, J¼8.1),

7418
H.-F. Chow, G.-X. Wang / Tetrahedron 63 (2007) 7407–7418
Miwa, Y.; Taga, T.; Nakano, M.; Handa, T. J. Am. Chem. Soc.
2001, 123, 11817–11818; (g) Mamiya, J.-i.; Kanie, K.;
Hiyama, T.; Ikeda, T.; Kato, T. Chem. Commun. 2002, 1870–
1871; (h) Loiseau, J.; Lescanne, M.; Colin, A.; Fages, F.;
Verlhac, J.-B.; Vincent, J.-M. Tetrahedron 2002, 58, 4049–
4052; (i) Jung, J. H.; Shinkai, S.; Shimizu, T. Chem.—Eur. J.
2002, 8, 2684–2690; (j) van Gorp, J. J.; Vekemans,
J. A. J. M.; Meijer, E. W. J. Am. Chem. Soc. 2002, 124,
14759–14769; (k) Yun, Y. J.; Park, S. M.; Kim, B. H. Chem.
Commun. 2003, 254–255; (l) Ikeda, M.; Takeuchi, M.;
8.29 (2H, d, J¼7.8), 7.99 (1H, t, J¼7.8), 7.34–7.20 (10H, m),
5.89 (2H, t, J¼5.7), 4.79 (2H, q, J¼7.8), 3.29–3.05 (8H, m),
1.40–1.25 (4H, m), 1.25–1.10 (4H, m), 0.85 (6H, t, J¼7.2);
13C NMR (CDCl3): d 170.3, 163.3, 148.4, 138.9, 136.8,
129.4, 128.8, 127.0, 125.3, 55.4, 39.3, 38.5, 31.3, 19.9,
13.7; MS (FAB): m/z 572 [(M+H)+, 90%]; HRMS
(L-SIMS): calcd for C33H42N5O4 (M+H)+: 572.3231, found
572.3233.
4.10. CD experiments
ꢀ
Shinkai, S. Chem. Commun. 2003, 1354–1355; (m) D’Aleo,
A.; Pozzo, J.-L.; Fages, F.; Schmutz, M.; Mieden-Gundert,
1-Phe (45 mg) was dissolved in hot p-xylene (3 mL) and
transferred to a quartz cell (1 cm path length). It was then
cooled down to allow for gel formation. The temperature
of the cell was then increased to the specified temperature
via the temperature controller. The measurement was done
from the gel state (20–60 ꢁC) to the solution state (100 ꢁC)
at increasing temperature.
€
G.; Vogtle, F.; Caplar, V.; Zinic, M. Chem. Commun. 2004,
190–191; (n) Reichwagen, J.; Hopf, H.; Del Guerzo, A.;
Belin, C.; Bouas-Laurent, H.; Desvergne, J.-P. Org. Lett.
2005, 7, 971–974.
3. For examples of low molecular weight amino acid-based gela-
tors containing long aliphatic hydrocarbon chains for organic
solvents, see (a) Hanabusa, K.; Itoh, A.; Kimura, M.; Shirai,
H. Chem. Lett. 1999, 767–768; (b) Hanabusa, K.; Matsumoto,
M.; Kimura, M.; Kakehi, A.; Shirai. J. Colloid Interf. Sci.
2000, 224, 231–244; (c) Luo, X.; Liu, B.; Liang, Y. Chem.
Commun. 2001, 1556–1557; (d) Suzuki, M.; Waraksa, C. C.;
Nakayama, H.; Hanabusa, K.; Kimura, M.; Shirai, H. Chem.
Commun. 2001, 2012–2013; (e) Wang, G.; Hamilton, A. D.
Chem.—Eur. J. 2002, 8, 1954–1961; (f) Suzuki, M.; Sato, T.;
Kurose, A.; Shirai, H.; Hanabusa, K. Tetrahedron Lett. 2005,
46, 2741–2745.
4.11. SEM experiments
1-Phe (15 mg) and 1-Asp b-benzyl ester (15 mg) were dis-
solved in the specified solvent (p-xylene or CCl4) (1 mL)
separately. The samples were freeze-dried on a Labconco
Freezone 6LT Freezer Dry System under 50ꢃ10ꢂ3 mbar at
ꢂ47 ꢁC for 7 days. The SEM images were taken by a Leo
Scanning Electron Microscope as described previously.6a
4. For example see Yoza, K.; Amanokura, N.; Ono, Y.; Akao, T.;
Shinmori, H.; Takeuchi, M.; Shinkai, S.; Reinhoudt, D. N.
Chem.—Eur. J. 1999, 5, 2722–2729.
5. For examples of low molecular weight amino acid-based gela-
tors that do not contain long aliphatic hydrocarbon chains for
Acknowledgements
The work described in this paper was supported by a Direct
Grant (Account No. 2060251) and a Focused Investment into
Areas of Strength: Specialized Areas (Scheme B) by The
Chinese University of Hong Kong. H.-F.C. is a recipient of
the Croucher Senior Research Fellowship, Hong Kong
(2006–07).
´
´
´
organic solvents, see (a) Makarevic, J.; Jokic, M.; Peric, B.;
Tomisic, V.; Kojic-Prodic, B.; Zinic, M. Chem.—Eur. J. 2001,
´
ˇ
ꢁ ´
´
´
´
´
7, 3328–3341; (b) Makarevic, J.; Jokic, M.; Frkanec, L.;
ˇ
´
´
Katalenic, D.; Zinic, M. Chem. Commun. 2002, 2238–2239;
(c) Becerril, J.; Burguete, M. I.; Escuder, B.; Galindo, F.;
Gavara, R.; Miravet, J. F.; Luis, S. V.; Peris, G. Chem.—Eur.
J. 2004, 10, 3879–3890; (d) Broose, N.; Barth, D.; Jamart-
References and notes
ꢀ
1. For reviews on organogelators on organic solvents, see: (a)
Terech, P.; Weiss, R. G. Chem. Rev. 1997, 97, 3133–3159; (b)
van Esch, J. H.; Feringa, B. L. Angew. Chem., Int. Ed. 2000,
39, 2263–2266; (c) Cronwald, O.; Snip, E.; Shinkai, S. Curr.
Gregoire, B. Tetrahedron Lett. 2004, 45, 9521–9524; (e)
Chow, H.-F.; Zhang, J.; Lo, C.-M.; Cheung, S.-Y.; Wong,
K.-W. Tetrahedron 2007, 63, 363–373.
6. (a) Chow, H.-F.; Zhang, J. Chem.—Eur. J. 2005, 11, 5817–
5831; (b) Chow, H.-F.; Zhang, J. Tetrahedron 2005, 61,
11279–11290.
ˇ
Opin. Colloid Interf. Sci. 2002, 7, 148–156; (d) Zinic, M.;
€
Vogtle, F.; Fages, F. Top. Curr. Chem. 2005, 256, 39–76; (e)
ˇ
€
Fages, F.; Vogtle, F.; Zinic, M. Top. Curr. Chem. 2005, 256,
77–131; (f) Araki, K.; Yoshikawa, I. Top. Curr. Chem. 2005,
256, 133–165; (g) Kato, T.; Mizoshita, N.; Moriyama, M.;
Kitamura, T. Top. Curr. Chem. 2005, 256, 219–236.
7. Mong, T. K.-K.; Niu, A.; Chow, H.-F.; Wu, C.; Li, L.; Chen, R.
Chem.—Eur. J. 2001, 7, 686–699.
8. Parquette, J. R. Chimie 2003, 6, 779–789 and references cited
therein.
2. For selected examples of low molecular weight gelators con-
taining long aliphatic hydrocarbon chains for organic solvents,
see (a) Hanabusa, K.; Yamada, M.; Kimura, M.; Shirai, H.
Angew. Chem., Int. Ed. 1996, 35, 1949–1951; (b) van Esch,
J.; Schoonbeek, F.; de Loos, M.; Kooijman, H.; Spek, A. L.;
Kellogg, R. M.; Feringa, B. L. Chem.—Eur. J. 1999, 5, 937–
950; (c) Hafkamp, R. J. H.; Feiters, M. C.; Nolte, R. J. M.
J. Org. Chem. 1999, 64, 412–416; (d) Beginn, U.; Tartsch, B.
Chem. Commun. 2001, 1924–1925; (e) Ajayaghosh, A.;
George, S. J. J. Am. Chem. Soc. 2001, 123, 5148–5149; (f)
Tomioka, K.; Sumiyoshi, T.; Narui, S.; Nagaoka, Y.; Iida, A.;
9. Pyridine-2,6-dicarboxamides bearing two dipeptide pendant
chains had been reported. However, no gelation property was
noted for these compounds, see Yu, Q.; Baroni, T. E.; Liable-
Sands, L.; Yap, G. P. A.; Rheingold, A. L.; Borovik, A. S.
Chem. Commun. 1999, 1467–1468.
10. To our knowledge, there are only two examples where both
intra- and inter-molecular hydrogen bondings are involved in
the gelation, see (a) Yabuuchi, K.; Marfo-Owusu, E.; Kato, T.
Org. Biomol. Chem. 2003, 1, 3464–3469; (b) Tsou, C.-C.;
Sun, S.-S. Org. Lett. 2006, 8, 387–390.
11. Bauer, T.; Gajewiak, J. Tetrahedron 2004, 60, 9163–9170.