Sugara-oligoamides: Synthesis of DNA minor groove binders

Article abstract of DOI:10.1021/jo302238u

Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydratea-minor groove DNA interactions. Here we report an efficient solution-phase synthetic strategy to obtain two broad families of sugara-oligoamides. The first type, structure vector A (-Py[Me]-γ-Py-Ind), has a methyl group present as a substituent on the nitrogen of pyrrole B, connected to the C terminal of the oligoamide fragment. The second type, structure vector B (-Py[(CH₂) ₁₁OH]-γ-Py-Ind), has an alkyl chain present on the nitrogen of pyrrole B connected to the C terminal of the oligoamide fragment and has been designed to access to di-and multivalent sugara-oligoamides. By using sequential DIPC/HOBt coupling reactions, the oligoamide fragment-Py[R]-γ-Py-Ind has been constructed. The last coupling reaction between the anomeric amino sugar and the oligoamide fragment was carried out by activating the acid derivative as a BtO-ester, which has been performed by using TFFH. The isolated esters (BtO-Py[R]-γ-Py-Ind) were coupled with selected amino sugars using DIEA in DMF. The synthesis of two different selective model vectors (vector A (1) and vector B (2)) and two types of water-soluble sugara-oligoamide ligands, with vector A structure (compounds 3a-7) and with vector B structure (compound 8), was carried out.

Full text of DOI:10.1021/jo302238u

Article
pubs.acs.org/joc
Sugar−Oligoamides: Synthesis of DNA Minor Groove Binders
́
Concepcion Badıa, Florence Souard, and Cristina Vicent*
́
́
́
Departamento de Sıntesis, Estructura y Propiedades de los Compuestos Organicos, Instituto de Quımica Organica General, CSIC,
́
́
c/Juan de la Cierva 3, 28006 Madrid, Spain
S
* Supporting Information
ABSTRACT: Sugar-oligoamides have been designed and
synthesized as structurally simple carbohydrate-based ligands
to study carbohydrate−minor groove DNA interactions. Here
we report an efficient solution-phase synthetic strategy to
obtain two broad families of sugar−oligoamides. The first type,
structure vector A (-Py[Me]-γ-Py-Ind), has a methyl group
present as a substituent on the nitrogen of pyrrole B, connected
to the C terminal of the oligoamide fragment. The second type,
structure vector B (-Py[(CH2)11OH]-γ-Py-Ind), has an alkyl
chain present on the nitrogen of pyrrole B connected to the C
terminal of the oligoamide fragment and has been designed to access to di- and multivalent sugar−oligoamides. By using
sequential DIPC/HOBt coupling reactions, the oligoamide fragment -Py[R]-γ-Py-Ind has been constructed. The last coupling
reaction between the anomeric amino sugar and the oligoamide fragment was carried out by activating the acid derivative as a
BtO- ester, which has been performed by using TFFH. The isolated esters (BtO-Py[R]-γ-Py-Ind) were coupled with selected
amino sugars using DIEA in DMF. The synthesis of two different selective model vectors (vector A (1) and vector B (2)) and
two types of water-soluble sugar−oligoamide ligands, with vector A structure (compounds 3−7) and with vector B structure
(compound 8), was carried out.
a residue that is able to bind to the minor groove (selective
vector) in order to bring monosaccharides to a selective
sequence of DNA. We have chosen Py-γ-Py-Ind as the selective
vector structure, which resembles the structures of the naturally
occurring antibiotics distamycin A and netropsin (two minor
groove binders).43−45 We have shown that this vector can be
used as a sugar carrier to target the DNA. Thus, a series of
sugar−oligoamides were synthesized (R-Py-γ-Py-Ind, where R
= β-Gal-, β-Glc, β-Xyl-, α-Xyl-, β-L-Fuc-),46 and subsequent
NMR studies39,40,42 suggested that they presented a noticeable
percentage of hairpin conformations in the free state, which was
retained upon binding to DNA polymers.39,40 Furthermore,
competition NMR experiments suggested that the designed
glycoconjugates bind to the DNA minor groove.39 In addition,
the complex formed by β-Gal-Py-γ-Py-Ind (5) and the
Dikerson dodecamer has been elucidated, showing that β-
Gal-Py-γ-Py-Ind (5) binds to d(CGCGAATTCGCG)2 through
the minor groove at the central -AATT- region of the
oligonucleotide.42
INTRODUCTION
■
Over the past few decades, a number of small molecules,
peptides, and proteins have been identified that target both the
major and the minor grooves of B-DNA and have been shown
to interfere with transcription processes.1−6 Although there has
been extensive progress in the design of small molecules
capable of recognizing the minor groove of B-DNA,4,5,7−9
a
more relevant goal is the design of compounds that bind
preferentially to a specific DNA sequence at a particular
site.1,10−28 For instance, a successful rational design of selective
groove binders has been achieved by employing aromatic
polyamides1,3,22 and PNAs.4,29−31 Studies of the interaction of
natural glycoconjugates7,32−34 or nuclear glycoproteins35−38
with DNA have suggested that the glyco portion of the
conjugate is responsible for sequence selectivity and that the
sugar moiety of glycoproteins might act as a switch for its
function.
Consequently, the study of the molecular basis of
carbohydrate−DNA interactions shows great promise for the
design of new carbohydrate-base selective ligands and addi-
tionally may also shed light on the molecular mechanism of
action of some nuclear glycoproteins that act as transcription
factors.
We report a common and efficient synthetic strategy for the
solution-phase synthesis of two different selective vectors
(vectors A and B). As a model of vector A, Cycl-Py-γ-Py-Ind
(1) has been synthesized; a methyl group as a substituent on
the nitrogen of pyrrole B and a cyclohexyl group as the C-
terminal structure are present. This general structure (-Py-γ-Py-
Ind) has been used to bring simple carbohydrates to the
We have designed sugar−oligoamides as types of small
molecules that bind to the minor groove of DNA. They are
monosaccharide ligands designed to study carbohydrate−minor
groove DNA interactions.39−42
The general strategy that we are carrying out to study
carbohydrate−DNA interactions is to join the carbohydrate to
Received: October 11, 2012
© XXXX American Chemical Society
A
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selective sequence of the DNA.39−42 As a model of vector B,
Cycl-Py[(CH2)11OH]-γ-Py-Ind (2) has also been synthesized.
It contains an alkyl chain on the nitrogen of pyrrole B and a
cyclohexyl group at the C terminus and has been designed to
enable access to di- and multivalent sugar−oligoamides by
modifying the extreme of the alkyl chain (Figure 1)
occurs with cyclohexylamine (Figure 1). Additionally, we report
the synthesis of sugar−oligoamides with the vector A structure
(3−7) and with the vector B structure (8) (Figure 3)
In previous studies regarding the solution-phase synthesis of
polyamides, as well as analogues of netropsin and distamycin,
the amide bonds have been constructed by preactivation of the
acid (conversion to the acid chloride,47−51 trichloroacetyl
condensation reactions,52−54 or activated esters55) or by in situ
activation (either cyanophosphonates as DECP56 or carbodii-
mide derivates54,57−59). Also, advances in the solid-phase
synthesis of polyamides have been reported, including Boc-
and Fmoc-based approaches.60−63 Solid-phase methodologies
offer many advantages for milligram-scale polyamide syntheses,
including rapid and reliable amino acid couplings and facile
purifications, owing to immobilization of the polyamide
oligomer on a solid support. However, these techniques
intrinsically limit the scale of synthesis and usually expensive
reactants are needed. Conversely, efficient gram-scale solution-
phase methods for polyamide synthesis are less well developed
due mainly to the problem of solubility and difficult
purification. Recently, Dervan et al. have developed a general
solution-phase polyamide synthesis method that would allow
access to gram quantities of material in high yield with minimal
chromatography.55
Figure 1. Models of vectors A and B: Cycl-Py-γ-Py-Ind (1) and Cycl-
Py[(CH2)11OH]-γ-Py-Ind (2).
This substitution was designed on the basis of the bound
state conformation of the sugar−oligoamides (with vector A
structure)40 in the complex with ctDNA polymers. These data
suggest that the methyl groups of the pyrroles are close to the
outer region of the DNA groove; thus, its substitution would
not modify the interaction properties of the ligands.
Here we report a convenient solution-phase method for the
synthesis of two broad families of sugar−oligoamides. The
common strategy allows DNA ligands with structural diversity
to be obtained, both at the C terminal and at the nitrogen of
the pyrrole connected to the carbohydrate, on a convenient
scale.
The synthetic strategy (Figure 2) we describe here allows us
to obtain the two different oligoamide fragments (II) on a large
RESULTS AND DISCUSSION
■
The retrosynthetic approach for the preparation of the
precursor (II) of the two different selective vector models (1
and 2) and the glyco-oligoamide type vectors A (3−7) and B
(8) is shown in Figure 4. The common fragment for each
family is compound 16. This will be coupled with pyrrole B (V)
to give II. We start with the reaction between the
trichloroacetyl pyrrole 11 and the amine hydrochloride 12,
following on to a sequential method that involves the reduction
of the nitro group to the corresponding amine and a
subsequent coupling reaction with the corresponding carboxylic
acid using DIPC/HOBt. The quantitative reduction of the nitro
compound to an amine is a crucial step in utilizing the building
Figure 2. Retrosynthetic strategy for the solution-phase synthesis of
sugar−oligoamides (I).
scale. The last chemical step to obtain the sugar−oligoamides
(I) is based on the coupling of the amine with the carboxylic
acid residue at the C terminal of the oligoamide. In the case of
the vector models (1 and 2) the coupling of the oligoamide
Figure 3. Sugar−oligoamides with vector A structure (3−7) and with vector B structure (8).
B
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construct the oligoamide fragment -Py[R]-γ-Py-Ind. There are
two crucial elements in utilizing the building blocks for the
construction of the oligoamide fragment -Py[R]-γ-Py-Ind using
the DCC/HOBT coupling reaction. One is the quantitative
reduction of the nitro compound to an amine, and the other is
the preparation of the activated ester. The solubility of the
sample is an important factor for the preparation of high-quality
activated esters. Higher yields are usually associated with higher
solubility of the starting materials. The reactions are carried out
in DMF to be sure that all the reactants are dissolved.
The nitro group of compound 13 was reduced with NaBH4
in the presence of a Pd/C catalyst to give the corresponding
amino compound. The amine was obtained in 1 h and used
without purification in the coupling reaction with 2-indole
carboxylic acid 14 using HOBt/DIPC. This afforded the
product EtO-γ-Py-Ind (15) in a yield of 68%. The hydrolysis of
15 with LiOH·H2O in THF/H2O at room temperature for 12 h
gave the corresponding acid HO-γ-Py-Ind (16). Therefore, 8 g
of the common fragment 16 for the two selective vectors was
obtained with a global yield of 41% in six synthetic steps
(Figure 5).
Figure 4. Retrosynthetic scheme for the synthesis of the oligoamide
fragment II.
blocks for the construction of the oligoamide fragment by the
DIPC/HOBt activation and coupling reaction.
The large-scale synthesis of HO-γ-Py-Ind (16), which is the
common oligoamide fragment of the ligands described, is
shown in Figure 5. The first two steps consist of the synthesis
The next step in the synthetic route, as shown in the
retrosynthetic scheme in Figure 4, was the introduction of the
pyrrole ring B (Figure 6), in which substitution at the nitrogen
atom would render diversity in the preparation of the glyco-
oligoamides, allowing the synthesis of both families of ligands
with vector A and vector B structures.
Thus, activation of the acid 16 in the presence of DIPC/
HOBt in DMF followed by a coupling reaction with N-
substituted amino pyrroles, which had been obtained by the
reduction of N-substituted nitro pyrroles 17 and 18, gave the
oligoamides MeO-Py-γ-Py-Ind (19) and EtO-Py-
[(CH2)11OBn]-γ-Py-Ind (20). Hydrolysis of these esters in
the presence of LiOH·H2O in dioxane/H2O afforded the
correspondencing acids HO-Py-γ-Py-Ind (21) and HO-Py-
[(CH2)11OBn]-γ-Py-Ind (22) in yields of 91% and 90%,
respectively.
Afterward, the activated esters BtO-Py-γ-Py-Ind (23) and
BtO-Py[(CH2)11OBn]-γ-Py-Ind (24) were obtained as pure
solids by treatment of the corresponding acids 21 and 22 with
N-hydroxybenzotriazole hydrate (HOBt) and fluoro-
N,N,N′,N′-tetramethylformamidinium hexafluorophosphate
(TFFH)64−66 using DMF as solvent (Figure 6). This
preactivation allowed us to obtain a variety of sugar oligoamide
ligands with a number of different sugars attached to the C
terminus.67
Figure 5. Scheme for the synthesis of HO-γ-Py-Ind (16).
At this point, the common core of vectors A and B had been
synthesized and was ready to be coupled with cyclohexylamine
and the β-glycosyl amines 25−28.
of the preactivated trichloroacetyl pyrrole 11 following the
procedure described in the literature.60 Thus, 11 was coupled
with N-(tert-butoxycarbonyl)-γ-aminobutyric acid 12 in the
presence of triethylamine using ethyl acetate as the solvent to
afford the desired compound EtO-γ-Py-NO2 (13) in a
quantitative yield. The main advantage of using reactants with
C termini containing trichloroacetyl groups is that they are
easily dissolved in CHCl3, EtOAc, and EtOH. However,
polyamides containing two or three heterocycles are largely
insoluble in ordinary organic solvents except DMF and DMSO.
This feature greatly facilitated the purification of the product,
because common organic solvents could be used to wash away
the reactants, leaving only product after filtration.
The synthesis of the β-glycosyl amines 25−28 was needed.
All of them were synthesized using the synthetic sequence (i)
acetylation of the free sugar using AcONa/(AcO)2O (if
needed) and (ii) formation of the azide using SnCl4 and
trimethylsilyl azide68 (iii) followed by catalytic hydrogenation
(5% Pd−C, MeOH)69 of the azide to obtain the amine. After
purification, pure β-glycosyl amines were obtained. (Figure 7)
The next step in the synthesis of the sugar−oligoamides was
the formation of the amidoglycosidic bond. The most widely
employed method for the synthesis of glycosyl amides is the
condensation of protected or unprotected glycosylamines with
carboxylic acid derivatives. Our methodological efforts have
shown that the best results are obtained by using the ester
Afterward, by using in situ activation with DIPC/HOBt54 in
DMF, the building blocks have been effectively connected to
C
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Figure 6. Scheme for the synthesis of BtO-Py[R]-γ-Py-Ind esters 23 and 24.
As a result, after coupling the activated esters 23 and 24 with
the corresponding β-glycosyl amines 25−28 the protected
glyco-oligoamides 30a,b−34a,b and the cyclohexyl models and
29 were obtained (Table 1). Anomerization occurred during
the coupling reaction,73 and the anomers were separated by
chromatography at this step. Table 1 shows the yields of the
coupling reactions as well as the differences in the α:β ratio,
Figure 7. Scheme for the synthesis of the β-glycosyl amines 25−28.
1
previously prepared and isolated as mentioned above, instead of
the more widely used in situ activation70−72 (Figure 8).
which were calculated using H NMR.
For the deprotection steps of the two families of sugar−
oligoamides, in the case of ligands with the vector B structure
(29 and 34), the first step was to remove the benzyl group from
the alkyl chain. Thus, the benzyl group of 29 and 34b was
removed by catalytic hydrogenolysis (Pd/C (5%), MeOH) to
give Cycl-Py[(CH2)11OH]-γ-Py-Ind (2) and (AcO)3-β-Xyl-
Py[(CH2)11OH]-γ-Py-Ind (35) in yields of 90% and 85%,
respectively. Then, the common and last step in the synthesis of
both families of sugar−oligoamides (vector types A and B) was
the deprotection of the acetylated sugar residues. Subsequently,
the acetylated sugar−oligoamides 30a,b−33a,b with the vector
A structure and 35 with vector B structure were deprotected
using MeONa/MeOH74 to afford the target sugar−oligoamides
3−8 in yields between 65% and 80%.
Figure 8. General scheme for the synthesis of the cyclohexyl models 1
and 29 and the protected sugar−oligoamides 30a,b−34a,b).
Table 1. Results of the Coupling Reaction
a
amine
ester
product
Cycl-Py[Me]-γ-Py-Ind (1)
α:β
yield, %
Cycl-NH2
Cycl-NH2
BtO-Py[Me]-γ-Py-Ind (23)
95
70
95
75
82
80
60
BtO-Py[(CH2)11OBn]-γ-Py-Ind (24)
BtO-Py[Me]-γ-Py-Ind (23)
Cycl-Py[(CH2)11OBn]-γ-Py-Ind (29)
(AcO)3-β-Xyl-NH2 (25)
(AcO)3-β-L-Fuc-NH2 (26)
(AcO)4-β-Glc-NH2 (27)
(AcO)4-β-Gal-NH2 (28)
(AcO)3-β-Xyl-NH2 (25)
(AcO)3-α-/β-Xyl-Py[Me]-γ-Py-Ind (30a,b)
(AcO)3-α-/β-L-Fuc-Py[Me]-γ-Py-Ind (31a,b)
(AcO)4-α-/β-Glc-Py[Me]-γ-Py-Ind (32a,b)
(AcO)4-α/β-Gal-Py[Me]-γ-Py-Ind (33a,b)
(AcO)3-α-/β-Xyl-Py[(CH2)11OBn]-γ-Py-Ind (34a,b)
1:1
1:3
1:5
1:5
1:1
BtO-Py[Me]-γ-Py-Ind (23)
BtO-Py[Me]-γ-Py-Ind (23)
BtO-Py[Me]-γ-Py-Ind (23)
BtO-Py[(CH2)11OBn]-γ-Py-Ind (24)
a
1
The anomer population (α:β) was measured by integration of the anomeric proton resonance in the H NMR spectra.
D
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The Journal of Organic Chemistry
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(t, J = 7.0 Hz, CH3, 3H), 1.74−1.76 (m, CH2γb, 2H), 2.33 (t, J = 7.4
Hz, CH2γc, 2H), 3.21 (c, J = 6.0 Hz, CH2γa, 2H), 3.83 (s, CH3, 3H),
4.05 (c, J = 7.0 Hz, CH2, 2H), 6.88 (d, J = 1.8 Hz, CH Py, 1H), 7.05
(t, J = 7.5 Hz, CH Ind, 1H), 7.19 (t, J = 8.0 Hz, CH Ind, 1H), 7.28−
7.30 (m, CH x 2, 2H), 7.46 (d, J = 7.8 Hz, CH Ind, 1H), 7.65 (d, J =
7.8 Hz, CH Ind, 1H), 8.11 (t, J = 5.8 Hz, NH, 1H), 10.31 (s, NH, 1H),
11.31 (s, NH, 1H). 13C NMR (75 MHz, DMSO-d6): δ 14.1 (CH3),
24.8 (CH2), 31.1 (CH2), 36.1 (CH3), 37.8 (CH2), 59.8 (CH2), 102.8
(CH), 104.1 (CH), 112.3 (CH), 118.2 (CH), 119.8 (CH), 121.6
(CH), 121.7 (C), 123.2 (C), 123.4 (CH), 127.2 (C), 131.7 (C), 136.6
(C), 158.3 (CO), 161.3 (CO), 172.8 (CO). MS (ES+; m/z (%)): 397
[M + 1]+, 419 [M + Na]+, 816 [2 M + Na]+. IR (KBr) (cm−1): 1717,
1653, 1640. Anal. Calcd for C21H24N4O4 (396.44): C, 63.62; H, 6.10;
N, 14.13. Found: C, 63.50; H, 6.10; N, 14.00.
HO-γ-Py-Ind (16). To a solution of EtO-γ-Py-Ind (15; 9.0 g, 22.7
mmol) in THF (120 mL) was added LiOH·H2O (6.3 g, 154 mmol) in
a THF/H2O mixture (70 mL/70 mL). After 12 h, the residue was
washed with HCl (1 M) and extracted with AcOEt and the organic
layer was dried over Na2SO4 and filtered. After solvent evaporation,
the residue was purified by column chromatography (SiO2, AcOEt
(100%) to AcOEt/MeOH (4/1)) afforded the title compound as an
off-white amorphous solid (8.00 g, 95%), Mp: 196−199 °C. 1H NMR
(400 MHz, DMSO-d6): δ 1.70−1.74 (m, CH2γb, 2H), 2.23 (t, J = 7.3
Hz, CH2γc, 2H), 3.19 (dd, J = 6.6 Hz, J = 12.6 Hz, CH2γa, 2H), 3.83 (s,
CH3, 3H), 6.90 (d, J = 1.9 Hz, H-3 Py, 1H), 7.04 (ddd, J = 0.8 Hz, J =
7.1 Hz, J = 7.9 Hz, H-5 Ind, 1H), 7.19 (ddd, J = 1.0 Hz, J = 7.1 Hz, J =
8.1 Hz, H-6 Ind, 1H), 7.30 (m, H-3 Ind y H-5 Py, 2H), 7.46 (d, J = 8.3
Hz, H-7 Ind, 1H), 7.64 (d, J = 8.0 Hz, H-4 Ind, 1H), 8.20 (t, J = 5.0
Hz, NH-3, 1H), 10.42 (s, NH-2, 1H), 11.74 (s, NH-1, 1H). 13C NMR
(75 MHz, DMSO-d6): δ 24.9 (CH2γb), 32.0 (CH2γc), 36.0 (CH3),
38.1 (CH2γa), 102.9 (C-3 Ind), 104.0 (C-3 Py), 112.2 (C-7 Ind), 118.0
(C-5 Py), 119.7 (C-5 Ind), 121.4 (C-4 Ind), 121.6 (C), 123.2 (C),
123.3 (C-6 Ind), 127.1 (C), 131.7 (C), 136.6 (C), 158.1 (CO), 161.1
(CO), 175.0 (CO). MS (ES+; m/z (%)): 369 [M + 1]+, 391 [M +
Na]+, 759 [2 M + Na]+. IR (KBr) (cm−1): 3137, 2928, 1718, 1511,
1317, 1100, 847. Anal. Calcd for C19H20N4O4 (368.39): C, 61.95; H,
5.47; N, 15.21. Found: C, 61.67; H, 5.31; N, 15.40.
CONCLUSION
■
A convenient synthetic route using solution-phase methods has
been developed to obtain sugar−oligoamides, DNA minor
groove binders, on a convenient scale for interaction studies.
Using this method, two different selective models of vectors A
and B (Cycl-Py-γ-Py-Ind (1) and Cycl-Py[(CH2)11OH]-γ-Py-
Ind (2)) (Figure 1) have been obtained. Additionally, glyco-
oligoamides containing β-xylose (β-Xyl-Py-γ-Py-Ind (3) and β-
Xyl-Py[(CH2)11OH]-γ-Py-Ind (8)), α-sylose (α-Xyl-Py-γ-Py-
Ind (4)), β-galactose (β-Gal-Py-γ-Py-Ind (5)), β-glucose (β-
Glc-Py-γ-Py-Ind (6)), and β-L-fucose (β-L-Fuc-Py-γ-Py-Ind
(7)) have been reached by the same synthetic route (Figure
3). This efficient synthetic method described has been proved
to be general for the synthesis of sugar−oligoamides with
structural diversity both at the C terminus of the oligoamide
fragment and at the pyrrole amino acid connected to the
carbohydrate. This last modification allows us to assess the
synthesis of divalent and multivalent DNA ligands which
incorporated other sugars, amino acids, or phosphate groups.
EXPERIMENTAL SECTION
■
General Procedures. Flash chromatography was carried out with
silica gel 60 (230−400 ASTM mesh). Silica gel 60 F254 aluminum
TLC plates of 0.2 mm thickness were used to monitor the reactions.
NMR spectra were obtained on 300, 400, and 500 MHz
spectrometers. COSY, HSQC, and HMBC 2D-NMR experiments
were performed for further assignment of the structures when
required. Chemical shifts were referenced on residual solvent peaks:
CDCl3 (δ 7.26 ppm for H NMR and 77.00 ppm for 13C NMR),
1
DMSO-d6 (δ 2.50 ppm for H NMR and 39.43 ppm for 13C NMR),
1
methanol-d4 (δ 3.31 ppm for 1H NMR and 49.00 ppm for 13C NMR),
1
and acetone-d6 (δ 2.06 ppm for H NMR and 30.84/206.7 ppm for
13C NMR). Optical rotations were measured at room temperature in a
1.0 dm cell. Mass spectra were acquired by electrospray ionization.
54
Synthesis of Vector A Glyco-Oligoamides. MeO-Py-NO2 (17).
A solution of Cl3CO-Py(B)-NO260 (11; 10 g, 0.037 mol) in anhydrous
methanol (100 mL) was treated with MeONa (0.384 g, 0.007 mol).
After the reaction mixture was stirred for 30 min, it was quenched with
HCl (50 mL, 1 M); after filtration, the title compound was afforded as
a white amorphous solid (6 g, 88%). 1H NMR (200 MHz, CDCl3):60 δ
3.86 (s, CH3, 3H), 3.98 (s, CH3, 3H), 7.41 (d, J = 1.8 Hz, CH Py, 1H),
7.60 (d, J = 1.0 Hz, CH Py, 1H).
EtO-γ-Py-NO2 (13). Et3N (30 mL, 0.221 mol) was added
dropwise to a solution of 1-methyl-4-nitro-2-trichloroacetylpyrrole
(11;53 20.0 g, 0.074 mol) and ethyl-4-aminobutyrate hydrochloride
(12; 15.0 g, 0.088 mol) in AcOEt (200 mL). After 4 h at room
temperature the Et3N hydrochloride was removed by filtration and the
solvent was removed under reduced pressure to afford the title
1
compound as a white solid (22.0 g, quantitative). Mp: 68−70 °C. H
NMR (300 MHz, CDCl3): δ 1.26 (t, J = 7.2 Hz, CH3, 3H), 1.94 (t, J =
6.6 Hz, CH2γb, 2H), 2.44 (t, J = 6.6 Hz, CH2γc, 2H), 3.43 (c, J = 6.6
Hz, CH2γa, 2H), 3.98 (s, CH3, 3H), 4.16 (c, J = 7.2 Hz, CH2, 2H),
6.59 (sa, NH, 1H), 7.09 (d, J = 1.8 Hz, CH Py, 1H), 7.55 (d, J = 1.8
Hz, CH Py, 1H). 13C NMR (75 MHz, CDCl3): δ 14.0 (CH3), 24.2
(CH2), 31.8 (CH2), 37.8 (CH3), 39.1 (CH2), 60.7 (CH2), 106.9
(CH), 126.4 (C), 126.6 (CH), 134.7 (C), 160.4 (CO), 173.7 (CO).
MS (ES+; m/z (%)): 284 [M + H]+, 306 [M + Na]+. Anal. Calcd for
C12H17N3O5 (283.28): C, 50.88; H, 6.05; N, 14.83. Found: C, 51.02;
H, 6.05; N, 15.10.
MeO-Py-γ-Py-Ind (19). A mixture of NaBH4 (0.35 g, 9.2 mmol) in
water (5 mL) was added dropwise to a mixture of MeO-Py-NO2 (17;
0.72 g, 3.0 mmol) and Pd/C (5%) (0.70 g) in EtOAc/MeOH (10/10)
at 0 °C. After the mixture was stirred for 30 min and filtered through
Celite to remove the Pd/C and the solvent was evaporated, a brown
oil was afforded. This mixture was added in DMF (10 mL) to the acid
HO-γ-Py-Ind (16; 1.45 g, 3.9 mmol) previously activated during 7 h
with HOBt (0.54 g, 3.9 mmol) and DIPC (0.62 mL, 3.9 mmol) in
anhydrous DMF. After the addition of the amine, the reaction was
stirred 24 h. The residue was washed with saturated solution of
CuSO4, dried over Na2SO4, and filtered. After solvent evaporation, the
residue was purified by column chromatography (SiO2, hexane/
acetone (2/1 to 1/1)), affording the title compound as an off-white
EtO-γ-Py-Ind (15). To a mixture of EtO-γ-Py-NO2 (13; 22.0 g,
0.077 mol) and Pd/C (5.5 g, 5%) in AcOEt/ethanol (200 mL/200
mL) at 0 °C was added NaBH4 (8.7 g, 0.231 mol) in H2O (80 mL).
After 3 h at room temperature the crude mixture was filtered through
Celite to remove the Pd/C and the solvent was removed under
reduced pressure to afford a brown oil. This mixture was added in
CH2Cl2 (100 mL) to a mixture of the 2-indole carboxylic acid 14 (16.0
g, 0.098 mol) previously activated over 7 h with DMAP (12.0 g, 0.098
mol), HOBt (13.2 g, 0.098 mol), and DIPC (15.0 mL, 0.098 mol) in
anhydrous CH2Cl2 (200 mL). After addition of the amine, the reaction
mixture was stirred for 24 h. The residue was washed with HCl (1 M)
and then with aqueous sodium hydrogen carbonate, dried over
Na2SO4, and filtered. After solvent evaporation, the residue was
purified by column chromatography (SiO2, hexane/acetone (2/1 to 1/
1)) afforded the title compound as an off-white amorphous solid (21.4
1
amorphous solid (1.2 g, 65%). H NMR (400 MHz, DMSO-d6): δ 1.
80 (t, J = 7.2 Hz, CH2γb, 2H), 2.28 (t, J = 7.2 Hz, CH2γc, 2H), 3.23 (c,
J = 6.6 Hz, CH2γa, 2H), 3.7 (s, CH3, 3H), 3.8 (s, CH3, 3H), 3.8 (s,
CH3, 3H), 6.7 (d, J = 1.9 Hz, CH Py, 1H), 6.9 (d, J = 1.8 Hz, CH Py,
1H), 7.05 (dt, J = 0.7 Hz, J = 7.9 Hz, CH Ind, 1H), 7.2 (dt, J = 1.0 Hz,
J = 8.2 Hz, CH Ind, 1H), 7.29 (d, J = 1.7 Hz, 2H), 7.36 (d, J = 1.9 Hz,
CH Py, 1H), 7.46 (dd, J = 0.6 Hz, J = 8.2 Hz, CH Ind, 1H), 7.65 (d, J
= 8.0 Hz, CH Ind, 1H), 8.10 (t, J = 5.6 Hz, NH, 1H), 9.91 (sa, NH,
1H), 10.33 (sa, NH, 1H), 11.63 (d, J = 1.4 Hz, NH, 1H). 13C NMR
(100 MHz, DMSO-d6): δ 25.6 (CH2), 33.3 (CH2), 36.1 (CH3), 36.2
(CH3), 38.2, (CH2) 51.0 (OCH3), 102.9 (CH Ind), 104.2 (CH Py),
107.7 (CH Py), 112.4 (CH Ind), 118.1 (C), 118.6 (CH Py), 119.9
1
g, 68%). Mp: 165−166 °C. H NMR (300 MHz, DMSO-d6): δ 1.18
E
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(CH Ind), 120.5 (CH Py), 121.6 (CH Ind), 121.7 (C), 122.8 (C),
123.3 (C), 123.5 (CH Ind), 127.2 (C), 131.6 (C), 136.6 (C), 158.2
(CO), 160.7 (CO), 161.2 (CO), 169.4 (CO). MS (ES+; m/z (%)):
505 [M + H]+, 528 [M + Na]+. IR (KBr; cm−1): 3434, 3289, 1691,
1648, 1577, 1555, 1447, 1254. Anal. Calcd for C26H28N6O5 (504.54):
C, 61.89; H, 5.59; N, 16.66. Found: C, 61.74; H, 5.60; N, 16.85.
HO-Py-γ-Py-Ind (21). To a solution of MeO-Py-γ-Py-Ind (19; 0.700
g, 1.387 mmol) in dioxane (20 mL) was added LiOH·H2O (0.398 g,
9.709 mmol) in H2O (20 mL). After 1 week, the residue was washed
with HCl (1 M) and extracted with EtOAc and the organic layer was
dried over Na2SO4 and filtered. After solvent evaporation, the residue
was purified by column chromatography (SiO2, EtOAc (100%) to
EtOAc/MeOH (4/1)), affording the title compound as an off-white
h in the absence of light. The mixture was added to a solution of
(AcO)4-β-Xyl75 (6.00 g, 18.85 mmol) and trimethylsilyl azide
(TMSN3; 3.07 mL, 37.70 mmol) in CH2Cl2. The mixture was stirred
at room temperature. After 3 h the residue was washed with saturated
aqueous NaHCO3 and extracted with CH2Cl2, and the organic layer
was dried over Na2SO4 and filtered. After solvent evaporation, the
residue was purified by column chromatography (SiO2, hexane/AcOEt
68
(7/3)), affording the title compound (AcO)3-β-Xyl-N3 as an off-
white amorphous solid (5.18 g, 91.3%). Mp: 84−85 °C. [α]D = −79.8°
(c = 1 in CHCl3). 1H NMR (200 MHz, CDCl3): δ 2.04 (s, CH3, 3H),
2.05 (s, CH3, 3H), 2.08 (s, CH3, 3H), 3.43 (dd, J = 9.6 Hz, J = 11.7
Hz, CH, 1H), 4.21 (dd, J = 5.0 Hz, J = 11.7 Hz, CH, 1H), 4.63 (d, J =
8.0 Hz, CH-1, 1H), 4.87 (dd, J = 8.0 Hz, J = 8.8 Hz, CH, 1H), 4.97−
5.01 (m, CH, 1H), 5.19 (t, J = 8.8 Hz, CH, 1H). 13C NMR (200 MHz,
CDCl3): δ 20.6 (CH3 × 2), 20.7 (CH3), 64.2 (CH), 68.3 (CH), 70.3
(CH), 71.4 (CH), 88.3 (CH-1), 169.3 (CO), 169.7 (CO), 170.0
(CO). MS (ES+; m/z (%)): 319 [M + NH4]+, 324 [M + Na]+, 625 [2
M + Na]+. Anal. Calcd for C11H15O7N3 (301.25): C, 43.86; H, 5.02;
N, 13.95. Found: C, 43.80; H, 4.98; N, 13.89.
(AcO)3-β-Xyl-NH2 (25). To a solution of (AcO)3-β-Xyl-N3 (1.0 g,
3.32 mmol) in anhydrous CH2Cl2 was added Pd/C (5%) (1.0 g). The
mixture was stirred under H2 at atmospheric pressure for 2 h. The Pd/
C (5%) was removed by filtration through Celite, and the filtrate was
concentrated in vacuo to remove the CH2Cl2. Purification of the
residue by column chromatography (SiO2, hexane/AcOEt (3/2))
afforded the title compound (AcO)3-β-Xyl-NH2 (25)76 as an off-white
amorphous solid (0.550 g, 60%). Mp: 101−102 °C. [α]D = −22.4° (c
= 1 in CHCl3). 1H NMR (300 MHz, CDCl3): δ 2.00 (s, CH3CO, 3H),
2.01 (s, CH3CO, 3H), 2.05 (s, CH3CO, 3H), 3.29 (t, J = 11.3 Hz, CH-
5, 1H), 4.01 (dd, J = 5.7 Hz, J = 11.4 Hz, CH-5′, 1H), 4.08 (d, J = 8.9
Hz, CH-1, 1H), 4.74 (t, J = 9.3 Hz, CH-2, 1H), 4.95 (dc, J = 5.7 Hz, J
= 9.6 Hz, CH-4, 1H), 5.21 (t, J = 9.5 Hz, CH-3, 1H). 13C NMR (300
MHz, CDCl3): δ 21.1 (CH3CO × 2), 21.2 (CH3CO), 63.8 (CH-5),
69.5 (CH-4), 72.3 (CH-2), 72.7 (CH-3), 85.4 (CH-1), 169.9 (CO),
169.9 (CO), 170.3 (CO). MS (ES+; m/z (%)): 276 [M + H]+, 298
[M + Na]+. Anal. Calcd for C11H17O7N (275.14): C, 47.97; H, 6.23;
N, 5.17. Found: C, 48.51; H, 6.31; N:, 5.09.
1
amorphous solid (0.620 g, 91%). H NMR (300 MHz, DMSO-d6): δ
1.76−1.78 (m, CH2γb, 2H), 2.27−2.29 (m, CH2γc, 2H), 3.17−3.19 (m,
CH2γa, 2H), 3.78 (s, CH3, 3H), 3.81 (s, CH3, 3H), 6.64 (d, J = 2.0 Hz,
CH Py, 1H), 6.90 (d, J = 1.8 Hz, CH, 1H), 7.05 (ddd, J = 0.9 Hz, J =
7.0 Hz, J = 7.9 Hz, CH Ind 5, 1H), 7.2 (ddd, J = 1.1 Hz, J = 7.0 Hz, J =
8.1 Hz, CH Ind, 1H), 7.28 (sa, CH × 3, 3H), 7.46 (d, J = 8.2 Hz, CH
Ind, 1H), 7.64 (d, J = 8.0 Hz, CH Ind, 1H), 8.24 (t, J = 5.3 Hz, NH,
1H), 10.26 (s, NH, 1H), 10.81 (s, NH, 1H), 11.99 (s, NH, 1H). 13C
NMR (75 MHz, DMSO-d6): δ 25.7 (CH2), 33.3 (CH2), 36.1 (2 ×
CH3), 38.2 (CH2), 104.0 (CH), 104.3 (CH), 105.5 (CH), 112.3
(CH), 118.1 (CH), 119.4 (CH), 119.7 (CH), 121.5 (CH), 121.8 (2 ×
C), 122.5 (C), 123.2 (C), 123.3 (CH), 127.1 (C), 131.9 (C), 136.6
(C), 158.0 (CO), 161.3 (CO), 169.3 (CO), 170.4 (CO). MS (ES+;
m/z (%)): 491 [M + H]+, 513 [M + Na]+, 981 [2 M + H]+, 1003 [2 M
+ Na]+. IR (KBr; cm−1): 3440, 3280, 1699, 1650, 1560, 1556, 1437,
1250. Anal. Calcd for C25H26N6O5 (490.51): C, 61.22; H, 5.34; N,
17.13. Found: C, 61.28; H, 5.30; N, 17.15.
BtO-Py-γ-Py-Ind (23). A mixture of HO-Py-γ-Py-Ind (21; 120.00
mg, 0.244 mmol), HOBt (66.33 mg, 0.488 mmol), TFFH (142.00 mg,
0.538 mmol), and DIEA (0.17 mL, 0.976 mmol) in anhydrous DMF
(2.4 mL) was stirred at room temperature. After 24 h the residue was
washed with saturated aqueous CuSO4 and extracted with EtOAc and
the organic layer was dried over Na2SO4 and filtered. After solvent
evaporation, the residue was purified by column chromatography
(SiO2, hexane/EtOAc (1/40)), affording the title compound as an off-
white amorphous solid (133 mg, 90%). 1H NMR (500 MHz, DMSO-
d6): δ 1.82−1.86 (m, CH2γb, 2H), 2.34 (t, J = 7.4 Hz, CH2γc, 2H),
3.29−3.21 (m, CH2γa, 2H), 3.85 (s, CH3, 3H), 3.87 (s, CH3, 3H), 6.91
(d, J = 1.7 Hz, CH-3 Py, 1H), 7.05 (t, J = 7.5 Hz, CH-5 Ind, 1H), 7.19
(t, J = 7.6 Hz, CH-6 Ind, 1H), 7.27−7.31 (m, CH-5 Py, CH-3 Py, CH-
3 Ind, 3H), 7.46 (d, J = 8.2 Hz, CH-7 Ind, 1H), 7.53 (t, J = 7.6 Hz,
CH-5 BtO, 1H), 7.62−7.68 (m, CH-6 BtO, CH-4 Ind, 2H), 7.75 (d, J
= 1.7 Hz, CH-5 Py-B, 1H), 7.83 (d, J = 8.3 Hz, CH-7 BtO, 1H), 8.10−
8.18 (m, H-4 BtO, NH-3, 2H), 10.14 (s, NH-4, 1H), 10.30 (s, NH-2,
1H), 11.61 (s, NH-1, 1H). 13C NMR (125 MHz, DMSO-d6): δ 25.5
(CH2γb), 33.2 (CH2γc), 36.0 (CH3), 36.3 (CH3), 38.1 (CH2γa), 102.7
(CH-3 Ind), 104.0 (CH-3 Py), 109.3 (CH-7 BtO), 110.3 (CH-3 Py),
112.2 (CH-7 Ind, C-2 Py B), 118.0 (CH-5 Py A), 119.7 (2 × CH-5
Ind, CH-4 BtO), 121.5 (CH-4 Ind, C-4 Py A), 123.2 (C-2 Py A),
123.3 (CH-6 Ind), 124.2 (C-4 Py B), 125.1 (CH-5 Py-B y CH-5 BtO),
127.1 (C-3a Ind), 128.6 (C-7a BtO), 129.1 (CH-6 BtO), 131.6 (C-2
Ind), 136.5 (C-7a Ind), 142.7 (C-3a BtO), 156.0 (CO-4), 158.1 (CO),
161.1 (CO), 169.7 (CO). MS (ES+; m/z (%)): 608 [M + H]+, 630
[M + Na]+, 1215 [2 M + H]+. IR (KBr; cm−1): 3354, 3105, 2926,
2856, 2477, 2353, 1764, 1649, 1577, 1523, 1496, 1461, 1408, 1190,
1153, 1101, 1001, 982, 742. Anal. Calcd for C31H29N9O5 (607.62): C,
61.28; H, 4.81; N, 20.75. Found: 61.35; H, 4.90; N, 20.68.
(AcO)3-β-L-Fuc-N3. This compound was prepared as mentioned
above for (AcO)3-β-Xyl-N3 from L-fucose (10.0 g, 60.9 mmol). After
solvent evaporation, the residue was purified by column chromatog-
raphy (SiO2, hexane/AcOEt (7/3)), affording the title compound as
an off-white amorphous solid (14.8 g, 85%). [α]D = 10.8° (c = 0.25 in
methanol). 1H NMR (CDCl3, 300 MHz): δ 1.25 (d, J = 6.6 Hz, CH3,
3H), 1.98 (s, CH3CO, 3H), 2.08 (s, CH3CO, 3H), 2.19 (s, CH3CO,
3H), 3.90 (dc, J = 6.3 Hz, J = 1.2 Hz, CH-5, 1H), 4.58 (d, J = 8.4 Hz,
CH-1, 1H), 5.02 (dd, J = 10.2 Hz, J = 3.6 Hz, CH-3, 1H), 5.13 (dd, J =
10.2 Hz, J = 8.7 Hz, CH-2, 1H), 5.26 (dd, J = 3.3 Hz, J = 1.2 Hz, CH-
4, 1H).
(AcO)3-β-L-Fuc-NH2 (26).77 This compound was prepared as
mentioned above for (AcO)3-β-Xyl-NH2 (25) from (AcO)3-β-L-Fuc-
N3 (1.0 g, 3.17 mmol) to afford the title compound as an off-white
amorphous solid (0.734 g, 80%). 1H NMR (CDCl3, 300 MHz): δ 1.14
(d, CH3, J = 6.5 Hz, 3H), 1.95 (s, CH3CO, 3H), 2.04 (s, CH3CO,
3H), 2.14 (s, CH3CO, 3H), 3.76 (dc, J = 6.5 Hz, J = 1.0 Hz, H-5, 1H),
4.09 (d, J = 8.0 Hz, CH-1, 1H), 4.96 (dd, J = 8.0 Hz, J = 10.5 Hz, CH-
2, 1H), 5.02 (dd, J = 3.0 Hz, J = 10.5 Hz, CH-3, 1H), 5.21 (dd, J = 1.0
Hz, J = 3.0 Hz, CH-4, 1H).
(AcO)4-β-Glc-N3. A solution of (AcO)5-β-Glc (10.00 g, 25.6 mmol),
trimethylsilyl azide (TMSN3; 3.85 mL, 29.0 mmol), and fuming SnCl4
(2.58 mL, 22.0 mmol) in anhydrous CH2Cl2 (200 mL) was stirred at
room temperature. After 2 h the residue was washed with saturated
aqueous NaHCO3 and H2O and extracted with EtOAc and the organic
layer was dried over Na2SO4, and filtered. The solvent was removed
under reduced pressure to afford the title compound as an off-white
amorphous solid (9.5 g, 99%). Mp: 124−126 °C. [α]D = −33.0° (c =
2.485, CHCl3). 1H NMR (200 MHz, CDCl3): δ 2.00 (s, CH3CO, 3H),
2.02 (s, CH3CO, 3H), 2.07 (s, CH3CO, 3H), 2.09 (s, CH3CO, 3H),
3.78 (ddd, J = 2.4 Hz, J = 4.6 Hz, J = 9.8 Hz, CH-5, 1H), 4.15 (dd, J =
2.4 Hz, J = 12.4 Hz, CH-6′), 4.27 (dd, J = 4.6 Hz, J = 12.4 Hz, CH-6),
4.64 (d, J = 8.8 Hz, CH-1, 1H), 4.95 (dd, J = 8.8 Hz, J = 9.2 Hz, CH-2,
(AcO)3-β-Xyl-N3. A mixture of D-xylose (20.0 g, 133.2 mmol),
EtOAc (5.0 g, 60.9 mmol), and anhydrous acetic acid (80.9 mL, 847.9
mmol) was refluxed. The solution was cooled, and a mixture of ice and
water (200 mL) was added. The mixture was stirred for 3 h at room
temperature. The mixture was filtered, and the white solid was washed
with water and recrystallized in 95% ethanol (150 mL) to afford
(AcO)4-β-Xyl as a white solid (21 g, 80%). After that, a solution of
SnCl4 (221.00 μL, 1.88 mmol) in toluene (6.0 mL) was added to a
suspension of AgClO4 (390.00 mg, 1.88 mmol) in CH2Cl2 (65 mL) at
room temperature. The mixture was stirred at room temperature for 1
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1H), 5.09 (dd, J = 9.4 Hz, J = 9.5 Hz, CH-4, 1H), 5.22 (dd, J = 9.2 Hz,
(COCH3). MS (ES+; m/z (%)): 748 [M + H]+, 770 [M + Na]+, 1495
[2 M + H]+, 1517 [2 M + Na]+. IR (KBr; cm−1): 3412, 2931, 1754,
1648, 1527, 1439, 1403, 1370, 1229, 1146, 1058, 748, 604. Anal. Calcd
for C36H41N7O11 (747.75): C, 57.82; H, 5.53; N, 13.11. Found: C,
57.85; H, 5.57; N, 13.16.
+
J = 9.4 Hz, H-3, 1H). MS (ES+; m/z): 331 [M − N3] , 391 [M +
NH4]+, 396 [M + Na]+. IR (KBr; cm‑1): 2118, 1756, 1733, 1371, 1242,
1213, 1059, 1039.
(AcO)4-β-Glc-NH2 (27).78,79 This compound was prepared as
mentioned above for (AcO)3-β-Xyl-NH2 (25) from (AcO)4-β-Glc-
N3 (1.0 g, 0.26 mmol) to afford the title compound as an off-white
amorphous solid (0.791 g, 85%). Mp: 120−122 °C. [α]D = +11.1° (c =
(AcO)3-α-/β-L-Fuc-Py-γ-Py-Ind (31a,b). This compound was
prepared as mentioned above for (AcO)3-β-Xyl-Py-γ-Py-Ind (30a,b)
from BtO-Py-γ-Py-Ind (23; 206 mg, 0.340 mmol) and (AcO)4-β-Fuc-
NH2 (26; 200 mg, 0.68 mmol). The residue was purified by column
chromatography (SiO2, EtOAc (100%)), affording the title compound
(AcO)3-α-/β-L-Fuc-Py-γ-Py-Ind (31a,b) as mixture of α/β anomers
(1/3) (195 mg, 75%). An analytical sample of the β isomer was
separated and characterized. Data for (AcO)3-β-L-Fuc-Py-γ-Py-Ind
(31b) are as follows. 1H NMR (200 MHz, CDCl3): δ 1.17 (d, J = 6.4
Hz, CH3, 3H), 1.93−1.97 (m, CH2, 2H), 1.99 (s, CH3, 3H), 2.00 (s,
CH3, 3H), 2.05 (s, CH3, 3H), 2.30 (m, CH2, 2H), 3.32−3.36 (m, CH2,
2H), 3.79 (s, CH3, 3H), 3.82 (s, CH3, 3H), 3.92−3.96 (m, CH, 1H),
5.05−5.35 (m, 4 × CH, 4H), 6.43−6.47 (m, NH, 1H), 6.48 (d, J = 1.8
Hz, CH, 1H), 6.69 (d, J = 1.6 Hz, CH, 1H), 7.08−7.35 (m, NH + CH
× 6, 7H), 7.42 (d, J = 8.2 Hz, CH, 1H), 7.63 (d, J = 7.6 Hz, CH, 1H),
8.52 (s, NH, 1H), 8.65 (s, NH, 1H), 9.87 (s, NH, 1H). 13C NMR (125
MHz, CDCl3): δ 16.1 (CH3), 20.3 (CH3), 20.6 (CH3), 20.8 (CH3),
25.7 (CH2), 33.7 (CH2), 36.3 (CH3), 36.6 (CH3), 38.5 (CH2), 68.5
(CH), 70.4 (CH), 70.7 (CH), 71.5 (CH), 78.4 (CH), 103.7 (CH),
104.6 (CH), 104.7 (CH), 112.0 (CH), 119.8 (CH), 120.5 (CH),
120.6 (CH), 121.1 (C), 121.6 (C), 121.7 (C), 121.9 (CH), 123.1 (C),
124.5 (CH), 127.5 (C), 130.7 (C), 136.7 (C), 159.5 (CO), 161.5
(CO), 162.3 (CO), 170.0 (CO), 170.4 (CO), 170.7 (CO), 171.6
(CO). MS (ES+; m/z (%)): 762 [M + H]+, 1523 [2 M + H]+, 1545 [2
M + Na]+. IR (KBr; cm−1): 3376, 2928, 1750, 1710, 1531, 1443, 1371,
1227, 1078, 912, 824, 749, 602.
1
0.543 in CHCl3). H NMR (200 MHz, CDCl3): δ 2.00 (s, CH3CO,
3H), 2.01 (s, CH3CO, 3H), 2.06 (s, CH3CO, 3H), 2.08 (s, CH3CO,
3H), 3.70 (ddd, J = 2.4 Hz, J = 4.8 Hz, J = 9.90 Hz, CH-5, 1H), 4.12
(dd, J = 2.4 Hz, J = 12.3 Hz, CH-6′, 1H), 4.16−4.26 (m, CH-6 y CH-
1, 2H), 4.82 (dd, J = 9.0 Hz, J = 9.9 Hz, CH-2, 1H), 5.03 (dd, J = 9.3
Hz, J = 9.9 Hz, CH-4, 1H), 5.28 (dd, J = 9.3 Hz, J = 9.5 Hz, CH-3,
1H). MS (ES+; m/z): 331 [M − NH2]+, 348 [M + H]+, 370 [M +
Na]+, 694 [2 M + H]+, 717 [2 M + Na]+. IR (KBr; cm‑1): 1755, 1732,
1378, 1244, 1226, 1038.
(AcO)4-β-Gal-N3. This compound was prepared as mentioned above
for (AcO)4-β-Glc-N3 from (AcO)5-β-Gal (2.60 g, 6.66 mmol). After
solvent evaporation, the residue was purified by column chromatog-
raphy (SiO2, hexane/AcOEt (7/3)), affording the title compound as
an off-white amorphous solid (2.04 g, 85%). Mp: 93−95 °C. [α]D
=
−16.2° (c = 2.886 in CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.99 (s,
CH3CO, 3H), 2.06 (s, CH3CO, 3H), 2.09 (s, CH3CO, 3H), 2.17 (s,
CH3CO, 3H), 4.01 (td, J = 1.0 Hz, J = 6.2 Hz, CH-5, 1H), 4.16 (m,
CH2-6, 2H), 4.60 (d, J = 8.6 Hz, CH-1, 1H), 5.02 (dd, J = 3.3 Hz, J =
10.3 Hz, CH-3, 1H), 5.16 (dd, J = 8.8 Hz, J = 10.3 Hz, CH-2, 1H),
5.42 (dd, J = 1.2 Hz, J = 3.3 Hz, CH-4, 1H). MS (ES+; m/z): 391 [M
+ NH4]+, 396 [M + Na]+. IR (KBr; cm‑1): 2120, 1760, 1777, 1365,
1250, 128, 1067, 1029.
(AcO)4-β-Gal-NH2 (28).80 This compound was prepared as
mentioned above for (AcO)3-β-Xyl-NH2 (25) from (AcO)4-β-Gal-
N3 (1.0 g, 0.26 mmol) to afford the title compound as an off-white
amorphous solid (0.722 g, 80%). Mp: 134−136 °C. [α]D = +26.7° (c =
(AcO)4-β-Glc-Py-γ-Py-Ind (32b). This compound was prepared as
mentioned above for (AcO)3-β-Xyl-Py-γ-Py-Ind (30b) from BtO-Py-γ-
Py-Ind (23) (330 mg, 0.540 mmol) and (AcO)4-β-Glc-NH2 (27; 360
mg, 1.08 mmol). (AcO)4-α/β-Glc-Py-γ-Py-Ind (32a,b) was obtained
as a mixture of anomers (α/β = 1/5). The residue was purified by
column chromatography (SiO2, AcOEt (100%)), affording the β
anomer (AcO)4-β-Glc-Py-γ-Py-Ind (32b) as a white solid (301 mg,
1
1.004 in CHCl3). H NMR (400 MHz, CDCl3): δ 1.90 (s, CH3CO,
3H), 1.97 (s, CH3CO, 3H), 2.00 (s, CH3CO, 3H), 2.07 (s, CH3CO,
3H), 3.82 (dt, J = 1.0 Hz, J = 6.6 Hz, CH-5, 1H), 4.01−4.03 (m, CH2-
6, 2H), 4.08 (d, J = 8.1 Hz, CH-1, 1H), 4.94 (dd, J = 8.1 Hz, J = 10.4
Hz, CH-2, 1H), 4.97 (dd, J = 3.0 Hz, J = 10.4 Hz, CH-3, 1H), 5.32
(dd, J = 1.0 Hz, J = 3.3 Hz, CH-4, 1H). MS (ES+; m/z): 331 [M −
NH2]+, 348 [M + H]+, 370 [M + Na]+. IR (KBr; cm‑1): 1760, 1738,
1384, 1248, 1230, 1040.
(AcO)3-α-/β-Xyl-Py-γ-Py-Ind (30a,b). A solution of BtO-Py-γ-Py-
Ind (23; 100 mg, 0.16 mmol), (AcO)3-β-Xyl-NH2 (25; 90.46 mg,
0.329 mmol), and DIEA (103.4 μL, 0.64 mmol) in anhydrous DMF
was stirred at room temperature. After 72 h, the residue was washed
with saturated aqueous CuSO4, and extracted with AcOEt and the
organic layer was dried over Na2SO4 and filtered. After solvent
evaporation, the residue was purified by column chromatography
(SiO2, AcOEt (100%)), affording the title compound (AcO)3-Xyl-Py-
γ-Py-Ind (30a,b) as a mixture of α/β anomers (1/1) (92 mg, 95%). An
analytical sample of the β isomer was separated and characterized.
1
68%). Mp: 160−161 °C. [α]D = +10.6° (c = 1.56 in DMSO-d6). H
NMR (400 MHz, DMSO-d6): δ 1.78−1.82 (m, CH2γ, 2H), 1.90 (s,
CH3 (AcO), 3H), 1.94 (s, CH3 (AcO), 3H), 1.99 (s, CH3 (AcO), 3H),
2.00 (s, CH3 (AcO), 3H), 2.28 (t, J = 7.4 Hz, CH2γ, 2H), 3.21−3.25
(m, CH2γ, 2H), 3.79 (s, CH3, 3H), 3.84 (s, CH3, 3H), 4.00 (dd, J = 1.9
Hz, J = 12.3 Hz, CH, 1H), 4.10 (ddd, J = 2.1 Hz, J = 4.3 Hz, J = 10.0
Hz, CH, 1H), 4.19 (dd, J = 4.5 Hz, J = 12.4 Hz, CH, 1H), 4.91 (dd, J =
9.7 Hz, J = 9.9 Hz, CH, 1H), 5.09 (dd, J = 9.3 Hz, J = 9.5 Hz, CH,
1H), 5.36 (dd, J = 9.5 Hz, J = 9.7 Hz, CH, 1H), 5.50 (dd, J = 9.3 Hz, J
= 9.5 Hz, CH, 1H), 6.77 (d, J = 2.0 Hz, CH Py, 1H), 6.90 (d, J = 1.8
Hz, CH Py, 1H), 7.05−7.07 (m, CH, 1H), 7.17−7.23 (m, 2 × CH,
2H), 7.27−7.29 (m, 2 × CH, 2H), 7.46 (dd, J = 0.9 Hz, J = 8.2 Hz,
CH, 1H), 7.65 (d, J = 7.9 Hz, CH, 1H), 8.09 (dd, J = 5.5 Hz, J = 5.9
Hz, CH, 1H), 8.66 (d, J = 9.5 Hz, NH, 1H), 9.84 (s, NH, 1H), 10.27
(s, NH, 1H), 11.59 (d, J = 1.8 Hz, NH, 1H). 13C NMR (400 MHz,
DMSO-d6): δ 20.3 (CH3 (AcO)), 20.3 (CH3 (AcO)), 20.4 (CH3
(AcO)), 20.5 (CH3 (AcO)), 25.6 (CH2γ), 33.2 (CH2γ), 36.0 (CH3),
36.1 (CH3), 38.2 (CH2γ), 61.7 (CH2-6), 67.9 (CH), 70.6 (CH), 72.0
(CH), 73.1 (CH), 77.7 (C-1), 102.8 (CH), 104.1 (CH), 104.9 (CH),
112.3 (CH), 118.1 (CH), 119.2 (CH), 119.8 (CH), 121.4 (CH),
121.5 (C), 121.6 (C), 122.2 (C), 123.3 (C), 123.4 (CH), 127.1 (C),
127.1 (C), 136.6 (C), 158.2 (CO), 160.9 (CO), 161.2 (CO), 169.0
(CO), 169.3 (CO), 169.3 (CO), 169.5 (CO), 170.0 (CO). MS (ES+;
m/z (%)): 820 [M + H]+, 842 [M + Na]+. IR (KBr; cm−1): 1749,
1645, 1234. Anal. Calcd for C39H45N7O13·1.2H2O: C, 55.67; H, 5.68;
N, 11.65. Found: C, 55.42; H, 5.49; N, 11.44.
Data for (AcO)3-β-Xyl-Py-γ-Py-Ind (30b) are as follows. [α]D
=
1
−12.88° (c = 0.1 in CHCl3). H NMR (200 MHz, DMSO-d6): δ
1.78−1.80 (m, CH2γb, 2H), 1.91 (s, CH3, 3H), 1.97 (s, CH3, 3H), 2.00
(s, CH3, 3H), 2.25−2.29 (m, CH2γ, 2H), 3.19−3.23 (m, CH2γ, 2H),
3.54−3.58 (m, CH, 1H), 3.77 (s, CH3, 3H), 3.83 (s, CH3, 3H), 3.87−
3.91 (m, CH, 1H), 4.79−4.83 (m, CH, 1H), 5.06 (dd, J = 9.2 Hz, J =
9.4 Hz, CH-1, 1H), 5.28−5.32 (m, CH × 2, 2H), 6.72 (d, J = 1.4 Hz,
CH, 1H), 6.89 (d, J = 1.8 Hz, CH, 1H), 7.04 (dd, J = 7.8 Hz, J = 7.2
Hz, CH, 1H), 7.18−7.22 (m, CH × 2, 2H), 7.27 (s, CH × 2, 2H), 7.45
(d, J = 8.0 Hz, CH, 1H), 7.64 (d, J = 7.8 Hz, CH, 1H), 8.10 (m, NH-3,
1H), 8.58 (d, J = 9.2 Hz, NH-5, 1H), 9.85 (s, NH-4, 1H), 10.28 (s,
NH-2, 1H), 11.60 (s, NH-1, 1H). 13C NMR (200 MHz, DMSO-d6): δ
20.2 (3 × CH3), 25.5 (CH2), 33.2 (CH2), 35.8 (2 × CH3), 38.1
(CH2), 63.2 (CH2-5), 68.6 (CH), 70.6 (CH), 72.7 (CH), 77.6 (CH),
102.7 (CH), 104.1 (CH), 104.8 (CH),112.1 (CH), 118.0 (CH), 118.9
(CH), 119.6 (CH), 121.5 (CH), 121.9 (3 × C), 122.0 (C), 123.2
(CH), 127.0 (C), 131.6 (C), 136.5 (C), 158.1(HNCO), 160.9
(HNCO), 161.1 (HNCO), 168.9 (COCH3), 169.2 (COCH3), 169.4
(AcO)4-β-Gal-Py-γ-Py-Ind (33b). This compound was prepared as
mentioned above for (AcO)3-β-Xyl-Py-γ-Py-Ind (30b) from BtO-Py-γ-
Py-Ind (23; 320 mg, 0.525 mmol) and (AcO)4-β-Gal-NH2 (28; 364
mg, 1.05 mmol). (AcO)4-α-/β-Gal-Py-γ-Py-Ind (33a,b) (α/β = 1/5)
was obtained as a mixture of anomers (α/β = 1/5). The residue was
purified by column chromatography (SiO2, AcOEt (100%)), affording
G
dx.doi.org/10.1021/jo302238u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
the β anomer (AcO)4-β-Gal-Py-γ-Py-Ind (33b) as a white solid (280
mg, 66%). Mp: 165−167 °C. [α]D = +0.925° (c = 3.09 in acetone). 1H
NMR (500 MHz, DMSO-d6): δ 1.80 (t, J = 7.5 Hz, CH2γb, 2H), 1.91
(s, CH3 (AcO), 3H), 1.92 (s, CH3 (AcO), 3H), 1.99 (s, CH3 (AcO),
3H), 2.12 (s, CH3 (AcO), 3H), 2.29 (t, J = 7.5 Hz, CH2γ, 2H), 3.22−
3.34 (m, CH2γ, 2H), 3.78 (s, CH3, 3H), 3.84 (s, CH3, 3H), 4.02 (m,
2H), 4.32 (t, J = 6.0 Hz, CH, 1H), 5.22 (t, J = 9.3 Hz, CH, 1H), 5.30
(m, 2H), 5.45 (t, J = 9.3 Hz, CH, 1H), 6.78 (s, CH Py, 1H), 6.90 (s,
CH Py, 1H), 7.05 (t, J = 7.5 Hz, CH Ind, 1H), 7.20 (t, J = 7.8 Hz, CH
Ind, 1H), 7.24 (s, CH, 1H), 7.28 (s, 2 × CH, 2H), 7.46 (d, J = 8.0 Hz,
CH Ind, 1H), 7.65 (d, J = 8.0 Hz, CH Ind, 1H), 8.07 (m, NH, 1H),
8.74 (d, J = 9.5 Hz, NH, 1H), 9.82 (s, NH, 1H), 10.30 (s, NH, 1H),
11.58 (s, NH, 1H). 13C NMR (500 MHz, DMSO-d6): δ 20.3 (CH3
(AcO)), 20.4 (CH3 (AcO)), 20.4 (CH3 (AcO)), 20.4 (CH3 (AcO)),
25.6 (CH2γ), 33.2 (CH2γ), 36.0 (CH3), 36.1 (CH3), 38.2 (CH2γ),
61.4 (CH2), 67.6 (CH), 68.3 (CH), 71.1 (CH), 71.3 (CH), 77.5 (C-
1), 102.8 (CH), 104.1 (CH), 104.9 (CH), 112.2 (CH), 118.0 (CH),
119.2 (CH), 119.7 (CH), 121.5 (CH), 121.5 (C), 121.6 (C), 122.1
(C), 123.3 (C), 123.3 (CH), 127.1 (C), 131.6 (C), 136.5 (C), 158.2
(CO), 160.9 (CO), 161.2 (CO), 169.0 (CO), 169.3 (CO), 169.4
(CO), 169.8 (CO), 169.9 (CO). MS (ES+; m/z (%)): 821 [M + H]+,
(CH), 104.6 (CH), 112.3 (CH), 118.1 (CH), 118.5 (CH), 119.7
(CH), 121.5 (CH), 121.6 (C), 121.9 (C), 122.2 (C), 123.2 (C), 123.3
(CH), 127.1 (C), 131.6 (C), 136.5 (C), 158.2 (C), 161.2 (C), 161.3
(C), 169.2 (C). MS (ES+; m/z (%)): 622 [M + H]+, 644 [M + Na]+.
IR (KBr; cm−1): 3401, 3269, 2930, 1630, 1576, 1530, 1463, 1440,
1402, 1319, 1263, 1233, 1207, 1151, 1053, 1007, 819, 747, 617. Anal.
Calcd for C30H35N7O8 (621.64): C, 57.96; H, 5.67; N, 15.77. Found:
C, 57.89; H, 5.68; N, 15.69. Data for (HO)3-α-Xyl-Py-γ-Py-Ind (4) are
as follows. [α]D = −7.8° (c = 0.11 in methanol). 1H NMR (400 MHz,
DMSO-d6): δ 1.78−1.80 (m, CH2γb, 2H), 2.28 (t, J = 7.4 Hz, CH2γc,
2H), 3.21 (m, CH2γa, 2H), 3.30−3.76 (m, CH × 5, 5H), 3.77 (s, CH3,
3H), 3.83 (s, CH3, 3H), 4.98 (s, OH, 1H), 5.04 (s, OH, 1H), 5.17 (s,
OH, 1H), 5.36 (dd, J = 8.4 Hz, J = 3.2 Hz, CH-1 Xyl, 1H), 6.80 (d, J =
1.6 Hz, CH Py, 1H), 6.89 (d, J = 1.6 Hz, CH Py, 1H), 7.05 (dd, J = 7.2
Hz, J = 8.0 Hz, CH Ind, 1H), 7.17−7.21 (m, CH × 2, 2H), 7.28 (sa,
CH Ind + CH Py, 2H), 7.45 (d, J = 8.4 Hz, CH Ind, 1H), 7.64 (d, J =
8.0 Hz, CH Ind, 1H), 7.70 (d, J = 8.8 Hz, NH-5, 1H), 8.11 (t, J = 5.6
Hz, NH-3, 1H), 9.81 (s, NH-4, 1H), 10.32 (s, NH-2, 1H), 11.65 (s,
NH-1, 1H). 13C NMR (300 MHz, DMSO-d6): δ 21.7 (CH2γ), 33.3
(CH2 γ), 36.1 (2 × CH3), 38.2 (CH2 γ), 64.9 (CH2), 68.8 (CH), 70.5
(CH), 70.6 (CH), 75.8 (CH), 102.9 (CH), 104.1 (CH), 104.6 (CH),
112.3 (CH), 118.1 (CH), 118.6 (C), 119.8 (CH), 121.5 (CH), 121.6
(CH), 122.0 (C), 122.1 (C), 123.2 (C), 123.4 (CH), 127.1 (C), 131.7
(C), 136.6 (C), 158.2 (CO), 161.1 (CO), 161.2 (CO), 169.3 (CO).
MS (ES+; m/z (%)): 622 [M + H]+, 644 [M + Na]+. IR (KBr; cm−1):
3338, 3020, 2926, 2855, 1717, 1666, 1530, 1464, 1215, 1051, 756, 668.
Anal. Calcd for C30H35N7O8 (621.64): C, 57.96; H, 5.67; N, 15.77.
Found: C, 57.99; H, 5.75; N, 15.81.
(HO)3-β-L-Fuc-Py-γ-Py-Ind (7). This compound was prepared as
mentioned above for (HO)3-α/β-Xyl-Py-γ-Py-Ind (3/4) from (AcO)3-
α-/β-L-Fuc-Py-γ-Py-Ind (31a,b) (1/3; 100 mg, 0.131 mmol). The
residue was purified by column chromatography (SiO2, EtOAc 100%
to EtOAc/MeOH 7/3), affording the title compound (HO)3-α-/β-L-
Fuc-Py-γ-Py-Ind (28 mg, 59%) (1:3) as a white solid. The β isomer
was separated and characterized. Data for (HO)3-β-L-Fuc-Py-γ-Py-Ind
(7) are as follows. [α]D = −21.43° (c = 0.1 in DMSO). 1H NMR (300
MHz, DMSO-d6): δ 1.10 (d, J = 6.3 Hz, CH3, 3H), 1.78−1.80 (m,
CH2γb, CH2, 2H), 2.27−2.29 (m, CH2γc, 2H), 3.20−3.24 (m, CH2γa,
2H), 3.15−3.60 (m, CH × 4, 4H), 3.79 (s, CH3, 3H), 3.84 (s, CH3,
3H), 4.37 (d, J = 4.2 Hz, OH, 1H), 4.58 (d, J = 5.1 Hz, OH, 1H), 4.67
(d, J = 5.7 Hz, OH, 1H), 4.80 (dd, J = 8.7 Hz, J = 9.0 Hz, CH, 1H),
6.84 (d, J = 1.8 Hz, CH Py, 1H), 6.89 (d, J = 1.8 Hz, CH Py, 1H), 7.05
(t, J = 7.4 Hz, CH Ind, 1H), 7.16−7.22 (m, CH × 2, 2H), 7.27 (s, CH
× 2, 2H), 7.45 (d, J = 8.4 Hz, CH Ind, 1H), 7.64 (d, J = 7.5 Hz, CH
Ind, 1H), 8.08 (t, J = 5.4 Hz, NH, 1H), 8.29 (d, J = 8.7 Hz, NH, 1H),
9.79 (s, NH, 1H), 10.27 (s, NH, 1H), 11.59 (s, NH, 1H). 13C NMR
(75 MHz, DMSO-d6): δ 16.7 (CH3), 25.6 (CH2), 33.2 (CH2), 36.1
(CH3), 36.2 (CH3), 38.2 (CH2), 68.8 (CH), 71.2 (CH), 71.4 (CH),
74.5 (CH), 80.0 (CH), 102.9 (CH), 104.1 (CH), 104.5 (CH), 112.3
(CH), 118.1 (CH), 118.5 (CH), 119.7 (CH), 121.5 (CH), 121.6 (C),
121.9 (C), 122.2 (C), 123.2 (C), 123.3 (CH), 127.1 (C), 131.7 (C),
136.6 (C), 158.2 (CO), 161.2 (CO), 161.3 (CO), 169.2 (CO). MS
(ES+; m/z (%)): 636 [M + H]+, 658 [M + Na]+, 1272 [2 M + 2H]+,
1293 [2 M + Na]+. IR (KBr; cm−1): 3401, 2932, 2461, 2390, 1643,
1581, 1530, 1462, 1403, 1307, 1251, 1146, 1073, 746, 579. Anal. Calcd
for C31H37N7O8 (635.67): C, 58.57; H, 5.87; N, 15.42. Found: C,
58.55; H, 5.99; N, 15.50.
+
+
843 [M + Na] , 1641 [2 M + H] , 1663 [2 M + Na]+. IR (KBr;
cm−1): 1748, 1646, 1531, 1248, 1232. Anal. Calcd for C39H45N7O13
(819.81): C, 57.14; H, 5.53; N, 11.96. Found: C, 56.78; H, 5.60; N,
11.69.
Cycl-Py-γ-Py-Ind (1). This compound was prepared as mentioned
above for (AcO)3-β-Xyl-Py-γ-Py-Ind (30b) from BtO-Py-γ-Py-Ind
(23; 305 mg, 0.50 mmol) and Cycl-NH2 (100 mg, 1.01 mmol). The
residue was purified by column chromatography (SiO2, AcOEt
(100%)), affording the title compound (550 mg, 95%). Mp: 224−
1
226 °C. H NMR (300 MHz, DMSO-d6): δ 1.25−1.27 (m, CH2 × 2,
4H), 1.59 (d, J = 11.8 Hz, CH2, 2H), 1.73−1.91 (m, CH2 × 3, 6H),
2.28 (t, J = 7.5 Hz, CH2γ, 2H), 3.20−3.22 (m, CH2γ, 2H), 3.65 (sa,
CH-1 cHx, 1H), 3.76 (s, CH3, 3H,), 3.84 (s, CH3, 3H), 6.69 (d, J = 1.8
Hz, CH Py, 1H), 6.89 (d, J = 1.8 Hz, CH Py, 1H), 7.02−7.07 (m, 2 ×
CH, 2H), 7.19 (dd, J = 7.2 Hz, J = 8.1 Hz, 1H), 7.28 (s, 2H), 7.46 (d, J
= 8.2 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 8.08
(t, J = 5.5 Hz 1H), 9.71 (s, NH, 1H), 10.26 (s, NH, 1H), 11.58 (s,
NH, 1H). 13C NMR (50 MHz, DMSO-d6): δ 24.9 (CH2), 25.2 (CH2),
25.6 (CH2), 32.4 (CH2), 33.2 (CH2), 35.7 (CH3), 35.8 (CH3), 38.3
(CH2γ), 47.4 (CH-1 cHx), 102.8 (CH), 103.6 (CH), 104.1 (CH),
112.2 (CH), 117.3 (CH), 118.0 (CH), 119.6 (CH), 121.4 (CH),
121.6 (C), 121.7 (C), 123.2 (C + CH), 127.1 (C), 131.6 (C),
136.5(C), 158.1 (CO), 160.2 (CO), 161.1 (CO), 169.1 (CO). MS
(ES+; m/z (%)): 571 [M + H]+; 594 [M + Na]+. IR (KBr; cm−1):
3400, 1632, 1577, 1532, 1461, 1439, 1403, 1306, 1241, 1147. Anal.
Calcd for C31H37N7O4 (571.67): C, 65.13; H, 6.52; N, 17.15. Found:
C, 64.95; H, 6.52%: N, 16.90.
(HO)3-β-Xyl-Py-γ-Py-Ind (3) and (HO)3-α-Xyl-Py-γ-Py-Ind (4). A
solution of (AcO)3-α-/β-Xyl-Py-γ-Py-Ind (30a,b; 100 mg, 0.133
mmol) in MeOH (10 mL) was treated with sodium methoxide (100
mg, 4.34 mmol) in MeOH (10 mL) in one portion to immediately
produce a deeper yellow color, indicative of completion of the
reaction. After solvent evaporation, the residue was purified by column
chromatography (SiO2, CH2Cl2/MeOH (5/1)) to afford (HO)3-α/β-
Xyl-Py-γ-Py-Ind (3/4) (66 mg, 81%). Both anomers are separable by
column chromatography. Data for (HO)3-β-Xyl-Py-γ-Py-Ind (3) are as
follows. [α]D = +5.5° (c = 1 in DMSO). 1H NMR (400 MHz, DMSO-
d6): δ 1.78−1.80 (m, CH2γ, 2H), 2.28 (t, J = 7.6 Hz, CH2γ, 2H), 3.04
(t, J = 10.8 Hz, CH2γ, 2H), 3.10−3.36 (m, CH 4, 4H), 3.65 (m, CH,
1H), 3.77 (s, CH3, 3H), 3.83 (s, CH3, 3H), 4.77 (t, J = 8.8 Hz, CH-1,
1H), 4.86 (d, J = 5.6 Hz, OH), 4.95 (d, J = 5.2 Hz, OH), 5.04 (d, J =
4.8 Hz, OH), 6.83 (d, J = 1.6 Hz, CH Py, 1H), 6.89 (d, J = 2.0 Hz, CH
Py, 1H), 7.05 (dd, J = 6.8 Hz, J = 8.0 Hz, CH, 1H), 7.17−7.21 (m, CH
× 2, 2H), 7.28 (sa, CH Py + CH Ind, 2H), 7.45 (d, J = 8.4 Hz, CH,
1H), 7.64 (d, J = 8.0 Hz, CH, 1H), 8.12 (t, J = 5.6 Hz, NH-3, 1H),
8.35 (d, J = 8.8 Hz, NH-5, 1H), 9.83 (s, NH-4, 1H), 10.31 (s, NH-2,
1H), 11.62 (s, NH-1, 1H). 13C NMR (500 MHz, DMSO-d6): δ 26.6
(CH2), 33.2 (CH2), 35.9 (CH3), 36.1 (CH3), 38.2 (CH2), 67.3 (CH2),
69.7 (CH), 71.6 (CH), 77.6 (CH), 80.5 (CH-1), 102.8 (CH), 104.1
(HO)4-β-Gal-Py-γ-Py-Ind (5). This compound was prepared as
mentioned above for (HO)3-α-/β-Xyl-Py-γ-Py-Ind (3/4) from
(AcO)4-β-Gal-Py-γ-Py-Ind (33b; 92 mg, 0.112 mmol). The residue
was purified by column chromatography (SiO2, CH2Cl2: MeOH (5/
1)), affording the title compound as a white solid (50 mg, 65%). Mp:
1
200 °C. [α]D = +23.7° (c = 1.35 in DMSO-d6). H NMR (400 MHz,
DMSO-d6): δ 1.78−1.80 (m, CH2γb, 2H), 2.26−2.30 (m, CH2γa, 2H),
3.22 (m, CH2γc, 2H), 3.30−3.54 (m, 3H), 3.57−3.64 (m, 2H), 3.70 (d,
J = 2.7 Hz, CH, 1H), 3,79 (s, CH3, 3H), 3.84 (s, CH3, 3H), 4.83 (t, J =
8.9 Hz, CH, 1H), 6.85 (d, J = 1.7 Hz, CH Py, 1H), 6.89 (d, J = 1.7 Hz,
CH Py, 1H), 7.05 (t, J = 8.0 Hz, CH Ind, 1H), 7.19−7.21 (m, CH × 2,
2H), 7.28 (s, CH × 2, 2H), 7.53 (d, J = 8.2 Hz, CH Ind, 1H), 7.64 (d,
J = 8.2 Hz, CH Ind, 1H), 8.12 (t, J = 5.7 Hz, NH-3), 8.36 (d, J = 8.8
H
dx.doi.org/10.1021/jo302238u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Hz, NH-5, 1H), 9.83 (s, NH, 1H), 10.30 (s, NH, 1H), 11.61 (d, J = 1.5
Hz, NH, 1H). 13C NMR (125 MHz, DMSO-d6): 25.6 (CH2γ), 33.3
(CH2γ), 36.0 (CH3), 36.1 (CH3), 38.2 (CH2γ), 60.4 (CH2), 66.3
(CH), 69.1 (CH), 74.3 (CH), 76.6 (CH), 80.1 (CH-1), 102.8 (CH),
104.1 (CH), 104.5 (CH), 112.2 (CH), 118.0 (CH), 118.4 (CH),
119.6 (CH), 121.4 (CH), 121.5 (C), 121.8 (C), 122.2 (C), 123.2
(CH), 127.0 (C), 131.5 (C), 136.5 (C), 141.3 (C), 158.1 (CO), 161.1
(CO), 161.1 (CO), 169.2 (CO). MS (ES+; m/z (%)): 653 [M + H]+,
675 [M + Na]+, 1304 [2 M + H]+. IR (KBr; cm−1): 3600−2500, 1643,
1584, 1530. Anal. Calcd for C31H37N7O9 (651.67) + 2H2O: C, 54.14;
H, 6.01; N, 14.26. Found: C, 54.14; H, 6.02; N, 14.35.
(m, CH2 γ, 2H), 3.46 (t, J = 6.5 Hz, CH2O, 2H), 3.93 (s, CH3, 3H),
4.22 (c, J = 7.1 Hz, J = 7.1 Hz, CH2, 2H), 4.28−4.35 (m, CH2N, 2H),
4.48 (s, CH2 Bn, 2H), 6.79 (d, J = 2.0 Hz, CH Py, 1H), 6.91 (d, J = 1.9
Hz, CH Py, 1H), 7.08 (ddd, J = 8.0 Hz, J = 7.1 Hz, J = 0.9 Hz, H-5
Ind, 1H), 7.19 (d, J = 1.5 Hz, H-3 Ind, 1H), 7.24 (ddd, J = 8.2 Hz, J =
7.0 Hz, J = 1.1 Hz, H-6 Ind, 1H), 7.31 (d, J = 1.9 Hz, CH Py, 1H),
7.32−7.36 (m, CH × 5 Bn, 5H), 7.51 (d, J = 2.0 Hz, CH Py, 1H), 7.57
(d, J = 7.5 Hz, H-7 Ind, 1H), 7.64 (d, J = 8.1 Hz, H-4 Ind, 1H), 7.93
(d, J = 8.4 Hz, NH-3, 1H), 9.30 (s, NH-4, 1H), 9.67 (s, NH-2, 1H),
10.82 (s, NH-1, 1H). 13C NMR (400 MHz, acetone-d6): δ 15.4 (CH3),
27.6 (CH2γb), 27.9 (CH2), 29.9 (CH2), 30.12−31.17 (CH2 × 6), 33.1
(CH2CH2O), 35.2 (CH2γc), 37.3 (CH3), 40.1 (CH2γa), 50.1 (CH2N),
60.8 (CH2), 71.6 (CH2O), 73.8 (CH2 Bn), 103.7 (CH Ind), 105.0
(CH Py), 109.4 (CH Py), 113.7 (CH Ind), 119.6 (CH Py), 120.3 (C),
121.1 (CH Py), 121.6 (CH Ind), 123.2 (CH Ind), 123.8 (C), 124.6
(C), 124.7 (C), 125.2 (CH Ind), 128.69 (CH Bn), 128.9 (CH × 2
Bn), 129.5 (C), 129.7 (CH × 2 Bn), 133.3 (C), 138.5 (C), 140.7 (C),
159.9 (CO), 162.0 (CO), 163.2 (CO), 171.1 (CO). MS (ES+; m/z
(%)): 765.3 [M + H]+, 788.3 [M + Na]+; IR (KBr; cm−1): 3286, 2925,
1700, 1577, 1530, 1258, 1091, 811, 747. Anal. Calcd for C44H56N6O6
(764.95): C, 69.09; H, 7.38; N, 10.99; O, 12.55. Found: C, 68.79; H,
7.27; N, 11.01.
HO-Py[(CH2)11OBn]-γ-Py-Ind (22). This compound was prepared as
mentioned above for HO-Py-γ-Py-Ind (21) from EtO-Py-
[(CH2)11OBn]-γ-Py-Ind (20; 1.9 g, 2.4 mmol). The title compound
was afforded as an off-white amorphous solid (1.5 g, 90%). Mp: 115−
117 °C. 1H NMR (400 MHz, acetone-d6): δ 1.29−1.43 (m, CH2 × 7,
14H), 1.54−1.64 (m, CH2CH2O, 2H), 1.65−1.79 (CH2CH2N, 2H),
1.91−1.93 (m, CH2γb, 2H), 2.41 (t, J = 7.0 Hz, CH2γc, 2H), 3.39 (dd, J
= 6.3 Hz, J = 12.5 Hz, CH2γa, 2H), 3.46 (t, J = 6.4 Hz, CH2O, 2H),
3.93 (s, CH3, 3H), 4.32 (t, J = 7.3 Hz, CH2N, 2H), 4.48 (s, CH2 Bn,
2H), 6.81 (d, J = 1.8 Hz, CH-3 Py(B), 1H), 6.92 (d, J = 1.6 Hz, CH-3
Py(A), 1H), 7.08 (t, J = 7.8 Hz, CH-5 Ind, 1H), 7.20 (d, J = 1.1 Hz,
CH-3 Ind, 1H), 7.24 (t, J = 7.3 Hz, CH-6 Ind, 1H), 7.31 (d, J = 1.2 Hz,
CH-5 Py(A), 1H), (7.32−7.34) (m, CH × 5 Bn, 5H), 7.56 (d, J = 1.7
Hz, CH-5 Py(B), 1H), 7.56−7.57 (m, NH-3, 1H), 7.57 (d, J = 8.1 Hz
CH-7 Ind, 1H), 7.63 (d, J = 8.1 Hz, CH-4 Ind, 1H), 9.32 (s, NH-4,
1H), 9.68 (s, NH-2, 1H), 10.85 (s, NH-1, 1H); 13C NMR (100 MHz,
acetone-d6): δ 27.6 (CH2), 28.1 (CH2), 28.6 (CH2), 30.0−31.0 (CH2
γ + CH2 × 5), 33.6 (CH2CH2O), 35.7 (CH2γ), 37.8 (CH3), 40.5
(CH2γ), 50.5 (CH2N), 72.1 (CH2O), 74.3 (CH2 Bn), 104.1 (CH
Ind), 105.4 (CH Py), 110.2 (CH Py), 114.1 (CH Ind), 120.1 (CH
Ind), 120.2 (C), 121.7 (CH Ind), 122.1 (CH Ind), 123.7 (C), 124.2
(C), 124.3 (C), 125.0 (C), 125.1 (C), 125.8 (CH Py), 129.2 (CH Bn),
129.4 (CH × 2 Bn), 129.9 (C), 130.2 (CH × 2 Bn), 133.7 (C), 138.8
(C), 141.3 (C), 163.2 (CO), 171.5 (CO), 171.6 (CO); MS (ES−; m/
z): 735.3 [M − H]−, 736.3 [M]−. IR (KBr; cm−1): 3434, 2927, 2252,
2126, 1703, 1663, 1537, 1234, 1053, 1027, 1006, 823, 761. Anal. Calcd
for C42H52N6O6 (736.90): C, 68.46; H, 7.11; N, 11.40; O, 13.03.
Found: C, 68.15; H, 7.26; N, 11.54.
(HO)4-β-Glc-Py-γ-Py-Ind (6). This compound was prepared as
mentioned above for (HO)3-α-/β-Xyl-Py-γ-Py-Ind (3/4) from
(AcO)4-β-Glc-Py-γ-Py-Ind (32b; 100 mg, 0.122 mmol). The residue
was purified by column chromatography (SiO2, CH2Cl2: MeOH (5/
1)), affording the title compound as a white solid (50 mg, 65%). Mp:
196−197 °C. [α]D = +12.9° (c = 0.760 in DMSO-d6). 1H NMR (200
MHz, DMSO-d6): δ 1.78−1.80 (m, CH2γb, 2H), 2.28−2.30 (m,
CH2γc, 2H), 3.19−3.21 (m, CH2γa, 2H), 3.63−3.65 (m, CH, 1H), 3.79
(s, CH3, 3H), 3.84 (s, CH3, 3H), 4.51 (t, J = 5.7 Hz, CH, 1H), 4.81 (d,
J = 5.3 Hz, CH, 1H), 4.87 (d, J = 4.4 Hz, CH, 1H), 4.96 (d, J = 4.0 Hz,
CH, 1H), 6.85 (d, J = 1.7 Hz, CH Py, 1H), 6.90 (d, J = 1.7 Hz, CH Py,
1H), 7.05−7.07 (m, CH, 1H), 7.18−7.20 (m, CH × 2, 2H), 7.28 (s,
CH × 2, 2H), 7.46 (d, J = 8.2 Hz, CH, 1H), 7.65 (d, J = 7.9 Hz, CH
Ind, 1H), 8.13 (t, J = 4.9 Hz, NH, 1H), 8.36 (d, J = 8.8 Hz, CH Ind,
1H), 9.82 (s, NH, 1H), 10.29 (s, NH, 1H), 11.60 (s, NH, 1H). 13C
NMR (200 MHz, DMSO-d6): δ 25.6 (CH2γ), 33.3 (CH2γ), 35.8
6
(CH3), 36.0 (CH3), 38.2(CH2γ), 61.0 (CH2 ), 70.1 (CH), 71.8 (CH),
77.6 (CH), 78.4 (CH), 79.6 (C-1), 103.2 (CH Ind), 104.1 (CH Py),
104.5 (CH Py), 112.5 (CH Ind), 118.2 (CH Py), 119.6 (CH Py),
121.5 (CH Ind), 121.8 (CH Ind), 121.8 (C), 122.2 (C), 123.2 (C),
123.2 (CH), 127.0 (C), 131.6 (C), 136.5 (C), 141.3 (C), 158.1 (CO),
161.1 (CO), 161.1 (CO), 169.6 (CO). MS (ES+; m/z (%)): 652 [M +
H]+, 674 [M + Na]+, 1304 [2 M + H] +. IR (KBr; cm−1): 3600−2800,
1638, 1584, 1532. Anal. Calcd for C31H37N7O9 (651.67): C, 57.14; H,
5.72; N, 15.05. Found: C, 57.19; H, 5.68; N, 15.1.
Synthesis of Vector B Type Glyco-Oligoamides. EtO-Py-
81,82
[(CH2)11OBn]-NO2 (18). A suspension of EtO-Py-NO2
(975 mg,
5.3 mmol), K2CO3 (21.970 g, 159 mmol), and Bu4N+Br− (1.7 mg,
0.0053 mmol) in acetonitrile (15 mL) was added dropwise to a
solution of Br(CH2)11OBn83 (2.184 mg, 6.4 mmol) in acetonitrile (15
mL). After 96 h the residue was washed with HCl (1 M) and then with
aqueous sodium hydrogen carbonate, dried over Na2SO4, and filtered.
After solvent evaporation, the residue was purified by column
chromatography (SiO2, hexane/EtOAc (20/1 to 3/1)), affording the
title compound as an off-white amorphous solid (1.5 g, 65%). 1H
NMR (300 MHz, CDCl3): δ 1.22−1.42 (m, CH2 × 7, 14H), 1.36 (t, J
= 7.1 Hz, CH3, 3H), 1.53−1.67 (m, CH2CH2O, 2H), 1.71−1.86 (m,
CH2CH2N, 2H), 3.46 (t, J = 6.6 Hz, CH2O, 2H), 4.32 (c, J = 7.1 Hz, J
= 7.1 Hz, CH2, 2H), 4.27−4.37 (m, CH2N, 2H), 4.50 (s, CH2 Bn,
2H), 7.24−7.39 (m, CH × 5 Bn, 5H), 7.43 (d, J = 2.0 Hz, CH Py),
7.61 (d, J = 2.0 Hz, CH Py). 13C NMR (75 MHz, CDCl3): δ 14.2
(CH3 EtO), 26.1 (CH2), 26.4 (CH2), 29.0 (CH2), 29.3 (CH2), 29.4
(CH2 × 2), 29.4 (CH2), 29.7 (CH2), 31.1 (CH2), 50.4 (CH2), 60.8
(CH2), 70.5 (CH2), 72.8 (CH2), 113.0 (CH Py), 122.4 (CH Py),
126.6 (C), 127.4 (C), 127.5 (CH × 2 Bn), 127.6 (C), 128.3 (CH × 2
Bn), 138.7 (C), 159.9 (CO). MS (ES+; m/z (%)): 445.3 [M + H]+,
467.1 [M + Na]+, 483.1 [M + K]+. IR (KBr; cm−1): 3137, 2928
(CH2), 1718 (CO), 1511 (NO2), 1317, 1100, 847. Anal. Calcd for
C25H36N2O5 (444.56): C, 67.54; H, 8.16; N, 6.30. Found: C, 67.29; H,
7.93; N, 6.32.
BtO-Py[(CH2)11OBn]-γ-Py-Ind (24). This compound was prepared
as mentioned above for BtO-Py-γ-Py-Ind (23) from HO-Py-
[(CH2)11OBn]-γ-Py-Ind (22; 1.51 g, 2.04 mmol). The title compound
1
was afforded as an off-white amorphous solid (1.6 g, 90%). H NMR
(400 MHz, acetone-d6): δ 1.14−1.40 (m, CH2 × 7, 14H), 1.52−1.60
(m, CH2CH2O, 2H), 1.68−1.80 (m, CH2CH2N, 2H), 1.93−2.00 (m,
CH2γb, 2H), 2.47 (t, J = 7.0 Hz, CH2 γ, 2H), 3.40−3.46 (m, CH2 γ,
2H), 3.44 (t, J = 6.5 Hz, CH2O, 2H), 3.93 (s, CH3, 3H), 4.28−4.34
(m, CH2N, 2H), 4.47 (s, CH2 Bn, 2H), 6.69 (d, J = 1.7 Hz, CH Py,
1H), 7.08 (ddd, J = 1.0 Hz, J = 7.0 Hz, J = 8.0 Hz, CH-5 Ind, 1H), 7.19
(dd, J = 0.7 Hz, J = 2.0 Hz, CH-3 Ind, 1H), 7.23 (ddd, J = 1.2 Hz, J =
7.0 Hz, J = 8.2 Hz, CH-6 Ind, 1H), 7.31 (d, J = 1.8 Hz, CH Py, 1H),
7.31−7.36 (m, CH × 5 Bn, 5H), 7.37 (d, J = 1.2 Hz, CH Py, 1H),
7.48−7.53 (m, CH BtO, 1H), 7.55−7.58 (m, NH-3, 1H), 7.56 (dd, J =
0.9 Hz, J = 8.3 Hz, CH-7 Ind, 1H), 7.62 (dd, J = 0.8 Hz, J = 8.0 Hz,
CH-4 Ind, 1H), 7.62−7.67 (m, CH BtO, 1H), 7.75 (td, J = 0.9 Hz, J =
8.4 Hz, CH BtO, 1H), 7.91 (d, J = 1.9 Hz, CH Py, 1H), 8.09 (td, J =
0.9 Hz, J = 8.4 Hz, CH BtO, 1H), 9.63 (s, NH-4, 1H), 9.74 (s, NH-2,
1H), 10.86 (s, NH-1, 1H). 13C NMR (100 MHz, acetone-d6): δ 27.5
(CH2γ), 28.0 (CH2), 28.1 (CH2), 30.3 (CH2), 30.8 (CH2), 31.2
EtO-Py[(CH2)11OBn]-γ-Py-Ind (20). This compound was prepared as
mentioned above for MeO-Py-γ-Py-Ind (19) from HO-γ-Py-Ind (16;
1.450 g, 3.9 mmol) and EtO-Py[(CH2)11OBn]-NO2 (18; 1.4 g, 3.0
mmol). Purification of the residue by column chromatography (SiO2,
hexane/acetone (2/1; 1/1)) afforded the title compound as an off-
1
white amorphous solid (1.9 g, 65%). H NMR (400 MHz, acetone-
d6): δ 1.20−1.42 (m, CH2 × 7, 14H), 1.29 (t, J = 7.1 Hz, CH3 EtO,
3H), 1.52−1.64 (m, CH2CH2O, 2H), 1.66−1.79 (m, CH2CH2N, 2H),
1.88−1.95 (m, CH2 γ, 2H), 2.40 (t, J = 7.0 Hz, CH2 γ, 2H), 3.35−3.42
I
dx.doi.org/10.1021/jo302238u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(CH2), 31.3 (CH2), 31.4 (CH2), 31.5 (CH2CH2O), 33.1,
(CH2CH2N), 35.6 (CH2γ), 37.7 (CH3), 40.4 (CH2γ), 50.9 (CH2N),
71.9 (CH2O), 74.1 (CH2 Bn), 104.1 (C-3 Ind), 105.5 (CH Py), 110.8
(CH HOBt), 112.6 (CH Py), 114.1 (C-7 Ind), 120.0 (CH Py), 121.9
(CH BtO), 122.0 (C-6 Ind), 123.6 (CH BtO), 124.2 (C), 125.5 (C),
125.6 (C-4 Ind), 126.0 (C), 126.3 (CH Ind), 126.6 (CH Py), 126.7
(CH BtO), 129.1 (CH), 129.2 (CH × 2 Bn), 129.8 (C), 130.0 (CH ×
2 Bn), 130.7 (CH), 131.1 (C), 133.6 (C), 141.2 (C), 145.3 (C),
158.15 (CO), 160.3 (CO), 163.7 (CO), H172.0 (CO). MS (ES+; m/
z): 855 [M + 1]+, 877 [M + Na]+. IR (KBr; cm−1): 3417, 3286, 3132,
2929, 2855, 1774, 1641, 1581, 1407, 1308, 1252, 1147, 1096, 965, 851,
781, 744, 558. Anal. Calcd for C48H55N9O6 (854.01): C, 67.51; H,
6.49; N, 14.76; O, 11.24. Found: C, 67.58; H, 6.55; N, 14.82.
Cycl-Py[(CH2)11OBn]-γ-Py-Ind (29). This compound was prepared
as mentioned above for (AcO)3-α-/β-Xyl-Py-γ-Py-Ind (30a,b) from
BtO-Py[(CH2)11OBn]-γ-Py-Ind (24; 1.20 g, 1.4 mmol) and cHx-NH2
(277 mg, 2.8 mmol). Purification of the residue by column
chromatography (SiO2, AcOEt (100%)) afforded the title compound
as an off-white amorphous solid (800 mg, 70%). Mp: 122−125 °C; 1H
NMR (acetone-d6, 400 MHz): δ 1.00−1.40 (m, CH2 × 7 + CH2 × 2
cHx, 18H), 1.40−1.60 (m, CH2CH2O, + CH2 cHx, 4H), 1.6−1−75
(m, CH2CH2N + CH2 cHx, 4H), 1.75−1.95 (m, CH2γb + CH2 cHx,
4H), 2.35 (t, J = 7.1 Hz, CH2γc, 2H), 3.30−3.40 (m, CH2γa, 2H), 3.42
(t, J = 6.5 Hz, CH2O, 2H), 3.70−3.90 (m, CH-1 cHx, 1H), 3.98 (s,
CH3, 3H), 4.28 (t, J = 7.2 Hz, CH2N, 2H), 4.47 (s, CH2 Bn, 2H), 6.65
(d, J = 1.9 Hz, CH Py, 1H), 6.91 (d, J = 1.9 Hz, CH Py, 1H), 7.05
(ddd, J = 8.0 Hz, J = 7.0 Hz, J = 1.0 Hz, CH Ind, 1H), 7.05 (d, J = 8.1
Hz, NH-5), 7.20−7.22 (m, CH Ind, 1H), 7.22−7.24 (m, CH Py + CH
Ind, 2H), 7.29−7.32 (m, CH × 5 Bn + CH Py, 6H), 7.50 (m, CH Ind
+ NH-3, 2H), 7.60 (d, J = 8.0 Hz, CH Ind, 1H), 9.27 (s, NH-4, 1H),
9.77 (s, NH-2, 1H), 10.93 (s, NH-1, 1H). 13C NMR (acetone-d6, 100
MHz): δ 26.5 (CH2), 27.0 (CH2 × 2), 27.3 (CH2), 27.6 (CH2), 27.9
(CH2 × 2), 28.3 (CH2), 31.0 (CH2), 31.2 (CH2), 31.2 (CH2), 31.3
(CH2), 31.3 (CH2), 31.5 (CH2), 33.7 (CH2), 34.7 (CH2γ), 37.7
(CH3), 40.4, (CH2γ), 49.9 (CH-1 cHx), 50.0 (CH2N), 71.9 (CH2O),
74.9 (CH2 Bn), 104.2 (CH Ind), 105.1 (CH Py), 105.5 (CH Py),
114.0 (CH Ind), 118.5 (CH Py), 120.2 (CH Py), 121.9 (CH Ind),
123.5 (C), 124.1 (C), 124.2 (CH Ind), 125.1 (C), 125.4 (C), 125.6
(CH Ind), 129.0 (CH Bn), 129.2 (CH × 2 Bn), 129.8 (C), 130.0 (CH
× 2 Bn), 133.6 (C), 138.8 (C), 141.1 (C Bn), 160.4 (C), 162.7 (CO),
171.4 (CO), 171.4 (CO), 171.5 (CO). MS (ES+; m/z (%)): 818.3 [M
+ H]+, 819.3 [M + 3]+. IR (KBr; cm−1): 3428, 3302, 2928, 2853, 1635,
1578, 1524, 1451, 1401, 1307, 1251, 1145, 1101, 773, 745, 698. Anal.
Calcd for C48H63N7O5: C, 70.47; H, 7.76; N, 11.99; O, 9.78. Found:
C, 70.18; H, 7.48; N, 11.98.
(AcO)3-α-/β-Xyl-Py[(CH2)11OBn]-γ-Py-Ind (34a,b). This compound
was prepared as mentioned above for (AcO)3-α-/β-Xyl-Py-γ-Py-Ind
(30a,b) from BtO-Py[(CH2)11OBn]-γ-Py-Ind (24; 1.22 g, 1.4 mmol)
and (AcO)3-β-Xyl-NH2 (25; 790 mg, 2.8 mmol). The residue was
purified by column chromatography (SiO2, EtOAc (100%)), affording
the title compound as a mixture of anomers (α/β = 1/1) (840 mg, R =
60%). The anomers were separated by column chromatography. Data
for (AcO)3-β-Xyl-Py[(CH2)11OBn]-γ-Py-Ind (34b) are as follows.
Mp: 95−97 °C. [α]D = −35.33° (c = 0.15 in acetone). 1H NMR (400
MHz, acetone-d6): δ 1.18−1.42 (m, CH2 × 7, 14H), 1.54−1.64 (m,
CH2CH2O, 2H), 1.64−1.75 (m, CH2CH2N, 2H), 1.91 (t, J = 6.8 Hz,
CH2γ, 2H), 1.95 (s, CH3 (AcO), 3H), 1.99 (s, CH3 (AcO), 3H), 2.00
(s, CH3 (AcO), 3H), 2.39 (t, J = 7.0 Hz, CH2 γ, 2H), 3.35−3.43 (m,
CH2 γ, 2H), 3.46 (t, J = 6.5 Hz, CH2O, 2H), 3.57 (t, J = 11.0 Hz, CH-
5ec Xyl, 1H), 3.92 (s, CH3), 4.00 (dd, J = 11.3 Hz, J = 5.9 Hz, CH-5ax
Xyl, 1H), 4.23−4.38 (m, CH2N, 2H), 4.48 (s, CH2 Bn, 2H), 4.90−
4.96 (m, CH-4 Xyl, 1H), 5.05 (t, J = 9.4 Hz, CH-2 Xyl, 1H), 5.35 (t, J
= 9.6 Hz, CH-3 Xyl, 1H), 5.40 (t, J = 9.5 Hz, CH-1 Xyl, 1H), 6.65 (d, J
= 1.8 Hz, CH-3 Py B, 1H), 6.92 (d, J = 1.8 Hz, CH-3 Py A, 1H), 7.08
(t, J = 7.1 Hz, CH-6 Ind, 1H), 7.20 (d, J = 1.5 Hz, CH-3 Ind, 1H), 7.24
(ddd, J = 1.0 Hz, J = 7.1 Hz, J = 8.2 Hz, CH-5 Ind, 1H), 7.31 (d, J =
1.8 Hz, CH Py, 1H), 7.32−7.35 (m, CH × 5 Bn, 5H), 7.44 (d, J = 1.8
Hz, CH Py, 1H), 7.52 (t, J = 5.6 Hz, NH-3, 1H), 7.56 (d, J = 8.3 Hz,
CH-4 Ind, 1H), 7.63 (d, J = 8.7 Hz, NH-5, 1H), 7.77 (d, J = 10.2 Hz,
CH-7 Ind, 1H), 9.32 (s, NH-4, 1H), 9.68 (s, NH-2, 1H), 10.88 (s,
NH-1, 1H). 13C NMR (100 MHz, acetone-d6): δ 21.7 (CH3 (AcO)),
21.8 (CH3 (AcO)), 21.9 (CH3 (AcO)), 27.6 (CH2γ), 28.0 (CH2), 28.4
(CH2), 30.0 (CH2CH2O + CH2 × 4), 33.7 (CH2CH2N), 35.6
(CH2γ), 37.7 (CH3), 40.5 (CH2γ), 50.4 (CH2N), 65.8 (CH2-5 Xyl),
71.0 (CH-4 Xyl), 72.9 (CH2O), 74.2 (CH-2 Xyl), 74.6 (CH2 Bn), 74.8
(CH-3 Xyl), 80.5 (CH-1 Xyl), 104.1 (CH-3 Ind), 105.1 (CH Py),
106.2 (CH Py), 114.2 (CH-4 Ind), 120.1 (CH Py), 120.5 (CH Py),
122.0 (CH-6 Ind), 123.3 (CH-7 Ind), 123.6 (CH-5 Ind), 124.2 (C),
125.6 (C), 125.7 (C), 129.1 (CH Bn), 129.3 (CH × 2 Bn), 129.9 (C),
130.1 (CH × 2 Bn), 133.7 (C), 138.9 (C), 141.2 (C Bn), 160.4 (CO),
162.9 (CO), 163.7 (CO), 171.2 (CO), 171.4 (CO AcO), 171.5 (CO
AcO), 171.7 (CO AcO); MS (ES+; m/z (%)):994.5 [M + H]+, 995.5
[M + 2]+, 1016.5 [M + Na]+, 1017.5 [M + Na + 1] +; IR (KBr; cm−1):
3379, 2928, 2855, 1755, 1654, 1579, 1526, 1441, 1403, 1369, 1307,
1227, 1145, 1064, 1036, 937, 903, 812, 747, 698, 605; Anal. Calcd for
C53H67N7O12 (994.14): C, 64.03; H, 6.79; N, 9.86; O, 19.31. Found:
C, 63.79; H, 6.58; N, 9.81. Data for (AcO)3-α-Xyl-Py-[(CH2)11OBn]-
γ-Py-Ind (34a) are as follows. Mp: 90−95 °C. [α]D = 12.74° (c = 1 in
acetone). 1H NMR (400 MHz, acetone-d6): δ 1.18−1.41 (m, CH2 × 7,
14H), 1.53−1.64 (m, CH2CH2O, 2H), 1.64−1.76 (m, CH2CH2N,
2H), 1.89−1.94 (m, CH2 γ, 2H), 2.02 (s, CH3 (AcO), 3H), 2.04 (s,
CH3 (AcO), 3H), 2.06 (s, CH3 (AcO), 3H), 2.39 (t, J = 7.0 Hz, CH2 γ,
2H), 3.36−3.41 (m, CH2 γ, 2H), 3.46 (t, J = 6.5 Hz, CH2O, 2H), 3.87
(dd, J = 5.6 Hz, J = 12.6 Hz, CH2-5 Xyl, 2H), 3.93 (s, CH3, 3H), 4.27−
4.32 (m, CH2N, 2H), 4.48 (s, CH2 Bn, 2H), 4.83 (dt, J = 4.4 Hz, J =
6.8 Hz, CH-4 Xyl, 1H), 4.95 (dd, J = 4.2 Hz, J = 7.4 Hz, CH-2 Xyl,
1H), 5.46 (t, J = 7.1 Hz, CH-3 Xyl, 1H), 5.92 (dt, J = 3.8 Hz, J = 7.5
Hz, CH-1 Xyl, 1H), 6.85 (d, J = 1.8 Hz, CH Py, 1H), 6.93 (d, J = 1.9
Hz, CH Py, 1H), 7.08 (ddd, J = 1.0 Hz, J = 7.0 Hz, J = 8.0 Hz, CH-6
Ind, 1H), 7.20 (d, J = 0.6 Hz, CH-3 Ind, 1H), 7.24 (ddd, J = 1.1 Hz, J
= 7.0 Hz, J = 8.2 Hz, CH-5 Ind, 1H), 7.32 (d, J = 1.8 Hz, CH Py, 1H),
7.32−7.35 (m, CH × 5 Bn), 7.38 (d, J = 1.9 Hz, CH Py), 7.56 (dd, J =
8.3 Hz, J = 0.7 Hz CH-4 Ind, 1H), 7.50−7.60 (sa, NH-3, 1H), 7.63 (d,
J = 8.0 Hz, CH-7 Ind, 1H), 8.03 (d, J = 9.4 Hz, NH-5, 1H), 9.33 (s,
NH-4, 1H), 9.73 (s, NH-2, 1H), 10.87 (s, NH-1, 1H). 13C NMR (100
MHz, acetone-d6): δ 21.7 (CH3 (AcO)), 21.7 (CH3 (AcO)), 21.7
(CH3 (AcO)), 27.6 (CH2γb), 27.9 (CH2), 28.3 (CH2), 30.9 (CH2),
31.1 (CH2), 31.1 (CH2), 31.2 (CH2), 31.3 (CH2), 31.5 (CH2), 33.6
(CH2CH2N), 35.4 (CH2γ), 37.6 (CH3), 39.7, (CH2γ), 50.2 (CH2N),
63.5 (CH2-5 Xyl), 69.8 (CH-4 Xyl), 70.2 (CH-2 Xyl), 70.9 (CH-3
Xyl), 71.9 (CH2O), 74.1 (CH2 Bn), 80.5 (CH-1 Xyl), 104.1 (CH Ind),
105.3 (CH Py), 106.9 (CH Py), 114.0 (CH Ind), 119.9 (CH Py),
120.1 (CH Ind), 121.9 (CH Ind), 123.3 (C), 123.3 (C), 123.5 (CH
Ind), 124.0 (C), 124.4 (C), 125.6 (CH Py), 129.0 (CH Bn), 129.2
(CH × 2 Bn), 129.7 (C), 130.0 (CH × 2 Bn), 138.7 (C), 138.8 (C),
141.1 (C Bn), 163.1 (CO), 163.6 (CO), 163.6 (CO), 170.9 (CO),
171.2 (CO (AcO)), 171.3 (CO (AcO)), 171.4 (CO (AcO)). MS (ES
+; m/z): 994.5 [M + H]+, 995.5 [M + 2H]+, 1016.5 [M + Na]+,
1017.5 [M + Na + H]+. IR (KBr; cm−1): 3377, 2928, 2854, 1753,
1646, 1579, 1523, 1440, 1403, 1369, 1307, 1223, 1145, 1044, 874, 804,
746, 698, 638, 604. Anal. Calcd for C53H67N7O12: C, 64.03; H, 6.79; N,
9.86; O, 19.31. Found: C, 64.07; H, 6.82; N, 9.89.
Cycl-Py[(CH2)11OH]-γ-Py-Ind (2). To a solution of Cycl-Py-
[(CH2)11OBn]-γ-Py-Ind (29; 60 mg, 0.085 mmol) in methanol was
added Pd/C (5%) (180 mg). The mixture was stirred under H2 at
atmospheric pressure for 10 h. The Pd/C (5%) was removed by
filtration through filter paper, and the filtrate was concentrated in
vacuo to remove the methanol. Purification of the residue by column
chromatography (SiO2, hexane/AcOEt (1/40)) afforded the title
compound as an off-white amorphous solid (40 mg, 90%). Mp: 140−
144 °C. 1H NMR (acetone-d6, 400 MHz): δ 1.16−1.44 (m, CH2 × 7 +
CH2 × 3 cHx, 20H), 1.44−1.55 (m, CH2CH2O, 2H), 1.62−1−80 (m,
CH2CH2N + CH2 cHx, 4H), 1.84−1.95 (m, CH2γb + CH2 cHx, 4H),
2.37 (t, J = 7.0 Hz, CH2γc, 2H), 3.33−3.41 (m, CH2γa, 2H), 3.42−3.46
(m, OH), 3.48−3.56 (m, CH2O, 2H), 3.70−3.84 (m, CH-1 cHx, 1H),
3.90 (s, CH3, 3H), 4.28−4.36 (m, CH2N, 2H), 6.63 (d, J = 1.9 Hz, CH
Py, 1H), 6.90 (d, J = 1.9 Hz, CH Py, 1H), 7.03 (d, J = 7.8 Hz, NH-5
cHx, 1H), 7.08 (ddd, J = 1.0 Hz, J = 7.0 Hz, J = 8.0 Hz, CH Ind, 1H),
7.17−7.20 (sa, CH Ind, 1H), 7.20−7.27 (m, 2 × CH, 2H), 7.31 (d, J =
1.9 Hz, CH Py, 1H), 7.56 (dd, J = 0.8 Hz, J = 8.3 Hz, CH Ind, 1H),
J
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Article
7.54−7.60 (sa, NH-3, 1H), 7.64 (d, J = 7.9 Hz, CH Ind, 1H), 9.66 (s,
NH-4, 1H), 9.92 (s, NH-2, 1H), 10.81 (s, NH-1, 1H). 13C NMR
(acetone-d6, 125 MHz): δ 27.1 (2 × CH2), 27.4 (CH2), 27.6 (CH2),
27.7 (CH2), 28.7 (CH2), 30.00−31.50 (7 × CH2), 33.6 (CH2), 33.7
(CH2), 35.6 (CH2), 37.6 (CH3), 40.4 (CH2), 49.8 (CH-1 cHx), 49.9
(CH2N), 63.5 (CH2O), 103.9 (CH Ind), 104.8 (CH Py), 105.3 (CH
Py), 114.3 (CH Ind), 118.3 (CH Py), 119.9 (CH Py), 121.9 (CH
Ind), 123.5 (CH), 124.2 (C), 124.3 (C), 125.1 (C), 125.5 (C), 125.6
(CH Ind), 128.0 (C), 131.8 (CH Ind), 134.4 (C), 138.7 (C), 162.5
(CO), 163.6 (CO), 169.9 (CO), 171.3 (CO). MS (ES+; m/z): 728.8
[M + H]+, 729.8 [M + 2]+, 750 [M + Na]+. IR (KBr; cm−1): 3000−
3800, 2928, 2854, 1637, 1579, 1521, 1447, 1403, 1308, 1253, 1146,
853, 745, 559. Anal. Calcd for C41H57N7O5: C, 67.65; H, 7.89; N,
13.47; O, 10.99. Found: C, 67.68; H, 7.92; N, 13.50.
(CH2γ), 28.0 (CH2), 28.4 (CH2), 30.9 (CH2), 31.1 (CH2), 31.2
(CH2), 31.4 (CH2), 31.5 (CH2), 31.5 (CH2), 33.7 (CH2CH2N), 35.5
(CH2γ), 37.6 (CH3), 40.4 (CH2γ), 50.3 (CH2N), 62.8 (CH2O), 68.1
(CH2-5 Xyl), 71.3 (CH Xyl), 73.5 (CH Xyl), 78.2 (CH Xyl), 79.4
(CH-1 Xyl), 104.2 (CH Ind), 105.5 (CH Py), 106.1 (CH Py), 114.6
(CH Py), 119.8 (CH Py), 120.0 (CH Ind), 120.9 (CH Ind), 121.9
(C), 123.5 (CH Ind), 123.8 (C), 124.1 (C), 124.5 (C), 125.5 (C),
125.6 (CH Ind), 129.1 (C), 138.1 (C), 163.8 (CO × 2), 171.5 (CO ×
2). MS (ES+; m/z): 778.3 [M + H]+, 779.3 [M + 2H]+, 800.3 [M +
Na]+. IR (KBr; cm−1): 3000−3600, 2968, 2920, 2860, 1740, 1655,
1445, 1265, 1027. Anal. Calcd for C47H61N7O9 (777.91): C, 65.03; H,
7.08; N, 11.30; O, 16.59. Found: C, 65.13; H, 7.10; N, 11.32.
ASSOCIATED CONTENT
■
(AcO)3-β-Xyl-Py[(CH2)11OH]-γ-Py-Ind (35). This compound was
prepared as mentioned above for Cycl-Py[(CH2)11OH]-γ-Py-Ind (2)
from (AcO)3-β-Xyl-Py[(CH2)11OBn]-γ-Py-Ind (34b; 185 mg, 0.186
mmol) to afford the title compound as an off-white amorphous solid
(140 mg, 85%). Mp: 105−110 °C. [α]D = −21° (c = 0.1, acetone). 1H
NMR (400 MHz, acetone-d6): δ 1.20−1.38 (m, CH2 × 7, 14H), 1.46−
1.54 (m, CH2CH2O, 2H), 1.66−1.74 (m, CH2CH2N, 2H), 1.91 (m,
CH2γ, 2H), 1.95 (s, CH3, (AcO), 3H), 1.99 (s, CH3, (AcO), 3H), 2.01
(s, CH3, (AcO), 3H), 2.39 (t, J = 7.0 Hz, CH2 γ, 2H), 3.38 (dd, J = 6.4
Hz, J = 12.5 Hz, CH2 γ, 2H), 3.41−3.48 (m, OH, 1H), 3.53 (t, J = 6.5
Hz, CH2O, 2H), 3.56 (dd, J = 19.7 Hz, J = 8.8 Hz, CH-5′ Xyl, 1H),
3.92 (s, CH3, 3H), 4.00 (dd, J = 11.3 Hz, J = 5.6 Hz, CH-5 Xyl, 1H),
4.22−4.41 (m, CH2N, 2H), 4.92 (dt, J = 10.2 Hz, J = 10.0 Hz, J = 5.6
Hz, CH-4 Xyl, 1H), 5.04 (t, J = 9.4 Hz, CH-2 Xyl, 1H), 5.35 (t, J = 9.6
Hz, CH-3 Xyl, 1H), 5.37 (t, J = 9.6 Hz, CH-1 Xyl, 1H), 6.64 (d, J = 1.7
Hz, CH Py, 1H), 6.91 (d, J = 1.8 Hz, CH Py, 1H), 7.08 (t, J = 7.0 Hz,
CH-5 Ind, 1H), 7.18−7.20 (s, CH-3 Ind, 1H), 7.24 (ddd, J = 8.2 Hz, J
= 7.0 Hz, J = 1.1 Hz, CH-6 Ind, 1H), 7.31 (d, J = 1.8 Hz, CH Py, 1H),
7.44 (d, J = 1.8 Hz, CH Py, 1H), 7.53−7.57 (sa, NH-3, 1H), 7.56 (dd,
J = 8.3 Hz, J = 0.8 Hz, CH-7 Ind, 1H), 7.61−7.67 (CH-4 Ind + NH-5,
2H), 9.33 (s, NH-4, 1H), 9.69 (s, NH-2, 1H), 10.84 (s, NH-1, 1H).
13C NMR (100 MHz, acetone-d6): δ 21.6 (CH3 × 2 (AcO)), 21.7
(CH3 (AcO)), 27.5 (CH2γ), 27.7 (CH2), 28.2 (CH2), 30.9 (CH2) 31.1
(CH2), 31.2 (CH2), 31.2 (CH2), 31.4 (CH2), 33.6 (CH2CH2N), 34.8
(CH2CH2O), 35.5 (CH2γ), 37.6 (CH3), 40.4 (CH2γ), 50.3 (CH2N),
63.5 (CH2O), 65.8 (CH2-5 Xyl), 71.0 (CH Xyl), 72.8 (CH-4 Xyl),
74.6 (CH Xyl), 80.4 (CH-1 Xyl), 104.0 (CH Ind), 105.3 (CH Py),
106.1 (CH Py), 114.0 (CH Ind), 119.9 (CH Py), 120.4 (CH Py),
121.9 (CH Ind), 123.1 (C), 123.5 (CH Ind), 124.1 (C), 124.7 (C),
125.6 (CH Ind), 129.8 (C), 133.7 (C), 138.8 (C), 160.2 (C), 160.2
(CO), 162.8 (CO), 163.6 (CO), 171.2 (CO), 171.3 (CO), 171.4
(CO), 171.6 (CO). MS (ES+; m/z): 904.3 [M + H]+, 905.3 [M +
2H]+, 926.3 [M + Na]+. IR (KBr; cm−1): 3420, 2926, 2854, 1755,
1646, 1580, 1524, 1440, 1404, 1370, 1260, 1063, 804, 747. Anal. Calcd
for C46H61N7O12: C, 61.12; H, 6.80; N, 10.85; O, 21.24. Found: C,
61.18; H, 6.84; N, 10.90.
S
* Supporting Information
1H and 13C NMR spectra of all the new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: +34-91-564-48-53. E-mail: cvicent@iqog.csic.es.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the MEC
(CTQ2006-10874-C02-01 and -02, CTQ2009-10547, and
CTQ2012-32025) and a European RTN project (HPRN-CT-
2002-00190). C.B. thanks the MEC for FPI predoctoral
fellowships.
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