Synthesis and Conformational Analysis of Alternately N-Alkylated Aromatic Amide Oligomers

Article abstract of DOI:10.1021/acs.joc.8b02045

Alternately N-alkylated aromatic amides such as 1-3 bearing various side chains were designed and synthesized as novel helical foldamers. The CD spectra of oligomers with chiral side chains showed a positive Cotton effect, which indicates that these oligo

Full text of DOI:10.1021/acs.joc.8b02045

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Article
Synthesis and Conformational Analysis of
Alternately N-Alkylated Aromatic Amide Oligomers
Ko Urushibara, Hyuma Masu, Hirotoshi Mori, Isao Azumaya,
Tomoya Hirano, Hiroyuki Kagechika, and Aya Tanatani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02045 • Publication Date (Web): 05 Nov 2018
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Synthesis and Conformational Analysis of Alternately N-Alkylated Aromatic Amide
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Oligomers
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Ko Urushibara,1 Hyuma Masu,2 Hirotoshi Mori,1 Isao Azumaya,3 Tomoya Hirano,4
Hiroyuki Kagechika,4 Aya Tanatani1*
1
Department of Chemistry and Biochemistry, Graduate School of Humanities and
Sciences, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
2
Center for Analytical Instrumentation, Chiba University, 1-33 Yayoi, Inage, Chiba
263-8522, Japan
3
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Ch
iba 274-8510, Japan
4 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University,
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Corresponding author’s e-mail address:
tanatani.aya@ocha.ac.jp
Tel/FAX: 81-3-5978-2716.
Table of Contents/Abstract Graphic
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Abstract
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Alternately N-alkylated aromatic amides such as 1 to 3 bearing various side chains were
designed and synthesized as novel helical foldamers. The CD spectra of oligomers with
chiral side chains showed a positive Cotton effect, which indicates that these oligomers
take helical conformations in solution. The CD intensity gradually increased with
increasing chain-length, and pentamer 3d showed remarkably strong CD signals in
chloroform. The absorption maxima of the UV spectra were increasingly red-shifted
with increasing chain length, in contrast to the case of poly(p-N-alkylbenzamide)s.
Structure optimization of the oligomers based on the crystal structure of 1a as the
monomer unit supported the formation of helical structure with a large cavity, and also
suggested intramolecular hydrogen bond formation between secondary amides. The
results of calculation were consistent with the observed spectroscopic features.
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Introduction
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Helixes are important conformational motifs in nature, as exemplified by the structures
of DNA and various proteins.1 In order to understand the relationships between the
helical structures and functions of biopolymers, and to apply them to develop new
functional molecules, various artificial helical polymers2, supramolecules3 and
oligomers4 have been synthesized. Generally, helical polymers can be classified into
two types, i.e., static and dynamic. For example, PTrMA5 and poly(tert-butyl
isocyanide)s6 are static helical polymers with a large reversal barrier, and they maintain
one-handed helical structure even in solution. On the other hand, polyisocyanate7 and
polyacetylene8 show rapid helical inversion; notably, the introduction of chiral
element(s) into such dynamically helical molecules can lead to biased formation of
one-handed helices. Oligomers with dynamic helical behavior are classified as
foldamers,9 and control of their helical conformation can afford functional molecules
with interesting optical activity or liquid-crystal properties.10 Particularly aromatic
secondary amide oligomers are well-known representations of foldamer. Gong and Li
introduced alkoxy group to aryl moieties, restricted the rotation of amide bond by
intramolecular hydrogen bond and constructed the helical conformation.11 Lehn and
Huc developed various kinds of heterocyclic oligomers connected by secondary amide
bond.12
We previously reported on the conformational properties of aromatic amides.13
Aromatic secondary amides such as benzanilide exist in trans form both in the crystal
and in solution, whereas their N-alkylated derivatives exist in cis form (Figure 1 (a)).14
In the cis conformation, two aromatic rings lie in a face-to-face position with a dihedral
angle of about 60 degrees. Poly(N-alkylated p-benzamide)s with repeating folded
structure take helical conformations in solution (Figure 1 (b)).15 The phenyl ring is
oriented parallel to the helical axis with three monomer units per turn. Introduction of
chiral N-substituents induced one-handed helical structures, whose absolute structure
was determined by empirical and theoretical studies of the CD spectra. The folded
structure of the aromatic cis-amide moiety provides a useful building block for
construction of dynamic helical structures16, and their helical properties can be tuned by
modifying the aromatic structure.17 We assumed that oligomers with longer aromatic
moieties linked by a cis-amide bond would form helical structures with larger diameter.
Such helical molecules might have a cavity that could include guest molecules having
an appropriate molecular shape and size. In the case of poly(N-alkylated p-benzamide)s,
the cavity is too small to include other molecules. Therefore, in this study, we designed
and synthesized novel oligoamides, and obtained helical foldamers with larger diameter
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and cavity size, based on the conformational properties of secondary and tertiary amide
bonds.
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Figure 1. (a) Cis conformational preference of benzanilide caused by N-methylation.(b)
Structures of helical Poly(N-alkylated p-benzamide)s. N-Substituents are omitted in the
three-dimensional structures.
Results and Discussion
1. Design and syntheses of alternately N-alkylated amide oligomers
As novel oligoamides with larger diameter and cavity size, we designed alternately
N-alkylated amide oligomers (Chart 1), in which we expected that the secondary
benzanilides with trans conformation would be linked by N-alkylated amide bonds with
cis conformation. Our previous studies showed that a macrocycle consisting of alternate
secondary and tertiary amide bonds exists as alternate cis and trans amide moieties,
forming a triangular-shaped cavity.18 Based on those results, we anticipated that acyclic
oligoamides with alternately N-alkylated amide bonds would form folding structures.
Using compound 1 as a monomer unit, we synthesized trimer 2 and pentamer 3.
Considering the solubility of the oligomers, methyl (a series), n-propyl (b series) or
n-octyl (c series) groups were chosen as the N-alkyl groups. In addition, we synthesized
oligomers possessing N-(R)-2-(methoxyethoxyethoxy)propyl, (R)-Tg groups, as chiral
side chains (d series) in order to examine the possibility of bias to one-handed helix
formation.
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Chart 1
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The monomers 1a-1c were prepared as shown in Scheme 1. N-Alkylated amide 5 was
prepared from methyl p-benzoate in two steps. Demethylation of 5 with lithium iodide
afforded carboxylic acid 6 and reduction of the nitro group of 5 afforded amine 7.
Amide bond formation between these two compounds afforded key monomers 1a-1c.
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Scheme 1. Syntheses of monomers 1a - c bearing alkyl side chains.
In the synthesis of monomer 1d, introduction of a chiral substituent was performed by
means of Fukuyama’s nosyl methodology (Scheme 2).19 Thus, methyl p-aminobenzoate
was converted to sulfonamide 8 by treatment with o-nitrobenzenesulfonyl chloride.
Alkylation of 8 was carried out under Mitsunobu conditions, using (R)-9 synthesized
from (R)-1,2-propanediol according to the reported method.20 Removal of the
o-nitrobenzenesulfonyl group of 10 was performed by treatment with PhSH and Cs2CO3
to give 11. Amide bond formation with p-nitrobenzoyl chloride afforded alkylated
amide 5d, which was converted to the carboxyl compound 6d and the amino compound
7d by hydrolysis and by reduction, respectively. Condensation of 6d and 7d afforded
monomer 1d.
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Scheme 2. Synthesis of monomer 1d bearing chiral N-substituents.
Trimer 2 and pentamer 3 were synthesized similarly by condensation of the
corresponding carboxylic acid and amine. However, trimers bearing N-methyl (2a) and
N-n-propyl (2b) groups showed poor solubility. Thus, only the pentamers 3c with
N-n-octyl and 3d with chiral Tg groups were synthesized (Scheme 3).
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Scheme 3. Syntheses of trimers 2a-d and pentamers 3c-d.
2. 1H NMR spectra of oligomers
1
The conformations of monomers 1 in solution were examined by comparing the H
NMR spectra with that of compound 5a, which exists in cis conformation (Figure S1,
Supporting Information). The chemical shifts of monomers 1a and 1c in the aromatic
region were almost the same as those of the corresponding proton signals of compound
5a. In the case of 1d with chiral N-substituents, the signals of H3 and H8 were shifted to
lower field (ca 0.15 ppm), while the chemical shifts of the other aromatic protons were
similar to those of 5a. These results suggest that monomers 1 predominantly exist in
(cis, trans, cis) form in solution. This tendency was independent of the solvent (Figure
S2).
1
To analyze the monomer conformation in more detail, VT H NMR spectra of 1a, 1c
and 1d were measured in CD2Cl2 (Figure S3). Only monomer 1d showed signal
broadening at low temperature, and the aromatic signals were observed at higher field,
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presumably due to aggregation of 1d at low temperature as a result of interaction
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between the side chains, such as CH-O interaction.
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In the H NMR spectra of 1a, minor peaks were observed downfield of the aromatic
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region and upfield of the aliphatic region at under 233 K, while only one set of signals
was observed for 1c, even at low temperature (Figure S4). The minor peaks of 1a
coalesced with the major peaks at 243 K, and the major and minor conformers were
assigned to the (cis, trans, cis) and (trans, trans, cis) forms, respectively.
In the 1H NMR spectra of the oligomers in CDCl3 at 293 K, pentamer 3c showed very
broad signals, while the signals of monomer 1c and trimer 2c were sharp (Figure S5).
However, pentamer 3c showed relatively sharp signals in DMSO-d6. These observations
suggest that pentamer 3c would be aggregated by intermolecular hydrogen bonding in
CDCl3. On the other hand, the amide NH signals of 2c appeared at 8.5 - 9.0 ppm, while
that of 3c was shifted downfield at 10.3 ppm. These results suggest that intramolecular
hydrogen bonding along the helical axis occurs only in the longer pentamer 3 with two
helical turns, but not in the shorter trimer 2c with essentially one helical turn.
3. Crystal structures of monomers
Monomer 1a with the N-methyl group exhibits three polymorphs, depending on the
recrystallization solvent, and each crystal contains a different conformer of 1a (Figure 2,
Table S1). In the crystal obtained from DMSO-d6, 1a exists in all-trans-amide form and
the packing structure indicated the existence of intermolecular aromatic interaction and
CH-O interaction (Figure S7). In the crystal obtained from CH2Cl2/n-hexane, 1a exists
in (trans, trans, cis) form, which corresponds to the minor conformation in CD2Cl2. In
the packing structure, intermolecular hydrogen bonding and CH-O interaction are
observed. In the crystal obtained from PhCl/n-hexane, 1a exists in (cis, trans, cis) form,
which corresponded to the major conformation in CD2Cl2. This crystal contains solvent
of crystallization, and there are CH-Cl interaction between 1a and the solvent molecule.
On the other hand, single crystals of 1b obtained from DMSO-d6 and CHCl3/n-hexane
were the same, and contained the (cis, trans, cis) form, as is also found in solution.
Overall, it can be concluded that intermolecular interaction and solvent effects strongly
influence the conformation of 1a with the small N-methyl group, and the most stable
conformation differs depending on the environment. Such effects should be less
important for 1b bearing the larger N-n-propyl group, and indeed, the most stable
conformation depended simply on the amide conformational properties. Thus,
monomers 1 with longer or larger N-substituents would be more useful as units for
constructing helical oligomers.
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Figure 2. Crystal structures of 1a from (a) DMSO-d6, (b) CH2Cl2/n-hexane (two
independent molecules exist in the asymmetric unit cell), (c) PhCl/n-hexane and 1b (d)
from CHCl3 / n-hexane. (top : top view, bottom : side views).
4. UV and CD spectra of oligomers
UV and CD spectra of monomer 1d and oligomers 2d and 3d possessing the chiral Tg
side chain were measured in CHCl3 (Figure 3). The spectrum of simple tertiary amide
5d with cis structure was also measured for comparison. These compounds showed
broad electronic absorption in the 240-350 nm region. The absorption maxima were
increasingly red-shifted with increasing chain length. This feature was also observed in
the UV spectra of oligomers 1c-3c bearing the N-n-octyl group (Figure 4). Such red
shifts were not observed in the UV spectra of oligo(N-alkylated p-benzamide)s.13
Therefore, this is a characteristic feature of oligomers bearing alternatively N-alkylated
amide bonds.
In the CD spectra, a positive Cotton effect was observed in the 240-350 nm region.
The CD spectrum of trimer 2d was similar in shape to that of monomer 1d, but different
from that of 5d. However, the intensity was much larger for 2d, which suggested
induction of chiral folded structure of the oligomer by the chiral N-substituent. Further,
pentamer 3d showed remarkably strong CD signals. The CD intensity of each
compound gradually decreased with increase of temperature (Figure S8). Such chain-
and temperature-dependence of the CD signals suggests that the oligomers take helical
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conformation in solution.
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Figure 3. (a) CD and (b) UV spectra of 1d (green line), 2d (orange line), 3d (red line)
and 5d (blue line), bearing (R)-Tg side chains in chloroform at 20oC. Concentration:
[1d] = 143 M, [2d] = 77 M, [3d] = 46 M, and [5d] = 262 μM.
Figure 4. UV spectra of oligomers 5c (blue line), 1c (green line), 2c (orange line) and 3c
(red line) bearing the n-octyl group in CHCl3 at 20oC. Concentration: [5c] = 232 M,
[1c] = 126 M, [2c] = 60 M and [3c] = 37 M.
The CD and UV spectra of oligomers in DMSO were slightly different from those in
CHCl3 (Figure 5). The UV spectrum of 3d showed a red shift compared to that of 2d,
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though the change in maximum wavelength was small (302.5 nm in CHCl3 and 297.5
nm in DMSO). Similarly, the CD signal also depended on the chain-length in DMSO,
though the change from 2d to 3d was small, and no red-shift of maximum wavelength
was observed in DMSO. The difference between the spectra in CHCl3 and DMSO
should be due to the presence or absence of hydrogen bond interactions of the secondary
amides. The UV spectrum of 3c was independent of concentration in the range of 4 - 80
M (Figure S9). Therefore, the marked increase of CD intensity of 3d in CHCl3 is
presumably due to stabilization of the helical structure by intramolecular hydrogen bond
interactions. The oligomer 3d would form two helical turns, which could make three
intramolecular hydrogen bonds. Thus, pentamer 3d with two helical turns formed a
rather tight helical structure in CHCl3, whereas it formed loose helical structure in
DMSO, like the shorter oligomer 2d. The red-shift in the UV spectra should be due to
electronic interaction between the closely stacked aromatic groups as a result of
intramolecular hydrogen bonding, which would make the HOMO-LUMO gap
narrower.21
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Figure 5. (a) CD and (b) UV spectra of oligomers 5d (blue line), 1d (green line), 2d
(orange line) and 3d (red line) bearing (R)-Tg side chains in DMSO at 20oC.
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5. Theoretical study on the Structural and Spectral Properties of Oligomers
NMR and UV/CD spectra indicated the helical structures of oligoamides, while the
detailed structural features could not be determined. To consider the relationship
between the helical structure of oligomers and the specific spectral features, we
performed DFT geometry optimization of N-methylated oligomers 2a and 3a at the
RI-B3LYP/def-SV(P) level, based on the crystal structure of (cis, trans, cis)-form
monomer 1a. The optimized conformations take helical structures and possess a cavity
(Figure 6). As predicted from the CD and UV spectra of oligomers, the secondary
amides form intramolecular hydrogen bonds along the helical axis. The cavity’s size is
approximately 9 Å.
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Figure 6. Optimized conformations of (a) 1a, (b) 2a, (c) 3a and (d) top view of 3a.
We also employed time-dependent DFT at the RI-B3LYP/def-SV(P) level to calculate
the UV and CD spectra of the optimized conformations of monomer 1a, and oligomers
2a and 3a (Figure 7). The calculated CD spectra were different from the measured
spectra. In the calculated CD spectra, trimer 2a and pentamer 3a showed bisignate CD
signals and 2a also showed relatively strong CD intensity. The reason of difference
shapes of spectra is not clear. This result suggests that trimer 2a forms one helical turn
with one intramolecular hydrogen bond, and the conformation is not stable. Thus,
structural fluctuation would lower the CD intensity. On the other hand, the red-shift of
the UV absorption maxima was reproduced. In the calculated UV spectra, the
absorption maxima were at 190 nm for 5a, 290 nm for 1a, 320 nm for 2a, and 340 nm
for 3a. Thus, the theoretical studies supported the putative helical structures of
oligomers with intramolecular hydrogen bond interactions deduced from empirical
experiments.
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Figure 7. Calculated spectra of the optimized structures of oligomer 1a-3a.
Conclusion
In conclusion, we synthesized alternately N-alkylated aromatic amide oligomers and
found that the oligomers formed helical structures with a larger cavity than that of
poly(N-alkylated p-benzamide)s. Introduction of a chiral N-substituent induced
one-handed helical conformations. The NMR, UV, and CD spectra, as well as
theoretical analysis, indicated intramolecular hydrogen bond interactions of secondary
amides contribute the stability of the helical conformation. These novel helical
oligomers are expected to have the ability to encapsulate a guest molecule in their
central cavity. Studies of their potential for application in molecular recognition and
chiral discrimination are in progress.
Experimental Section
All reagents were purchased from Sigma-Aldrich Chemical Co., Wako Pure Chemical
Industries, Tokyo Kasei Kogyo Co., and Kanto Kagaku Co., Inc. Silica Gel 60 N
(spherical, neutral) for column chromatography was purchased from Kanto Kagaku Co.,
Inc. H and 13C NMR spectra were recorded on JEOL JNM-ECS400 and Bruker
1
Avance 600 spectrometers with chloroform (7.26 ppm), methylene chloride (5.32 ppm),
methanol (3.31 ppm) or DMSO (2.50 ppm) as the internal standard. Mass spectral data
were obtained on a Bruker Daltonics micro TOF-2focus in the positive ion detection
mode. X-Ray crystallographic data for compounds 1a and 1b were collected at
Ochanomizu University on a Bruker SMART APEX II ULTRA diffractometer
equipped with a CCD detector using graphite-monochromated Mo Kα (λ = 0.71073 Å)
radiation, or at the Center for Analytical Instrumentation in Chiba University on a
Bruker SMART APEX II ULTRA diffractometer equipped with a CCD detector and
graphite-monochromated Cu Kα (λ = 0.71073 Å) radiation. Data were corrected for
absorption by the multiscan semiempirical method implemented in SADABS and the
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crystal structures were solved by the intrinsic phasing method in SHELXT and refined
by SHELXL-97.22 Full-matrix least-squares refinement was performed on F2 for all
unique reflections with anisotropic displacement parameters for non-hydrogen atoms.
All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were
included at their calculated positions. UV spectra were recorded with a JASCO V-650,
and CD spectra were recorded with a JASCO J-820 spectropolarimeter using a 2 mm
quartz cell. The concentration of each solution in CD experiments was adjusted so that
the absorbance of the oligomer was 1 at the maximum absorption wavelength in the
examined solvent.
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Synthesis of 4.23
Triethylamine (5 mL, 1.2 eq.) was added to a solution of methyl p-aminobenzoate
(4.60 g, 30.4 mmol) in dichloromethane (70 mL), and the mixture was stirred at 0°C. A
solution of p-nitrobenzoyl chloride (5.64 g, 1.0 eq.) in dichloromethane (70 mL) was
added to the cold amine solution and the mixture was stirred at rt for 12 h, then washed
successively with 2 M HCl, sat. NaHCO3, and brine. The organic layer was dried over
MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from ethyl
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acetate /n-hexane to give 5 (7.96 g, 26.5 mmol, 87%) as a colorless powder; H NMR
(400 MHz, DMSO-d6)  10.87 (s, 1 H), 8.39 (d, J = 9.2 Hz, 2 H), 8.20 (d, J = 8.7 Hz, 2
H), 7.99 (d, J = 9.2 Hz, 2 H), 7.95 (d, J = 9.2 Hz, 2 H), 3.85 (s, 3 H).
Synthesis of 5a.23
A solution of 4 (299 mg, 1.00 mmol) in DMF (10 mL) was added to a suspension of
NaH (60 %, 79.9 mg, 2.0 eq., washed with n-hexane twice) in DMF (9 mL) at 0°C. The
solution was stirred at rt for 30 min, and then MeI (514 mg, 3.6 eq.) was added to it at
0°C. The resulting solution was stirred at rt for 3 h. After removal of the solvent in
vacuo, the residue was poured into water, and extracted with ethyl acetate. The organic
layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by silica gel column chromatography (ethyl acetate /n-hexane 1:1)
to give 5a (231 mg, 0.74 mmol, 74%) as a yellow powder; 1H NMR (400 MHz,CDCl3)
 8.05 (d, J = 8.8 Hz, 2 H), 7.92 (d, J = 8.8 Hz, 2 H), 7.45 (d, J = 9.2 Hz, 2 H), 7.08 (d,
J = 8.7 Hz, 2 H), 3.89 (s, 3 H), 3.55 (s, 3 H) ; 13C NMR (150 MHz, CDCl3) δ 168.4,
166.0, 148.3, 147.9, 141.6, 131.0, 129.7, 128.8, 126.6, 123.4, 52.5, 38.2.
Synthesis of 5b.
A solution of 4 (2.52 g, 8.39 mmol) in DMF (50 mL) was added at 0°C to a suspension
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of NaH (60 %, 512 mg, 1.5 eq., washed with n-hexane twice) in DMF (9 mL). The
solution was stirred at rt for 30 min. 1-Iodopropane (4.59 g, 3.2 eq.) was added at 0°C.
The resulting solution was stirred at rt for 8 h and heated at 50°C for 16 h. After
removal of the solvent in vacuo, the residue was poured into water, and extracted with
ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by silica gel column chromatography
(ethyl acetate / n-hexane 1 : 5) to give 5b (1.48 g, 4.33 mmol, 56%) as a yellow
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amorphous solid; H NMR (400 MHz,CDCl3)  8.05 (d, J = 8.8 Hz, 2 H), 7.92 (d, J =
8.8 Hz, 2 H), 7.45 (d, J = 9.2 Hz, 2 H), 7.08 (d, J = 8.7 Hz, 2 H), 3.94 (m, 2H), 3.89 (s,
3 H), 1.66 (sext, J = 7.4 Hz, 2 H), 0.96 (t, J = 7.4 Hz, 3 H); 13C NMR (150 MHz,
CDCl3)  168.2, 166.0, 148.2, 146.7, 142.1, 131.0, 129.6, 129.0, 127.5, 123.4, 52.5,
52.0, 21.1, 11.4. HRMS (ESI+) m/z calcd for C18H19N2O5 [M+H]+ 343.1288, found
343.1295.
Synthesis of 5c.
A solution of 4 (105 mg, 0.35 mmol) in DMF (2 mL) was added at 0°C to a suspension
of NaH (60 %, 15.7 mg, 0.39 mmol, washed with n-hexane twice) in DMF (1 mL). The
solution was stirred at rt for 30 min, and then 1-iodooctane (172 mg, 0.72 mmol) was
added at 0°C. The resulting solution was stirred at rt for 2 h at 80°C. After removal of
the solvent in vacuo, the residue was poured into water, and extracted with ethyl acetate.
The organic layer was washed with brine, dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate /
dichloromethane=1/40) to give 5c (82.2 mg, 0.20 mmol, 57%) as a yellow oil; 1H NMR
(400 MHz, CDCl3)  8.04 (d, J = 8.7 Hz, 2 H), 7.92 (d, J = 8.7 Hz, 2 H), 7.43 (d, J = 8.7
Hz, 2 H), 7.08 (d, J = 8.7 Hz, 2 H), 3.96 (dd, J = 7.8, 7.8 Hz, 2 H), 3.89 (s, 3 H), 1.62
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(sext, J = 7.3 Hz, 2 H), 1.34-1.25 (m, 10 H), 0.87 (t, J = 6.9 Hz, 3 H); C NMR (150
MHz, CDCl3)  168.1, 166.0, 148.2, 146.7, 142.1, 131.0, 129.7, 129.0, 127.5, 123.4,
52.5, 50.6, 31.9, 29.4, 29.3, 27.8, 27.0, 22.7, 14.2. HRMS (ESI+) m/z calcd for
C23H29N2O5 [M+H]+ 413.2071, found 413.2077.
Synthesis of 5d.
Triethylamine (1 mL, 7.17 mmol) was added to a solution of 11 (1.0073 g, 3.24 mmol)
in dichloromethane (10 mL), and the mixture was stirred at 0°C. A solution of
p-nitrobenzoyl chloride (659.7 mg, 3.56 mmol) in dichloromethane (10 mL) was added
to the cold amine solution and the mixture was stirred at rt for 6 h. The mixture was
washed successively with 2 M hydrochloric acid, 2 M NaOH and brine. The organic
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layer was dried over MgSO4, filtered and concentrated in vacuo to give 5d (1.4354 g,
3.12 mmol, 96%) as a yellow oil; 1H NMR (400 MHz, CDCl3)  8.03 (d, J = 8.7 Hz, 2
H), 7.87 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H), 7.27 (d, J = 6.8 Hz, 2 H), 4.13 (d,
J = 12.8 Hz, 1 H), 3.94 (d, J = 12.8 Hz, 1 H), 3.88 (s, 3 H), 3.76-3.57 (m, 6 H),
3.53-3.49 (m, 3 H), 3.35 (s, 3 H), 1.21 (d, J = 6.0 Hz, 3 H); 13C NMR (150 MHz,
CDCl3)  168.7, 166.2, 148.2, 142.2, 132.2, 130.7, 129.8, 128.5, 127.8, 123.4, 73.3,
72.0, 70.9, 70.6, 68.4, 59.1, 56.7, 52.4, 17.4. HRMS (ESI+) m/z calcd for
C23H28N2NaO8 [M+Na]+ 483.1738, found 483.1729.
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Synthesis of 6a.23
LiI (870 mg, 21 eq.) was added to a solution of 5a (96.8 mg, 0.31 mmol) in pyridine
(10 mL) and the resulting mixture was stirred for 41 h at 115°C. The mixture was
cooled to 0°C, diluted with CH2Cl2 (50 mL), and washed with 2 M HCl (70 mL). The
aqueous layer was repeatedly extracted with CH2Cl2, and the combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by
silica gel column chromatography (ethyl acetate / n-hexane 4 : 1) to give 6a (84.2 mg,
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0.28 mmol, 90%) as a pale yellow powder; H NMR (400 MHz, CDCl3)  8.07 (d, J =
8.7 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H),
3.56 (s, 3H).
Synthesis of 6b.
LiI (109 mg, 5.1 eq.) was added to a solution of 5b (55.0 mg, 0.16 mmol) in pyridine
(3 mL) and the resulting mixture was stirred for 4 days at 115°C. After removal of the
solvent in vacuo, the residue was extracted with CH2Cl2. The organic layer was washed
with 2 M HCl, dried over MgSO4, filtered and concentrated in vacuo to give 6b (57.2
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mg, quant.) as a colorless amorphous solid; H NMR (400 MHz,CDCl3)  8.04 (d, J =
8.7 Hz, 2 H), 7.98 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2
H), 3.89 (m, 2H), 3.95 (m, 2 H), 1.67 (sext, J = 7.3 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H);
13C NMR (150 MHz, CDCl3)  170.4, 168.3, 148.3, 147.5, 142.0, 131.7, 129.7, 128.0,
127.6, 123.4, 52.1, 21.1, 11.4. HRMS (ESI+) m/z calcd for C17H17N2O5 [M+H]+
329.1132, found 329.1129.
Synthesis of 6c.
LiI (147 mg, 1.10 mmol) was added to a solution of 5c (89.9 mg, 0.22 mmol) in
pyridine (2.5 mL) and the resulting mixture was stirred for 3 days at 115°C. After
removal of the solvent in vacuo, the residue was extracted with CH2Cl2. The organic
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layer was washed with 2 M HCl, dried over MgSO4, filtered and concentrated in vacuo
to give 6c (86.8 mg, quant.) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J =
8.7 Hz, 2 H), 7.97 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.10 (d, J = 8.7 Hz, 2
H), 3.97 (dd, J = 7.8, 7.8 Hz, 2 H), 1.62 (sext, J = 7.3 Hz, 2 H), 1.32-1.25 (m, 10 H),
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0.87 (t, J = 6.9 Hz, 3 H); C NMR (150 MHz, CDCl3)  170.6, 168.2, 148.3, 147.5,
142.0, 131.7, 129.7, 128.0, 127.6, 123.4, 50.7, 31.9, 29.3, 29.3, 27.8, 27.0, 22.7, 14.2.;
HRMS (ESI+) m/z calcd for C22H27N2O5 [M+H]+ 399.1914, found 399.1916.
Synthesis of 6d.
LiI (899.5 mg, 6.72 mmol) was added to a solution of 5d (460.8 mg, 1.32 mmol) in
pyridine (15 mL) and the resulting mixture was stirred for 4 days at 115°C. After
removal of the solvent in vacuo, the residue was extracted with CH2Cl2. The organic
layer was washed with 2 M HCl, dried over MgSO4, filtered and concentrated in vacuo
to give 6d (590.4 mg, quant.) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J =
8.7 Hz, 2 H), 7.92 (d, J = 8.7 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2
H), 4.16 (d, J = 12.8 Hz, 1 H), 3.98 (br, 1 H), 3.78-3.74 (m, 1 H), 3.70-3.48 (m, 8 H),
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3.45 (s, 3 H), 1.22 (d, J = 6.4 Hz, 3 H); C NMR (150 MHz, CDCl3)  170.0, 168.7,
148.3, 142.1, 131.6, 131.3, 129.8, 127.8, 127.0, 123.4, 73.3, 72.0, 70.9, 70.6, 68.4, 59.1,
56.8, 17.4. HRMS (ESI+) m/z calcd for C22H26N2NaO8 [M+Na]+ 469.1581, found
469.1583.
Synthesis of 7a. 24
A solution of 5a (199 mg, 0.63 mmol) in dry methanol (12 mL) was hydrogenated
with Pd-C (10%, 20.4 mg) for 80 min at rt. The reaction mixture was filtered on Celite,
and the filtrate was concentrated in vacuo to give 7a (194 mg, quant.) as a pale pink
solid; 1H NMR (400 MHz, CDCl3)  7.90 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H),
7.08 (d, J = 8.7 Hz, 2H), 6.44 (d, J = 8.2Hz, 2H), 3.89 (s, 3H), 3.49 (s, 3H).
Synthesis of 7b.
A solution of 5b (37.1 mg, 0.11 mmol) in MeOH (3 mL) was hydrogenated with Pd-C
(10%, 5.3 mg) for 90 min at rt. The reaction mixture was filtered on Celite, and the
filtrate was concentrated in vacuo to give 7b (31.8 mg, 0.10 mmol, 94%) as a colorless
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amorphous solid; H NMR (400 MHz, CDCl3)  7.89 (d, J = 8.7 Hz, 2H), 7.12 (d, J =
8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.40 (d, J = 8.7 Hz, 2H), 3.89 (m, 2H), 3.89 (s,
3H), 3.78 (br, 2H), 1.64 (sext, J = 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). ; 13C NMR (150
MHz, CDCl3)  170.6, 166.6, 149.1, 148.3, 131.3, 130.6, 127.4, 12.0, 125.3, 113.8,
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52.3, 51.1, 21.3, 11.5. HRMS (ESI+) m/z calcd for C18H21N2O3 [M+H]+ 313.1547,
found 313.1556.
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Synthesis of 7c.
A solution of 5c (1.15 g, 2.81 mmol) in dry methanol (30 mL) was hydrogenated with
Pd-C (10%, 262 mg) for 5 h at rt. The reaction mixture was filtered on Celite, and the
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filtrate was concentrated in vacuo to give 7c (1.11 g, quant.) as a yellow oil; H NMR
(400 MHz, CDCl3)  7.89 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 8.7
Hz, 2 H), 6.40 (d, J = 8.7 Hz, 2 H), 3.91 (dd, J = 7.8, 7.8 Hz, 2 H), 3.79 (s, 3 H), 1.62
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(sext, J = 7.3 Hz, 2 H), 1.34-1.25 (m, 10 H), 0.85 (t, J = 6.9 Hz, 3 H); C NMR (150
MHz, CDCl3)  170.3, 166.6, 149.0, 148.4, 131.2, 130.6, 127.3, 127.0, 125.1, 113.7,
52.3, 50.7, 31.9, 29.4, 29.3, 28.0, 27.1, 22.7, 14.2. HRMS (ESI+) m/z calcd for
C23H31N2O3 [M+H]+ 383.2329, found 383.2338.
Synthesis of 7d.
A solution of 5d (48.6 mg, 0.11 mmol) in dry methanol (1.5 mL) was hydrogenated
with Pd-C (10%, 5.8 mg) for 8 h at rt. The reaction mixture was filtered on Celite, and
the filtrate was concentrated in vacuo to give 7d (45.1 mg, quant.) as a colorless oil; 1H
NMR (400 MHz, CDCl3)  7.86(d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 7.15 (d, J
= 8.2 Hz, 2 H), 6.49 (d, J = 8.2 Hz, 2 H), 4.15 (dd, J = 14.4, 4.0 Hz, 1 H), 3.94 (m, 1 H),
3.87 (s, 3 H), 3.85-3.49 (m, 9 H), 3.45 (s, 3 H), 1.19 (d, J = 6.4 Hz, 3 H); 13C NMR (150
MHz, CDCl3)  170.7, 166.7, 150.2, 148.5, 131.3, 130.4, 127.0, 126.9, 125.0, 113.7,
74.2, 72.0, 70.8, 70.6, 68.5, 59.1, 57.0, 52.2, 17.8. HRMS (ESI+) m/z calcd for
C23H30N2NaO6 [M+Na]+ 453.1996, found 453.1985.
Synthesis of 1a.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.98 g, 1.9 eq.) and
N,N-dimethyl-4-aminopyridine (1.24 g, 1.9 eq.) were added to a solution of 6a (1.80 g,
5.99 mmol) and 7a (1.55 g, 1.1 eq.) in DMF (10 mL). The resulting mixture was stirred
at rt for 12 h. After removal of the solvent in vacuo, the residue was extracted with
dichloromethane. The organic layer was washed successively with 2 M HCl, sat.
NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue
was washed with ethyl acetate to give 1a (2.50 g, 4.41 mmol, 81%) as a white powder;
1H NMR (600 MHz, CDCl3)  8.06 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.8Hz, 2H), 7.73 (d,
J = 8.2 Hz, 2H), 7.69 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.30 (d,
J = 7.8 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 3.88 (s, 3H), 3.55 (s,
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3H), 3.52(s, 3H); 13C NMR (150 MHz, CDCl3)  167.0, 168.4, 166.3, 164.3, 149.2,
148.5, 147.3, 141.7, 139.3, 133.2, 131.6, 130.8, 130.3, 129.7, 128.6, 128.0, 127.1,
126.5, 123.5, 119.1, 52.4, 38.4, 38.3. HRMS (ESI+) m/z calcd for C31H26N4NaO7
[M+Na]+ 589.1694, found 589.1685.
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Synthesis of 1b.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg, 1.65 mmol)
and N,N-dimethyl-4-aminopyridine (199 mg, 1.63 mmol) were added to a solution of 6b
(415 mg, 1.26 mmol) and 7b (390 mg, 1.25 mmol) in DMF (12 mL). The resulting
mixture was stirred for 4 h at rt. After removal of the solvent in vacuo, the residue was
extracted with dichloromethane. The organic layer was washed successively with 2 M
HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, ethyl acetate / n-hexane =1 /
5) to give 1b (616 mg, 0.99 mmol, 87%) as a yellow solid; 1H NMR (400 MHz, CDCl3)
 8.04 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.69 (s,
1H), 7.44 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.12 (d,
J = 8.2 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 3.92 (m, 4H), 3.88 (s, 3H), 1.65 (sext, J = 7.3
Hz, 4H), 0.96 (t, J = 7.3 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3)
 169.7, 168.2, 166.4, 164.3, 148.2, 148.0, 142.1, 139.2, 133.3, 131.9, 130.7, 130.1,
129.6, 128.6, 128.0, 127.9, 127.3, 123.4, 119.1, 52.4, 52.1, 21.2, 21.1, 11.5, 11.4.;
HRMS (ESI+) m/z calcd for C35H35N4O7 [M+H]+ 623.2500, found 623.2486.
Synthesis of 1c.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44.0 mg, 0.23 mmol)
and N,N-dimethyl-4-aminopyridine (27.9 mg, 0.23 mmol) were added to a solution of
6c (71.8 mg, 0.18 mmol) and 7c (76.8 mg, 0.20 mmol) in DMF (2 mL). The resulting
mixture was stirred for 5 h at rt. After removal of the solvent in vacuo, the residue was
extracted with dichloromethane. The organic layer was washed successively with 2 M
HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, ethyl acetate /
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dichloromethane =1 / 5) to give 1c (117.8 mg, 0.15 mmol, 86%) as a yellow solid; H
NMR (400 MHz, CDCl3)  8.04 (d, J = 8.7 Hz, 2 H), 7.89 (d, J = 8.2 Hz, 2 H), 7.70 (d,
J = 8.7 Hz, 2 H), 7.64 (s, 1 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.41 (d, J = 8.7 Hz, 2 H), 7.28
(d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 7.06 (d, J = 8.2 Hz, 2 H), 3.94 (m, 4 H),
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3.88 (s, 3 H), 1.61 (m, 4 H), 1.38-1.15 (m, 20 H), 0.86 (dt, J = 7.2, 2.2 Hz, 6 H); C
NMR (150 MHz, CDCl3)  169.6, 168.1, 166.4, 164.3, 148.3, 148.1, 146.0, 142.2, 139.2,
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133.4, 132.0, 130.7, 130.2, 129.6, 128.6, 128.1, 128.0, 127.3, 123.4, 119.1, 52.4, 50.7,
31.9, 31.9, 29.4, 29.4, 29.3, 29.3, 28.0, 27.8, 27.1, 27.0, 22.7, 14.2. HRMS (ESI+) m/z
calcd for C45H55N4O7 [M+H]+ 763.4065, found 763.4048.
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Synthesis of 1d.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.3 mg, 0.16 mmol)
and N,N-dimethyl-4-aminopyridine (21.1 mg, 0.17 mmol) were added to a solution of
6d (36.2 mg, 0.08 mmol) and 7d (45.1 mg, 0.10 mmol) in DMF (2 mL). The resulting
mixture was stirred for 20 h at rt. After removal of the solvent in vacuo, the residue was
extracted with dichloromethane. The organic layer was washed successively with 2 M
HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, ethyl acetate/methanol
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=15/1) to give 1d (45.9 mg, 0.06 mmol, 72%) as a yellow oil; H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.7 Hz, 2 H), 7.85 (d, J = 8.7 Hz, 2 H), 7.82 (s, 1 H), 7.69 (d, J =
8.7 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.31 (d, J = 8.7 Hz, 2
H), 7.23 (d, J = 8.7 Hz, 2 H), 4.16(dd, J = 10.5, 3.7 Hz, 2 H), 3.96 (m, 2 H),3.87 (s, 3 H),
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3.75-3.47 (m, 18 H), 3.36 (s, 3 H), 3.33 (s, 3 H), 1.21 (m, 6 H); C NMR (150 MHz,
CDCl3)  170.0, 166.5, 164.6, 149.3, 148.3, 142.2, 139.5, 133.0, 131.8, 130.5, 130.3,
129.8, 128.3, 128.2, 127.7, 127.4, 123.4, 119.0, 73.9, 73.5, 72.0, 70.9, 70.9, 70.6, 70.5,
68.5, 68.3, 59.2, 59.1, 56.8, 56.6, 52.3, 17.7, 17.4. HRMS (ESI+) m/z calcd for
C45H54N4NaO13 [M+Na]+ 881.3580, found 881.3577.
Synthesis of 8. 25
2-Nitrobenzenesulfonyl chloride (1.4687 g, 6.63 mmol) was added to a solution of
methyl p-aminobenzoate (1.0069 g, 6.66 mmol) in dry pyridine (5 mL) at 0°C, and the
reaction mixture was stirred for 1 h at room temperature. The solvent was removed in
vacuo, then the residue was poured into 2 M hydrochloric acid, and extracted with
chloroform. The organic layer was washed with brine, dried over MgSO4, filtered, and
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evaporated to give 8 (2.0189 g, 6.00 mmol, 90%) as a red solid; H NMR (400
MHz,DMSO-d6)  11.3 (s, 1 H), 8.04 (d, J = 6.4 Hz, 1 H), 8.01 (d, J = 8.2 Hz, 1 H),
7.89 (d, J = 7.2 Hz, 1 H), 7.87 (d, J = 8.7 Hz, 2 H), 7.82 (d, J = 7.3 Hz, 1 H), 7.24 (d, J
= 8.7 Hz, 2 H), 3.79 (s, 3 H).
Synthesis of 10.
Diethyl azodicarboxylate (40% in toluene, 345.6 mg, 0.79 mmol) in dry
tetrahydrofuran (1 mL) was added to a mixture of 8 (132.0 mg, 0.39 mmol), (R)-9 (73.5
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mg, 0.41 mmol), and triphenylphosphine (210.2 mg, 0.80 mmol) in dry tetrahydrofuran
(3 mL) under an argon atmosphere at 0°C. The reaction mixture was stirred for 2 days at
room temperature, then the solvent was removed in vacuo, and the residue was purified
by column chromatography (silica gel, ethyl acetate/n-hexane=2/1) to give 10 (146.7
mg, 0.30 mmol, 75%) as a yellow oil; 1H NMR (400 MHz, CDCl3)  7.96 (d, J = 8.4 Hz,
2 H), 7.61 (m, 2 H), 7.52 (d, J = 7.2 Hz, 1 H), 7.44 (td, J = 6.4, 2.3 Hz, 1 H), 7.38 (d, J
= 8.8 Hz, 2 H), 3.91 (s, 3 H), 3.87 (m, 2 H), 3.63-3.39 (m, 9 H), 3.37 (s, 3 H), 1.18 (t, J
= 6.4 Hz, 3 H); 13C NMR (150 MHz, CDCl3)  166.3, 148.0, 143.5, 133.9, 132.1, 131.8,
131.3, 130.7, 129.6, 129.0, 124.1, 74.9, 72.0, 70.7, 70.6, 68.3, 59.2, 57.0, 52.5, 17.4.
HRMS (ESI+) m/z calcd for C22H28N2NaO9S [M+Na]+ 519.1408, found 519.1407.
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Synthesis of 11.
A solution of 10 (1.7309 g, 3.49 mmol) in dry acetonitrile (20 mL) and cesium
carbonate (1.4856 g, 4.57 mmol) were added to a solution of benzenethiol (0.5 mL,
4.90 mmol) in acetonitrile (10 mL). The mixture was stirred for 1 h at 45°C, then
poured into water, and extracted with ethyl acetate. The organic layer was washed with
brine, dried over MgSO4, filtered, and evaporated. The residue was purified by column
chromatography (silica gel, ethyl acetate/n-hexane=1/1) to give 11 (1.0073 g, 3.27
1
mmol, 93%) as a yellow oil; H NMR (400 MHz, CDCl3)  7.74 (d, J = 8.7 Hz, 2 H),
6.56 (d, J = 8.7 Hz, 2 H), 4.88 (br, 1 H), 3.84 (s, 3 H), 3.79-3.71 (m, 2 H), 3.70-3.60 (m,
4 H), 3.59-3.55 (m, 3 H), 3.39 (s, 3 H), 3.30-3.25 (m, 1 H), 3.11-3.05 (m, 1 H), 1.23 (d,
J = 6.4 Hz, 3 H); 13C NMR (150 MHz, CDCl3)  167.5, 152.3, 131.6, 118.0, 111.7, 74.3,
72.0, 70.8, 70.6, 68.0, 59.2, 51.6, 48.4, 17.9. HRMS (ESI+) m/z calcd for C16H25NNaO5
[M+Na]+ 334.1625, found 334.1628.
Synthesis of 12a.
LiI (123.4 mg, 5.1 eq.) was added to a solution of 1a (99.8 mg, 0.18 mmol) in pyridine
(5 mL), and the resulting mixture was stirred for 4 days at 115°C. After removal of the
solvent in vacuo, the residue was dissolved in water and the solution was poured into 2
M HCl. The gray precipitate was collected and dried to give 12a (82.3 mg, 0.15 mmol,
83%); 1H NMR (400 MHz, DMSO-d6)  10.2 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.80 (d,
J = 8.2 Hz, 4H), 7.59 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz,
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2H), 7.25 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8Hz, 2H), 3.43 (s, 3H), 3.40 (s, 3H); C
NMR (125 MHz, DMSO-d6)  169.2, 167.7, 166.6, 164.7, 148.7, 147.6, 146.5, 142.5,
140.3, 132.6, 130.7, 130.1, 129.5, 129.2, 128.8, 128.0, 126.9, 126.6, 123.2, 119.1, 37.6.
HRMS (ESI+) m/z calcd for C30H25N4O7 [M+H]+ 553.1718, found 553.1706.
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Synthesis of 12b.
LiI (55.2 mg, 5.1 eq) was added to a solution of 1b (51.4 mg, 0.08 mmol) in pyridine
(1.5 mL) and the resulting mixture was stirred for 4 days at 115°C. After removal of the
solvent in vacuo, the residue was poured into 2 M HCl and the precipitate was collected
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by filtration to give 12b (48.6 mg, 97%) as a yellow-brown solid; H NMR (400
MHz,CDCl3)  8.02 (d, J = 8.7 Hz, 2 H), 7.93 (d, J = 8.7 Hz, 2 H), 7.76 (s, 1 H), 7.71
(d, J = 8.7 Hz, 2 H), 7.43 (d, J = 6.9 Hz, 4 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7
Hz, 2 H), 7.10 (d, J = 8.7 Hz, 2 H), 3.93 (m, 4 H), 3.95 (m, 2 H), 1.65 (m, 4 H), 0.94 (m,
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6 H). C NMR (150 MHz, DMSO-d6) 169.0, 167.8, 166.7, 164.8, 147.5, 147.4, 145.0,
142.8, 140.2, 132.9, 131.1, 130.2, 129.4, 129.3, 128.8, 128.3, 127.9, 127.5, 125.8,
123.3, 119.2, 50.9, 50.9, 20.6, 20.5, 11.2, 11.2. HRMS (ESI+) m/z calcd for C34H33N4O7
[M+H]+ 609.2344, found 609.2343.
Synthesis of 12c.
LiI (36.2 mg, 0.27 mmol) was added to a solution of 1c (34.7 mg, 0.05 mmol) in
pyridine (1.5 mL) and the resulting mixture was stirred for 4 days at 115°C. After
removal of the solvent in vacuo, the residue was extracted with CH2Cl2 and washed
with 2 M HCl. The organic layer was dried over MgSO4, filtered and concentrated in
vacuo to give 12c (34.1 mg, quant.) as a brown oil; 1H NMR (400 MHz, CDCl3)  8.02
(d, J = 8.7 Hz, 2 H), 7.93 (d, J = 8.2 Hz, 2 H), 7.72 (d, J = 8.7 Hz, 2 H), 7.43 (d, J = 8.7
Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 7.09 (d, J = 8.7 Hz, 2 H),
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3.97 (m, 4 H), 1.61 (m, 4 H), 1.38-1.15 (m, 20 H), 0.86 (t, J = 6.8 Hz, 6 H); C NMR
(150 MHz, CDCl3)  169.8, 169.3, 168.2, 164.5, 148.2, 146.8, 142.1, 139.6, 139.3,
133.3, 131.8, 131.2, 130.1, 129.6, 128.7, 128.0, 127.9, 127.3, 125.1, 123.4, 119.2, 50.7,
31.9, 31.9, 29.4, 29.4, 29.3, 29.3, 27.9, 27.8, 27.0, 27.0, 22.7, 14.2. HRMS (ESI+) m/z
calcd for C44H53N4O7 [M+H]+ 749.3909, found 749.3903.
Synthesis of 12d.
LiI (199.7 mg, 1.49 mmol) was added to a solution of 1d (240.6 mg, 0.28 mmol) in
pyridine (3 mL) and the resulting mixture was stirred for 4 days at 115°C. After
removal of the solvent in vacuo, the residue was extracted with CH2Cl2 and washed
with 2 M HCl. The organic layer was dried over MgSO4, filtered and concentrated in
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vacuo to give 12d (272.8 mg, quant.) as a brown oil; H NMR (400 MHz, CDCl3) 
8.03 (d, J = 8.7 Hz, 2 H), 7.95 (s, 1H), 7.88 (d, J = 8.7 Hz, 2 H), 7.69 (d, J = 8.7 Hz, 2
H), 7.49 (d, J = 8.2 Hz, 2 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.33-7.25 (m, 6 H), 4.17 (d, J
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= 11.4 Hz, 2 H), 3.97 (m, 2 H), 3.75-3.47 (m, 18 H),3.36 (s, 3 H), 3.33 (s, 3 H), 1.21 (d,
J = 6.0 Hz, 6 H); 13C NMR (150 MHz, CDCl3)  170.6, 169.0, 165.1, 163.1, 149.2,
148.1, 146.0, 142/1. 140.0, 131.1, 131.0, 130.1, 129.8, 128.8, 128.0, 127.5, 127.4, 123.4,
119.4, 73.9, 73.4, 71.9, 71.8, 70.8, 70.7, 70.4, 70.4, 68.2, 68.1, 59.1, 59.0, 56.6, 56.4,
53.6, 36.8, 31.7, 17.6, 17.4. HRMS (ESI+) m/z calcd for C44H52N4NaO13 [M+Na]+
867.3423, found 867.3426.
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Synthesis of 13a.
A solution of 1a (41.2 mg, 0.07 mmol) in THF (5 mL) was hydrogenated with Pd-C
(10%, 4.9 mg) for 19 h at rt. The reaction mixture was filtered on Celite, and the filtrate
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was concentrated in vacuo to give 13a (38.0 mg, quant.) as a white powder; H NMR
(400 MHz, CDCl3)  7.90 (d, J = 8.7 Hz, 2H), 7.75 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H),
7.46 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.12 (d, J =
8.2 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H), 3.53 (s,
3H), 3.49 (s, 3H); 13C NMR (150 MHz, CDCl3)  170.1, 166.4, 164.9, 161.5, 149.2,
148.6, 139.7, 131.6, 131.2, 131.1, 130.8, 130.2, 128.2, 127.9, 126.6, 126.5, 126.5,
124.5, 119.1, 113.8, 52.4, 38.4, 38.3. HRMS (ESI+) m/z calcd for C31H29N4O5 [M+H]+
537.2132, found 537.2123.
Synthesis of 13b.
A solution of 1b (63.9 mg, 0.10 mmol) in MeOH (5 mL) was hydrogenated with Pd-C
(10%, 9.7 mg) for 90 min at rt. The reaction mixture was filtered on Celite, and the
filtrate was concentrated in vacuo to give 13b (62.8 mg, 0.10 mmol, quant.) as a white
solid; 1H NMR (400 MHz, CDCl3)  7.90 (d, J = 8.7 Hz, 2H), 7.71 (s, 1 H), 7.68 (d, J =
8.7 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.10 (m, 6 H), 6.40 (d,
J = 8.7 Hz, 2 H), 3.90 (m, 4 H), 3.88 (s, 3 H), 3.86 (br, 2H), 1.63 (m, 4 H), 0.93 (m, 6
H); 13C NMR (150 MHz, CDCl3)  170.5, 149.9, 166.4, 165.0, 148.5, 148.0, 148.0,
139.8, 131.7, 131.4, 131.1, 130.7, 130.0, 128.2, 128.0, 127.3, 127.2, 124.9, 119.1, 113.7,
52.4, 52.2, 52.1, 21.2, 21.2, 11.5, 11.5.
HRMS (ESI+) m/z calcd for C35H37N4O5 [M+H]+ 593.2758, found 593.2744.
Synthesis of 13c.
A solution of 1c (356.4 mg, 0.47 mmol) in dry ethyl acetate (5 mL) was hydrogenated
with Pd-C (10%, 61.7 mg) for 7 h at rt. The reaction mixture was filtered on Celite, and
the filtrate was concentrated in vacuo to give 13c (342.3 mg, quant.) as a white solid; 1H
NMR (400 MHz, CDCl3)  7.89 (d, J = 8.7 Hz, 2 H), 7.81 (s, 3 H), 7.68 (d, J = 8.2 Hz,
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2 H), 7.43 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.7 Hz, 2 H), 7.09 (m, 6 H), 6.39 (d, J = 8.7
Hz, 2 H), 3.93 (m, 4 H), 3.88 (s, 3 H), 1.61 (m, 4 H), 1.38-1.15 (m, 20 H), 0.85 (dt, J =
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6.7, 2.3 Hz, 6 H); C NMR (150 MHz, CDCl3)  170.4, 169.7, 166.4, 164.9, 148.4,
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148.1, 148.1, 139.6, 131.7, 131.6, 131.2, 130.7, 130.2, 128.1, 127.9, 127.3, 127.3, 125.1,
119.0, 113.8, 52.4, 50.8, 50.6, 31.9, 29.4, 29.4, 29.3, 29.3, 28.0, 27.9, 27.1, 27.0, 22.7,
14.2. HRMS (ESI+) m/z calcd for C45H57N4O5 [M+H]+ 733.4323, found 733.4307.
Synthesis of 13d.
A solution of 1d (246.3 mg, 0.29 mmol) in dry ethyl acetate (4 mL) was hydrogenated
with Pd-C (10%, 30.6 mg) for 24 h at rt. The reaction mixture was filtered on Celite,
and the filtrate was concentrated in vacuo to give 13d (231.1 mg, 0.28 mmol, 97%) as a
yellow oil; 1H NMR (400 MHz, CDCl3)  7.99 (s, 1 H), 7.86 (d, J = 8.7 Hz, 2 H), 7.66
(d, J = 8.7 Hz, 2 H), 7.46(d, J = 8.7 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7,24 (m, 4 H),
7.13 (d, J = 8.7 Hz, 2 H), 6.39 (d, J = 8.7 Hz, 2 H), 4.15 (m, 2 H), 3.97 (m, 2 H), 3.88 (s,
3 H), 3.82 (s, 2 H), 3.75-3.46 (m, 18 H), 3.36 (s, 3 H), 3.33 (s, 3 H), 1.20 (t, J = 6.4 Hz,
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6 H); C NMR (150 MHz, CDCl3)  170.7, 170.2, 166.5, 165.2, 149.4, 148.6, 139.9,
131.4, 131.3, 130.5, 130.3, 128.0, 127.6, 127.4, 124.8, 119.0, 113.7, 74.4, 73.9, 72.0,
72.0, 71.0, 70.9, 70.6, 70.4, 68.5, 68.4, 60.6, 59.2, 59.1, 56.8, 52.3, 21.2, 17.7, 17.7,
14.3. HRMS (ESI+) m/z calcd for C45H56N4NaO11 [M+Na]+ 851.3838, found
851.3832.
Synthesis of 2a.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40.5 mg, 0.21 mmol)
and N,N-dimethyl-4-aminopyridine (25.2 mg, 0.21 mmol) were added to a solution of
12a (89.3 mg, 0.16 mmol) and 13a (85.1 mg, 0.16 mmol) in DMF (1 mL). The resulting
mixture was stirred for 31 h at rt and heated at 50°C for 19 h. After removal of the
solvent in vacuo, the residue was extracted with THF. The organic layer was washed
successively with 2 M HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and
concentrated in vacuo. THF was added to the residue and the resulting pale yellow
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precipitate was collected and dried to give 2a (45.4 mg, 26%); H NMR (400 MHz,
DMSO-d6)  10.3 (s, 1H), 10.3 (s, 1H), 10.3 (s, 1H), 8.09 (d, J = 8.7 Hz, 2H), 7.80 (m,
8H), 7.59 (m, 8H), 7.35 (d, J = 8.2 Hz, 2H), 7.27 (m, 12H), 3.79 (s, 3H), 3.42 (s, 3H),
3.40 (s, 3H), 3.40 (s, 3H), 3.39 (s, 3H); 13C NMR (150 MHz, DMSO-d6)  169.2, 167.8,
165.6, 164.9, 149.1, 147.9, 147.6, 146.5, 142.5, 140.5, 140.4, 140.3, 132.6, 131.9,
130.9, 130.8, 130.6, 130.0, 129.5, 128.8, 128.7, 126.9, 126.9, 126.8, 126.6, 123.2,
119.2, 119.2, 119.1, 52.2, 37.8, 37.6. HRMS (ESI+) m/z calcd for C61H50N8NaO11
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[M+Na]+ 1093.3491, found 1093.3463.
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1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol)
and N,N-dimethyl-4-aminopyridine (89.8 mg, 0.74 mmol) were added to a solution of
12b (223 mg, 0.37 mmol) and 13b (234 mg, 0.39 mmol) in DMF (4 mL). The resulting
mixture was stirred for 5 day. After removal of the solvent in vacuo, the residue was
extracted with dichloromethane. The organic layer was washed successively with 2 M
HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, ethyl acetate / n-hexane = 4
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/ 1) to give 2b (264 mg, 0.22 mmol, 61%) as a yellow solid; H NMR (400 MHz,
CDCl3)  9.10 (s, 1 H), 8.83 (s, 1 H), 8.65 (s, 1 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.88 (d, J
= 8.7 Hz, 2 H), 7.76 (m, 4 H), 7.59 (d, J = 8.2 Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.43
(d, J = 8.7 Hz, 2 H), 7.44 (m, 6 H), 7.07 (m, 12 H), 3.87 (m, 8 H), 3.86 (s, 3 H), 1.63
(m, 8 H), 0.92 (m, 12 H); 13C NMR (150 MHz, DMSO-d6)  169.1, 167.7, 165.6, 165.0,
147.8, 147.6, 146.4, 142.8, 140.4, 140.3, 140.2, 132.9, 132.2, 131.2, 130.9, 130.1,
129.4, 129.3, 128.8, 128.7, 127.9, 127.6, 127.4, 127.1, 123.2, 119.2, 119.1, 52.2, 51.0,
50.9, 20.6, 20.6, 20.5, 11.2, 11.2. HRMS (ESI+) m/z calcd for C69H66N8NaO11 [M+Na]+
1205.4743, found 1205.4719.
Synthesis of 2c.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
(175.5 mg,
0.92 mmol) and N,N-dimethyl-4-aminopyridine (110.2 mg, 0.90 mmol) were added to a
solution of 12c (330.0 mg, 0.44 mmol) and 13c (342.2 mg, 0.47 mmol) in DMF (5 mL).
The resulting mixture was stirred for 2 days at rt. After removal of the solvent in vacuo,
the residue was extracted with dichloromethane. The organic layer was washed
successively with 2 M HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chromatography (silica gel,
ethyl acetate/n-hexane=2/1) to give 2c (480.2 mg, 0.33 mmol, 74%) as a yellow solid;
1H NMR (400 MHz, CDCl3)  8.64 (br, 1 H), 8.41 (br, 1 H), 8.33 (br, 1 H), 8.00 (d, J =
8.7 Hz, 2 H), 7.89 (d, J = 8.7 Hz, 2 H), 7.73 (d, J = 8.2 Hz, 4 H), 7.63 (d, J = 8.7 Hz, 2
H), 7.46 (d, J = 8.2 Hz, 2 H), 7.43 (d, J = 6.8 Hz, 2 H), 7.30-7.20 (m, 4 H), 7.16-7.01 (m,
12 H), 3.90 (m, 8 H), 3.86 (s, 3 H), 1.61 (m, 8 H), 1.40-1.20 (m, 40 H), 0.86 (m, 12 H);
13C NMR (150 MHz, CDCl3)  169.9, 166.4, 165.6, 165.1, 164.9, 148.1, 148.0, 146.7,
142.3, 140.2, 139.4, 139.2, 132.9, 132.8, 132.0, 131.7, 131.2, 131.0, 130.7, 130.1, 130.0,
129.6, 128.9, 128.8, 128.6, 128.2, 128.0, 127.8, 127.6, 127.4, 127.3, 127.2, 123.4, 120.1,
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119.8, 119.2, 119.0, 52.4, 50.8, 50.8, 50.7, 31.9, 29.4, 29.4, 29.4, 29.4, 29.3, 27.9, 27.9,
27.8, 27.1, 27.0, 27.0, 22.8, 14.3. HRMS (ESI+) m/z calcd for C89H107N8O11 [M+H]+
1463.8054, found 1463.8035.
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Synthesis of 2d.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
(108.8 mg,
0.57 mmol) and N,N-dimethyl-4-aminopyridine (70.0 mg, 0.57 mmol) were added to a
solution of 12d (236.7 mg, 0.28 mmol) and 13d (231.1 mg, 0.28 mmol) in DMF (4 mL).
The resulting mixture was stirred for 24 h at rt. After removal of the solvent in vacuo,
the residue was extracted with dichloromethane. The organic layer was washed
successively with 2 M HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chromatography (silica gel,
ethyl acetate/methanol =10/1) to give 2d (353.6 mg, 0.21 mmol, 76%) as a pale yellow
solid; 1H NMR (400 MHz, CDCl3)  8.46 (br, 1 H), 8.43 (br, 1 H), 8.33 (br, 1 H), 8.02
(d, J = 8.7 Hz, 2 H), 8.75 (d, J = 8.7 Hz, 2 H), 7.69 (d, J = 8.7 Hz, 4 H), 7.61 (d, J = 8.7
Hz, 2 H), 7.47 (d, J = 8.2 Hz, 4 H), 7.38 (m, 4 H), 7.22 (m, 12 H), 4.13 (m, 4 H), 3.92
(m, 4 H), 3.85 (s, 3 H), 3.75-3.40 (m, 36 H), 3.35 (s, 3 H), 3.31 (s, 3 H), 3.30 (s, 3 H),
3.28 (s, 3 H), 1.19 (d, J = 6.0 Hz , 12 H); 13C NMR (150 MHz, CDCl3)  170.4, 170.2,
170.2, 166.5, 165.8, 165.2, 162.7, 149.2, 148.2, 142.2, 140.3, 139.8, 139.7, 132.7, 132.2,
132.0, 131.6, 131.5, 131.1, 130.5, 130.3, 130.1, 129.9, 129.8, 128.6, 128.5, 128.4, 128.0,
127.6, 127.5, 127.3, 123.4, 119.7, 119.1, 77.4, 77.2, 76.9, 74.0, 73.9, 72.0, 71.9, 71.9,
71.9, 70.9, 70.9, 70.9, 70.6, 70.5, 70.5, 70.4, 68.4, 68.3, 68.3, 68.2, 60.5, 59.2, 59.1,
59.0, 59.0, 56.8, 56.7, 56.5, 52.3, 36.7, 31.6, 29.8, 21.2, 17.7, 17.6, 17.4, 14.3. HRMS
(ESI+) m/z calcd for C89H107N8O23 [M+H]+ 1655.7444, found 1655.7416.
Synthesis of 14d.
LiI (33.0 mg, 0.25 mmol) was added to a solution of 2d (79.0 mg, 0.05 mmol) in
pyridine (2 mL) and the resulting mixture was stirred for 6 days at 115°C. After
removal of the solvent in vacuo, the residue was extracted with CH2Cl2 and washed
with 2 M HCl. The organic layer was dried over MgSO4, filtered and concentrated in
1
vacuo to give 14d (71.9 mg, 88%) as a brown oil; H NMR (400 MHz, CDCl3) δ 9.00
(br, 2 H), 8.83 (br, 1 H), 8.00 (m, 2 H), 7.78 (m, 6 H), 7.50 (m, 8 H), 7.18 (m, 16 H),
4.12 (m, 8H), 3.95 (m, 8 H), 3.70-3.50 (m, 36 H), 3.33-3.26 (m, 12 H), 1.20-1.10 (m, 12
13
H). C NMR (150 MHz, CDCl3)  170.7, 170.4, 165.3, 148.1, 142.2, 140.1, 132.2,
131.3, 131.0, 130.8, 130.0, 129.9, 129.8, 129.0, 128.7, 128.2, 127.8, 127.6, 127.4, 127.3,
123.4, 120.0, 119.7, 119.3, 74.0, 71.8, 71.7, 71.6, 70.8, 70.7, 70.6, 70.5, 70.4, 70.3, 68.3,
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68.1, 59.1, 59.1, 59.0, 59.0, 56.5, 56.5, 56.4, 17.6, 17.6, 17.4. HRMS (ESI+) m/z calcd
for C88H104N8NaO23 [M+Na]+ 1663.7107, found 1663.7100.
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Synthesis of 15c.
A solution of 2c (51.9 mg, 0.04 mmol) in dry ethyl acetate (6 mL) was hydrogenated
with Pd-C (10%, 10.5 mg) for 24 h at rt. The reaction mixture was filtered on Celite,
and the filtrate was concentrated in vacuo to give 15c (44.2 mg, 0.03 mmol, 87%) as a
white solid; 1H NMR (400 MHz, CDCl3) δ 8.70 (br, 2 H), 8.43 (br, 1 H), 7.88 (d, J = 8.7
Hz, 2 H), 7.73 (d, J = 8.7 Hz, 2 H), 7.65 (d, J = 8.2 Hz, 4 H), 7.62 (d, J = 8.7 Hz, 2 H),
7.45 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 6.8 Hz, 2 H), 7.31-7.18 (m, 8 H), 7.18-7.01 (m, 12
H), 6.38 (d, J = 8.7 Hz, 2 H), 3.89 (m, 8 H), 3.86 (s, 3 H), 1.61 (m, 8 H), 1.40-1.20 (m,
40 H), 0.86 (m, 12 H); 13C NMR (150 MHz, CDCl3)  170.6, 170.0, 169.8, 166.4, 165.7,
165.2, 148.6, 148.0, 140.1, 139.5, 139.4, 131.8, 131.6, 131.2, 131.0, 130.7, 129.9, 129.6,
128.7, 128.6, 128.4, 127.9, 127.5, 127.2, 124.9, 120.0, 119.9, 119.2, 113.7, 52.4, 50.8,
50.7, 31.8, 29.4, 29.4, 29.3, 29.3, 28.1, 27.9, 27.8, 27.1, 27.0, 22.7, 22.7, 14.2. HRMS
(ESI+) m/z calcd for C89H109N8O9 [M+H]+ 1433.8312, found 1433.8313.
Synthesis of 3c.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.6 mg, 0.16 mmol)
and N,N-dimethyl-4-aminopyridine (19.5 mg, 0.16 mmol) were added to a solution of
12c (84.6 mg, 0.11 mmol) and 15c (117.9 mg, 0.08 mmol) in DMF (4 mL). The
resulting mixture was stirred for 36 h at rt. After removal of the solvent in vacuo, the
residue was extracted with dichloromethane. The organic layer was washed
successively with 2 M HCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by GPC to give 3c (33.1 mg, 0.02
mmol, 19%) as a pale brown solid; 1H NMR (400 MHz, DMSO-d6)  10.28-10.24(m, 5
H), 8.06 (d, J = 7.8 Hz, 2 H), 7.81-7.75 (m, 12 H), 7.57-7.55 (m, 12 H), 7.33 (d, J = 7.8
Hz, 2 H), 7.25-7.19 (m, 20 H), 3.85 (br, 12 H), 3.77 (s, 3 H), 1.48(br, 12 H), 1.19 (br, 60
13
H), 0.83-0.81 (m, 18 H); C NMR (150 MHz, CDCl3)  172.9, 166.4, 164.9, 144.8,
144.5, 142.1, 132.6, 130.7, 130.1, 129.4, 127.9, 127.4, 126.9, 124.1, 123.5, 119.9, 119.3,
52.3, 52.2, 50.8, 50.7, 31.9, 31.8, 29.8, 29.4, 29.4, 29.4, 29.3, 29.2, 29.0, 28.9, 28.7,
28.2, 28.0, 27.1, 27.0, 26.9, 26.5, 26.4, 22.8, 22.8, 22.6, 14.3, 14.2. HRMS (ESI+) m/z
calcd for C133H158N12NaO15 [M+Na]+ 2186.1867 , found 2186.1862.
Synthesis of 3d.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.7 mg, 2.4 eq.) and
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N,N-dimethyl-4-aminopyridine (9.0 mg, 2.7 eq.) were added to a solution of 14d (43.6
mg, 0.027 mmol) and 13d (29.5 mg, 1.3 eq.) in DMF (2 mL). The resulting mixture was
stirred for 3 days at rt. After removal of the solvent in vacuo, the residue was extracted
with dichloromethane. The organic layer was washed successively with 2 M HCl, sat.
NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by preparative-TLC (ethyl acetate / methanol = 8 / 1) to give 3d (15.9 mg,
6.5 mol, 24%) as a pale yellow solid; 1H NMR (400 MHz, DMSO-d6)  10.24 (s, 5 H),
8.07 (br, 2 H), 7.79-7.74 (m, 12 H), 7.58-7.40 (m, 10 H), 7.40 (br, 4 H), 7.34 (m, 10 H),
7.33-7.20 (m, 10 H), 3.99 (m, 6 H), 3.78 (s, 3 H), 3.70-3.68 (m, 14 H), 3.56 (m, 6 H),
3.46-3.31 (m, 36 H), 3.31-3.17 (m, 18 H), 1.10 (s, 18 H); 13C NMR (150 MHz, CDCl3)
 173.1, 164.8, 144.1, 141.6, 132.6, 130.4, 129.9, 129.2, 129.0, 127.2, 123.3, 119.8,
71.9, 71.6, 70.8, 70.6、70.5, 70.4, 68.2, 59.2, 59.1, 59.0, 59.0, 56.7, 52.1, 29.7, 16.9.
HRMS (ESI+) m/z calcd for C133H158N12NaO33 [M+Na]+ 2474.0946 , found
2474.0897.
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Supporting Information
1H NMR spectra of 1 and 5a, X-ray crystallography data of 1a and 1b, CD and UV
spectra of 5d and 1d-3d, computational data and NMR spectra of all compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgments
This work was partly supported by JSPS KAKENHI Grant No 16K08318 (to A.T.),
17J00036 (to K.U.) and JSPS Core-to-Core Program, A. Advanced Research Networks.
A.T. gratefully acknowledges funding from The Sumitomo Foundation and The Naito
Foundation. K.U. is grateful for financial support from JSPS (Research Fellowship for
Young Scientists).
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