A 1,4-diphenyl-1,2,3-triazole-based β-turn mimic constructed by click chemistry

Article abstract of DOI:10.1021/jo300063u

A series of 1,4-diphenyl-1,2,3-triazole-incorporated amide derivatives have been designed and prepared. X-ray crystallographic and (1D and 2D) ¹H NMR studies reveal that these compounds fold into stable U-shaped conformations driven by three-center intramolecular C-H???O hydrogen-bonding formed between the triazole C-5 H atom and the two ether O atoms. Such folded structures make this 1,4-diphenyl-1,2,3-triazole skeleton a good candidate to be used as β-turn mimic. To prove this, the formation of a β-hairpin structure induced by this β-turn motif has been further demonstrated.

Full text of DOI:10.1021/jo300063u

Article
pubs.acs.org/joc
A 1,4-Diphenyl-1,2,3-Triazole-Based β-Turn Mimic Constructed by
Click Chemistry
Chun-Fang Wu, Xin Zhao,* Wen-Xian Lan, Chunyang Cao, Jin-Tao Liu, Xi-Kui Jiang, and Zhan-Ting Li*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A series of 1,4-diphenyl-1,2,3-triazole-incorpo-
rated amide derivatives have been designed and prepared. X-
1
ray crystallographic and (1D and 2D) H NMR studies reveal
that these compounds fold into stable U-shaped conformations
driven by three-center intramolecular C−H···O hydrogen-
bonding formed between the triazole C-5 H atom and the two
ether O atoms. Such folded structures make this 1,4-diphenyl-
1,2,3-triazole skeleton a good candidate to be used as β-turn
mimic. To prove this, the formation of a β-hairpin structure induced by this β-turn motif has been further demonstrated.
employing acyclic artificial peptides, which folded into U-
shaped conformations driven by intramolecular N−H···O
hydrogen-bonding. In this context, the Nowick group
succeeded in designing a series of urea derivatives10 and 5-
amino-2-methoxybenzoic acid,11 on the basis of which a variety
of mimic structures have been constructed. On the other hand,
a convergent method, in which two peptide strands are first
constructed respectively and then combined by intermolecular
ligation to form a β-sheet structure, should also be attractive
because it provides an efficient access to structurally diverse β-
turn-containing molecules. In 2006, Guan et al. reported a
convergent synthesis of β-turn mimics via the Cu (I)-catalyzed
azide−alkyne cycloaddition,12 in which the β-turn structures
were induced and stabilized by intramolecular NH···OC
INTRODUCTION
■
As one of the most typical secondary structures, β-sheets have
been found in most proteins.1 To facilitate the formation of a β-
sheet, one peptide strand usually needs to adopt a U-shaped
conformation, in which two segments of the peptide strand can
be arranged in a parallel or antiparallel manner stabilized by
intramolecular CO···HN hydrogen bonds formed be-
tween the amides of the two peptide segments arranged in
reverse directions. In nature, this process is usually induced by
several specific glycin- and proline-rich peptide sequences
named β-turns.2 For this reason, β-turns have been considered
to be extremely important in many biological processes
including protein−protein, protein−peptide, and protein−
DNA interactions, biomolecular recognition, phosphorylation,
glycosylation, and hydroxylation.3 In the past decades, the
development of artificial β-turn mimics has attracted a great
deal of interest because progress along this line not only
provides insight into the basic principles governing the high-
order structures of biological macromolecules, but also is useful
in designing potential drug candidates that can mimic the
functions of natural β-turns.
Currently, a variety of chemical structures have been
designed to resemble β-turns. The representative examples
include 2,2′-substituted tolan adopted by the Kemp group,4
phenoxathiin derivatives developed by Figel5 and Sogah,6
dibenzofuran-based amino acids reported by Kelly et al.,7
tetrasubstituted alkenes reported by the Gellman group,8 as
well as amino(oxo)piperidinecarboxylate scaffolds designed by
Borggraeve and co-workers.9 In these examples, β-turn motifs
have been constructed through arranging two docking sites
(amino group and carboxyl group) in nearby positions on a
rigid skeleton, and then two peptide strands designed to
construct artificial β-sheet structures could be attached to the β-
turn skeleton in a step by step manner. In another approach,
the mimics of β-turn structures have been achieved by
hydrogen bonds between the two clicked dipeptide strands.13
A
similar strategy has also been employed by Burgess et al. to
construct cyclic β-turn motifs.14 We recently reported a series
of 1,4-di(2-methoxyl and/or i-butoxy)phenyl-1,2,3-triazole
derivatives whose structures were fixed into folded conforma-
tions through the formation of intramolecular six-membered
three-center C−H···O hydrogen bonding between the C−H of
triazole unit and the oxygen atoms of the methoxyl or i-butoxy
groups substituted at the ortho positions of the phenyl rings.15
We anticipated that this skeleton could be further exploited as a
novel β-turn mimic because of the stable folded conformation,
the high efficiency structure construction (via click chemistry),
and most importantly, the convergent approach to independ-
ently introduce two peptide strands. In this paper, we report a
systematic investigation on the feature of this 1,4-diphenyl-
1,2,3-triazole-based β-turn mimic through X-ray crystallo-
1
graphic and (1D and 2D) H NMR studies on a series of
rationally designed derivatives. We further demonstrate the
Received: January 12, 2012
Published: April 10, 2012
© 2012 American Chemical Society
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Scheme 1. Structures of Compounds T1−T5 and the 1,4-Diphenyl-1,2,3-triazole Skeleton with Related Atoms Being Labeled
capacity of this motif by using it to nucleate a β-hairpin, the
shortest β-sheet structure.
2.31 Å, while the other ring has a little bit longer distance of
2.34 Å. The H···N distance between N2 of the triazole unit and
C13−H of the N1-substituted benzene ring was 2.38 Å, and the
H···N distance between N3 of the triazole unit and C7−H of the
C4-substituted benzene ring was 2.47 Å. Both of them were
notably shorter than the sum of the van der Waals radii (2.65
Å), indicating the formation of two five-membered C−H···N
hydrogen bonds. Furthermore, intramolecular hydrogen
bonding was also observed between the OCH2CO of the
upper chain and the oxygen of the carbonyl group of the
bottom chain with a distance of 2.35 Å. The torsion angles
between the triazole unit and the two benzenes are 2.62° (the
one at C4) and 3.43° (the one at N1), respectively, suggesting
that all the three rings almost lay in the same plane. With the
cooperation of these hydrogen bonds, compound T1 adopts a
planar U-shaped conformation, which nicely meets the
structural requirement for a β-turn unit. Thus, it should
facilitate the formation of β-sheets when the two carboxyl units
are extended by suitable peptide strands.
RESULTS AND DISCUSSION
■
Design and Synthesis. Compound T1 was designed as the
model of β-turn mimic, while compounds T2−T4 carry two
amide chains with different terminal alkyl groups and different
spacer lengths between the triazole unit and a docking site to
test the conformation and stability of this β-turn mimic. T5 was
designed to examine the capability of this β-turn mimic to
induce the formation of β-sheet structure (Scheme 1).
All the target compounds were synthesized using a
convergent strategy. That is, coupling one segment bearing
an azide group with another one bearing an alkynyl group via
Cu (I)-catalyzed azide−alkyne cycloaddition. For the synthesis
of T1 (Scheme 2), 2-iodophenol was first reacted with ethyl 2-
chloroacetate in the presence of potassium carbonate to give
compound 2 in 97% yield, which was then coupled with
trimethylsilylacetylene catalyzed by PdCl2(PPh3)2 and CuI to
afford compound 3 in 95% yield. Treatment of 3 with TBAF
generated alkyne 4 in 80% yield. For the azide segment, 2-
aminophenol was first treated with sodium nitrite and
hydrochloric acid (2 M), and then the resulting solution was
treated with sodium azide to give compound 6 in 85% yield.
This intermediate was further treated with ethyl 2-chloroacetate
to generate azide 7 in 95% yield. With the alkyne and azide
precursors available, compound T1 was obtained via a 1,3-
dipolar cycloaddition reaction in the presence of sodium
ascorbate and copper sulfate in 70% yield. For the preparation
of compounds T2−T5, similar procedures were followed using
corresponding phenylacetylenes and azides, which are shown in
Scheme 2. Compounds T1−T5 have been characterized by 1H
and 13C NMR spectroscopies and (high resolution) mass
Structures in Solution. The conformations of compounds
1
T1−T4 were investigated in CDCl3 solutions by H NMR
spectroscopy. For compound T1, the signal of the triazole C5−
H appeared at 9.20 ppm, which is considerably lower than the
C5−H resonance of 1,4-bis(4-methoxyphenyl)-1,2,3-triazole
(8.00 ppm).14 Compared with the corresponding signals of
its precursors 4 and 7, the signals of C7−H and C13−H of T1
were also shifted downfield pronouncedly by 1.00 and 0.96
ppm, respectively (Figure S2, Supporting Information),
suggesting that both protons were also hydrogen-bonded,
which is in agreement with the observation in its crystal
structure. In the case of T2, compared to those of its precursors
9 and 12 of the same concentration, its amide proton Ha was
shifted downfield by 0.68 ppm, while the amide Hb just showed
very little change (ca. 0.06 ppm) (Figure 2). This result
suggests that the former amide proton was hydrogen-bonded,
while the latter was mainly solvent-exposed. Furthermore, the
resonances of C5−H, C7−H, and C13−H also appeared in the
far-low field. All these observations support the existence of the
intramolecular hydrogen-bonds that induce the molecule to
form a U-shaped conformation similar to that shown by T1 in
the crystal structure.
1
spectrometry, and their signals in the H NMR spectra have
1
been assigned on the basis of the 2D NOESY, and COSY H
NMR and/or DEPT135°, HMQC, HMBC experiments.
Crystal Structure of T1. Single crystals of compound T1
suitable for X-ray crystallographic analysis were grown from a
mixture of ethyl acetate and cyclohexane by slow evaporation of
the solvent. As shown in Figure 1, its crystal structure revealed
the formation of two intramolecular C5−H···O hydrogen
bonds. One is six-membered ring with the H···O distance being
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Scheme 2. Synthetic Routes for Compounds T1−T5
1
The H NMR spectra of compounds T3−T4 in CDCl3
and C13−H signals, which could be attributed to the formation
of the C−H···O and C−H···N hydrogen bonds, as revealed by
T1 and T2, the amide proton Ha of T3 was shifted downfield
by 0.69 ppm with respect to the amide signal of its precursors.
exhibit similar trends (Figures S3−S4, Supporting Informa-
tion), supporting the β-turn feature of their structures. In
addition to the large downfield shifting of the C5−H, C7−H,
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indicated T2 folded into a β-turn conformation driven by
intramolecular hydrogen-bonding.
For compounds T1 and T3−T4, similar interstrand NOE
contacts were observed (Figures S8, S10, and S11, Supporting
Information). In the case of T1, C5−H of the triazole exhibited
NOE connections with protons of both the OCH2CO units of
upper and bottom strands. For compound T3, in addition to
the similar NOE connections as described above for T1, NOEs
between the C5−H of the triazole ring and the two amide
protons and between the NCH2 of the upper strand and the
terminal methyl group of the lower strand were also observed.
The NOESY spectrum of compound T4 also revealed NOEs
between the C5−H of the triazole ring and the amide protons
as well as the protons of two OCH2 units and between the
terminal methyl group of the upper strand and the amide
proton of the lower strand. The NOE contacts are summarized
in Figure 4. These results confirmed that all these compounds
adopted β-turn structures in solution. The fact that NOEs are
observed between the C5−H of triazole unit and both the
amide protons of the upper and lower strands for T2−T4
suggests that the two strands might rotate to some extent,
which leads to two folded conformations. On the basis of the
1H NMR results above, conformer-a was considered to be
favorable over conformer-b.
Construction of a β-Hairpin Structure. Compound T5,
which bears two artificial dipeptide strands, was further
prepared to test the capability of this “clicked” unit to induce
the formation of β-hairpin, the shortest β-sheet analogue. The
1H NMR spectra of T5 and its precursors 22 and 25 of the
same concentration in CDCl3 are provided in Figure 5. It can
be found that, compared to the related signals of the two
controls, the amide protons of the two strands of T5 are all
shifted downfield considerably, indicating that they are involved
in intramolecular hydrogen bonding. In principle, the two
peptide chains of T5 may form two different conformations
(T5-a and T5-b), both of which can be stabilized by the
intramolecular hydrogen bonds, as illustrated in Figure 5. Since
amide proton Ha experienced a larger downfield shifting (0.53
ppm) than amide proton Hc (0.32 ppm), conformer T5-a may
be the preferred one. Diluting the solution of T5 from 100 mM
to 0.5 mM caused the signals of the Ha, Hb, Hc, and Hd protons
to shift upfield by 0.16, 0.30, 0.37, and 0.44 ppm, respectively
(Figure S12, Supporting Information). The fact that Ha
experienced the smallest shift seems to indicate that it was
involved in the strongest intramolecular hydrogen-bonding,
while the other protons might be engaged in intermolecular
hydrogen bonding to a higher extent at high concentration.
Figure 1. The crystal structure of compound T1, highlighting its β-
turn character.
The shifting value is the same as that of T2, indicating that the
terminal alkyl groups in these molecules did not have much
impact on the turn conformation. After combining the two
strands by the click chemistry, the amide proton of the bottom
chain of T4 exhibited a downfield shift of 0.35 ppm. This result
suggested that this hydrogen was also involved in the formation
of the intramolecular hydrogen bonding, and the molecule also
adopted a U-shaped conformation. However, the change of this
chemical shifting for T4 is just half of the value observed for T2
and T3, implying that the folded conformation of T4 is not as
stable as those of T2 and T3. This might be attributed to the
longer distance (one more carbon) between the β-turn unit and
the docking site (carboxyl group) in T4 than that in T2 and T3,
which weakens the β-sheet-inducing capability of the triazole
moiety. 1H NMR dilution experiments were also carried out for
compounds T2−T4 (Figure S5−S7, Supporting Information).
It was found that diluting their solutions from 50 mM to 0.5
mM just caused very small shifting of the NH signals,
suggesting that no important intermolecular hydrogen-bond-
ing-driven aggregation took place in the range of the
concentrations tested.
More compelling evidence for the formation of β-turn
1
mimics were provided by 2D NOESY H NMR experiments.
The NOESY spectrum of T2 is provided in Figure 3 as an
example. The spectrum gave rise to a number of NOE contacts,
including those between the C5−H of the triazole ring and
amide protons Ha and Hb and methylene protons H1 and that
3
between the terminal methyl groups (CH32 and CH3 ). Similar
NOE correlations were also observed for a solution of T2 at 2
mM (Figure S9, Supporting Information). These results clearly
1
Figure 2. Partial H NMR (400 MHz) spectra of (a) 9, (b) T2, and (c) 12 in CDCl3 (20 mM) at 25 °C.
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Figure 3. NOESY spectrum (400 MHz) of compound T2 in CDCl3 (20 mM) at 25 °C (mixing time = 0.8 s).
Figure 4. NOE contacts observed for compounds T1, T3, and T4 in CDCl3.
This result again supports that conformer T5-a is favorable over
conformer T5-b.
typical structure of a β-hairpin. The existence of NOE
connections between C5−H and both H1 and H5 also suggested
that compound T5 adopted two different conformations.
Further analysis of the NOESY spectrum of T5 revealed that
the intensity of NOE between C5−H and H5 was weaker than
that between C5−H and H1, which again supported that
conformer T5-a was favorable over conformer T5-b. In
contrast, under similar condition no NOE correlations between
the protons of the two dipeptide strands could be observed for
a mixture of compounds 22 and 25 (1:1, 20 mM), the
precursors of T5 (Figure S14, Supporting Information). This
2D NOESY 1H NMR experiment was further carried out for
compound T5 to obtain more evidence for the formation of β-
hairpin structure (Figure 6). Strong NOE connections were
exhibited between C5−H of the trazole ring and the methylene
protons H1 and H5 as well was the amide protons Ha and Hc.
Furthermore, interstrand NOE cross-peaks were also observed
between H2 and H6, H2 and Hc, H7 and Hb, and H4 and H7.
These results clearly indicated that the two dipeptide strands
were orientated in close proximity, well corresponding to the
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1
Figure 5. Partial H NMR (400 MHz) spectra of (a) 22, (b) T5, and (c) 25 in CDCl3 (20 mM) at 25 °C.
Figure 6. NOESY spectrum (400 MHz) of T5 in CDCl3 (20 mM) at 25 °C (mixing time = 0.6 s). NOESY spectrum (600 MHz) was also
performed for a solution of T5 in CDCl3 at 2 mM, and a similar result was obtained; see Figure S13 (Supporting Information) for details.
control experiment confirmed again that the NOE connections
detected in T5 should originate from a β-hairpin structure, not
from a result of intermolecular aggregation of the molecules.
U-shaped conformation mediated by intramolecular N−H···O
hydrogen-bonding, the new β-turn mimic is realized by the
formation of a folded conformation driven by intramolecular
C−H··O hydrogen-bonding. Because of the unique feature of
the click chemistry, this approach provides some advantages:
(i) mild reaction condition, high efficiency, and tolerance of
various functional groups, (ii) a convergent approach by which
the two peptide strands designed to construct artificial β-sheets
can be prepared separately and efficiently, and (iii)
CONCLUSION
■
To conclude, we have developed a novel β-turn mimic based on
a hydrogen-bonded triazole motif. Different from previously
reported rigid cyclic skeletons, which point two docking sites in
the same direction, or artificial acylic peptides, which fold into
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1
compound 4 as an oily liquid (607 mg, 80%): H NMR (300 MHz,
CDCl3) δ 7.49 (d, J = 7.5 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 1 H), 6.96 (t, J
= 7.5 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 4.73 (s, 2 H), 4.26 (q, J = 7.2
Hz, 2 H), 3.32 (s, 1 H), 1.29 (t, J = 7.2 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 168.6, 159.0, 134.4, 130.1, 121.6, 112.4, 112.1, 81.7,
79.6, 66.0, 61.4, 14.1; MS (ESI) m/z 205.0 [M + 1]+. HRMS (ESI)
Calcd. for C12H12O3Na [M + Na]+: 227.06787. Found: 227.06810.
Compound 6. 2-Aminophenol (764 mg, 7 mmol) was dissolved in
2 M HCl (aq, 10 mL) and chilled with stirring in an ice−salt mixture.
An ice-cold solution of sodium nitrite (580 mg, 8.4 mmol) in water (2
mL) was added dropwise during 5 min with the temperature of the
reaction mixture maintained at −3 to −5 °C. After a further 5 min,
urea (50 mg) was added to destroy the excess of nitrous acid. This
diazonium salt solution was then added dropwise to a stirred ice-cold
solution of sodium azide (910 mg, 14 mmol) and sodium acetate (1.65
mg) in water (10 mL). The mixture was stirred in an ice-bath for 2 h.
The black oily product was then extracted into diethyl ether (2 × 25
mL). The combined organic phase was dried with sodium sulfate.
After being concentrated, the crude product was purified by flash
chromatography (PE/CH2Cl2, 5:1) to give compound 6 as a black
synchronously forming β-turn motif when the two peptide
strands are intermolecular ligated. The successful construction
of β-hairpin structure T5 here implies that more complex β-
sheet structures nucleated by this triazole-based β-turn mimic
could be expected. This potential will be explored in the next
step.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under a dry
nitrogen atmosphere. All solvents were dried before use following the
standard procedures. Unless otherwise indicated, all starting materials
were obtained from commercial suppliers and were used without
further purification. Analytical thin-layer chromatography (TLC) was
performed on 0.2 mm silica 60 coated on glass plates with F254
indicator. The 1H and 13C NMR spectra were recorded on 300 or 400
MHz spectrometers in the indicated solvents. Chemical shifts are
expressed in parts per million (δ) using residual solvent protons as
internal standards (chloroform δ 7.26 ppm).
Safety Comment. Sodium azide is very toxic, and personal
protection precautions should be taken. As low molecular weight
organic azides are potential explosives, care must be taken during their
handling. Generally, when the total number of carbon (NC) plus
oxygen (NO) atoms is less than the total numbers of nitrogen atoms
(NN) by a ratio of three, i.e., (NC + NO)/NN < 3, the compound is
considered as an explosive hazard. In those instances, the compound
was prepared prior to use and used immediately. A standard PVC blast
shield should be used when necessary.
1
solid (805 mg, 85%): mp 35−36 °C; H NMR (400 MHz, CDCl3) δ
8.61 (s, 1 H), 7.01 (m, 2 H), 6.89 (m, 2 H).
Compound 7. A suspension of 6 (752 mg, 5.6 mmol), K2CO3
(1.84 g, 11.4 mmol), KI (1.85 g, 16.8 mmol), and ethyl 2-chloroacetate
(1.2 mL, 11.4 mmol) in DMF (30 mL) was stirred for 12 h, and then
the solid was filtrated off. The filtrate was concentrated with a rotary
evaporator, and the resulting residuum was dissolved in ethyl acetate
(100 mL). The organic phase was washed with water (50 mL) and
brine (50 mL) and dried over sodium sulfate. Upon removal of the
solvent under reduced pressure, the crude product was purified by
flash chromatography (PE/CH2Cl2, 2:1) to give compound 7 as a
Compound 2. A suspension of 2-iodophenol (6.62 g, 30 mmol),
K2CO3 (14.45 g, 90 mmol), and ethyl 2-chloroacetate (3.8 mL, 36
mmol) in DMF (35 mL) was stirred for 12 h at room temperature,
and then the solid was filtrated off. The filtrate was concentrated under
reduced pressure, and the resulting residuum was dissolved in ethyl
acetate (100 mL). The organic phase was washed with water (50 mL)
and brine (50 mL) and dried over sodium sulfate. Upon removal of
the solvent under reduced pressure, the crude product was purified by
flash chromatography (PE/EA, 15:1) to give compound 2 as a
colorless oil (8.91 g, 97%): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J =
7.8 Hz, 1 H), 7.28 (t, J1 = 8.4 Hz, J2 = 7.5 Hz, 1 H), 6.75(t, J1 = 8.4 Hz,
J2 = 7.8 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 1 H), 4.68 (s, 2 H), 4.27 (q, J =
7.2 Hz, 2 H), 1.30 (t, J = 7.6 Hz,3 H); MS (ESI) m/z 306.9 [M + 1]+.
Compound 3. Compound 2 (4.60 g, 15 mmol), PdCl2(PPh3)2
(199 mg, 0.28 mmol), and CuI (57 mg, 0.28 mmol) were placed in a
two-neck flask, which was degassed under a high vacuum and
backfilled with argon three times. Degassed tetrahydrofuran (15 mL)
and triethylamine (15 mL) were added and then followed by dropwise
addition of trimethylsilylacetylene (2.6 mL, 18 mmol). The reaction
mixture was stirred for 12 h at room temperature. The solid was
filtrated off, the filtrate was concentrated with a rotary evaporator, and
the resulting residuum was washed with water (50 mL), extracted with
diethyl ether (2 × 60 mL), dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (PE/EA, 25:1) to give compound 3 as a yellow oil
(3.95 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.45 (dd, J1 = 7.5 Hz, J2
= 1.5 Hz, 1 H), 7.25 (dd, J1 = 6.3 Hz, J2 = 1.2 Hz 1 H), 6.94 (t, J = 7.8
Hz, 1 H), 6.79 (d, J = 8.1 Hz,1H), 4.70 (s, 2 H), 4.28 (q, J = 7.2 Hz, 2
H), 1.30 (t, J = 7.2 Hz, 3 H), 0.26 (s, 9 H); 13C NMR (100 MHz,
CDCl3) δ 168.6, 158.8, 134.2, 129.8, 121.7, 113.4, 113.2, 100.8, 99.0,
66.4, 61.3, 14.2, 0.0 (3C); MS (ESI) m/z 277.2 [M + 1]+. HRMS
(ESI) Calcd. for C15H20O3SiNa [M + Na]+: 299.10739. Found:
299.10684.
1
yellow oil (1.15 g, 95%): H NMR (400 MHz, CDCl3) δ 7.03 (m, 3
H), 6.82 (d, J = 8.0 Hz, 1 H), 4.68 (s, 2 H), 4.27 (q, J = 7.6 Hz, 2 H),
1.29 (t, J = 7.6 Hz,3 H); 13C NMR (100 MHz, CDCl3) δ 168.5, 150.3,
129.3, 125.6, 122.8, 120.9, 114.0, 66.4, 61.6, 14.2; MS (ESI) m/z 244.1
[M + Na]+ HRMS (EI) Calcd. for C10H11N3O3: 221.0800. Found:
221.0797.
Compound T1. Compound 4 (135 mg, 0.61 mmol), compound 7
(112 mg, 0.55 mmol), CuSO4·5H2O (9 mg, 0.036 mmol), and sodium
ascorbate (15 mg, 0.076 mmol) were placed in a two-neck flask, which
was degassed under a high vacuum and backfilled with argon three
times. THF (4 mL), methanol (4 mL), and water (4 mL) were added.
The mixture was stirred about 12 h. After removal of the solvents
under vacuo, the resulting residuum was dissolved in CH2Cl2 (40 mL).
The solution was washed with water (20 mL × 2) and brine (20 mL ×
2) and dried over sodium sulfate. Upon removal of the solvent under
reduced pressure, the crude product was purified by recrystallization
(ethyl acetate/petroleum ether) to give compound T1 as a white
crystal (173 mg, 70%): mp 114−115 °C; 1H NMR (300 MHz,
CDCl3) δ 9.21 (s, 1 H), 8.48 (dd, J1 = 7.5 Hz, J2 = 1.5 Hz, 1 H), 7.93
(dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1 H), 7.39 (td, J1 = 7.8 Hz, J2 = 1.5 Hz, 1
H), 7.30 (td, J1 = 7.8 Hz, J2 = 1.5 Hz, 1 H), 7.17 (m, 2 H), 7.00 (d, J =
7.8 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 4.79 (s, 2 H), 4.76 (s, 2 H),
4.24 (m, 4 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.23 (t, J = 7.2 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 168.6, 168.4, 153.8, 149.6, 142.6, 129.6,
128.7, 128.1, 127.4, 126.2, 125.7, 122.4, 122.1, 120.4, 113.7, 111.6,
66.1, 65.5, 61.5, 61.4, 14.2, 14.1; MS (ESI) m/z 426.4 [M + 1]+. Anal.
Calcd. For C22H23N3O6: C, 62.11; H, 5.45; N, 9.88. Found: C, 61.92;
H, 5.49; N, 9.86.
Compound 8. A solution of compound 4 (208 mg, 1.02 mmol)
and LiOH·H2O (85 mg, 2.02 mmol) in a 1:1 mixture of THF/H2O (8
mL) was stirred at room temperature for 12 h. After removal of the
organic solvents, water was added (7 mL), followed by the addition of
hydrochloric acid until pH = 4. The resulting solid was filtrated and
Compound 4. A flask was charged with compound 3 (1.03 g, 3.73
mmol) and THF (15 mL), and the mixture was stirred in ice bath. A
solution of tetrabutyl ammonium fluoride (TBAF, 1.08 g, 4.12 mmol)
in THF (12 mL) was added dropwise to the former solution during 5
min. After work up, the reaction mixture was concentrated under
reduced pressure. The resulting residuum was dissolved in ethyl
acetate (40 mL), washed with water (20 mL) and brine (20 mL), and
dried over sodium sulfate. After being concentrated, the crude product
was purified by flash chromatography (PE/CH2Cl2, 3:1) to give
1
dried to give compound 8 (163 mg, 90%): mp 97−99 °C; H NMR
(300 MHz, CDCl3) δ 7.50 (dd, J1 = 8.4 Hz, J2 = 1.5 Hz, 1 H), 7.32 (td,
J1 = 7.8 Hz, J2 = 1.5 Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.83 (d, J = 8.4
Hz, 1 H), 4.78 (s, 2 H), 3.35 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ
173.4, 158.5, 134.4, 130.3, 122.2, 112.8, 112.3, 82.1, 79.4, 65.7; MS
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(ESI) m/z 175.04 [M − 1]−. HRMS (ESI) Calcd. for C10H7O3:
175.04007. Found: 175.03935.
CDCl3) δ 173.9, 149.5, 129.3, 125.6, 123.1, 120.6, 114.2, 65.8; MS
(ESI) m/z 192.0 [M − 1]−. HRMS (ESI) Calcd. for C8H6N3O3:
192.04146. Found: 192.04138.
Compound 9. A solution of compound 8 (352 mg, 2 mmol),
EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlor-
ide) (192 mg, 2.4 mmol), DMAP (10 mg), and butylamine (0.2 mL
2 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 4 h.
The solution was then washed with saturated aqueous NH4Cl (30
mL), saturated aqueous NaHCO3 (30 mL), and brine (30 mL) and
dried over MgSO4. After being concentrated, the crude product was
purified by column chromatography (PE/EA, 8:1) to give compound
9 as a yellow oil (566 mg, 80%): 1H NMR (400 MHz, CDCl3) δ 7.50
(dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1 H), 7.35 (m, 1 H), 7.00 (td, J1 = 7.2 Hz,
J2 = 0.8 Hz, 1 H), 6.96 (b, 1 H), 6.85 (d, J = 8.0 Hz,1 H), 4.54 (s, 2
H), 3.36 (m, 2 H), 3.32 (s, 1 H), 1.55 (m, 2 H), 1.39 (m, 2 H), 0.94 (t,
J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 167.6, 158.5, 134.0,
130.6, 121.9, 112.5, 111.8, 81.7, 79.8, 67.9, 38.7, 31.4, 20.0, 13.7; MS
(ESI) m/z 232.2 [M + 1] +. HRMS (EI) Calcd. for C14H17N1NaO2 [M
+ Na]+: 254.11515. Found: 254.11557.
Compound 14. A solution (in a sealed tube) of compound 13
(386 mg, 2 mmol), EDCI (499 mg, 2.6 mmol), DMAP (10 mg),
aminomethane hydrochloride (675 mg, 10 mmol), and DIPEA (N,N-
diisopropyl ethyl amine) (1.7 mL) in CH2Cl2 (20 mL) was stirred at 0
°C for 12 h. The solution was then washed with saturated aqueous
NH4Cl (30 mL), saturated aqueous NaHCO3 (30 mL), and brine (30
mL) and dried over MgSO4. After being concentrated, the crude
product was purified by column chromatography (PE/EA, 2:1) to give
1
compound 14 as a yellow power (125 mg, 30%): mp 61−63 °C; H
NMR (400 MHz, CDCl3) δ 7.06 (m, 3 H), 6.87 (d, J = 8.0 Hz, 1 H),
6.78 (b, 1 H), 4.51 (s, 2 H), 2.92 (d, 3 H); 13C NMR (100 MHz,
CDCl3) δ 168.4, 149.4, 128.8, 126.2, 123.1, 120.6, 114.4, 68.6, 25.9;
MS (ESI) m/z 229.0 [M + Na]+. HRMS (ESI) Calcd. for
C9H10N4O2Na [M + Na]+: 229.06960, Found: 229.06983.
Compound T3. Prepared in 96% yield as white powder from the
Compound 11. Isopropylamine (0.85 mL, 10 mmol) and Et3N
(2.7 mL, 20 mmol) were dissolved in CH2Cl2 (50 mL) and chilled
with stirring in an ice−salt mixture. Then chloro-acetyl chloride (1 mL,
13 mmol) was added dropwise to the solution, and stirring was
continued for 3 h in the ice−salt bath. The solution was then washed
with water (20 mL) and brine (20 mL) and dried over sodium sulfate.
After being concentrated, the crude product was purified by
recrystallization (ethyl acetate/petroleum ether) to give compound
reaction of compounds 9 and 14 according to a procedure similar to
that described for compound T2: mp 118−120 °C; H NMR (400
1
MHz, CDCl3) δ 8.33 (s, 1 H), 7.96 (dd, J1 = 4.0 Hz, J2 = 1.6 Hz, 1 H),
7.65 (b, 1 H), 7.60 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz,1 H), 7.52 (td, J1 = 8.0
Hz, J2 = 1.6 Hz,1 H), 7.39 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1 H), 7.22 (td,
J1 = 7.6 Hz, J2 = 1.2 Hz, 1 H), 7.16 (t, J = 7.2 Hz, 1 H), 7.12 (d, J = 8.0
Hz, 1 H), 6.99 (d, J = 8.0 Hz, 1 H), 6.90 (b, 1 H), 4.67 (s, 2 H), 4.62
(s, 2 H), 3.35 (m, 2 H), 2.83 (d, J = 4.8 Hz, 3 H), 1.53 (m, 2 H), 1.31
(m, 2 H), 0.86 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
168.1, 168.0, 154.1, 150.1, 143.9, 130.8, 129.6, 128.4, 126.5, 125.9,
124.5, 122.4, 122.1, 119.3, 113.8, 112.6, 68.0, 67.8, 38.9, 31.3, 25.7,
20.0, 13.6; MS (ESI) m/z 438.5 [M + 1]+. HRMS (MALDI-TOF)
Calcd. for C23H28N5O4: 438.2128. Found: 438.2136.
1
11 as a yellow powder (1.15 g, 85%): mp 50−52 °C; H NMR (400
MHz, CDCl3) δ 6.37 (b, 1 H), 4.10 (m, 1 H), 4.029 (s, 2 H), 1.21 (d, J
= 6.4 Hz, 6 H); MS (ESI) m/z 136.0 [M + 1]+.
Compound 12. Prepared in 68% yield as a yellow powder from
the reaction of compounds 6 and 11 according to a procedure similar
1
to that described for compound 7: mp 55−56 °C; H NMR (400
Compound 16. To a stirred solution of 3-chloropropanoic acid
(1.08 g, 10 mmol) in ice−water (3 mL), a solution of NaOH (0.4 g, 10
mmol) in ice−water (3 mL) was added. The resulting cold solution
was stirred for 30 min and added dropwise to a refluxing aqueous
solution (4 mL) containing 9 mmol of sodium 2-iodophenolate
(prepared from 1.98 g of 2-iodophenol and 0.4 g NaOH). After the
addition was completed, the reaction mixture was refluxed for an
additional 12 h. Upon being cooled to room temperature, the aqueous
solution was washed with CH2Cl2 (5 mL × 3). The aqueous solution
was then acidified to pH = 1 with dilute HCl and extracted with ether
(20 mL × 2). The combined ether extracts were washed with water
and brine and dried over sodium sulfate. After being concentrated, the
crude product was purified by recrystallization (ethyl acetate/
petroleum ether) to give compound 16 as a yellow powder (632
mg, 22%): mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (dd,
J1 = 8.0 Hz, J2 = 1.6 Hz, 1 H), 7.30 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1 H),
6.85 (d, J = 8.0 Hz, 1 H), 6.73 (t, J = 7.6 Hz, 1 H), 4.31 (t, J = 6.4 Hz,
2 H), 2.94 (t, J = 6.4 Hz, 2 H); MS (ESI) m/z 290.9 [M − 1]−.
Compound 17. Compound 16 (584 mg, 2 mmol), PdCl2 (PPh3)2
(42 mg, 0.06 mmol), and CuI (30 mg, 0.16 mmol) were placed in a
two-neck flask, which was degassed under a high vacuum and
backfilled with argon three times. Degassed THF (5 mL) and Et3N (5
mL) were added and followed by the dropwise addition
trimethylsilylacetylene (0.31 mL, 22 mmol). The reaction mixture
was stirred for 12 h at room temperature. The solid was filtrated off,
and the filtrate was concentrated with a rotavapor. The resulting
residuum was dissolved in aqueous NaOH (1 M, 10 mL) and stirred
for 5 min. The aqueous solution was then acidified to pH = 1 with
dilute HCl and extracted with ether (20 mL × 2). The combined ether
extracts were washed with water and brine, dried over sodium sulfate,
and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (PE/EA, 3:1) to give
compound 17 as a yellow powder (211 mg, 55%): mp 101−102 °C;
1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1
H), 7.30 (t, J = 8.0 Hz, 1 H), 6.94 (t, J = 7.6 Hz, 1 H), 6.92 (t, J = 8.0
Hz, 1 H), 4.34 (t, J = 5.6 Hz, 2 H), 3.25 (s, 1 H), 2.93 (t, J = 6.4 Hz, 2
H); 13C NMR (100 MHz, CDCl3) δ 175.7, 159.5, 134.2,130.2, 121.2,
112.2, 112.2, 81.4, 79.7, 64.2, 34.2; MS (ESI) m/z 189.0 [M − 1]−.
HRMS (ESI) Calcd. for C11H9O3:189.05572. Found: 189.05599.
MHz, DMSO) δ (d, J = 7.6 Hz, 1 H), 7.13 (m, 1 H), 7.05 (m, 1 H),
7.00 (m, 2 H), 4.53 (s, 2 H), 3.92 (m, 1 H), 1.08 (d, J = 7.6 Hz, 6 H);
13C NMR (100 MHz, (CD3)2CO) δ 166.9, 151.7, 129.3, 127.0, 123.4,
121.8, 115.5, 69.5, 41.7, 22.7 (2C); MS (ESI) m/z 257.0 [M + Na]+.
HRMS (EI) Calcd. for C11H14N4O2: 234.1117. Found: 234.1111.
Compound T2. Compound 9 (143 mg, 0.6 mmol), 12 (143 mg,
0.6 mmol), CuSO4·5H2O (14 mg, 0.056 mmol), sodium ascorbate (24
mg, 0.12 mmol), and TBTA (tris-(benzyl-triazolylmethyl)amine) (16
mg, 0.03 mmol) were placed in a two-neck flask, which was degassed
under a high vacuum and backfilled with argon three times. THF (5
mL), methanol (5 mL), and water (5 mL) were added. The mixture
was stirred about 12 h. After removal of the solvents under vacuo, the
resulting residuum was dissolved in CH2Cl2 (80 mL). The solution
was washed with water (30 mL × 2) and brine (30 mL × 2) and dried
over sodium sulfate. After being concentrated, the crude product was
purified by column chromatography (PE/EA, 1:4) to give compound
1
T2 as a white powder (241 mg, 87%): mp 122−123 °C; H NMR
(400 MHz, CDCl3) δ 8.29 (s, 1 H), 7.97 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz,1
H), 7.64 (b, 1 H), 7.61 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1 H), 7.52 (td, J1
= 8.0 Hz, J2 = 1.6 Hz, 1 H), 7.38 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1 H),
7.22 (t, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 8.4 Hz,
1 H), 6.99 (d, J = 7.6 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 4.67 (s, 2 H),
4.56 (s, 2 H), 4.05 (m, 1 H), 3.33 (m, 2 H), 1.52 (m, 2 H), 1.29 (m, 2
H), 1.06 (d, J = 6.4 Hz, 6 H), 0.86 (t, J = 7.2 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 168.2, 166.2, 154.3, 150.7, 144.4, 131.6, 130.1, 128.9,
126.6, 126.4, 124.1, 122.6, 122.4, 119.4, 113.9, 112.9, 68.1, 68.0, 41.3,
39.1, 31.6, 22.5 (2C), 20.2, 13.8; MS (ESI) m/z 466.4 [M + 1]+. Anal.
Calcd. for C25H31N5O4: C, 64.50; H, 6.71; N, 15.04. Found: C, 64.65;
H, 6.71; N, 15.13.
Compound 13. A solution of compound 7 (450 mg, 2.03 mmol)
and LiOH·H2O (168 mg, 4 mmol) in a 1:1 mixture of THF−H2O (20
mL) was stirred at room temperature for 12 h. After removal of the
organic solvents, water was added (5 mL), followed by the addition of
hydrochloric acid until pH = 4. The resulting solid was filtrated and
dried. The crude product was purified by recrystallization (ethyl
acetate/n-hexane) to give compound 13 as a yellow powder (351 mg,
1
80%): mp 106−107 °C; H NMR (300 MHz, DMSO) δ 7.08 (m, 3
H), 6.86 (d, J = 7.2 Hz, 1 H), 4.74 (s, 2 H); 13C NMR (100 MHz,
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Article
Compound 18. A solution (in a sealed tube) of compound 17
(190 mg, 1 mmol), EDCI (230 mg, 1.2 mmol), DMAP (10 mg), and
2-aminopropane (1.2 mL, 14 mmol) in CH2Cl2 (10 mL) was stirred at
0 °C for 12 h. After being stirred an additional 12 h at room
temperature, the solution was then washed with saturated aqueous
NH4Cl, saturated aqueous NaHCO3, and brine and dried over MgSO4.
After being concentrated, the crude product was purified by
chromatography (PE/EA, 2:1) to give compound 18 as a white
powder (160 mg, 70%): mp 136−137 °C; 1H NMR (400 MHz,
CDCl3) δ 7.47 (d, J = 8.0 Hz, 1 H), 7.32 (t, J = 7.2 Hz, 1 H), 6.94 (t, J
= 7.6 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 6.13 (b, 1 H), 4.28 (t, J = 6.0
Hz, 2 H), 4.09 (m, 1 H), 3.26 (s, 1 H), 2.69 (t, J = 5.2 Hz, 2 H), 1.15
(t, J = 6.4 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 169.8, 159.3,
134.2, 130.4, 121.0, 111.8, 111.4, 81.4, 80.2, 65.0, 41.5, 37.1, 29.7, 22.7,
22.7; MS (ESI) m/z 232.2 [M + 1]+. HRMS (ESI) Calcd. for
C14H17N1NaO2 [M + Na]+: 254.11515. Found: 254.11566.
Compound 19. Prepared in 37% yield as a white powder from the
reaction of compound 13 and aminoethane hydrochloride according
to a procedure similar to that described for compound 14: mp 54−55
°C; 1H NMR (400 MHz, CDCl3) δ 7.07 (m, 3 H), 6.90 (d, J = 7.6 Hz,
1 H), 6.76 (b, 1 H), 4.52 (s, 2 H), 3.41 (m, 2 H), 1.20 (t, J = 7.6 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 167.4, 149.5, 128.7, 126.0, 123.0,
120.6, 114.3, 68.6, 34.0, 14.6; MS (ESI) m/z 243.1 [M + Na]+. HRMS
(ESI) Calcd. for C10H12N4O2Na [M + Na]+: 243.08576. Found:
243.08525.
MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H),
3.89 (m, 1 H), 3.80 (m, 1 H), 1.56 (m, 1 H), 1.37 (m, 11 H), 1.03 (dd,
J1 = 10 Hz, J2 = 6.4 Hz, 6 H), 0.85 (t, J = 7.2 Hz, 6 H); MS (ESI) m/z
273.3 [M + 1]+.
Compound 25. Prepared in 85% yield as a yellow powder from
the reaction of compounds 13 and 24 according to a procedure similar
1
to that described for compound 22: mp 85−87 °C; H NMR (400
MHz, CDCl3) δ 7.09 (m, 4 H), 6.90 (d, J = 8.0 Hz, 1 H), 5.86 (d, J =
7.6 Hz 1 H), 4.55 (s, 2 H), 4.43 (m, 1 H), 4.04 (m, 1 H), 1.73 (m, 1
H), 1.61 (m, 2 H), 1.14 (m,6 H), 0.94 (m, 6 H); 13C NMR (100 MHz,
CDCl3) δ 170.4, 168.1, 149.5, 129.4, 126.1, 123.5, 120.7, 115.0, 68.9,
51.7, 41.7, 41.0, 24.9, 23.0, 22.8, 22.7, 22.2; MS (ESI) m/z 348.2 [M +
1]+. Anal. Calcd. for C17H25N5O3: C, 58.77; H, 7.25; N, 20.16. Found:
C, 58.75; H, 7.30; N, 19.99.
Compound T5. Prepared in 82% yield as white powder from the
reaction of compounds 22 and 25 according to a procedure similar to
1
that described for compound T2: mp 170−172 °C; H NMR (400
MHz, CDCl3) δ 8.88 (s, 1 H), 8.27 (d, J = 7.6 Hz, 1 H), 8.06 (t, J = 4.2
Hz, 1 H), 7.8 (d, J = 8 Hz, 1 H), 7.45 (t, J = 8 Hz, 1 H), 7.35 (t, J = 7.6
Hz, 2 H),7.19 (m, 2 H), 7.09 (d, J = 8 Hz, 1 H), 6.97 (d, J = 8 Hz, 1
H), 6.52 (m, 1 H), 6.38 (d, J = 8 Hz, 1 H), 4.72 (d, J = 2.8 Hz, 2 H),
4.62 (dd, J1 = 48.4 Hz, J2 = 14 Hz, 2 H), 4.29 (m, 1 H), 4.00 (t, J = 6.4
Hz, 2 H), 3.93 (m, 1 H), 3.13 (m, 2 H), 1.37 (m, 7 H), 1.10 (t, J = 6.8
Hz, 6 H), 0.86 (t, J = 7.2 Hz, 3 H), 0.73 (dd, J1 = 14.8 Hz, J2 = 6.4 Hz,
6 H); 13C NMR (100 MHz, CDCl3) δ 171.0, 169.4, 168.9, 168.1,
154.2, 150.0, 143.4, 130.6, 129.5, 128.8, 127.0, 126.2, 125.2, 122.7,
122.6, 120.0, 113.8, 112.6, 68.4, 68.2, 52.0, 43.2, 41.7, 40.7, 39.4, 31.5,
24.8, 22.8, 22.6, 22.5, 21.9, 20.1, 13.8; MS (ESI) m/z 636.4 [M + 1]+.
Anal. Calcd. For C33H45N7O6: C, 62.34; H, 7.13; N, 15.42. Found: C,
62.13; H, 7.26; N, 15.30.
Compound T4. Prepared in 84% yield as a white powder from the
reaction of compounds 18 and 19 according to a procedure similar to
1
that described for compound T2: mp 125−126 °C; H NMR (400
MHz, CDCl3) δ 8.51 (s, 1 H), 8.37 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1 H),
7.64 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.33
(t, J = 7.6 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.10 (m, 3 H), 7.03 (d, J
= 8.4 Hz, 1 H), 5.74 (d, J = 6.4 Hz, 1 H), 4.58 (s, 2 H), 4.43 (t, J = 6.4
Hz, 2 H), 3.93 (m, 1 H), 3.30 (m, 2 H), 2.65 (t, J = 6.4 Hz, 2 H), 1.08
(t, J = 7.6 Hz, 3 H), 0.95 (d, J = 6.4 Hz, 6 H); 13C NMR (100 M Hz,
CDCl3) δ 169.2, 167.4, 154.5, 150.5, 143.1, 130.7, 129.2, 128.0, 126.9,
126.2, 125.0, 122.5, 121.5 119.4, 113.9, 111.9, 68.2, 64.4, 41.5, 36.6,
34.2, 22.4 (2C), 14.4; MS (ESI) m/z 452.5 [M + 1]+. HRMS (ESI)
Calcd. for C24H30N5O4: 452.22923. Found: 452.22996.
ASSOCIATED CONTENT
■
S
* Supporting Information
Thermal ellipsoid plot of the crystal structure of compound T1
1
and CIF file, copies of additional H NMR and 2D COSY and
1
1
NOESY H NMR spectra. Copies of H NMR and 13C NMR
spectra of the new compounds. This information is available
free of charge via the Internet at http://pubs.acs.org/.
Compound 21. A solution of Boc-Glycine (5.26 g, 30 mmol),
EDCI (6.91 g, 36 mmol), DMAP (50 mg), and n-butylamine (3 mL)
in CH2Cl2 (100 mL) was stirred at room temperature for 12 h. The
solution was then washed with saturated aqueous NH4Cl (30 mL),
saturated aqueous NaHCO3 (30 mL), and brine (30 mL) and dried
over MgSO4. After being concentrated, the crude product was purified
by column chromatography (PE/EA, 2:1) to give compound 21 as a
colorless oil (4.83 g, 70%): 1H NMR (400 MHz, CDCl3) δ 6.28 (b, 1
H), 5.28 (b, 1 H), 3.75 (d, J = 6.4 Hz, 2 H), 3.24 (q, J = 6.4 Hz, 2 H),
1.47 (m, 2 H), 1.43 (s, 9 H), 1.26 (m, 2 H), 0.90 (t, 3 H).
Compound 22. A solution of 21 (553 mg, 2.4 mmol) and
trifluoroacetic acid (1.9 mL, 24 mmol) in CH2Cl2 (10 mL) was stirred
at room temperature for 6 h. Upon removal of the solvents under
vacuo, the resulting residuum was dissolved in CH2Cl2 (25 mL).
Compound 8 (418 mg, 2.4 mmol), EDCI (600 mg. 3.1 mmol), DMAP
(20 mg), and DIPEA (1.2 mL) were added into the solution and
stirred for 12 h at room temperature. The solution was then washed
with saturated aqueous NH4Cl (30 mL), saturated aqueous NaHCO3
(30 mL), and brine (30 mL) and dried over MgSO4. After being
concentrated, the crude product was purified by column chromatog-
raphy (PE/EA, 3:1) to give compound 22 as a white powder (500 mg,
73%): mp 102−103 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (b, 1 H),
7.50 (d, J = 7.6 Hz, 1 H), 7.34 (t J = 7.6 Hz, 1 H), 7.01 (t J = 7.6 Hz, 1
H), 6.86 (d, J = 8.4 Hz, 1 H), 5.93 (b, 1 H), 4.60 (s, 2 H), 4.01 (d, J =
5.6 Hz, 2 H), 3.43 (s, 1 H), 3.27 (q, J = 6.8 Hz, 2 H), 1.49 (m, 2 H),
1.34 (m, 2 H), 0.92 (t, 3 H); 13C NMR (100 MHz, CDCl3) δ 168.6,
168.0, 158.3, 134.0, 130.5, 122.2, 112.5, 112.2, 82.5, 79.3, 67.7, 43.1,
39.4, 31.5, 20.0, 13.7; MS (ESI) m/z 289.2 [M + 1]+. HRMS (ESI)
Calcd. for C16H21N2O3: 289.15467. Found: 289.15546.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xzhao@mail.sioc.ac.cn; ztli@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation of China
(20732007, 20921091, 20872167, 20974118) and STCSM
(10PJ1412200) for the financial support.
REFERENCES
■
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