Convergent preparation of DimLex hexasaccharide analogues

Article abstract of DOI:10.1002/ejoc.201101342

We report the convergent preparation of four hexasaccharides to be used towards the synthesis of a safe anticancer vaccine based on the tumor-associated carbohydrate antigen dimLe^x. A common trisaccharide intermediate was first synthesized as a precursor to the tetrasaccharide backbones. These tetrasaccharides were then converted into diol acceptors and fucosylated at O-3 of both glucosamine residues. The conditions required to promote fucosylation at O-3 of the reducing end glucosamine units led to some loss of the fucosyl units already introduced at O-3 of the nonreducing end glucosamine residues. Despite this hurdle, optimization of the glycosylation conditions provided the desired hexasaccharides in sufficient quantities to prepare the final analogues. Propyl glycosides and cysteamine adducts were prepared easily in two steps from the protected allyl glycoside hexasaccharides, and a one-step deprotection under metal-dissolving conditions was key to our deprotection strategy.

Full text of DOI:10.1002/ejoc.201101342

FULL PAPER
DOI: 10.1002/ejoc.201101342
Convergent Preparation of DimLex Hexasaccharide Analogues
Jenifer L. Hendel[a,b] and France-Isabelle Auzanneau*[a]
Keywords: Fucosylation / Glycosylation / Antitumor agents / Oligosaccharides
We report the convergent preparation of four hexasaccha-
rides to be used towards the synthesis of a safe anticancer
vaccine based on the tumor-associated carbohydrate antigen
dimLex. A common trisaccharide intermediate was first syn-
thesized as a precursor to the tetrasaccharide backbones.
These tetrasaccharides were then converted into diol ac-
ceptors and fucosylated at O-3 of both glucosamine residues.
The conditions required to promote fucosylation at O-3 of the
reducing end glucosamine units led to some loss of the fuco-
syl units already introduced at O-3 of the nonreducing end
glucosamine residues. Despite this hurdle, optimization of
the glycosylation conditions provided the desired hexasac-
charides in sufficient quantities to prepare the final ana-
logues. Propyl glycosides and cysteamine adducts were pre-
pared easily in two steps from the protected allyl glycoside
hexasaccharides, and a one-step deprotection under metal-
dissolving conditions was key to our deprotection strategy.
Galp(1Ǟ4)-[α-l-Fucp(1Ǟ3)]-d-GlcNAcp} displayed at the
nonreducing end of dimLex is also present on normal cells
and tissues such as kidney tubules, gastrointestinal epithe-
lial cells, and cells of the spleen and brain.[2] Thus, using
TACA dimLex as a target candidate for anticancer vaccine
development is precarious, as such a structure is likely to
elicit an immune response against the X determinant that
would eventually lead to the destruction of healthy cells.
In this context, our research program aims at discovering
analogues of the dimLex hexasaccharide that would retain
internal epitopes displayed on the surface of cancer cells by
dimLex (see ref.[1a,1f]) but no longer possess epitopes associ-
ated with the Lex trisaccharide AЈ(BЈ)CЈ. Indeed we re-
cently reported[3] that a Lex analogue in which the galactose
residue (C) was replaced by a glucose unit was no longer
recognized by the anti-Lex antibody SH1.[1f] Thus, we pos-
tulate that a vaccine candidate displaying an analogue of
dimLex in which the nonreducing end galactosyl residue
(CЈ) is replaced by a glucose unit (Figure 1) will no longer
trigger the production of antibodies that cross-react with
Lex. Most importantly, because the galactose residue C-4
CЈ hydroxy group is not likely involved in the internal epi-
topes displayed by the TACA dimLex,[1a,1f] we may expect
that this vaccine candidate will trigger the production of
antibodies that are cross-reactive with the internal epitopes
presented by the TACA dimLex. Thus, we report here the
synthesis of dimLex analogues 2 and 3 (Figure 1) in which
the nonreducing end galactosyl residue (CЈ) has been re-
placed by a glucose unit; these analogues will be further
referred to as GlcLexLex derivatives for short. Whereas pro-
pyl glycoside 2 will be employed as a soluble inhibitor in
binding studies, cysteamine adduct 3 will be used to pre-
pare[3,4] BSA (bovine serum albumin) and tetanous toxoid
based glycoconjugates. In addition to analogues 2 and 3,
Introduction
The dimeric Lex hexasaccharide (dimLex, Figure 1) has
been identified as a tumor-associated carbohydrate antigen
(TACA) in colon and liver carcinoma and has been associ-
ated with the progression of colorectal cancer.[1] However,
the Lex antigenic determinant or X determinant {β-d-
Figure 1. DimLex and the analogues synthesized in this study..
[a] Department of Chemistry, University of Guelph,
50 Stone Road East, Guelph, ON, N1G 2W1, Canada
Fax: +1-519-766-1499
E-mail: fauzanne@uoguelph.ca
[b] School of Chemistry, National University of Ireland Galway,
University Road, Galway, Ireland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101342.
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Convergent Preparation of DimLex Hexasaccharide Analogues
we also report here the preparation of dimLex derivatives 4 that compound 8 resulted from the opening at C-1 of a 1,2-
and 5 to be used as soluble inhibitors for propyl glycoside hemiorthoacetate likely formed upon attack of water on the
4 and hapten in the preparation of glycoconjugates for cys- intermediate cyclic acetoxonium ion. We had, indeed, over-
teamine adduct 5.
looked this migration in our previous study, because when
intermediate 8 is treated with DBU and trichloroacetoni-
trile it promptly undergoes base-catalyzed O-1 to O-2 acetyl
migration concurrently to the formation of desired tri-
chloroacetimidate 9 (Scheme 1).
Results and Discussion
Two general strategies have been used to prepare dimLex
analogues: a block synthesis[5] involving the coupling of two
Lex trisaccharides usually prepared in a convergent ap-
proach, and a linear synthesis[6] that involves the difucosyl-
ation of a dilactosamine tetrasaccharide acceptor. Because
we aimed at preparing both GlcLexLex analogues 2 and 3
and dimLex derivatives 4 and 5 in a convergent synthesis,
we prepared trisaccharide 17 as the common intermediate
for all four final targets. Trisaccharide 17 was prepared step-
wise from monosaccharide building blocks 9,[7] 12, and 15[8]
(Schemes 1 and 2). We report an improved synthesis of do-
nor 9 from known[9] thioglycoside 6. Thus, triol 6 was con-
verted into the corresponding 3,4-orthoacetate, then acety-
lated at O-2, and the orthoacetate was opened in situ to the
corresponding C-4 acetate. The remaining 3-OH was then
chloroacetylated to give fully protected intermediate 7 in
84% yield over the four steps (Scheme 1).
Acceptor 12 was prepared in two steps from known[10]
allyl glycoside 10: treatment with 2,2,2-trichloroethyl chlo-
roformate gave Troc-protected intermediate 11, which was
submitted without purification to the regioselective re-
ductive opening at O-6 of the benzylidene acetal
(Scheme 1). It is well known that the hydroxy group at C-4
of N-acetylglucosamine is a poor nucleophile and has re-
duced reactivity towards glycosylation when compared to
other acceptors.[11] However, we have reported the efficient
glycosylation of such acceptors by using peracetylated tri-
chloroacetimidate donors (5 equiv.) activated at 20–40 °C
with BF3·OEt2 (2 equiv.).[12] Thus, acceptor 12 was treated
under these conditions with donor 9 (5 equiv.) at 40 °C and
desired disaccharide 13 was isolated in 87% yield. Whereas
higher yields were achieved when using 5 equiv. of the do-
nor, larger-scale couplings were performed by using only
3 equiv. of high value-added donor 9 and gave 13 in accept-
able yield (Scheme 1). Treatment of disaccharide 13 with
thiourea gave disaccharide acceptor 14, which was, in turn,
glycosylated with trichloroacetimidate donor 15[8] under
TMSOTf (2.0 equiv.) activation at 0 °C (Scheme 2).
Scheme 1.
This represents an improvement over our reported syn-
thesis of 7, which required five steps (64% overall) from the
analogous 3,4-O-isopropylidene p-thiotolyl galactoside.[7]
Thiotolyl galactoside 7 was then converted into trichloro-
Scheme 2.
Desired trisaccharide 16 was obtained in 87% yield after
acetimidate donor 9 by using the same conditions as those precipitation from EtOAc/hexanes (1:1, 54%) and
we have described:[7] hydrolysis of the thioglycoside and chromatography of the mother liquors (33%). Reductive
conversion of the expected hemiacetal into a trichloroacet- opening of the benzylidene acetal in 16 gave trisaccharide
1
imidate. Interestingly, full H NMR spectroscopic charac- acceptor 17 free at O-4ЈЈ and precursor to hexasaccharides
terization of the compound formed after hydrolysis revealed 2–5 (Scheme 3). Trisaccharide acceptor 17 was coupled with
that intermediate 8 carried an α-acetate at the anomeric po- the known[13] trichloroacetimidate glucosyl and galactosyl
sition (δ1-H = 6.31 ppm, J1-H,2-H = 3.8 Hz) and a free equa- donors 18 and 19 by applying once again the conditions
torial hydroxy group at C-2 (δ2-H = 4.22 ppm). We propose used above for the preparation of disaccharide 13.[12] Under
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FULL PAPER
these conditions, glucosylation of acceptor 17 with donor
18 gave desired tetrasaccharide 20 in good yields after
45 min of reaction. In contrast, galactosylation of acceptor
17 with donor 19 was difficult to follow by TLC, as degra-
dation products (from donor 19) co-migrated with acceptor
17. To ensure maximum conversion into the tetrasaccha-
ride, an additional amount of the donor (1.5 equiv.) was
added, and the reaction was left to proceed an additional
hour. Under these conditions, desired tetrasaccharide 21
was obtained pure in 72% yield upon purification by flash
chromatography and RP-HPLC. Tetrasaccharides 20 and
21 were then treated with an excess amount of thiourea to
give acceptors 22 and 23, respectively, free at O-3 of the
nonreducing end glucosamine residue (AЈ). In turn, the si-
multaneous removal of the Troc group and reduction of
the N-trichloroacetate to an acetamido in 22 and 23 was
attempted by treatment with freshly activated zinc in acetic
acid. However, while the trichloroethoxy carbonate groups
were quickly removed under these conditions, the conver-
sion of the N-trichloroacetyl groups into N-acetyl groups
was more difficult. For example, extended reaction time,
higher temperature (up to 80 °C), and repeated additions of
zinc only gave desired N-acetylated acceptor 24 in 37%
yield, whereas chloroacetamido analogue 25 was obtained
in 57% yield. Revising our strategy, we thus decided to use
N-chloroacetylated analogues 25 and 27 as the acceptors
in the fucosylation reactions (Scheme 4) and optimized this
reaction to maximize their formation. Thus, tetrasaccha-
rides 22 and 23 were treated with an excess amount of zinc
in AcOH at 40 °C for 1 h and diol acceptors 25 and 27 were
isolated in 77% yield, whereas chloroacetamido analogues
24 and 26 were isolated in 15 and 11% yield, respectively
(Scheme 3).
Scheme 3.
Difucosylation of diol 25 was first attempted by using
known[14] fucosyl donor 28 activated with CuBr2 and tetra-
butylammonium bromide; a method that we have applied
successfully to the synthesis of various Lex derivatives.[7,12b]
However, no fucosylation was observed under these condi-
tions. Indeed, after an extended reaction time, using up to
4 equiv. of donor and raising the temperature to 35 °C, un-
reacted acceptor 25 was recovered and no fucosylated prod-
uct was isolated. Thus, we investigated the activation of do-
nor 28 (4 equiv.) with NIS (5 equiv.) and TMSOTf
(0.3 equiv.) while running the reaction at 0 °C for 1 h before
quenching with NEt3. Following workup and purification
(CH2Cl2/MeOH = 100:1 to 20:1), some unreacted tetrasac-
charide 25 was recovered (ca. 20%) and two new products
were isolated. These products were identified by NMR
spectroscopy and HRMS as hexasaccharide 29 (ca. 10%)
and pentasaccharide 31 (ca. 50%). The chemical shifts
(ΔδNH = ca. 1 ppm) measured for the NH signals of N-
acetylated residue A and N-chloroacetylated residue AЈ
were key to determine accurate chemical shifts for 2-H and
3-H of the two residues A and AЈ. Thus, fucosylation at O-
3 of both glucosamine residues (A and AЈ) in hexasaccha-
ride 29 led to a ca. 0.2 ppm downfield shift of both 3A-H
and 3AЈ-H (Table 1) when compared to these signals in diol
acceptor 25. In pentasaccharide 31, the nonreducing end Scheme 4.
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Convergent Preparation of DimLex Hexasaccharide Analogues
3AЈ-H underwent a ca. 0.2 ppm downfield shift when com- whereas C-3A did not. The results of these two reactions
pared to the same signal in acceptor 25, whereas 3A-H was suggest that at low temperature pentasaccharide 31 was
found at the same chemical shift as that in acceptor 25.
formed first and then slowly fucosylated at O-3A when the
temperature was increased, giving hexasaccharide 29. How-
ever, the conditions that were required to complete the fu-
cosylation at O-3A and maximize the yield of desired hexa-
saccharide 29 led, in turn, to the loss of the fucosyl residue
first introduced at O-3AЈ and gave pentasaccharide 33. On
the basis of observations reported previously by us[3,12a] and
others,[15] the poor stability observed for the α-fucosyl unit
at O-3 of a glucosamine residue was not surprising. Numer-
ous conditions, varying the temperature, time of reaction,
concentration of fucosyl donor, and amounts of NIS and
TMSOTf, were investigated to optimize the yield of hexa-
saccharide 29 while minimizing that of pentasaccharide 33.
In all cases the desired hexasaccharide was never isolated
in better than 40–45% yield after multiple purifications on
silica gel and RP-HPLC. In our hands, the best results were
Table 1. Selected 1H and 13C NMR chemical shifts for compounds
25, 27, and 29–34.
Compound
3A-H[a]
3AЈ-H[a]
C-4A[b]
C-4AЈ[b]
25
27
29
30
31
32
33
34
3.90
3.90
4.07
4.08
3.92
3.90
4.10
4.10
3.95
3.98
4.15
4.18
4.14
4.18
3.95
3.98
81.1[c]
81.3[c]
81.1[c]
73.7[c]
73.7[c]
81.2
81.4[c]
74.8[c]
74.3[c]
74.8
81.2
74.2
81.4
81.4
73.8
73.8[d]
[a] δH in ppm. [b] δC in ppm. [c] Assignments C-4A and C-4AЈ may
be reversed. [d] Alternate chemical shift possible: δ = 74.2 or δ =
74.1 ppm.
Interestingly, the chemical shift measured for C-4 of the obtained when the reaction was carried out at room tem-
glucosamine residues (A or AЈ) was greatly affected by the perature by using 5 and 0.3 equiv. of NIS and TMSOTf,
presence or absence of a fucose on the vicinal O-3. As respectively, to activate 4 equiv. of donor 28 for 40 min,
shown in Table 1, C-4A was found at δ ≈ 81 ppm when the then adding an one additional equivalent of donor and al-
vicinal OH group was not fucosylated in acceptor 25 or lowing the reaction to proceed for another 20 min. Under
pentasaccharide 31, whereas the same signal was found at these reaction conditions, desired hexasaccharide 29 was
δ ≈ 74 ppm upon fucosylation in hexasaccharide 29. Simi- isolated in 43% yield and pentasaccharide 33 was obtained
larly, C-4AЈ was found at δ = 81.3 ppm in acceptor 25, in 20% yield, whereas no pentasaccharide 31 was recovered.
whereas it gave a signal upfield at δ = 74.8 ppm in both
Galactosylated acceptor 27 was thus submitted to difu-
hexasaccharide 29 and pentasaccharide 31. Indeed, this fea- cosylation at O-3A and O-3AЈ by applying the optimized
ture was characteristic in all derivatives described here: the conditions described above for the glycosylation of ana-
C-4 signal of N-acylated glucosamine units carrying a free logue 25. After RP-HPLC, protected dimeric Lex hexasac-
OH at C-3 was found at δ ≈ 81 ppm, whereas the C-4 signal charide 30 was obtained in 48% yield, and pentasaccharides
in glucosamine residues that were protected (Troc or ClAc) 32 and 34 were isolated in 9 and 13% yield, respectively.
or fucosylated at O-3 was found between δ = 73 ppm and δ The structure of hexasaccharide 30 and those of pentasac-
= 77 ppm.
charides 32 and 34 were confirmed by HRMS and NMR
Although we did isolate desired hexasaccharide 29 in spectroscopy. The position of the fucosyl residues at O-3AЈ
small amounts, the fact that the major product of this reac- and O-3A in pentasaccharides 32 and 34, respectively, was
tion was the pentasaccharide fucosylated at the nonreduc- confirmed by looking at the chemical shifts measured for
ing end glucosamine suggested that these conditions were 3A-H and 3AЈ-H as well as that of C-4A and C-4AЈ as
not efficient to promote fucosylation at the hindered 3-OH described above for the characterization of pentasaccha-
group of the reducing end glucosamine. Therefore, this re- rides 31 and 33 (Table 1). It is interesting to notice that, in
action was repeated starting at 0 °C with NIS (1.7 equiv.), contrast to the results obtained with fucosylating acceptor
TMSOTf (0.2 equiv.), and donor 28 (1.5 equiv.) and left to 25, not all pentasaccharide 32 was converted into hexasac-
proceed at 0 °C for 1.5 h to allow fucosylation at O-3AЈ. charide 30 and then further degraded to pentasaccharide
Additional amount of NIS (4.5 equiv.) and donor 34. Although difficult to rationalize, this observation sug-
(4.5 equiv.) were then added, and the reaction was placed gests an overall lower reactivity of acceptors 27 and 32
at room temperature for 2 h to promote fucosylation at the towards fucosylation and degradation when compared to
less-reactive O-3A. TLC showed the formation of three that of acceptors 25 and 31.
products that were purified by a combination of flash
Even though protected hexasaccharides 29 and 30 were
chromatography and RP-HPLC. These three products were obtained in rather moderate yield, enough material was iso-
identified as hexasaccharide 29 (ca. 35%), pentasaccharide lated in both cases to allow the preparation of GlcLexLex
33 (ca. 20%), and pentasaccharide 31 (ca. 6%). Fucosyl- analogues 2 and 3 and dimLex derivatives 4 and 5. The
ation at the reducing end glucosamine residue (A) in penta- syntheses of propyl GlcLexLex (2) and dimLex (4) were ac-
saccharide 33 was confirmed by the chemical shift of 3A-H complished in two steps: (1) Reduction of the allyl group
that underwent a ca. 0.2 ppm downfield shift when com- (H2, 10% Pd/C) to a propyl group. (2) Full deprotection/
pared to the same signal in acceptor 25. In addition, the reduction under dissolving-metal reduction conditions [Na/
chemical shift measured for C-4A was found at δ = NH3(l) –78 °C, in THF]. Indeed, dissolving-metal condi-
73.8 ppm, whereas that of C-4AЈ was found at δ = 81.4 ppm tions were shown to efficiently and concurrently remove
(Table 1), indicating that C-3AЈ carried a free OH group, protecting groups such as benzyl, benzylidene, acyl, and tri-
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J. L. Hendel, F.-I. Auzanneau
FULL PAPER
chloroacetamido and also reduce azido groups to amino for the vicinal C-4 carbon atoms in the 13C NMR spectra.
groups.[3,7,16] After such reactions, GlcLexLex propyl glyco- This signal was found at δ ≈ 80–81 ppm for 3-OH ana-
side (2) and dimLex propyl glycoside (4) were purified by logues, whereas it was found between δ = 75 ppm and δ =
size-exclusion chromatography on a Biogel P2 column and 77 ppm in the 3 O-substituted derivatives. Hexasaccharides
obtained pure in 71 and 65% yield, respectively. Fortu- 29 and 30 were, in turn, easily and efficiently converted into
nately, these Birch reduction conditions led to the reduction final target analogues 2–5. The allyl aglycones were either
of the N-chloroacetates to N-acetates, rather than to their hydrogenated to propyl glycosides or submitted to addition
transamidation leading to free amines that would require of cysteamine hydrochloride, and the resulting intermedi-
re-acetylation. Thus, we could follow a similar one-step de- ates were submitted without further purification to full de-
protection strategy to prepare free amine analogues 3 and protection and reduction of the N-chloroacetate by using
5 from protected analogues 29 and 30. UV-promoted ad- metal-dissolving reduction conditions. From the protected
dition of cysteamine hydrochloride to allyl hexasaccharides hexasaccharides, propyl hexasaccharides 2 and 4 were ob-
29 and 30 afforded the corresponding protected 3-(2-amino- tained in 71 and 65%, respectively, and cysteamine adducts
ethylthio)propyl glycosides, which were obtained free of ex- 3 and 5 were isolated in 75 and 65% yield, respectively.
cess cysteamine by washing with 1 m NaOH. The crude ad- Thus, we have established an efficient convergent synthesis
ducts were then submitted to metal-dissolving deprotection of new GlcLexLex hexasaccharide analogues 2 and 3 as well
to fully remove all protecting groups and reduce the chloro- as that of dimLex analogues 4 and 5, which were all ob-
acetamido groups. To prevent adsorption on the Biogel sup- tained in a very acceptable ca. 7% overall yield from the
port, adducts 3 and 5 were purified on a P2 column eluted protected monosaccharide building blocks by using trisac-
with 0.1 m aqueous ammonium acetate and repeated freeze- charide 7 as a common intermediate for all final targets.
drying from water provided the acetate salts of analogues 3
and 5 in 75 and 65% yield, respectively, over the two steps.
Experimental Section
General: 1H NMR (400.13 and 600.13 MHz) and 13C NMR (100.6
Conclusions
and 150.9 MHz) spectra were recorded in CDCl3 (internal stan-
1
dard, for H residual CHCl3 δH = 7.24 ppm; for 13C: CDCl3 δC
=
The synthetic strategy adopted in this work was shown
to be efficient to prepare dimLex derivatives 4 and 5 and
closely related new GlcLexLex analogues 2 and 3, which
carry a glucose residue at the nonreducing end replacing
the galactose unit present in the naturally occurring TACA.
Our stepwise preparation of the tetrasaccharide backbones
by using an excess amount of the cheaper monosaccharide
glycosyl donors was shown to produce the desired com-
pounds in excellent overall yields. The tetrasaccharides were
then converted into diol acceptors ready for difucosylation
at O-3 of both glucosamine residues. Characterization of
the fucosylated products by NMR spectroscopy showed
that all fucosylations proceeded stereoselectively to give α-
fucosidic linkages. However, difucosylations proved to be
challenging reactions due to the difference in reactivities of
the two glucosamine hydroxy groups at the 3-position. Our
results suggest that fucosylation at the nonreducing AЈ ring
happened first followed by fucosylation of the reducing end
A glucosamine, which occurred slowly. Thus, despite the
presence of an electron-withdrawing N-chloroacetate at the
nonreducing end glucosamine residue (AЈ), this residue was
more rapidly fucosylated than the reducing end N-acety-
lated glucosamine unit. We propose that steric hindrance
around the hydroxy group at C-3 of the reducing end glu-
cosamine residue (A) reduced its reactivity toward fucosyl-
ation when compared to that of the nonreducing end glu-
cosamine unit. The conditions that most efficiently led to
desired hexasaccharides 29 and 30 in usable yields also led
to some loss of the more labile nonreducing end fucosyl
residue (BЈ) that had been introduced first. Interestingly, it
appears that the presence or absence of substituents (pro-
tecting groups or sugar residue) at C-3 of the glucosamine
1
77.0 ppm), CD3OD (internal standard, for H residual CH3OD δH
= 3.30 ppm; for 13C: CD3OD δC = 49.0 ppm), D2O (external stan-
dard, sodium 2,2-dimethyl-2-silapentane-5-sulfonate, DSS, δH and
δC = 0.0 ppm), or [D6]DMSO (internal standard, for 1H residual
Me2SO δH = 2.49 ppm; for 13C: [D6]DMSO δC = 39.5 ppm). Cou-
pling constants (J) were obtained from first-order analysis of 1D
spectra. Assignments of proton and carbon resonances were based
1
on 2D H–1H COSY and 13C–1H HSQC correlation experiments
as well as 1D TOCSY experiments. Multiplicities are abbreviated
as follows: singlet (s), doublet (d), triplet (t), quartet (q), and mul-
tiplet (m). Analytical thin-layer chromatography (TLC) was per-
formed by using silica gel 60 F254 precoated plates (250 μm) with
visualization under UV light and/or charring with 10% H2SO4 in
EtOH. Flash chromatography was performed by using silica gel 60
(230–400 mesh) from EM science. All reactions were carried out
under a nitrogen atmosphere with anhydrous freshly distilled sol-
vents unless otherwise noted. Solvents were distilled and dried ac-
cording to standard procedures,[17] and organic solutions were
dried with Na2SO4 and concentrated under reduced pressure. Mo-
lecular sieves were activated by flame drying under reduced pres-
sure. All reagents were purchased from commercial suppliers and
used without further purification unless otherwise noted. Reverse-
phase HPLC purifications were carried out with Prep Nova Pak
HR C18, 6 μm 60 Å columns by using mixtures of acetonitrile and
water as eluent. Purifications by gel permeation chromatography
were carried out with a Biogel P2 column (95 cmϫ1.5 cm) eluted
with water unless otherwise stated. UV irradiation was ac-
complished with a Rayonet photochemical reactor. Optical rota-
tions were measured at 298 K and are uncorrected. Purity and
structure of all new compounds were confirmed by NMR (see Sup-
porting Information) and HRMS. HRESI mass spectra were re-
corded by the analytical services of the McMaster Regional Center
for Mass Spectrometry, Hamilton, Ontario.
Propyl 2-Acetamido-2-deoxy-3-O-(α-
L
-fucopyranosyl)-4-O-{3-O-[2-
-gluco-
residues has a large impact on the chemical shifts measured acetamido-2-deoxy-3-O-(α- -fucopyranosyl)-4-O-(β-
L
D
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Convergent Preparation of DimLex Hexasaccharide Analogues
pyranosyl)-β- -glucopyranosyl]-β- -galactopyranosyl}-β- -glucopyr-
D
D
D
resulting powder was freeze-dried from water an additional two
times to remove the excess amount of ammonium acetate. The am-
monium salt of cysteamine adduct 3 (15 mg, 75%) was obtained
pure as a white solid. [α]D = –62 (c = 0.5, H2O). 1H NMR
(600 MHz, D2O, 295 K): δ = 5.12 (d, J = 4.0 Hz, 1 H, 1BЈ-H), 5.08
(d, J = 4.0 Hz, 1 H, 1B-H), 4.81 (m, 1 H, 5B-H), 4.75 (m, 1 H,
5BЈ-H), 4.69 (d, J = 8.4 Hz, 1 H, 1AЈ-H), 4.52 (m, 2 H, 1A-H, 1CЈ-
H), 4.42 (d, J = 7.9 Hz, 1 H, 1C-H), 4.09 (d, J = 3.4 Hz, 1 H, 4C-
H), 4.00–3.91 (m, 6 H, 6aA-H, 2AЈ-H, 4AЈ-H, 6AaЈ-H, 6bCЈ-H,
OCHHCH2), 3.91–3.79 (m, 8 H, 2A-H, 3A-H, 4A-H, 6Ab-H, 3B-
H, 3AЈ-H, 6AbЈ-H, 3BЈ-H), 4.76 (br. s, 2 H, 4B-H, 4BЈ-H), 3.72–
3.64 (m, 5 H, 2B-H, 3C-H, 6abC-H, 2BЈ-H), 3.60–3.54 (m, 5 H,
5A-H, 5C-H, 5AЈ-H, 6CaЈ-H, OCHHCH2), 3.50 (t, J = 8.9 Hz, 2
H, 2C-H, 3CЈ-H), 3.42 (m, 1 H, 5CЈ-H), 3.22–3.17 (m, 4 H, 2CЈ-
H, 4CЈ-H, SCH2CH2N), 2.83 (m, 2 H, SCH2CH2N), 2.60 (m, 2 H,
OCH2CH2CH2S), 2.03, 2.01 (2 s, 6 H, 2 COCH3), 1.84 (m, 2 H,
OCH2CH2CH2S), 1.17 (d, J = 6.7 Hz, 3 H, 6BЈ-H), 1.14 (d, J =
anoside (2): To a solution of hexasaccharide 29 (29 mg,
0.014 mmol) dissolved in MeOH (1 mL) was added 10 % Pd/C
(13 mg), and the mixture was stirred under an atmosphere of H2.
After 18 h, the reaction mixture was filtered, the solids were washed
with MeOH (5ϫ10 mL), and the filtrate was concentrated to give
the crude propyl hexasaccharide. A solution of the crude hexasac-
charide in THF (5 mL) was added at –78 °C to a solution of liquid
NH3 (ca. 20 mL) containing Na (60 mg, 2.6 mmol, 186 equiv.). Af-
ter 1 h at –78 °C, the reaction was quenched with MeOH (10 mL),
and ammonia was allowed to evaporate at room temperature. The
remaining solution was neutralized with AcOH (202 μL, ca.
1.1 equiv. to Na) and the solvent was evaporated. The resulting
solid was dissolved in water and passed through a Biogel P2 col-
umn eluted with H2O. After freeze-drying, propyl glycoside 2
(11 mg, 71%) was obtained pure as a white amorphous powder.
1
[α]D = –52 (c = 0.5, H2O). H NMR (600 MHz, D2O, 295 K): δ =
5.13 (d, J = 4.0 Hz, 1 H, 1BЈ-H), 5.09 (d, J = 4.0 Hz, 1 H, 1B-H), 6.6 Hz, 3 H, 6B-H) ppm. 13C NMR (150 MHz, D2O, 295 K): δ =
4.81 (m, 1 H, 5B-H), 4.74 (m, 1 H, 5BЈ-H), 4.69 (d, J = 8.5 Hz, 1 174.6, 174.2 (C=O), 102.5 (C-1AЈ), 101.7 (C-1C), 101.2 (C-1A),
H, 1AЈ-H), 4.53 (d, J = 7.9 Hz, 2 H, 1A-H, 1CЈ-H), 4.42 (d, J = 101.0 (C-1CЈ), 98.7 (C-1B, C-1BЈ), 81.6 (C-3C), 76.0 (C-5CЈ), 75.4
7.9 Hz, 1 H, 1C-H), 4.09 (d, J = 3.4 Hz, 1 H, 4C-H), 4.00–3.92 (m,
5 H, 6Aa-H, 2AЈ-H, 4AЈ-H, 6AaЈ-H, 6CbЈ-H), 3.91–3.80 (m, 9 H,
(C-3CЈ), 75.3, 75.0, 74.9, 74.8, 74.4 (C-3A, C-5A, C-5C, C-3AЈ, C-
5AЈ), 73.6 (C-4CЈ), 73.3, 73.0 (C-4A, C-4AЈ), 71.9, 71.8 (C-4B, C-
2A-H, 3A-H, 4A-H, 6Ab-H, 3B-H, 3AЈ-H, 6AbЈ-H, 3BЈ-H, 4BЈ), 70.4 (C-2C, C-4CЈ), 69.2, 69.1 (C-3B, C-3BЈ), 68.6
OCHHCH2CH3), 3.76 (br. s, 2 H, 4B-H, 4BЈ-H), 3.74–3.65 (m, 5 (OCH2CH2), 68.2 (C-4C), 67.6 (C-2B, C-2 BЈ), 66.7, 66.4 (C-5B,
H, 2B-H, 3C-H, 6Cab-H, 2BЈ-H), 3.60–3.52 (m, 5 H, 5A-H, 5C- C-5BЈ), 61.6, 61.4, (C-6C, C-6CЈ), 59.7, 59.5 (C-6A, C-6AЈ), 55.9
H, 5AЈ-H, 6caЈ-H, OCHHCH2CH3), 3.48 (t, J = 9.2 Hz, 2 H, 2C-
H, 3CЈ-H), 3.42 (m, 1 H, 5CЈ-H), 3.22–3.16 (m, 2 H, 2CЈ-H, 4CЈ-
(C-2A, C-2AЈ), 38.2 (SCH2CH2N), 28.4 (OCH2CH2CH2S), 28.1
(SCH2CH2N), 26.9 (OCH2CH2CH2S), 22.2 (COCH3), 15.3, 15.2
H), 2.02, 2.01 (2 s, 6 H, 2 COCH3), 1.54 (m, 2 H, OCH2CH2CH3), (C-6B, C-6BЈ) ppm. HRMS: calcd. for C45H79N3O29S [M + H]+
1.17 (d, J = 6.7 Hz, 3 H, 6BЈ-H), 1.14 (d, J = 6.6 Hz, 3 H, 6B-H), 1158.1800; found 1158.4637.
0.86 (t, J = 7.5 Hz, 3 H, OCH2CH2CH3) ppm. 13C NMR
Propyl 2-Acetamido-2-deoxy-3-O-(α-
acetamido-2-deoxy-3-O-(α-
pyranosyl)-β- -glucopyranosyl]-β-
L
-fucopyranosyl)-4-O-{3-O-[2-
-fucopyranosyl)-4-O-(β- -galacto-
-galactopyranosyl}-β- -gluco-
(150 MHz, D2O, 295 K): δ = 174.6, 174.3 (C=O), 102.5 (C-1AЈ),
101.7 (C-1C), 101.2 (C-1CЈ), 100.8 (C-1A), 98.7 (C-1B, C-1BЈ), 81.6
(C-3C), 76.0 (C-5CЈ), 75.4 (C-3CЈ), 75.3, 75.0, 74.9, 74.4 (C-3A,C-
5A, C-5C, C-3AЈ, C-5AЈ), 73.6 (C-4CЈ), 73.3, 73.0 (C-4A, C-4AЈ),
72.4 (OCH2CH2CH3), 71.9, 71.8 (C-4B, C-4BЈ), 70.4 (C-2C, C-
2CЈ), 69.2, 69.1 (C-3B, C-3BЈ), 68.2 (C-4C), 67.6 (C-2B, C-2BЈ),
66.6, 66.4 (C-5B, C-5BЈ), 61.6, 61.4, (C-6C, C-6CЈ), 59.7, 59.5 (C-
6A,C-6AЈ), 55.9 (C-2A, C-2AЈ), 22.2 (OCH2CH2CH3), 22.1, 22.0
(COCH3), 15.3, 15.2 (C-6B, C-6BЈ), 9.5 (OCH2CH2CH3) ppm.
HRMS: calcd. for C43H74N2O29 [M + H]+ 1083.4456; found
1083.4485.
L
D
D
D
D
pyranoside (4): Reduction of the allyl aglycon and deprotection of
hexasaccharide 30 (21 mg, 0.01 mmol) to give analogue 4 was car-
ried out as described for the preparation of compound 2 from hexa-
saccharide 29. After freeze-drying, propyl glycoside 4 (7 mg, 65%)
was obtained pure as an amorphous white solid. [α]D = –59 (c =
0.5, H2O). 1H NMR (600 MHz, D2O, 295 K): δ = 5.13 (d, J =
4.0 Hz, 1 H, 1BЈ-H), 5.09 (d, J = 4.0 Hz, 1 H, 1B-H), 4.82 (m, 2
H, 5B-H, 5BЈ-H), 4.69 (d, J = 8.5 Hz, 1 H, 1AЈ-H), 4.53 (br. d, J
= 8.2 Hz, 1 H, 1A-H), 4.46 (d, J = 7.9 Hz, 1 H, 1CЈ-H), 4.43 (d, J
= 7.9 Hz, 1 H, 1C-H), 4.09 (d, J = 3.3 Hz, 1 H, 4C-H), 3.99–3.92
(m, 4 H, 6Aa-H, 2AЈ-H, 4AЈ-H, 6AaЈ-H), 3.92–3.81 (m, 10 H, 2A-
H, 3A-H, 4A-H, 6Ab-H, 3B-H, 3AЈ-H, 6AbЈ-H, 3BЈ-H, 4CЈ-H,
OCHHCH2CH3), 3.78 (br. d, J = 3.8 Hz, 1 H, 4BЈ-H), 3.76 (br. d,
J = 3.8 Hz, 1 H, 4B-H), 3.75–3.66 (m, 7 H, 2B-H, 3C-H, 6Cab-H,
2BЈ-H, 6CabЈ-H), 3.64 (dd, J = 9.9, 3.4 Hz, 1 H, 3CЈ-H), 3.61–3.52
(m, 4 H, 5A-H, 5C-H, 5AЈ-H, 5CЈ-H, OCHHCH2CH3), 3.49 (m,
2 H, 2C-H, 2CЈ-H), 2.02 (s, 6 H, 2 COCH3), 1.54 (m, 2 H,
OCH2CH2CH3), 1.16 (d, 3 H, J = 6.7 Hz, 6BЈ-H), 1.14 (d, J =
6.7 Hz, 3 H, 6B-H), 0.86 (t, J = 7.4 Hz, 3 H, OCH2CH2CH3). 13C
NMR (150 MHz, D2O, 295 K): δ = 174.6, 174.3 (C=O), 102.5 (C-
1AЈ), 101.7 (C-1C, C-1CЈ), 100.9 (C-1A), 98.7 (C-1B), 98.5 (C-1BЈ),
81.5 (C-3C), 75.3, 75.0, 74.9, 74.7, 74.4 (C-3A, C-5A, C-5C, C-
3AЈ, C-5AЈ, C-5CЈ), 73.0, 72.9 (C-4A, C-4AЈ), 72.4 (C-3CЈ), 72.3
(OCH2CH2CH3), 71.8 (C-4B, C-4BЈ), 71.0, 70.5 (C-2C, C-2CЈ),
69.1 (C-3B, C-3BЈ), 68.3, 68.2 (C-4C, C-4CЈ), 67.6 (C-2B, C-2BЈ),
66.6 (C-5B, C-5BЈ), 61.5, 61.4 (C-6C, C-6CЈ), 59.7, 59.5 (C-6A, C-
6AЈ), 55.9 (C-2A, C-2AЈ), 22.1 (COCH3), 22.0 (OCH2CH2CH3),
15.2 (C-6B, C-6BЈ), 9.5 (OCH2CH2CH3) ppm. HRMS: calcd. for
C43H74N2O29 [M + Na]+ 1105.4275; found 1105.4281.
Aminoethylthiopropyl 2-Acetamido-2-deoxy-3-O-(α-
syl)-4-O-{3-O-[2-acetamido-2-deoxy-3-O-(α- -fucopyranosyl)-4-O-
(β- -glucopyranosyl)-β- -glucopyranosyl]-β- -galactopyranosyl}-β-
-glucopyranoside (3): MeOH (600 μL) and 2-aminoethanethiol hy-
L-fucopyrano-
L
D
D
D
D
drochloride (94 mg, 0.86 mmol, 45 equiv.) were added to a solution
of allyl glycoside 29 (39 mg, 0.018 mmol) dissolved in a minimum
amount of CH2Cl2 (200 μL) and placed into a quartz tube. The
mixture was stirred until full dissolution and irradiated by UV light
for 90 min. The solution was then diluted with CHCl3 (50 mL) and
washed with 1 m NaOH (5ϫ50 mL). The aqueous layers were re-
extracted with CHCl3 (50 mL), and the organic layers were com-
bined, dried, filtered, and concentrated to give the crude cyste-
amine adduct (39 mg). A solution of this adduct in THF (5 mL)
was added at –78 °C to a solution of liquid NH3 (ca. 20 mL) con-
taining Na (60 mg, 2.6 mmol, 145 equiv.). After 50 min at –78 °C,
the reaction was quenched with MeOH (10 mL), and the ammonia
was allowed to evaporate at room temperature. The remaining solu-
tion was neutralized with AcOH (260 μL, ca. 1.1 equiv. to Na), and
the solvent was evaporated. The resulting solid was dissolved in
0.1 m ammonium acetate solution and was passed through a Biogel
P2 column eluted with 0.1 m ammonium acetate. The fractions con-
taining hexasaccharide 3 were combined and lyophilized, and the
Aminoethylthiopropyl 2-Acetamido-2-deoxy-3-O-(α-
L-fucopyrano-
syl)-4-O-{3-O-[2-acetamido-2-deoxy-3-O-(α- -fucopyranosyl)-4-O-
L
Eur. J. Org. Chem. 2011, 6864–6876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6869

J. L. Hendel, F.-I. Auzanneau
FULL PAPER
(β-
β-
D
-galactopyranosyl)-β-
D
-glucopyranosyl]-β-
D
-galactopyranosyl}-
and concentrated. Flash chromatography of the residue (EtOAc/
hexanes = 1:1) gave alcohol 8 (6.6 g, 71%) pure as a colorless glass.
1H NMR (400 MHz, CDCl3): δ = 6.31 (d, J = 3.8 Hz, 1 H, 1-H),
5.47 (d, J = 3.4 Hz, 1 H, 4-H), 5.26 (dd, J = 10.5, 3.3 Hz, 1 H, 3-
H), 4.31 (t, J = 9.2 Hz, 1 H, 5-H), 4.22 (dd, J = 10.6, 4.0 Hz, 1 H,
2-H), 4.13–4.05 (m, 4 H, 6ab-H, CH2Cl), 2.19, 2.15, 2.04 (3s, 9 H,
3 COCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4, 170.3,
169.4, 167.1 (C=O), 91.8 (C-1), 72.1 (C-3), 68.5 (C-5), 67.2 (C-
4), 65.7 (C-2), 61.1 (C-6), 40.4 (CH2Cl), 20.9, 20.6 (COCH3) ppm.
Trichloroacetonitrile (10.4 mL, 6.1 equiv.) and DBU (1.0 mL,
D-glucopyranoside (5): Cysteamine addition and deprotection of
hexasaccharide 30 (23 mg, 0.011 mmol) to give analogue 5 was car-
ried out as described for the preparation of compound 3 from hexa-
saccharide 29. After freeze-drying, cysteamine adduct 5 (8 mg,
65%) was obtained pure as an amorphous white solid. [α]D = –54
1
(c = 0.5, H2O). H NMR (600 MHz, D2O, 295 K): δ = 5.12 (d, J
= 4.0 Hz, 1 H, 1BЈ-H), 5.09 (d, J = 3.9 Hz, 1 H, 1B-H), 4.81 (m, 2
H, 5B-H, 5BЈ-H), 4.69 (d, J = 8.4 Hz, 1 H, 1AЈ-H), 4.52 (br. d, J
= 8.2 Hz, 1 H, 1A-H), 4.45 (d, J = 7.8 Hz, 1 H, 1CЈ-H), 4.42 (d, J
= 7.9 Hz, 1 H, 1C-H), 4.09 (d, J = 3.3 Hz, 1 H, 4C-H), 4.04–3.91 0.4 equiv.) were added a solution of alcohol 8 (6.6 g, 17.3 mmol) in
(m, 5 H, 6Aa-H, 2AЈ-H, 4AЈ-H, H6AaЈ, OCHHCH2), 3.91–3.80 anhydrous CH2Cl2 (90 mL) at room temperature under an atmo-
(m, 9 H, 2A-H, 3A-H, 4A-H, 6Ab-H, 3B-H, 3AЈ-H, 6AbЈ-H, 3BЈ- sphere of N2. The reaction was stirred at room temperature for 1 h,
H, 4CЈ-H), 3.78 (d, J = 2.9 Hz, 1 H, 4BЈ-H), 3.76 (d, J = 2.4 Hz,
1 H, 4B-H), 3.75–3.66 (m, 8 H, 2B-H, 3C-H, 6Cab-H, 2BЈ-H,
the solvent was evaporated, and flash chromatography of the resi-
due (EtOAc/hexanes = 4:6 with 0.1% Et3N) gave trichloroacetimid-
6CabЈ-H, OCHHCH2), 3.64 (dd, J = 9.9, 3.4 Hz, 1 H, 3CЈ-H), ate 9 as a yellow amorphous powder (6.6 g, 73 %). 1H NMR
3.61–3.54 (m, 4 H, 5A-H, 5C-H, 5AЈ-H, 5CЈ-H), 3.49 (m, 2 H, 2C- (400 MHz, CDCl3): δ = 8.66 (s, 1 H, NH), 6.59 (d, J = 3.6 Hz, 1
H, 2CЈ-H), 3.20 (t, J = 6.7 Hz, 2 H, SCH2CH2N), 2.83 (m, 2 H,
SCH2CH2N), 2.60 (m, 2 H, OCH2CH2CH2S), 2.03, 2.01 (2 s, 6 H,
H, 1-H), 5.53 (d, J = 3.2 Hz, 1 H, 4-H), 5.47 (dd, J = 10.8, 3.2 Hz,
1 H, 3-H), 5.38 (dd, J = 10.8, 3.6 Hz, 1 H, 2-H), 4.42 (t, J = 6.7 Hz,
2 COCH3), 1.84 (m, 2 H, OCH2CH2CH2S), 1.17 (d, J = 6.7 Hz, 3 1 H, 5-H), 4.15 (dd, J = 11.3, 6.7 Hz, 1 H, 6a-H), 4.07 (dd, J =
H, 6BЈ-H), 1.14 (d, J = 6.7 Hz, 3 H, 6B-H) ppm. 13C NMR 11.3, 6.7 Hz, 1 H, 6b-H), 3.97 (s, 2 H, ClCH2CO), 2.14, 2.00 (2 s,
(150 MHz, D2O, 295 K): δ = 174.6, 174.2 (C=O), 102.4 (C-1AЈ), 6 H, 2 COCH3) ppm. The NMR spectroscopic data are in agree-
101.7 (C-1C, C-1CЈ), 101.0 (C-1A), 98.7 (C-1B), 98.5 (C-1BЈ), 81.6 ment with those reported previously.[7]
(C-3C), 75.3, 75.0, 74.8, 74.7, 74.4 (C-3A, C-5A, C-5C, C-3AЈ, C-
5AЈ, C-5CЈ), 72.9 (C-4A, C-4AЈ), 72.4 (C-3CЈ), 71.8 (C-3B, C-3BЈ),
Allyl 2-Acetamido-6-O-benzyl-2-deoxy-3-O-trichloroethyloxyl-
carbonyl-β-D
-glucopyranoside (12): A solution of known[10] alcohol
71.0 (C-2C, C-2CЈ), 69.1 (C-3B, C-3BЈ), 68.6 (OCH2CH2), 68.3,
68.2 (C-4C, C-4CЈ), 67.6, 67.5 (C-2B, C-2BЈ), 66.6 (C-5B, C-5BЈ),
61.5 (C-6C, C-6CЈ), 59.7, 59.5 (C-6A, C-6AЈ), 55.9 (C-2A, C-2AЈ),
38.2 (SCH2CH2N), 28.4 (OCH2CH2CH2S), 28.1 (SCH2CH2N),
26.9 (OCH2CH2CH2S), 22.2 (COCH3), 15.2 (C-6B, C-6BЈ) ppm.
HRMS: calcd. for C45H79N3O29S [M + H]+ 1158.1800; found
1158.4630.
10 (1.8 g, 5.16 mmol) in pyridine (40 mL) was cooled to 0 °C under
an atmosphere of N2. 2,2,2-Trichloroethyl chloroformate (1.2 mL,
8.98 mmol, 1.7 equiv.) was added slowly to the stirred mixture over
15 min, and the mixture was allowed to warm up slowly to room
temperature and was stirred for 2 h. The mixture was co-concen-
trated with toluene (2ϫ100 mL), and the crude residue containing
benzylidene acetal 11 was dried under high vacuum overnight and
dissolved in anhydrous THF (90 mL). Activated 3 Å molecular si-
eves (4.5 g), NaCNBH3 (3.2 g, 51 mmol, 10 equiv.), and methyl
orange indicator were added, and the mixture was stirred for 2 h
under an atmosphere of N2 and cooled to 0 °C. A 2 m solution of
HCl in Et2O (ca. 20 mL) was added dropwise to the reaction mix-
ture at 0 °C until the methyl orange indicator turned pink, remained
as such for 10 min, and H2(g) was no longer generated. The reaction
mixture was stirred for 1 h at room temperature and filtered through
Celite, and the solids were washed with THF; the pooled filtrate
and washings were concentrated. Flash chromatography (CH2Cl2/
MeOH = 50:1) of the crude residue gave alcohol 12 (2.07 g, 77%)
pure as a colorless glass. [α]D = –33 (c = 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H, Ar), 5.86–5.78 (m, 2 H,
NH, CH=CH2), 5.24 (m, 2 H, CH=CH2), 5.17 (t, J = 10.0 Hz, 1
H, 3-H), 4.83 (d, J = 11.9 Hz, 1 H, CHHCCl3), 4.78 (d, J = 8.2 Hz,
1 H, 1-H), 4.67 (d, J = 11.9 Hz, 1 H, CHHCCl3), 4.56 (2d, J =
12.0 Hz, 2 H, CH2Ph), 4.31 (m, 1 H, CHHCH=CH2), 4.04 (m, 1
H, CHHCH=CH2), 3.80–3.63 (m, 4 H, 2-H, 4-H, 6ab-H), 3.57 (m,
1 H, 5-H), 3.19 (br. d, J = 3.2 Hz, 1 H, OH), 1.90 (s, 3 H, COCH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4, 154.5 (C=O), 137.5
(quat. Ar), 133.6 (CH2=CH), 128.5, 127.9, 127.7 (Ar), 117.6
(CH2=CH), 99.2 (C-1), 94.4 (CCl3), 79.7 (C-3), 76.9 (CH2CCl3),
73.7 (CH2Ph), 73.6 (C-5), 70.8 (C-4), 70.1 (CH2CH=CH2), 69.9 (C-
6), 55.0 (C-2), 23.4 (COCH3 ) ppm. HRMS: calcd. for
C21H26Cl3NO8 [M + H]+ 526.0802; found 526.0756.
2,4,6-Tri-O-acetyl-3-O-chloroacetyl-α-D-galactopyranosyl trichloro-
acetimidate (9): Triethylorthoacetate (17.9 mL, 100 mmol,
4.0 equiv.) and CSA (1.1 g, 0.16 equiv.) were added to a solution of
known[9] triol 6 (8.0 g, 24.4 mmol) in anhydrous MeCN (400 mL)
under an atmosphere of N2. The solution was stirred at room tem-
perature for 30 min, pyridine (96 mL) and Ac2O (56 mL) were then
added, and the mixture was stirred 2 h at 50 °C. The mixture was
co-concentrated with toluene (4ϫ100 mL), and the resulting oily
residue was left under high vacuum overnight. It was dissolved in
a mixture of AcOH (76 mL) and H2O (19 mL), and the mixture
was stirred for 10 min, then poured into sat. aq. NaHCO3
(200 mL). The solution was extracted with CH2Cl2 (3ϫ100 mL),
and the combined organic layers were dried, filtered, and concen-
trated to give the corresponding triacetate (8.6 g, 86% from 6) as
a white amorphous powder. Chloroacetyl chloride (4.0 mL,
2.0 equiv.) was added to a mixture of the triacetate in anhydrous
CH2Cl2 (245 mL) and pyridine (10.0 mL, 5.0 equiv.) at 0 °C. The
reaction mixture was stirred for 15 min, the solvent were evapo-
rated, and the residue was co-concentrated with toluene
(2 ϫ 50 mL). The resulting residue was dissolved in CH2Cl2
(400 mL) and washed sequentially with 8% HCl (200 mL), sat. aq.
NaHCO3 (200 mL), and brine (200 mL). The combined organic
layers were dried, filtered, and concentrated to give chloroacetate
7 (10.1 g, 98 %) as a white amorphous powder. NIS (6.4 g,
1.1 equiv.) and TfOH (0.40 mL, 0.2 equiv.) were added to a solu-
tion of chloroacetate 7 (10.1 g, 20.9 mmol) in a mixture of MeCN
(300 mL) and H2O (3 mL) at 0 °C. The reaction mixture was stirred
for 30 min at 0 °C, the reaction was quenched with Et3N (0.52 mL,
3.7 mmol), and the solvents were evaporated. The residue was dis-
solved in CH2Cl2 (300 mL) and was washed with a 20% w/w solu-
tion of aq. Na2S2O3 (100 mL). The organic layer was dried, filtered,
Allyl 2-Acetamido-4-O-(2,4,6-tri-O-acetyl-3-O-chloroacetyl-β-
lactopyranosyl)-6-O-benzyl-2-deoxy-3-O-trichloroethyloxylcarbonyl-
β- -glucopyranoside (13): A stirred solution of alcohol 12 (680 mg,
D-ga-
D
1.29 mmol) and galactosyl trichloroacetimidate 9 (2.10 g,
3.08 mmol, 3.1 equiv.) in CH2Cl2 (62 mL) was warmed up to 40 °C
in a round-bottomed flask equipped with drying tube containing
6870
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6864–6876

Convergent Preparation of DimLex Hexasaccharide Analogues
Drierite. BF3·OEt2 (325 μL, 2.0 equiv.) was added to the mixture,
which was stirred for 1 h at 40 °C. More donor 9 (0.10 g,
0.19 mmol, 0.15 equiv.) was added, and the reaction was left to
proceed for an additional 30 min. The reaction was quenched with
Et3N (430 μL) and diluted with CH2Cl2 (50 mL). The mixture was
washed with sat. aq. NaHCO3 (50 mL), the aqueous layer was re-
extracted with CH2Cl2 (2ϫ20 mL), and the combined organic lay-
ers were dried, filtered, and concentrated. Column chromatography
(EtOAc/hexanes = 45:55 Ǟ 70:30) of the residue gave disaccharide
13 (860 mg, 75%) pure as a colorless glass. [α]D = +5 (c = 1.0,
CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 7.42–7.22 (m, 5 H, Ar),
(480 mg, 0.589 mmol) and known[8] donor 15 (1.18 g, 1.77 mmol,
3.0 equiv.) were dissolved in CH2Cl2 (30 mL) under an atmosphere
of N2. The mixture was cooled to 0 °C and freshly distilled
TMSOTf (212 μL, 1.18 mmol, 3.0 equiv.) was added. After stirring
at 0 °C for 45 min, the reaction was quenched with Et3N (200 μL.
1.41 mmol), the solids were filtered off and washed with CH2Cl2,
and the combined filtrate and washing were concentrated. A mix-
ture of EtOAc/hexanes (1:1, ca. 50 mL) was added to the residue,
and a white amorphous solid was filtered off and washed with
EtOAc/hexanes (1:1). It was identified as pure trisaccharide 16
(400 mg, 54%). The mother liquor and washing were combined
5.85 (m, 1 H, CH=CH), 5.77 (d, J = 8.5 Hz, 1 H, NH), 5.29–5.14 and concentrated, and column chromatography (CH2Cl2/MeOH =
(m, 4 H, 3-H, 4Ј-H, CH2=CH), 5.04 (dd, J = 10.4, 8.0 Hz, 1 H, 2Ј- 50:1) on the residue gave additional trisaccharide 16 (250 mg, 33%)
H), 4.92 (d, J = 11.8 Hz, 1 H, CHHCCl3), 4.88 (dd, J = 10.4,
pure as a white amorphous powder. [α]D = –65 (c = 0.5, DMSO).
3.5 Hz, 1 H, 3Ј-H), 4.75 (m, 2 H, 1-H, CHHPh), 4.66 (d, J = 1H NMR (600 MHz, [D6]DMSO): δ = 9.00 (d, J = 9.2 Hz, 1 H,
11.9 Hz, 1 H, CHHCCl3), 4.45 (d, J = 12.1 Hz, 1 H, CHHPh), 4.42 NHЈЈ), 8.00 (d, J = 9.1 Hz, 1 H, NH), 7.30 (m, 10 H, Ar), 5.83 (m,
(d, J = 8.0 Hz, 1 H, 1Ј-H), 4.32 (m, 1 H, OCHHCH=CH2), 4.14–
1 H, OCH2CH=CH2), 5.65 (s, 1 H, CHPh), 5.44 (t, J = 9.9 Hz, 1
4.03 (m, 3 H, 6abЈ-H, OCHHCH=CH2), 4.01–3.91 (m, 3 H, 4-H, H, 3ЈЈ-H), 5.30 (br. d, J = 3.7 Hz, 1 H, 4Ј-H), 5.20 (m, 1 H, -
CH2Cl), 3.78 (q, J = 8.4 Hz, 1 H, 2-H), 3.73 (s, 2 H, 6ab-H), 3.69 CH=CHH), 5.11 (m, 1 H, CH=CHH), 5.00 (d, J = 12.3 Hz, 1 H,
(m, 1 H, 5Ј-H), 3.53 (m, 1 H, 5-H), 2.13, 2.03, 1.96, 1.92 (4s, 12 H, CHHCCl3), 4.91 (d, J = 7.9 Hz, 1 H, 1ЈЈ-H), 4.83 (t, J = 9.8 Hz, 1
4 COCH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.4, 170.3,
169.2, 166.5, 153.7 (C=O), 137.7 (quat. Ar), 133.6 (CH=CH2),
H, 3-H), 4.76 (dd, J = 10.5, 8.3 Hz, 1 H, 2Ј-H), 4.67 (d, J = 12.3 Hz,
1 H, CHHCl3), 4.59 (d, J = 12.2 Hz, 1 H, CHHPh), 4.55 (d, J =
128.6, 128.1 (Ar), 117.6 (CH2=CH), 100.3 (C-1Ј), 99.0 (C-1), 94.4 8.4 Hz, 1 H, 1-H), 4.49 (d, J = 12.2 Hz, 1 H, CHHPh), 4.46–4.40
(CCl3), 76.8 (C-3, CH2CCl3), 75.2 (C-4), 74.1 (C-5), 73.7 (CH2Ph), (m, 2 H, 1Ј-H, CHHCl), 4.21–4.15 (m, 3 H, 6aЈЈ-H, CHHCl,
72.5 (C-3Ј), 70.3 (C-5Ј), 69.8 (OCH2CH=CH2), 68.7 (C-2Ј), 67.4 CHHCH=CH2), 4.01–3.96 (m, 2 H, 6aЈ-H, CHHCH=CH2), 3.92
(C-6), 66.5 (C-4Ј), 60.5 (C-6Ј), 54.6 (C-2), 40.3 (CH2Cl), 23.3, 20.7,
(dd, J = 10.3, 3.2 Hz, 1 H, 3Ј-H), 3.89–3.66 (m, 8 H, 2-H, 4-H, 6a-
20.6 (COCH3) ppm. HRMS: calcd. for C35H43Cl4NO17 [M + H]+ H, 5Ј-H, 6bЈ-H, 2ЈЈ-H, 4ЈЈ-H, 6bЈЈ-H), 3.58 (dd, J = 11.0, 4.5 Hz,
890.1363; found 890.1371.
1 H, 6b-H), 3.49 (m, 1 H, 5-H), 3.40 (m, 1 H, 5ЈЈ-H), 2.00, 1.97,
1.94, 1.66 (4s, 12 H, 4 COCH3) ppm. 13C NMR (150 MHz, [D6]
DMSO): δ = 170.1, 169.7, 169.1, 168.7, 166.7, 161.5, 153.0 (C=O),
138.1, 137.1 (quat. Ar), 134.4 (CH=CH2), 128.9, 128.4, 128.1,
127.6, 127.5, 126.1, 126.0 (Ar), 116.4 (CH2=CH-CH2), 100.2
(CHPh), 100.1 (C-1Ј), 99.3 (C-1), 98.7 (C-1ЈЈ), 94.8, 92.5 (CCl3),
78.3 (C-3), 77.3 (C-4ЈЈ), 75.9 (CH2CCl3), 75.7 (C-4, C-3Ј), 73.7 (C-
5), 72.7 (C-3ЈЈ), 72.4 (CH2Ph), 70.1 (C-5Ј), 69.7 (C-2Ј), 69.0
(CH2CH=CH2), 67.7 (C-6), 67.6 (C-4Ј), 67.3 (C-6ЈЈ), 65.8 (C-5ЈЈ),
61.5 (C-6Ј), 55.9 (C-2ЈЈ), 53.0 (C-2), 40.7 (CH2Cl), 22.7, 20.7, 20.6
(COCH3) ppm. HRMS: calcd. for C50H57Cl7N2O22 [M + H]+
1283.1300; found 1283.1344.
Allyl 2-Acetamido-4-O-(2,4,6-tri-O-acetyl-β-
O-benzyl-2-deoxy-3-O-trichloroethyloxylcarbonyl-β-
D
-galactopyranosyl)-6-
D
-gluco-
pyranoside (14): To a solution of disaccharide 13 (850 mg,
0.954 mmol) dissolved in pyridine/EtOH (1:1, 20 mL) was added
thiourea (362 mg, 5 equiv.), and the solution was stirred at 80 °C
for 2 h. The solvents were evaporated, and the residue was co-con-
centrated with toluene (3ϫ50 mL). The residue was dissolved in
CH2Cl2 and washed with 2 m HCl (100 mL), NaHCO3 (50 mL),
and brine (50 mL), and the aqueous layers were re-extracted with
CH2Cl2 (50 mL). The combined organic layers were dried, filtered,
and concentrated. Column chromatography (EtOAc/hexanes = 7:3)
of the residue gave alcohol 14 (660 mg, 84%) pure as a colorless
Allyl 2-Acetamido-4-O-[2,4,6-tri-O-acetyl-3-O-(6-O-benzyl-3-
1
glass. [α]D = –22 (c = 1.0, CH2Cl2). H NMR (600 MHz, CDCl3):
chloroacetyl-2-deoxy-2-trichloroacetamido-β-
D
-glucopyranosyl)-β-
δ = 7.40–7.25 (m, 5 H, Ar), 5.85 (m, 1 H, CH=CH2), 5.69 (d, J =
8.5 Hz, 1 H, NH), 5.28–5.13 (m, 4 H, 3-H, 4Ј-H, CH2=CH-), 4.91
(d, J = 11.9 Hz, 1 H, CHHCCl3), 4.78 (dd, J = 10.1, 8.0 Hz, 1 H,
2Ј-H), 4.72 (d, J = 7.9 Hz, 1 H, 1-H),4.70 (d, J = 12.2 Hz, 1 H,
CHHPh), 4.62 (d, J = 11.8 Hz, 1 H, CHHCCl3), 4.47 (d, J =
12.1 Hz, 1 H, CHHPh), 4.40 (d, J = 8.0 Hz, 1 H, 1Ј-H),4.30 (m, 1
H, CHHCH=CH2), 4.09 (m, 3 H, 6abЈ-H, CHHCH=CH2), 3.94 (t,
J = 8.7 Hz, 1 H, 4-H), 3.81–3.70 (m, 3 H, 2-H, 6ab-H), 3.67–3.59
(m, 2 H, 3Ј-H, 5Ј-H), 3.52 (m, 1 H, 5-H), 2.52 (d, J = 6.1 Hz, 1 H,
OH), 2.12, 2.02, 2.01, 1.92 (4s, 12 H, 4 COCH3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 171.0, 170.8, 170.5, 170.2, 153.7 (C=O),
137.9 (quat. Ar), 133.6 (CH=CH2), 128.8, 128.6 (Ar), 117.6
(CH=CH2), 100.4 (C-1Ј), 99.1 (C-1), 94.5 (CCl3), 77.3 (C-3), 76.7
(CH2CCl3), 75.3 (C-4), 74.3 (C-5), 73.6 (CH2Ph), 72.7 (C-2Ј), 71.3
(C-3Ј), 70.6 (C-5Ј), 69.8 (CH2CH=CH2), 69.2 (C-4Ј), 67.6 (C-6),
61.1 (C-6Ј), 54.6 (C-2), 23.3, 21.9, 20.8, 20.7 (COCH3) ppm.
HRMS: calcd. for C33H42Cl3NO16 [M + H]+ 814.1647; found
814.1605.
D
-galactopyranosyl]-6-O-benzyl-2-deoxy-3-O-trichloroethyloxyl-
carbonyl-β-D-glucopyranoside (17): Benzylidene acetal 16 (300 mg,
0.233 mmol) was reductively opened as described for the synthesis
of acceptor 12. Flash chromatography (CH2Cl2/MeOH = 100:1Ǟ
40:1) of the crude residue gave alcohol 17 (228 mg, 76%) pure as
a colorless glass. [α]D = –21 (c = 1.0, CH2Cl2). 1H NMR (600 MHz,
CDCl3): δ = 7.41–7.25 (m, 10 H, Ar), 6.84 (d, J = 8.7 Hz, 1 H,
NHЈЈ), 5.81 (m, 1 H, CH=CH2), 5.75 (d, J = 8.9 Hz, 1 H, NH),
5.34 (br. d, J = 3.4 Hz, 1 H, 4Ј-H), 5.26–5.21 (m, 2 H, 3ЈЈ-H,
CH=CHH), 5.15 (m, 1 H, CH=CHH), 5.05 (t, J = 9.8 Hz, 1 H, 3-
H), 4.96 (t, J = 8.2 Hz, 1 H, 2Ј-H), 4.86 (d, J = 11.9 Hz, 1 H,
CHHCCl3), 4.70 (d, J = 8.1 Hz, 1 H, 1ЈЈ-H), 4.67 (d, J = 12.1 Hz,
1 H, CHHPh), 4.66–4.60 (m, 3 H, 1-H, CHHPh, CHHCCl3), 4.54
(d, J = 11.8 Hz, 1 H, CHHPh), 4.46 (d, J = 12.1 Hz, 1 H, CHHPh),
4.30 (d, J = 8.1 Hz, 1 H, 1Ј-H), 4.28 (m, 1 H, CHH=CH2), 4.12–
3.89 (m, 7 H, 2-H, 4-H, 6aЈ-H, 6bЈ-H, CHH=CH2, CH2Cl), 3.82
(dd, J = 10.1, 5.0 Hz, 1 H, 6aЈЈ-H), 3.78–3.62 (m, 7 H, 6a-H, 6b-
H, 3Ј-H, 5Ј-H, 2ЈЈ-H, 4ЈЈ-H, 6bЈЈ-H), 3.58 (m, 1 H, 5ЈЈ-H), 3.52 (m,
1 H, 5-H), 3.15 (d, J = 3.5 Hz, OH), 2.09, 2.00, 1.90 (3s, 12 H, 3
COCH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.5, 170.1,
170.0, 169.3, 168.0, 162.0, 153.5 (C=O), 137.9, 137.3 (quat. Ar),
133.5 (CH=CH2), 128.6, 128.5, 128.1, 127.9, 127.8 (Ar), 117.4
Allyl 2-Acetamido-4-O-[2,4,6-tri-O-acetyl-3-O-(4,6-O-benzylidene-
3-chloroacetyl-2-deoxy-2-trichloroacetamido-β-
D-glucopyranosyl)-β-
D
-galactopyranosyl]-6-O-benzyl-2-deoxy-3-O-trichloroethyloxyl-
carbonyl-β-D-glucopyranoside (16): Disaccharide acceptor 14
Eur. J. Org. Chem. 2011, 6864–6876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6871

J. L. Hendel, F.-I. Auzanneau
FULL PAPER
(CH=CH2), 100.4 (C-1Ј), 99.4 (C-1ЈЈ), 99.1 (C-1), 94.4, 92.1 (CCl3),
(c = 0.8, CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 7.41–7.25 (m,
77.1 (CH2CCl3), 76.7 (C-3), 75.5 (C-3ЈЈ), 75.1 (C-4ЈЈ), 74.5 (C-4), 10 H, Ar), 6.70 (d, J = 8.6 Hz, 1 H, NHAЈ), 5.82 (m, 1 H,
74.3 (C-5), 73.9 (C-5ЈЈ), 73.8, 73.6 (CH2Ph), 70.9 (C-3Ј, C-5Ј), 70.6
(C-2Ј), 70.1 (C-6ЈЈ), 69.6 (CH2=CHCH2), 68.4 (C-4Ј), 67.8 (C-6),
61.4 (C-6Ј), 56.1 (C-2ЈЈ), 53.3 (C-2), 40.6 (CH2Cl), 23.3, 21.1, 20.8,
20.7 (COCH3) ppm. HRMS: calcd. for C50H59Cl7N2O22 [M + H]+
1285.1460; found 1285.1431.
CH=CH2), 5.74 (d, J = 8.9 Hz, 1 H, NHA), 5.36 (d, J = 3.2 Hz, 1
H, 4C-H), 5.29–5.20 (m, 3 H, 3AЈ-H, 4CЈ-H, CHH=CH), 5.15 (m,
1 H, CHH=CH-), 5.06 (br. t, J = 8.3 Hz, 1 H, 3A-H), 5.00 (dd, J
= 10.0, 8.1 Hz, 1 H, 2C-H), 4.97 (dd, J = 10.4, 8.0 Hz, 1 H, 2CЈ-
H), 4.87 (d, J = 11.9 Hz, 1 H, CHHCCl3), 4.82 (dd, J = 10.4,
3.5 Hz, 1 H, 3CЈ-H), 4.75 (d, J = 11.9 Hz, 1 H, CHHCCl3), 4.70–
4.60 (m, 4 H, 1A-H, 1AЈ-H, 2 CHHPh), 4.52–4.45 (m, 2 H, 2
CHHPh), 4.43 (d, J = 8.0 Hz, 1 H, 1CЈ-H), 4.31 (d, J = 8.0 Hz, 1
H, 1C-H), 4.28 (m, 1 H, CHHCH=CH2), 4.10–3.88 (m, 10 H, 2A-
H, 4A-H, 6abC-H, 4AЈ-H, 6abCЈ-H, CH2Cl, CHHCH=CH2),
3.77–3.64 (m, 8 H, 6abA-H, 3C-H, 5C-H, 2AЈ-H, 6abAЈ-H, 5CЈ-
H), 3.53 (m, 1 H, 5A-H or 5AЈ-H), 3.46 (m, 1 H, 5A-H or 5AЈ-H),
2.11, 2.10, 2.06, 1.99, 1.97, 1.94, 1.91 (8s, 24 H, 8 COCH3) ppm.
13C NMR (150 MHz, CDCl3): δ = 170.5, 170.4, 170.2, 170.1, 170.0,
169.2, 168.9, 166.9, 161.8, 153.5 (C=O), 137.9, 137.5 (quat. Ar),
133.5 (CH=CH2), 128.7, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8,
127.5 (Ar), 117.4 (CH=CH2), 100.4 (C-1C, C-1CЈ), 99.6 (C-1AЈ),
99.1 (C-1A), 94.4, 92.0 (CCl3), 76.7 (C-3A, CHCCl3), 75.4 (C-3C),
74.9, 74.5, 74.3 (C-4A, C-4AЈ, C-5A, C-5AЈ), 73.6 (CH2Ph), 72.8
(C-3AЈ), 71.0, 70.9, 70.8, 70.7 (C-2C, C-5C, C-3CЈ, C-5CЈ), 69.6
(CH2CH=CH2), 69.0 (C-2CЈ), 68.4 (C-4C), 67.8, 67.0 (C-6A, C-
6AЈ), 66.8 (C-4CЈ), 61.5, 61.1 (C-6C, C-6CЈ), 56.0 (C-2AЈ), 53.3 (C-
2A), 40.5 (CH2Cl), 23.3, 21.2, 20.8, 20.7 (COCH3) ppm. HRMS:
calcd. for C6 4 H7 7 Cl7 N2 O3 1 [M + H]+ 1615.2410; found
1615.2451.
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-
O-acetyl-β-
2-trichloroacetamido-β-
O-benzyl-2-deoxy-3-O-trichloroethyloxylcarbonyl-β-
D
-glucopyranosyl)-6-O-benzyl-3-chloroacetyl-2-deoxy-
-glucopyranosyl]-β- -galactopyranosyl}-6-
-gluco-
D
D
D
pyranoside (20): A stirred solution of alcohol 17 (115 mg,
0.09 mmol) and glucosyl trichloroacetimidate 18[13] (221 mg,
0.45 mmol, 5.0 equiv.) in CH2Cl2 (5.0 mL) was warmed up to
40 °C. BF3·OEt2 (23 μL, 2.0 equiv.) was added, and the reaction
mixture was stirred for 45 min at 40 °C. The reaction was quenched
with Et3N (29 μL) and diluted with CH2Cl2 (20 mL). The mixture
was washed with sat. aq. NaHCO3 (20 mL), the aqueous layer was
re-extracted with CH2Cl2 (2ϫ20 mL), and the combined organic
layers were dried, filtered, and concentrated. Column chromatog-
raphy (EtOAc/hexanes = 6:4) gave tetrasaccharide 20 (126 mg,
85%) pure as a colorless glass. [α]D = –11 (c = 1.0, CH2Cl2). 1H
NMR (600 MHz, CDCl3): δ = 7.39–7.21 (m, 10 H, Ar), 6.52 (d, J =
8.6 Hz, 1 H, NHAЈ), 5.81 (m, 1 H, CH=CH2), 5.70 (d, J = 8.8 Hz, 1
H, NHA), 5.37 (d, J = 3.1 Hz, 1 H, 4C-H), 5.27–5.19 (m, 2 H,
3AЈ-H, CHH=CH), 5.15 (m, 1 H, CHH=CH), 5.06 (dd, J = 8.5,
7.8 Hz, 1 H, 3A-H), 5.05–4.95 (m, 3 H, 2C-H, 3CЈ-H, 4CЈ-H), 4.87
(d, J = 11.9 Hz, 1 H, CHHCCl3), 4.82 (t, J = 8.2 Hz, 1 H, 2CЈ-H),
4.77 (d, J = 11.9 Hz, 1 H, CHHPh), 4.70–4.62 (m, 4 H, 1A-H, 1AЈ-
H, CHHPh, CHHCCl3), 4.53–4.46 (m, 3 H, 1CЈ-H, 2 CHHPh),
4.43 (dd, J = 12.7, 3.9 Hz, 1 H, 6aCЈ-H), 4.33 (d, J = 8.0 Hz, 1 H,
1C-H), 4.29 (m, 1 H, OCH2CH=CH2), 4.13 (d, J = 15.4 Hz, 1 H,
CHHCl), 4.09 (dd, J = 11.4, 6.8 Hz, 1 H, 6aC-H), 4.05–3.89 (m, 7
H , 2 A - H , 4 A - H , 6 b C - H , 4 A Ј - H , 6 b C - H , C H H C l ,
OCHHCH=CH2), 3.78–3.69 (m, 7 H, 6abA-H, 3C-H, 5C-H, 2AЈ-
H, 6abAЈ-H), 3.53 (m, 1 H, 5A-H), 3.43 (m, 2 H, 5AЈ-H, 5CЈ-H),
2.09, 2.06, 1.97, 1.95, 1.94, 1.89 (8s, 24 H, 8 COCH3) ppm. 13C
NMR (150 MHz, CDCl3): δ = 170.5, 170.4, 170.2, 170.1, 170.0,
169.3, 169.1, 168.8, 167.1, 161.9, 153.6 (C=O), 138.0, 137.6 (quat.
Ar), 133.6 (CH=CH2), 128.7, 128.5, 128.3, 128.1, 127.9 (Ar), 117.4
(CH=CH2), 100.5 (C-1 C), 100.3 (C-1CЈ), 99.7 (C-1AЈ), 99.1 (C-
1A), 94.4 (CCl3), 76.9 (C-3A, CH2CCl3), 75.4 (C-3 C), 74.94 (C-
5AЈ), 74.6, 74.5 (C-4A, C-4AЈ), 74.3 (C-5A), 73.7, 73.6 (CH2Ph),
72.9 (C-3CЈ), 72.6 (C-3AЈ), 72.0 (C-5CЈ), 71.4 (C-2CЈ), 71.1 (C-
5C), 70.9 (C-2C), 69.6 (OCH2CH=CH2), 68.5 (C-4C), 67.9 (C-6A
or C-6AЈ), 67.4 (C-4CЈ), 66.9 (C-6A or C-6AЈ), 61.6 (C-6C), 61.1
(C-6CЈ), 56.3 (C-2AЈ), 53.4 (C-2A), 40.4 (CH2Cl), 23.3, 21.2, 20.8,
20.7 20.6, 20.5 (COCH3) ppm. HRMS: calcd. for C64H77Cl7N2O31
[M + H]+ 1615.4210; found 1615.2452.
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-
O-acetyl-β-
acetamido-β-
deoxy-3-O-trichloroethyloxylcarbonyl-β-
D
-glucopyranosyl)-6-O-benzyl-2-deoxy-2-trichloro-
-glucopyranosyl]-β- -galactopyranosyl}-6-O-benzyl-2-
-glucopyranoside (22): To
D
D
D
a solution of tetrasaccharide 20 (126 mg, 0.077 mmol) dissolved in
pyridine/EtOH (1:1, 10 mL) was added thiourea (58 mg, 10 equiv.),
and the solution was heated at 80 °C for 24 h. The mixture was co-
concentrated with toluene (2ϫ20 mL), and the residue was dis-
solved in CH2Cl2 (100 mL) and washed with 1 m HCl (100 mL),
NaHCO3 (50 mL), and brine (50 mL). The aqueous layers were re-
extracted with CH2Cl2 (50 mL), and the combined organic layers
were dried, filtered, and concentrated. Column chromatography
(CH2Cl2/MeOH = 60:1) of the residue gave alcohol 22 (97 mg,
80%) pure as a colorless glass. [α]D = +5 (c = 1.0, CH2Cl2). 1H
NMR (600 MHz, CDCl3): δ = 7.41–7.25 (m, 10 H, Ar), 6.71 (d, J =
7.4 Hz, 1 H, NHAЈ), 5.81 (m, 1 H, CH=CH2), 5.71 (d, J = 8.8 Hz, 1
H, NHA), 5.37 (d, J = 3.4 Hz, 1 H, 4C-H), 5.24 (m, 1 H,
CHH=CH), 5.17–5.11 (m, 2 H, 3CЈ-H, CHH=CH), 5.06 (br. t, J
= 8.5 Hz, 1 H, 3A-H), 4.99 (dd, J = 10.0, 8.0 Hz, 1 H, 2C-H), 4.97–
4.91 (m, 3 H, 1AЈ-H, 2CЈ-H, 4CЈ-H), 4.86 (d, J = 11.9 Hz, 1 H,
CHHCCl3), 4.71 (d, J = 12.0 Hz, 1 H, CHHPh), 4.68–4.61 (m, 3
H, 1A-H, CHHPh, CHHCCl3), 4.54–4.45 (m, 3 H, 1CЈ-H, 2
CHHPh), 4.31–4.15 (m, 2 H, 1CЈ-H, OCHHCH=CH2), 4.15 (dd,
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-
O-acetyl-β-
deoxy-2-trichloroacetamido-β-
galactopyranosyl}-6-O-benzyl-2-deoxy-3-O-trichloroethyloxyl-
carbonyl-β-
D-galactopyranosyl)-6-O-benzyl-3-chloroacetyl-2- J = 12.3, 2.5 Hz, 1 H, 6aCЈ-H), 4.10–3.90 (m, 7 H, 2A-H, 4A-H,
D
-glucopyranosyl]-β-
D
-
6abC-H, 3AЈ-H, 6bCЈ-H, CHHCH=CH2), 3.88 (d, J = 1.6 Hz, 1
H, OH), 3.76–3.58 (m, 8 H, 6abA-H, 3C-H, 5C-H, 4AЈ-H, 6abAЈ-
D-glucopyranoside (21): Alcohol 17 (120 mg, 0.09 mmol) H, 5CЈ-H), 3.53 (m, 1 H, 5A-H or 5AЈ-H), 3.48 (m, 1 H, 5A-H or
was coupled to donor 19[13] (229 mg, 0.605 mmol, 5.0 equiv.) in
CH2Cl2 (5.0 mL) as described above for the preparation of tetrasac-
charide 20. After 1 h of reaction at 40 °C, additional donor 19
(60 mg, 1.5 equiv.) was added, and the reaction was left to proceed
for another 1 h at 40 °C. The reaction was quenched with Et3N
(29 μL) and worked up as described above for the preparation of
compound 20. Column chromatography (EtOAc/hexanes = 6:4),
followed by RP HPLC (CH3CN/H2O = 60:40 Ǟ 100:0) gave tetra-
saccharide 21 (108 mg, 72%) pure as a colorless glass. [α]D = –10
5AЈ-H), 3.37 (m, 1 H, 2AЈ-H), 2.05, 1.98, 1.97, 1.94, 1.93, 1.91,
1.90, 1.87 (8s, 24 H, 8 COCH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 170.5, 170.0, 169.3, 169.2, 169.1, 161.7, 153.5 (C=O),
138.0, 137.9 (quat. Ar), 133.5 (CH=CH2), 128.1 (Ar), 117.4
(CH=CH2), 101.1 (C-1CЈ), 100.5 (C-1C), 99.1 (C-1A), 99.0 (C-
1AЈ), 94.4 (CCl3), 81.4 (C-4AЈ), 77.1 (CH2CCl3), 76.7 (C-3A), 75.4
(C-3C), 74.4 (C-4A), 74.3, 74.1 (C-5A, C-5AЈ), 73.7, 73.6 (CH2Ph),
72.5, 72.01 (C-5C or C-5CЈ, C-3CЈ), 71.1 (C-5C or C-5CЈ, C-2C),
70.7 (C-2CЈ), 70.3 (C-3AЈ), 69.6 (CH2CH=CH2), 68.8 (C-4C), 68.3
6872
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6864–6876

Convergent Preparation of DimLex Hexasaccharide Analogues
(C-4CЈ), 67.9 (C-6A, C-6AЈ), 61.9 (C-6CЈ), 61.6 (C-6C), 58.8 (C- CH=CH2), 4.21 (dd, J = 12.4, 5.5 Hz, 1 H, 6aCЈ-H), 4.13 (dd, J =
2AЈ), 53.3 (C-2A), 23.3, 21.2, 20.9, 20.6 (COCH3) ppm. HRMS:
12.4, 2.4 Hz, 1 H, 6bCЈ-H), 4.10 (dd, J = 11.7, 4.6 Hz, 1 H, H6aC),
4.65 (m, 1 H, CHH-CH=CH2), 3.98 (dd, J = 11.5, 8.2 Hz, 1 H,
6bC-H), 3.89 (m, 1 H, 5C-H), 3.83 (dd, J = 10.0, 3.5 Hz, 1 H, 3C-
H), 3.81 (m, 1 H, 5CЈ-H), 3.78–3.68 (m, 5 H, 2AЈ-H, 6abA-H,
6abAЈ-H), 3.65 (dd, J = 10.3, 8.5 Hz, 1 H, 3A-H), 3.60–3.54 (m, 3
H, 4A-H, 3AЈ-H, 4AЈ-H), 3.51 (dd, J = 10.4, 8.5 Hz, 1 H, 2A-H),
3.49–3.42 (m, 2 H, 5A-H, 5AЈ-H), 2.13, 2.05, 2.04, 2.02, 2.00, 1.97,
1.96, 1.95, 1.93 (9s, 27 H, 9 COCH3) ppm. 13C NMR (150 MHz,
CD3OD): δ = 173.6, 173.5, 172.5, 172.1, 171.7, 171.4, 171.1 (C=O),
139.9, 139.8 (quat. Ar), 135.6 (CH=CH2), 129.8, 129.7, 129.3, 129.1
(Ar), 117.2 (CH=CH2), 103.2 (C-1C), 102.5 (C-1A), 102.0 (C-1AЈ),
101.8 (C-1CЈ), 81.9, 81.6 (C-4A, C-4AЈ), 78.3 (C-3C), 75.7 (C-5A,
C-5AЈ), 75.0, 74.8 (CH2Ph), 74.3 (C-3CЈ), 74.1 (C-3AЈ), 73.2 (C-
3A), 73.1 (C-5C), 73.0 (C-5CЈ), 72.9 (C-2CЈ), 71.9 (C-2C), 71.4 (C-
4C), 71.0 (CH2CH=CH2) 69.9 (C-4CЈ), 69.8, 69.5 (C-6A, C-6AЈ),
63.6 (C-6CЈ), 63.1 (C-6C), 57.3 (C-2AЈ), 56.6 (C-2A), 23.3, 23.0,
21.4, 20.9, 20.8 (COCH3) ppm. HRMS: calcd. for C59H78N2O28
[M + H]+ 1263.4819; found 1263.4850. Data for 25: [α]D = –8 (c =
calcd. for C62H76Cl6N2O30 [M + H]+ 1539.2656; found 1539.2692.
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-
O-acetyl-β-
acetamido-β-
2-deoxy-3-O-trichloroethyloxylcarbonyl-β-
D
-glucopyranosyl)-6-O-benzyl-2-deoxy-2-trichloro-
-glucopyranosyl]-β- -galactopyranosyl}-6-O-benzyl-
-glucopyranoside (23):
D
D
D
Tetrasaccharide 21 (70 mg, 0.043 mmol) was dechloroacetylated as
described for the synthesis of acceptor 22. Column chromatography
(CH2Cl2/MeOH = 60:1 Ǟ 20:1) of the crude residue gave alcohol
23 (64 mg, 95%) pure as a colorless glass. [α]D = +10 (c = 0.7,
CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 7.42–7.23 (m, 10 H,
Ar), 6.75 (d, J = 7.3 Hz, 1 H, NHAЈ), 5.82 (m, 1 H, CH=CH2),
5.75 (d, J = 8.8 Hz, 1 H, NHA), 5.36 (d, J = 3.5 Hz, 1 H, 4C-H),
5.33 (d, J = 3.5 Hz, 1 H, 4CЈ-H), 5.24 (m, 1 H, CHH=CH), 5.18–
5.12 (m, 2 H, 2CЈ-H, CHH=CH), 5.05 (br. d, J = 8.6 Hz, 1 H, 3A-
H), 4.98 (dd, J = 10.0, 7.9 Hz, 1 H, 2C-H), 4.96 (d, J = 8.1 Hz, 1
H, 1AЈ-H), 4.92 (dd, J = 10.7, 3.3 Hz, 1 H, 3CЈ-H), 4.86 (d, J =
11.9 Hz, 1 H, CHHCCl3), 4.71 (d, J = 12.0 Hz, 1 H, CHHPh), 4.68
(d, J = 12.1 Hz, 1 H, CHHPh), 4.63 (d, J = 7.2 Hz, 1 H, 1A-H),
4.61 (d, J = 12.1 Hz, 1 H, CHHCCl3), 4.51 (d, J = 11.9 Hz, 1 H,
CHHPh), 4.48 (d, J = 8.3 Hz, 1 H, 1CЈ-H), 4.46 (d, J = 12.1 Hz,
1 H, CHHPh), 4.29 (m, 2 H, 1C-H, CHHCH=CH2), 4.12–3.89 (m,
10 H, 2A-H, 4A-H, 5C-H, 6abC-H, 3AЈ-H, 6abC Ј- H,
CHHCH=CH2, OH), 3.76–3.57 (m, 7 H, 6abA-H, 3C-H, 4AЈ-H,
6abAЈ-H, 5CЈ-H), 3.55–3.48 (m, 2 H, 5A-H, 5AЈ-H), 3. 24 (m, 1
H, 2AЈ-H), 2.15, 2.12, 2.04, 2.01, 1.99, 1.98, 1.94 (8s, 24 H, 8
COCH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.5, 170.4,
170.1, 170.0, 169.9, 169.2, 161.7, 153.5 (C=O), 138.0, 137.9 (quat.
Ar), 133.6 (CH=CH2), 128.6, 128.5, 128.4, 128.2, 128.0, 127.9,
127.7, 127.4 (Ar), 117.4 (CH=CH2), 101.5 (C-1CЈ), 100.5 (C-1C),
99.1 (C-1A), 99.0 (C-1AЈ), 94.4, 92.4 (CCl3), 81.5 (C-4AЈ), 76.8
(CH2CCl3), 76.7 (C-3A), 75.5 (C-3C), 74.4 (C-4A), 74.2, 74.1 (C-
5A, C-5AЈ), 73.7, 73.6 (CH2Ph), 71.3, 71.0 (C-5C, C-5CЈ), 70.7 (C-
2C, C-3CЈ), 70.1 (C-3AЈ), 69.6 (CH2CH=CH3), 68.8 (C-4C), 68.6
(C-2CЈ), 67.9, 67.8 (C-6A, C-6AЈ), 66.8 (C-4CЈ), 61.6 (C-6C, C-
6CЈ), 58.8 (C-2AЈ), 53.3 (C-2A), 23.3, 21.2, 20.9, 20.7, 20.6
(COCH3) ppm. HRMS: calcd. for C62H76Cl6N2O30 [M + H]+
1539.2692; found 1539.2692.
1
0.6, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.42–7.23 (m, 10
H, Ar), 6.51 (d, J = 8.7 Hz, 1 H, NHAЈ), 5.85 (m, 1 H, CH=CH2),
5.58 (d, J = 8.9 Hz, 1 H, NHA), 5.33 (br. d, J = 3.4 Hz, 1 H, 4C-
H), 5.23 (m, 1 H, CHH=CH), 5.15 (m, 1 H, CHH=CH), 5.13 (t, J
= 9.3 Hz, 1 H, 3CЈ-H), 5.07 (dd, J = 9.7, 8.1 Hz, 1 H, 2C-H), 4.97
(t, J = 9.7 Hz, 1 H, 4CЈ-H), 4.94 (dd, J = 9.7, 8.1 Hz, 1 H, 2CЈ-
H), 4.85 (d, J = 8.0 Hz, 1 H, 1AЈ-H), 4.75–4.65 (m, 3 H, 1A-H, 2
CHHPh), 4.54–4.46 (m, 3 H, 1CЈ-H, 2 CHHPh), 4.34–4.26 (m, 2
H, 1C-H, CHHCH=CH2), 4.16–3.85 (m, 9 H, 3A-H, 6abC-H, 3AЈ-
H, 6abCЈ-H, CH2Cl, CHHCH=CH2), 3.74–3.42 (m, 12 H, 2A-H,
4A-H, 5A-H, 6abA-H, 3C-H, 5C-H, 4AЈ-H, 5AЈ-H, 6abAЈ-H, 5CЈ-
H), 3.25 (m, 1 H, 2ЈЈ-H), 2.16, 2.13, 2.06, 2.03, 2.02, 1.99, 1.97 (8s,
24 H, 8 COCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5,
170.4, 170.1, 170.0, 169.3, 169.0, 166.1 (C=O), 138.2, 138.0 (quat.
Ar), 133.9 (CH=CH2), 128.6, 128.4, 127.9, 127.7, 127.6 (Ar), 117.5
(CH=CH2), 101.2 (C-1C), 101.0 (C-1CЈ), 99.9 (C-1AЈ), 99.3 (C-
1A), 81.3, 81.1 (C-4A, C-4AЈ), 76.0 (C-3C), 74.0 (C-5A, C-5AЈ),
73.6 (CH2Ph) 72.5 (C-3CЈ), 72.0, 71.7, 71.3 (C-5A, C-3A or C-3AЈ,
C-5AЈ), 71.1 (C-2CЈ), 70.5 (C-3A or C-3AЈ, C-2C), 69.7
(CH2CH=CH2), 69.0 (C-4C), 68.2 (C-4CЈ), 68.0 (C-6A, C-6AЈ),
62.2, 61.8 (C-6C, C-6CЈ), 57.5 (C-2AЈ), 56.5 (C-2A), 42.6 (CH2Cl),
23.5, 21.0, 20.7, 20.5 (COCH3) ppm. HRMS: calcd. for
C59H77ClN2O28 [M + H]+ 1297.4430; found 1297.4458.
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[2-acetamido-4-O-
(2,3,4,6-tetra-O-acetyl-β-
-glucopyranosyl]-β- -galactopyranosyl}-6-O-benzyl-2-deoxy-β-
glucopyranoside (24) and allyl 2-acetamido-4-O-{2,4,6-tri-O-acetyl-
3-O-[4-O-(2,3,4,6-tetra-O-acetyl-β-
2-chloroacetamido-2-deoxy-β- -glucopyranosyl]-β-
pyranosyl}-6-O-benzyl-2-deoxy-β- -glucopyranoside (25): To a solu-
D-glucopyranosyl)-6-O-benzyl-2-deoxy-β-
D
D
D-
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[2-acetamido-4-O-
D
-glucopyranosyl)-6-O-benzyl- (2,3,4,6-tetra-O-acetyl-β-
-galacto- β- -glucopyranosyl]-β- -galactopyranosyl}-6-O-benzyl-2-deoxy-β-
-glucopyranoside (26) and allyl 2-acetamido-4-O-{2,4,6-tri-O-ace-
tyl-3-O-[4-O-(2,3,4,6-tetra-O-acetyl-β- -galactopyranosyl)-6-O-
benzyl-2-chloroacetamido-2-deoxy-β- -glucopyranosyl]-β-
galactopyranosyl}-6-O-benzyl-2-deoxy-β- -glucopyranoside (27):
Tetrasaccharide 23 (65 mg, 0.042 mmol) was treated with Zn in
D-galactopyranosyl)-6-O-benzyl-2-deoxy-
D
D
D
D
D
D
tion of tetrasaccharide 22 (30 mg, 0.020 mmol) dissolved in AcOH
(1.2 mL) was added activated Zn (140 mg, 100 equiv.). The mixture
was heated to 40 °C for 1 h, diluted with EtOAc (10 mL), and fil-
tered. The solids were washed with EtOAc (2ϫ10 mL) and CH2Cl2
D
D
D-
D
(2ϫ10 mL), and the combined filtrate and washings were concen- AcOH as described for the synthesis of diol 25. Column
trated. Column chromatography (CH2Cl2/MeOH = 60:1) of the
residue gave N-chloroacetamido 25 (19 mg, 77%) pure as a color-
less glass, followed by N-acetamido 24 (3 mg, 15%) pure as a color-
less glass. Data for 24: [α]D = –12 (c = 0.5, MeOH). 1H NMR
(600 MHz, CD3OD): δ = 7.49–7.20 (m, 10 H, Ar), 5.90 (m, 1 H,
CH=CH2), 5.42 (d, J = 3.4 Hz, 1 H, 4C-H), 5.25 (m, 1 H,
CHH=CH-), 5.18 (t, J = 9.5 Hz, 1 H, 3CЈ-H), 5.13 (m, 1 H,
chromatography (CH2Cl2/MeOH = 60:1) gave N-chloroacetamido
27 (42 mg, 77%) pure as a colorless class, followed by N-acetamido
26 (5 mg, 11%) pure as a colorless glass. Data for 26: [α]D = –12
(c = 0.8, CH2Cl2). 1H NMR (600 MHz, CD3OD): δ = 7.38–7.16
(m, 10 H, Ar), 5.87 (m, 1 H, CH=CH2), 5.42 (d, J = 3.7 Hz, 1 H,
4C-H), 5.35 (d, J = 2.2 Hz, 1 H, 4CЈ-H), 5.25 (m, 1 H, CHH=CH2),
5.13 (m, 1 H, CHH=CH2), 5.09–5.05 (m, 2 H, 2CЈ-H, 3CЈ-H), 5.01
CHH=CH), 5.01 (dd, J = 10.0, 8.5 Hz, 1 H, 2C-H), 4.99 (t, J = (dd, J = 10.0, 8.2 Hz, 1 H, 2C-H), 4.75–4.66 (m, 3 H, 1CЈ-H, 2
9.8 Hz, 1 H, 4CЈ-H), 4.88 (dd, J = 9.8, 8.2 Hz, 1 H, 2CЈ-H), 4.72 CHHPh), 4.57 (d, J = 11.9 Hz, 1 H, CHHPh), 4.53–4.48 (m, 3 H,
(m, 2 H, 1CЈ-H, CHHPh), 4.68 (d, J = 12.0 Hz, 1 H, CHHPh), 1C-H, 1A-H, CHHPh), 4.41 (d, J = 8.5 Hz, 1 H, 1AЈ-H), 4.29 (m,
4.56 (d, J = 11.8 Hz, 1 H, CHHPh), 4.54–4.47 (m, 3 H, 1C-H, 1A- 1 H, CHHCH=CH2), 4.16–4.02 (m, 5 H, 6aC-H, 5CЈ-H, 6abCЈ-H,
H, CHHPh), 4.40 (d, J = 8.5 Hz, 1 H, 1AЈ-H), 4.29 (m, 1 H, CHH-
CHHCH=CH2), 4.98 (dd, J = 11.5, 8.2 Hz, 1 H, 6bC-H), 3.90 (m,
Eur. J. Org. Chem. 2011, 6864–6876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6873

J. L. Hendel, F.-I. Auzanneau
FULL PAPER
1 H, 5C-H), 3.84 (dd, J = 10.1, 3.6 Hz, 1 H, 3C-H), 3.79–3.68 (m, room temperature. The reaction was quenched with Et3N (2 μL),
5 H, 2AЈ-H, 6abA-H, 6abAЈ-H), 3.66 (dd, J = 10.3, 8.5 Hz, 1 H, the mixture was filtered through Celite, and the solids were washed
3A-H), 3.60–3.51 (m, 4 H, 2A-H, 4A-H, 3AЈ-H, 4AЈ-H), 3.48 (m, with CH2Cl2 (15 mL). The combined filtrate and washing were
1 H, 5AЈ-H), 3.44 (m, 1 H, 5A-H), 2.03, 2.02, 1.96, 1.92, 1.89,
1.85, 1.84, 1.83 (9s, 27 H, 9 COCH3) ppm. 13C NMR (150 MHz,
CD3OD): δ = 173.5, 173.3, 172.3, 172.2, 171.9, 171.8, 171.3, 171.2,
171.0 (C=O), 139.8, 139.7 (quat. Ar), 135.5 (CH=CH2), 129.7,
washed with 20% Na2S2O3 (15 mL), and the aqueous layer was re-
extracted with CH2Cl2 (15 mL). The combined organic layers were
dried, filtered, and concentrated. Flash chromatography (EtOAc/
hexanes = 1:1) gave first semipure hexasaccharide 29 (13 mg, ca.
1
129.6, 129.5, 129.3, 129.1, 129.0, 128.9, 128.8, 128.7 (Ar), 117.1 85% pure as assessed by H NMR, 35%) followed by a mixture of
(CH=CH2), 103.1 (C-1A, C-1C), 102.2 (C-1CЈ), 101.8 (C-1AЈ), pentasaccharides 31 and 33. Flash chromatography (EtOAc/hex-
81.8, 81.7 (C-4A, C-4AЈ), 78.2 (C-3C), 75.6, 75.5 (C-5A, C-5AЈ), anes = 6:4) on the pentasaccharide mixture gave first pentasaccha-
1
74.9, 74.7 (CH2Ph), 74.0 (C-3AЈ), 73.1 (C-3A), 72.9 (C-5C), 72.3
ride 33 (6.2 mg, ca. 85% pure as assessed by H NMR, 21%) fol-
(C-2CЈ or C-3CЈ, C-5CЈ), 71.8 (C-2C), 71.2 (C-4CЈ), 70.9 lowed by pure pentasaccharide 31 (1.5 mg, 6%). Both hexasaccha-
(CH2CH=CH2), 70.4 (C-2CЈ or C-3CЈ), 69.7, 69.4 (C-6A, C-6AЈ), ride 29 and pentasaccharide 33 were obtained pure after RP HPLC
68.7 (C-4CЈ), 63.5 (C-6C), 62.6 (C-6CЈ), 57.1 (C-2A), 56.5 (C-2AЈ), (CH3CN/ H2O = 60:40 Ǟ 100:0).
23.1, 22.9, 21.3, 20.8 (COCH3) ppm. HRMS: calcd. for
Method 2: A mixture of acceptor 25 (24 mg, 0.019 mmol), thiogly-
C59H78N2O28 [M + H]+ 1263.4820; found 1263.4814. Data for 27:
coside 28 (35 mg, 0.074 mmol, 4.0 equiv.) and activated powdered
[α]D = –7 (c = 1.0, CH2Cl2). 1H NMR (600 MHz, CDCl3): δ =
7.41–7.22 (m, 10 H, Ar), 6.53 (d, J = 7.6 Hz, 1 H, NHAЈ), 5.85 (m,
1 H, CH=CH2), 5.55 (d, J = 8.0 Hz, 1 H, NHA), 5.33 (d, J =
4 Å molecular sieves (100 mg) in CH2Cl2 (2 mL) was stirred for
2 h at room temperature under an atmosphere of N2. NIS (21 mg,
5.0 equiv.) and 10 μL of a 100 μL/mL solution of TMSOTf in
3.4 Hz, 2 H, 4C-H, 4CЈ-H), 5.24 (m, 1 H, CHH=CH), 5.18–5.12
CH2Cl2 (1 μL of TMSOTf, 0.005 mmol, 0.3 equiv.) were added,
(m, 2 H, 2CЈ-H, CHH=CH2), 5.07 (dd, J = 10.0, 8.5 Hz, 1 H, 2C-
and the mixture was stirred at room temperature for 40 min. Ad-
H), 4.93 (dd, J = 10.4, 3.4 Hz, 1 H, 3CЈ-H), 4.87 (d, J = 8.0 Hz, 1
ditional donor 28 (9 mg, 1 equiv.) was added to the mixture and
H, 1AЈ-H), 4.72–4.66 (m, 3 H, 1A-H, 2 CHHPh), 4.54–4.47 (m, 3
the reaction was allowed to proceed for an additional 20 min. The
reaction was quenched and worked up as described above in
Method 1. A first chromatography (CH2Cl2/MeOH = 50:1) of the
crude residue gave a mixture of hexa- and pentasaccharides
H, 1CЈ-H, 2 CHHPh), 4.33–4.27 (m, 2 H, 1C-H, CHHCH=CH2),
4.20–3.89 (m, 12 H, 3A-H, 5C-H, 6abC-H, 3AЈ-H, 6abCЈ-H, 2 OH,
CH2Cl, CHHCH=CH2), 3.76–3.43 (m, 11 H, 6abA-H, 2A-H, 4A-
H, 5A-H, 3C-H, 4AЈ-H, 5AЈ-H, 6abAЈ-H, 5CЈ-H), 3.24 (m, 1 H,
(45 mg), which were submitted to a second flash chromatography
2AЈ-H), 2.14, 2.13, 2.05, 2.02, 1.99, 1.97 (8s, 24 H, 8 COCH3) ppm.
(EtOAc/hexanes = 6:4) to give first semipure hexasaccharide 29
13C NMR (150 MHz, CDCl3): δ = 170.6, 170.4, 170.1, 170.0, 169.9,
1
(20 mg, ca. 85% pure as assessed by H NMR, 43%) followed by
169.3, 169.2, 166.1 (C=O), 138.2, 138.1 (quat. Ar), 133.8
(CH=CH2), 128.5, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 127.3
pure pentasaccharide 33 (6 mg, 20%). Hexasaccharide 29 was ob-
tained pure as a colorless glass by RP HPLC (CH3CN/H2O = 60:40
(Ar), 117.5 (CH=CH2), 101.4 (C-1CЈ), 101.2 (C-1C), 99.9 (C-1AЈ),
Ǟ 100:0).
99.2 (C-1A), 81.4, 81.1 (C-4A, C-4AЈ), 76.0 (C-3C), 74.0 (C-5A, C-
1
29: [α]D = –3 (c = 0.6, CH2Cl2). H NMR (600 MHz, CDCl3): δ =
7.43–7.10 (m, 40 H, Ar), 6.52 (d, J = 8.6 Hz, 1 H, NHAЈ), 6.01 (d,
J = 8.9 Hz, 1 H, NHA), 5.77 (m, 1 H, CH=CH2), 5.34 (d, J =
3.5 Hz, 1 H, 4C-H), 5.24 (m, 1 H, CH=CHH), 5.11–5.07 (m, 3 H,
1B-H, 1BЈ-H, CH=CHH), 5.15 (t, J = 9.4 Hz, 1 H, 3CЈ-H), 4.99
(dd, J = 9.8, 8.5 Hz, 1 H, 2C-H), 4.96–4.91 (m, 3 H, 1AЈ-H, 2
CHHPh), 4.88 (t, J = 9.8 Hz, 1 H, 4CЈ-H), 4.85–4.68 (m, 12 H,
1A-H, 1CЈ-H, 2CЈ-H, 4 CH2Ph, CHHPh), 4.66–4.62 (m, 2 H, 2
CHHPh), 4.58–4.48 (m, 4 H, 5B-H, CH2Ph, CHHPh), 4.42 (dd, J
= 12.7, 4.2 Hz, 1 H, 6aCЈ-H), 4.38 (d, J = 12.1 Hz, 1 H, CHHPh),
4.36 (d, J = 8.1 Hz, 1 H, 1C-H), 4.19–4.10 (m, 4 H, 6aC-H, 3AЈ-
H, 5BЈ-H, CHHCH=CH2), 4.10–4.04 (m, 3 H, 3A-H, 2B-H, 2BЈ-
H), 4.02–3.77 (m, 10 H, 4A-H, 6aA-H, 3B-H, 6bC-H, 4AЈ-H,
6aAЈ-H, 3BЈ-H 6bCЈ-H, CHHCH=CH2, CHHCl), 3.77–3.64 (m, 6
H, 2A-H, 6bA-H, 4B-H or 4BЈ-H, 3C-H, 6bAЈ-H, CHHCl), 3.62–
3.55 (m, 3 H, 5A-H, 4B-H or 4BЈ-H, 5C-H), 3.44 (m, 1 H, 2AЈ-
H), 3.39 (m, 1 H, 5AЈ-H), 3.34 (m, 1 H, 5CЈ-H), 1.98, 1.97, 1.95,
1.94, 1.90, 1.85, 1.81 (7s, 24 H, 8 COCH3), 1.20 (d, J = 6.5 Hz, 3 H,
6BЈ-H), 1.09 (d, J = 6.4 Hz, 3 H, 6B-H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 170.3, 170.2, 170.1, 169.8, 169.5, 168.7, 166.0 (C=O),
138.9, 138.8, 138.7, 138.6, 138.1, 137.9 (quat. Ar), 133.9
(CH=CH2), 128.6, 128.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 127.2, 126.9 (Ar), 117.0 (CH2=CH), 99.4 (C-
1A, C-1C), 99.1 (C-1AЈ), 98.6 (C-1CЈ), 97.5, 97.0 (C-1B, C-1BЈ),
79.7, 79.5 (C-3B, C-3BЈ), 78.1 (C-3C), 77.2 (C-4B or C-4BЈ), 76.4,
76.3 (C-2B, C-2BЈ), 75.2 (C-5AЈ), 75.0 (C-4B or C-4BЈ), 74.8 (C-
4A or C-4AЈ), 74.7, 74.5 (CH2Ph), 74.0, 73.9 (C-3AЈ), 73.9 (C-5A),
73.7 (C-4A or C-4AЈ), 73.5, 73.4, 73.2 (CH2Ph), 73.0 (C-3CЈ), 72.8
(C-3A), 72.7 (CH2Ph), 72.0 (C-5CЈ), 71.3, 71.2 (C-5C, C-2CЈ), 70.8
(C-2C), 69.4 (CH2CH=CH2), 69.0 (C-6AЈ), 68.8 (C-4C), 67.8 (C-
4CЈ), 67.6 (C-6A), 66.7, 66.5 (C-5B, C-5BЈ), 61.6, 61.5 (C-6C, C-
5AЈ), 73.6 (2 CH2Ph), 71.7, 71.6 (C-5C, C-5CЈ), 71.2 (C-3A), 70.6
(C-3AЈ), 70.5 (C-3CЈ), 70.4 (C-2C), 69.7 (CH2CH=CH2), 69.0 (C-
4C), 68.7 (C-2CЈ), 68.0, 67.9 (C-6A, C-6AЈ), 66.8 (C-4CЈ), 62.2,
61.5 (C-6C, C-6CЈ), 57.5 (C-2AЈ), 56.5 (C-2A), 42.6 (CH2Cl), 23.6,
21.0, 20.7, 20.6, 20.5 (COCH3) ppm. HRMS: calcd. for
C59H77ClN2O28 [M + H]+ 1297.4430; found 1297.4443.
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-
O-acetyl-β-
D-glucopyranosyl)-6-O-benzyl-3-O-(2,3,4-tri-O-benzyl-α-
L
-fucopyranosyl)-2-chloroacetamido-2-deoxy-β- -glucopyranosyl]-
D
β-
D
-galactopyranosyl}-6-O-benzyl-3-O-(2,3,4-tri-O-benzyl-α-
L
-
-
fucopyranosyl)-2-deoxy-β-
4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-O-acetyl-β-
glucopyranosyl)-6-O-benzyl-3-O-(2,3,4-tri-O-benzyl-α-
pyranosyl)-2-chloroacetamido-2-deoxy-β- -glucopyranosyl]-β-
galactopyranosyl}-6-O-benzyl-2-deoxy-β- -glucopyranoside (31);
and allyl 2-acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-
tetra-O-acetyl-β- -glucopyranosyl)-6-O-benzyl-2-chloroacetamido-
2-deoxy-β- -glucopyranosyl]-β- -galactopyranosyl}-6-O-benzyl-3-
-fucopyranosyl)-2-deoxy-β- -gluco-
D-glucopyranoside (29); allyl 2-acetamido-
D
L
-fuco-
D
D-
D
D
D
D
O-(2,3,4-tri-O-benzyl-α-
L
D
pyranoside (33)
Method 1: A mixture of acceptor 25 (20 mg, 0.015 mmol), thiogly-
coside 28[14] (11 mg, 0.023 mmol, 1.5 equiv.) and activated pow-
dered 4 Å molecular sieves (0.1 g) in CH2Cl2 (2 mL) was stirred for
1 h at room temperature under an atmosphere of N2 and then co-
oled to 0 °C. NIS (6 mg, 1.7 equiv.) and 10 μL of a 50 μL/mL solu-
tion of TMSOTf in CH2Cl2 (0.5 μL of TMSOTf, 0.003 mmol,
0.2 equiv.) were added, and the mixture was stirred at 0 °C for
1.5 h. More NIS (15 mg, 4.5 equiv.) followed by a solution of donor
28 (32 mg, 0.067 mmol, 4.5 equiv.) in CH2Cl2 (1 mL) were added,
and the reaction was allowed to proceed for an additional 2 h at
6874
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6864–6876

Convergent Preparation of DimLex Hexasaccharide Analogues
6CЈ), 58.4 (C-2AЈ), 53.2 (C-2A), 42.4 (CH2Cl), 23.2, 21.0, 20.7,
20.6 (COCH3), 16.7, 16.6 (C-6B, C-6BЈ) ppm. HRMS: calcd. for
C113H133N2ClO36 [M + H]+ 2129.8410; found 2129.8398.
Allyl 2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-
O-acetyl-β- -galactopyranosyl)-6-O-benzyl-3-O-(2,3,4-tri-O-benzyl-
α- -fucopyranosyl)-2-chloroacetamido-2-deoxy-β- -glucopyranosyl]-
β- -galactopyranosyl}-6-O-benzyl-3-O-(2,3,4-tri-O-benzyl-α- -fuco-
pyranosyl)-2-deoxy-β- -glucopyranoside (30); allyl 2-acetamido-4-
O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-O-acetyl-β- -galacto-
pyranosyl)-6-O-benzyl-3-O-(2,3,4-tri-O-benzyl-α- -fucopyranosyl)-
2-chloroacetamido-2-deoxy-β- -glucopyranosyl]-β- -galacto-
pyranosyl}-6-O-benzyl-2-deoxy-β- -glucopyranoside (32); and Allyl
2-Acetamido-4-O-{2,4,6-tri-O-acetyl-3-O-[4-O-(2,3,4,6-tetra-O-ace-
tyl-β- -galactopyranosyl)-6-O-benzyl-2-chloroacetamido-2-deoxy-β-
-glucopyranosyl]-β- -galactopyranosyl}-6-O-benzyl-3-O-(2,3,4-
tri-O-benzyl-α- -fucopyranosyl)-2-deoxy-β- -glucopyranoside (33):
Alcohol 27 (42 mg, 0.032 mmol) was coupled to donor 28 (77 mg,
0.16 mmol, 5.0 equiv.) in CH2Cl2 (3.5 mL) at room temperature as
described above in Method 2 for the preparation of hexasaccharide
29. Column chromatography of the residue (EtOAc/hexanes = 4:6
Ǟ 7:3) gave hexasaccharide 30 contaminated with succinimide
(37 mg) followed by a mixture containing pentasaccharides 32 and
34 (14 mg, 25%). Additional purification of the hexasaccharide was
achieved using RP HPLC (60:40 Ǟ 100:0 CH3CN/H2O) to give 30
pure as a colorless glass (33 mg, 48%). RP HPLC (60:40 Ǟ 100:0
CH3CN/H2O) provided pure pentasaccharides 34 (7 mg, 13%) and
32 (5 mg, 9%). Data for 30: [α]D = –9 (c = 0.5, CH2Cl2). 1H NMR
(600 MHz, CDCl3): δ = 7.42–7.15 (m, 40 H, Ar), 6.50 (d, J =
D
L
D
D
L
1
31: [α]D = –6 (c = 0.5, CH2Cl2). H NMR (600 MHz, CDCl3): δ =
D
7.43–7.11 (m, 25 H, Ar), 6.58 (d, J = 7.4 Hz, 1 H, NHAЈ), 5.85 (m,
1 H, CH=CH2), 5.52 (d, J = 8.0 Hz, 1 H, NHA), 5.31 (d, J =
3.5 Hz, 1 H, 4C-H), 5.24 (m, 1 H, CHH=CH2), 5.16 (m, 1 H,
CHH=CH2), 5.11–5.05 (m, 2 H, 2C-H, 1BЈ-H), 5.02–4.96 (m, 2 H,
1AЈ-H, 3CЈ-H), 4.94 (d, J = 11.4 Hz, 1 H, CHHPh), 4.88 (t, J =
9.8 Hz, 1 H, 4CЈ-H), 4.86–4.79 (m, 2 H, 2CЈ-H, CHHPh), 4.78–
4.73 (m, 2 H, 2 CHHPh), 4.72–4.63 (m, 5 H, 1A-H, 1CЈ-H, 3
CHHPh), 4.58–4.46 (m, 4 H, 5BЈ-H, 3 CHHPh), 4.43 (dd, J = 12.5,
4.1 Hz, 1 H, 6aCЈ-H), 4.34–4.27 (m, 2 H, 1C-H, CHHCHCH2),
4.18–4.12 (m, 2 H, 6aC-H, 3AЈ-H), 4.09 (dd, J = 10.1, 3.7 Hz, 1
H, 2BЈ-H), 4.05 (m, 1 H, CHHCHCH2), 3.99 (br. t, J = 8.7 Hz, 1
H, 4AЈ-H), 3.97–3.87 (m, 3 H, 3A-H, 3BЈ-H, H6bC), 3.86–3.78 (m,
3 H, 6aAЈ-H, 6bCЈ-H, CHCl), 3.76–3.69 (m, 4 H, 3C-H, 5C-H,
6bAЈ-H, CHCl), 3.68–3.58 (m, 3 H, 6abA-H, 4BЈ-H), 3.56 (br. t, J
= 8.7 Hz, 1 H, 4A-H), 3.51 (m, 1 H, 2A-H), 3.47 (m, 1 H, 5A-H),
3.46–3.38 (m, 2 H, 2AЈ-H, 5AЈ-H), 3.33 (m, 1 H, 5CЈ-H), 2.06,
2.02, 1.98, 1.97, 1.92, 1.85 (8s, 24 H, 8 COCH3), 1.20 (d, J = 6.5 Hz,
3 H, 6BЈ-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.6, 170.4,
170.3, 170.2, 169.5, 169.4, 168.7, 166.0 (C=O), 138.6, 138.2, 137.8
(quat. Ar), 133.8 (CH=CH2), 128.2, 128.1, 127.9, 127.6, 127.4,
127.2 (Ar), 117.6 (CH=CH2), 101.3 (C-1C), 99.5, 99.3, 99.2 (C-1A,
D
L
D
D
D
D
D
D
L
D
C-1AЈ C-1CЈ), 97.5 (C-1BЈ), 81.2 (C-4A), 79.8 (C-3BЈ), 78.1 (C- 7.6 Hz, 1 H, NHAЈ), 6.01 (d, J = 8.2 Hz, 1 H, NHA), 5.77 (m, 1
4BЈ), 76.5 (C-2BЈ), 75.4 (C-3C), 75.1 (C-5AЈ), 74.8 (C-4AЈ, H, CH=CH2), 5.35 (d, J = 3.6 Hz, 1 H, 4C-H), 5.27–5.21 (m, 2 H,
CH2Ph), 74.1 (C-5A, C-3AЈ), 73.6, 73.5, 73.4 (CH2Ph), 73.0 (C- 4CЈ-H, CHH=CH2 ), 5.12–5.08 (m, 3 H, 1B-H, 1BЈ-H,
3CЈ), 72.6 (CH2Ph), 72.0 (C-5CЈ), 71.8, 71.7 (C-3A, C-5C), 71.3
(C-2CЈ), 70.5 (C-2C), 69.8 (CH2CH=CH2), 68.8 (C-4C), 68.1 (C-
6A), 67.8 (C-4CЈ), 67.6 (C-6AЈ), 66.6 (C-5BЈ), 62.3 (C-6C), 61.5
(C-6CЈ), 58.5 (C-2AЈ), 56.5 (C-2A), 42.4 (CH2Cl), 23.6, 21.0, 20.7,
2 0. 6 (C OCH3 ), 1 6. 7 ( C- 6BЈ) pp m. HR MS : c al cd . for
C86H105ClN2O32 [M + H]+ 1713.6426; found 1713.6417.
CHH=CH2), 5.03–4.98 (m, 3 H, 1AЈ-H, 2C-H, 2CЈ-H), 4.97–4.93
(br. d, 2 H, 2 CHHPh), 4.85–4.59 (m, 15 H, 1A-H, 5B-H or 5-BЈ-
H, 1CЈ-H, 3CЈ-H, 4 CH2Ph, 3 CHHPh), 4.55 (d, J = 11.9 Hz, 1 H,
CHHPh), 4.51 (d, J = 12.0 Hz, 1 H, CHHPh), 4.41 (d, J = 12.0 Hz,
1 H, CHHPh), 4. 38 (d, J = 8.1 Hz, 1 H, 1C-H), 4.23–4.08 (m, 8
H, 3A-H, 2B-H, 5B-H or 5BЈ-H, 6aC-H, 3AЈ-H, 2BЈ-H, 6aCЈ-H,
CHHCH=CH2), 4.02–3.78 (m, 10 H, 4A-H, 6aA-H, 3B-H, 6bC-
H, 4AЈ-H, 6aAЈ-H, 3BЈ-H, 6bCЈ-H, CHHCl, CHHCH=CH2),
3.78–3.73 (m, 4 H, 2A-H, 6bA-H, 6bAЈ-H, CHHCl), 3.71–3.67 (m,
2 H, 3C-H, 4B-H or 4BЈ-H), 3.62–3.54 (m, 4 H, 5AЈ-H, 4B-H or
4BЈ-H, 5C-H, 5CЈ-H), 3.44–3.35 (m, 2 H, 2AЈ-H, 5A-H), 1.99, 1.98,
1.96, 1.94, 1.90, 1.82 (8s, 24 H, 8 COCH3), 1.20, 1.10 (2d, J =
6.5 Hz, 6 H, 6B-H, 6BЈ-H) ppm. 13C NMR (150 MHz, CDCl3): δ
= 170.3, 170.1, 170.0, 169.8, 168.8, 166.1 (C=O), 138.9, 138.8,
138.7, 138.6, 138.2, 137.9 (quat. Ar), 134.0 (CH=CH2), 127.4, 127.3
(Ar), 117.1 (CH2=CH), 99.7 (C-1CЈ), 99.5 (C-1C), 99.1 (C-1AЈ),
98.6 (C-1A), 97.6, 97.0 (C-1B, C-1BЈ), 80.1, 79.6 (C-3, C-3BЈ), 77.0,
76.8 (4B, 4BЈ), 76.3, 75.9 (C-2B, C-2BЈ), 75.3 (C-5A), 75.1 (C-3C),
74.5 (CH2Ph), 74.3 (C-4A or C-4AЈ), 74.2 (CH2Ph), 74.0 (C-5AЈ),
73.7 (C-4A or C-4AЈ), 73.6, 73.5, 73.4, 73.2 (CH2Ph), 73.2 (C-3AЈ),
72.8 (C-3A), 72.7, 72.5 (2 CH2Ph), 71.2 (C-5C or C-5CЈ), 70.8 (C-
3CЈ, C-2C or C-2CЈ), 70.4 (C-5C or C-5CЈ), 69.4 (CH2CH=CH2),
69.0 (C-6A or C-6AЈ), 68.9, 68.8 (C-2C or C-2CЈ, C-4C), 67.5 (C-
6A or C-6AЈ), 66.6 (C-5B or C-5BЈ, C-4CЈ), 66.4 (C-5B or C-5BЈ),
61.6, 60.1 (C-6C, C-6CЈ), 58.7 (C-2AЈ), 53.1 (C-2A), 42.4 (CH2Cl),
23.2, 21.1, 20.7 (COCH3), 16.7, 16.6 (C-6B, C-6BЈ) ppm. HRMS:
calcd. for C113H133N2ClO36 [M + H]+ 2129.8410; found 2129.8379.
Data for 32: [α]D = –9 (c = 0.4, CH2Cl2). 1H NMR (600 MHz,
CDCl3): δ = 7.42–7.21 (m, 25 H, Ar), 6.52 (d, J = 7.4 Hz, 1 H,
NHAЈ), 5.85 (m, 1 H, CH=CH2), 5.50 (d, J = 8.0 Hz, 1 H, NHA),
5.31 (d, J = 3.5 Hz, 1 H, 4C-H), 5.27–5.22 (m, 2 H, 4CЈ-H,
CHH=CH), 5.15 (m, 1 H, CHH=CH), 5.09 (dd, J = 9.8, 8.3 Hz, 1
H, 2C-H), 5.06 (d, J = 3.7 Hz, 1 H, 1BЈ-H), 5.01 (br. d, J = 7.8 Hz,
1 H, 1AЈ-H), 4.98 (d, J = 10.3, 8.3 Hz, 1 H, 2CЈ-H), 4.93 (d, J =
11.8 Hz, 1 H, CHHPh), 4.85 (d, J = 12.0 Hz, 1 H, CHHPh), 4.81–
1
33: [α]D = –8 (c = 0.5, CH2Cl2). H NMR (600 MHz, CDCl3): δ =
7.42–7.10 (m, 25 H, Ar), 6.48 (d, J = 7.7 Hz, 1 H, NHAЈ), 5.95 (d,
J = 8.0 Hz, 1 H, NHA), 5.78 (m, 1 H, CH=CH), 5.35 (d, J =
3.5 Hz, 1 H, 4C-H), 5.23 (m, 1 H, CHH=CH), 5.14 (t, J = 9.5 Hz,
1 H, 3CЈ-H), 5.09 (m, 1 H, CHHCH2), 5. 07 (d, J = 3.7 Hz, 1 H,
1B-H), 5.01–4.90 (m, 4 H, 2C-H, 2CЈ-H, 4CЈ-H, CHHPh), 4.84–
4.66 (m, 7 H, 1A-H, 1AЈ-H, 2 CH2Ph CHHPh), 4.64 (d, J =
11.8 Hz, 1 H, CHHPh), 4.58–4.45 (m, 3 H, 1C-H, 2 CHHPh), 4.38
(d, J = 12.1 Hz, 1 H, CHHPh), 4.46 (d, J = 8.1 Hz, 1 H, 1CЈ-H),
4.22–4.06 (m, 7 H, 3A-H, 6aC-H, 6abCЈ-H, 2B-H, 5B-H,
CHHCH=CH2), 4.03–3.79 (m, 8 H, 6aA-H, 6bC-H, 3AЈ-H, 4A-H,
3B-H, O-CHHCH=CH2, CH2Cl), 3.75 (dd, J = 10.3, 3.9 Hz, 1 H,
6bA-H), 3.71–3.52 (m, 9 H, 2A-H, 4AЈ-H, 5A-H, 4B-H, 3C-H, 5C-
H, 6abAЈ-H, 5CЈ-H), 3.47 (m, 1 H, 5AЈ-H), 3.25 (m, 1 H, 2AЈ-H),
2.05, 2.02, 1.98, 1.96, 1.90, 1.78 (8s, 24 H, 8 COCH3), 1.10 (d, J =
6.5 Hz, 3 H, 6B-H). 13C NMR (150 MHz, CDCl3): δ = 170.5,
170.2, 170.1, 170.0, 169.8, 169.6, 169.3, 169.1, 166.1 (C=O), 138.9,
138.8, 138.5, 138.1, 138.0, 136.3 (quat. Ar), 133.9 (CH=CH2),
128.5, 128.4, 127.9, 127.8, 127.5, 127.3 (Ar), 117.1 (CH2=CH),
101.0 (C-1C or C-1CЈ), 99.8 (C-1AЈ), 99.4 (C-1C or C-1CЈ), 98.6
(C-1A), 97.0 (C-1B), 81.4 (C-4AЈ), 81.3 (C-4), 79.7 (C-3B), 77.1 (C-
4B), 76.3 (C-2B), 75.6 (C-3C), 74.5 (CH2Ph), 74.1, 74.0 (C-5A, C-
5AЈ), 73.8 (C-4A), 73.7, 73.4, 73.3 (CH2Ph), 72.9 (C-3A), 72.6
(CH2Ph), 72.5 (C-3CЈ), 72.0 (C-5C), 71.1, 71.0, 70.7, 70.6 (C-2C,
C-3AЈ, C-2CЈ, C-5CЈ), 69.5 (CH2CH=CH2), 69.0 (C-4C), 68.6 (C-
6A or C-6AЈ), 68.2 (C-4CЈ), 67.8 (C-6A or C-6AЈ), 66.6 (C-5B),
61.8, 61.5 (C-6C, C-6CЈ), 57.4 (C-2AЈ), 54.1 (C-2A), 42.6 (CH2Cl),
23.2, 21.0, 20.7, 20.6, 20.5 (COCH3), 16.6 (C-6B) ppm. HRMS:
calcd. for C86H105ClN2O32 [M + H]+1713.6447; found 1713.6417.
Eur. J. Org. Chem. 2011, 6864–6876
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6875

J. L. Hendel, F.-I. Auzanneau
FULL PAPER
4.56 (m, 9 H, 1A-H, 1CЈ-H, 3CЈ-H, 6 CHHPh), 4.59 (m, 1 H,
5BЈ-H), 4.51–4.36 (m, 2 H, 2 CHHPh), 4.34–4.26 (m, 2 H, 1C-H,
CHHCH=CH2), 4.20–3.85 (m, 10 H, 3A-H, 4AЈ-H, 6abC-H, 3AЈ-
H, 2BЈ-H, 3BЈ-H, 6abCЈ-H, CHHCH2=CH2), 3.85–3.44 (m, 13 H,
2A-H, 5A-H, 6abA-H, 3C-H, 5C-H, 6abAЈ-H, 4A-H, 4BЈ-H, 5CЈ-
H, CH2Cl), 3.38 (m, 2 H, 2AЈ-H, 5AЈ-H), 2.06, 2.01, 1.99, 1.98,
1.93, 1.92, 1.81, 1.56 (8s, 24 H, 8 COCH3), 1.19 (d, J = 6.5 Hz, 3
H, 6BЈ-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.6, 170.4,
170.1, 170.0, 169.8, 169.4, 168.8, 166.0 (C=O), 138.7, 138.5, 138.3,
137.8 (quat. Ar), 133.8 (CH=CH2), 128.6, 128.4, 128.2, 128.1,
127.7, 127.6, 127.3, 127.1, 127.0 (Ar), 117.6 (CH2=CH), 101.3 (C-
1C), 99.7 (C-1CЈ), 99.3 (C-1A), 99.1 (C-1AЈ), 97.6 (C-1B), 81.2 (C-
4A), 80.1 (C-3BЈ), 77.0 (C-4BЈ), 76.0 (C-2BЈ), 75.4 (C-3C), 75.2 (C-
5AЈ), 74.3 (CH2Ph), 74.2 (C-4AЈ), 74.1 (C-5A), 73.6, 73.6, 73.4 (3
CH2Ph), 73.3 (C-3AЈ), 72.5 (CH2Ph), 71.8, 77.7 (C-3AЈ, C-5C or
C-5CЈ), 70.8 (C-3CЈ), 70.6 (C-2C), 70.4 (C-5C or C-5CЈ), 69.8
(OCH2CH=CH2), 68.8 (C-4C, C-2CЈ), 68.1, 67.5 (C-6A, C-6AЈ),
66.7 (C-4CЈ), 66.3 (C-5BЈ), 62.3, 60.1 (C-6C, C-6CЈ), 58.9 (C-2AЈ),
56.5 (C-2A), 42.4 (CH2Cl), 23.6, 21.0, 20.7, 20.6, 20.5 (COCH3),
16.7 (C-6BЈ) ppm. HRMS: calcd. for C86H105ClN2O32 [M + H]+
1713.6417; found 1713.6384. Data for 34: [α]D = –13 (c = 0.4,
CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 7.41–7.12 (m, 25 H,
Ar), 6.49 (d, J = 7.7 Hz, 1 H, NHAЈ), 5.95 (d, J = 8.0 Hz, 1 H,
NHA), 5.79 (m, 1 H, CH=CH2), 5.36 (d, J = 3.6 Hz, 1 H, 4C-H),
5.34 (d, J = 3.6 Hz, 1 H, 4CЈ-H), 5.22 (m, 1 H, CH=CHH), 5.16
(dd, J = 10.4, 8.0 Hz, 1 H, 2CЈ-H), 5.09 (m, 1 H, CH=CHH), 5.08
(d, J = 3.7 Hz, 1 H, 1BЈ-H), 4.99–4.91 (m, 3 H, 2C-H, 3CЈ-H,
CHHPh), 4.86–4.69 (m, 7 H, 1A-H, 1AЈ-H, 5 CHHPh), 4.64 (d, J
= 11.8 Hz, 1 H, CHHPh), 4.57 (d, J = 12.0 Hz, 1 H, CHHPh), 4.53
(d, J = 12.1 Hz, 1 H, CHHPh), 4.50 (d, J = 8.0 Hz, 1 H, 1CЈ-H),
4.39 (d, J = 12.3 Hz, 1 H, CHHPh), 4.36 (d, J = 8.4 Hz, 1 H, 1C-
H), 4.23–4.15 (m, 1 H, 5B-H, CHHCH=CH2), 4.14–4.04 (m, 5 H,
3A-H, 2B-H, 6abC-H or 6abCЈ-H, 6aC-H or 6aCЈ-H), 4.03–3.82
(m, 9 H, 4A-H, 6aA-H, 3B-H, 5C-H, 6bC-H or 6bCЈ-H, 3AЈ-H,
CH2Cl, CHHCH=CH2), 3.75 (dd, J = 10.4, 3.9 Hz, 2 H, 6bA-H),
3.69–3.51 (m, 8 H, 2A-H, 5A-H, 4B-H, 3C-H, 4AЈ-H, 6abAЈ-H,
5CЈ-H), 3.49 (m, 1 H, 5AЈ-H), 3.24 (m, 1 H, 2AЈ-H), 2.13, 2.03,
2.01, 1.97, 1.96, 1.90, 1.78 (8s, 24 H, 8 COCH3), 1.10 (d, J = 6.5 Hz,
3 H, 6B-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.5, 170.3,
170.2, 170.1, 170.0, 169.8, 169.6, 169.3, 166.1 (C=O), 138.9, 138.6,
[1] a) Y. Fukushi, S.-I. Hakomori, E. Nudelman, N. Cochran, J.
Biol. Chem. 1984, 259, 4681–4685; b) Y. Fukushi, S.-I. Hako-
mori, T. Shepard, J. Exp. Med. 1984, 159, 506–520; c) Y. Fuku-
shi, R. Kannagi, S.-I. Hakomori, T. Shepard, B. G. Kulander,
J. W. Singer, Cancer Res. 1985, 45, 3711–3717; d) S. H. Itzkow-
itz, M. Yuan, Y. Fukushi, A. Palekar, P. C. Phelps, A. M.
Shamsuddin, B. T. Trump, S.-I. Hakomori, Y. S. Kim, Cancer
Res. 1986, 46, 2627–2632; e) H. Nakasaki, T. Mitomi, T. Noto,
K. Ogoshi, H. Hanaue, Y. Tanaka, H. Makuuchi, H. Clausen,
S.-I. Hakomori, Cancer Res. 1989, 49, 3662–3669; f) A. K.
Singhal, T. F. Ørntoft, E. Nudelman, S. Nance, L. Schibig,
M. R. Stroud, H. Clausen, S.-I. Hakomori, Cancer Res. 1990,
50, 1375–1380.
[2] a) S. Zhang, H. S. Zhang, C. Cordon-Cardo, V. E. Reuter,
A. K. Singhal, K. O. Lloyd, P. O. Livingston, Int. J. Cancer
1997, 73, 50–56; b) J. Satoh, S. U. Kim, J. Neurosci. Res. 1994,
37, 466–474; c) M. V. Croce, M. Isla-Larrain, M. E. Rabassa,
S. Demichelis, A. G. Golussi, M. Crespo, E. Lacunza, A. Segal-
Eiras, Pathol. Oncol. Res. 2007, 13, 130–138.
[3] J.-W. Wang, A. Asnani, F.-I. Auzanneau, Bioorg. Med. Chem.
2010, 18, 7174–7185.
[4] F.-I. Auzanneau, B. M. Pinto, Bioorg. Med. Chem. 1996, 4,
2003–2010.
[5] a) S. Sato, Y. Ito, T. Ogawa, Tetrahedron Lett. 1988, 29, 5267–
5270; b) K. C. Nicolaou, C. W. Hummel, Y. Iwabuchi, J. Am.
Chem. Soc. 1992, 114, 3126–3128; c) A. Toepfer, R. R.
Schmidt, Tetrahedron Lett. 1992, 33, 5161–5164; d) R. Wind-
muller, R. R. Schmidt, Tetrahedron Lett. 1994, 35, 7927–7930;
e) H. Tanaka, N. Matoba, H. Tsukamoto, H. Takimoto, H.
Yamada, T. Takahashi, Synlett 2005, 824–828; f) S. Bregant, Y.
Zhang, J.-M. Mallet, A. Brodzki, P. Sinaÿ, Glycoconjugate J.
1999, 16, 757–765; g) A. Miermont, Y. Zeng, Y. Jing, X.-S. Ye,
X. Huang, J. Org. Chem. 2007, 72, 8958–8961; h) T. Zhu, G.-
J. Boons, J. Am. Chem. Soc. 2000, 122, 10222–10223; i) S. Fi-
gueroa-Perez, V. Verez-Bencomo, Tetrahedron Lett. 1998, 39,
9143–9146; j) G. Hummel, R. R. Schmidt, Tetrahedron Lett.
1997, 38, 1173–1176.
[6] a) M. Nilsson, T. Norberg, Glycoconjugate J. 1987, 4, 219–223;
b) M. Nilsson, T. Norberg, Carbohydr. Res. 1988, 183, 71–82;
c) E. Nudelman, K. Sadozai, H. Clausen, S.-I. Hakomori, M.
Stroud, U.S Patent, 5,421,733, June 6, 1995.
[7] A. Wang, J. L. Hendel, F.-I. Auzanneau, Beilstein J. Org. Chem.
2010, 6, 17 DOI:10.3762/bjoc.6.17.
[8] G. Blatter, J.-C. Jacquinet, Carbohydr. Res. 1996, 288, 109–125.
138.2, 138.1 (quat. Ar), 134.0 (CH=CH2), 128.6, 128.4, 127.9, [9] P.-H. Liang, Y.-J. Lu, T.-H. Tang, Tetrahedron Lett. 2010, 51,
6928–6931.
127.8, 127.7, 127.6, 127.4 (Ar), 117.1 (CH=CH2), 101.5 (C-1CЈ),
99.9 (C-1A or C-1AЈ), 99.4 (C-1C), 98.6 (C-1A or C-1AЈ), 97.1 (C-
1B), 81.5 (C-4AЈ), 79.7 (C-3B), 76.9 (C-4B), 76.3 (C-2B), 75.7 (C-
3C), 74.5 (CH2Ph), 74.2, 74.1, 73.8 (C-5A, C-4A, C-5AЈ), 73.7,
73.4, 73.3 (3 CH2Ph), 72.9 (C-3A), 72.6 (CH2Ph), 71.3, 71.1, (C-
5C, C-5CЈ), 70.7, 70.6 (C-2C, C-3AЈ, C-3CЈ), 69.5 (CH2CH=CH2),
69.0 (C-4C), 68.7 (C-2CЈ), 68.0 (C-6A, C-6AЈ), 66.8 (C-4CЈ), 66.6
(C-5B), 61.6, 61.5 (C-6C, C-6CЈ), 57.5 (C-2AЈ), 54.0 (C-2A), 42.7
(CH2Cl), 23.2, 21.1, 20.8, 20.7, 20.6 (COCH3), 16.6 (C-6B) ppm.
HRMS: calcd. for C86H105ClN2O32 [M + Na]+ 1735.6237; found
1735.6288.
[10] M. A. E. Shaban, V. N. Reinhold, R. W. Jean-loz, Carbohydr.
Res. 1977, 55, 213–233; B. Aguilera, J. Jiménez-Barbero, A.
Fernández-Mayoralas, Carbohydr. Res. 1998, 308, 19–27; J. M.
Vega-Pérez, J. I. Candela, E. Blanco, F. Iglesias-Guerra, Tetra-
hedron: Asymmetry 2002, 13, 2471–2483.
[11] a) H. Paulsen, Angew. Chem. 1982, 94, 184; Angew. Chem. Int.
Ed. Engl. 1982, 21, 155–173; b) D. Crich, V. Dudkin, J. Am.
Chem. Soc. 2001, 123, 6819–6825; c) L. Liao, F.-I. Auzanneau,
Org. Lett. 2003, 5, 2607–2610.
[12] a) J. L. Hendel, J. W. Wang, T. A. Jackson, K. Hardmeier, R.
De los Santos, F.-I. Auzanneau, J. Org. Chem. 2009, 74, 8321–
8331; b) J. L. Hendel, A. Cheng, F.-I. Auzanneau, Carbohydr.
Res. 2008, 343, 2914–2923.
[13] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 19, 731–732.
[14] H. Lönn, Carbohydr. Res. 1985, 139, 105–113.
[15] H. Shimizu, Y. Yoshimura, S.-I. Nishimura, Tetrahedron 2008,
64, 10091–10096.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for compounds 2–5,
12–14, 16, 17, 20–27, and 29–34.
[16] Y. Kwon, R. L. Soucy, D. A. Snyder, P. H. Seeberger, Chem.
Eur. J. 2005, 11, 2493–2504.
Acknowledgments
[17] W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory
Chemicals, 4th ed., Elsevier, 2003.
We thank the National Science and Engineering Research Council
of Canada for financial support of this work.
Received: September 14, 2011
Published Online: October 31, 2011
6876
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6864–6876