Phthalic Anhydride-Mediated Direct Glycosylation of Anomeric Hydroxy Arabinofuranose: Synthesis of Repeating Oligoarabinofuranoside and Tetradecasaccharide Arabinan Motif of Mycobacterial Cell Wall

Article abstract of DOI:10.1021/acs.joc.6b01723

An efficient direct phthalic anhydride-mediated one-pot glycosylation method employing anomeric hydroxy arabinofuranose as glycosyl donor and triflic anhydride as activating agent has been developed. This method afforded the desired di- and oligoarabinofu

Full text of DOI:10.1021/acs.joc.6b01723

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Note
Phthalic Anhydride-Mediated Direct Glycosylation of Anomeric Hydroxy
Arabinofuranose: Synthesis of Repeating Oligoarabinofuranoside
and Tetradecasaccharide Arabinan Motif of Mycobacterial Cell Wall
Bo-Young Lee, Jungwoo Oh, Ju-Yuel Baek, Heung Bae Jeon, and Kwan Soo Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01723 • Publication Date (Web): 10 Oct 2016
Downloaded from http://pubs.acs.org on October 25, 2016
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Phthalic AnhydrideꢀMediated Direct Glycosylation of Anomeric Hydroxy
Arabinofuranose: Synthesis of Repeating Oligoarabinofuranoside and
Tetradecasaccharide Arabinan Motif of Mycobacterial Cell Wall
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BoꢀYoung Lee, Jung Woo Oh, Ju Yuel Baek, Heung Bae Jeon,*,§ and Kwan Soo Kim*
Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University,
Seoul 120ꢀ749, Korea
§Department of Chemistry, Kwangwoon University, Seoul 139ꢀ701, Korea
*Eꢀmail: (Kwan Soo Kim) kwan@yonsei.ac.kr;
(Heung Bae Jeon) hbj@kw.ac.kr
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Abstract
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An efficient direct phthalic anhydrideꢀmediated oneꢀpot glycosylation method employing
anomeric hydroxy arabinofuranose as glycosyl donor and triflic anhydride as activating agent
has been developed. This method afforded the desired diꢀ and oligoarabinofuranosides in
good yields even in gram scale glycosylation when tꢀbutylphthalic anhydride was used.
Moreover, our new method can be further extended to the syntheses of repeating
oligoarabinofuranoside and tetradecasaccharide arabinan motif found in mycobacterial cell
wall.
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Mycobacterial infections have received significant attention due to their increasing
incidence over the world. In particular, Mycobacterium tuberculosis, the causative agent of
tuberculosis, is the most wellꢀknown the pathogenic strain of mycobacteria.1 Recently,
tuberculosis (TB) has ‘reappeared’ as a major threat to human health. Successful treatment of
TB requires a regimen of multiple antibiotics that must be administered over a number of
months,2 and failure to complete this process is a major cause of drug resistance.3 Inhibition
of the biosynthesis of the mycobacterial cell wall represents an exciting therapeutic
opportunity for the development of new drugs to combat TB.4 In particular, assembly of the
carbohydrate sections of the cell wall, many of which are unique to mycobacteria, has been a
field of intense interest over recent years. Several research groups have been attempting to
inhibit mycobacterial cell wall biosynthesis by inhibition of particular enzymes involved in
the proposed biosynthetic pathways.5
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Two major components of the mycobacterial cell wall are arabinogalactan and
lipoarabinomannam, both of which have mycobacterial arabinan moiety as a common
constituent containing large domains of
Dꢀarabinofuranose (Araf) units that are
predominantly linked α(1→5) as shown in Fig. 1.6 In addition, the further complexity have
been found at the 2ꢀOꢀposition of inner 3,5ꢀbranchedꢀAraf connected by 2ꢀaminoꢀ2ꢀdeoxyꢀ
galactose (GalNH2) or succinate ester in arabinan domain.6b,7 Recently, Lowary group
reported the synthesis of the tetrasaccharide containing both GalNH2 anomers attached to the
triarabinofuranoside (3,5ꢀbranchedꢀAraf) and the elucidation of GalNH2 connected by αꢀ
linkage to core Araf by the comparison with natural arabinan by NMR spectra.8 Although
many groups have achieved the synthesis of oligosaccharide arabinan motifs of
mycobacterial cell wall,9ꢀ28 there is no previous study for the synthesis of oligofuranoside
containing GalNH2 except this report as far as we know. In addition, because the formation of
furanosyl linkage is generally more difficult than that of pyranosyl linkage, the leaving
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groups at furanosyl donors have been essential for the successful furanosylation and most of
them have employed only a few representative leaving groups such as thioaryl or alkylate,9ꢀ
8
9
23,29
pentenyl,23ꢀ26 and trichloroacetimidate.9,17,30 Accordingly, there still remains a need for
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new and efficient furanosylation methodologies. In our efforts to develop the furanosylation
method, we achieved recently an efficient direct furanosylation protocol. We herein describe
the direct phthalic anhydrideꢀmediated oneꢀpot furanosylation method employing anomeric
hydroxy arabinofuranose as glycosyl donor and the efficient synthesis of repeating
oligoarabinofuranoside using our new method. We also report the synthesis of suitably
protected compound 2 of tetradecasaccharide 1, which is composed of αꢀGalNH2 and α(1→
5)ꢀ(Araf)13, for selective deprotection at 3,5ꢀO positions to be connected with α(1→3)ꢀ(Araf)n
and α(1→5)ꢀ(Araf)n in arabinan domain (Fig. 1).
Fig 1. Structure of a mycobacterial arabinan terminus and tetradecasaccharide 1
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For the preparation of arabinofuranosyl acceptor 6 and donor 8, compound 331 was
transformed in 87% yield to the corresponding allyl glycoside 4 on treatment of allyl alcohol
and BF3—OEt2 (Scheme 1). Removal of the acetyl groups in 4 was achieved by stirring with
NaOMe in MeOH, affording diol in 98% yield. The resulting diol was then converted to
compound 5 upon reaction with BzCl and pyridine in CH2Cl2. The fully protected glycoside 5
was transformed upon treatment with 2% HCl to give the glycosyl acceptor 6 in 90% yield.
For the selective deprotection with Bz group at later stage, the levulinylation of compound 6
was conducted to give 7 in 93% yield prior to the Pdꢀcatalyzed cleavage of the allyl ether
group providing 8 with free anomeric hydroxyl group in 85% yield.
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Scheme 1. Synthesis of Cꢀ1 hydroxy sugar 8 and glycosyl acceptor 6
The oneꢀpot direct mannosylation protocol,32 which was developed by our group, was
applied to the arabinosylation of Cꢀ1 hydroxy arabinofuranose employing various phthalic
anhydrides (Table 1). In those experiments, the arabinosylation with compound 8 was carried
out by a sequence of three steps in oneꢀpot in CH2Cl2: (1) stirring the solution of 8,
substituted phthalic anhydride, and DBU in the presence of 4Å molecular sieves for 15 min at
room temperature in CH2Cl2, (2) addition of DTBMP and 6 to the above solution at ꢀ40 °C
and stirring the resulting solution, and (3) slow addition of Tf2O at ꢀ40 °C and stirring the
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reaction mixture at ꢀ40 °C to 0 °C. The reaction of 8 with 6 under the modified condition
afforded αꢀdiarabinofuranoside 9.
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Table 1. Synthesis of αꢀdiarabinofuranoside 9 employing various substituted phthalic
anhydrides
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8 (Scale)
60 mg
substituted phthalic anhydride
9 (Yield)a
83%
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73%
110 mg
279 mg
603 mg
70 mg
150 mg
245 mg
578 mg
65 mg
528 mg
845 mg
1.35 g
a Isolated yield.
At first, when phthalic anhydride was used, the reaction afforded desired disaccharide 9 along
with selfꢀcondensed ester and decomposed donor. In the reactions up to 110 mg scale,
disaccharide 9 was obtained in high yield. However, gradual decrease of product yield was
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observed as the reaction scale increased. When we changed phthalic anhydride to 3ꢀ
fluorophthalic anhydride,33 we obtained slightly better results up to 245 mg scale, but not at
larger scale. On the other hand, coupling reaction with tꢀbutylphthalic anhydride produced the
desired disaccharide 9 in 68~75% yield independent to the scale of anomeric hydroxy sugar
8. Although the reason that tꢀbutylphthalic anhydride is better activator than others is not
clear, these surprising results encouraged us to prepare the repeating oligoarabinofuranoside
by oneꢀpot direct glycosylation.
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Toward the synthesis of triarabinofuranoside, compound 9 was converted into disaccharide
anomeric hydroxy sugar 10 as the next glycosyl donor upon deallylation over PdCl2 in MeOH
(Scheme 2). Reaction of anomeric hydroxy sugar 10 and acceptor 6 under the standard
glycosylation conditions afforded αꢀtrisaccharide 11 in 77% yield. The NMR spectrum of 11
in CDCl3 showed three anomeric carbon peaks at δ 104.9, 105.9, and 106.1. For the
preparation of trisaccharide donor and acceptor suited for the synthesis of the repeating
oligosaccharide, compound 11 was transformed to anomeric hydroxy sugar 12 and 13 by
deallylation and delevulinylation respectively.
Scheme 2. Synthesis of trisaccharide Cꢀ1 hydoxy sugar 12 and trisaccharide acceptor 13
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Repetitive glycosylation of the trisaccharide anomeric hydroxy sugar 12 with the
trisaccharide 13 as an acceptor resulted αꢀhexasaccharide 14 in 65% yield, which then was
converted into the hexasaccharide acceptor 15 by removal of its levulinyl group with
hydrazine (Scheme 3). Glycosylation of the trisaccharide donor 12 with the glycosyl acceptor
15 afforded αꢀnonasaccharide 16 in 63% yield. Deprotection of the levulinyl group in 16 with
hydrazine gave the nonasaccharide acceptor 17 in 90% yield. The arabinosylation of the
trisaccharide donor 12 with the nonasaccharide acceptor 17 proceeded smoothly under the
standard conditions to afford dodecasaccharide 18 in 67% yield. Deprotection of the levulinyl
group proceeded uneventfully to give dodecasaccharide acceptor 19 in 90% yield. This new
protocol would be considered as one of the most convenient and efficient methods to prepare
oligoarabinofuranoside.
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Scheme 3. Synthesis of dodecasaccharide acceptor 19
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For the synthesis of the tetradecasaccharide 2 in arabinan, the suitably protected αꢀGalNH2ꢀ
(1→2)ꢀarabinofuranosyl trichloroacetimidate (25) was prepared from 2ꢀazidoꢀgalactosyl
trichloroacetimidate 2034 and arabinofuranosyl acceptor 2134 (Scheme 4). The crucial
stereoselective αꢀgalactosylation was readily achieved by activation of the glycosyl donor 20
with TMSOTf, followed by the addition of the acceptor 21. The desired αꢀdisaccharide 22
was obtained in 94% yield. Reduction of the azide group by treatment of 22 with Ph3P and
acetylation of the resulting amine afforded the Nꢀacetyl protected disaccharide 23. Compound
23 was converted into disaccharide anomeric hydroxy sugar 24 by deallylation over PdCl2 in
MeOH. Subsequent treatment with trichloroacetonitrile and DBU provided the expected
trichloroacetimidate donor 25. Finally, the coupling of the disaccharide donor 25 and the
dodecasaccharide acceptor 19 in the presence of TMSOTf afforded the desired suitably
protected tetradecasaccharide 2 in 65% yield.
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Scheme 4. Synthesis of tetradecasaccharide 2 in arabinan
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In conclusion, we have established a reliable direct oneꢀpot gycosylation of Cꢀ1 hydroxy
arabinofuranose without a leaving group at furanosyl donor by employing tꢀbutylphthalic
anhydride as activator in good yield even in gram scale reaction. The power of the present
arabinofuranosylation method was demonstrated by the efficient synthesis of repeating
oligoarabinofuranoside and tetradecasaccharide arabinan motif found in mycobacterial cell
wall.
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EXPERIMENTAL SECTION
General Information: All reactions were conducted under a positive pressure of dry argon with dry,
freshly distilled solvents unless otherwise noted. All reagents were purchased from commercial
suppliers and used without further purification unless otherwise noted. Dichloromethane and
acetonitrile were distilled from calcium hydride. Ethyl acetate and hexane were distilled. Flash
column chromatography was performed employing 230ꢀ400 mesh silica gel. Thinꢀlayer
chromatography was performed using silica gel 60 F254 precoated plates (0.25 mm thickness) with a
fluorescent indicator. Visualization on TLC was achieved by UV light (254 nm) and a typical TLC
indication solution (cerium sulfate / molybdic acid solution). NMR spectra were recorded on a 400
MHz NMR spectrometer. Chemical shifts were reported in parts per million (ppm) downfield from
tetramethylsilane (TMS).
Allyl 2,3ꢀdiꢀOꢀacetylꢀ5ꢀOꢀtꢀbutyldiphenylsilylꢀαꢀDꢀarabinofuranoside (4). To a solution of
compound 331 (7.65 g, 14.9 mmol) in CH2Cl2 (50 mL) were added allyl alcohol (2.02 mL, 29.7 mmol)
and BF3—Et2O (2.83 mL, 22.3 mmol) at 0 oC. The resulting solution was stirred at 0 oC for 1.5 h. The
reaction mixture was quenched with saturated aqueous NaHCO3, and then extracted with CH2Cl2. The
combined organic layer was washed with aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc, 5:1)
20
to afford compound 4 (6.63 g, 87%) as a colorless oil. Rf = 0.73 (hexane/EtOAc, 3:1, v/v); [α]D
=
+34.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 9H), 2.03 (s, 3H), 2.06 (s, 3H), 3.87 (dd,
J = 11.2, 4.0 Hz, 1H), 3.91 (dd, J = 11.2, 4.4 Hz, 1H), 4.04 (dd, J = 13.2, 6.0 Hz, 1H), 4.15 (dd, J =
9.2, 4.0 Hz, 1H), 4.21 (dd, J = 13.2, 4.8 Hz, 1H), 5.07 (s, 1H), 5.11 (d, J = 1.2 Hz, 1H), 5.20 (dd, J =
10.4, 0.8 Hz, 1H), 5.26 (dd, J = 5.2, 0.8 Hz 1H), 5.32 (dd, J = 17.2, 1.6 Hz, 1H), 5.85ꢀ5.97 (m, 1H),
7.34ꢀ7.45 (m, 6H), 7.68ꢀ7.74 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 19.4, 20.85, 20.90, 26.8, 63.3,
67.9, 77.2, 82.2, 82.8, 104.8, 117.4, 127.7, 127.8, 129.78, 129.81, 133.35, 133.39, 134.0, 135.75,
135.78, 169.9, 170.2. Anal. Calcd for C28H36O7Si: C, 65.60; H, 7.08. Found: C, 65.55; H, 7.21.
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Allyl 2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀtꢀbutyldiphenylsilylꢀαꢀ
D
ꢀarabinofuranoside (5).
A
mixture of
5
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8
compound 4 (8.29 g, 16.2 mmol) and NaOMe (175 mg, 3.23 mmol) in MeOH (50 mL) was stirred at
room temperature for 1 h. The reaction mixture was neutralized with DOWEX CCRꢀ3 (H+ mode)
resin, filtered through Celite®, and concentrated in vacuo. The residue was purified by flash column
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chromatography on silica gel (hexane/EtOAc, 3:1) to afford allyl 5ꢀOꢀtꢀbutyldiphenylsilylꢀαꢀDꢀ
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arabinofuranoside (6.79 g, 98%) as a colorless oil. Rf = 0.30 (hexane/EtOAc, 3:1, v/v); [α]D
=
+184.3 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.06 (s, 9H), 3.00 (d, J = 11.2 Hz, 1H), 3.75 (dd,
J = 11.6, 1.2 Hz, 1H), 3.83 (dd, J = 11.6, 2.4 Hz, 1H), 4.01ꢀ4.09 (m, 2H), 4.11ꢀ4.19 (m, 3H), 4.24 (dd,
J = 12.8 5.2 Hz, 1H), 5.14 (s, 1H), 5.20 (dd, J = 10.0, 1.2 Hz, 1H), 5.28 (dd, J = 17.2, 1.2 Hz, 1H),
5.84ꢀ5.96 (m, 1H), 7.37ꢀ7.48 (m, 6H), 7.65ꢀ7.72 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 19.1, 26.8,
64.2, 68.2, 78.1, 78.6, 87.6, 107.6, 117.8, 128.0, 128.1, 130.2, 130.3, 131.9, 132.0, 133.8, 135.7, 135.8.
Anal. Calcd for C24H32O5Si: C, 67.26; H, 7.53. Found: C, 67.25; H, 7.45.
To a solution of allyl 5ꢀOꢀtꢀbutyldiphenylsilylꢀαꢀDꢀarabinofuranoside (6.79 g, 15.8 mmol) in CH2Cl2
(50 mL) were added benzoyl chloride (5.52 mL, 47.5 mmol), pyridine (7.69 mL, 95.1 mmol) and 4ꢀ
dimethylaminopyridine (387 mg, 3.17 mmol). After stirred at room temperature for 2 h, the reaction
mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (2 × 50 mL).
The combined organic layer was washed with 1N HCl (2 × 30 mL), saturated aqueous NaHCO3 (50
mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexane/EtOAc, 8:1) to afford compound 5 (9.49 g, 94%)
as a white solid. Rf = 0.45 (hexane/EtOAc, 8:1, v/v); mp 113ꢀ114 ˚C; [α]D20 = ꢀ92.7(c 2.2, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 1.07 (s, 9H), 4.01ꢀ4.09 (m, 2H), 4.12 (dd, J = 8.8, 6.0 Hz, 1H), 4.26ꢀ4.34
(m, 1H), 4.43 (dd, J = 9.6, 4.4 Hz, 1H), 5.22 (dd, J = 10.8, 1.6 Hz, 1H), 5.29 (s, 1H), 5.37 (dd, J =
17.2, 1.6 Hz, 1H), 5.53 (d, J = 1.2 Hz, 1H), 5.67 (dd, J = 5.2, 1.2 Hz, 1H), 5.90ꢀ6.03 (m, 1H), 7.29ꢀ
7.58 (m, 12H), 7.71ꢀ7.77 (m, 4H), 7.96ꢀ8.10 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 19.4, 26.9, 63.7,
67.9, 77.5, 82.6, 83.1, 105.0, 117.4, 127.8, 128.4, 128.9, 129.3, 129.6, 129.8, 130.0, 130.6, 133.2,
133.3, 133.4, 134.0, 134.6, 135.7, 165.5, 165.7. Anal. Calcd for C38H40O7Si: C, 71.67; H, 6.33. Found:
C, 71.63; H, 6.15.
Allyl 2,3ꢀdiꢀOꢀbenzoylꢀαꢀDꢀarabinofuranoside (6). To a solution of compound 5 (7.26 g, 11.4
mmol) in CH2Cl2 (10 mL) was added 2% HCl (40 mL) in MeOH (40 mL). The resulting solution was
stirred at room temperature for 10 h, and then the reaction mixture was extracted with CH2Cl2 (3 × 50
mL). The combined organic layer was washed with saturated aqueous NaHCO3 (3 × 50 mL) and brine
(50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc, 3:1) to afford compound 6 (4.09 g, 90%) as a colorless
oil. Rf = 0.30 (hexane/EtOAc, 3:1, v/v); [α]D20 = ꢀ34.7 (c 2.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ
2.36 (dd, J = 7.6, 5.2 Hz, 1H), 3.94ꢀ4.06 (m, 2H), 4.12 (dd, J = 13.2, 6.0 Hz, 1H), 4.30 (dd, J = 13.2,
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4.8 Hz, 1H), 4.35 (dd, J = 8.8, 4.4 Hz, 1H), 5.22 (dd, J = 10.4, 1.6 Hz, 1H), 5.30 (s, 1H), 5.37 (dd, J =
17.2, 1.6 Hz, 1H), 5.46 (d, J = 4.8 Hz, 1H), 5.57 (d, J = 1.2 Hz, 1H), 5.89ꢀ6.01 (m, 1H), 7.42ꢀ7.49 (m,
4H), 7.55ꢀ7.62 (m, 2H), 8.02ꢀ8.11 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 62.5, 68.0, 78.0, 82.1,
83.8, 104.9, 117.6, 128.6, 128.7, 129.2, 129.3, 130.0, 130.1, 133.7, 133.8, 165.5, 166.4. Anal. Calcd
for C22H22O7: C, 66.32; H, 5.57. Found: C, 66.26; H, 5.54.
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Allyl 2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀDꢀarabinofuranoside (7). To a solution of compound 6
(7.80 g, 19.6 mmol) in CH2Cl2 (50 mL) were added levulinic acid (3.41 g, 29.4 mmol), N,Nꢀ
diisopropylcarbodimide (4.55 mL, 29.4 mmol) and 4ꢀdimethylaminopyridine (239 mg, 1.96 mmol).
After stirred at room temperature for 4 h, the reaction mixture was quenched with H2O (30 mL) and
extracted with CH2Cl2 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (2 ×
50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexane/EtOAc, 3:1) to afford compound 7 (9.04 g, 93%)
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as a colorless oil. Rf = 0.25 (hexane/EtOAc, 3:1, v/v); [α]D = ꢀ6.6 (c 1.9, CHCl3); H NMR (400
MHz, CDCl3) δ 2.15 (s, 3H), 2.59ꢀ2.65 (m, 2H), 2.71ꢀ2.77 (m, 2H), 4.12 (dd, J = 13.2, 6.0 Hz, 1H),
4.31 (dd, J = 12.8, 4.8 Hz, 1H), 4.41 (dd, J = 11.6, 5.6 Hz, 1H), 4.48 (dd, J = 8.4, 5.2 Hz, 1H), 4.57
(dd, J = 11.6, 3.6 Hz, 1H), 5.23 (dd, J = 10.4, 1.6 Hz, 1H), 5.31 (s, 1H), 5.38 (dd, J = 17.2, 1.6 Hz,
1H), 5.42 (d, J = 4.8 Hz, 1H), 5.53 (d, J = 0.8 Hz, 1H), 5.89ꢀ6.02 (m, 1H), 7.43ꢀ7.50 (m, 4H), 7.56ꢀ
7.63 (m, 2H), 8.04ꢀ8.10 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 28.0, 29.9, 38.0, 63.9, 68.1, 77.9,
81.1, 81.9, 105.1, 117.5, 128.6, 128.7, 129.2, 129.3, 130.0, 130.1, 133.65, 133.74, 133.8, 165.5, 165.9,
172.6, 206.5. Anal. Calcd for C27H28O9: C, 65.31; H, 5.68. Found: C, 65.23; H, 5.66.
2,3ꢀDiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀα/βꢀDꢀarabinofuranose (8). A mixture of compound 7 (7.04 g, 14.2
mmol) and PdCl2 (503 mg, 2.84 mmol) in MeOH/H2O (100 mL, 10:1, v/v) was stirred at room
temperature for 8 h. The reaction mixture was filtered through Celite® and concentrated in vacuo.
The residue was purified by flash column chromatography (hexane/EtOAc, 3:2) to afford compound 8
(5.51 g, 85%, α/β = 2:1) as a colorless amorphous form. Rf = 0.20 (hexane/EtOAc, 3:2, v/v); 1H NMR
(400 MHz, CDCl3) δ 2.15 (s, 3H), 2.18 (s, 1.5H), 2.58ꢀ2.88 (m, 6H), 3.85 (d, J = 3.6 Hz, 1H), 4.26ꢀ
4.31 (m, 0.5H), 4.35ꢀ4.45 (m, 2H), 4.58 (dd, J = 11.6, 3.6 Hz, 1H), 4.61ꢀ4.66 (m, 1H), 4.72 (dd, J =
12.0, 4.0 Hz, 0.5H), 5.41 (d, J = 4.0 Hz, 1H), 5.50 (dd, J = 6.8, 4.4 Hz, 0.5H), 5.52 (s, 1H), 5.66 (d, J
= 4.0 Hz, 1H), 5.80 (t, J = 4.8 Hz, 0.5H), 5.86 (t, J = 6.0 Hz, 0.5H), 7.40ꢀ7.49 (m, 6H), 7.53ꢀ7.62 (m,
13
3H), 8.03ꢀ8.11 (m, 6H); C NMR (100 MHz, CDCl3) δ 27.9, 28.0, 29.89, 29.93, 37.96, 38.02, 64.0,
64.6, 75.9, 77.5, 77.9, 78.8, 81.2, 82.3, 95.2, 101.0, 128.57, 128.61, 128.63, 128.7, 129.0, 129.1,
129.96, 130.04, 130.1, 133.6, 133.70, 133.72, 133.8, 165.6, 165.9, 165.95, 166.02, 172.6, 172.8, 206.8,
207.8. HRMS (ESI) calcd for C24H24O9Na [M + Na]+: 479.1318. Found: 479.1317.
Allyl
(2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀDꢀarabinofuranosyl)ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀDꢀ
arabinofuranoside (9). A solution of 8 (1.35 g, 2.96 mmol, 1.0 equiv), tꢀbutylphthalic anhydride (906
mg, 4.44 mmol, 1.5 equiv), and DBU (0.538 mL, 3.55 mmol, 1.2 equiv) in CH2Cl2 (15 mL) in the
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presence of 4Å molecular sieves was stirred for 15 min at room temperature and cooled down to −40
oC. Then a solution of a glycosyl acceptor 6 (1.53 g, 3.84 mmol, 1.3 equiv) and DTBMP (1.52 g, 7.39
mmol, 2.5 equiv) in CH2Cl2 (15 mL) were added sequentially at −40 oC and the resulting solution was
o
stirred for further 15 min at −40 C. After dropwise addition of a solution of Tf2O (0.647 mL, 3.84
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mmol, 1.3 equiv) in CH2Cl2 (6.5 mL) to the above solution via cannula, the reaction mixture was
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stirred at −40 oC for 15 min, allowed to warm up over 1 h to 0 C, quenched with saturated aqueous
NaHCO3, and then extracted with CH2Cl2. The combined organic phase was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography
(hexane/EtOAc, 2:1) to afford compound 9 (1.81 g, 73%) as a colorless oil. Rf = 0.45 (hexane/EtOAc,
3:2, v/v); [α]D20 = −2.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.13 (s, 3H), 2.56ꢀ2.63 (m, 2H),
2.68ꢀ2.75 (m, 2H), 3.96 (dd, J = 11.2, 2.8 Hz, 1H), 4.09 (dd, J = 12.8, 6.0 Hz, 1H), 4.22 (dd, J = 11.2,
4.4 Hz, 1H), 4.28 (dd, J = 13.2, 4.8 Hz, 1H), 4.40 (dd, J = 12.0, 5.2 Hz, 1H), 4.48 (dd, J = 7.2, 4.4 Hz,
1H), 4.53ꢀ4.65 (m, 2H), 5.21 (dd, J = 10.4, 0.8 Hz, 1H), 5.28 (s, 1H), 5.35 (dd, J = 17.2, 1.2 Hz, 1H),
5.40 (d, J = 4.4 Hz, 1H), 5.43 (s, 1H), 5.55 (s, 1H), 5.61 (s, 1H), 5.63 (d, J = 5.2 Hz, 1H), 5.88ꢀ6.01
(m, 1H), 7.24ꢀ7.64 (m, 12H), 7.90ꢀ8.11 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 27.9, 29.9, 38.0,
63.8, 66.3, 67.9, 77.5, 77.8, 81.3, 81.5, 82.0, 82.1, 104.9, 106.0, 117.5, 128.5, 128.58, 128.63, 128.7,
129.1, 129.15, 129.23, 129.4, 129.92, 129.94, 130.00, 130.03, 133.5, 133.55, 133.59, 133.7, 133.9,
165.2, 165.5, 165.80, 165.83, 172.6, 206.5. Anal. Calcd for C46H44O15: C, 66.02; H, 5.30. Found: C,
66.00; H, 5.28.
(2,3ꢀDiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀα/βꢀDꢀ
arabinofuranose (10). A mixture of compound 9 (8.55 g, 10.2 mmol) and PdCl2 (362 mg, 2.04
mmol) in MeOH/H2O (100 mL, 10:1, v/v) was stirred at room temperature for 8 h. The reaction
mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by flash
column chromatography (hexane/EtOAc, 1:1) to afford compound 10 (7.16 g, 88%, α/β = 2:1) as a
1
colorless amorphous form. Rf = 0.30 (hexane/EtOAc, 1:1, v/v); H NMR (400 MHz, CDCl3) δ 2.127
(s, 3H), 2.133 (s, 1.5H), 2.55ꢀ2.65 (m, 3H), 2.68ꢀ2.76 (m, 3H), 3.73 (d, J = 3.6 Hz, 1H), 3.96 (dd, J =
11.2, 2.8 Hz, 1H), 4.00 (dd, J = 11.6, 2.4 Hz, 0.5H), 4.19 (dd, J = 11.2, 4.8 Hz, 1H), 4.23 (dd, J = 9.6,
4.4 Hz, 0.5H), 4.29ꢀ4.33 (m, 0.5H), 4.35 (d, J = 7.6 Hz, 0.5H), 4.37ꢀ4.44 (m, 1.5H), 4.55ꢀ4.69 (m,
4H), 5.38ꢀ5.44 (m, 2.5H), 5.47 (d, J = 4.4 Hz, 0.5H), 5.52ꢀ5.57 (m, 2H), 5.58ꢀ5.65 (m, 3H), 5.77 (dd,
J = 7.2, 4.8 Hz, 0.5H), 5.98 (t, J = 6.0 Hz, 0.5H), 7.28ꢀ7.61 (m, 18H), 7.93ꢀ8.08 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 27.9, 29.9, 38.0, 63.77, 63.82, 66.7, 67.8, 75.8, 77.45, 77.50, 77.7, 78.0, 79.9,
81.0, 81.2, 81.5, 82.0, 82.1, 82.5, 95.3, 100.9, 106.1, 106.4, 128.4, 128.48, 128.52, 128.54, 128.60,
128.63, 128.7, 128.88, 128.94, 128.99, 129.03, 129.11, 129.14, 129.2, 129.88, 129.93, 129.98, 130.01,
130.1, 133.5, 133.56, 133.59, 133.64, 133.7, 133.9, 165.2, 165.6, 165.7, 165.76, 165.79, 165.87,
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165.94, 166.0, 172.58, 172.60, 206.7, 206.8. HRMS (ESI) calcd for C43H40O15Na [M + Na]+:
819.2265. Found: 819.2265.
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Allyl
[(2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀ
arabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranoside (11). A solution of 10 (966
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mg, 1.21 mmol, 1.0 equiv), tꢀbutylphthalic anhydride (371 mg, 1.82 mmol, 1.5 equiv), and DBU
(0.220 mL, 1.45 mmol, 1.2 equiv) in CH2Cl2 (15 mL) in the presence of 4Å molecular sieves was
o
stirred for 15 min at room temperature and cooled down to −40 C. Then a solution of a glycosyl
acceptor 6 (628 mg, 1.58 mmol, 1.3 equiv) and DTBMP (622 mg, 3.03 mmol, 2.5 equiv) in CH2Cl2
(10 mL) were added sequentially at −40 oC and the resulting solution was stirred for further 15 min at
−40 oC. After dropwise addition of a solution of Tf2O (0.265 mL, 1.58 mmol, 1.3 equiv) in CH2Cl2 (3
mL) to the above solution via cannula, the reaction mixture was stirred at −40 oC for 15 min, allowed
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to warm up over 1 h to 0 C, quenched with saturated aqueous NaHCO3, and then extracted with
CH2Cl2. The combined organic phase was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography (hexane/EtOAc, 3:2) to afford
compound 11 (1.10 g, 77%) as a colorless amorphous form. Rf = 0.40 (hexane/EtOAc, 1:1, v/v);
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[α]D = +4.0 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 2.12 (s, 3H), 2.55ꢀ2.61 (m, 2H), 2.67ꢀ
2.73 (m, 2H), 3.93 (dd, J = 10.8, 2.4 Hz, 1H), 3.96 (dd, J = 10.8, 2.8 Hz, 1H), 4.09 (dd, J = 13.2, 6.0
Hz, 1H), 4.16ꢀ4.24 (m, 2H), 4.24ꢀ4.31 (m, 1H), 4.39 (dd, J = 11.2, 4.8 Hz, 1H), 4.43ꢀ4.49 (m, 1H),
4.52ꢀ4.65(m, 3H), 5.20 (dd, J = 10.4, 1.2 Hz, 1H), 5.27 (s, 1H), 5.35 (dd, J = 17.2, 1.6 Hz, 1H), 5.38ꢀ
5.42 (m, 2H), 5.44 (s, 1H), 5.55 (d, J = 1.2 Hz, 1H), 5.60 (s, 1H), 5.61ꢀ5.67 (m, 3H), 5.87ꢀ6.00 (m,
1H), 7.24ꢀ7.30 (m, 4H), 7.37ꢀ7.61 (m, 14H), 7.88ꢀ7.94 (m, 4H), 7.99ꢀ8.08 (m, 8H); 13C NMR (100
MHz, CDCl3) δ 27.9, 29.9, 38.0, 63.7, 66.0, 66.2, 67.9, 77.4, 77.8, 81.2, 81.6, 81.7, 82.0, 82.1, 104.9,
105.9, 106.1, 117.4, 128.39, 128.41, 128.5, 128.6, 128.7, 129.0, 129.2, 129.3, 129.4, 129.88, 129.92,
129.97, 130.01, 133.3, 133.4, 133.5, 133.7, 133.9, 165.2, 165.3, 165.5, 165.75, 165.80, 172.6, 206.4.
Anal. Calcd for C65H60O21: C, 66.32; H, 5.14. Found: C, 66.40; H, 5.25.
[(2,3ꢀDiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀ
arabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀα/βꢀ
D
ꢀarabinofuranose (12). A mixture of compound
11 (3.98 g, 3.38 mmol) and PdCl2 (120 mg, 0.677 mmol) in MeOH/H2O (40 mL, 10:1, v/v) was
stirred at room temperature for 8 h. The reaction mixture was filtered through Celite® and
concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc,
1:1) to afford compound 12 (3.35 g, 87%, α/β = 2:1) as a colorless oil. Rf = 0.28 (hexane/EtOAc, 1:1,
1
v/v); H NMR (400 MHz, CDCl3) δ 2.12 (s, 9H), 2.55ꢀ2.62 (m, 6H), 2.68ꢀ2.72 (m, 6H), 3.28 (d, J =
3.6 Hz, 1H), 3.90ꢀ3.99 (m, 5H), 4.01 (dd, J = 11.6, 2.8 Hz, 1H), 4.14ꢀ4.24 (m, 6H), 4.26ꢀ4.31 (m,
1H), 4.37ꢀ4.43 (m, 3H), 4.53ꢀ4.64 (m, 10H), 4.67ꢀ4.72 (m, 1H), 5.38ꢀ5.45 (m, 9H), 5.52ꢀ5.63 (m,
16H), 5.68 (d, J = 5.2 Hz, 1H), 5.76 (dd, J = 7.6, 4.8 Hz, 1H), 5.97 (t, J = 6.0 Hz, 1H), 7.27ꢀ7.60 (m,
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54H), 7.90ꢀ8.07 (m, 36H); 13C NMR (100 MHz, CDCl3) δ 28.0, 29.9, 38.0, 63.8, 66.4, 66.5, 67.5,
75.8, 77.1, 77.4, 77.5, 77.8, 78.2, 80.1, 81.2, 81.3, 81.6, 81.8, 81.9, 82.1, 82.3, 82.5, 95.4, 101.0,
105.97, 106.04, 106.1, 106.3, 128.45, 128.51, 128.54, 128.61, 128.63, 128.65, 128.68, 128.9, 129.05,
129.07, 129.11, 129.16, 129.18, 129.22, 129.24, 129.3, 129.96, 130.00, 130.02, 130.1, 133.39, 133.43,
133.5, 133.58, 133.61, 133.7, 133.8, 165.3, 165.4, 165.7, 165.79, 165.82, 165.9, 166.0, 166.1, 172.6,
206.5. Anal. Calcd for C62H56O21: C, 65.49; H, 4.96. Found: C, 65.50; H, 4.75.
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Allyl
[(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀ
arabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀarabinofuranoside (13). A solution of compound
11 (4.21 g, 3.58 mmol) and 66% hydrazineꢀacetic acid (1:2, v/v, 15 mL) in THFꢀMeOH (10:1, v/v, 44
mL) was stirred at room temperature for 1h. The solvent was removed and the resulting oil was
dissolved in EtOAc (70 mL). The EtOAc solution was washed with saturated aqueous NaHCO3 (2 ×
50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo, and the residue was purified by
silica gel flash column chromatography (hexane/EtOAc, 2:1) to afford compound 13 (3.48 g, 90%) as
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a colorless amorphous form. Rf = 0.63 (hexane/EtOAc, 1:1, v/v); [α]D = ꢀ5.3 (c 0.6, CHCl3); H
NMR (400 MHz, CDCl3) δ 2.39 (brs, 1H), 3.89ꢀ4.04 (m, 4H), 4.09 (dd, J = 13.2, 6.0 Hz, 1H), 4.16ꢀ
4.24 (m, 2H), 4.25ꢀ4.32 (m, 1H), 4.43ꢀ4.51 (m, 2H), 4.63(dd, J = 7.2, 4.4 Hz, 1H), 5.20 (dd, J = 10.8,
1.2 Hz, 1H), 5.27 (s, 1H), 5.35 (dd, J = 17.2, 1.6 Hz, 1H), 5.40ꢀ5.45 (m, 3H), 5.56 (s, 1H), 5.61ꢀ5.68
(m, 4H), 5.87ꢀ6.00 (m, 1H), 7.23ꢀ7.31 (m, 4H), 7.37ꢀ7.61 (m, 14H), 7.87ꢀ7.94 (m, 4H), 8.00ꢀ8.08 (m,
8H); 13C NMR (100 MHz, CDCl3) δ 62.4, 66.0, 66.2, 67.9, 77.4, 77.5, 77.8, 81.7, 81.8, 82.00, 82.02,
82.1, 83.8, 104.9, 105.86, 105.91, 117.5, 128.39, 128.42, 128.56, 128.63, 129.07, 129.14, 129.16,
129.19, 129.3, 129.4, 129.88, 129.93, 129.97, 130.01, 133.35, 133.41, 133.5, 133.57, 133.64, 133.9,
165.2, 165.3, 165.5, 165.80, 165.84, 166.2. Anal. Calcd for C60H54O19: C, 66.78; H, 5.04. Found: C,
66.81; H, 4.87.
Allyl
[(2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀ
ꢀarabinofuranoside (14). A solution of 12 (942 mg, 0.828 mmol, 1.0 equiv), tꢀbutylphthalic
Dꢀ
arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
D
D
αꢀ
D
anhydride (254 mg, 1.24 mmol, 1.5 equiv), and DBU (0.151 mL, 0.994 mmol, 1.2 equiv) in CH2Cl2
(15 mL) in the presence of 4Å molecular sieves was stirred for 15 min at room temperature and
cooled down to −40 oC. Then a solution of a glycosyl acceptor 13 (1.16 g, 1.08 mmol, 1.3 equiv) and
o
DTBMP (425 mg, 2.07 mmol, 2.5 equiv) in CH2Cl2 (15 mL) were added sequentially at −40 C and
the resulting solution was stirred for further 15 min at −40 oC. After dropwise addition of a solution of
Tf2O (0.181 mL, 1.08 mmol, 1.3 equiv) in CH2Cl2 (2 mL) to the above solution via cannula, the
o
o
reaction mixture was stirred at −40 C for 15 min, allowed to warm up over 1 h to 0 C, quenched
with saturated aqueous NaHCO3, and then extracted with CH2Cl2. The combined organic phase was
washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash
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column chromatography (hexane/EtOAc, 3:2) to afford compound 14 (1.19 g, 65%) as a colorless
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amorphous form. Rf = 0.35 (hexane/EtOAc, 1:1, v/v); [α]D = +3.7 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 2.11 (s, 3H), 2.53ꢀ2.61 (m, 2H), 2.66ꢀ2.73 (m, 2H), 3.85ꢀ3.96 (m, 5H), 4.08 (dd, J =
12.8, 5.6 Hz, 1H), 4.12ꢀ4.22 (m, 5H), 4.27 (dd, J = 13.2, 4.8 Hz, 1H), 4.37 (dd, J = 11.2, 4.8 Hz, 1H),
4.43ꢀ4.49 (m, 1H), 4.51ꢀ4.63 (m, 6H), 5.20 (d, J = 10.4 Hz, 1H), 5.26 (s, 1H), 5.31ꢀ5.42 (m, 7H),
5.53ꢀ5.66 (m, 11H), 5.87ꢀ5.99 (m, 1H), 7.20ꢀ7.61 (m, 36H), 7.83ꢀ8.08 (m. 24H); 13C NMR (100 MHz,
CDCl3) δ 28.0, 29.9, 38.0, 63.8, 65.9, 66.0, 66.2, 67.9, 77.3, 77.36, 77.41, 77.7, 81.2, 81.5, 81.7, 82.0,
82.1, 82.2, 104.9, 105.9, 106.0, 106.1, 117.5, 128.4, 128.6, 128.7, 129.0, 129.15, 129.21, 129.3, 129.4,
129.99, 130.03, 133.25, 133.31, 133.4, 133.48, 133.52, 133.7, 133.9, 165.19, 165.24, 165.3, 165.5,
165.7, 165.75, 165.77, 165.82, 172.6, 206.5. Anal. Calcd for C122H108O39: C, 66.66; H, 4.95. Found:
C, 66.53; H, 5.14.
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Allyl [(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀarabinofuranosyl)ꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀ
D
ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranoside (15). A solution of compound 14 (2.24 g, 1.02 mmol) and 66% hydrazineꢀ
acetic acid (1:2, v/v, 9 mL) in THFꢀMeOH (10:1, v/v, 22 mL) was stirred at room temperature for 1h.
The solvent was removed and the resulting oil was dissolved in EtOAc (30 mL). The EtOAc solution
was washed with saturated aqueous NaHCO3 (2 × 20 mL) and brine (30 mL), dried over MgSO4,
concentrated in vacuo, and the residue was purified by silica gel flash column chromatography
(hexane/EtOAc/CH2Cl2, 5:2:2) to afford compound 15 (1.99 g, 93%) as a colorless amorphous form.
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Rf = 0.23 (hexane/EtOAc/CH2Cl2, 5:2:2, v/v/v); [α]D = +7.4 (c 0.5, CHCl3); H NMR (400 MHz,
CDCl3) δ 2.35 (brs, 1H), 3.87ꢀ4.01 (m, 7H), 4.08 (dd, J = 13.2, 6.0 Hz, 1H), 4.13ꢀ4.22 (m, 5H), 4.27
(dd, J = 13.2, 4.8 Hz, 1H), 4.43ꢀ4.49 (m, 2H), 4.55ꢀ4.63 (m, 4H), 5.20 (d, J = 10.4 Hz, 1H), 5.27 (s,
1H), 5.31ꢀ5.44 (m, 7H), 5.56 (s, 1H), 5.60ꢀ5.67 (m, 10H), 5.87ꢀ6.00 (m, 1H), 7.20ꢀ7.59 (m, 36H),
7.83ꢀ8.08 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 62.4, 65.9, 66.0, 66.2, 67.9, 77.3, 77.35, 77.39,
77.8, 81.7, 81.8, 82.0, 82.1, 82.2, 83.7, 104.9, 105.7, 105.89, 105.94, 106.0, 117.4, 128.0, 128.3,
128.4, 128.5, 128.6, 128.9, 129.06, 129.09, 129.14, 129.17, 129.21, 129.3, 129.4, 129.6, 129.85,
129.92, 129.95, 130.00, 133.2, 133.25, 133.27, 133.4, 133.45, 133.50, 133.6, 133.9, 165.19, 165.22,
165.3, 165.5, 165.69, 165.72, 165.8, 166.1. Anal. Calcd for C117H102O37: C, 66.92; H, 4.90. Found: C,
66.97; H, 5.10.
Allyl
[(2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀ
ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranoside (16). A solution
Dꢀ
arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
D
D
αꢀ
D
D
benzoylꢀαꢀ
D
D
of 12 (859 mg, 0.755 mmol, 1.0 equiv), tꢀbutylphthalic anhydride (231 mg, 1.13 mmol, 1.5 equiv),
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and DBU (0.137 mL, 0.907 mmol, 1.2 equiv) in CH2Cl2 (10 mL) in the presence of 4Å molecular
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o
sieves was stirred for 15 min at room temperature and cooled down to −40 C. Then a solution of a
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glycosyl acceptor 15 (2.06 g, 0.982 mmol, 1.3 equiv) and DTBMP (388 mg, 1.89 mmol, 2.5 equiv) in
o
CH2Cl2 (15 mL) were added sequentially at −40 C and the resulting solution was stirred for further
15 min at −40 oC. After dropwise addition of a solution of Tf2O (0.165 mL, 0.982 mmol, 1.3 equiv) in
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CH2Cl2 (2 mL) to the above solution via cannula, the reaction mixture was stirred at −40 C for 15
o
min, allowed to warm up over 1 h to 0 C, quenched with saturated aqueous NaHCO3, and then
extracted with CH2Cl2. The combined organic phase was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column chromatography
(hexane/EtOAc/CH2Cl2, 5:2:2) to afford compound 16 (1.53 g, 63%) as a colorless amorphous form.
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Rf = 0.38 (hexane/EtOAc/CH2Cl2, 2:1:1, v/v/v); [α]D = +0.25 (c 1.2, CHCl3); H NMR (400 MHz,
CDCl3) δ 2.11 (s, 3H), 2.53ꢀ2.60 (m, 2H), 2.65ꢀ2.72 (m, 2H), 3.84ꢀ3.95 (m, 8H), 4.07 (dd, J = 13.2,
6.0 Hz, 1H), 4.11ꢀ4.21 (m, 8H), 4.27 (dd, J = 13.2, 4.8 Hz, 1H), 4.37 (dd, J = 10.8, 4.4 Hz, 1H), 4.43ꢀ
4.48 (m, 1H), 4.50ꢀ4.63 (m, 9H), 5.19 (d, J = 10.4 Hz, 1H), 5.26 (s, 1H), 5.31ꢀ5.42 (m, 10H), 5.54 (s,
1H), 5.57 (s, 1H), 5.59ꢀ5.66 (m, 15H), 5.86ꢀ5.99 (m, 1H), 7.18ꢀ7.60 (m, 54H), 7.81ꢀ8.08 (m. 36H);
13C NMR (100 MHz, CDCl3) δ 27.9, 29.9, 38.0, 63.7, 65.9, 66.0, 66.1, 67.9, 77.2, 77.3, 77.4, 77.7,
81.2, 81.5, 81.6, 81.7, 82.0, 82.1, 82.2, 104.9, 105.9, 106.0, 106.1, 117.5, 128.36, 128.41, 128.6,
128.7, 129.0, 129.1, 129.21, 129.24, 129.4, 129.9, 129.98, 130.02, 133.2, 133.3, 133.4, 133.46,
133.52, 133.7, 133.9, 165.17, 165.20, 165.3, 165.5, 165.69, 165.71, 165.73, 165.75, 165.80, 172.6,
206.4. Anal. Calcd for C179H156O57: C, 66.79; H, 4.88. Found: C, 66.72; H, 4.92.
Allyl [(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀarabinofuranosyl)ꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀ
Dꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀ
αꢀ
D
ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranoside (17). solution of
D
A
compound 16 (2.50 g, 0.777 mmol) and 66% hydrazineꢀacetic acid (1:2, v/v, 9 mL) in THFꢀMeOH
(10:1, v/v, 22 mL) was stirred at room temperature for 1h. The solvent was removed and the resulting
oil was dissolved in EtOAc (30 mL). The EtOAc solution was washed with saturated aqueous
NaHCO3 (2 × 20 mL) and brine (30 mL), dried over MgSO4, concentrated in vacuo, and the residue
was purified by silica gel flash column chromatography (hexane/EtOAc/CH2Cl2, 5:2:2) to afford
compound 17 (2.19 g, 90%) as a colorless amorphous form. Rf = 0.18 (hexane/EtOAc/CH2Cl2, 5:2:2,
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v/v/v); [α]D = +0.29 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 2.31 (brs, 1H), 3.85ꢀ4.00 (m,
10H), 4.08 (dd, J = 13.2, 6.0 Hz, 1H), 4.12ꢀ4.21 (m, 8H), 4.27 (dd, J = 13.2, 4.8 Hz, 1H), 4.42ꢀ4.48
(m, 2H), 4.53ꢀ4.62 (m, 7H), 5.19 (dd, J = 10.8, 1.2 Hz, 1H), 5.26 (s, 1H), 5.31ꢀ5.42 (m, 10H), 5.55 (s,
1H), 5.59ꢀ5.65 (m, 16H), 5.87ꢀ5.99 (m, 1H), 7.18ꢀ7.59 (m, 54H), 7.83ꢀ8.05 (m, 36H); 13C NMR (100
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MHz, CDCl3) δ 62.4, 65.9, 66.0, 66.2, 67.9, 77.3, 77.35, 77.40, 77.8, 81.6, 81.7, 81.8, 81.9, 82.0, 82.1,
82.2, 83.7, 104.9, 105.7, 105.9, 106.0, 117.5, 128.36, 128.42, 128.56, 128.60, 129.06, 129.09, 129.14,
129.18, 129.22, 129.3, 129.4, 129.87, 129.94, 129.98, 130.03, 133.2, 133.3, 133.4, 133.47, 133.54,
133.6, 133.9, 165.21, 165.23, 165.3, 165.5, 165.70, 165.74, 165.76, 165.81, 166.2. Anal. Calcd for
C174H150O55: C, 66.96; H, 4.84. Found: C, 66.93; H, 4.82.
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Allyl
[(2,3ꢀdiꢀOꢀbenzoylꢀ5ꢀOꢀlevulinylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀ
Oꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀ
diꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranoside (18). A solution of 12 (490 mg, 0.431 mmol, 1.0 equiv), tꢀ
Dꢀ
arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
D
D
αꢀ
D
D
benzoylꢀαꢀ
D
D
D
D
D
butylphthalic anhydride (132 mg, 0.646 mmol, 1.5 equiv), and DBU (78.3 ꢀL, 0.517 mmol, 1.2 equiv)
in CH2Cl2 (7 mL) in the presence of 4Å molecular sieves was stirred for 15 min at room temperature
and cooled down to −40 oC. Then a solution of a glycosyl acceptor 17 (1.75 g, 0.560 mmol, 1.3 equiv)
o
and DTBMP (221 mg, 1.08 mmol, 2.5 equiv) in CH2Cl2 (15 mL) were added sequentially at −40 C
o
and the resulting solution was stirred for further 15 min at −40 C. After dropwise addition of a
solution of Tf2O (94.2 ꢀL, 0.560 mmol, 1.3 equiv) in CH2Cl2 (1 mL) to the above solution via
cannula, the reaction mixture was stirred at −40 oC for 15 min, allowed to warm up over 1 h to 0 oC,
quenched with saturated aqueous NaHCO3, and then extracted with CH2Cl2. The combined organic
phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane/EtOAc/CH2Cl2, 2:1:1) to afford compound 18 (1.23 g,
20
67%) as a colorless amorphous form. Rf = 0.23 (hexane/EtOAc/CH2Cl2, 2:1:1, v/v/v); [α]D = +0.33
1
(c 0.8, CHCl3); H NMR (400 MHz, CDCl3) δ 2.11 (s, 3H), 2.53ꢀ2.60 (m, 2H), 2.65ꢀ2.72 (m, 2H),
3.84ꢀ3.95 (m, 10H), 4.08 (dd, J = 13.2, 6.0 Hz, 1H), 4.12ꢀ4.21 (m, 10H), 4.27 (dd, J = 12.8, 4.8 Hz,
1H), 4.38 (dd, J = 11.2, 4.4 Hz, 1H), 4.43ꢀ4.48 (m, 1H), 4.52ꢀ4.62 (m, 11H), 5.19 (d, J = 11.2 Hz,
1H), 5.26 (s, 1H), 5.31ꢀ5.42 (m, 12H), 5.54ꢀ5.68 (m, 22H), 5.87ꢀ5.99 (m, 1H), 7.18ꢀ7.59 (m, 72H),
7.82ꢀ8.08 (m, 48H); 13C NMR (100 MHz, CDCl3) δ 27.9, 29.9, 38.0, 63.7, 65.9, 66.0, 66.2, 67.9,
77.26, 77.32, 77.36, 77.42, 77.7, 81.2, 81.5, 81.6, 81.7, 82.0, 82.1, 82.18, 82.19, 104.9, 105.9, 106.0,
106.1, 117.5, 128.35, 128.42, 128.55, 128.59, 128.7, 129.0, 129.16, 129.23, 129.4, 129.86, 129.93,
129.98, 130.02, 133.2, 133.4, 133.45, 133.50, 133.7, 133.9, 165.2, 165.3, 165.5, 165.7, 165.75, 165.79,
172.6, 206.4. Anal. Calcd for C236H204O75: C, 66.85; H, 4.85. Found: C, 66.81; H, 4.92. MALDIꢀTOF:
Calcd for C236H204O75Na [M + Na]+: 4263.09, Found: 4263.13.
Allyl [(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
Dꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀDꢀarabinofuranosyl)ꢀ
(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀDꢀ
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arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀ
Oꢀbenzoylꢀαꢀ ꢀarabinofuranoside (19). A solution of compound 18 (1.88 g, 0.443 mmol) and 66%
D
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀD
αꢀ
Dꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀD
benzoylꢀαꢀ
D
D
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D
hydrazineꢀacetic acid (1:2, v/v, 6 mL) in THFꢀMeOH (10:1, v/v, 11 mL) was stirred at room
temperature for 1h. The solvent was removed and the resulting oil was dissolved in EtOAc (30 mL).
The EtOAc solution was washed with saturated aqueous NaHCO3 (2 × 20 mL) and brine (30 mL),
dried over MgSO4, concentrated in vacuo, and the residue was purified by silica gel flash column
chromatography (hexane/EtOAc/CH2Cl2, 2:1:1) to afford compound 19 (1.66 g, 90%) as a colorless
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amorphous form. Rf = 0.23 (hexane/EtOAc/CH2Cl2, 2:1:1, v/v/v); [α]D = +0.21 (c 0.6, CHCl3); H
NMR (400 MHz, CDCl3) δ 3.82ꢀ4.02 (m, 13H), 4.08 (dd, J = 13.2, 6.0 Hz, 1H), 4.11ꢀ4.22 (m, 11H),
4.27 (dd, J = 13.2, 4.8 Hz, 1H), 4.42ꢀ4.48 (m, 2H), 4.51ꢀ4.63 (m, 10H), 5.20 (dd, J = 10.4, 0.8 Hz,
1H), 5.26 (s, 1H), 5.30ꢀ5.43 (m, 13H), 5.55 (s, 1H), 5.56ꢀ5.68 (m, 22H), 5.87ꢀ5.99 (m, 1H), 7.16ꢀ7.60
(m, 72H), 7.81ꢀ8.07 (m, 48H); 13C NMR (100 MHz, CDCl3) δ 62.4, 65.86, 65.91, 66.0, 66.2, 67.9,
77.2, 77.3, 77.4, 77.8, 81.6, 81.7, 81.8, 81.9, 82.0, 82.1, 82.2, 83.7, 104.9, 105.7, 105.88, 105.92,
106.0, 117.5, 128.35, 128.38, 128.42, 128.56, 128.59, 128.62, 128.63, 129.05, 129.08, 129.12, 129.2,
129.3, 129.4, 129.86, 129.93, 129.97, 130.02, 133.2, 133.27, 133.29, 133.4, 133.45, 133.51, 133.53,
133.6, 133.9, 165.18, 165.21, 165.3, 165.5, 165.68, 165.72, 165.74, 165.8, 166.2. Anal. Calcd for
C231H198O73: C, 66.98; H, 4.82. Found: C, 66.96; H, 4.77. MALDIꢀTOF: Calcd for C231H198O73Na [M
+ Na]+: 4164.99, Found: 4164.74.
pꢀMethoxyphenyl 3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀ
mixture of acetyl 3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀ
D
ꢀglucopyranoside (S2). To a stirred
D
ꢀglucopyranoside (S1)35 (4.09 g, 11.0
mmol) and pꢀmethoxyphenol (2.04 g, 16.4 mmol) in CH2Cl2 (50 mL) was added dropwise TfOH
(0.97 mL, 11.0 mmol) at 0 oC for 30 min. The reaction mixture was stirred at room temperature for 5
h, quenched with saturated aqueous NaHCO3, and then extracted with CH2Cl2. The combined organic
phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane/EtOAc, 2:1) to afford compound S2 (4.13 g, 86%,
α/β = 10:1): α form, colorless amorphous form. Rf = 0.28 (hexane/EtOAc, 4:1, v/v); IR (CHCl3 film)
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2111, 1747, 1507, 1367, 1212, 1034, 829 cmꢀ1; [α]D = +1.78 (c 0.55, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 2.05 (s, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 3.45 (dd, J = 10.8, 3.2 Hz, 1H), 3.78 (s, 3H), 4.08 (d,
J = 12.0 Hz, 1H), 4.17ꢀ4.23 (m, 1H), 4.29 (dd, J = 12.4, 4.8 Hz, 1H), 5.13 (t, J = 9.6 Hz, 1H), 5.51 (d,
J = 3.2 Hz, 1H), 5.69 (t, J = 10.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 20.6, 20.7, 20.8, 55.7, 60.8, 61.8, 68.3, 68.5, 70.4, 97.5 (JCꢀH = 174.1 Hz)
114.8, 118.0, 150.1, 155.8, 169.7, 170.1, 170.5. Anal. Calcd for C19H23N3O9: C, 52.17; H, 5.30; N,
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9.61. Found: C, 52.17; H, 5.33; N, 9.48. β form, colorless amorphous form, Rf = 0.20 (hexane/EtOAc,
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4:1, v/v); IR (CHCl3 film) 2113, 1748, 1507, 1367, 1212, 1037, 829 cmꢀ1; [α]D = +0.13 (c 0.55,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 3.72ꢀ3.82 (m, 2H),
8
3.77 (s, 3H), 4.14 (dd, J = 12.0, 2.0 Hz, 1H), 4.30 (dd, J = 12.0, 5.2 Hz, 1H), 4.82 (d, J = 8.0 Hz, 1H),
5.01ꢀ5.10 (m, 2H), 6.81ꢀ6.87 (m, 2H), 7.00ꢀ7.06 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.6, 20.69,
20.70, 55.6, 62.0, 63.6, 68.4, 71.9, 72.4, 101.6 (JCꢀH = 165.9 Hz), 114.7, 118.8, 150.8, 156.0, 169.6,
169.9, 170.5. Anal. Calcd for C19H23N3O9: C, 52.17; H, 5.30; N, 9.61. Found: C, 52.14; H, 5.25; N,
9.49.
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pꢀMethoxyphenyl 4,6ꢀOꢀbenzylideneꢀ2ꢀdeoxyꢀ2ꢀazidoꢀαꢀDꢀglucopyranoside (S3). A mixture of
compound S2 (5.75 g, 13.1 mmol) and NaOMe (142 mg, 2.63 mmol) in MeOHꢀCH2Cl2 (10:1, v/v, 55
mL) was stirred at room temperature for 1 h. The reaction mixture was neutralized with DOWEX
CCRꢀ3 (H+ mode) resin, filtered through Celite®, and concentrated in vacuo. Rf = 0.08
(hexane/EtOAc, 1:2, v/v); 1H NMR (400 MHz, CD3OD) δ 3.24 (dd, J = 10.4, 3.2 Hz, 1H), 3.47 (t, J =
8.8 Hz, 1H), 3.69ꢀ3.81 (m, 3H), 3.75 (s, 3H), 4.03 (dd, J = 10.4, 8.8 Hz, 1H), 5.41 (d, J = 3.2 Hz, 1H),
6.81ꢀ6.88 (m, 2H), 7.04ꢀ7.10 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 54.0, 60.1, 62.3, 69.7, 70.5,
72.4, 97.7, 113.5, 117.4, 150.2, 154.8.
The residue was dissolved in DMF (30 mL) containing benzaldehyde dimethyl acetal (2.90 mL, 19.3
mmol) and CSA (599 mg, 2.58 mmol), and the solution was stirred for 10 h at 60ꢀ65 oC. The reaction
mixture was quenched with water (5 mL) and diluted with EtOAc (50 mL). The combined organic
layer was washed with saturated aqueous NH4Cl and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 3:1) to
afford compound S3 (4.78 g, 91%) as a white solid. Rf = 0.30 (hexane/EtOAc, 3:1, v/v); IR (CHCl3
20
film) 3371, 3014, 2108, 1508, 1377, 1209, 1108, 1094, 1034, 1019, 982, 831 cmꢀ1; [α]D = +1.10 (c
0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.96 (d, J = 2.0 Hz, 1H), 3.38 (dd, J = 10.0, 3.6 Hz, 1H),
3.58 (t, J = 9.2 Hz, 1H), 3.73 (t, J = 10.0 Hz, 1H), 3.88 (s, 3H), 4.00ꢀ4.09 (m, 1H), 4.25 (dd, J = 10.4,
4.8 Hz, 1H), 4.39 (dt, J = 9.6, 2.0 Hz, 1H), 5.43 (d, J = 3.6 Hz, 1H), 5.55 (s, 1H), 6.82ꢀ6.88 (m, 2H),
7.00ꢀ7.05 (m, 2H), 7.35ꢀ7.41 (m, 3H), 7.46ꢀ7.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 55.8, 63.0,
63.1, 68.78, 68.84, 81.8, 98.4 (JCꢀH = 173.8 Hz), 102.3, 114.9, 118.3, 126.4, 128.5, 129.6, 136.9, 150.4,
155.7. Anal. Calcd for C20H21N3O6: C, 60.14; H, 5.30; N, 10.52. Found: C, 60.15; H, 5.32; N, 10.47.
pꢀMethoxyphenyl 3ꢀOꢀbenzoylꢀ4,6ꢀOꢀbenzylideneꢀ2ꢀdeoxyꢀ2ꢀazidoꢀαꢀDꢀglucopyranoside (S4). To
a solution of compound S3 (5.46 g, 13.7 mmol) in CH2Cl2 (50 mL) were added benzoyl chloride (3.17
mL, 27.3 mmol), pyridine (4.42 mL, 54.7 mmol) and 4ꢀdimethylaminopyridine (334 mg, 2.73 mmol).
After stirred at room temperature for 2 h, the reaction mixture was quenched with saturated aqueous
NH4Cl (10 mL) and extracted with CH2Cl2 (2 × 50 mL). The combined organic layer was washed
with 1N HCl (2 × 30 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4,
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and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
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(hexane/EtOAc, 3:1) to afford compound S4 (6.51 g, 95%) as a white solid. Rf = 0.35 (hexane/EtOAc,
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3:1, v/v); IR (CHCl3 film) 3011, 2109, 1728, 1507, 1367, 1214, 1179, 1094, 1035, 828 cmꢀ1; [α]D
=
1
+1.80 (c 0.45, CHCl3); H NMR (400 MHz, CDCl3) δ 3.50 (dd, J = 10.4, 3.2 Hz, 1H), 3.76 (s, 3H),
3.80 (t, J = 10.0 Hz, 1H), 3.89 (t, J = 9.6 Hz, 1H), 4.19ꢀ4.33 (m, 2H), 5.53 (s, 1H), 5.58 (d, J = 3.6 Hz,
1H), 6.07 (t, J = 10.0 Hz, 1H), 6.82ꢀ6.89 (m, 2H), 7.05ꢀ7.12 (m, 2H), 7.25ꢀ7.32 (m, 3H), 7.37ꢀ7.47 (m,
4H), 7.52ꢀ7.59 (m, 1H), 8.08ꢀ8.14 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 55.7, 61.8, 63.5, 68.7, 69.5,
79.5, 98.6 (JCꢀH = 174.1 Hz), 101.8, 114.8, 118.1, 126.2, 128.3, 128.5, 129.2, 129.5, 130.0, 133.4, 136.8,
150.1, 155.7, 165.6. Anal. Calcd for C27H25N3O7: C, 64.41; H, 5.00; N, 8.35. Found: C, 64.47; H, 5.02;
N, 8.34.
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pꢀMethoxyphenyl 3ꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀαꢀDꢀglucopyranoside (S5). To a solution of
compound S4 (6.17 g, 12.3 mmol) in MeOHꢀ1,4ꢀdioxane (2:1, v/v, 90 mL) was added pꢀTsOH—H2O
o
(233 mg, 1.23 mmol). The mixture was stirred for 1 h at 65ꢀ70 C, neutralized with Et3N, and
evaporated in vacuo. The residue was purified by flash column chromatography on silica gel
(hexane/EtOAc, 1:6) to afford compound S5 (4.71 g, 93%) as a white solid. Rf = 0.55 (hexane/EtOAc,
1:6, v/v); IR (CHCl3 film) 3337, 2974, 2110, 1508, 1380, 1216, 1088, 1046, 880 cmꢀ1; [α]D20 = +1.88
1
(c 0.4, CH3OH); H NMR (400 MHz, CD3CD) δ 3.51 (dd, J = 10.4, 3.6 Hz, 1H), 3.77 (s, 3H), 3.81ꢀ
3.96 (m, 4H), 5.57 (d, J = 3.6 Hz, 1H), 5.80 (dd, J = 10.6, 8.4 Hz, 1H), 6.84ꢀ6.91 (m, 2H), 7.11ꢀ7.17
13
(m, 2H), 7.47ꢀ7.53 (m, 2H), 7.59ꢀ7.66 (m, 1H), 8.10ꢀ8.15 (m, 2H); C NMR (100 MHz, CD3CD) δ
54.4, 60.0, 60.7, 67.6, 72.5, 72.7, 97.7 (JCꢀH = 174.1 Hz), 113.9, 117.6, 127.7, 129.0, 129.1, 132.6,
150.0, 155.0, 165.8. Anal. Calcd for C20H21N3O7: C, 57.83; H, 5.10; N, 10.12. Found: C, 57.86; H,
5.14; N, 10.08.
pꢀMethoxyphenyl 3,6ꢀdiꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀDꢀglucopyranoside (S6). To a solution of
compound S5 (3.44 g, 8.28 mmol) in CH2Cl2ꢀpyridine (5:3, v/v, 24 mL) was added benzoyl chloride
o
(0.962 mL, 8.28 mmol) at 0 oC. After stirred at 0 C for 3 h, the reaction mixture was quenched with
saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organic
layer was washed with 1N HCl (2 × 20 mL), saturated aqueous NaHCO3 (30 mL) and brine (30 mL),
dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc, 1:1) to afford compound S6 (3.69 g, 86%) as a white
solid. Rf = 0.70 (hexane/EtOAc, 1:1, v/v); IR (CHCl3 film) 3415, 2106, 1702, 1508, 1451, 1269, 1221,
1117, 1083, 1070, 1038, 825 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 3.50 (d, J = 5.2 Hz, 1H, OHα), 3.54
(dd, J = 10.4, 3.2 Hz, 1H, Hαꢀ2), 3.61 (d, J = 4.8 Hz, 0.25H, OHβ), 3.74 (s, 3.75H, OMeα,β), 3.80ꢀ
3.93 (m, 1.75H, Hαꢀ4, Hβꢀ2, 4, 5), 4.25ꢀ4.32 (m, 1H, Hαꢀ5), 4.56ꢀ4.76 (m, 2.5H, Hαꢀ6a,6b, Hβꢀ6a,
6b), 4.95 (d, J = 8.0 Hz, 0.25H, Hβꢀ1), 5.21 (dd, J2,3 = 9.6 Hz, J3,4 = 9.2 Hz, 0.25H, Hβꢀ3), 5.55 (d, J =
3.6 Hz, 1H, Hαꢀ1), 5.82 (dd, J2,3 = 10.0 Hz, J3,4 = 9.6 Hz, 1H, Hαꢀ3), 6.70ꢀ6.80 (m, 2.5H), 7.02ꢀ7.13
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(m, 2.5H), 7.39ꢀ7.48 (m, 5H), 7.54ꢀ7.62 (m, 2.5H), 7.95ꢀ8.14 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
5
6
55.7, 62.1, 63.6, 63.75, 63.81, 69.8, 70.0, 71.1, 73.9, 74.5, 76.2, 97.8 (JCꢀH = 174.4 Hz), 101.7 (JCꢀH
=
7
8
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165.6 Hz), 114.7, 114.8, 118.3, 118.8, 128.49, 128.53, 128.6, 129.0, 129.1, 129.7, 129.9, 130.2, 133.39,
133.43, 133.8, 133.9, 150.2, 151.0, 155.7, 155.9, 166.8, 166.9, 167.1, 167.2. Anal. Calcd for
C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.39; H, 4.78; N, 8.07.
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pꢀMethoxyphenyl 3,6ꢀdiꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀ
Dꢀgalactopyranoside (S7). To a solution
of compound S6 (5.04 g, 9.71 mmol) in CH2Cl2ꢀpyridine (10:3, v/v, 39 mL) was added dropwise Tf2O
o
o
(4.09 mL, 24.3 mmol) at 0 C. After stirred at 0 C for 2 h, the reaction mixture was diluted with
CH2Cl2 (20 mL), washed with 1N HCl (2 × 20 mL), saturated aqueous NaHCO3 (30 mL) and brine
(30 mL), dried over MgSO4, and concentrated in vacuo. To the brown foam were added dry DMF (40
ml) and NaNO2 (6.69 g, 97.1 mmol), and the mixture was stirred for 2 h at room temperature. The
mixture was diluted with EtOAc (100 mL), washed with 1N HCl (2 × 50 mL), saturated aqueous
NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 3:1) to afford
compound S7 (4.41 g, 88%) as a white solid. Rf = 0.25 (hexane/EtOAc, 3:1, v/v); IR (CHCl3 film)
3465, 2112, 1717, 1507, 1451, 1316, 1270, 1213, 1117, 1095, 1039, 829 cmꢀ1; H NMR (400 MHz,
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CDCl3) δ 3.74 (s, 3.6H, OMeα,β), 4.03 (t, J = 6.0 Hz, 0.2H, Hβ), 4.10 (dd, J = 10.8, 3.2 Hz, 1H, Hαꢀ
2), 4.25 (dd, J = 10.8, 8.4 Hz, 0.2H, Hβ), 4.28 (d, J = 2.8 Hz, 0.2H, Hβ), 4.42ꢀ4.69 (m, 4.4H, Hαꢀ4, 5,
6a, 6b, Hβꢀ6a, 6b), 4.87 (d, J = 8.0 Hz, 0.2H, Hβꢀ1), 5.03 (dd, J2,3 = 10.4 Hz, J3,4 = 2.8 Hz, 0.2H, Hβꢀ
3), 5.60 (d, J = 3.2 Hz, 1H, Hαꢀ1), 5.75 (dd, J2,3 = 11.2 Hz, J3,4 = 2.8 Hz, 1H, Hαꢀ3), 6.70ꢀ6.79 (m,
2.4H), 7.04ꢀ7.12 (m, 2.4H), 7.34ꢀ7.62 (m, 7.2H), 7.83ꢀ8.14 (m, 4.8H); 13C NMR (100 MHz, CDCl3) δ
55.7, 57.6, 60.9, 63.1, 63.7, 66.4, 67.5, 69.0, 71.3, 72.7, 74.1, 98.1 (JCꢀH = 175.2 Hz), 102.1 (JCꢀH = 165.3
Hz), 114.6, 114.8, 118.5, 118.9, 128.5, 128.57, 128.59, 128.7, 129.15, 129.24, 129.5, 129.6, 129.9,
130.1, 130.3, 133.4, 133.5, 133.75, 133.80, 150.4, 151.1, 155.6, 155.9, 165.8, 166.6, 166.7. Anal.
Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.43; H, 4.82; N, 8.01.
pꢀMethoxyphenyl 3,4,6ꢀtriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀ
D
ꢀgalactopyranoside (S8). To
a
solution of compound S7 (2.96 g, 5.70 mmol) in pyridine (20 mL) were added benzoyl chloride (1.98
o
mL, 17.1 mmol) and 4ꢀdimethylaminopyridine (139 mg, 1.14 mmol). After stirred at 40 C for 14 h,
the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and diluted with CH2Cl2
(50 mL). The combined organic layer was washed with 1N HCl (2 × 20 mL), saturated aqueous
NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 5:1) to afford
compound S8 (3.30 g, 93%) as a colorless amorphous form. Rf = 0.20 (hexane/EtOAc, 5:1, v/v); IR
(CHCl3 film) 2112, 1723, 1602, 1506, 1451, 1315, 1264, 1212, 1178, 1107, 1068, 1039, 1026, 828
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.74 (s, 2.1H), 4.09 (dd, J = 11.2, 3.2 Hz, 1H), 4.27
(dd, J = 10.8, 8.0 Hz, 0.7H), 4.34 (dd, J = 6.8, 6.0 Hz, 0.7H), 4.39 (dd, J = 11.6, 4.8 Hz, 1H), 4.48 (dd,
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J = 11.6, 5.2 Hz, 0.7H), 4.59 (dd, J = 11.2, 8.0 Hz, 1H), 4.65 (dd, J = 11.6, 8.0 Hz, 0.7H), 4.78 (dd, J
= 7.6, 4.8 Hz, 1H), 5.02 (d, J = 8.0 Hz, 0.7H), 5.34 (dd, J = 10.8, 3.2 Hz, 0.7H), 5.73 (d, J = 3.2 Hz,
1H), 5.93 (d, J = 3.2 Hz, 0.7H), 6.00ꢀ6.09 (m, 2H), 6.72ꢀ6.79 (m, 3.4H), 7.09ꢀ7.15 (m, 3.4H), 7.29ꢀ
7.63 (m, 15.3H), 7.87ꢀ8.11 (m, 10.2H); 13C NMR (100 MHz, CDCl3) δ 55.60, 55.63, 58.2, 61.3, 62.4,
62.8, 67.3, 68.1, 68.6, 68.9, 71.67, 71.69, 98.1 (JCꢀH = 175.9 Hz), 102.0 (JCꢀH = 168.3 Hz), 114.7, 114.8,
118.4, 118.8, 128.4, 128.5, 128.9, 128.99, 129.03, 129.1, 129.46, 129.49, 129.8, 129.9, 130.0, 130.2,
133.3, 133.4, 133.50, 133.52, 133.76, 133.79, 150.2, 150.9, 155.7, 155.9, 165.36, 165.43, 166.0. Anal.
Calcd for C34H29N3O9: C, 65.48; H, 4.69; N, 6.74. Found: C, 65.45; H, 4.67; N, 6.66.
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3,4,6ꢀTriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀDꢀgalactopyranose (S9). To a solution of compound S8
(4.56 g, 7.31 mmol) and ceric ammonium nitrate (20.0 g, 36.6 mmol) in tolueneꢀMeCNꢀH2O (1:1.6:1,
v/v/v, 180 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (100 mL)
and washed with CH2Cl2 (2 × 150 mL). The combined organic layer was washed with water (100 mL)
and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (hexane/EtOAc, 3:1) to afford compound S9 (3.02 g,
80%, α/β = 1.5:1) as a white solid. Rf = 0.25 (hexane/EtOAc, 3:1, v/v); IR (CHCl3 film) 3446, 3014,
2115, 1727, 1452, 1316, 1270, 1215, 1093, 1069, 1027 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 3.99ꢀ4.05
(m, 2.5H), 4.24 (t, J = 6.4 Hz, 1H), 4.30ꢀ4.46 (m, 4H), 4.59 (dd, J = 11.2, 6.4 Hz, 1.5H), 4.64 (dd, J =
11.2, 6.4 Hz, 1H), 4.80 (t, J = 6.8 Hz, 1.5H), 4.92 (d, J = 7.6 Hz, 1H), 5.13 (brs, 1H), 5.28 (dd, J =
10.8, 3.2 Hz, 1H), 5.62 (d, J = 2.4 Hz, 1.5H), 5.86 (dd, J = 11.2, 3.2 Hz, 1.5H), 5.91 (d, J = 3.2 Hz,
1H), 6.03 (d, J = 2.8 Hz, 1.5H), 7.30ꢀ7.62 (m, 22.5H), 7.87ꢀ8.08 (m, 15H); 13C NMR (100 MHz,
CDCl3) δ 58.9, 62.2, 62.5, 62.7, 66.9, 67.5, 68.7, 69.1, 71.3, 71.9, 92.7 (JCꢀH = 174.4 Hz), 96.7 (JCꢀH
=
163.6 Hz), 128.45, 128.47, 128.50, 128.54, 128.7, 128.9, 128.97, 129.00, 129.2, 129.3, 129.8, 129.86,
129.88, 130.0, 133.4, 133.5, 133.6, 133.7, 133.8, 165.61, 165.64, 166.4. Anal. Calcd for C27H23N3O8:
C, 62.67; H, 4.48; N, 8.12. Found: C, 62.64; H, 4.58; N, 8.04.
3,4,6ꢀTriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀα/βꢀDꢀgalactopyranosyl trichloroacetimidate (20). To a
solution of compound S9 (735 mg, 1.42 mmol) and CCl3CN (1.42 mL, 14.2 mmol) in CH2Cl2 (5 mL)
was added K2CO3 (336 mg, 2.41 mmol). After stirred at room temperature for 30 min, the reaction
mixture was heated at 30 oC for 5h, filtered through Celite®, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (hexane/EtOAc, 3:1) to afford compound
20 (784 mg, 83%, α/β = 0.3:1) as a colorless amorphous form. Rf = 0.43 (hexane/EtOAc, 3:1, v/v); 1H
NMR (400 MHz, CDCl3) δ 4.26 (dd, J = 10.4, 8.4 Hz, 1H), 4.33 (dd, J = 10.8, 3.6 Hz, 0.3H), 4.36ꢀ
4.42 (m, 2.3H), 4.56 (dd, J = 11.6, 7.2 Hz, 0.3H), 4.65 (dd, J = 13.6, 9.2 Hz, 1H), 4.79 (t, J = 6.4 Hz,
0.3H), 5.37 (dd, J = 10.4, 3.6 Hz, 1H), 5.82 (dd, J = 10.8, 3.2 Hz, 0.3H), 5.91 (d, J = 8.4 Hz, 1H, Hβꢀ
1), 5.95 (d, J = 3.2 Hz, 1H), 6.10 (d, J = 2.8 Hz, 0.3H), 6.71 (d, J = 3.6 Hz, 0.3H, Hαꢀ1), 7.32ꢀ7.67
(m, 11.7H), 7.86ꢀ8.09 (m, 7.8H), 8.84 (s, 0.3H, NHꢀα), 8.85 (s, 1H, NHꢀβ); 13C NMR (100 MHz,
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CDCl3) δ 57.9, 61.2, 61.7, 62.3, 67.1, 68.0, 69.5, 69.9, 72.0, 72.3, 94.9 (Cαꢀ1), 97.1 (Cβꢀ1), 128.5,
128.6, 128.8, 128.86, 128.93, 129.0, 129.1, 129.5, 129.7, 129.87, 129.94, 130.0, 130.1, 133.4, 133.7,
133.86, 133.92, 160.85, 160.89, 165.3, 165.4, 166.0. Anal. Calcd for C29H23Cl3N4O8: C, 52.62; H,
3.50; N, 8.46. Found: C, 52.64; H, 3.51; N, 8.37.
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1,2ꢀOꢀisopropylideneꢀ3,5ꢀdiꢀOꢀlevulinylꢀβꢀ
Dꢀarabinofuranose (S11). To a solution of 1,2ꢀOꢀ
isopropylideneꢀα/βꢀ
D
ꢀarabinofuranose (S10)23 (4.71 g, 24.8 mmol) in CH2Cl2 (70 mL) were added
levulinic acid (8.63 g, 74.3 mmol), N,Nꢀdiisopropylcarbodimide (11.5 mL, 74.3 mmol) and 4ꢀ
dimethylaminopyridine (605 mg, 4.95 mmol). After stirred at room temperature for 4 h, the reaction
mixture was quenched with H2O (30 mL) and extracted with CH2Cl2 (100 mL). The organic layer was
washed with saturated aqueous NaHCO3 (2 × 70 mL) and brine (100 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
(hexane/EtOAc/CH2Cl2, 1:2:3) to afford compound S11 (8.80 g, 92%) as a colorless oil. Rf = 0.43
(hexane/EtOAc/CH2Cl2, 1:2:3, v/v/v); [α]D20 = +0.087 (c 2.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.32 (s, 3H), 1.56 (s, 3H), 2.19 (s, 3H), 2.20 (s, 3H), 2.55ꢀ2.66 (m, 4H), 2.73ꢀ2.83 (m, 4H), 4.23ꢀ4.33
(m, 3H), 4.61 (d, J = 3.6 Hz, 1H), 5.08 (s, 1H), 5.93 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 26.0, 26.8, 27.8, 27.9, 29.89, 29.93, 37.8, 38.0, 63.9, 77.6, 82.8, 84.4, 106.0, 113.2, 171.8, 172.4,
206.5, 206.6. Anal. Calcd for C18H26O9: C, 55.95; H, 6.78. Found: C, 55.97; H, 6.79.
Allyl 3,5ꢀdiꢀOꢀlevulinylꢀα/βꢀDꢀarabinofuranoside (21). To a solution of compound S11 (6.36 g,
16.5 mmol) in CH2Cl2 (100 mL) were added allyl alcohol (2.24 mL, 32.9 mmol) and pꢀTsOH—H2O
(4.70 g, 24.7 mmol) at room temperature. The resulting solution was stirred at room temperature for 5
h. The reaction mixture was quenched with saturated aqueous NaHCO3, and then extracted with
CH2Cl2. The combined organic layer was washed with aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography
(hexane/EtOAc/CH2Cl2, 1:2:3) to afford compound 21 (5.09 g, 80%, α/β = 1:0.2) as a colorless oil. Rf
1
= 0.18 (hexane/EtOAc/CH2Cl2, 1:2:3, v/v/v); H NMR (400 MHz, CDCl3) δ 2.16ꢀ2.23 (m, 7.2H),
2.58ꢀ2.65 (m, 4.8H), 2.75ꢀ2.81 (m, 4.8H), 3.02 (d, J = 8.8 Hz, 0.2H), 3.49 (d, J = 5.2 Hz, 1H), 4.01
(dd, J = 13.2, 6.0 Hz, 1H), 4.05ꢀ4.13 (m, 0.4H), 4.17ꢀ4.30 (m, 4.6H), 4.31 (dd, J = 7.6, 4.0 Hz, 0.2H),
4.40ꢀ4.47 (m, 1H), 4.75 (dd, J = 4.8, 1.6 Hz, 1H), 5.03ꢀ5.08 (m, 1.4H), 5.20 (dd, J = 10.4, 1.2 Hz,
1H), 5.22 (dd, J = 10.0, 0.8 Hz, 0.2H), 5.31 (dd, J = 17.2, 1.2 Hz, 1.2H), 5.85ꢀ5.97 (m, 1.2H); 13C
NMR (100 MHz, CDCl3) δ 27.77, 27.83, 29.78, 29.81, 29.9, 37.75, 37.82, 37.9, 63.3, 65.5, 68.0, 68.7,
76.3, 79.1, 79.4, 79.8, 80.5, 80.8, 100.3, 107.0, 117.2, 118.0, 133.4, 134.0, 172.4, 172.8, 173.1, 206.5,
206.7, 207.1. Anal. Calcd for C18H26O9: C, 55.95; H, 6.78. Found: C, 55.83; H, 6.89.
Allyl (3,4,6ꢀtriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀazidoꢀαꢀ
D
ꢀgalactopyranosyl)ꢀ(1→2)ꢀ3,5ꢀdiꢀOꢀlevulinylꢀα/βꢀ
D
ꢀarabinofuranoside (22). A mixture of a galactosyl trichloroacetimidate donor 20 (2.33 g, 3.52
mmol) and an arabinosyl acceptor 21 (1.05 g, 2.71 mmol) in CH2Cl2 (10 mL) was stirred for 5 min at
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room temperature and cooled down to –40 oC. After the addition of TMSOTf (0.192 mL, 1.06 mmol),
the reaction mixture was stirred at –40 oC for 1 h, allowed to warm up over 30 min to 0 oC, quenched
with triethylamine and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane/EtOAc, 1:1) to afford compound 22 (2.26 g, 94%): αꢀα form: colorless
amorphous form, Rf = 0.35 (hexane/EtOAc, 1:1, v/v); IR (CHCl3 film) 3022, 2113, 1720, 1602, 1452,
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1360, 1315, 1268, 1155, 1094, 1068, 1026 cmꢀ1; [α]D = +1.40 (c 0.6, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 2.16 (s, 6H), 2.53ꢀ2.80 (m, 8H), 3.96 (dd, J = 13.2, 6.0 Hz, 1H), 4.06 (dd, J = 11.2, 3.2 Hz,
1H), 4.19 (dd, J = 12.8, 4.8 Hz, 1H), 4.25ꢀ4.37 (m, 4H), 4.43 (dd, J = 10.4, 2.4 Hz, 1H), 4.55ꢀ4.63 (m,
2H), 5.07 (d, J = 3.6 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 5.26 (s, 1H), 5.28 (d, J = 16.0 Hz, 1H), 5.53
(d, J = 3.2 Hz, 1H), 5.71 (dd, J = 11.2, 2.8 Hz, 1H), 5.80ꢀ5.92 (m, 1H), 5.99 (d, J = 2.8 Hz, 1H), 7.30ꢀ
7.65 (m, 9H), 7.84ꢀ8.05 (m. 6H); 13C NMR (100 MHz, CDCl3) δ 27.9, 29.8, 29.9, 37.9, 38.0, 58.1,
62.6, 63.5, 67.9, 68.0, 68.4, 69.1, 77.9, 79.9, 85.5, 97.5 (JCꢀH = 178.6 Hz), 105.2, 117.5, 128.4,
128.5, 128.7, 129.0, 129.1, 129.5, 129.86, 129.91, 133.3, 133.5, 133.7, 133.9, 165.4, 166.0, 172.4,
172.6, 206.2, 206.6. Anal. Calcd for C45H47N3O16: C, 61.01; H, 5.35; N, 4.74. Found: C, 61.02; H,
5.41; N, 4.62. αꢀβ form: colorless oil, Rf = 0.23 (hexane/EtOAc, 1:1, v/v); IR (CHCl3 film) 3021,
2113, 1720, 1452, 1360, 1316, 1268, 1215, 1156, 1094, 1068, 1026 cmꢀ1; [α]D = +0.77 (c 1.9,
20
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.175 (s, 3H), 2.184 (s, 3H), 2.58ꢀ2.66 (m, 4H), 2.72ꢀ2.82 (m,
4H), 3.87 (dd, J = 11.2, 3.2 Hz, 1H), 3.95 (dd, J = 12.8, 6.0 Hz, 1H), 4.06ꢀ4.13 (m, 1H), 4.22 (dd, J =
11.6, 7.6 Hz, 1H), 4.27ꢀ4.35 (m, 3H), 4.41ꢀ4.50 (m, 2H), 4.84 (t, J = 6.4 Hz, 1H), 5.07ꢀ5.14 (m, 2H),
5.28 (d, J = 17.2 Hz, 1H), 5.35 (d, J = 3.2 Hz, 1H), 5.38 (dd, J = 7.2, 6.0 Hz, 1H), 5.85 (dd, J = 11.2,
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3.2 Hz, 1H), 5.84ꢀ5.95 (m, 1H), 6.02 (d, J = 1.6 Hz, 1H), 7.29ꢀ7.65 (m, 9H), 7.84ꢀ8.04 (m. 6H); C
NMR (100 MHz, CDCl3) δ 27.8, 28.0, 29.9, 30.0, 37.99, 38.01, 57.9, 61.8, 65.9, 67.8, 68.3, 68.4, 68.5,
76.5, 78.4, 83.6, 99.8 (JCꢀH = 179.5 Hz), 100.7, 117.8, 128.4, 128.6, 128.7, 129.1, 129.2, 129.3,
129.8, 129.9, 133.39, 133.43, 133.5, 133.7, 165.3, 165.4, 166.0, 172.4, 172.5, 206.5, 206.7. Anal.
Calcd for C45H47N3O16: C, 61.01; H, 5.35; N, 4.74. Found: C, 61.07; H, 5.20; N, 4.67.
Allyl (3,4,6ꢀtriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀacetamidoꢀαꢀ
Dꢀgalactopyranosyl)ꢀ(1→2)ꢀ3,5ꢀdiꢀOꢀlevulinylꢀ
α/βꢀ ꢀarabinofuranoside (23). To a solution of compound 22 (1.47 g, 1.66 mmol) in dry THF (10
D
o
mL) was added PPh3 (653 mg, 2.49 mmol) at 0 C. After added H2O (59.7 ꢀL, 3.32 mmol), the
reaction mixture was stirred at room temperature for 1 h, quenched with water, and then extracted
with Et2O. The combined organic layer was washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. Colorless oil, Rf = 0.45 (hexane/EtOAc, 1:2, v/v). To a solution of amine
compound (1.72 g, 2.00 mmol) in CH2Cl2 (20 mL) were added Ac2O (0.377 mL, 4.00 mmol),
pyridine (0.647 mL, 8.00 mmol) and 4ꢀdimethylaminopyridine (48.8 mg, 0.400 mmol). After stirred
at room temperature for 5 h, the reaction mixture was quenched with saturated aqueous NH4Cl (10
mL) and extracted with CH2Cl2 (2 × 10 mL). The combined organic layer was washed with 1N HCl
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(20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over MgSO4, and concentrated
in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:4)
to afford compound 23 (1.71 g, 95%): αꢀα form: colorless amorphous form, Rf = 0.18 (hexane/EtOAc,
1:4, v/v); IR (CHCl3 film) 3378, 3019, 1721, 1677, 1602, 1521, 1452, 1364, 1316, 1269, 1215, 1157,
20
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1112, 1068, 1026 cmꢀ1; [α]D = +1.28(c 0.45, CHCl3); H NMR (400 MHz, CDCl3) δ 1.94 (s, 3H),
2.11 (s, 3H), 2.15 (s, 3H), 2.55ꢀ2.84 (m, 8H), 3.84 (dd, J = 12.4, 5.2 Hz, 1H), 4.09 (dd, J = 12.4, 3.6
Hz, 1H), 4.18 (s, 1H), 4.26ꢀ4.40 (m, 3H), 4.43 (dd, J = 11.6, 3.6 Hz, 1H), 4.53ꢀ4.66 (m, 2H), 4.95ꢀ
5.05 (m, 2H), 5.15 (d, J = 10.4 Hz, 1H), 5.18ꢀ5.28 (m, 3H), 5.52 (dd, J = 10.8 2.0 Hz, 1H), 5.75ꢀ5.87
(m, 1H), 5.94 (s, 1H), 6.60 (d, J = 9.2 Hz, 1H), 7.28ꢀ7.70 (m, 9H), 7.82ꢀ8.10 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 23.0, 27.8, 28.0, 29.7, 37.8, 37.9, 47.8, 62.5, 62.8, 67.9, 68.1, 68.4, 69.3, 78.3, 78.6,
88.8, 100.0 (JCꢀH = 174.1 Hz), 104.9, 117.3, 128.36, 128.40, 128.44, 128.56, 128.60, 129.1, 129.2,
129.5, 129.8, 130.0, 131.9, 131.96, 132.01, 132.1, 133.0, 133.2, 133.3, 133.5, 133.7, 165.7, 166.0,
166.1, 170.7, 172.4, 172.6, 206.1, 206.9. Anal. Calcd for C47H51NO17: C, 62.59; H, 5.70; N, 1.55.
Found: C, 62.62; H, 5.78; N, 1.40. αꢀβ form: colorless oil, IR (CHCl3 film) 3378, 3019, 1720, 1677,
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CHCl3); H NMR (400 MHz, CDCl3) δ 1.90 (s, 3H), 2.16 (s, 3H), 2.19 (s, 3H), 2.53ꢀ2.65 (m, 4H),
2.74ꢀ2.82 (m, 4H), 3.95 (dd, J = 12.8, 6.0 Hz, 1H), 4.13ꢀ4.24 (m, 3H), 4.25ꢀ4.36 (m, 3H), 4.48 (dd, J
= 11.2, 6.0 Hz, 1H), 4.73 (t, J = 6.4 Hz, 1H), 4.95ꢀ5.03 (m, 1H), 5.08ꢀ5.14 (m, 2H), 5.18 (d, J = 3.6
Hz, 1H), 5.29 (dd, J = 17.2, 1.2 Hz, 1H), 5.47 (dd, J = 7.2, 5.6 Hz, 1H), 5.59 (dd, J = 11.2, 3.2 Hz,
1H), 5.82ꢀ5.94 (m, 1H), 5.95 (d, J = 2.4 Hz, 1H), 6.35 (d, J = 9.6 Hz, 1H), 7.28ꢀ7.61 (m, 9H), 7.84ꢀ
8.09 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 23.1, 27.9, 28.2, 29.7, 29.9, 38.0, 38.2, 47.8, 62.2, 65.4,
67.9, 68.37, 68.44, 69.5, 77.0, 77.4, 84.2, 100.4 (JCꢀH = 178.7 Hz), 100.5, 117.7, 128.4, 128.6, 128.7,
129.3, 129.40, 129.44, 129.7, 129.9, 130.0, 133.25, 133.34, 133.4, 133.5, 165.8, 166.0, 166.2, 170.5,
172.51, 172.53, 206.4, 206.6. Anal. Calcd for C47H51NO17: C, 62.59; H, 5.70; N, 1.55. Found: C,
62.55; H, 5.73; N, 1.43.
(3,4,6ꢀTriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀacetamidoꢀαꢀ
D
ꢀgalactopyranosyl)ꢀ(1→2)ꢀ3,5ꢀdiꢀOꢀlevulinylꢀα/βꢀ
D
ꢀarabinofuranose (24). A mixture of compound 23 (1.30 g, 1.20 mmol) and PdCl2 (42.5 mg, 0.24
mmol) in MeOH (10 mL) was stirred at room temperature for 8 h. The reaction mixture was filtered
through Celite® and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane/EtOAc, 1:4) to afford compound 24 (1.09 g, 88%, α/β = 1:1) as a colorless
amorphous form. Rf = 0.10 (hexane/EtOAc, 1:4, v/v); IR (CHCl3 film) 3378, 3019, 1720, 1678, 1524,
1
1452, 1362, 1316, 1270, 1215, 1158, 1112, 1069, 1026 cmꢀ1; H NMR (400 MHz, CDCl3) δ 1.90 (s,
3H), 1.91 (s, 3H), 2.11 (s, 3H), 2.16 (s, 6H), 2.18 (s, 3H), 2.54ꢀ2.85 (m, 16H), 3.43 (s, 1H), 4.10 (dd, J
= 9.2, 5.2 Hz, 1H), 4.15 (dd, J = 6.4, 4.4 Hz, 1H), 4.18 (s, 1H), 4.25 (dd, J = 12.0, 5.2 Hz, 1H), 4.29
(dd, J = 11.2, 6.4 Hz, 1H), 4.32ꢀ4.40 (m, 3H), 4.43 (dd, J = 9.2, 4.4 Hz, 1H), 4.49 (dd, J = 12.0, 4.0
Hz, 1H), 4.56ꢀ4.66 (m, 4H), 4.91 (t, J = 6.4 Hz, 1H), 4.95ꢀ5.04 (m, 3H), 5.21 (s, 1H), 5.25 (d, J = 2.0
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Hz, 1H), 5.42ꢀ5.48 (m, 2H), 5.51 (dd, J = 11.2, 3.2 Hz, 1H), 5.56ꢀ5.62 (m, 2H), 5.89ꢀ5.94 (m, 2H),
6.53 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 7.28ꢀ7.64 (m, 18H), 7.81ꢀ8.11 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 23.2, 28.0, 28.05, 28.12, 28.2, 29.7, 29.8, 29.9, 38.06, 38.10, 38.2, 47.9, 48.0,
62.6, 62.9, 63.0, 64.4, 67.9, 68.1, 68.4, 68.5, 69.3, 69.6, 76.5, 77.6, 78.4, 78.9, 83.6, 88.7, 96.1, 99.88,
99.93, 101.0, 128.46, 128.49, 128.6, 128.7, 129.2, 129.3, 129.4, 129.5, 129.6, 129.86, 129.89, 129.92,
130.0, 130.1, 133.3, 133.41, 133.44, 133.57, 133.64, 165.88, 165.90, 166.22, 166.24, 166.3, 166.5,
172.5, 172.6, 172.7, 172.8, 206.5, 206.6, 207.3, 207.9. Anal. Calcd for C44H47NO17: C, 61.32; H, 5.50;
N, 1.63. Found: C, 61.30; H, 5.57; N, 1.50.
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(3,4,6ꢀTriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀacetamidoꢀαꢀ
D
ꢀgalactopyranosyl)ꢀ(1→2)ꢀ3,5ꢀdiꢀOꢀlevulinylꢀα/βꢀ
D
ꢀarabinofuranosyl trichloroacetimidate (25). To a solution of compound 24 (498 mg, 0.578 mmol)
in CH2Cl2 (5 mL) were added Cl3CCN (0.579 mL, 5.78 mmol) and DBU (8.75 ꢀL, 0.0578 mmol) at 0
oC. The resulting solution was stirred at 0 oC for 15 min, and then concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc, 1:4) to afford compound 25 (474 mg,
82%) as a colorless amorphous form. Rf = 0.30 (hexane/EtOAc, 1:4, v/v); 1H NMR (400 MHz, CDCl3)
δ 1.94 (s, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 2.53ꢀ2.78 (m, 6H), 2.80ꢀ2.85 (m, 2H), 4.31ꢀ4.41 (m, 2H),
4.48 (s, 1H), 4.52 (dd, J = 12.0, 4.8 Hz, 1H), 4.57 (dd, J = 8.4, 4.0 Hz, 1H), 4.63 (dd, J = 11.6, 6.8 Hz,
1H), 4.72 (t, J = 6.4 Hz, 1H), 4.97ꢀ5.04 (m, 1H), 5.06 (d, J = 4.4 Hz, 1H), 5.44 (d, J = 3.6 Hz, 1H),
5.55 (dd, J = 11.2, 3.2 Hz, 1H), 5.97 (d, J = 2.4 Hz, 1H), 6.49 (s, 1H), 6.57 (d, J = 9.2 Hz, 1H), 7.28ꢀ
7.70 (m, 9H), 7.80ꢀ8.09 (m, 6H), 8.56 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.1, 27.8, 28.1, 29.76,
29.81, 37.8, 38.1, 48.1, 62.4, 62.6, 68.25, 68.30, 69.1, 77.3, 82.6, 85.9, 99.2 (JCꢀH = 175.1 Hz), 104.5,
128.49, 128.53, 128.65, 128.70, 129.1, 129.2, 129.6, 129.86, 129.89, 130.1, 132.0, 132.05, 132.12,
132.2, 133.2, 133.4, 133.6, 160.3, 165.8, 166.1, 166.3, 170.8, 172.4, 172.8, 206.1, 207.3. Anal. Calcd
for C46H47Cl3N2O17: C, 54.91; H, 4.71; N, 2.78. Found: C, 54.89; H, 4.77; N, 2.59.
Allyl
[(3,4,6ꢀtriꢀOꢀbenzoylꢀ2ꢀdeoxyꢀ2ꢀacetamidoꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
diꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
arabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀOꢀbenzoylꢀαꢀ
ꢀarabinofuranosyl)]ꢀ(1→5)ꢀ2,3ꢀdiꢀOꢀbenzoylꢀαꢀ ꢀarabinofuranoside (2). A mixture of donor 25
D
ꢀgalactopyranosyl)ꢀ(1→2)ꢀ(3,5ꢀdiꢀOꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀdiꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ(2,3ꢀ
ꢀarabinofuranosyl)ꢀ(1→5)ꢀ
ꢀarabinofuranosyl)ꢀ
levulinylꢀαꢀ
D
D
Oꢀbenzoylꢀαꢀ
D
D
D
D
D
D
D
Dꢀ
D
D
D
(73.9 mg, 0.0734 mmol) and acceptor 19 (234 mg, 0.0565 mmol) in CH2Cl2 (3 mL) was stirred for 5
min at room temperature and cooled down to –40 oC. After the addition of TMSOTf (4.0 ꢀL, 0.0220
o
o
mmol), the reaction mixture was stirred at –40 C for 1 h, allowed to warm up over 30 min to 0 C,
quenched with triethylamine and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane/EtOAc, 1:4) to afford compound 2 (182 mg, 65%) as a colorless amorphous
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form. Rf = 0.60 (hexane/EtOAc, 1:4, v/v); IR (CHCl3 film) 3022, 2925, 1718, 1601, 1452, 1366, 1315,
5
6
7
8
1261, 1177, 1108, 1070, 1026, 962, 857 cmꢀ1; [α]D = +0.44 (c 0.5, CHCl3); H NMR (400 MHz,
CDCl3) δ 1.94 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.26ꢀ2.45 (m, 2H), 2.48ꢀ2.82 (m, 6H), 3.59 (d, J =
8.8 Hz, 1H), 3.83ꢀ3.97 (m, 12H), 4.05ꢀ4.23 (m, 13H), 4.25ꢀ4.33 (m, 3H), 4.35 (dd, J = 11.2, 5.2 Hz,
1H), 4.43 (dd, J = 13.2, 4.4 Hz, 1H), 4.45ꢀ4.50 (m, 2H), 4.53ꢀ4.68 (m, 13H), 4.92 (d, J = 4.8 Hz, 1H),
4.94ꢀ5.02 (m, 1H), 5.16 (d, J = 2.8 Hz, 1H), 5.20 (dd, J = 15.2, 4.0 Hz, 1H), 5.26ꢀ5.43 (m, 13H), 5.46ꢀ
5.53 (m, 3H), 5.55ꢀ5.59 (m, 2H), 5.61ꢀ5.69 (m, 20H), 5.88ꢀ6.01 (m, 1H), 5.93 (d, J = 1.6 Hz, 1H),
6.59 (d, J = 9.2 Hz, 1H), 7.18ꢀ7.71 (m, 81H), 7.81ꢀ8.10 (m. 54H); 13C NMR (100 MHz, CDCl3) δ 23.1,
27.7, 28.1, 29.6, 29.7, 37.7, 38.0, 47.9, 62.4, 62.9, 65.3, 65.8, 66.0, 66.1, 67.8, 68.2, 68.4, 69.1, 69.3,
77.0, 77.2, 77.3, 77.4, 78.6, 78.8, 81.6, 81.8, 81.9, 82.0, 82.1, 89.0, 100.4 (JCꢀH = 175.5 Hz), 104.9,
105.5, 105.6, 105.8, 105.85, 105.94, 117.4, 128.3, 128.42, 128.44, 128.5, 128.7, 129.1, 129.2, 129.28,
129.32, 129.4, 129.5, 129.6, 129.8, 129.9, 129.95, 130.04, 132.0, 132.1, 132.2, 133.18, 133.24, 133.3,
133.4, 133.5, 133.7, 133.8, 165.1, 165.15, 165.21, 165.46, 165.49, 165.55, 165.63, 165.7, 165.75,
165.79, 166.0, 166.1, 170.7, 172.6, 172.7, 206.1, 207.1. MALDIꢀTOF: Calcd for C275H243NO89Na [M
+ Na]+: 5008.81, Found: 5008.34.
20
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACKNOWLEDGEMENTS
This work was supported by a grant from the Korea National Research Foundation of Korea
through the Center for Bioactive Molecular Hybrids (CBMH). Authors also acknowledge the
support by the BK 21 program from the Ministry of Education and Human Resources
Development of Korea and H.B.J. thanks to the research grant of Kwangwoon University in
2015 for this work.
SUPPORTING INFORMATION
The supporting information is available free of charge on the ACS Publication website at
DOI: .
Scheme S1 for the synthesis of compound 20 and Scheme S2 for the synthesis of compound
21. 1H and 13C NMR spectra for all reported compounds.
REFERENCES
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