Reagent controlled glycosylations for the assembly of well-defined pel oligosaccharides

Article abstract of DOI:10.1021/acs.joc.0c00703

A new additive, methyl(phenyl)formamide (MPF), is introduced for the glycosylation of 2-azido-2-deoxyglucose building blocks. A linear α-(1,4)-glucosamine tetrasaccharide was assembled to prove the utility of MPF. Next, a hexasaccharide fragment of the Pseudomonas aeruginosa exopolysaccharide Pel was assembled using a [2 + 2 + 2] strategy modulated by MPF. The used [galactosazide-α-(1,4)-glucosazide] disaccharide building blocks were synthesized using a 4,6-O-DTBS protected galactosyl azide donor.

Full text of DOI:10.1021/acs.joc.0c00703

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Article
Reagent Controlled Glycosylations for the
Assembly of Well-defined Pel Oligosaccharides
Liming Wang, Yongzhen Zhang, Herman S. Overkleeft, Gijsbert A. van der Marel, and Jeroen D. C. Codée
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00703 • Publication Date (Web): 07 May 2020
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The Journal of Organic Chemistry
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Reagent Controlled Glycosylations for the Assembly of Well-defined
Pel Oligosaccharides
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Liming Wang, Yongzhen Zhang, Herman S. Overkleeft, Gijsbert A. van der Marel, and Jeroen D. C.
Codée*
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Supporting Information Placeholder
ABSTRACT: A new additive, methyl(phenyl)formamide (MPF), is introduced for the glycosylation of 2-azido-2-deoxyglucose
building blocks. A linear α-(1,4)-glucosamine tetrasaccharide was assembled to prove the utility of MPF. Next, a hexasaccha-
ride fragment of the Pseudomonas aeruginosa exopolysaccharide Pel was assembled using a [2+2+2] strategy modulated by
MPF. The used [galactosazide-α-(1,4)-glucosazide] disaccharide building blocks were synthesized using a 4,6-O-DTBS pro-
tected galactosyl azide donor.
Introduction
Pel is one of the exopolysaccharides that is involved in the
biofilm formation of Pseudomonas aeruginosa, an opportun-
istic Gram-positive pathogen that is the major cause of mor-
bidity and mortality in cystic fibrosis patients.1 Pel is a lin-
ear polysaccharide composed of 1,4-linked α-N-acetyl ga-
lactosamine (GalNAc) and α-N-acetyl glucosamine (GlcNAc)
residues, present in a ±6 : 1 ratio, of which some of the res-
idues have been de-acetylated to generate positively
charged galactosamine (GalN) and glucosamine (GlcN) moi-
eties (Figure 1).1b Well-defined Pel fragments can be used to
Figure 1. The repeating structures of Pel.
unravel their role in biofilm formation, to study their bio-
synthesis and possibly as synthetic antigens in the develop-
ment of a (semi)-synthetic vaccine against P. aeruginosa. Be-
cause of the random distribution of the monosaccharides in
Pel, it is impossible to isolate well-defined oligosaccharides
from natural sources and therefore organic synthesis is nec-
essary to provide these structures.
The key challenge in the generation of these oligosaccha-
rides is the stereoselective construction of the 1,2-cis-glyco-
sidic linkages. Four kinds of cis-glycosidic linkages, namely
α-D-GlcN-(1 → 4)-D-GlcN, α-D-GlcN-(1 → 4)-D-GalN, α-D-
GalN-(1→4)-D-GlcN and α-D-GalN-(1→4)-D-GalN, have to
be constructed. Zhang et al. have recently reported an effec-
tive synthetic strategy to assembly galactosaminogalactans
(GAGs), fungal polysaccharides composed of 1,4-linked α-D-
Gal, α-D-GalN and α-D-GalNAc moieties.2 For the formation
of the 1,2-cis-linkages in these structures, 4,6-di-tert-
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butylsilylene (4,6-O-DTBS) protected GalN-donors were
Scheme 1. The relative reactivity of DMF and NFM glycosyl
adducts.
We here describe a strategy to synthesize Pel oligosaccha-
rides using additive-controlled glycosylations to match the
reactivities of the GlcN3-donor and the Pel acceptors. Be-
cause of the relatively low nucleophilicity of the GlcN3-C4-
OH and especially the GalN3-C4-OH, a new additive is intro-
duced that generates intermediates that are more reactive
than the previously introduced DMF and NFM-imidinium
ions.
used to control the selectivity.3 This strategy allowed the
use of galactosamine donors bearing differently masked
amine functionalities. Galactosazide and trichloroacetyl
protected GalN donors were used to combine GalN and Gal-
NAc at pre-determined sites in the target GAG oligosaccha-
rides. Of note, the stereodirecting capacity of the DTBS
group in GalN donors effectively overrides the neighboring
group participation by C2-particpating functionalities such
as the trichloroacetamide. Thus, DTBS-GalN donors also
represent attractive building blocks for Pel-assembly. For
the stereoselective introduction of α-D-GlcN linkages no
general solution exists, even though the construction of this
type of glycosidic linkage has attracted significant atten-
tion,4,5 as it is present in many important natural polysac-
charides and glycoconjugates, such as heparin, heparan sul-
fate,6 GPI anchors and various bacterial polysaccharides.7
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Results and discussion
First, we paid attention to the formation of α-D-GlcN-(1→
4)-D-GlcN linkages. In line with previous work, solely benzyl
type protecting group (PMB, Nap, Bn) were used -besides
the azide at C2- to generate orthogonally protected building
blocks of uniform reactivity. With donor 1 and acceptor 4
(See SI for the syntheses of these building blocks), DMF was
investigated as an additive to control the selectivity accord-
ing to previous successful experiments. Thus, donor α-D-
GlcN 1, acceptor 4 and the additive were mixed in DCM with
molecular sieves and cooled to -78 oC. Next, TfOH was added
Additive controlled glycosylations are gaining increasing
interest for the stereoselective construction of glycosidic
linkages.8 In these approaches the nature of the additive de-
termines the reactivity of in situ formed glycosylating spe-
cies and the influence of the additive can be tuned to match
the reactivity of the glycosyl donor9 and acceptor10 building
blocks. We have recently reported on the fully stereoselec-
tive assembly of a branched α-glucan with an α-(1→4)-
linked backbone from Mycobacterium tuberculosis, α-(1,3)-
glucans from the Aspergillus fumigatus fungal cell wall as
well as the assembly of α-(1,3)-glucans found attached to
lipoteichoic acids of Enterococcus faecalis.11 The synthetic
strategy used in these approaches hinged on the use of ad-
ditive controlled glycosylation reactions in combination
with the use of a single benzyl-type protecting group (Bn,
PMB, Nap). For glycosylations with relatively reactive pri-
mary alcohol acceptors, the trimethylsilyliodide (TMSI)-
triphenylphosphine oxide (Ph3P=O) activator couple was
used, while the condensations with less reactive secondary
alcohols required the use of the trifluoromethanesulfonic
acid (TfOH)-dimethylformamide (DMF) pair. The successful
construction of multiple 1,4-α-glucosidic linkages was an
incentive to explore this strategy for the assembly of the Pel
oligasaccharides. Mong and co-workers have previously de-
scribed how formamide additives can be used for the con-
struction of 1,2-cis-GalN3 and GlcN3 linkages. They intro-
duced N-formyl-morpholine (NFM) to modulate the reactiv-
ity of tri-O-benzyl GlcN3 and 4,6-benzylidene-GalN3 donors
and showed that glycosylations mediated by NFM pro-
ceeded with higher stereoselectivity than the correspond-
ing DMF-modulated condensations.7c Because of the
stronger electron withdrawing effect of the azide group
with respect to a benzyl ether, 2-azido donors are generally
less reactive than their 2-O-benzyl counterparts. This lower
reactivity can be counterbalanced by the use of a somewhat
less nucleophilic additive, resulting in a better leaving group
Y, thereby explaining why NFM outperforms DMF in these
glycosylations (See Scheme 1).
o
and after stirring for 0.5h, the mixture was placed at 0 C
and allowed to stir for 24h. As shown in Table 1, this pro-
duced the desired disaccharide product 8 with complete α-
selectivity, but the yield was only 32% (entry 1). Performing
the reaction at room temperature did not lead to erosion of
stereoselectivity but only marginally improved the yield
(entry 2). Likely, the low reactivity of the donor and accep-
tor led to the observed poor yield and therefore NFM was
probed as additive.6c Use of this additive provided complete
α-selectivity, and raised the yield of the condensation to 55%
yield. To further improve the reaction, a slightly less nucle-
ophilic additive was sought and N-methyl-N-phenylforma-
mide (MPF) was explored. It was expected that the im-
idinium ion formed from this additive would be more reac-
tive because the aniline-type nitrogen would be less capable
of supporting the (partial) positive charge in the ion (See
Scheme 1). The reaction of donor 1 and acceptor 4 pro-
o
ceeded with excellent yield (91%) when performed at 0 C,
and the disaccharide 8 was obtained with 15:1 α:β-selectiv-
ity (entry 4). Although the stereoselectivity of this conden-
sation is somewhat less than the DMF or NFM mediated gly-
cosylations, the improved yield allows for an overall more
productive reaction.12
Next, our attention was turned to the formation of the α-
GlcN-(1 →4)-GalN-linkage exploring the additives as de-
scribed above. First donor 2 was coupled with acceptor 5
using DMF to provide product 9 in low yield and poor selec-
tivity (Table 1, entry 5). The use of NFM instead of DMF did
not improve the outcome of this glycosylation (entry 6).
Likely the poor reactivity of the GalN3-C4-OH hampers the
union of the two carbohydrate building blocks. Next, the use
o
of MPF was explored. At 0 C, disaccharide 9 was obtained
in high yield (83%), but with moderate α:β-selectivity (5:1).
Performing the same reaction at -10oC increased the α-se-
lectivity (α:β = 10:1), but led to a relatively low yield (43%,
entry 8). To increase the yield of the reaction, the concen-
tration was raised from 0.1 M to 0.2 M (entry 9). This led to
the formation of the desired compound 9 with a yield of 88%
and a 10:1 α:β ratio. Having defined adequate conditions for
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Next we probed the robustness of the MPF-mediated pro-
the construction of α-GlcN-(1→4)-GlcN and α-GlcN-(1→4)-
1
tocol in the synthesis of Pel-type oligosaccharides. First the
assembly of an all-1,2-cis linked tetraglucosamine was ex-
plored as depicted in Scheme 2. Thus, donor 1 and acceptor
4 were coupled under the above identified reaction condi-
tions to provide the desired disaccharide 8. The PMB was
removed using a catalytic amount of HCl to give disaccha-
ride acceptor 12 in 88% yield.13 Next, compound 12 was
glycosylated with donor 1 under the MPF-conditions to
form the desired trisaccharide 13 in 83% yield and excel-
lent stereoselectivity (α:β > 19:1). Repetition of the depro-
tection and glycosylation reactions then uneventfully pro-
vided tetrasaccharide 15. The successful assembly of this
tetrasaccharide indicates that the yield and stereoselectiv-
ity do not decrease with the growing of the sugar chain.
GalN linkages, the use of MPF in combination with galac-
tosazide donor 3 was explored for the construction of the
target α-GalN-(1→4)-GlcN and α-GalN-(1→4)-GalN link-
ages. Under the conditions established above, donor 3 was
coupled with glucosyl acceptor 6 to give the disaccharide 10
in excellent yield and 8:1 α/β-stereo selectivity (entry 10).
Contrary, disaccharide 11, formed from donor 3 and galac-
tosyl acceptor 7, was obtained with relatively poor selectiv-
ity (α:β = 4:1, entry 11). From these model reactions, it can
be concluded that three out of four Pel-type linkages can ef-
fectively be installed using the MPF-mediated glycosyla-
tions. For the α-GalN-(1→4)-GalN linkages, the previously
reported approach using 4,6-O-DTBS galactosamine donors
is clearly superior.
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3
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Table 1. Glycosylation between 2-azido Glu/Gal donors and 4-OH-2-azido Glu/Gal acceptors.
entry
1
donor
acceptor c(mmol/ml)
additive
DMF
DMF
NFM
MPF
DMF
NFM
MPF
MPF
MPF
MPF
MPF
T(oC)
0
product
yielda
32%
38%
55%
91%
23%
24%
83%
43%
88%
88%
80%
α:βb
>20:1
>20:1
>20:1
~15:1
6:1
eq
16
16
16
16
16
16
16
16
16
16
16
1
1
1
1
2
2
2
2
2
3
3
4
4
4
4
5
5
5
5
5
6
7
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.1
0.1
8
8
2
rt
3
rt
8
4
0
8
5
0
8
6
0
9
6:1
7
0
9
5:1
8
-10
-10
-10
-10
9
10:1
10:1
8:1
9
9
10
11
10
11
4:1
a Isolated yield. b The α:β ratio was determined by 1H NMR.
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Scheme 3 A and B. First donor 16 was coupled with gluco-
1
2
3
4
5
6
7
8
azide 17 in a chemoselective glycosylation to form disac-
charide 18 as a single anomer. Next, the silylidene ketal was
cleaved with HF-pyridine, after which a benzyl ether was re-
gioselectively introduced under the aegis of Taylor’s borinic
acid catalyst.14 Protection of the remaining C4’-OH with a
naphthyl group delivered compound 21. Next the anomeric
thiophenol group was removed using N-iodosuccinimide in
acetone/water, and the resulting hydroxyl group turned
into the desired N-phenyltrifluoroimidate functionality to
provide donor 23. Acceptor 26 was obtained from donor 16
and acceptor 4. These two building blocks were united to
stereoselectively provide disaccharide 24. Removal of the
silylidene ketal and introduction of the C6’-O-benzyl ether
as described above provided 26. With building blocks 23
and 26 in hand, the assembly of the target hexasaccharides
was undertaken (Scheme 3C). First, donor 23 was glycosyl-
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o
ated with acceptor 26 using MPF as additive at -10 C at a
0.2 M concentration to form tetrasaccharide 27 in 89% yield
as a 10:1 α/β-mixture. Then the Nap ether was removed us-
ing HCl and triethylsilane in DCM/HFIP to give the tetrasac-
charide acceptor 28. Compound 28 was treated with donor
23 under the optimal MPF-mediated glycosylation condi-
tions to deliver hexasaccharide 29 in high yield and stere-
oselectivity. Reduction of the six azides and removal of the
benzyl ester and ethers were accomplished in a one-step re-
duction to give the compound 30, of which the amino
groups were acetylated with acetic anhydride to afford the
Pel-structure 31.
(a) MPF, TfOH, DCM, -78-0 oC, 8: 91%, α:β = 15:1; 13: 83%,
α:β > 19:1; 15: 90%, α:β > 20:1. (b) 0.2 M HCl/HFIP, TES,
HFIP/DCM, 12: 88%; 14: 78%.
Scheme 2. Assembly of an α-glucosazide tetrasaccharide
using MPF mediated glycosylations.
Next the synthesis of a Pel hexasaccharide, featuring both
GalN and GlcN residues, was undertaken. A [2+2+2] strat-
egy was designed to streamline the assembly of the struc-
tures, building on MFP-mediated glycosylations of the
GalN3-GlcN3 donor 23. The procedure for the synthesis of
the required building blocks 23 and 26 is depicted in
(a) TfOH, DCM, 18: 70%; 24: 92%. (b) HF-pyridine, THF, 19: 98%, 25: 91%. (c) BnBr, borinic acid-catalyzed, K2CO3, KI,
CH3CN, 60 oC, 20: 96%; 26: 95%. (d) NapBr, NaH, DMF, 21: 93%. (e) NIS, acetone, H2O. (f) 2,2,2-trifluoro-N-phenylacetimidoyl
chloride, Cs2CO3, acetone, 23: 83% over two steps. (g) MPF, TfOH, DCM, -10 oC, 48 h, 27: 89%, α:β = 10:1; 29: 91%, α:β = 10:1.
(h) 0.2 M HCl/HFIP, TES, HFIP/DCM, 28: 73%. (i) H2, Pd(OH)2/C, CH3COOH, THF/H2O/t-BuOH, 30: 76%. (k) Ac2O, NaHCO3,
H2O, 31: 86%.
Scheme 3. A: Synthesis of donor 23. B: synthesis of acceptor 26. C: Assembly of Pel fragment 31.
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to be complete. The solution was diluted and the reaction
Conclusion
1
quenched with saturated Na2S2O3. The organic phase was
washed with water and brine, dried with anhydrous MgSO4,
filtered and concentrated in vacuo. The products were puri-
fied by size exclusion and silica gel column chromatography.
In conclusion, MPF is here reported for the first time as a
moderator to enable the stereoselective construction of α-
GlcN3 linkages. This additive complements previously intro-
duced glycosylation additives, such as DMF and NFM and
expands the “nucleophilic additive toolbox”, that can be
used to match the reactivity of glycosyl donor-acceptor
pairs. The applicability of the MPF-mediated glycosylations
in oligosaccharide synthesis has been demonstrated by the
hand of the assembly of Pel-type oligosaccharides. A linear
glucosazide tetrasaccharide was assembled, through highly
stereoselective glycosylation reactions, using building
blocks, solely equipped with benzyl type (Bn and PMB) hy-
droxyl protecting groups. A [2+2+2] strategy was devel-
oped for the assembly of a (GalN-GlcN)3 hexasaccharide in
which the α-GlcN linkages were constructed in glycosyla-
tion reactions using MPF as an additive.
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8
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Procedure C for deprotection of the PMB and Nap pro-
tecting group:13
The starting material (1 eq) was dissolved in DCM:HFIP (1:1,
0.1 M). TES (2.0 eq) and 0.2M HCl/HFIP (0.1-1eq) were
added to the mixture. The reaction stirred until TLC-
analysis indicated full consumption of the starting material
(15min-2h). Then the mixture was diluted with DCM and
the reaction quenched with saturated NaHCO3. The organic
phase was washed with water and brine, dried with anhy-
drous MgSO4, filtered and concentrated in vacuo. The prod-
uct was purified by silica gel column chromatography.
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Experimental Procedures and Characterization Data of
Products
Experiment section
For the synthesis procedure and data of known compounds
915a, S115a, S215b, S315c and S105e see references. We used "a",
"b", "c", "d", "e", "f", "g", “h” and “i” to specify the H-1 and C-
13 NMR signals of sugar rings from the “reducing” to the
“non-reducing” end and “°” to specify the H-1 and C-13 NMR
signals of the spacer.
General experimental procedures
All reagents were of commercial grade and used as received.
All moisture sensitive reactions were performed under an
argon atmosphere. DCM used in the glycosylation reactions
was dried with flamed 4Å molecular sieves before being
used. Reactions were monitored by TLC analysis with detec-
tion by UV (254 nm) and where applicable by spraying with
N-phenyl trifluoroacetimidate 2-N3-glucose donor 1:
20% sulfuric acid in EtOH or with
a solution of
(NH4)6Mo7O24∙4H2O (25 g/L) and (NH4)4Ce(SO4)4∙2H2O (10
g/L) in 10% sulfuric acid (aq.) followed by charring at
~150 °C. Column chromatography was carried out using sil-
ica gel (0.040-0.063 mm). Size-exclusion chromatography
Compound S1 (9.1 g, 15.2 mmol) was dissolved in ace-
tone:H2O (10:1, 150 mL). N-Iodosuccinimide (NIS) (6.9 g,
30.5 mmol) was added in one portion and the reaction was
stirred at room temperature for 2 hours. The solution was
diluted with DCM and the reaction was quenched with sat-
urated aqueous Na2S2O3. Then the organic layer was washed
with water and brine. The organic layer was dried with an-
hydrous MgSO4, filtered and concentrated in vacuo, and the
product purified by column chromatography (pentane :
ethyl acetate (EA) = 3:1). The lactol (7.2 g, 14.3 mmol) was
obtained as colourless syrup. Next, the lactol was dissolved
in acetone (150 mL). Cs2CO3 (7.0 g, 21.3 mmol) and 2,2,2-
trifluoro-N-phenylacetimidoyl chloride (3.4 mL, 21.3 mmol)
were added to the solution respectively. The reaction was
stirred overnight, then quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by column
chromatography (pentane:EA = 40:1-20:1). Compound 1
(8.5 g, 79% over two steps, pentane:EA = 10:1, Rf = 0.45-
0.55) was obtained as yellow syrup. IR (neat, cm-1) ν 697,
737, 1029, 1082, 1119, 1210, 1251, 1312, 1514, 1720, 2112
1
was carried out using Sephadex LH-20. H and 13C spectra
were recorded on a Bruker AV 400 and Bruker AV 500 in
CDCl3 or D2O. Chemical shifts (δ) are given in ppm relative
to tetramethylsilane as internal standard (1H NMR in CDCl3)
or the residual signal of the deuterated solvent. Coupling
constants (J) are given in Hz. All 13C spectra are proton de-
coupled. NMR peak assignments were made using COSY and
HSQC experiments, where applicable Clean TOCSY, HMBC
and GATED experiments were used to further elucidate the
structure. The anomeric product ratios were analyzed
through integration of proton NMR signals.
Procedure A for the glycosylation of secondary alcohols:
A mixture of donor (1.0 eq), acceptor (0.7 eq) (donors and
acceptors co-evaporated with toluene three times), MPF
(16 eq) in dry DCM were stirred over fresh flame-dried mo-
lecular sieves 3A under nitrogen. The solution was cooled
to -78 ℃, after which TfOH (1.0 eq) was added. After 30 min,
the reaction was stirred at 0 or -10 ℃ until TLC-analysis
showed complete conversion of the acceptor. The reaction
was quenched with Et3N, filtered and concentrated in vacuo.
The products were purified by size exclusion and silica gel
column chromatography.
1
(N3), 2872, 2912. H-NMR (CDCl3, 500 MHz, 60℃) δ 7.38-
7.20 (m, aromatic H), 7.11-7.06 (m, aromatic H), 6.82-6.78
(m, aromatic H), 6.37 (bs, 1 H), 5.41 (bs, 1 H), 4.92-4.80 (m),
4.74-4.69 (m), 4.60-4.48 (m), 3.96 (t, J = 10.0 Hz, 1 H), 3.90
(bd, 1 H), 3.77-3.58 (m), 3.43 (t), 3.33 (bs, 1 H). 13 C-APT
(CDCl3, 125 MHz, 60℃) δ 159.8, 159.8, 143.6, 143.5, 138.3,
138.2, 138.1, 130.3 (aromatic C), 129.7, 128.9, 128.6, 128.6,
128.5, 128.1, 128.0, 1278.0, 127.9, 127.9, 127.8, 124.7,
124.6, 119.6, 114.2, 114.2 (aromatic CH), 96.2 (C-1), 94.4 (C-
1), 83.3, 80.5, 77.7, 77.3, 76.4, 75.7, 75.0, 74.8, 73.9, 73.8,
Procedure B for the glycosylation of primary alcohols:
A mixture of donor (1.0 eq), acceptor (0.7 eq) (donors and
acceptors co-evaporated with toluene three times), Ph3P=O
(6 eq) in dry DCM were stirred over fresh flame-dried mo-
lecular sieves 3A under nitrogen. Then TMSI (1.0 eq) was
added slowly in the mixture. The reaction was stirred at
room temperature until TLC-analysis indicated the reaction
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73.7, 68.5, 65.8, 63.5, 55.4. HRMS (ESI) m/z: Calculated for
2,2,2-trifluoro-N-phenylacetimidoyl chloride (1.5 mL, 9
[M-[O(C=NPh)CF3]+OH+Na]+ C28H31O6N3Na: 582.21051,
found: 582.20943.
mmol) were added to the solution respectively. The reac-
tion was stirred overnight, then quenched with Et3N, fil-
tered and concentrated in vacuo. The product was purified
by column chromatography (pentane:EA = 40:1-20:1).
Compound 3 (3.3 g, 86%) was obtained as yellow syrup. IR
(neat, cm-1) ν 695, 734, 751, 986, 1027, 1153, 1316, 1364,
1
2
3
4
5
6
7
Synthesis of N-phenyl trifluoroacetimidate 2-N3-glucose do-
nor 2:
1
1454, 1490, 1497, 1590, 1717, 2114 (N3), 2870, 2915. H-
NMR (CDCl3, 400 MHz) δ 7.56-6.79 (m, aromatic H), 6.35 (bs,
1 H, H-1), 5.49 (bs, 1 H, H-1), 5.28 (d), 4.90-4.84 (m, CHH),
4.78-4.31 (m), 4.15-3.83 (m), 3.76 (dd), 3.65-3.31 (m). 13 C-
APT (CDCl3, 100 MHz) δ 143.5, 143.4, 138.5, 138.3, 138.3,
138.2, 138.1, 137.7, 137.7, 137.6, 137.6, 137.4, 137.3, 135.2
(aromatic C), 129.5, 128.8, 128.7, 128.6, 128.6, 128.6, 128.5,
128.5, 128.43, 128.37, 128.3, 128.19, 128.17, 128.15,
128.14, 128.07, 128.03, 128.00, 127.95, 127.9, 126.48,
124.46, 120.6, 119.4 (aromatic CH), 96.5 (C-1), 92.5 (C-1),
80.9, 80.7, 77.4, 75.1, 74.9, 74.8, 74.7, 74.6, 73.8, 73.67,
73.65, 73.62, 73.5, 72.9, 72.7, 72.6, 72.5, 72.4, 72.3, 72.2,
71.9, 69.7, 69.3, 68.7, 68.3, 68.1, 64.7, 62.2, 60.4, 59.2. HRMS
(ESI) m/z: [M+Na]+ Calculated for C27H29O5N3Na: 669.22953,
found: 669.22913.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
34
35
36
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38
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45
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47
48
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50
51
52
53
54
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58
59
60
Compound S2 (8.5 g, 15 mmol) was dissolved in ace-
tone:H2O (10:1, 150 mL). N-Iodosuccinimide (NIS) (6.7 g, 30
mmol) was added in one portion and the reaction was
stirred at room temperature for 2 hours. The solution was
diluted with DCM and the reaction was quenched with sat-
urated aqueous Na2S2O3. Then the organic layer was washed
with water and brine. The organic layer was dried with an-
hydrous MgSO4, filtered and concentrated in vacuo, and the
product purified by column chromatography (pentane :
ethyl acetate (EA) = 3:1). The lactol (6.1 g, 13 mmol) was
obtained as colorless syrup. Next, the lactol was dissolved
in acetone (150 mL). Cs2CO3 (6.4 g, 19.6 mmol) and 2,2,2-
trifluoro-N-phenylacetimidoyl chloride (3.4 mL, 21.3 mmol)
were added to the solution respectively. The reaction was
stirred overnight, then quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by column
chromatography (pentane:EA = 40:1-20:1). Compound 2
(7.3 g, 87%) was obtained as yellow syrup. IR (neat, cm-1) ν
694, 734, 1027, 1073, 1116, 1150, 1208, 1312, 1361, 1452,
1490, 1497, 1598, 1717, 2110 (N3), 2869, 3032. 1H-NMR
(CDCl3, 500 MHz, 60℃) δ 7.52-6.81 (m, aromatic H), 6.37
(bs, 1 H, H-1α), 5.43 (bs, 1 H, H-1β), 4.89-4.76 (m, CHH),
4.60-4.48 (m, CHH), 3.98 (t, J = 9.5 Hz, 1 H), 3.91 (bd, 1 H),
3.80-3.59 (m), 3.46 (t), 3.36 (bs, 1 H). 13 C-APT (CDCl3, 125
MHz, 60℃) δ 143.6, 143.5, 138.2, 138.2, 138.1, 138.1, 138.1
(aromatic C), 129.5, 128.9, 128.8, 128.6, 128.6, 128.5, 128.2,
128.1, 128.1, 128.0, 128.0, 127.97, 127.95, 127.91, 127.9,
126.5, 124.7, 124.6, 120.8, 119.6 (aromatic CH), 96.2 (C-1),
94.4 (C-1), 83.3, 80.5, 78.0, 77.6, 76.3, 75.7, 75.7, 75.4, 75.2,
73.9, 73.8, 73.7, 68.5, 65.8, 63.5. HRMS (ESI) m/z: Calculated
for [M-[O(C=NPh)CF3]+OH+Na]+ C27H29O5N3Na: 498.19994,
found: 498.19848.
Synthesis of monosaccharide 4:
The reaction was carried out according to the standard pro-
cedure B. A mixture of donor 1 (1.0 g, 1.5 mmol), benzyl 6-
hydroxyhexanoate (520 mg) (donors and acceptors co-
evaporated with toluene three times), Ph3P=O (2.6 g, 9.3
mmol) in dry DCM (15 mL) were stirred over fresh flame-
dried molecular sieves 3A under nitrogen. Then TMSI (222
μL, 1.5 mmol) was added slowly in the mixture. The reaction
was stirred at room temperature until TLC-analysis indi-
cated the reaction to be complete. The solution was diluted
and the reaction quenched with saturated Na2S2O3. The or-
ganic phase was washed with water and brine, dried with
anhydrous MgSO4, filtered and concentrated in vacuo. The
products were purified by silica gel column chromatog-
raphy (pentane:EA = 8:1, Rf = 0.63). Compound S4 (800 mg,
75% yield, α:β = 5:1) was obtained as a colorless syrup. IR
(neat, cm-1) ν 697, 736, 1002, 1029, 1037, 1075, 1150, 1248,
1
1358, 1454, 1611, 1733 (C=O), 2105 (N3), 2866, 2933. H-
NMR (CDCl3, 400 MHz) δ 7.40-7.21 (m, 15 H, aromatic H),
7.00 (bd, 2 H, aromatic H), 6.79 (bd, 2 H, aromatic H), 5.09
(s, 2 H, PhCH2), 4.90 (d, J = 3.6 Hz, 1 H, H-1a), 4.88 (s, 2 H,
PhCH2),4.71 (d, J = 10.4 Hz, 1 H, CHH), 4.63 (d, J = 12.4 Hz, 1
H, CHH), 4.49 (d, J = 12.4 Hz, 1 H, CHH), 4.43 (d, J = 10.4 Hz,
1 H, CHH), 3.975 (t, t, J = 9.6 Hz, 1 H, H-3a), 3.79-3.63 (m, 5
H, H-2a, H-4a, H-5a, H-6a, H-1ºa), 3.47-3.37 (m, 1 H, H-1ºb),
3.33 (dd, 1 H, J1 = 10.0 Hz, J2 = 2.0 Hz, H-2a), 2.36 (t, J = 7.6
Hz, 2H, H-5o), 1.70-1.58 (m, 4 H, H-2º, H-4º), 1.43-1.36 (m, 2
H, H-3º). 13C-APT (CDCl3, 100 MHz) δ 173.4 (C=O), 159.4,
138.1, 137.9, 130.1 (aromatic C), 129.6, 128.6, 128.5, 128.5,
128.2, 127.99, 127.96, 127.9, 127.8, 113.9 (aromatic CH),
97.9 (C-1a), 80.2 (C-3a), 78.0 (C-4a), 75.3, 74.8, 73.6 (CH2),
70.7 (C-5a), 68.3 (C-6a), 68.0 (C-1º), 66.1 (PhCH2), 63.4 (C-
2a), 55.3 (OCH3), 34.2 (C-5º), 29.1 (C-2º), 25.7 (C-3º), 24.7
(C-4º). HRMS (ESI) m/z: [M+NH4]+ Calculated for
C41H51N4O8: 727.37014, found: 727.37015.
Synthesis of N-phenyl trifluoroacetimidate 2-N3-galactose
donor 3:
Compound S3 (3.7 g, 6.0 mmol) was dissolved in ace-
tone:H2O (10:1, 150 mL). N-Iodosuccinimide (NIS) (2.7 g, 12
mmol) was added in one portion and the reaction was
stirred at room temperature for 2 hours. The solution was
diluted with DCM and the reaction was quenched with sat-
urated aqueous Na2S2O3. Then the organic layer was washed
with water and brine. The organic layer was dried with an-
hydrous MgSO4, filtered and concentrated in vacuo, and the
product purified by column chromatography (pentane:EA =
3:1). The lactol was obtained as colourless syrup. Next, the
lactol was dissolved in acetone. Cs2CO3 (3.0 g, 9 mmol) and
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Then the reaction was carried out according to the standard Hz, 1 H, CHH), 4.12 (t, J = 1.5 Hz, 1 H, H-4a), 3.98 (t, J = 6.0
1
2
3
4
5
6
7
8
procedure C. The starting material S4 (700 mg, 0.99 m mol)
was dissolved in DCM:HFIP (1:1, 0.1 M). TES (314 mL) and
0.2M HCl/HFIP (0.5 mL) were added to the mixture. The re-
action stirred until TLC-analysis indicated full consumption
of the starting material (15min). Then the mixture was di-
luted with DCM and the reaction quenched with saturated
NaHCO3. The organic phase was washed with water and
brine, dried with anhydrous MgSO4, filtered and concen-
trated in vacuo. The product was purified by silica gel col-
umn chromatography (pentane:EA = 4:1, Rf = 0.34). Com-
pound 4 (350 mg, 60% yield) was obtained as a colorless
Hz, 1 H, H-5a), 3.93 (dd, 1 H, J1 = 10.5 Hz, J2 = 3.0 Hz, H-3a),
3.90-3.86 (m, 1 H, H-1ºa), 3.77-3.63 (m, 4 H, H-2a, H-6ª, H-
1ºb), 3.57-3.52 (m, 1 H, H-2ºa), 3.37-3.33 (m, 1 H, H-2ºb),
2.61 (bt, 1 H, OH), 1.21-1.18 (bt, 6 H, 2 CH3). 13C-APT (CDCl3,
125 MHz) δ 137.9, 137.3 (aromatic C), 128.8, 128.6, 128.4,
128.2, 127.9, 127.8 (aromatic CH), 98.5 (C-1a), 76.0 (C-3a),
73.8, 72.1 (CH2), 69.6 (C-6a), 69.2 (C-5a), 67.2 (C-1º), 66.8
(C-4a), 59.0 (C-2a), 50.8 (C-2º). HRMS (ESI) m/z: [M+NH4]+
Calculated for C22H30O5N7: 472.23029, found: 472.23003.
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10
11
12
13
14
15
16
17
18
19
20
21
22
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26
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41
42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of acceptor 6:
20
syrup. [α]D +59.3 (c=1, CHCl3). IR (neat, cm-1) ν 697, 737,
1050, 1147, 1455, 1734 (C=O), 2105 (N3), 2866, 2926, 3478.
1H-NMR (CDCl3, 400 MHz) δ 7.41-7.23 (m, 15 H, aromatic H),
5.10 (s, 2 H, PhCH2), 4.90 (d, J = 11.2 Hz, 1 H, CHH), 4.87 (d,
J = 3.6 Hz, 1 H, H-1a), 4.81 (d, J = 11.2 Hz, 1 H, CHH), 4.59 (d,
J = 12.0 Hz, 1 H, CHH), 4.53 (d, J = 12.0 Hz, 1 H, CHH), 3.86-
3.64 (m, 6 H, H-2a, H-3a, H-4a, H-5a, H-6a, H-1ºa), 3.47-3.41
(m, 1 H, H-1ºb), 3.25 (dd, 1 H, J1 = 10.0 Hz, J2 = 2.0 Hz, H-2a),
2.37 (t, J = 7.6 Hz, 2H, H-5o), 1.72-1.61 (m, 4 H, H-2º, H-4º),
1.47-1.37 (m, 2 H, H-3º). 13C-APT (CDCl3, 100 MHz) δ 173.6
(C=O), 138.2, 137.9, 136.1 (aromatic C), 128.7, 128.6, 128.5,
128.3, 128.3, 128.1, 128.05, 127.9, 127.7, 127.5 (aromatic
CH), 98.0 (C-1a), 79.8 (C-3a), 75.0 (C-6a), 73.7 (CH2), 72.2
(c-4a), 70.2 (c-5a), 69.8 (PhCH2), 68.1 (C-1º), 66.2 (PhCH2),
62.8 (C-2a), 34.2 (C-5º), 29.1 (C-2º), 25.7 (C-3º), 24.7 (C-4º).
HRMS (ESI) m/z: [M+NH4]+ Calculated for C33H43O7N4:
607.31263, found: 607.31238.
Donor 1 (820 mg, 1.2 mmol), isopropanol (200 μL, 2.6 mmol)
and Ph3P=O (2 g) were dissolved in DCM (12 mL), and TMSI
(173 μL) was added at room temperature. The reaction was
stirred at rt until TLC-analysis showed complete conversion
of the donor. The reaction was quenched with Et3N after
completed checking by TLC, filtered and concentrated in
vacuo, purified by column chromatography. Compound S7
was obtained with α:β = 5:1. Then compound S7 was dis-
solved in DCM/HFIP (1.5 mL: 1.5 mL). TES (380 μL) and
0.2M HCl/HFIP (600 μL) were added to the mixture. The re-
action stirred until TLC-analysis indicated full consumption
of the starting material (30min). Then the mixture was di-
luted with DCM and the reaction quenched with saturated
NaHCO3. The organic phase was washed with water and
brine, dried with anhydrous MgSO4, filtered and concen-
trated in vacuo. The product was purified by silica gel col-
umn chromatography (pentane:EA = 5:1). Compound 6
(240 mg, 47% yield over two steps) was obtained as color-
Synthesis of acceptor 5
20
less syrup. [α]D +83.4 (c=1, CHCl3). IR (neat, cm-1) ν 697,
735, 1029, 1047, 1120, 1454, 2105 (N3), 2920, 2974, 3476.
1H-NMR (CDCl3, 400 MHz) δ 7.40-7.20 (m, 10 H, aromatic H),
4.97 (d, J = 3.6 Hz, 1 H, H-1a), 4.88 (d, J = 11.2 Hz, 1 H, CHH),
4.78 (d, J = 11.2 Hz, 1 H, CHH), 4.57 (d, J = 12.0 Hz, 1 H, CHH),
4.50 (d, J = 12.0 Hz, 1 H, CHH), 3.93-3.82 (m, 3 H, H-3a, H-5a,
H-1º), 3.73-3.61 (m, 3 H, H-4a, H-6a), 3.18 (dd, 1 H, J1 = 10.0
Hz, J2 = 3.6 Hz, H-2a), 2.76 (bs, 1 H, OH), 1.23, (d, J = 8.4 Hz,
3 H, CH3), 1.21 (d, J = 8.4 Hz, 3 H, CH3). 13C-APT (CDCl3, 100
MHz) δ 138.2, 137.8 (aromatic C), 128.5, 128.4, 128.0, 127.9,
127.7, 127.6 (aromatic CH), 96.4 (C-1a), 79.6 (C-3a), 74.9,
73.6 (CH2), 72.1 (C-4a), 70.8 (C-1º), 70.1 (C-5a), 69.7 (C-6a),
62.5 (C-2a), 23.2 (CH3), 21.5 (CH3). HRMS (ESI) m/z:
[M+NH4]+ Calculated for C23H33O5N4: 445.24455, found:
445.24441.
Donor 16 (620 mg, 1.0 mmol) and 2-azidoethanol (178 mg,
o
2.0 mmol) were dissolved in DCM, cooled to 0 C and TfOH
(15 μL, 0.1 mmol) was added. The reaction was stirred at 0 ℃
until TLC-analysis showed complete conversion of the do-
nor. The reaction was quenched with Et3N after completed
checking by TLC, filtered and concentrated in vacuo. Com-
pound S5 (370 mg, 73%) was obtained with full α-selectiv-
ity. Then compound S5 was dissolved in THF. HF-pyridine
was added to the solution. After TLC-analysis showed com-
plete consumption of the starting material, the reaction was
quenched with saturated NaHCO3. The mixture was diluted
with ethyl acetate, washed with H2O and brine, dried with
anhydrous MgSO4, filtered, concentrated in vacuo. Crude
compound S6, K2CO3, KI, and borinic acid-catalyzed were
mixed in CH3CN, and then BnBr was added in the solution.
The reaction was stirred at 60 ℃ until TLC-analysis showed
complete conversion of the starting material. The reaction
was quenched with H2O after completed checking by TLC,
filtered and concentrated in vacuo, purified by column chro-
matography (pentane:EA = 5:1). Compound 5 (280 mg, 84%
Synthesis of acceptor 7:
20
yield over two steps) was obtained as colorless syrup. [α]D
+89.9 (c=1, CHCl3). IR (neat, cm-1) ν 698, 738, 1052, 1096,
1146, 1454, 2108 (N3), 2873, 2923, 3483. H-NMR (CDCl3,
Donor 16 (2.77 g, 4.6 mmol) and isopropanol were
1
o
dissolved in DCM (40 mL), cooled to 0 C and TfOH (40 μL)
500 MHz) δ 7.40-7.28 (m, 10 H, aromatic H), 4.95 (d, J = 3.5
Hz, 1 H, H-1a), 4.71 (d, J = 11.5 Hz, 1 H, CHH), 4.68 (d, J = 11.5
Hz, 1 H, CHH), 4.60 (d, J = 12.0 Hz, 1 H, CHH), 4.57 (d, J = 12.0
was added. The reaction was stirred at 0 ℃ until TLC-
analysis showed complete conversion of the donor. The re-
action was quenched with Et3N after completed checking by
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TLC, filtered and concentrated in vacuo. Compound S8 was (aromatic CH), 97.8 (C-1b), 97.7 (C-1a), 80.9 (C-3a), 80.3 (C-
1
2
3
4
5
6
7
8
obtained with full α-selectivity. Then compound S8 was dis-
solved in THF (20 mL). HF-pyridine (1 mL) was added to the
solution. After TLC-analysis showed complete consumption
of the starting material, the reaction was quenched with sat-
urated NaHCO3. The mixture was diluted with ethyl acetate,
washed with H2O and brine, dried with anhydrous MgSO4,
filtered, concentrated in vacuo, purified by column chroma-
tography (pentane:EA = 3:1). Compound S9 (1.45 g) was ob-
tained with 94% yield over two steps. Then compound S9
(665 mg, 1.97 mmol), K2CO3 (293 mg), KI (327 mg), and bo-
rinic acid-catalyzed (44 mg) were mixed in CH3CN (20 mL),
and then BnBr was added in the solution. The reaction was
stirred at 60 ℃ in oil bath until TLC-analysis showed com-
plete conversion of the starting material. The reaction was
quenched with H2O after completed checking by TLC, fil-
tered and concentrated in vacuo, purified by column chro-
matography (pentane:EA = 5:1). Compound 7 (745 mg, 80%
3b), 77.8 (C-4b), 75.5, 74.7, 74.5, 73.6, 73.5 (PhCH2), 73.4 (c-
4a), 71.6 (c-5b), 70.2 (C-5a), 69.1 (C-6a), 68.2 (C-6b), 67.9
(C-1º), 66.2 (PhCH2), 63.8 (C-2), 63.4 (C-2), 55.4 (OCH3),
34.2 (C-5º), 29.2 (C-2º), 25.8 (C-3º), 24.8 (C-4º). HRMS (ESI)
m/z: [M+NH4]+ Calculated for C61H72N7O12: 1094.52335,
found: 1094.52388.
Synthesis of disaccharide 9: The reaction was carried out
according to the standard procedure A. A mixture of donor
2 (146 mg, 0.22 mmol), acceptor 5 (50 mg, 0.11 mmol) (do-
nors and acceptors co-evaporated with toluene three times),
MPF (216 μL) in dry DCM were stirred over fresh flame-
dried molecular sieves 3A under nitrogen. The solution was
cooled to -78 ℃, after which TfOH (19 μL) was added. After
30 min, the reaction was stirred at -10 ℃ until TLC-analysis
showed complete conversion of the acceptor. The reaction
was quenched with Et3N, filtered and concentrated in vacuo.
The product was purified by size exclusion (DCM:MeOH =
1:1). Compound 9 (86 mg, 87%, α:β = 10:1) was obtained as
a colorless syrup. IR (neat, cm-1) ν 697, 736, 1027, 1046,
1093, 1127, 1150, 1259, 1359, 1454, 2105 (N3), 2869, 2923.
1H-NMR (CDCl3, 400 MHz) δ 7.40-7.05 (m, 25 H, aromatic H),
4.99 (bt, 2 H, H-1a and H-1b), 4.90-4.76 (m, 3 H, 3 CHH), 4.69
(d, J = 10.8 Hz, 1 H, CHH), 4.63 (d, J = 10.8 Hz, 1 H, CHH),
4.59-4.53 (m, 2 H, 2 CHH), 4.39 (bt, 2 H, 2 CHH), 4.31 (d, J =
2.4 Hz, 1 H), 4.13-3.49 (m, 13 H), 3.39-3.29 (m, 2 H), 3.22
(dd, J1 = 12.4 Hz, J2 = 2.0 Hz, 1 H), 2.96 (dd, J1 = 10.8 Hz, J2 =
2.0 Hz, 1 H), 4.48 (d, J1 = 10.8 Hz, J2 = 1.6 Hz, 1 H). 13C-APT
(CDCl3, 100 MHz) δ 138.1, 137.8, 137.7, 137.5 (aromatic C),
128.6, 128.5, 128.4, 128.4, 128.2, 128.07, 128.06, 127.9,
127.82, 127.78, 127.75, 127.7, 127.2 (aromatic CH), 98.9 (C-
1), 98.5 (C-1), 80.2, 78.1, 75.6, 75.4, 74.9, 73.7, 73.3, 73.3,
72.0, 70.9, 69.6, 67.3, 67.3, 67.0, 64.0, 59.4, 50.7. HRMS (ESI)
m/z: [M+NH4]+: Calculated for C49H57O9N10: 929.43045,
found: 929.43039.
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10
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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
20
yield) was obtained as colorless syrup. [α]D +102.7 (c=1,
CHCl3). IR (neat, cm-1) ν 698, 737, 1052, 1454, 2108 (N3),
2892, 2926. 2972. 1H-NMR (CDCl3, 400 MHz) δ 7.42-7.27 (m,
10 H, aromatic H), 5.02 (d, J = 3.6 Hz, 1 H, H-1a), 4.71 (bs, 2
H, PhCH2), 4.58 (bs, 2 H, PhCH2), 4.15 (t, J = 1.6 Hz, 1 H, H-
4a), 4.01 (bt, 1 H, H-5a), 3.95-3.89 (m, 2 H, H-3a, H-1º), 3.76
(dd, 1 H, J1 = 10.0 Hz, J2 = 6.0 Hz, H-6aa), 3.70-3.62 (m, 2 H,
H-6ab, H-2a), 2.60 (bs, 1 H, OH), 1.23 (d, 3 H, J = 10.4 Hz, CH3),
1.21 (d, 3 H, J = 10.4 Hz, CH3). 13C-APT (CDCl3, 100 MHz) δ
138.0, 137.5 (aromatic C), 128.8, 128.6, 128.3, 128.1, 127.9,
127.8 (aromatic CH), 96.7 (C-1a), 76.1 (C-3a), 73.8, 72.0
(CH2), 70.9 (C-1º), 69.6 (C-6a), 68.7 (C-5a), 66.8 (C-4a), 59.0
(C-2a), 23.3 (CH3), 21.6 (CH3). HRMS (ESI) m/z: [M+NH4]+
Calculated for C23H33O5N4: 445.24455, found: 445.24455.
Synthesis of disaccharide 8: The reaction was carried out
according to the standard procedure A. A mixture of donor
1 (320 mg, 0.47 mmol), acceptor 4 (185 mg, 0.31 mmol)
(donors and acceptors co-evaporated with toluene three
times), MPF (610 μL) in dry DCM (3 mL) were stirred over
fresh flame-dried molecular sieves 3A under nitrogen. The
solution was cooled to -78 ℃, after which TfOH (42 μL) was
added. After 30 min, the reaction was stirred at -10 ℃ until
TLC-analysis showed complete conversion of the acceptor.
The reaction was quenched with Et3N, filtered and concen-
trated in vacuo. The product was purified by size exclusion
(DCM:MeOH = 1:1). Compound 8 (304 mg, 88% yield, α:β =
15:1, PE:EA = 4:1, Rf = 0.51) was obtained as a colorless
syrup. IR (neat, cm-1) ν 697, 736, 1027, 1147, 1249, 1358,
Synthesis of disaccharide 10: The reaction was carried out
according to the standard procedure A. A mixture of donor
3 (77 mg, 0.12 mmol), acceptor 6 (34 mg, 0.08 mmol) (do-
nors and acceptors co-evaporated with toluene three times),
MPF (156 μL) in dry DCM were stirred over fresh flame-
dried molecular sieves 3A under nitrogen. The solution was
cooled to -78 ℃, after which TfOH (8 μL) was added. After
30 min, the reaction was stirred at -10 ℃ until TLC-analysis
showed complete conversion of the acceptor. The reaction
was quenched with Et3N, filtered and concentrated in vacuo.
The product was purified by size exclusion (DCM:MeOH =
1:1). Compound 10 (56 mg, 88% yield, α:β = 8:1) was ob-
tained as a colorless syrup. IR (neat, cm-1) ν 697, 737, 1050,
1097, 1122, 1258, 1454, 2108 (N3), 2869, 2928. 1H-NMR
(CDCl3, 400 MHz) δ 7.41-7.19 (m, 25 H, aromatic H), 5.64 (d,
J = 3.6 Hz, 1 H, H-1a), 5.03 (d, J = 3.6 Hz, 1 H, H-1b), 4.96 (d,
J = 10.0 Hz, 1 H, CHH), 4.91 (d, J = 10.0 Hz, 1 H, CHH), 4.81
(d, J = 11.2 Hz, 1 H, CHH), 4.67 (d, J = 11.2 Hz, 1 H, CHH), 4.61
(d, J = 11.2 Hz, 1 H, CHH), 4.56 (d, J = 12.4 Hz, 1 H, CHH), 4.48
(d, J = 11.2 Hz, 1 H, CHH), 4.44 (d, J = 12.4 Hz, 1 H, CHH), 4.29
(d, J = 11.6 Hz, 1 H, CHH), 4.22 (d, J = 11.6 Hz, 1 H, CHH), 4.07
(dd, J = 8.0, 10.0 Hz, 1 H, H-3b), 3.98-3.78 (m, 7 H), 3.72-3.63
(m, 2 H, H-6), 3.48-3.37 (m, 2 H, H-6), 3.29 (dd, J = 3.6, 10.0
Hz, 1H, H-2b), 1.28 (d, J = 6.4 Hz, 1 H, CH3), 1.24 (d, J = 6.4
1
1454, 1514, 1734 (C=O), 2103 (N3), 2866, 2928. H-NMR
(CDCl3, 400 MHz) δ 7.39-7.21 (m, 25 H, aromatic H), 7.00 (bd,
2 H, aromatic H), 6.79 (bd, 2 H, aromatic H), 5.66 (d, J = 4.0
Hz, 1 H, H-1b), 5.11 (s, 2 H, PhCH2), 4.98(d, J = 10.4 Hz, 1 H,
CHH), 4.93 (d, J = 4.0 Hz, 1 H, H-1a), 4.89-4.82 (m, 3 H, 3
CHH), 4.66 (d, J = 10.0 Hz, 1 H, CHH), 4.54-4.47 (m, 3 H, 3
CHH), 4.37 (d, J = 10.4 Hz, 1 H, CHH), 4.23 (d, J = 10.4 Hz, 1
H, CHH), 4.07 (t, J = 9.2 Hz, 1 H, H-3a), 3.98 (t, J = 9.2 Hz, 1 H,
H-4a), 3.87-3.61 (m, 10 H, H-3b, H-4b, H-5a, H-5b, H-6a, H-
6ba, OCH3), 3.54-3.44 (m, 2 H, H-6bb, H-1ºa), 3.35-3.29 (m, 3
H, H-2a, H-2b, H-1ºb), 2.38 (t, J = 7.6 Hz, 2H, H-5o), 1.73-1.63
(m, 4 H, H-2º, H-4º), 1.46-1.38 (m, 2 H, H-3º). 13C-APT (CDCl3,
100 MHz) δ 173.5 (C=O), 159.4, 138.2, 138.0, 137.84, 137.82,
136.2, 130.2 (aromatic C), 129.7, 128.7, 128.5, 128.4, 128.2,
128.1, 128.0, 127.9, 127.84, 127.78, 127.6, 127.4, 113.9
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The Journal of Organic Chemistry
Hz, 1 H, CH3). 13C-APT (CDCl3, 100 MHz) δ 138.4, 138.2,
5.11 (s, 2 H, PhCH2), 4.98 (d, J = 10.4 Hz, 1 H, CHH), 4.93 (d,
1
2
3
4
5
6
7
8
137.9, 137.6 (aromatic C), 128.62, 128.57, 128.5, 128.42,
128.37, 128.3, 128.0, 127.92, 127.89, 127.85, 127.8, 127.5,
127.4 (aromatic CH), 98.0 (C-1a), 96.2 (C-1b), 80.8 (C-3b),
77.6 (C-3a), 74.9, 74.5 (PhCH2), 74.0 (C-2a), 73.6, 73.2
(PhCH2), 72.9 (C-4b), 72.2 (PhCH2), 71.1 (C-4a), 70.2 (C-5b),
70.1 (C-5a), 69.5 (C-6), 68.5 (C-6), 63.6 (C-2b), 59.8 (C-1º),
23.4 (CH3), 21.7 (CH3). HRMS (ESI) m/z: [M+NH4]+
Calculated for C50H60O9N7: 902.44470, found: 902.44467.
J = 3.6 Hz, 1 H, H-1a), 4.89-4.82 (m, 3 H, 3 CHH), 4.55 (d, J =
12.0 Hz, 1 H, CHH), 4.51 (d, J = 12.0 Hz, 1 H, CHH), 4.08 (dd,
J1 = 8.8 Hz, J2 = 10.0 Hz, 1 H, H-3a), 3.99 (t, J = 8.8 Hz, 1 H, H-
4a), 3.86-3.65 (m, 7 H, H-3b, H-4b, H-5a, H-5b, H-6b, H-6aa),
3.53-3.44 (m, 2 H, H-6ab, H-1ºa), 3.40-3.33 (m, 2 H, H-2a, H-
1ºb), 3.24 (dd, J1 = 3.6 Hz, J2 = 10.0 Hz, 1 H, H-2b), 2.68 (bs, 1
H, OH), 2.38 (t, J = 7.6 Hz, 2H, H-5o), 1.73-1.64 (m, 4 H, H-2º,
H-4º), 1.47-1.39 (m, 2 H, H-3º). 13C-APT (CDCl3, 100 MHz) δ
173.56 (C=O), 138.23, 138.17, 137.8, 137.7, 136.2 (aromatic
C), 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0,
127.9, 127.83, 127.79, 127.6, 127.4 (aromatic CH), 97.7 (C-
1a), 97.6 (C-1b), 80.9 (C-3a), 79.7 (C-3b), 75.2, 74.5, 73.7,
73.4 (PhCH2), 73.1 (C-4b), 72.8 (c-4a), 70.6 (c-5b), 70.2 (C-
5a), 69.9 (C-6a), 69.0 (C-6b), 68.2 (C-1º), 66.3 (PhCH2), 63.8
(C-2a), 62.8 (C-2b), 34.3 (C-5º), 29.2 (C-2º), 25.8 (C-3º), 24.8
(C-4º). HRMS (ESI) m/z: [M+NH4]+ Calculated for
C53H64N7O11: 974.46583, found: 974.46576.
9
Synthesis of disaccharide 11: The reaction was carried out
according to the standard procedure A. A mixture of donor
3 (77 mg, 0.12 mmol), acceptor 7 (34 mg, 0.08 mmol) (do-
nors and acceptors co-evaporated with toluene three times),
MPF (156 μL) in dry DCM were stirred over fresh flame-
dried molecular sieves 3A under nitrogen. The solution was
cooled to -78 ℃, after which TfOH (8 μL) was added. After
30 min, the reaction was stirred at -10 ℃ until TLC-analysis
showed complete conversion of the acceptor. The reaction
was quenched with Et3N, filtered and concentrated in vacuo.
The product was purified by size exclusion (DCM:MeOH =
1:1). Compound 11 (62 mg, 80% yield, α:β = 4:1) was ob-
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
Synthesis of trisaccharide 13: The reaction was carried out
according to the standard procedure A. A mixture of donor
1 (160 mg, 0.24 mmol), acceptor 12 (150 mg, 0.16 mmol)
(donors and acceptors co-evaporated with toluene three
times), MPF (307 mL) in dry DCM (1.5 mL) were stirred
over fresh flame-dried molecular sieves 3A under nitrogen.
The solution was cooled to -78 ℃, after which TfOH (300 μL)
was added. After 30 min, the reaction was stirred at -10 ℃
until TLC-analysis showed complete conversion of the ac-
ceptor. The reaction was quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by size ex-
clusion (DCM:MeOH = 1:1). Compound 13 (186 mg, 81%
yield, α:β > 19:1, PE:EA = 4:1, Rf = 0.40) was obtained as a
20
tained as a colorless syrup. [α]D +85.8 (c=1, CHCl3). IR
(neat, cm-1) ν 697, 736, 986, 1037, 1117, 1209, 1261, 1454,
1
2106 (N3), 2870, 2925. H-NMR (CDCl3, 400 MHz) δ 7.43-
7.12 (m, 25 H, aromatic H), 5.05 (d, J = 3.6 Hz, 1 H, H-1a),
4.98 (d, J = 3.6 Hz, 1 H, H-1b), 4.88 (d, J = 12.0 Hz, 1 H, CHH),
4.80 (d, J = 10.8 Hz, 1 H, CHH), 4.72 (d, J = 11.2 Hz, 1 H, CHH),
4.63 (d, J = 11.2 Hz, 1 H, CHH), 4.54 (bd, 3 H,3 CHH), 4.47 (d,
J = 10.8 Hz, 1 H, CHH), 4.36 (dd, J = 5.2, 9.2 Hz, 1 H, H-5a),
4.28 (d, J = 2.8 Hz, 1 H, H-4a), 4.10 (s, 1 H, H-4b), 4.03-3.85
(m, 8 H, H-6ba, H-5b, H-3b, H-3a, H-2b, H-2a, H-1º), 3.60 (dd,
J = 3.6, 11.2 Hz, 1H, H-2a), 3.56-3.49 (m, 2 H, H-6bb, H-6aa),
3.14-3.09 (m, 2 H, H-6ab), 1.20 (d, J = 6.0 Hz, 1 H, CH3), 1.19
(d, J = 6.0 Hz, 1 H, CH3). 13C-APT (CDCl3, 100 MHz) δ 138.7,
138.0, 137.7, 137.6 (aromatic C), 128.64, 128.58, 128.55,
128.4, 128.3, 128.2, 128.12, 128.09, 128.0, 127.90, 127.87,
127.75, 127.74, 127.6, 127.3 (aromatic CH), 98.2 (C-1b),
96.8 (C-1a), 77.4 (C-3b), 75.9 (C-3a), 75.0, 73.7, 73.2
(PhCH2), 73.0 (C-4b), 72.9 (C-4a), 71.9, 71.9 (PhCH2), 71.0
(C-1º), 69.4 (C-5b), 69.2 (C-5a), 67.7 (C-6a), 67.2 (C-6b),
60.4 (C-2b), 59.5 (C-2a), 23.4 (CH3), 21.7 (CH3). HRMS (ESI)
m/z: [M+NH4]+ Calculated for C50H60O9N7: 902.44470, found:
902.44482.
20
colorless syrup. [α]D +75.8 (c=1, CHCl3). IR (neat, cm-1) ν
697, 736, 1029, 1147, 1249, 1359, 1454, 1514, 1734 (C=O),
1
2106 (N3), 2866, 2932. H-NMR (CDCl3, 400 MHz) δ 7.39-
7.21 (m, 35 H, aromatic H), 7.00 (bd, 2 H, aromatic H), 6.79
(bd, 2 H, aromatic H), 5.69 (d, J = 3.6 Hz, 1 H, H-1), 5.67 (d, J
= 3.6 Hz, 1 H, H-1), 5.11 (s, 2 H, PhCH2), 5.02-4.82 (m, 7 H, 6
CHH, H-1a), 4.66 (d, J = 10.0 Hz, 1 H, CHH), 4.56-4.46 (m, 3
H, 3 CHH), 4.39-4.33 (m, 2 H, 2 CHH), 4.26 (d, J = 12.0 Hz, 1
H, CHH), 4.18 (d, J = 12.0 Hz, 1 H, CHH), 4.14-3.98 (m, 4 H),
3.90-3.59 (m, 11 H), 3.56-3.44 (m, 3 H), 3.37-3.24 (m, 3 H),
2.38 (t, J = 7.6 Hz, 2H, H-5o), 1.73-1.63 (m, 4 H, H-2º, H-4º),
1.47-1.39 (m, 2 H, H-3º). 13C-APT (CDCl3, 100 MHz) δ 173.5
(C=O), 159.4, 138.3, 138.2, 138.0, 137.8, 137.7, 137.6, 136.1,
130.3 (aromatic C), 129.6, 128.6, 128.57, 128.55, 128.4,
128.3, 128.26, 128.1, 127.9, 127.86, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 113.8 (aromatic CH), 97.8, 97.7, 97.4 (C-
1a, 1b and 1c), 81.0, 80.7, 79.9 (C-3a, 3b and 3c), 77.7 (C-4c),
75.3, 74.7, 74.6, 74.2, 73.6, 73.5 (PhCH2), 73.0, 72.5 (C-4a
and 4b), 71.5, 71.1, 70.2 (c-5a, 5b and 5c), 68.9, 68.7 (2 C-6),
68.2 (C-1º), 67.7 (C-6), 66.2 (PhCH2), 63.9, 63.6, 63.1 (C-2a,
2b and 2c), 55.3 (OCH3), 34.2 (C-5º), 29.1 (C-2º), 25.7 (C-3º),
24.7 (C-4º). HRMS (ESI) m/z: [M+NH4]+ Calculated for
C81H93N10O16: 1461.67655, found: 1461.67594.
Synthesis of disaccharide 12: The reaction was carried out
according to the standard procedure C. Compound 8 (200
mg, 0.18 mmol) was dissolved in DCM:HFIP (1:1, 0.1 M). TES
(60 μL) and 0.2M HCl/HFIP (100 μL) were added to the mix-
ture. The reaction stirred until TLC-analysis indicated full
consumption of the starting material (30 min). Then the
mixture was diluted with DCM and the reaction quenched
with saturated NaHCO3. The organic phase was washed
with water and brine, dried with anhydrous MgSO4, filtered
and concentrated in vacuo. The product was purified by sil-
ica gel column chromatography (pentane:EA = 5:1, Rf =
0.22). Compound 12 (152 mg, 88% yield) was obtained as a
Synthesis of trisaccharide acceptor 14: The reaction was
carried out according to the standard procedure C. The
starting material 13 (320 mg, 0.22 mmol) was dissolved in
DCM:HFIP (1:1, 0.1 M). TES (71 μL) and 0.2M HCl/HFIP
(110 μL) were added to the mixture. The reaction stirred
20
colorless syrup. [α]D +62.9 (c=1, CHCl3). IR (neat, cm-1) ν
697, 736, 1029, 1043, 1146, 1261, 1454, 1734 (C=O), 2105
1
(N3), 2868, 2926, 3491. H-NMR (CDCl3, 400 MHz) δ 7.42-
7.20 (m, 25 H, aromatic H), 5.64 (d, J = 3.6 Hz, 1 H, H-1b),
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The Journal of Organic Chemistry
Page 10 of 15
until TLC-analysis indicated full consumption of the starting (PhCH2), 73.1 (C-4), 72.4 (C-4), 72.1 (C-4), 71.5, 71.2, 71.1,
1
2
3
4
5
6
7
8
material (15min). Then the mixture was diluted with DCM
and the reaction quenched with saturated NaHCO3. The or-
ganic phase was washed with water and brine, dried with
anhydrous MgSO4, filtered and concentrated in vacuo. The
product was purified by silica gel column chromatography
(pentane:EA = 4:1). Compound 14 (230 mg, 78% yield) was
70.2 (c-5a, 5b, 5c and 5d), 68.9, 68.6, 68.3 (3 C-6), 68.29 (C-
1º), 67.8 (C-6), 66.3 (PhCH2), 63.8, 63.7, 63.6, 63.2 (C-2a, 2b,
2c and 2d), 55.4 (OCH3), 34.3 (C-5º), 29.2 (C-2º), 25.8 (C-3º),
24.8 (C-4º).
Synthesis of N-phenyl trifluoroacetimidate 2-N3-galactose
donor 16:
20
obtained as a colorless syrup. [α]D +51.0 (c=3mg/mL,
CHCl3). IR (neat, cm-1) ν 697, 737, 1028, 1148, 1454, 1736
1
(C=O), 2106 (N3), 2866, 2926. H-NMR (CDCl3, 400 MHz) δ
9
7.42-7.17 (m, 35 H, aromatic H), 5.67-5.65 (m, 2 H, H-1b and
H-1c), 5.12 (s, 2 H, PhCH2), 5.01-4.85 (m, 7 H, 6 CHH, H-1a),
4.56 (d, J = 12.0 Hz, 1 H, CHH), 4.50 (d, J = 12.0 Hz, 1 H, CHH),
4.37-4.32 (m, 3 H, 3 CHH), 4.22 (d, J = 12.0 Hz, 1 H, CHH),
4.14-3.99 (m, 4 H), 3.87-3.62 (m, 8 H), 3.56-3.43 (m, 3 H),
3.37-3.30 (m, 4 H), 3.18 (dd, J1 = 3.6 Hz, J2 = 10.0 Hz, 1 H, H-
2c), 2.76 (bs, 1 H, OH), 2.39 (t, J = 7.6 Hz, 2H, H-5o), 1.74-1.64
(m, 4 H, H-2º, H-4º), 1.47-1.41 (m, 2 H, H-3º). 13C-APT (CDCl3,
100 MHz) δ 173.6 (C=O), 138.3, 138.20, 138.17, 137.8, 137.6,
137.5, 136.2 (aromatic C), 138.7, 128.7, 128.6, 128.55, 128.5,
128.4, 128.3, 128.13, 128.09, 128.0, 127.95, 127.9, 127.8,
127.7, 127.5, 127.48, 127.3 (aromatic CH), 97.8, 97.7, 97.4
(C-1a, 1b and 1c), 81.1, 80.8, 79.1 (C-3a, 3b and 3c), 75.0,
74.6, 74.3, 73.7, 73.5, 73.4 (PhCH2), 73.0, 72.9, 72.3 (C-4a, 4b
and 4c), 71.1, 70.3, 70.2 (c-5a, 5b and 5c), 70.0, 68.9, 68.6
(C-6a, 6b and 6c), 68.3 (C-1º), 66.26 (PhCH2), 63.9, 63.7,
62.5 (C-2a, 2b and 2c), 34.3 (C-5º), 29.2 (C-2º), 25.8 (C-3º),
24.8 (C-4º). HRMS (ESI) m/z: Calculated for C73H85N10O15:
1341.61904, found: 1341.61923.
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
NIS (9.15 g, 40.68 mmol) was added to the solution of com-
pound S3 (18 g, 31.3 mmol) in Acetone/H2O (210 ml/72ml)
at 0 oC. The reaction was slowly warmed to room tempera-
ture and stirred until TLC-analysis indicated full consump-
tion of the starting material (± 1h). Then the mixture was
diluted with DCM and washed with saturated Na2S2O3 and
brine, dried with anhydrous MgSO4, filtered and concen-
trated in vacuo. The lactol was purified by silica gel column
chromatography (pentane:EA = 4:1). Cs2CO3 was added to
the solution of The lactol (10.59g, 24.33 mmol) in 140 ml
acetone. The mixture was stirred at 0 oC for 15 minutes.
Then CF3C(=NPh)Cl (6.06 g, 29.2 mmol) was added to the
solution. which was slowly warmed to room temperature
and stirred overnight. The reaction was quenched with Et3N
and concentrated in vacuo. The product 16 was purified by
silica gel column chromatography (pentane:Et2O = 30:1 –
10:1). Compound 16 (13.3 g, a/b = 2:1, 90% yield, PE: Et2O
= 10:1, Rf = 0.45-0.55) was obtained as white solid. α isomer:
1H-NMR (CDCl3, 400 MHz) δ 7.50 – 7.24 (m, 7H, aromatic H),
7.15 – 7.05 (m, 1H, aromatic H), 6.84 (d, J = 7.7 Hz, 2H, aro-
matic H), 6.47 (bs, 1H, H-1), 4.78 (d, J = 11.4 Hz, 1H, CH2Ph),
4.69 (d, J = 11.4 Hz, 1H, CH2Ph), 4.63 (s, 1H, H-4), 4.22 (q, J =
12.8 Hz, 2H. H-6), 4.10 (t, J = 6.3 Hz, 1H, H-2), 3.89 (d, J = 9.5
Synthesis of tetrasaccharide 15: The reaction was carried
out according to the standard procedure A. A mixture of do-
nor 1 (40 mg, 0.06 mmol), acceptor 14 (35 mg, 0.03 mmol)
(donors and acceptors co-evaporated with toluene three
times), MPF (52 μL) in dry DCM (0.3 mL) were stirred over
fresh flame-dried molecular sieves 3A under nitrogen. The
solution was cooled to -78 ℃, after which TfOH (5 μL) was
added. After 30 min, the reaction was stirred at -10 ℃ until
TLC-analysis showed complete conversion of the acceptor.
The reaction was quenched with Et3N, filtered and concen-
trated in vacuo. The product was purified by size exclusion
(DCM:MeOH = 1:1). Compound 15 (43 mg, 87% yield, α:β >
Hz, 1H, H-3), 3.76 (s, 1H, H-5), 1.09-1.02 (m, 18H, CH3). 13
C
NMR (100 MHz, CDCl3) δ 143.29, 137.45, 128.74, 128.56,
128.01, 127.91, 124.40, 119.35 (aromatic C/CH), 94.73 (C-
1), 76.04 (C-3), 70.71 (CH2Ph), 69.89 (C-5), 69.16 (C-4),
66.76 (C-6), 57.71 (C-2), 27.59 (CH3), 27.23 (CH3), 23.38 (C-
Si), 20.73 (C-Si). β isomer: 1H-NMR (CDCl3, 400 MHz) δ 7.48
– 7.25 (m, 7H, aromatic H), 7.14 – 7.04 (m, 1H, aromatic H),
6.85 (d, J = 7.7 Hz, 2H, aromatic H), 5.50 (bs, 1H, H-1), 4.77
(d, J = 11.9 Hz, 1H, CH2Ph), 4.66 (d, J = 11.9 Hz, 1H, CH2Ph),
4.43 (s, 1H, H-5), 4.19 (s, 2H, H-6), 4.02 (s, 1H, H-4), 3.30 (s,
2H, H-2, 3), 1.15 – 1.00 (m, 18H, CH3). 13C NMR (100 MHz,
CDCl3) δ 143.5, 137.5, 128.8, 128.7, 128.2, 128.0, 124.5,
119.4 (aromatic C/CH), 95.8 (C-1), 79.6 (C-3), 72.2 (C-2),
71.0 (CH2Ph), 68.6 (C-5), 66.8 (C-6), 60.8 (C-4), 27.7 (CH3),
27.4 (CH3), 23.6 (C-Si), 20.9 (C-Si). HRMS (ESI) m/z:
[M+NH4]+ Calculated for C21H37N3O5Si: 629.2383, found:
629.2376.
20
20:1) was obtained as a colorless syrup. [α]D +94.8 (c=1,
CHCl3). IR (neat, cm-1) ν 697, 737, 1029, 1148, 1251, 1359,
1
1454, 1514, 1735 (C=O), 2106 (N3), 2868, 2928. H-NMR
(CDCl3, 400 MHz) δ 7.42-7.15 (m, 45 H, aromatic H), 7.00 (bd,
2 H, aromatic H), 6.79 (bd, 2 H, aromatic H), 5.70-5.67 (m, 3
H, H-1b, 1c, 1d), 5.11 (s, 2 H, PhCH2), 5.02-4.87 (m, 8 H, 7
CHH, H-1a), 4.81 (d, J = 10.4 Hz, 1 H, CHH), 4.66 (d, J = 10.4
Hz, 1 H, CHH), 4.54 (s, 2 H, PhCH2), 4.65 (d, J = 12.0 Hz, 1 H,
CHH), 4.38-4.28 (m, 4 H, 4 CHH), 4.22-4.00 (m, 8 H), 3.90-
3.59 (m, 15 H), 3.52-3.44 (m, 3 H), 3.39-3.34 (m, 7 H), 2.38
(t, J = 7.6 Hz, 2H, H-5o), 1.73-1.64 (m, 4 H, H-2º, H-4º), 1.47-
1.38 (m, 2 H, H-3º). 13C-APT (CDCl3, 100 MHz) δ 173.5 (C=O),
159.4, 138.3, 138.2, 138.0, 137.84, 137.78, 137.6, 136.2,
130.3 (aromatic C), 129.7, 128.7, 128.65, 128.61, 128.59,
128.48, 128.45, 128.4, 128.33, 128.30, 128.2, 128.02,
127.98, 127.93, 127.87, 127.8, 127.74, 127.71, 127.6, 127.5,
127.4, 127.3, 113.9 (aromatic CH), 97.9, 97.8, 97.5, 97.48 (C-
1a, 1b, 1c and 1d), 81.0, 80.9, 80.8, 80.0 (C-3a, 3b, 3c and 3d),
77.8 (C-4), 75.3, 74.7, 74.4, 74.3, 73.6, 73.6, 73.54, 73.51
Synthesis of disaccharide 18: Donor 16 (5 g, 8.2 mmol) and
acceptor 17 (3.32 g, 6.95 mmol) (donors and acceptors co-
evaporated with toluene three times) were dissolved in
o
DCM (65 mL), cooled to 0 C and TfOH (60 μL) was added.
The reaction was stirred at 0 ℃ until TLC-analysis showed
complete conversion of the donor. The reaction was
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The Journal of Organic Chemistry
quenched with Et3N after completed checking by TLC, fil-
[M+NH4]+ Calculated for C46H52N7O8S: 862.35926, found:
862.35895.
1
2
3
4
5
6
7
8
tered and concentrated in vacuo. The product 16 was puri-
fied by silica gel column chromatography (pentane:Et2O =
10:1). Compound 18 (4.36g, 70% yield) was obtained with
Synthesis of thio-disaccharide 21: The compound 20 (3.83
g, 4.53 mmol) was dissloved in DMF (10 mL). Then NaH
(544 mg) and NapBr (1.5 g) were added in the mixture. The
reaction stirred until TLC-analysis indicated full consump-
tion of the starting material (2 h). Then the mixture was di-
luted with ethyl acetate and the reaction quenched with ice
water. The organic phase was washed with water and brine,
dried with anhydrous MgSO4, filtered and concentrated in
vacuo. The product was purified by silica gel column chro-
matography (pentane:Et2O = 10:1). Compound 21 (4.15 g,
93% yield) was obtained as a colorless syrup. [α]D20 +208.6
(c=1, CHCl3). IR (neat, cm-1) ν 697, 737, 1028, 1049, 1093,
20
full α-selectivity as a colorless syrup. [α]D +153.3 (c=1,
CHCl3). IR (neat, cm-1) ν 651, 698, 738, 797, 826, 984, 1043,
1
1066, 1100, 1171, 1364, 1473, 2107 (N3), 2859, 2933. H-
NMR (CDCl3, 400 MHz) δ 7.53-7.51 (m, 2 H, aromatic H),
7.44-7.22 (m, 18 H, aromatic H), 5.64 (d, J = 3.6 Hz, 1 H, H-
1b), 5.59 (d, J = 5.2 Hz, 1 H, H-1a), 5.00 (d, J = 10.4 Hz, 1 H,
CHH), 4.91 (d, J = 10.4 Hz, 1 H, CHH), 4.73 (d, J = 11.6 Hz, 1
H, CHH), 4.63 (d, J = 11.6 Hz, 1 H, CHH), 4.43-4.37 (m, 4 H, 2
CHH, H-4b, H-5a), 3.96-3.77 (m, 6 H, H-2a, H-2b, H-3a, H-4a,
H-6), 3.72-3.64 (m, 2 H, H-3b, H-6a), 3.53 (dd, J1 = 2.0 Hz, J2
= 10.8 Hz, 1 H, H-6b), 3.42 (s, 1 H, H-5b), 1.03 (s, 9 H, 3 CH3),
0.97 (s, 9 H, 3 CH3). 13C-APT (CDCl3, 100 MHz) δ 137.9, 137.8,
137.4, 133.5 (aromatic C), 132.1, 129.2, 128.62, 128.58,
128.51, 128.48, 128.00. 127.98, 127.8, 127.5 (aromatic CH),
97.7 (C-1b), 87.1 (C-1a), 82.3 (C-3a), 75.5 (C-3b), 75.0, 73.3
(PhCH2), 72.8 (c-4a), 71.3 (c-5a), 70.5 (PhCH2), 69.6 (C-4b),
68.9 (C-6), 68.0 (C-5b), 66.9 (C-6), 64.6 (C-2a), 58.1 (C-2b),
27.7 (3 CH3), 27.3 (3 CH3), 23.4, 20.7. HRMS (ESI) m/z:
[M+NH4]+ Calculated for C47H62N7O8SSi: 912.41444, found:
912.41409.
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
1
1123, 1362, 1454, 2106 (N3), 2870. 2914. H-NMR (CDCl3,
400 MHz) δ 7.80-7.11 (m, 32 H, aromatic H), 5.64 (d, J = 3.6
Hz, 1 H, H-1b), 5.59 (d, J = 5.2 Hz, 1 H, H-1a), 5.01-4.89 (m, 3
H, 3 CHH), 4.70-4.62 (m, 3 H, 3 CHH), 4.50 (d, J = 12.0 Hz, 1
H, CHH), 4.44-4.40 (m, 2 H, CHH, 5b), 4.27 (d, J = 11.6 Hz, 1
H, CHH), 4.17 (d, J = 11.6 Hz, 1 H, CHH), 4.04 (s, 1 H, H-4b),
3.97-3.81 (m, 6 H, H-2a, H-2b, H-3a, H-3b, H-4a, H-5a), 3.77-
3.65 (m, 2 H, H-6), 3.51-3.40 (m, 2 H, H-6). 13C-APT (CDCl3,
100 MHz) δ 138.3, 137.8, 137.60, 137.58, 135.6, 133.6,
133.2, 133.1 (aromatic C), 133.08, 129.2, 128.7, 128.6, 128.5,
128.4, 128.3, 128.1, 127.99, 127.97, 127.93, 127.80, 127.6,
127.4, 127.2, 126.5, 126.2, 126.1 (aromatic CH), 98.3 (C-1b),
87.1 (C-1a), 82.2 (C-3a), 77.5 (C-3b), 75.2, 74.9 (PhCH2),
74.1 (c-4a), 73.6, 73.1 (PhCH2), 72.8 (C-4b), 72.3 (PhCH2),
71.3 (C-5b), 70.4 (C-5a), 69.4 (C-6), 68.6 (C-6), 64.8 (C-2a),
69.8 (C-2b). HRMS (ESI) m/z: [M+NH4]+ Calculated for
C57H60N7O8S: 1002.42186, found: 1002.42125.
Synthesis of disaccharide 20: Compound 18 (4.1 g, 4.6
mmol) was dissoveld in THF (40 mL) in a round flusk. Then
HF-pyridine (1.2 mL) was added in the solution. The reac-
tion stirred until TLC-analysis indicated full consumption of
the starting material (30 min). Then the mixture was diluted
with DCM and the reaction quenched with saturated Na-
HCO3. The organic phase was washed with water and brine,
dried with anhydrous MgSO4, filtered and concentrated in
vacuo. The crude compound 19 was dissloved in CH3CN (47
mL). Then BnBr (880 μL), borinic acid-catalyzed (110 mg),
K2CO3 (710 mg), KI (800 mg) were added in the mixture.
N-phenyl trifluoroacetimidate disaccharide donor 23: Com-
pound 21 (4.15 g, 4.21 mmol) was dissolved in acetone:H2O
(10:1, 44 mL). N-Iodosuccinimide (NIS) (2.0 g, 8.8 mmol)
was added in one portion and the reaction was stirred at
room temperature for 2 hours. The solution was diluted
with DCM and the reaction was quenched with saturated
aqueous Na2S2O3. Then the organic layer was washed with
water and brine. The organic layer was dried with anhy-
drous MgSO4, filtered and concentrated in vacuo, and the
product purified by column chromatography (pentane:EA =
3:1). The lactol 22 was obtained as colourless syrup. Next,
the lactol was dissolved in acetone (40 mL). Cs2CO3 (1.9 g)
and 2,2,2-trifluoro-N-phenylacetimidoyl chloride (960 μL)
were added to the solution respectively. The reaction was
stirred overnight, then quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by column
chromatography (pentane:EA = 40:1-20:1). Compound 23
(3.7 g, 81% over two steps) was obtained as yellow syrup.
IR (neat, cm-1) ν 695, 734, 818, 1027, 1116, 1209, 1312,
1454, 1489, 1497, 1717, 2107, 2870, 2918. 1H-NMR (CDCl3,
500 MHz) δ 7.80-7.09 (m, aromatic H), 6.81 (bt, 1 H), 5.65
(dd, 1 H), 5.01-4.87 (m), 4.68-4.54 (m), 4.45-4.42 (m), 4.33-
4.18 (m), 4.03-3.41 (m). 13 C-APT (CDCl3, 125 MHz) δ 143.4,
143.2, 138.20, 138.18, 137.8, 137.6, 137.55, 137.5, 135.6,
133.3, 133.2 (aromatic C), 128.9, 128.7, 128.53, 128.52,
128.44, 128.43, 128.3, 128.08, 128.05, 128.0, 127.97, 127.9,
127.84, 127.81, 127.69, 127.66, 127.65, 127.6, 127.2,
127.17, 124.7, 124.6 (aromatic CH), 119.4 (C-1), 98.3 (C-1),
o
The reaction stirred at 60 C in oil bath until TLC-analysis
indicated full consumption of the starting material (24 h).
Then the mixture was diluted with ethyl acetate and the re-
action quenched with saturated NaHCO3. The organic phase
was washed with water and brine, dried with anhydrous
MgSO4, filtered and concentrated in vacuo. The product was
purified by silica gel column chromatography (pen-
tane:Et2O = 5:1). Compound 20 (3.6 g, 94% yield with two
steps) was obtained as a colorless syrup. [α]D20 +11.7 (c=1,
CHCl3). IR (neat, cm-1) ν 697, 737, 1029, 1046, 1077, 1266,
1
2106 (N3), 2870, 2919, 3493. H-NMR (CDCl3, 400 MHz) δ
7.54-7.51 (m, 2 H, aromatic H), 7.41-7.23 (m, 23 H, aromatic
H), 5.61 (d, J = 3.6 Hz, 1 H, H-1b), 5.60 (d, J = 5.2 Hz, 1 H, H-
1a), 5.00 (d, J = 10.4 Hz, 1 H, CHH), 4.94 (d, J = 10.4 Hz, 1 H,
CHH), 4.66 (s, 2 H, PhCH2), 4.50-4.37 (m, 3 H, 2 CHH, 5a),
4.08 (s, 1 H, H-4b), 3.97-3.91 (m, 2 H, H-2b, H-4a), 3.85-3.37
(m, 5 H), 3.66 (dd, J1 = 2.4 Hz, J2 = 10.8 Hz, 1 H, H-6b), 3.59
(dd, J1 = 5.6 Hz, J2 = 9.6 Hz, 1 H), 3.51 (dd, J1 = 5.6 Hz, J2 = 9.6
Hz, 1 H), 2.63 (s, 1 H, OH). 13C-APT (CDCl3, 100 MHz) δ 138.3,
137.8, 137.6, 137.2, 133.5 (aromatic C), 132.3, 128.8, 128.6,
128.5, 128.4, 128.3, 128.1, 128.o, 127.9, 127.86, 127.85,
127.6, 127.55 (aromatic CH), 98.2 (C-1b), 87.1 (C-1a), 82.1
(C-3a), 76.3 (C-3b), 75.1 (PhCH2), 74.4 (c-4a), 73.8, 73.2,
71.8 (PhCH2), 71.3 (c-5a), 69.5 (C-6), 69.4 (C-6), 69.3 (C-5b),
66.5 (C-4b), 64.8 (C-2b), 59.0 (C-2a). HRMS (ESI) m/z:
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Page 12 of 15
98.2 (C-1), 83.6, 81.0, 77.6, 77.3, 75.5, 75.18, 75.16, 75.0, 173.60 (C=O), 138.1, 137.80, 137.1, 136.1 (aromatic C),
1
2
3
4
5
6
7
8
74.9, 73.64, 73.60, 73.30, 73.2, 73.1, 73.0, 72.8, 72.7, 72.3,
72.2, 70.4, 70.3, 69.0, 68.5, 65.8, 63.7, 59.7, 59.6. HRMS (ESI)
128.8, 128.7, 128.6, 128.5, 128.4, 128.31, 128.29, 128.1,
127.9, 127.8, 127.7 (aromatic CH), 97.9 (C-1b), 97.7 (C-1a),
80.8 (C-3a), 76.1 (C-3b), 74.5 (PhCH2), 73.8 (c-4a), 73.7
(PhCH2), 71.9 (PhCH2), 70.3 (c-5b), 70.2 (C-5a), 69.7 (C-6),
68.3 (C-1º), 67.2 (C-4b), 66.3 (PhCH2), 63.8 (C-2a), 62.9 (C-
6), 58.8 (C-2b), 34.3 (C-5º), 29.2 (C-2º), 25.8 (C-3º), 24.8 (C-
4º). HRMS (ESI) m/z: [M+NH4]+ Calculated for C46H60N7O11:
884.41888, found: 884.41942.
m/z:
[M-[O(C=NPh)CF3]+OH+Na]+
Calculated
for
C59H56F3N7O9Na: 910.41340, found: 910.41374.
Synthesis of disaccharide 24: Donor 16 (1.09 g) and
acceptor 4 (790 mg) (donors and acceptors co-evaporated
with toluene three times) were dissolved in DCM (12 mL),
o
cooled to 0 C and TfOH (12 μL) was added. The reaction
9
Synthesis of disaccharide acceptor 26: The compound 25
(865 mg, 1.0 mmol) was dissloved in CH3CN (10 mL). Then
BnBr (182 μL), borinic acid-catalyzed (22 mg), K2CO3 (148
mg), KI (166 mg), were added in the mixture. The reaction
was stirred at 0 ℃ until TLC-analysis showed complete con-
version of the donor. The reaction was quenched with Et3N
after completed checking by TLC, filtered and concentrated
in vacuo. The product was purified by size exclusion
(DCM:MeOH = 1:1). Compound 24 (1.24 g, 92% yield) was
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
o
stirred at 60 C in oil bath until TLC-analysis indicated full
20
consumption of the starting material (24 h). Then the mix-
ture was diluted with ethyl acetate and the reaction
quenched with saturated NaHCO3. The organic phase was
washed with water and brine, dried with anhydrous MgSO4,
filtered and concentrated in vacuo. The product was puri-
fied by silica gel column chromatography (pentane:Et2O =
5:1). Compound 26 (910 mg, 95%) was obtained as a color-
obtained with full α-selectivity as a colorless syrup. [α]D
+95.9 (c=1, CHCl3). IR (neat, cm-1) ν 651, 698, 737, 765, 797,
826, 984, 1004, 1040, 1130, 1144, 1171, 1455, 1474, 1735
1
(C=O), 2106 (N3), 2860, 2933. H-NMR (CDCl3, 400 MHz) δ
7.44-7.24 (m, 20 H, aromatic H), 5.67 (d, J = 3.6 Hz, 1 H, H-
1b), 5.12 (s, 2 H, PhCH2), 4.96 (d, J = 10.4 Hz, 1 H, CHH), 4.92
(d, J = 3.6 Hz, 1 H, H-1a), 4.86 (d, J = 10.4 Hz, 1 H, CHH), 4.71
(d, J = 11.6 Hz, 1 H, CHH), 4.61 (d, J = 11.6 Hz, 1 H, CHH), 4.48
(s, 2 H, PhCH2), 4.36 (d, J = 2.0 Hz, 1 H, H-4b), 4.06 (dd, J1 =
10 Hz, J2 = 8.4 Hz, 1 H, H-3a), 3.91-3.78 (m, 4 H), 3.74-3.45
(m, 6 H), 3.34-3.30 (m, 2 H, H-2a, H-1ºb), 2.39 (t, J = 7.6 Hz,
2H, H-5o), 1.74-1.64 (m, 4 H, H-2º, H-4º), 1.48-1.42 (m, 2 H,
H-3º), 1.03 (s, 9 H, 3 CH3), 0.95 (s, 9 H, 3 CH3). 13C-APT (CDCl3,
100 MHz) δ 173.5 (C=O), 138.0, 137.9, 137.7, 136.2
(aromatic C), 128.7, 128.6, 128.3, 128.0, 127.96, 127.9,
127.86, 127.6 (aromatic CH), 97.9 (C-1b), 97.5 (C-1a), 81.0
(C-3a), 75.5 (C-3b), 74.3, 73.5 (PhCH2), 72.4 (c-4a), 70.5
(PhCH2), 70.1 (c-5a), 69.6 (C-4b), 69.1 (C-6), 68.3 (C-1º),
67.9 (C-5b), 66.9 (C-6), 66.3 (PhCH2), 63.6 (C-2a), 58.1 (C-
2b), 34.3 (C-5º), 29.2 (C-2º), 27.7 (3 CH3), 27.3 (3 CH3), 25.8
(C-3º), 24.8 (C-4º), 23.4, 20.7. HRMS (ESI) m/z: [M+NH4]+
Calculated for C54H74N7O11Si: 1024.52101, found:
1024.52157.
20
less syrup. [α]D +66.6 (c=1, CHCl3). IR (neat, cm-1) ν 697,
736, 1040, 1096, 1259, 1455, 1734 (C=O), 2106 (N3), 2869,
2928. 1H-NMR (CDCl3, 400 MHz) δ 7.40-7.21 (m, 25 H,
aromatic H), 5.64 (d, J = 3.6 Hz, 1 H, H-1b), 5.11 (s, 1 H,
PhCH2), 4.96 (d, J = 10.4 Hz, 1 H, CHH), 4.91 (d, J = 3.6 Hz, 1
H, H-1a), 4.88 (d, J = 10.4 Hz, 1 H, CHH), 4.63 (bs, 2 H, 2 CHH),
4.55 (d, J = 12.0 Hz, 1 H, CHH), 4.45 (d, J = 12.0 Hz, 1 H, CHH),
4.47-4.36 (m, 3 H, 3 CHH), 4.07-4.03 (m, 2 H, H-3a, H-5a),
3.91-3.44 (m, 12 H), 3.32 (dd, J1 = 11.2 Hz, J2 = 3.6 Hz, 1 H, H-
2a), 2.65 (s, 1 H, OH), 2.38 (t, J = 7.6 Hz, 2H, H-5o), 1.73-1.63
(m, 4 H, H-2º, H-4º), 1.47-1.39 (m, 2 H, H-3º). 13C-APT (CDCl3,
100 MHz) δ 173.5 (C=O), 138.3, 137.8, 137.3, 136.1
(aromatic C), 129.1, 128.7, 128.65, 128.54, 128.50, 128.4,
128.3, 128.0, 127.9, 127.8, 127.6, 127.6, 127.3 (aromatic
CH), 97.9 (C-1b), 97.7 (C-1a), 80.8 (C-3a), 76.3 (C-3b), 74.5
(PhCH2), 73.9 (C-4a), 73.8, 73.3, 71.7 (PhCH2), 70.1 (C-4b),
69.5, 69.4 (C-6), 69.2 (C-5b), 68.2 (C-1º), 66.4 (C-5a), 66.2
(PhCH2), 63.7 (C-2a), 58.9 (C-2b), 34.2 (C-5º), 29.1 (C-2º),
25.7 (C-3º), 24.8 (C-4º). HRMS (ESI) m/z: [M+NH4]+
Calculated for C53H64N7O11: 974.46583, found: 974.46660.
Synthesis of disaccharide 25: Compound 24 (1.16 g, 1.15
mmol) was dissoveld in THF (11 mL) in a round flusk. Then
HF-pyridine (300 μL) was added in the solution. The reac-
tion stirred until TLC-analysis indicated full consumption of
the starting material (30 min). Then the mixture was diluted
with DCM and the reaction quenched with saturated Na-
HCO3. The organic phase was washed with water and brine,
dried with anhydrous MgSO4, filtered and concentrated in
vacuo. The product was purified by silica gel column chro-
matography (pentane:Et2O = 3:1). Compound 25 (910 mg,
Synthesis of tetrasaccharide 27: The reaction was carried
out according to the standard procedure A. A mixture of do-
nor 23 (520 mg, 0.49 mmol), acceptor 26 (238 mg, 0.25
mmol) (donors and acceptors co-evaporated with toluene
three times), MPF (490 μL) in dry DCM (1 mL) were stirred
over fresh flame-dried molecular sieves 3A under nitrogen.
The solution was cooled to -78 ℃, after which TfOH (40 μL)
was added. After 30 min, the reaction was stirred at -10 ℃
until TLC-analysis showed complete conversion of the ac-
ceptor. The reaction was quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by size ex-
clusion (DCM:MeOH = 1:1). Compound 27 (280 mg, 89%,
α:β = 10:1) was obtained as a colorless syrup. IR (neat, cm-
1) ν 697, 736, 1028, 1096, 1258, 1319, 1356, 1454, 1497,
1731 (C=O), 2105 (N3), 2868, 2925. 1H-NMR (CDCl3, 400
MHz) δ 7.77-7.69 (m, 3 H, aromatic H), 7.60 (bs, 1 H,
aromatic H), 7.42-7.17 (m, 48 H, aromatic H), 5.73 (d, J = 3.6
Hz, 1 H, H-1d), 5.65 (d, J = 3.6 Hz, 1 H, H-1b), 5.10 (s, 1 H,
20
91% yield) was obtained as a colorless syrup. [α]D +80.6
(c=1, CHCl3). IR (neat, cm-1) ν 698, 738, 1040, 1145, 1262,
1
1354, 1455, 1733 (C=O), 2106 (N3), 2872, 2932, 3461. H-
NMR (CDCl3, 400 MHz) δ 7.38-7.25 (m, 20 H, aromatic H),
5.65 (d, J = 3.6 Hz, 1 H, H-1b), 5.12 (s, 1 H, PhCH2), 4.97 (d, J
= 10.4 Hz, 1 H, CHH), 4.92 (d, J = 3.6 Hz, 1 H, H-1a), 4.88 (d, J
= 10.4 Hz, 1 H, CHH), 4.67-4.54 (m, 4 H, 4 CHH), 4.05 (dd, J1
= 10.0 Hz, J2 = 8.4 Hz, 1 H, H-3a), 3.91-3.80 (m, 2 H, H-4a, H-
5), 3.74-3.57 (m, 8 H), 3.51-3.44 (m, 1 H, H-1ºb), 3.31 (dd, J1
= 10.0 Hz, J2 = 3.6 Hz, 1 H, H-2a), 2.65 (s, 1 H, OH), 2.39 (t, J
= 7.6 Hz, 2H, H-5o), 2.29 (s, 1 H, OH), 1.74-1.64 (m, 4 H, H-2º,
H-4º), 1.47-1.40 (m, 2 H, H-3º). 13C-APT (CDCl3, 100 MHz) δ
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PhCH2), 4.96-4.90 (m, 7 H), 4.74-4.48 (m, 7 H), 4.36-3.61 (m, fresh flame-dried molecular sieves 3A under nitrogen. The
1
2
3
4
5
6
7
8
22 H), 3.51-3.26 (m, 6 H), 3.20 (d, J = 10.0 Hz, 1 H), 3.03 (d,
J = 10.0 Hz, 1 H), 2.36 (t, J = 7.6 Hz, 2H, H-5o), 1.71-1.61 (m,
4 H, H-2º, H-4º), 1.45-1.37 (m, 2 H, H-3º). 13C-APT (CDCl3,
100 MHz) δ 173.4 (C=O), 138.4, 138.2, 137.7, 137.68, 137.6,
137.54, 137.47, 136.1, 135.6, 133.1, 133.0 (aromatic C),
128.6, 128.5, 128.4, 128.38, 128.35, 128.27, 128.25, 128.2,
128.1, 128.07, 128.0, 127.9, 127.88, 127.86, 127.78, 127.76,
127.66, 127.6, 127.4, 127.3, 127.1, 127.0, 126.4, 126.0,
125.9 (aromatic CH), 98.7 (C-1), 98.1 (C-1), 97.8 (C-1), 97.7
(C-1), 81.0 (C-3), 80.7 (C-3), 76.8 (C-3), 75.1 (C-3), 74.9, 74.5,
74.4 (CH2), 73.5 (C-4), 73.5, 73.3 (CH2), 73.2 (C-4), 72.9 (C-
4), 72.8 (C-4), 72.8, 72.2, 71.7 (CH2), 70.6 (C-5), 70.1 (C-5),
69.9 (C-5), 69.8 (C-5), 69.2, 68.4, 68.1, 67.9, 66.8, 66.1 (CH2),
64.7 (C-2), 63.7 (C-2), 59.5 (C-2), 59.4 (C-2), 34.1 (C-5º),
29.0 (C-2º), 25.6 (C-3º), 24.7 (C-4º). HRMS (ESI) m/z:
[M+NH4]+ Calculated for C104H114N13O19: 1848.83484, found:
1848.83541.
solution was cooled to -78 ℃, after which TfOH (44 μL) was
added. After 30 min, the reaction was stirred at -10 ℃ until
TLC-analysis showed complete conversion of the acceptor
(48 h). The reaction was quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by size ex-
clusion (DCM:MeOH = 1:1). Compound 29 (500 mg, 91%,
α:β = 10:1) was obtained as a colorless syrup. [α]D20 +123.0
(c=1, CHCl3). IR (neat, cm-1) ν 697, 736, 1039, 1099, 1261,
1
1319, 1359, 1454, 1734 (C=O), 2106 (N3), 2870, 2926. H-
9
NMR (CDCl3, 400 MHz) δ 7.77-7.69 (m, 3 H, aromatic H),
7.60 (bs, 1 H, aromatic H), 7.44-7.07 (m, 68 H, aromatic H),
5.73 (d, J = 3.6 Hz, 1 H, H-1), 5.71 (d, J = 3.2 Hz, 1 H, H-1),
5.65 (d, J = 3.6 Hz, 1 H, H-1), 5.09 (s, 1 H, PhCH2), 4.96-4.91
(m, 9 H), 4.77-4.65 (m, 5 H), 4.58-4.48 (m, 4 H), 4.33-3.62
(m, 37 H), 3.52-3.16 (m, 10 H), 3.05 (d, J = 10.0 Hz, 1 H), 2.99
(d, J = 10.0 Hz, 1 H), 2.36 (t, J = 7.6 Hz, 2H, H-5o), 1.71-1.61
(m, 4 H, H-2º, H-4º), 1.45-1.37 (m, 2 H, H-3º). 13C-APT (CDCl3,
100 MHz) δ 173.4 (C=O), 138.5, 138.4, 138.2, 137.7, 137.7,
137.6, 137.59, 137.57, 137.5, 137.4, 136.1, 135.7, 133.2,
133.0 (aromatic C), 128.6, 128.5, 128.49, 128.48, 128.45,
128.39, 128.36, 128.3, 128.2, 128.1, 128.05, 128.1, 128.0,
127.94, 127.90, 127.86, 127.82, 127.78, 127.77, 127.72,
127.67, 127.6, 127.42, 127.35, 127.3, 127.12, 127.11,
127.03, 127.0, 126.4, 126.0, 125.9 (aromatic CH), 98.8 (C-1),
98.7 (C-1), 98.1 (C-1), 97.9 (C-1), 97.8 (C-1), 97.7 (C-1), 80.9
(C-3), 80.8 (C-3), 80.7 (C-3), 76.9 (C-3), 76.1 (C-3), 75.7 (C-
3), 74.9, 74.5, 74.4, 73.5, 73.3 (CH2), 73.3 (C-4), 73.2 (C-4),
73.0 (CH2), 72.83 (C-4), 72.80 (CH2), 72.7 (C-4), 72.2, 71.9,
71.7 (CH2), 70.6 (C-5), 70.5 (C-5), 70.1 (C-5), 69.9 (C-5), 69.8
(C-5), 69.6 (C-5), 69.2, 68.3, 68.1, 67.9, 66.8, 66.5, 66.1 (CH2),
64.7 (2 C-2), 63.7 (C-2), 59.5 (C-2), 59.47 (C-2), 59.4 (C-2),
34.2 (C-5º), 29.1 (C-2º), 2575 (C-3º), 24.7 (C-4º).
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
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53
54
55
56
57
58
59
60
Synthesis of tetrasaccharide acceptor 28: The reaction was
carried out according to the standard procedure C. Com-
pound 27 (700 mg, 0.38 mmol) was dissolved in DCM:HFIP
(1:1, 0.1 M). TES (304 μL, 1.91 mmol) and 0.2M HCl/HFIP
(1.9 mL) were added to the mixture. The reaction stirred
until TLC-analysis indicated full consumption of the starting
material (15min). Then the mixture was diluted with DCM
and the reaction quenched with saturated NaHCO3. The or-
ganic phase was washed with water and brine, dried with
anhydrous MgSO4, filtered and concentrated in vacuo. The
product was purified by silica gel column chromatography
(pentane:Et2O = 5:1). Compound 28 (297mg, 73% yield)
was obtained as a colorless syrup. [α]D20 +106.7 (c=1, CHCl3).
IR (neat, cm-1) ν 696, 737, 1040, 1100, 1261, 1454, 1735
1
(C=O), 2106 (N3), 2869, 2926. H-NMR (CDCl3, 500 MHz) δ
7.42-7.17 (m, 45 H, aromatic H), 5.71 (d, J = 3.5 Hz, 1 H, H-
1d), 5.65 (d, J = 3.5 Hz, 1 H, H-1b), 5.10 (s, 1 H, PhCH2), 4.95-
4.89 (m, 6 H, H-1a, H-1c, 4 CHH), 4.72 (d, J = 12.0 Hz, 1 H,
CHH), 4.68 (s, 2 H, 2 CHH), 4.57-4.48 (m, 3 H), 4.36-4.17 (m,
7 H), 4.09-3.58 (m, 17 H), 3.51-3.30 (m, 3 H), 3.36-3.30 (m,
3 H), 3.91-3.44 (m, 12 H), 3.17 (dd, J1 = 11.5 Hz, J2 = 2.5 Hz,
1 H), 3.02 (dd, J1 = 11.5 Hz, J2 = 2.5 Hz, 1 H), 2.66 (s, 1 H, OH),
2.37 (t, J = 7.5 Hz, 2H, H-5o), 1.71-1.63 (m, 4 H, H-2º, H-4º),
1.45-1.39 (m, 2 H, H-3º). 13C-APT (CDCl3, 125 MHz) δ 173.5
(C=O), 138.5, 138.3, 137.8, 137.7, 137.68, 137.6, 137.4,
136.2 (aromatic C), 128.8, 128.7, 128.6, 128.6, 128.5, 128.3,
128.2, 128.18, 128.0, 127.9, 127.9, 127.86, 127.8, 127.7,
127.69, 127.5, 127.5, 127.3, 127.2 (aromatic CH), 98.8 (C-1),
98.1 (C-1), 97.9 (C-1), 97.8 (C-1), 80.9 (C-3), 80.8 (C-3), 76.1
(C-3), 75.8 (C-3), 74.54, 74.46, 73.7 (CH2), 73.6 (C-4), 73.56,
73.4 (CH2), 73.1 (2 C-4), 73.07 71.8, 71.75 (CH2), 70.7 (C-4),
70.2 (C-5), 69.9 (C-5), 69.3, 69.1 (CH2), 68.8 (C-5), 68.5, 68.3,
68.9 (CH2), 66.5 (C-5), 66.3 (PhCH2), 64.7 (C-2), 63.8 (C-2),
59.6 (C-2), 58.8 (C-2), 34.3 (C-5º), 29.2 (C-2º), 25.8 (C-3º),
24.8 (C-4º). HRMS (ESI) m/z: [M+NH4]+ Calculated for
C93H106N13O19: 1708.77224, found: 1708.77299.
Synthesis of hexasaccharide 30: Compound 29 (20 mg,
0.0078 mmol) was dissolved in THF/H2O/tert-BuOH (2
mL/2 mL/1 mL) before a catalytic amount of Pd(OH)2/C
was added. The reaction mixture was stirred for 3 days un-
der a H2 atmosphere, filtered and concentrated in vacuo. A
white powder 30 (6.7 mg, 76%) was obtained after purifi-
cation by gel filtration (HW-40, 0.15M NH4OAc in H2O). 1H-
NMR (D2O, 500 MHz) δ 5.40-5.35 (m, 3 H, 3 H-1), 4.85-4.81
(m, 3 H, 3 H-1), 4.13-4.06 (m, 2 H), 3.97-3.50 (m, 35 H), 3.41-
3.37 (m, 1 H), 3.15-3.08 (m, 2 H), 2.81 (dd, 2 H), 2.72-2.70
(m, 2 H), 2.06 (t, 2 H), 1.55-1.43 (m, 5 H), 1.29-1.23 (m, 2 H).
13C-APT (CDCl3, 125 MHz) δ 99.6 (C-1), 99.5 (C-1), 99.5 (C-
1), 99.2 (2 C-1), 97.4 (C-1), 76.9, 76.7, 76.6, 76.7, 73.7, 73.3,
72.4, 72.3, 71.9, 71.1, 71.0, 70.5, 69.2, 68.8, 68.4, 68.3, 61.2,
60.6, 60.4, 55.3, 55.3, 54.6, 51.1, 51.1, 51.0, 37.5, 28.3, 25.7,
25.4. HRMS (ESI) m/z: [M+2H]+/2 Calculated for
C42H80N6O27: 550.25302; found: 550.25247.
Synthesis of hexasaccharide 31: Compound 30 (5 mg) was
dissoled in H2O. Then Ac2O and NaHCO3 were added in the
solution. The reaction mixture was stirred for 3 days until
TLC-analysis showed complete conversion of the starting
martials. The product was purified by gel filtration (HW-40,
0.15M NH4OAc in H2O). Compound 31 (5.5 mg, 86%) was
obtained as a white solid. 1H-NMR (D2O, 500 MHz) δ 5.36-
5.34 (m, 4 H, 4 H-1), 5.27 (d, J = 4.0 Hz, 1 H, H-1), 4.79 (bt, 2
Synthesis of hexasaccharide 29: The reaction was carried
out according to the standard procedure A. A mixture of do-
nor 23 (540 mg, 0.5 mmol), acceptor 28 (360 mg, 0.21 mmol)
(donors and acceptors co-evaporated with toluene three
times), MPF (400 μL) in dry DCM (1 mL) were stirred over
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Stereoselectivity
Galactosylation. J. Org. Chem. 2016, 81, 9086-9104; b) A. Imamura,
H. Ando, S. Korogi, G. Tanabe, O. Muraoka, H. Ishida and M. Kiso, Di-
tert-butylsilylene
galactosylation
functionalitiesTetrahedron Lett. 2003, 44, 6725-6728.
(4) a) T. Polat and C.-H. Wong, Anomeric Reactivity-Based One-
Pot Synthesis of Heparin-Like Oligosaccharides. J. Am. Chem. Soc.
2007, 129, 12795-12800; b) Y.-P. Hu, S.-Y. Lin, C.-Y. Huang, M. M. L.
Zulueta, J.-Y. Liu, W. Chang and S.-C. Hung, Synthesis of 3-O-
sulfonated heparan sulfate octasaccharides that inhibit the herpes
simplex virus type 1 host–cell interaction. Nat. Chem. 2011, 3, 557-
563; c) M. M. L. Zulueta, S.-Y. Lin, Y.-T. Lin, C.-J. Huang, C.-C. Wang,
C.-C. Ku, Z. Shi, C.-L. Chyan, D. Irene, L.-H. Lim, T.-I. Tsai, Y.-P. Hu, S.
D. Arco, C.-H. Wong and S.-C. Hung, α-Glycosylation by D-
Glucosamine-Derived Donors: Synthesis of Heparosan and Heparin
Analogues That Interact with Mycobacterial Heparin-Binding
Hemagglutinin. J. Am. Chem. Soc. 2012, 134, 8988-8995; d) K.
Yoshida, B. Yang, W. Yang, Z. Zhang, J. Zhang and X. Huang, Chemical
Synthesis of Syndecan ‐ 3 Glycopeptides Bearing Two Heparan
in
Di-tert-butylsilylene-Directed
α-
H, 2 H-1), 4.73 (d, J = 3.0 Hz, 1 H, H-1), 4.21-4.06 (m, 5 H),
3.97-3.57 (m, 37 H), 3.40-3.35 (m, 1 H), 2.24 (bt, 2 H), 1.97-
1.91 (m, 18 H, 6 CH3), 1.80-1.74 (m, 2 H), 1.54-1.46 (m, 4 H),
1.32-1.26 (m, 2 H). 13C-APT (CDCl3, 125 MHz) δ 180.2, 174.7,
174.69, 174.6, 174.5, 174.46 (6 C=O), 98.2, 98.15, 96.6 (6 C-
1), 77.4, 77.2, 76.1, 75.7, 75.4, 72.5, 72.4, 71.8, 71.7, 71.3,
71.2, 70.7, 70.7, 70.4, 68.5, 68.1, 67.9, 67.6, 66.9, 61.6, 60.7,
60.3, 60.0, 54.4, 54.2, 49.9, 34.6, 28.2, 25.0, 24.4, 22.1 (CH3),
22.0 (CH3), 22.0 (CH3), 21.9 (CH3), 21.9 (2 CH3). HRMS (ESI)
m/z: [M+2H]+/2 Calculated for C54H92O33N6: 676.28472;
found: 676.28489.
1
2
3
4
5
6
7
8
(DTBS)
unaffected
group-directed
by C-2
α-selective
participating
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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40
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Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Full experimental details and characterization of all new com-
pounds (PDF). NMR spectra of all new compounds (PDF)
Sulfate Glycan Chains. Angew. Chem. Int. Ed. 2014, 53, 9051-9058;
e) C.-H. Chang, L. S. Lico, T.-Y. Huang, S.-Y. Lin, C.-L. Chang, S. D. Arco
and S.-C. Hung, Synthesis of the Heparin-Based Anticoagulant Drug
Fondaparinux. Angew. Chem. Int. Ed. 2014, 53, 9876-9879.
AUTHOR INFORMATION
(5) a) J. D. C. Codée, B. Stubba, M. Schiattarella, H. S. Overkleeft,
C. A. A. van Boeckel, J. H. van Boom and G. A. van der Marel, A
Modular Strategy Toward the Synthesis of Heparin-like
Oligosaccharides Using Monomeric Building Blocks in a Sequential
Glycosylation Strategy. J. Am. Chem. Soc. 2005, 127, 3767-3773; b)
S. Arungundram, K. Al-Mafraji, J. Asong, F. E. Leach, I. J. Amster, A.
Venot, J. E. Turnbull and G.-J. Boons, Modular Synthesis of Heparan
Sulfate Oligosaccharides for Structure-Activity Relationship
Studies. J. Am. Chem. Soc. 2009, 131, 17394-17405; c) H. A.
Orgueira, A. Bartolozzi, P. Schell and P. H. Seeberger,
Conformational Locking of the Glycosyl Acceptor for Stereocontrol
in the Key Step in the Synthesis of Heparin. Angew. Chem. Int. Ed.
2002, 41, 2128-2131; d) J. Park, S. Kawatkar, J.-H. Kim and G.-J.
Boons, Stereoselective Glycosylations of 2-Azido-2-deoxy-
glucosides Using Intermediate Sulfonium Ions. Org. Lett. 2007, 9,
1959-1962; e) B. Hagen, J. H. M. van Dijk, Q. Zhang, H. S. Overkleeft,
G. A. van der Marel and J. D. C. Codée, Synthesis of the
Staphylococcus aureus Strain M Capsular Polysaccharide Repeating
Unit. Org. Lett. 2017, 19, 2514-2517. f) Y. Zhang, H. Zhang, Y. Zhao,
Z. Guo and J. Gao, Efficient Strategy for α-Selective Glycosidation of
D-Glucosamine and Its Application to the Synthesis of a Bacterial
Capsular Polysaccharide Repeating Unit Containing Multiple α-
Linked GlcNAc Residues. Org. Lett. 2020, 22, 1520-1524.
(6) a) B. Casu, in Structure and Biological Activity of Heparin, Vol.
43 Eds.: R. S. Tipson and D. Horton, Academic Press, 1985, pp. 51-
134; b) J. Turnbull, A. Powell and S. Guimond, Heparan sulfate:
decoding a dynamic multifunctional cell regulator. Trends Cell Biol.
2001, 11, 75-82; c) N. S. Gandhi and R. L. Mancera, The structure of
glycosaminoglycans and their interactions with proteins. Chem.
Biol. Drug Des. 2008, 72, 455-482.
(7) a) P. Wei and R. J. Kerns, Factors Affecting Stereocontrol
during Glycosidation of 2,3-Oxazolidinone-Protected 1-Tolylthio-
N-acetyl-D-glucosamine. J. Org. Chem. 2005, 70, 4195-4198; b) J. Li,
Y. Dai, W. Li, S. Laval, P. Xu and B. Yu, Effective Synthesis of α -d-
GlcN-(1 → 4)-D-GlcA/L-IdoA Glycosidic Linkage under Gold(I)
Corresponding Author
* jcodee@chem.leidenuniv.nl
Author Contributions
The manuscript was written through contributions of all au-
thors. / All authors have given approval to the final version of
the manuscript.
Notes
Any additional relevant notes should be placed here.
ACKNOWLEDGMENT
This work was supported by the Chinese Scholarship Council
(CSC grant to L.W.) and the European Research Council (ERC-
CoG-726072-‘GLYCONTROL’, to J.D.C.C.).
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