Glucosamine derived DISAL donors for stereoselective glycosylations under neutral conditions

Article abstract of DOI:10.1016/j.tetasy.2005.02.029

DISAL (methyl 3,5-dinitrosalicylate) D-glucosyl, D-galactosyl, D-mannosyl, and L-quinovosyl donors have previously provided the efficient glycosylation of a range of substrates under either strictly neutral, mildly basic, or very mildly Lewis acidic (LiClO₄) conditions. Herein we report the synthesis of new glucosamine DISAL donors, carrying N-TCP, -Troc, or -TFAc protecting groups, and their use in β-(1,2-trans) selective glycosylations, primarily in NMP in the absence of any added Lewis acids, or in CH ₃NO₂ with LiClO₄. Finally, precise microwave heating proved effective in promoting the difficult glycosylation of the 3-OH of a glucosamine derivative.

Full text of DOI:10.1016/j.tetasy.2005.02.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1439–1448
Glucosamine derived DISAL donors for stereoselective
glycosylations under neutral conditions
Susanne Grathe,b, ,à Mikkel B. Thygesen,b,à,§ Kim Larsen,a
Lars Petersenb, and Knud J. Jensena,*
aDepartment of Natural Sciences, Section for Bioorganic Chemistry, Royal Veterinary and Agricultural University,
DK-1871 Frederiksberg, Denmark
bDepartment of Chemistry, Technical University of Denmark, Denmark
Received 16 December 2004; accepted 24 February 2005
Abstract—DISAL (methyl 3,5-dinitrosalicylate) D-glucosyl, D-galactosyl, D-mannosyl, and L-quinovosyl donors have previously
provided the efficient glycosylation of a range of substrates under either strictly neutral, mildly basic, or very mildly Lewis acidic
(LiClO4) conditions. Herein we report the synthesis of new glucosamine DISAL donors, carrying N-TCP, -Troc, or -TFAc protect-
ing groups, and their use in b-(1,2-trans) selective glycosylations, primarily in NMP in the absence of any added Lewis acids, or in
CH3NO2 with LiClO4. Finally, precise microwave heating proved effective in promoting the difficult glycosylation of the 3-OH of a
glucosamine derivative.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
can become glycosyl donors. Similarly, GlcNAc derived
glycosyl donors can glycosylate under harsh conditions,
without intermediate isolation of the oxazoline.3 How-
ever, it is most often preferable to avoid formation of
the rather unreactive oxazoline intermediate, by block-
ing the 2-amino group with either one or two mono-
valent protecting groups or a bivalent one. Protecting
groups, which provide b-selectivity include phthaloyl
(Phth),2 tetrachlorophthaloyl (TCP),4 dimethylmaleoyl
(DMM),5 1,3-dimethyl-2,4,6 (1H,3H,5H)-trioxopyrimi-
dine-5-ylidenemethyl (DTPM),6 trifluoroacetyl (TFAc),7
trichloroethoxycarbonyl (Troc),8 dibenzyl,9 allyloxycar-
bonyl (Alloc),10 dithiasuccinoyl (Dts),11 and dimeth-
oxybenzyl (Dmob)/acetyl12,13 Like Phth14, TCP
induces a very high b-selectivity, but TCP has been
favored over Phth due to the more reliable removal of
the TCP. Also, Troc has become a popular choice
however, N-TFAc is interesting due to the reported very
high degree of b-selectivity. Both Troc and TFAc groups
appear to be less prone to oxazoline formation.
Glycoconjugates play crucial roles in the development,
growth, and proper functioning of an organism.1 Amino
sugars are found in many biologically important poly-
and oligosaccharides, for example, in glycans of O-
and N-glycopeptides and -proteins, tumor associated
antigens, lipochitin nodulation factors, and amino gly-
coside antibiotics, such as streptomycin. The synthesis
of oligosaccharides of these glycoconjugates provides
important tools for glycobiology. Often D-glucosamine
(2-amino-2-deoxy-glucopyranose, GlcN) is linked by a
b-(1,2-trans)-glycosidic bond. However, the syntheses
of glycosides of amino sugars, such as GlcN and D-
galactosamine, involve special problems.2 Glycosyl do-
nors with a 2-acylamino group give, upon electrophilic
activation of an anomeric (C-1) leaving group, an
oxocarbenium ion, which can form an oxazolinium
ion. Abstraction of the amide proton then gives a rela-
tively stable oxazoline. At elevated temperatures and
in the presence of a competent Lewis acid, oxazolines
Novel methods for glycosylation in the absence of
strong Lewis acids, that is, under mild conditions, hold
great promise, for example, for combinatorial chemistry
and solid-phase synthesis applications.15 We have
recently reported a new and efficient method for glyco-
sylation under either strictly neutral, mildly basic, or
*
Corresponding author. E-mail: kjj@kvl.dk
Present address: QSI Pharma, DK-2800 Kgs. Lyngby.
à Authors contributed equally.
§ Present address: ACADIA Pharmaceuticals A/S, DK-2600, Glostrup.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.029

1440
S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
very mildly acidic (LiClO4) conditions.16 In this glyco-
sylation technique, the anomeric leaving group on the
benzyl or benzoyl protected donors is methyl 3,5-di-
nitro-sal-icylate (DISAL) or its para regioisomer. The
potential of DISAL glycosyl donors was demonstrated
in their successful application to solution16a,d and
solid-phase16b oligosaccharide synthesis, as well as intra-
molecular glycosylation via a novel 1,9-glycosyl shift.16c
glucosamine derived DISAL donors, carrying N-TCP,
-Troc, or N-TFAc protecting groups, and their use in
glycosylations, primarily in the absence of Lewis acids.
This study thus has two aims, (i) the synthesis and eval-
uation of novel glucosamine derived DISAL glycosides
and (ii) the comparison of amino protecting groups in
stereo selective glycosylations.
DISAL glycosyl donors are generally prepared by a con-
venient and robust nucleophilic aromatic substitution
protocol. Here, DMAP catalyzed formation of DISAL
glycosides predominantly gives a-anomers, while
dimethylpiperazine (DMP) catalysis predominantly
gives b-anomers. Whereas O-benzyl (Bn) protected DI-
SAL donors can O-glycosylate simply by dissolution
in N-methylpyrrolidinone (NMP) at 40–60 ꢁC (with a-
selectivity), the less reactive benzoyl (Bz) donors become
efficient donors in CH3NO2 or (CH2Cl)2 in the presence
of LiClO4 (with b-selectivity). These glycosylations are
operationally simple and can be carried out in standard
plastic vials.16
2. Results and discussion
The O-acyl and N-TCP and -Troc protected lactols 1, 3,
and 4 were prepared according to literature procedures
(Scheme 1, Table 1); TFAc protected lactol 2 was ob-
tained by 1-O-deacetylation, which proceeded through
the formation of the bromide followed by hydrolysis.
The two N-Troc protected lactols 3 and 4 were obtained
in higher overall yields than 1 and 2 (data not shown).
Then, treatment of the four lactols 1–4 with aryl fluoride
5 (DISAL-F) in CH2Cl2 in the presence of a previously
established Ôdouble base systemÕ16, DMAP and Li2CO3,
converted them into the corresponding DISAL glyco-
sides 6–9 in 61–95% yield.
Glucosamine derived glycosyl donors constitute a fur-
ther and important challenge to the DISAL methodol-
ogy. Herein we report the synthesis of novel
The efficiency of this reaction provided proof for the
robustness of our procedure for the synthesis of DISAL
OCH3
OCH3
OAc
O
OAc
O
O
O
AcO
AcO
AcO
AcO
NO2
F
NO2
O
OH
O
N
N
O
O
O
O2N
5
O2N
Li2CO3/DMAP
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1
6β
OAc
OAc
O
O
AcO
AcO
AcO
AcO
O
OCH3
OH
NH
O
NH
O
F3C
F3C
O
NO2
O2N
2
7α
OCH3
OR
OR
O
O
O
RO
RO
RO
RO
OH
NO2
O
NH
O
NH
O
O
O
O2N
Cl3C
Cl3C
3-4; R: Ac or Bz
8-9; R: Ac or Bz
Scheme 1. Synthesis of glucosamine-derived DISAL donors by nucleophilic aromatic substitution; Table 1.

S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
Table 1. Synthesis of DISAL donors; see Scheme 1
1441
Lactol
R
R1, R2
Base
a/b ratio
DISAL donor
Yield (%)
14
Ac
Ac
Ac
Ac
Bz
TCP
DMAP
DMAP
DMAP
DMP
b
a
a
1:1.6
2:1
6b
7a
8a
8b
9a
94
87
95
61
95
217
TFAc, H
Troc, H
Troc, H
Troc, H
38c,18
3
418b,19
DMAP
donors. The N-TCP protected lactol 1 (b-anomer) gave
the DISAL b-glycoside; this is in contrast to previous re-
sults, where DMAP promoted the formation of 2-O-Bn
while -Bz DISAL glucosides gave a-anomers. Form-
ation of a b-glycoside from N-TCP protected b-lactol
1 by retention could be due to the steric (b-directing)
effects from the TCP moiety or due to kinetic control
of the reaction (transient formation of the b-alkoxide
and its fast reaction). In contrast, the N-Troc and N-
TFAc protected lactols 2–4 (predominantly a-anomers),
respectively, gave highly selective a-anomers (Scheme 2).
Thus, the formation of DISAL glycosides under DMAP
catalysis did predominantly occur with retention of ano-
meric configuration (except for N-TCP, i.e., conversion
of 1 to 6), as observed in previous16a syntheses. The
synthesis of Troc protected DISAL glycoside 8 in the
presence of DMP, instead of DMAP, gave an a/b
ratio of 1:1.6 in 61% yield; this provided access to 8b.
These first results favored N-Troc for amino protection.
DISAL glycosyl donors could be stored for prolonged
periods at ꢀ18 ꢁC.
With the novel DISAL glycosides 6–9 in hand, their
ability as glycosyl donors was first evaluated in the
glycosylation of cyclohexanol 10. Initial screening of
solvents indicated that NMP was preferred over, for
example, CH3CN and CH3NO3. The glycosylations
were performed with 5 equivof alcohol 10 at 40 ꢁC for
15–24 h in the absence of an added Lewis acid. Form-
ation of the cyclohexyl glycosides proceeded with b-selec-
tivity, however, with some differences. While N-TCP
and -TFAc protected donors yielded the b-anomer, Troc
protected donors 8 and 9 gave slightly reduced a/b ratios
of 1:3 and 1:5, respectively (Scheme 2, Table 2).
OCH3
OR
HO
O
O
RO
RO
O
NO2
Table 2. Glycosylation of cyclohexanol 10
N
R2
R1
DISAL donor Conditions Glycoside a/b ratioa Yield (%)
6-9
10
O2N
6
A
B
B
B
B
B
11
n.a.
12
13
13
14
bb
n.a.
b
1:3
1:4
1:5b
51
0
OR
6
O
7
35
54
76
63
RO
RO
8a
8b
9
O
N
R2
R1
A: CH3NO2, LiClO4, 60 ꢁC; B: NMP, 60 ꢁC, 16–20 h.
a a/b ratio of product glycoside isolated after VLC.
b Isolated after prep. HPLC.
Scheme 2. Model glycosylation of cyclohexanol 10; Table 2.
OCH3
OR
OH
O
O
O
O
RO
+
NO2
RO
NH
R1
O
O
O
O
O2N
7-9
15
OR
O
RO
RO
O
O
NH
R1
16 R: Ac; R1: TFAc
17 R: Ac; R1: Troc
18 R: Bz; R1: Troc
O
O
O
16-18
O
Scheme 3. Glycosylation of monosaccharide 15; conditions: NMP, 40–60 ꢁC; see Table 3.

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S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
Table 3. Glycosylation of monosaccharide 15 in NMP
The TCP protected DISAL donor 6 was the least reac-
tive, as it required higher temperatures and activation
by LiClO4 for glycosylation. N-Troc protected DISAL
donors 8 and 9 were the most reactive and gave higher
yields. Furthermore, N-Troc protected donor 8b proved
more reactive than the corresponding a-anomer 8a, as
expected.
DISAL Time/temp
donor
Equiv. Glycoside a/b
donor
Yield
ratioa (%)
7
8
9
9
60 ꢁC/40 h
40 ꢁC/18 h
40 ꢁC/18 h
40 ꢁC/24 h
2 · 1.5
1.5
1.5
16
17
18
18
bb
1:1
1:7
1:6
45
71
63
85
1.5
then 60 ꢁC/2 h 1.5
a a/b ratio of product glycoside isolated after VLC.
Next, we turned to the synthesis of disaccharides, aban-
doning the N-TCP protected donor 6 due to its low reac-
tivity. In contrast to the above conditions, a slight excess
of the DISAL donor was used here. Adapting previ-
ously16a developed conditions for the glycosylation of
the 6-OH in 1,2:3,4-diisopropylidene-a-D-galactopyra-
nose 15, 1.5 equivof the DISAL donors 7–9 were used
in NMP at 40 ꢁC; as expected from these previous
results, higher yields were observed at 40 ꢁC with a sub-
sequent rise in temperature to 60 ꢁC and/or by an
additional 1.5 equivof DISAL donor ( Scheme 3, Table
3).
b Isolated after prep. HPLC.
Thus, the O-benzoyl, N-Troc protected DISAL donor 9
gave disaccharide 18 in 85% yield with an a/b ratio of
1:6. Moving on to glucosamine acceptors, the 6-OH in
methyl 2-acetamido-2-deoxy-3,4-di-O-benzyl-a-D-gluco-
pyranoside20 19 was glycosylated with O-benzoyl pro-
tected N-Troc protected DISAL donor 9 (3 equiv)
in 60% yield and with an a/b ratio of 1:4; this provided
a
simple analogue 20 of chitin oligosaccharides
OBz
O
OCH3
O
BzO
HO
BzO
O
O
NH
O
BnO
BnO
NO2
O
O2N
Cl3C
AcNH
9
OCH3
19
OBz
O
BzO
BzO
O
NH
2 × 1.5 equiv 9
O
O
40-60 oC, NMP
BnO
BnO
O
Cl3C
20
AcNH
OCH3
60%, α/β 1:4
Scheme 4. Glycosylation of GlcNAc derivative 19.
OBz
O
O
OCH3
O
BzO
BzO
O
O
O
O
NH
O
HO
AcNH
NO2
O2N
Cl3C
OCH3
21
9
O
O
O
O
O
AcNH
3 × 1.5 equiv 9
OCH3
BzO
BzO
NH
130 oC, 3 × 5 min
CH3NO2, LiClO4
O
22
O
BzO
38%
Cl3C
Scheme 5. Glycosylation of GlcNAc derivative 21.

S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
1443
(Scheme 4). Finally, the secondary hydroxyl in glucosa-
mine derivative 21 was glycosylated with DISAL donor
9 (Scheme 5). After conventional heating (40–60 ꢁC) of
the reactants in NMP or CH3NO2 with LiClO4 only
gave sluggish reactions, microwave heating was
applied to accelerate the reaction.21 Since microwave
heating can be slow in neat solvents in the absence
of salts, we added LiClO4 for this reaction. The glycosyl
acceptor appears to be stable under these conditions.
Thus, precise heating to 130 ꢁC for 15 min in a closed
vial caused this sterically demanding glycosylation to
proceed in a yield of 38%.
Program IB: 0.00 min: 1.00 mL/min, 95.0% A, 5.0% B;
7.00 min: 1.00 mL/min, 5.0% A, 95.0% B; 8.50 min:
1.00 mL/min, 5.0% A, 95.0% B; 9.00 min: 1.00 mL/
min, 95.0% A, 5.0% B; 15.00 min: 1.00 mL/min, 95.0%
A, 5.0% B.
Program IIA: 0.00 min: 1.2 mL/min, 100% C; 0.10 min:
1.2 mL/min, 100% C; 6.00 min: 1.2 mL/min, 5.0% C,
95.0% D; 7.00 min: 1.2 mL/min, 5% C, 95% D;
7.10 min: 1.2 mL/min, 100% C; 12.00 min: 1.2 mL/min,
100% C.
Program IIB: 0.00 min: 1.00 mL/min, 95.0% C, 5.0% D;
7.00 min: 1.00 mL/min, 5.0% C, 95.0% D; 8.50 min:
1.00 mL/min, 5.0% C, 95.0% D; 9.00 min: 1.00 mL/
min, 95.0% C, 5.0% D; 15.00 min: 1.00 mL/min, 95.0%
C, 5.0% D.
3. Conclusion
In conclusion, novel N-Troc, -TCP, and -TFAc pro-
tected D-glucosamine derived DISAL donors were
prepared and proved efficient for the glycosylation of
cyclohexanol. Glycosylations were carried out in stan-
dard plastic vials in the absence of any added Lewis
acids or in the presence of LiClO4, thus under very
mild conditions. While in general good b-selectivities
were obtained, N-Troc protected DISAL donors gave
the highest glycosylation yields, although, with lower
b-selectivities. The N-TCP protected donor was the
least reactive, thus only N-Troc and -TFAc protected
donors were used for the glycosylation of monosaccha-
rides. The O-Bz and N-Troc protected DISAL glycosyl
donor gave the best overall performance. In NMP and
CH3NO2, additional activation of less reactive donors
could be achieved by the addition of LiClO4. The
sluggish glycosylation of a secondary hydroxyl in a
glucosamine derivative was accelerated by precise
microwave heating. With these and earlier results, the
DISAL methodology has proven to be a competent
glycosylation protocol. While further improvements
would be required in all cases to reach the glycosyla-
tion yields of the very best literature methods, the
exceptional mildness and operational simplicity of the
DISAL methodology should make it applicable for
many syntheses.
Program C: 0.00 min: 1.00 mL/min, 95.0% A, 5.0% B;
12.00 min: 1.00 mL/min, 5.0% A, 95.0% B; 13.50 min:
1.00 mL/min, 5.0% A, 95.0% B; 14.00 min: 1.00 mL/
min, 95.0% A, 5.0% B; 20.00 min: 1.00 mL/min, 95.0%
A, 5.0% B.
Characteristic absorption maxima were: Bz: 228–229
and 273 nm, Bn: 256–257 nm, TCP: 235–239 and
337 nm, DISAL-OH: 220 and 286 nm.
Preparative HPLC was performed on a Waters 600 sys-
tem with a Waters 996 diode array detector and three
consecutive columns (40 · 100 mm prep. NOVA Pak
˚
HR C18 6 lm 60 A units). Linear gradients of CH3CN
and water (MilliQ) were used (Program IA, IB, IIA,
1
IIB, and C). H, 13C, gHSQC, and H,H-COSY NMR
spectra were recorded on Varian Mercury 300, Bruker
Avance 300, or Varian Unity Inova 500 spectrometers.
The chemical shifts are referred to the residual solvent
signal. In NMR data for disaccharide products, HA des-
ignates protons from the acceptor moiety, while HD
designates protons from the donor moiety. Infrared
spectroscopy was performed on a Perkin–Elmer System
2000 FT-IR. Mass determination (high resolution MS,
HR-MS) was performed on a Micromass LCT instru-
ment with an ESI probe.
4. Experimental
All the solvents used for the synthesis were distilled,
˚
either freshly or kept over 4 A molecular sieves (where
appropriate, glass equipment was dried prior to usage).
Uncorrected melting points were measured in open
capillary tubes.
Analytical HPLC was performed on a Waters 600 sys-
tem with a 996 diode array detector and a 717 Autosam-
pler equipped with a 3.9 · 50 mm Nova-Pak C18 4 lm
˚
60 A column. The following solvents were used: 0.1%
TFA/H2O (A); 0.1% TFA/CH3CN (B); H2O (C);
CH3CN (D). Analytical HPLC was performed on
microfiltered or centrifuged 0.1% solutions in MeCN
(for more hydrophilic compounds, solubility was im-
proved by addition of water).
For TLC Merck TLC Aluminum Sheets Silica Gel 60
F254 were used. Compounds containing UV-absorbing
groups were visualized under UV-light (254 nm); carbo-
hydrates were developed with 2 M H2SO4 followed by
charring with a heat gun. VLC was performed on col-
umns of Merck 60H silica (h 15 cm, d 2–4 cm depending
on amount of compound) packed under vacuum. The
crude product was dissolved in CH2Cl2, an equivalent
amount of silica added, concentrated, placed on the col-
umn and finally covered with acid rinsed sea sand. Chro-
matography was hereafter run with the appropriate
eluents until the product was collected.
The following programs were used:
Program IA: 0.00 min: 1.20 mL/min, 100.0% A;
0.10 min: 1.20 mL/min, 100.0% A; 6.00 min: 1.20 mL/
min, 5.0% A, 95.0% B; 7.00 min: 1.20 mL/min, 5.0%
A, 95.0% B; 7.10 min: 1.20 mL/min, 100.0% A;
12.00 min: 1.20 mL/min, 100.0% A.

1444
S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
4.1. General procedure for the synthesis of DISAL
glycosyl donors 6–9
124.7 (Ar-C-3), 117.4, 115.1 (CF3), 102.4 (C-1a), 72.2–
61.8 (C-3/4/5/6), 54.7, 52.9 (C-2 and OCH3(DISAL)),
21.3, 21.1, 21.0 (3 · CH3(Ac)). IR (neat) 3470–3250 (w),
1738 (s), 1542 (s), 1345 (s), 1219 (s). ESMS: m/z calcd
for C22H22F3N3O15, 625.10, m/z calcd for [M+Na]+,
648.09. Found 648.19. m/z calcd for [M+NH4]+, 643.13.
Found 643.22. m/z calcd for [MꢀDISAL-O]+ calcd
384.09. Found 384.41. HRMS (ES): calcd for
C22H22F3N3O15NH4 [M+NH4]+, 643.1347; Found,
643.1309.
In a dried flask, protected carbohydrate derivative lac-
tols 1–4, Li2CO3 (2 equiv), and methyl 2-fluoro-3,5-dini-
trobenzoic ester 5 (1.2 equiv) were suspended in CH2Cl2
(1–2 mL/mmol). Reactions proceeded in the presence of
1,4-dimethylpiperazine (DMP) or DMAP. (1) DMP
catalysis: DMP (0.5 equiv) was added to the suspension
and the mixture stirred for 2–3 h. (2) DMAP catalysis:
DMAP (0.3 equiv) was dissolved in CH2Cl2 (0.5 mL)
and added to the suspension in five portions over
20 min. After addition of the first portion, the color
changed from slightly discolored to a strong yellow/
brown. After stirring for an additional 10 min, products
were isolated by VLC chromatography eluting with
CH2Cl2–Et2O (1:0!9:1–19:1).
4.1.3. 2,4-Dinitro-6-(methoxycarbonyl)-phenyl 3,4,6-tri-
O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-
a-D-glucopyranose 8a. Yield 95%, a/b > 49:1. Mp 72–
1
82 ꢁC. [a]D = +95.8 (c 4.92 · 10ꢀ3, CHCl3). H NMR
(300 MHz, CDCl3): d 8.79 (d, 1H, Ar-H-3, JH,H
2.8 Hz), 8.67 (d, 1H, Ar-H-5, JH,H 2.8 Hz), 5.88 (d,
1H, NH, JNH,2 9.8 Hz), 5.73 (d, 1H, H-1a, J1,2
3.6 Hz), 5.41 (dd, 1H, H-3, J3,2 11.0 Hz J3,4 9.6 Hz),
5.10 (t, 1H, H-4, J4,3 9.6 Hz J4,5 10.1 Hz), 4.76 (d, 1H,
CHH(Troc), JH,H 12.0 Hz), 4.58 (d, 1H, CHH(Troc),
JH,H 12.0 Hz), 4.19 (ddd, 1H, H-2, J2,1 3.6 Hz J2,3
11.0 Hz J2,NH 9.8 Hz), 4.11 (dd, 1H, H-6, J6,5 4.6 Hz
4.1.1. 2,4-Dinitro-6-(methoxycarbonyl)-phenyl 3,4,6-tri-
O-acetyl-2-deoxy-2-(tetrachlorophthalimido)-b-D-gluco-
pyranose 6b. Yield 94%, a/b < 1:49. Mp 114–117 ꢁC.
[a]D = ꢀ4.7 (c 4.84 · 10ꢀ3, CHCl3). 1H NMR (500
MHz, CDCl3): d 8.9 (d, 1H, Ar-H-3), 8.7 (d, 1H, Ar-
H-5), 5.90 (dd, 1H, H-3, J3,2 10.66 Hz J3,4 9.38 Hz),
5.74 (d, 1H, H-1b, J1,2 8.11 Hz), 5.26 (t, 1H, H-4, J4,3
9.38 Hz, J4,5 9.81 Hz), 4.67 (ddd, 1H, H-2, J2,1 8.11 Hz
0
J6,6 12.6 Hz), 3.98 (s, 1H, CH3O(DISAL)), 3.90 (dd,
0
1H, H-60, J6 ,5 2.1 Hz J6 ,6 12.6 Hz), 4.02 (ddd, 1H, H-
0
0
5, J5,6 2.1 Hz J5,6 4.6 Hz J5,4 10.1 Hz), 2.1–2.0 (3 · s,
3 · 3H, 3 · CH3(Ac)). 13C NMR (75 MHz, CDCl3): d
171–169 (3 · CO(Ac)), 169 (CO(DISAL)), 154 (CO-
(Troc)), 152, 144, 142, 127 (Ar-C-1/2/4/6), 130.1 (Ar-C-
5), 124.1 (Ar-C-3), 102.0 (C-1a), 75.0 (CH2(Troc)),
71.5 (C-5), 69.8 (C-3), 67.5 (C-4), 61.5 (C-6), 54.3, 54.2
(C-2 and OCH3(DISAL)), 20.8 (3 · CH3(Ac)). IR (neat)
3520–3250 (w), 1743 (s), 1541 (s), 1259 (s), 815 (w).
ESMS: m/z calcd for C23H24Cl3N3O16, 703.02/705.02,
m/z calcd for [M+Na]+, 726.01/728.01. Found 726.02/
728.03. m/z calcd for [MꢀDISAL-O]+, 462.01. Found
462.01. m/z calcd for [MꢀDISAL-Oꢀ(AcOH)2]+,
341.99/343.99. Found 341.97/343.97. HRMS (ES): calcd
for C23H24Cl3N3O16NH4 [M+NH4]+, 721.0566; Found,
721.0519; calcd for C23H24Cl3N3O16Na [M+Na]+,
726.0120; Found, 726.0109.
0
J2,3 10.66 Hz), 4.17 (dd, 1H, H-6, J6,5 3.84 Hz J6,6
0
12 Hz), 4.02 (dd, 1H, H-60, J6 ,5 2.13Hz J6 ,6 12 Hz),
3.84 (s, 1H, CH3O(DISAL)), 3.76 (ddd, 1H, H-5, J5,4
0
0
9.81 Hz J5,6 3.84 Hz J5,6 2.13 Hz), 2.1–1.9 (3 · s,
3 · 3H, 3 · CH3(Ac)). 13C NMR (125 MHz, CDCl3): d
171.2, 171.0, 169.9 (3 · CO(Ac)), 168.4 (CO(TCP)),
162.8 (CO(DISAL)), 151.9, 147.5, 144.5, 124.0 (Ar-
C(DISAL)), 130.1 (Ar-C(TCP)), 100.3 (C-1b), 72.8,
70.7, 68.7, 61.7 (C-3/4/5/6), 55.7 (C-2), 53.9 (OCH3(DI-
SAL)), 21.3, 21.2, 21.2 (3 · CH3(Ac)). IR (neat): 3580–
3340 (w), 1735 (s), 1535 (s), 1346 (s), 1224 (s), 739 (m).
ESMS: m/z calcd for C28H21Cl4N3O16 794.97/796.97,
m/z calcd for [M+Na]+, 817.96/819.96. Found
817.85/819.87. m/z calcd for [M+NH4]+, 813.00/815.00.
Found 812.88/814.91. m/z calcd for [MꢀDISAL-Oꢀ
(AcOH)2]+, 433.94/435.94. Found 434.17/436.18.
HRMS
(ES):
calcd
for
C28H21Cl4N3O16NH4
4.1.4. 2,4-Dinitro-6-(methoxycarbonyl)-phenyl 3,4,6-tri-
O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-
b-D-glucopyranose 8b. Yield 61%, a/b 1.6:1. Anomers
were separated by VLC: 11b: 38%, mp 132–134 ꢁC.
[M+NH4]+, 813.0020; Found 812.9929; calcd for
C28H21Cl4N3O16Na [M+Na]+, 817.9574; Found,
817.9606.
1
11a: 23%. H NMR (500 MHz, CDCl3): d 8.85 (d, 1H,
4.1.2. 2,4-Dinitro-6-(methoxycarbonyl)-phenyl 3,4,6-tri-
O-acetyl-2-deoxy-2-(trifluoroacetamido)-a-D-glucopyranose
7a. Yield 87%, a/b > 49:1. Mp 66–71 ꢁC. [a]D = +62.1 (c
4.23 · 10ꢀ3, CHCl3). 1H NMR (500 MHz, CDCl3): d 8.92
(d, 1H, Ar-H-3), 8.76 (d, 1H, Ar-H-5), 7.59 (d, 1H, NH,
JNH,2 7.3 Hz), 5.77 (d, 1H, H-1a, J1,2 3.4 Hz), 5.48 (dd,
1H, H-3, J3,2 10.7 Hz J3,4 9.8), 5.10 (dd, 1H, H-4, J4,3
9.8 Hz J4,5 10.2 Hz), 4.57 (ddd, 1H, H-2, J2,1 3.4 Hz J2,3
10.7 Hz J2,NH 7.3 Hz), 4.21 (dd, 1H, H-6, J6,5 4.3 Hz
Ar-H-3), 8.75 (d, 1H, Ar-H-5) 5.62 (d, 1H, NH, JNH,2
8.53 Hz) 5.34–5.29 (m, 2H, H-1b/3), 5.15 (t, 1H, H-4),
4.76 (dd, 2H, CH2(Troc), JH,H 11.95 Hz), 4.12 (dd,
0
1H, H-6, J6,5 4.69 Hz J6,6 12.37 Hz), 4.07 (ddd, 1H,
H-2), 4.01 (s, 1H, CH3O(DISAL)), 3.98 (dd, 1H, H-60,
0
0
J6 ,5 2.56 Hz J6,6 12.37 Hz), 4.02 (ddd, 1H, H-5), 2.1–
2.0 (3 · s, 3 · 3H, 3 · CH3(Ac)). 13C NMR (125 MHz,
CDCl3): d 171.2, 171.1, 169.9 (3 · CO(Ac)), 168.2 (CO-
(DISAL)), 155.0 (CO(Troc)), 144.5, 143.4, 129.9, 123.9
(Ar-C(DISAL)), 102.8 (C-1b), 75.4–56.9 (CH2(Troc),
0
J6,6 12.4 Hz), 4.04 (s, 1H, CH3O(DISAL)), 4.00 (dd,
0
1H, H-60, J6 ,5 2.1 Hz J6 ,6 12.4 Hz), 3.86 (ddd, 1H, H-5,
C-2/3/4/5/6
and
OCH3(DISAL)),
21.3–21.2
0
0
J5,4 10.2 Hz J5,6 4.3 Hz J5,6 2.1 Hz), 2.07–2.06 (3 · s,
(3 · CH3(Ac)). ESMS: m/z calcd for C23H24Cl3N3O16,
703.02/705.02, m/z calcd for [M+NH4]+, 721.05/723.05.
Found 720.97/723.01, m/z calcd for [MꢀDISAL-O]+,
462.01/464.01. Found 461.95/463.95, m/z calcd for
3 · 3H, 3 · CH3(Ac)). 13C NMR (125 MHz, CDCl3): d
171.4, 171.0, 169.7 (3 · CO(Ac)), 163.5 (CO(DISAL)),
158.4 (CO(TFAc) JC,F 38.2), 152.6 (Ar-C-1), 145.0 (Ar-
C-4), 143.0 (Ar-C-6), 130.8 (Ar-C-5), 127.1 (Ar-C-2),
2
[MꢀDISAL-Oꢀ(AcOH)2]+, 341.99/343.99.
Found

S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
1445
341.94/343.94. HRMS (ES): calcd for C23H24Cl3N3O16-
Na [M+Na]+, 726.0120; Found, 726.0104.
10H, CH2(cyclohexyl)). 13C NMR (125 MHz, CDCl3):
d 171.4, 171.3, 170.1 (3 · CO(Ac)), 168.4 (CO(TCP)),
141.3, 130.7, 127.6 (3 · Ar-C(TCP)), 97.0 (C-1b), 78.6,
72.4, 71.8, 69.6, 62.9 (C-3/4/5/6 and CH-OGlc(cyclo-
hexyl)), 56.4 (C-2), 33.9, 32.3, 26.0, 24.5, 24.4
(5 · CH2(cyclohexyl)), 21.4, 21.3, 21.2 (3 · CH3(Ac)).
ESMS: m/z calcd for C26H27Cl4NO10, 653.04/655.04,
m/z calcd for [M+Na]+, 676.03/678.03. Found 676.19/
678.16. m/z calcd for [M+NH4]+, 671.07/673.07. Found
671.24/673.21, m/z calcd for [MꢀcC6H11Oꢀ(AcOH)2]+,
433.94/435.94. Found 434.24/436.25.
4.1.5. 2,4-Dinitro-6-(methoxycarbonyl)-phenyl 3,4,6-tri-
O-benzoyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl-
amino)-a-D-glucopyranose 9a. Yield 95%, a/b > 49:1.
1
Mp 91–98 ꢁC. H NMR (300 MHz, CDCl3): d 8.65 (d,
1H, Ar-H-3, JH,H 2.7 Hz), 8.57 (d, 1H, Ar-H-5, JH,H
2.7 Hz), 7.90–7.80, 7.52–7.40, and 7.36–7.25 (3 · m,
15H, Ar-H(Bz)), 5.94 (d, 1H, H-1a, J1,2 3.4 Hz), 5.93
(dd, 1H, H-3, J3,2 10.9 Hz J3,4 9.7 Hz), 5.86 (d, 1H,
NH, JNH,2 9.5 Hz), 5.59 (dd, 1H, H-4, J4,3 9.7 Hz J4,5
9.9 Hz); 4.64 (d, 1H, CHH(Troc), JH,H 12.0 Hz), 4.48
(m, 1H, H-2), 4.47 (d, 1H, CHH(Troc), JH,H 12.0 Hz)
4.2.2. Cyclohexyl 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-tri-
fluoracetamido)-b-D-glucopyranoside 12. Yield 35%, a/
b < 1:49. Mp 185–187 ꢁC. 1H NMR (500 MHz, CDCl3):
d 6.70 (d, 1H, NH, JNH,2 8.54 Hz), 5.35 (dd, 1H, H-3,
J3,2 10.67 Hz J3,4 9.38 Hz), 5.08 (dd, 1H, H-4, J4,3
9.38 Hz J4,5 9.82 Hz), 4.80 (d, 1H, H-1b, J1,2 8.1 Hz),
0
4.40 (dd, 1H, H-6, J6,5 2.5 Hz J6,6 12.4 Hz), 4.28 (dd,
1H, H-60, J6 ,5 5.4 Hz J6 ,6 12.4 Hz), 4.16 (m, 1H, H-5,
J5,6 2.5 Hz J5,6 5.4 Hz), 4.0 (s, 1H, CH3O(DISAL)).
13C NMR (75 MHz, CDCl3): d 167–165 (3 · CO(Bz)),
154.6 (CO(Troc)), 152–124.1 (24 · Ar-C(Bz and DIS-
AL)), 100.9 (C-1a), 74.9 (CH2(Troc)), 72.0 (C-5), 70.2
(C-3), 68.6 (C-4), 62 (C-6), 54.6, 54.2 (C-2 and
COOCH3(DISAL)). IR (neat) 3460–3300 (w), 1728 (s),
1540 (s), 1269 (s), 814 (m), 708 (s). ESMS: m/z calcd
for C38H30Cl3N3O16, 889.07, m/z calcd for [M+Na]+,
912.06. Found 911.06. m/z calcd for [M+NH4]+,
907.10. Found 906.50. m/z calcd for [MꢀDISAL-O]+
calcd 648.06. Found 649.86. HRMS (ES): calcd for
C38H30Cl3N3O16Na [M+Na]+, 912.0589; Found,
912.0635.
0
0
0
4.28 (dd, 1H, H-6, J6,5 5.12 Hz J6,6 12.37 Hz), 4.13
(dd, 1H, H-60, J6 ,5 2.56 Hz J6 ,6 12.37 Hz), 3.91 (dd,
1H, H-2, J2,3 10.67 Hz J2,NH 8.54 Hz), 3.73 (ddd, 1H,
0
0
0
H-5, J5,4 9.82 Hz J5,6 5.12 Hz J5,6 2.56 Hz), 3.64
(m, 1H, CH-OGlc(cyclohexyl)), 2.2–2.0 (3 · s, 9H,
3 · CH3(Ac)), 1.9–1.2 (m, 10H, CH2(cyclohexyl)). 13C
NMR (125 MHz, CDCl3): d 171.7, 171.4, 170.1, 168.2
(3 · CO(Ac) and CO(TFAc)), 99.2 (C-1 b), 78.6, 72.5,
72.4, 69.4, 62.9 (C-3/4/5/6 and CH-OGlc(cyclohexyl)),
56.0 (C-2), 36.2–24.2 (5 · CH2(cyclohexyl)), 21.4–21.1
(3 · CH3(Ac)). ESMS: m/z calcd for C20H28F3NO9,
483.17, m/z calcd for [M+Na]+, 506.16. Found 506.15.
m/z calcd for [M+NH4]+, 501.20. Found 501.18. m/z
calcd for [MꢀcC6H11O]+, 384.09. Found 384.07; m/z
calcd for [MꢀcC6H11Oꢀ(AcOH)2]+, 264.07. Found
264.02.
4.2. General procedure for glycosylations with DISAL
donors 6–9, synthesis of 11–14, 16–18, and 20
Glycosylations of cyclohexanol were performed under
reaction conditions according to Table 2. Glycosylations
of monosaccharide 15 were performed under the reac-
tion conditions according to Table 3. Glycosylation of
monosaccharide 20 was performed in NMP at 40 ꢁC
with donor 9 (1.5 equiv) for 19 h and then with an addi-
tional amount of 9 (1.5 equiv) for 5 h at 60 ꢁC.
4.2.3. Cyclohexyl 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-tri-
chlorethoxycarbonylamino)-a/b-D-glucopyranoside
13.
From 8a: Yield 54%, a/b 1:3. Mp 136–138 ꢁC. From
1
8b: Yield 76%, a/b 1:4. Mp 130–140 ꢁC. H NMR 13a
(500 MHz, CDCl3): d 5.25 (dd, 1H, H-3, J3,2 10.24 Hz
J3,4 9.81 Hz), 5.19 (d, 1H, NH, JNH,2 9.81 Hz), 5.09
(dd, 1H, H-4, J4,3 9.81 Hz J4,5 9.81 Hz), 5.02 (d, 1H,
H-1a, J1,2 3.41 Hz), 4.76 (d, 1H, CHH(Troc), JH,H
11.95 Hz), 4.68 (d, 1H, CHH(Troc), JH,H 11.95 Hz),
Glycosyl donor (1.5 equivunless stated otherwise), gly-
cosyl acceptor (1 equivunless stated otherwise), LiClO
4
˚
(3 equiv), crushed 3 A molecular sieves, and a magnet
0
were placed in a 5 mL plastic tube with a septum. The
tube was dried under high vacuum for 1–2 h, filled with
argon, CH3NO2 or NMP (0.7 mL) added and the reac-
tion mixture stirred at room temperature. The tempera-
ture was raised as indicated in Table 2 or Table 3 and
stirring was continued overnight. The reaction mixture
was filtered and purified by preparative HPLC.
4.24 (dd, 1H, H-6, J6,5 4.70 Hz J6,6 11.95 Hz), 4.11
(dd, 1H, H-60, J6 ,5 2.56 Hz J6 ,6 12.37 Hz), 4.12–4.06
(m, 2H, H-5/60), 4.03 (ddd, 1H, H-2, J2,3 10.24 Hz J2,1
3.41 Hz), 3.6 (m, 1H, CH-OGlc(cyclohexyl)), 2.09,
2.04, 2.01 (3 · s, 9H, 3 · CH3(Ac)), 1.9, 1.7, 1.6, 1.4,
1.3 (5 · m, 10H, CH2(cyclohexyl)). 13C NMR 13a
(125 MHz, CDCl3): d 171.6, 171.3, 170.1 (3 · CO(Ac)),
154.9 (CO(Troc)), 96.3 (d, C-1a), 75.3, 75.3, 71.9, 69.2,
68.5, 62.8 (C-3/4/5/6, CH2(Troc), and CH-OGlc(cyclo-
hexyl)), 54.7 (C-2), 36.3–24.6 (5 · CH2(cyclohexyl)),
21.4, 21.4, 21.3 (3 · CH3(Ac)). 1H NMR 13b
(500 MHz, CDCl3): d 5.37 (dd, 1H, H-3, J3,2 9.39 Hz
J3,4 9.81 Hz), 5.14 (d, 1H, H-1b), 5.05 (dd, 1H, H-4,
J4,3 9.81 Hz J4,5 9.38 Hz), 4.80–4.67 (m, 3H, CH2(Troc),
0
0
4.2.1. Cyclohexyl 3,4,6-tri-O-acetyl-2-deoxy-2-(tetra-
chlorophthalimido)-b-D-glucopyranoside 11. Yield 51%,
a/b < 1:49. Mp 194–195 ꢁC. 1H NMR (500 MHz,
CDCl3): d 5.69 (dd, 1H, H-3, J3,2 10.67 Hz J3,4
8.96 Hz), 5.45 (d, 1H, H-1b, J1,2 8.53 Hz), 5.17 (dd,
1H, H-4, J4,3 8.96 Hz J4,5 10.23 Hz), 4.33 (dd, 1H, H-
0
0
6, J6,5 4.69 Hz J6,6 12.37 Hz), 4.30 (dd, 1H, H-2, J2,3
0
NH), 4.28 (dd, 1H, H-6, J6,5 5.12 Hz J6,6 12.37 Hz), 4.11
0
10.67 Hz), 4.15 (dd, 1H, H-60, J6 ,5 2.56 Hz J6 ,6
12.37 Hz), 3.81 (ddd, 1H, H-5, J5,4 10.23 Hz J5,6
(dd, 1H, H-60, J6 ,5 2.56 Hz J6 ,6 12.37 Hz), 3.70 (m, 1H,
0
H-5, J5,6 2.56 Hz), 3.64 (m, 1H, CH-OGlc(cyclohexyl)),
0
0
0
4.69 Hz J5,6 2.56 Hz), 3.60 (m, 1H, CH-OGlc(cyclo-
hexyl)), 2.1–1.9 (3 · s, 9H, 3 · CH3(Ac)), 1.9–1.0 (m,
3.53 (m, 1H, H-2, J2,3 9.39 Hz), 2.1–1.9 (3 · s, 9H,
3 · CH3(Ac)), 1.9–1.2 (m, 10H, CH2(cyclohexyl)). 13C

1446
S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
NMR 13b (125 MHz, CDCl3): d 171.4–168.4 (3 ·
CO(Ac)), 154.6 (CO(Troc)), 99.7 (C-1b), 78.7–72.3 (C-
3/5, CH2(Troc), and CH-OGlc(cyclohexyl)), 69.7 (C-4),
63.0 (C-3), 57.4 (C-2), 34.0, 32.3, 26.2, 24.5, 24.4
(5 · CH2(cyclohexyl)), 21.4, 21.3, 21.3 (3 · CH3(Ac)).
ESMS: m/z calcd for C21H30Cl3NO10, 561.09/563.09,
m/z calcd for [M+Na]+, 584.08/586.08. Found 584.09/
586.10. m/z calcd for [MꢀcC6H11O]+, 462.01/464.01.
Found 462.01/464.01, m/z calcd for [MꢀcC6H11Oꢀ
(AcOH)2]+, 341.99/343.99. Found 341.97/343.97.
1.4–1.3 (4 · s, 12H, 4 · CH3C(isopropylidene)). 13C
NMR (125 MHz, CDCl3): 171.7, 171.4, 170.0
d
(3 · CO(Ac)), 158.3, 158.0 (CO(TFAc)), 116.3 (q,
CF3(TFAc)), 110.1, 109.5 (2 · C(CH3)2(OR)2), 101.4
(CD-1b), 96.9 (d, CA-1a), 73.0–68.9 (CD-3/4/5 and CA-
2/3/4/5/6), 62.7 (CD-6), 55.2 (CD-2), 26.6, 26.4, 25.5,
25.0 (4 · CH3C(isopropylidene)), 21.4, 21.2, 21.0
(3 · CH3(Ac)). IR (neat) 3600–3240 (w), 1749 (s), 1370
(m), 1221 (s), 1037 (s). HRMS (ES): calcd for
C26H36F3NO14NH4 [M+NH4]+,, 661.2432; Found,
661.2418; calcd for C26H36F3NO14Na [M+Na]+,,
666.1986; Found, 666.2025; calcd for C26H36F3NO14K
[M+K]+,, 682.1725; Found, 682.1661.
4.2.4. Cyclohexyl 3,4,6-tri-O-benzoyl-2-deoxy-2-(2,2,
2-trichlorethoxycarbonylamino)-a/b-D-glucopyranoside
14. Yield 14a: 11%. Mp 165–167 ꢁC. Yield 14b: 52%.
1
Mp. 82–86 ꢁC. Total yield 63%, a/b 1:5. H NMR 14a
4.2.6. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroeth-
oxycarbonylamino)-a/b-D-glucopyranosyl-(1!6)-(1,2; 3,4)-
diisopropylidene-a-D-galactopyranose 17. Yield 71%,
(500 MHz, CDCl3): d 8.1–7.0 (m, 15H, Ar-H(Bz)),
5.75 (dd, 1H, H-3, J3,2 10.67 Hz J3,4 9.81 Hz), 5.61
(dd, 1H, H-4, J4,3 9.81 Hz J4,5 9.38 Hz), 5.34 (d, 1H,
NH, JNH,2 9.81 Hz), 5.15 (d, 1H, H-1a, J1,2 3.83 Hz),
4.66 (d, 1H, CHH(Troc), JH,H 11.94 Hz), 4.57 (m, 1H,
H-6), 4.54 (d, 1H, CHH(Troc), JH,H 11.94 Hz), 4.5–4.4
(m, 2H, H-5/60), 4.32 (ddd, 1H, H-2, J2,1 3.83 Hz J2,3
10.67 Hz), 3.65 (m, 1H, CH-OGlc(cyclohexyl)), 2.04–
1.19 (m, 10H, CH2(cyclohexyl)). 13C NMR 14a
(75 MHz, CDCl3): d 166.5, 166.1, 165.2 (3 · CO(Bz)),
154.2 (CO(Troc)), 133.3–128.3 (18 · Ar-C(Bz)), 95.8
(C-1a); 77.3, 74.3, 71.5, 69.5, 68.2, 63.1, (C-3/4/5/6,
CH2(Troc), and CH-OGlc(cyclohexyl)), 54.4 (C-2)
33.4, 31.6, 25.3, 24.1, 23.9 (5 · CH2(cyclohexyl)). 1H
NMR 14b (500 MHz, CDCl3): d 8.1–7.2 (m, 15H, Ar-
H(Bz)), 5.86 (dd, 1H, H-3, J3,2 9.81 Hz J3,4 9.81 Hz),
5.58 (dd, 1H, H-4, J4,3 9.81 Hz J4,5 9.38 Hz), 5.35 (broad
d, 1H, NH), 4.96 (d, 1H, H-1b, J1,2 8.11 Hz), 4.71 (d,
1H, CHH(Troc), JH,H 11.51 Hz), 4.54 (d, 1H,
CHH(Troc), JH,H 11.51Hz), 4.60 (dd, 1H, H-6, J6,5
1
a/b 1:1, oil. H NMR 17a (500 MHz, CDCl3): d 5.56
(d, 1H, HA-1a, J1,2 5.12 Hz), 5.44 (d, 1H, NH, JNH,2
9.81 Hz), 5.25 (dd, 2H, HD-1a, and HD-3, J3,2
10.23 Hz J3,4 9.38 Hz), 5.12 (dd, 1H, HD-4, J4,3
9.38 Hz J4,5 9.81 Hz), 4.79 (d, 1H, CHH(Troc), JH,H
12.37 Hz), 4.64 (d, 1H, CHH(Troc), JH,H 12.37 Hz),
4.61 (dd, 1H, HA-3, J3,2 2.56 Hz), 4.33 (dd, 1H, HA-2,
J2,1 5.12 Hz J2,3 2.56 Hz), 4.27 (dd, 1H, HA-4, J4,5
1.71 Hz J4,3 8.11 Hz), 4.23 (m, 2H, HD-5/6), 4.13 (dd,
1H, HD-6), 4.05 (m, 1H, HD-2), 3.89–3.83 (m, 2H, HA-
5/6), 3.74 (dd, 1H, HA-60), 2.10, 2.03, 2.01 (3 · s, 9H,
3 · CH3(Ac)), 1.53, 1.45, 1.34 (3 · s, 12H, 4 · CH3C(iso-
propylidene)). 13C NMR 17a (75 MHz, CDCl3): d
171.0–169.4 (3 · CO(Ac)), 154.2 (CO(Troc)), 109.5,
108.7 (2 · C(CH3)2(OR)2), 96.2 (CA-1a), 91.7 (CD-1a),
75.4–62.0 (CD-3/4/5/6 and CA-2/3/4/5/6), 54.2 (CD-2),
26.0, 25.9, 24.9, 24.2 (4 · CH3C(isopropylidene)), 20.7–
1
20.6 (3 · CH3(Ac)). H NMR 17b (500 MHz, CDCl3):
2.56 Hz), 4.51 (dd, 1H, H-60, J6 ,5 5.97 Hz), 4.12 (m,
d 5.52 (d, 1H, HA-1a, J1,2 5.52 Hz), 5.25 (dd, 2H, HD-
3, and NH, J3,2 9.81 Hz J3,4 9.38 Hz), 5.07 (dd, 1H,
HD-4, J4,3 9.38 Hz J4,5 9.81 Hz), 4.92 (d, 1H,
CHH(Troc)), 4.80 (d, 1H, HD-1b, J1,2 8.53 Hz), 4.58
(dd, 1H, HA-3, J3,2 7.68 Hz J3,4 2.13 Hz), 4.52–4.51
(m, 1H, CHH(Troc)), 4.31 (dd, 1H, HA-2), 4.28 (m,
0
1H, H-5), 3.86 (m, 1H, H-2), 3.66 (m, 1H, CH-
OGlc(cyclohexyl)), 1.95–1.14 (m, 10H, CH2(cyclo-
hexyl)). 13C NMR 14b (75 MHz, CDCl3): d 166.3,
166.1, 165.3 (3 · CO(Bz)), 154.1 (CO(Troc)), 133.4–
128.4 (18 · Ar-C(Bz)), 99.4 (C-1b), 78.3, 74.4, 72.4,
71.9, 70.2, 63.5 (C-3/4/5/6, CH2(Troc), and CH-
OGlc(cyclohexyl)), 57.0 (C-2); 33.3, 31.7, 25.4, 23.7
1H, HD-6), 4.18 (dd, 1H, HA-4, J4,5 1.71 Hz J4,3
D
8.11 Hz), 4.13 (dd, 1H, H -60, J6,5 2.55 Hz J6 ,6
0
(5 · CH2(cyclohexyl)).
ESMS:
m/z
calcd
for
12.37Hz), 3.99–3.95 (m, 2H, HA-5/6), 3.78(dd, HA-60),
3.72–3.69 (m, 1H, HD-2/5), 2.09, 2.02, 2.01 (3 · s, 9H,
3 · CH3(Ac)), 1.54. 1.44, 1.32 (4 · s, 12H, 4 · CH3C(iso-
propylidene)). 13C NMR 17b (75 MHz, CDCl3): d 170.6,
170.5, 169.4 (3 · CO(Ac)), 154.2 (CO(Troc)), 109.4,
108.7 (2 · C(CH3)2(OR)2), 101.0 (CD-1b), 96.1 (CA-1a),
74.4–68.2 (CD-3/4/5 and CA-2/3/4/5/6), 62.0 (CD-6),
56.1 (CD-2), 26.0, 25.9, 24.9, 24.2 (4 · CH3C(isopropyl-
idene)), 21.4, 20.7, 20.5 (3 · CH3(Ac)). ESMS: m/z calcd
for C28H40Cl3NO15, 735.15/737.15, m/z calcd for
[M+NaꢀCH3]+ calcd 743.12. Found 743.13. m/z calcd
for [M+NH4ꢀCH3]+, 738.16/740.16. Found 739.13/
741.15, m/z calcd for [MꢀGalpO]+calcd 462.02/464.02.
Found 461.98/464.
C36H36Cl3NO10, 747.14/749.14, m/z calcd for [M+Na]+
calcd 770.13/772.13. Found 770/772.17. m/z calcd for
[M+NH4]+ calcd 765.17/767.17. Found 765.20/767.21.
m/z calcd for [MꢀcC6H11O]+, 648.06/650.06. Found
648/650.08. m/z calcd for [MꢀcC6H11Oꢀ(BzOH)2]+,
404.01/406.01. Found 404.01/405.98.
4.2.5. 3,4,6-Tri-O-acetyl-2-deoxy-2-(trifluoroacetamido)-
b-D-glucopyranosyl-(1!6)-(1,2;3,4)-diisopropylidene-a-D-
galactopyranose 16. Yield 45%, a/b < 1:49, oil. [a]D =
ꢀ21.7 (c 2.80 · 10ꢀ3, CHCl3). 1H NMR (500 MHz,
CDCl3): d 6.75 (broad s, 1H, NH), 5.48 (d, 1H, HA-
1a, J1,2 5.12 Hz), 5.24 (dd, 1H, HD-3, J3,2 10.66 Hz J3,4
9.39 Hz), 5.10 (dd, 1H, HD-4, J4,3 9.39 Hz J4,5
9.81 Hz), 4.79 (d, 1H, HD-1b, J1,2 8.10 Hz), 4.56 (dd,
1H, HA-3, J3,2 8.11 Hz J3,4 2.56 Hz), 4.31–4.27 (m, 2H,
HA-2, HD-6), 4.17–4.14 (m, 2H, HA-4, HD-60), 4.07
(dd, 1H, HD-2), 3.97–3.92 (m, 2H, HA-5/6), 3.79–3.71
(m, 2H, HA-60, HD-5), 2.1–2.0 (3 · s, 9H, 3 · CH3(Ac)),
4.2.7. 3,4,6-Tri-O-benzoyl-2-deoxy-2-(2,2,2-trichloroeth-
oxycarbonylamino)-a/b-D-glucopyranosyl-(1!6)-(1,2;3,4)-
diisopropylidene-a-D-galactopyranose 18. 18: Yield
1
63%, a/b 1:7, mp 91–96 ꢁC. 18: Yield 85%, a/b 1:6. H
NMR 18a (500 MHz, CDCl3): d 8.0–7.3 (m, 15H,

S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
1447
Ar-H(Bz)), 5.78 (dd, 1H, HD-3, J3,2 10.36 Hz J3,4 9.76 Hz),
5.70 (d, 1H, NH), 5.68 (dd, 1H, HD-4, J4,3 9.76 Hz J4,5
10.07 Hz), 5.55 (d, 1H, HA-1a, J1,2 4.88 Hz), 5.06 (d,
1H, HD-1a, J1,2 3.36 Hz), 4.75 (d, 1H, CHH(Troc),
JH,H 11.89 Hz), 4.68 (dd, 1H, HA-3, J3,2 7.93 Hz J3,4
2.44 Hz), 4.59 (dd, 1H, HD-6, J6,5 2.75 Hz), 4.49 (dd,
81.3–63.5 (CD-3/4/5/6, CH2(Troc), CA-3/4/5/6 and
2 · CH2(Bn)), 55.8 (CA-2), 55.2 (CD-2), 53.2 (CH3O),
24.1 (CH3(Ac)). 1H NMR 20b (300 MHz, CDCl3): d
8.0–7.3 (m, 25H, Ar-H(Bz/Bn)), 5.75 (dd, 1H, HD-3,
J3,2 10.3 Hz J3,4 9.5 Hz), 5.60 (dd, 1H, HD-4, J4,3
9.5 Hz J4,5 9.8 Hz), 5.29 (d, 1H, NHA, JNH,2 9.3
Hz), 5.21 (d, 1H, NHD, JNH,2 8.4 Hz), 4.85–4.78 (m,
2H, HD-1b, and CHH(Troc)), 4.63–4.46 (m, 8H, HA-
1a, HD-6/60, CHH(Troc), and 2 · CH2(Bn)), 4.23 (dd,
1H, HA-2), 4.15 (m, 2H, HA-6/60), 4.07 (m, 1H, HD-
5), 3.94 (ddd, 1H, HD-2), 3.78 (m, 1H, HA-5), 3.66
(dd, 1H, HA-3), 3.54 (dd, 1H, HA-4), 3.3 (s, 3H,
CH3O), 1.8 (s, 3H, CH3(Ac)). 13C NMR 20b
(125 MHz, CDCl3): d 170.4 (CO(Ac)), 166.9, 166.8,
165.9 (3 · CO(Bz)), 154.7 (CO(Troc)), 139.0–128.5
(30 · Ar-C(Bz/Bn)), 101.8 (CD-1b), 99.2 (CA-1a),
1H, HD-5, J5,4 10.1 Hz J5,6 2.75 Hz J5,6 4.27 Hz), 4.45
0
D
(dd, 1H, H -60, J6 ,5 4.27 Hz), 4.43 (d, 1H, CHH(Troc),
0
JH,H 11.89 Hz), 4.37–4.33 (m, 3H, HD-2, HA-2/4,
J2(D),3(D) 10.36 Hz J2(A),3(A) 7.93 Hz J2(A),1(A) 4.88 Hz
J4,3 2.44 Hz J4,5 1.83 Hz), 4.10 (ddd, 1H, HA-5, J5,4
1.83 Hz J5,6 6.40 Hz), 4.02 (dd, 1H, HA-6, J6,6
0
0
A
10.06 Hz), 3.79 (dd, 1H, H -60, J6 ,5 6.40 Hz J6 ,6
10.06 Hz), 1.6–1.3 (4 · s, 12H, 4 · CH3C(isopropylid-
ene)). 13C NMR 18a (125 MHz, CDCl3): d 166.9
(3 · CO(Bz)), 155.1 (CO(Troc)), 134.0–129.0 (18 · Ar-
C(Bz)), 110.3, 109.4 (2 · C(CH3)2(OR)2), 98.8 (d, CD-
1a), 97.0 (CA-1a), 75.2–66.5 (CD-3/4/5, CH2(Troc), and
CA-2/3/4/5/6), 63.6 (CD-6), 55.3 (CD-2), 26.9, 26.7, 25.6,
25.1 (4 · CH3C(isopropylidene)). 1H NMR 18b
(500 MHz, CDCl3): d 8.0–7.3 (m, 15H, Ar-H(Bz)),
5.72 (dd, 1H, HD-3, J3,2 10.23 Hz J3,4 9.81 Hz), 5.61
(dd, 1H, HD-4, J4,3 9.81 Hz J4,5 9.39 Hz), 5.55 (d, 1H,
HA-1a, J1,2 5.12 Hz), 5.35 (d, 1H, NH, JNH,2 8.95 Hz),
5.04 (d, 1H, HD-1b, J1,2 8.0 Hz), 4.85 (d, 1H,
0
0
81.1–64.0 (CD-3/4/5/6, CH2(Troc), CA-3/4/5/6
&
2 · CH2(Bn)), 57.2 (CA-2), 55.7 (CD-2), 53.1 (CH3O),
24.1 (CH3(Ac)). ESMS: m/z calcd for C54H55Cl3N2O15,
1076.27/1078.27, m/z calcd for [M+NH4ꢀMeO]+,
1063.28/1065.28. Found 1063.31/1065.29.
4.3. Microwave assisted synthesis of 3,4,6-tri-O-benzoyl-
2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-b-D-gluco-
pyranosyl-(1!3)-methyl-2-acetamido-4,6-O-benzylidene-
2-deoxy-a-D-glucopyranoside 22
CHH(Troc)), 4.62 (dd, 1H, HD-6, J6,5, 11.95Hz J6,6
0
2.99 Hz), 4.57 (dd, 1H, HA-3, J3,2 2.56 Hz J3,4
D
8.10 Hz), 4.47 (dd, 1H, H -60, J6 ,5 5.12 Hz J6 ,6
12.37 Hz), 4.39 (d, 1H, CHH(Troc)), 4.32 (ddd, 1H,
HA-2, J2,1 5.12 Hz J2,3 2.56 Hz), 4.17 (dd, 1H, HA-4,
Glycosyl donor 9 (0.05 mmol, 1.5 equiv), glycosyl accep-
tor 21 (0.033 mmol, 1 equiv), LiClO4 (10 mg) and
˚
crushed 3 A molecular sieves (15 mg) and a magnet were
0
0
J4,3 8.10 Hz), 4.10 (ddd, 1H, HD-5, J5,6 5.12 Hz),
placed in a 5 mL microwave reaction vial and fitted with
a septum. The tube was dried under high vacuum for 2 h
and filled with argon. Dry CH3NO2 (300 lL) was added
under argon and the reaction mixture subjected to
microwave radiation for 5 min at 130 ꢁC. The coupling
was repeated twice with 1.5 equivof donor 9 in dry
CH3NO2 (300 lL). The reaction mixture was centri-
fuged (3 min, 4000 rpm) and the supernatant concen-
trated under a stream of air. The residue was loaded
onto a preparative HPLC column with 2 mL of CH3CN
and purified.
0
4.05–3.98 (m, 3H, HD-2 & HA-5/6, J6,6 11.95 Hz), 3.89
0
A
(ddd, 1H, H -60, J6 ,6 11.95 Hz), 1.54, 1.42, 1.33, 1.31
0
(4 · s, 12H, 4 · CH3C(isopropylidene)). 13C NMR 18b
(125 MHz, CDCl3): d 166.9, 166.8, 165.9 (3 · CO(Bz)),
155 (CO(Troc)), 134.0–129 (18 · Ar-C(Bz)), 110.1,
109.5 (2 · C(CH3)2(OR)2), 102.0 (d,CD-1b), 96.5 (d,
CA-1a), 75.0–69.3 (CD-3/4/5/6, CH2(Troc), and CA-2/3/
4/5/6), 64.0 (CD-6), 57.2 (CD-2), 26.7, 26.6, 25.6, 25.0
(4 · CH3C(isopropylidene)). ESMS: m/z calcd for
C43H46Cl3NO15, 921.19/923.19, m/z calcd for
[M+NaꢀCH3]+, 929.16/931.16. Found 929.74/931.17.
m/z calcd for [M+NH4ꢀCH3]+ calcd 924.20/926.20.
Found 924.76/926.76. m/z calcd for [MꢀGalpO]+ calcd
648.06/650.06. Found 648/649.99.
Yield 38%, pure b, oil. [a]D = +57.3 (c 2.08 · 10ꢀ3
,
CHCl3). 1H NMR 22b (300 MHz, CDCl3): d 8.12,
7.93, 7.73 (3 · (d, 2H, Ar-H (Bz))), 7.65–6.87 (m, 14H,
Ar-H(Bz/benzylidene)), 6.47 (d, 1H), 6.17 (dd, 1H),
5.54 (dd, 1H), 5.51 (s, 1H, PhCH(benzylidene)), 5.44
(d, 1H, HD-1b, J1,2 8.73 Hz), 5.12 (d, 1H), 4.97 (dd,
1H), 4.82 (d, 1H, HA-1a, J1,2 3.28 Hz), 4.63 (dd, 1H),
4.27–4.14 (m, 5H), 4.08–4.00 (m, 4H), 3.21 (s, 3H,
CH3O), 3.18 (m, 1H), 2.02 (s, 3H, CH3(Ac)). 13C
NMR 20b (125 MHz, CDCl3): d 170.8 (CO(Ac)),
166.4, 165.3, 165.1 (3 · CO(Bz)), 153.6 (CO(Troc)),
136.3–125.9 (24 · Ar-C(Bz/Bn)), 102.5 (PhCH(benzyl-
idene)), 99.3 (CA-1a), 96.7 (CD-1b), 80.8–52.9 (CD-2/3/
4/5/6, CH2(Troc), and CA-2/3/4/5/6), 55.1 (CH3O), 23.1
(CH3(Ac)). IR (neat) 3500–3300 (w), 1729 (s), 1652
(m), 1532 (m), 1267 (s), 1096 (s), 709 (s). ESMS: m/z
calcd for C46H45Cl3N2O15, 970.22/972.22, m/z calcd for
[M+H]+, 971.22/973.22. Found 971.19/973.19. m/z calcd
for [M+Na]+, 993.21/995.21. Found 993.17/995.17.
HRMS (ES): calcd for C46H45Cl3N2O15H [M+H]+,
971.1964; Found, 971.1868.
4.2.8. 3,4,6-Tri-O-benzoyl-2-deoxy-2-(2,2,2-trichloroeth-
oxycarbonylamino)-a/b-D-glucopyranosyl-(1!6)-methyl-
2-acetamido-3,4-di-O-benzyl-2-deoxy-a-D-glucopyrano-
side 20. Yield 60%, a/b 1:4, oil. 1H NMR 20a
(300 MHz, CDCl3): d 8.1–7.2 (m, 25H, Ar-H(Bz/Bn)),
5.70 (dd, 1H, HD-3, J3,2 10.3 Hz J3,4 9.6 Hz), 5.60
(dd, 1H, HD-4, J4,3 9.6 Hz J4,5 9.5 Hz), 5.21 (d, 1H,
NHD, JNH,2 9.9 Hz), 5.29 (d, 1H, NHA, JNH,2
9.3 Hz), 5.06 (d, 1H, HD-1a, J1,2 3.4 Hz), 4.94–4.61
(m, 9H, HA-1a, HD-6/60, CH2(Troc), and 2 · CH2(Bn)),
4.39–4.34 (m, 1H, HD-5), 4.30 (dd, 1H, HD-2), 4.19
(ddd, 1H, HA-2), 3.88–3.75 (m, 3H, HA-5/6/60), 3.70
(dd, 1H, HA-3), 3.46 (dd, 1H, HA-4), 3.42 (s, 3H,
CH3O), 1.8 (s, 3H, CH3(Ac)). 13C NMR 20a
(125 MHz, CDCl3): d 170.3 (CO(Ac)), 167.2, 166.8,
165.9 (3 · CO(Bz)), 154 (CO(Troc)), 138.9–128.6
(30 · Ar-C(Bz/Bn)), 99.2 (d, CA-1a), 98.1 (d, CD-1 a),

1448
S. Grathe et al. / Tetrahedron: Asymmetry 16 (2005) 1439–1448
10. Boullanger, P.; Banoub, J.; Descotes, G. Can. J. Chem.
1987, 65, 1343–1348.
Acknowledgements
11. (a) Meinjohanns, E.; Meldal, M.; Paulsen, H.; Bock, K.
J. Chem. Soc., Perkin Trans. 1 1995, 405–415; (b) Jensen,
K. J.; Hansen, P. R.; Venugopal, D.; Barany, G. J. Am.
Chem. Soc. 1996, 118, 3148–3155.
12. Kelly, N. M.; Jensen, K. J. J. Carbohydr. Chem. 2001, 20,
537–548.
We wish to thank the Alfred Benzon Foundation, the
Leo Foundation, and the Lundbeck Foundation for
financial support. Thomas H. Hansen is acknowledged
for the HRMS spectra and Birgitte B. Rasmussen is
acknowledged for the FT-IR spectra.
13. The protecting groups can then be cleaved by H2NNH2 or
amines (Phth, TCP), NH3/CH3OH or aq NaOH (TFAc),
reduction (Troc), Pd(0) catalyzed hydrogen transfer (di-
benzyl); thiolysis (Dts), Pd(0) (Alloc); NaOH (DMM);
NH3, H2NNH2 (DTPM).
14. Silwanis, B. A.; El-Sokkary, R. I.; Nashed, M. A.;
Paulsen, H. J. Carbohydr. Chem. 1991, 10, 1067–
1078.
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