Study of the stereoselectivity of 2-azido-2-deoxygalactosyl donors: Remote protecting group effects and temperature dependency

Article abstract of DOI:10.1021/jo1025157

The stereoselectivity of glycosylation reactions is affected by many factors. Synthesis of 1,2-cis glycosidic linkages (such as α linkages in glucose and galactose like monosaccharides) is challenging due to lack of control of the stereoselectivity. Our s

Full text of DOI:10.1021/jo1025157

ARTICLE
pubs.acs.org/joc
Study of the Stereoselectivity of 2-Azido-2-deoxygalactosyl Donors:
Remote Protecting Group Effects and Temperature Dependency
Jane Kalikanda and Zhitao Li*
Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States
S Supporting Information
b
ABSTRACT:
The stereoselectivity of glycosylation reactions is affected by many factors. Synthesis of 1,2-cis glycosidic linkages (such as R linkages
in glucose and galactose like monosaccharides) is challenging due to lack of control of the stereoselectivity. Our systematic study of
GalN3 donors with different combination of protecting groups indicated that acetyl groups at the 3- and 4-positions are particularly
important for high R-selectivity. Temperature is also recognized as a major factor in control of stereoselectivity. Mechanisms
responsible for these experimental results are discussed and explored using computational methods. A remote participation model of
the acetyl groups is proposed to explain the directing effects of the acetyl groups.
’ INTRODUCTION
control and predict. In this report, we systematically studied the
influence of acetyl groups on the stereoselectivity of 2-azido-2-
deoxygalactosyl (GalN3) donors using both experimental and
theoretical methods. GalN3 donors have been widely used for the
introduction of R-galactosamine (GalNH2) linkages, due to the
nonparticipating nature of the azido group. Even though several
other methods have been reported in recent years, GalN3
remains a popular choice because of the easiness of preparation
and the convenience of conversion to amino group.22,23 How-
ever, the stereoselectivity of GalN3 donors is largely affected by a
number of factors, including the protecting groups, acceptors,
leaving groups and even reaction conditions, many of which are
not well understood.24ꢀ27 Our study on the protecting group
effect and reaction temperature effect indicated that the acetyl
groups and higher reaction temperature play critical roles in
improving the R-selectivity of GalN3 donors. The results of our
study will not only help develop more efficient synthesis of R-
galactosamine linkages, but will also be helpful for the develop-
ment of more stereoselective glycosylations of other galactose-
type monosaccharides.
Carbohydrates are important biopolymers playing pivotal
roles in many cellular processes.1 Glycomics, the comprehensive
study of all glycan structures, has become an increasingly
interesting research field for both life science and biomedical
research.2,3 At the same time, chemical synthesis provides one of
the major means to access large quantities of carbohydrate
compounds in homogeneous and structurally defined form.4,5
However, synthesis of oligosaccharides is much more challenging
than synthesis of other types of biopolymers (like peptides and
nucleotides), largely due to the difficulties in controlling the
stereoselectivity and regioselectivity. The control of the stereo-
chemistry (which is not present in cases of peptide linkages and
nucleotide linkages) is especially difficult because of the complex-
ity of the contributing factors to the stereoselectivity, including
the configuration of the glycosyl donor,6ꢀ11 the structure of the
leaving group,12 the reaction conditions, the reactivity of the
glycosyl acceptor,13,14 and the protecting groups on the donor.
Protecting groups, in particular, have a profound influence on the
stereoselectivity of donors.15ꢀ21 Neighboring group participa-
tion, for example, has been one of the most powerful strategies
for the stereoselective synthesis of 1,2-trans glycosidic linkages.
On the other hand, the effects of protecting groups on donors
without participating neighboring groups are more difficult to
Received: October 15, 2010
Published: May 16, 2011
r
2011 American Chemical Society
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Scheme 1. Preliminary Study of the Stereoselectivity of Donor 2 and 3
’ RESULTS AND DISCUSSION
conditions (room temperature in dichloromethane) for 30
min. The compound was then recovered and characterized with
1H NMR. There was no observable change in the anomer ratio,
which rules out the possibility of TMSOTf induced equilibrium
under this condition and indicates that the change of product
distribution is more likely due to kinetic reasons.
To understand how the protecting groups affect the stereo-
selectivity of GalN3 donors, especially the function of acetyl
groups at the remote positions, we decided to systematically
study a series of GalN3 donors with different protecting group
patterns. To perform this study, we selected a model reaction in
which the same leaving group, same reaction conditions, and
same glycosyl acceptor were used. In this way, the only factor that
can change the reaction results would be the combination of the
protecting groups. In this model reaction (Scheme 1), acceptor
128 was used as the common glycosyl acceptor; trichloroaceti-
midate was used as the common leaving group; TMSOTf was
used as the promoter; and room temperature and ꢀ78 °C were
chosen as two representative reaction temperatures.
A. Preliminary Study of Protecting Group and Tempera-
ture Dependency of GalN3 Donor Stereoselectivity. Two
donors (compound 229,30 and 3, Scheme 1) were first tested at
two different reaction temperatures (ꢀ78 °C and room
temperature) as a preliminary study. A protecting group depen-
dency and a reaction temperature dependency were observed in
this series of experiments. Acetyl-protected donor (2) showed
much higher R-selectivity than benzyl-protected donor (3).
At ꢀ78 °C, donor 2 gave a 3:1 R/β mixture, whereas donor 3
afforded a 1:3 R/β mixture. At room temperature, both donors
showed better R-selectivity. Donor 2 afforded an 11:1 R/β
mixture, while donor 3 afforded a 3:1 R/β mixture. The
preliminary study suggests that the acetyl-protected donor is
more R selective than the benzyl-protected donor at both
reaction temperatures. For both donors, room temperature is a
more favorable reaction condition for the R product.
B. Proposed Mechanism. To explain this apparent protecting
group and temperature dependence of the stereoselectivity, we
considered the mechanism of the glycosylation reactions. Even
though glycosylation reactions have been extensively studied, the
exact mechanism is still not well understood. Oxocarbenium
ions, glycosyl triflates, ion pairs, or other structures have been
proposed as the key intermediates in determining the stereo-
chemical outcome. A recent review by Demchenko et al. provides
a comprehensive overview of the mechanism of glycosylation
reactions.33 On the basis of the analysis of our reaction system,
we propose two possible reaction pathways that may help explain
the observed experimental results (Scheme 2). Upon activation
with a promoter (TMSOTf), the donors are expected to form
glycosyl triflate intermediates, which can then form contact ion
pairs (CIP), solution-separated ion pairs (SSIP), or free oxocar-
benium ions, depending on the reaction conditions and the
nature of the donor. Any of these intermediates can react with the
acceptor to afford the disaccharide product. Even though we have
no direct evidence to identify the true reaction intermediate
involved in our reactions, we envision that different intermedi-
ates will proceed in different processes to give different stereo-
isomers. In the case of glycosyl triflate or contact ion pair
intermediates, an SN2-like process that causes inversion of the
anomeric center should be a more favorable process, although a
process that causes retention of the stereochemistry has also
proven possible in theoretical study.34 In the case of solvent-
separated ion pair or free oxocarbenium ion intermediate, an
SN1-like process may be more favorable and the stereochemical
outcome may be determined by the stereoelectronic factors of
the oxocarbenium ion. The overall stereochemical outcome of
the glycosylation reaction could therefore be determined by the
reaction pathway and the conformation and configuration of the
reaction intermediates. As to the SN2 pathway, R-glycosyl
triflates, which are more stable due to the anomeric effect, are
expected to be dominant, as are the R-contact ion pairs. This
To further confirm the temperature dependency of the
stereoselectivity, two more reactions at temperatures between
ꢀ78 °C and room temperature were tested using donor 2
(scheme 1). At ꢀ20 °C, a 5:1 R/β mixture was observed;
at 0 °C, a 9:1 R/β mixture was observed. It seems that the
R-selectivity steadily increases as the reaction temperature
increases.
Another experiment was performed to test if the increased R-
selectivity was due to a thermodynamic equilibrium at higher
temperature.31,32 A 1:3 R/β mixture obtained from donor 3
at ꢀ78 °C was treated with TMSOTf under glycosylation
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ARTICLE
Scheme 2. Proposed Mechanism of Glycosylation Reaction
suggests that the β glycosides would be the major products
through the SN2 pathway due to the “Walden inversion”. In the
SN1 pathway, the stereochemical control is much more compli-
cated. Theoretical studies suggest that the stereoselectivity may
arise from the preferred conformation of the oxocarbenium ions,
which include half chairs, envelope, boat, and twist-boat con-
formations. For example, Woerpel and co-workers suggested that
when oxocarbenium ions are in the half-chair conformation, the
nucleophile will approach along a pseudoaxial trajectory with a
facial selectivity which allows the formation of the lower energy
chair product instead of a twist-boat product formed when the
nucleophile approaches from the opposite side.7 Therefore, the
oxocarbenium ions in 3H4 conformation will prefer nucleophilic
attack from the top face to afford β products, whereas the
oxocarbenium ions in 4H3 conformation will afford R products.
Even though further evidence is necessary to prove this hypoth-
esis, it has been used to explain some stereochemistry observa-
tions successfully. For example, Dinkelaar and coworks also used
this model to explain the stereoselectivity of a series of glycosyl
donors in their experiments.6 Since Whitfield reported that 4H3
conformation of galactose oxocarbenium ion is more stable than
3H4 in his computational study, we anticipate the R products to
be the preferred product of the SN1 pathway of GalN3 donors,
which have similar configuration to galactose.35
A computational study of the oxocarbenium ions of GalN3
donors was performed to investigate the relative stability of these
possible intermediates. Our results indicated that for both
4
donors 2 and 3, the H3 conformation of the corresponding
oxocarbenium ions is more stable than 3H4, by 11.0 and 14.2 kJ/mol,
respectively (Figure 1). This suggests that the oxocarbenium ion
intermediates prefer 4H3 conformation and thus favor the
formation of R products. On the basis of this analysis, if the
reaction takes the SN1 pathway, R glycosides would be the
preferred product.
This mechanistic analysis also explains the temperature de-
pendency of the stereoselectivity. Since the glycosyl triflates have
been reported to decompose at higher temperature, the SN1
process is expected to be the preferred reaction pathway at higher
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Figure 1. Relative stability of different conformations of oxocarbenium ions derived from donor 2 and 3 determined by computational study.
Scheme 3. Proposed Remote Participation of Acetyl Groups
reaction temperatures to afford more R product. The tempera-
ture dependency may also suggest that the two competing
mechanisms have significantly different ΔS‡ for the TSs. This
is consistent with the proposed SN1 vs SN2 competing mechan-
ism, because SN1 mechanism should have higher ΔSq than SN2.
However, we cannot explain the protecting group dependency of
the stereoselectivity. When the donor is more disarmed (i.e.,
triacetyl protected), the glycosyl triflates are expected to have
higher stability and the SN2 process is more likely than with the
armed donors, which means that more β product is expected
from disarmed donors (donor 2), which is opposite to our
observation.15
To explain this apparent controversy, a modified mechanism is
proposed (Scheme 3). The carbonyl oxygen of the acetyl groups
of donor 2 may be able to interact with the anomeric carbon of
the oxocarbenium ion and form a remote participating inter-
mediate. This remote participation may not only stabilize the
oxocarbenium ion, but also force the acceptor to attack from the
“R” face, because the participating acetyl groups would have
blocked the “β” face. Our hypothesis is that the participation of
the acetyl groups compensates the unfavorable disarming effect
and promotes the formation of R product. Participation of non-
neighboring acetyl groups has been suggested to be responsible
for unusual stereoselectivity in several literature reports.36,37 For
example, mannosyl donors with acetyl group at 3-position afford
more R mannoside than the donor with a 3-O-benzyl group.38ꢀ40
4-O-Ester groups have been shown to improve R selectivity in
galactose, fucose and β selectivity in glucose and mannose, which
may also be attributed to possible participation.18,20,41 However,
there are also reports that do not support this type of participa-
tion. Some recent work from Crich’s group showed lack of
participation of 3-O-acetyl in a benzylidene-protected mannosyl
donor.42 Crich’s work also excluded the possibility of participa-
tion of 4-O-ester of mannosyl donor, 6-O-ester of glucosyl donor
and 4-O-ester of galactosyl donor but indicated the possibility of
participation of the axial ester at O-3 of allose.
represents participation of 3-acetyl group in oxocarbenium ion
derived from donor 2, the same rules are used for other acetyl
participation intermediates), P4-2, and P6-2 were optimized
and their energy calculated using quantum mechanical methods
(Figure 2). All three intermediates were found to be significantly
more stable than the oxocarbenium ion. Intermediate P3-2 takes
a chair conformation close to 1C4 and is 37.9 kJ/mol more stable
than the nonparticipating 4H3-2 oxocarbenium ion. Intermediate
1
P4-2 takes a twist-boat conformation S5 and is 41.5 kJ/mol
4
more stable than H3-2. Intermediate P6-2 takes a chair con-
formation close to 1C4 and is 20.2 kJ/mol more stable than 4H3-
2. These results indicate that the participation of any of the three
acetyl groups is thermodynamically favorable and dramatically
stabilizes the oxocarbenium ion.
C. Further Study of the Protecting Group Effects. To
determine which acetyl group(s) is involved in this participating
process, we decided to study a series of donors with various
combination of protecting groups (Figure 3, compounds 4ꢀ9).
Compounds 4, 5, and 6 are trichloroacetimidate donors with
only one acetyl group, each at the 3-, 4-, or 6-position, respec-
tively. Compounds 7, 8 and 9 are donors with two acetyl groups
at different positions.
All six donors were prepared (see the Experimental Section for
their synthesis) and tested in glycosylation reactions with acceptor 1
at both ꢀ78 °C and room temperature (Table 1). Donor 4 showed
1.7:1 (entry 3) R selectivity at ꢀ78 °C and 6:1 (entry 3) at room
temperature. The R-selectivity is better than donor 3, at both
temperatures, but not as good as donor 2. Donor 5 gave a 1:1
R/βratio at ꢀ78 °Cand6:1(entry4) atroomtemperature, whichis
also better than donor 3 but not as good as donor 2. Donor 6, which
has acetyl group at 6-position, however, showed only 1:5 R-selectivity
at ꢀ78 °C and 1.5:1 (entry 5) at room temperature, which is actually
worse than donor 3. These results suggest that acetyl group at 3- or
4-position improves the R-selectivity, whereas acetyl group at
6-position decreases the R-selectivity. At the same time, similar
temperature dependency of the R-selectivity was observed.
For the donors with two acetyl groups, donor 7, which has
acetyl at the 3- and 4-positions, showed 1.5:1 R-selectivity
A series of calculations were carried out to test our hypo-
thesis. Three potential participating intermediates P3-2 (P3-2
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Figure 2. Computational results of participating intermediates compared with oxocarbenium ions.
Figure 3. Donors with different protecting group patterns.
Table 1. Glycosylation Results
at ꢀ78 °C
at rt
entry
donor
R1
R2
R3
product (yield, %)
R:β ratio
yield (%)
R:β ratio
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
9
Ac
Bn
Ac
Bn
Bn
Ac
Ac
Bn
Ac
Bn
Bn
Ac
Bn
Ac
Bn
Ac
Ac
Bn
Bn
Bn
Ac
Bn
Ac
Ac
10 (71)
11 (74)
12 (81)
13 (51)
14 (52)
15 (67)
16 (83)
17 (82)
3:1
75
66
66
53
75
50
89
81
11:1
3:1
1:3
1.7:1
1:1.1
1:5
6:1
6:1
1.5:1
R onlya
4:1
1.5:1
1:1.1
1.4:1
5:1
a No observable signals of β-anomer in 1H NMR of the product; a significant amount of acceptor (30%) was recovered from the reaction.
at ꢀ78 °C and exclusive R-selectivity at room temperature (entry
6). The selectivity at room temperature is even better than donor
2. On the other hand, donor 8, which has acetyl at 3- and 6-
positions, afforded a 1:1 R/β ratio at ꢀ78 °C and 4:1 R/β ratio at
room temperature (entry 7). Donor 9, which has acetyl groups at
the 4- and 6-positions, showed 1.1:1 R-selectivity at ꢀ78 °C and
5:1 at room temperature (entry 8). The results suggest that the
influence of acetyl groups at 3- and 4-positions is not only
favorable for R-selectivity but also cumulative when present at
the same time. The acetyl group at the 6-position, on the other
hand, has little influence when it is present with acetyl groups
at other positions. The temperature dependency of the R-
selectivity is still the same: much higher R-selectivity is obtained
at room temperature.
The effect of the 3-O-acetyl and 4-O-acetyl is consistent with
the computational study of donor 2 (Figure 2), which supports
the remote participation of acetyl groups, whereas the effect of
the 6-O-acetyl is opposite to the expected result. To further
study these donors, we calculated all corresponding oxocarbe-
nium ions and possible participating intermediates derived from
donors 4ꢀ9 using the same computational methods (Table 2,
4
entry 3ꢀ8). In all cases, the H3 conformation is consistently
3
more stable than the H4 conformation by 6.3ꢀ19.2 kJ/mol.
Interestingly, the 3H4 conformations of donor 5ꢀ9 are close to
3E after optimization. At the same time, the intermediates
involving the participation of acetyl group (P3-n, P4-n and
P6-n) are all more stable than the corresponding 4H3 oxocarbe-
nium ion (4H3-n). Noticeably, the energy benefits of the P3-n
and P4-n intermediates (34.3ꢀ43.6 kJ/mol) are generally larger
than that of the P6-n intermediates (12.4ꢀ26.0 kJ/mol). The
large energy benefit value of 3- and 4-acetyl group participa-
tion can help explain the R-beneficial effect of 3-O-acetyl and
The overall experimental results suggest that the acetyl groups
at the 3- and 4-positions can significantly improve the R-selectivity
compared to the benzyl group. On the other hand, an acetyl group
at the 6-position has only a marginal effect on the R-selectivity.
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Table 2. Computational Study of the Possible Participating Structures of the Reaction Intermediates
3-O-acetyl participation
(P3-n) (kJ/mol)
4-O-acetyl participation
(P4-n) (kJ/mol)
6-O-acetyl participation
(P6-n) (kJ/mol)
entry
donor
4H3 (4H3-n) (kJ/mol)
3H4 (3H4-n) (kJ/mol)
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
9
ꢀ37.9
ꢀ39.6
ꢀ41.5
ꢀ20.2
0
0
0
0
0
0
0
0
11.0
14.2
14.9
ꢀ41.3
ꢀ40.9
ꢀ40.0
19.2 (close to 3E)
11.3 (close to 3E)
13.1 (close to 3E)
6.3 (close to 3E)
12.2 (close to 3E)
ꢀ26.0
ꢀ43.6
ꢀ34.3
ꢀ12.4
ꢀ25.8
4-O-acetyl groups. On the other hand, the beneficial but less
substantial 6-acetyl participation may partially explain why
6-acetyl group does not favor the formation of R-product.
Another explanation for the β-directing effect of 6-acetyl in
donor 6 could be the potential H-bonding between the acceptor
and the acetyl of donor in the β face of the oxocarbenium ion in
SN1 type mechanisms, which has been demonstrated by Whit-
field et al.43 Finally, it could also be kinetic reasons that prevent
the 6-acetyl groups from participating. Whitfield studied the
participation of neighboring acetyl groups (2-acetyl) using
computational method and determined that the energy barriers
are between 20 and 40 kJ/mol, which could be a good reference
for the magnitude of the energy barrier for participation of acetyl
groups.44 In the case of 6-acetyl, the energy barrier is expected to
be even higher because the participation process has to start
from a higher energy conformation (3H4, Figure 2) in the first
place. Computational studies to search for the transition states
and determine the energy barrier of these processes using
methods similar to Whitfield’s are ongoing.
Acetyl groups at the 3- and 4-positions can dramatically increase
the R-selectivity. Higher reaction temperature can also dramati-
cally improve the R-selectivity. Our computational study sug-
gests that the acetyl group can stabilize the oxocarbenium ions by
participating in the reaction intermediate thus increasing the R-
selectivity. Our study demonstrates that protecting groups can
affect the stereoselectivity of glycosyl donors in a profound way.
Computational chemistry can be a useful tool to explain and
predict the reaction pathway. The methodology we used in this
study can also be used in understanding glycosylation reactions
of other sugar types.
’ EXPERIMENTAL SECTION
Materials and General Methods. Unless otherwise noted,
reagents and solvents were obtained from commercial suppliers and
were used without further purification. TLC was performed on pre-
coated glass plates (silica gel F254). Spots were detected by visualization
under UV lamp and/or by charring with p-anisaldehyde stain. All NMR
spectra were recorded on a 360 MHz spectrometer. All 1H NMR data
were obtained at 360 MHz, and all 13C NMR data were obtained at 90
MHz. Proton and carbon chemical shifts are reported in parts per million
(ppm) using CDCl3 as internal reference unless otherwise noted.
Coupling constants (J) are reported in hertz (Hz), and multiplicities
are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m), and broadened (br).
’ SUMMARY OF MECHANISM
On the basis of our current study, a possible mechanism for the
stereoselectivity observed in our experiments can be summarized
as follows: the stereochemical outcome is a comprehensive result
of the glycosylation pathway. The SN2 pathway is likely to be
responsible for the β-selectivity at lower temperature and in the
absence of acetyl group at the 3- and 4-positions. At room
temperature, the SN1 pathway through the oxocarbenium ion is
likely to be responsible for the R-selectivity deriving from the
facial selectivity of the preferred 4H3 half chair conformation. The
presence of acetyl group(s) at the 3- or (and) 4-position
enhances the preference of the SN1 pathway through stabilization
of the oxocarbenium ion and dramatically increases the forma-
tion of R-glycosides, especially at room temperature.
Computational Method. Computation of the oxocarbenium ion
was carried out in two phases. The structure of the intermediate was built
with Spartan software (Spartan’08 for Windows).45 The structure was
then subjected to a conformation distribution calculation at MMFF level
to identify all low energy conformations, which include the rotamers
derived from the rotation of the acetyl group around the CꢀO bond and
different dihedral angle of exocyclic side chain (C5ꢀC6). All of the
conformations were then optimized at semiempirical (AM1) level. The
optimized conformations were then reviewed to remove identical
structures. The coordinates of these structures were then transferred
to QCHEM (Version 3.2)46 and further optimized using the 6-31G basis
set at the HF level. The resultant structures were then visualized and
’ CONCLUSION
3
4
Our protecting group effect study indicated that the stereo-
selectivity of GalN3 donors is highly affected by the acetyl groups.
classified into different categories, like H4, H3 and participation
intermediates. The lowest energy structure in each category was
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Scheme 4. Synthesis of Donor 3
determined as the lowest energy conformation, further optimized at the
B3LYP/6-31G* level, subjected to frequency calculations at the same
level. No imaginary frequency was observed in the intermediates.
Further single-point calculations at the B3LYP/6-31þþG** level of
theory for better energy estimation were also computed at B3LYP/
6-31G*-optimized structures using QCHEM. All energies reported
throughout refers to B3LYP/6-31þþG** values. In the final structures,
all nonparticipating esters have the carbonyl eclipsed with the carbohy-
drate carbon; it was also noticed that in most intermediates, the gt
conformer of C5ꢀC6 side chain is slightly more stable than the tg
conformer (by around 0.8ꢀ4.2 kJ/mol).
(d, J = 5.5 Hz, 1H), 7.12ꢀ7.19 (m, 4H), 7.41 (d, J = 8.0 Hz, 2H), 7.51
(d, J = 8.0 Hz, 2H).50
A 4.6 g (0.01 mol) portion of 19 in MeOH (20 mL) was treated with
NaOMe (0.11 g, 2.13 mmol, 0.1 equiv) and stirred at room temperature
for 30 min. Amberlite resin IR-120 Hþ (2 g) was added to neutralize the
reaction. The resin was filtered, and the filtrate was concentrated to give
20 in quantitative yield: Rf = 0.5 (1:9 MeOH/CH2Cl2). To a solution of
20 (0.52 g, 1.67 mmol) and BnBr (1.2 mL, 10 mmol) in anhydrous DMF
(10 mL) was added NaH (60% in mineral oil, 0.24 g, 10 mmol) slowly at
0 °C. The reaction was warmed to room temperature and stirred for 4 h.
It was quenched with water (20 mL) and extracted with dichloro-
methane (3 ꢁ 10 mL). The organic layer was washed with water (3 ꢁ
10 mL) and brine (2 ꢁ 10 mL). It was dried, concentrated, and purified
by flash chromatography using EtOAc/hexanes (0ꢀ20%) to give 21
(0.7 g, 72%) as a (1:1) R/β mixture: 1H NMR (360 MHz, CDCl3) (β
isomer) 2.29 (s, 3H), 3.40 (dd, J = 2.7, 9.8 Hz, 1H), 3.55 (dt, J = 0.6, 6.7
Hz, 1H), 3.62 (s, 1H), 3.63 (d, J = 6.7 Hz, 1H), 3.79 (t, J = 9.9 Hz, 1H),
3.93 (d, J = 2.2 Hz, 1H), 4.33 (d, J = 10.1 Hz, 1H), 4.42 (d, J = 11.7 Hz,
1H), 4.47 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.65 (d, J = 11.6
Hz, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.86 (d, J = 11.4 Hz, 1H), 7.00 (dd,
J = 0.6, 8.4 Hz, 2H), 7.19ꢀ7.39 (m, 15H), 7.46 (d, J = 8.2 Hz, 2H); 13C
NMR (90 MHz, CDCl3) δ 21.1, 61.3, 68.4, 72.0, 72.3, 73.5, 74.3, 77.2,
82.4, 86.5, 127.4, 127.6, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5, 129.6,
General Procedure for Removal of a Nitrate Group from
the Anomeric Position47,48. To a solution of the nitrate compound
in dry CH3CN were added thiophenol (3.0 equiv) and DIEA (1.0 equiv)
at 0 °C. After 1 h, the reaction mixture was concentrated under reduced
pressure and the crude residue purified by flash chromatography to yield
the corresponding glycosyl hemiacetal.
General Procedure for Hydrolysis of Thioglycosides to
Glycosyl Hemiacetal. NBS (3 equiv) was added to a stirred solution
of the thioglycoside in 10ꢀ20 mL of (9:1 v/v) acetoneꢀwater and
stirred at room temperature until TLC showed disappearance of the
thioglycoside and formation of a more polar compound (30 min to 1 h).
Solid NaHCO3 was added to neutralize the reaction and the solvents
evaporated. The residue was dissolved in EtOAc and water. The organic
phase was separated and washed with brine. It was dried over Na2SO4,
concentrated, and purified by flash chromatography to give the corre-
sponding glycosyl hemiacetal.
General Procedure for Conversion of Glycosyl Hemiacetal
to Trichloroacetimidate. DBU (0.3 equiv) was added to a solution
of the glycosyl hemiacetal (1.0 equiv) and trichloroacetonitrile (10.0
equiv) in dry CH2Cl2 at 0 °C.The reaction was stirred at 0 °C for 1 h and
then at room temperature for 2 h. The crude product was evaporated
and purified by flash chromatography to give the corresponding
trichloroacetimidate.
1
133.3, 137.4, 137.7, 138.0, 138.4; (R isomer) H NMR (360 MHz,
CDCl3) δ 2.29 (s, 3H), 3.53 (dd, J = 6.1, 9.4 Hz, 1H), 3.61 (dd, J = 6.9,
9.4 Hz, 1H), 3.78 (dd, J = 2.7, 10.6 Hz, 1H), 4.04 (d, J = 1.6 Hz, 1H),
4.39ꢀ4.46 (m, 3H), 4.49 (t, J = 6.5 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H),
4.75 (s, 2H), 4.89 (d, J = 11.3 Hz, 1H), 5.53 (d, J = 5.4 Hz, 1H), 7.02 (d,
J = 7.9 Hz, 2H), 7.23 ꢀ7.43 (m, 17H); 13C NMR (90 MHz, CDCl3) δ
21.1, 60.4, 68.6, 70.4, 72.4, 73.4, 74.8, 79.1, 87.9, 127.6, 127.7, 127.8,
127.96, 128.0, 128.3, 128.4, 128.5, 129.5, 129.7, 132.8, 137.4, 137.8,
137.9, 138.250
Compound 21 was hydrolyzed as per the general described procedure
to give the known glycosyl hemiacetal29 in 67% yield. The corresponding
R-trichloroacetimidate 329 was obtained in 75% yield: Rf = 0.55 (1:3
EtOAc/hexane); 1H NMR (360 MHz, CDCl3) δ 3.61 (dd, J = 5.1, 9.0
Hz, 1H), 3.72 (t, J = 8.1 Hz, 1H), 4.09 (dd, J = 3.0, 10.7 Hz, 1H),
4.18ꢀ4.28 (m, 3H), 4.48, 4.53 (2d, J = 12.0 Hz, each 1H), 4.63, 4.97 (2d,
J = 10.7 Hz, each 1H), 4.75, 4.84 (d, J = 11.1 Hz, each 1H), 6.44 (d, J =
3.4 Hz, 1H), 7.28 ꢀ7.50 (m, 15H); 13C NMR (90 MHz, CDCl3) δ 59.1,
67.9, 72.1, 72.7, 73.5, 74.9, 77.4, 90.9, 95.4, 127.7ꢀ128.5, 137.1, 137.6,
138.1, 160.7.
3-O-Acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-R-D-galactopyranose-
1-O-trichloroacetimidate (4) (Scheme 5)51. A stirred solution of the
known triol52 (1.0 g, 6.8 mmol) in anhydrous DMF (10 mL) under
nitrogen at 0 °C was treated with of NaH (60% in mineral oil, 600 mg,
15.05 mmol, 2.2 equiv). After 2 h at 0 °C, the mixture was treated
dropwise and rapidly with BnBr (1.8 mL, 15.05 mmol, 2.2 equiv) and
then allowed to stand for 3 h at 0 °C. The mixture solidified and was
thawed out, diluted with dichloromethane (30 mL), and washed with
water (20 mL). The aqueous phase was back-extracted with (3 ꢁ 10 mL)
2-Azido-3,4,6-tri-O-benzyl-2-deoxy-R-D-galactopyranose-1-O-trichloro-
acetimidate (3) (Scheme 4). The known 1849 (4.5 g, 0.01 mol,
1.0 equiv) and p-thiocresol (2.2 g, 0.02 mol, 1.5equiv) were stirred in
anhydrous CHCl3 (20 mL) at room temperature. The reaction
mixture was cooled to 0 °C, and BF3 Et2O (9.0 mL, 0.07 mol,
3
6 equiv) slowly added. The reaction was stirred at 40 °C for 3 h. It was
carefully neutralized with NaHCO3, and the organic layer washed
with saturated NaCl, dried over Na2SO4, and concentrated. The
residue was purified by flash chromatography using EtOAc/hexanes
(10ꢀ50%) to give 19 (4.7 g, 90% yield) as a 1:1 R/β mixture: Rf = 0.6
1
(1:1 hexanes/EtOAc); H NMR (360 MHz, CDCl3,) 2.01 (s, 3H)
2.04 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.09 (s, 3H), 2.16 (s, 3H),
2.34 (s, 3H), 2.37 (s, 3H), 3.64 (t, J = 10.0 Hz, 1H), 3.87 (dt, J = 1.0,
6.5 Hz,1H), 4.07ꢀ4.12 (m, 3H), 4.16 (dd, J = 6.5, 11.0 Hz, 1H), 4.30
(dd, J = 5.5, 11.0 Hz, 1H), 4.48 (d, J = 10.0 Hz, 1H), 4.78 (t, J = 6.5 Hz,
1H), 4.86 (dd, J = 3.0, 10.0 Hz, 1H), 5.18 (dd, J = 3.5, 11.0 Hz, 1H),
5.35 (dd, J = 1.0, 3.5 Hz, 1H), 5.48 (dd, J = 1.0, 3.0 Hz, 1H), 5.62
5213
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The Journal of Organic Chemistry
ARTICLE
Scheme 5. Synthesis of Donor 4
of dichloromethane, and all the organic fractions were combined,
washed with brine (30 mL), and dried over anhydrous Na2SO4. The
fraction was concentrated and purified by flash chromatography
(0ꢀ30% EtOAc/hexanes). The main fraction contained 4,6-O-diben-
zylated product (30%),52 which crystallized out on cooling, 26% of the
perbenzylated product, 15% of another dibenzylated product with
recovery of 30% of starting material. The NMR data was comparable
to literature data: TLC Rf = 0.4 (3:1 hexanes/EtOAc); 1H NMR (360
MHz, CDCl3) δ 2.42 (d, J = 9.4 Hz, 1H), 3.65 (dd, J = 5.6, 11.0 Hz, 1H)
3.81 (dd, J = 6.4, 10.3 Hz, 1H), 3.91 (m, 1H), 4.20 (m, 1H), 4.33 (m,
1H), 4.35 (m, 1H, H-3), 4.49, 4.58 (2d, J = 12.4 Hz, each 1H), 4.68, 4.74
(2d, J = 11.6 Hz, each 1H), 4.76 (dddd, J = 1.0 Hz, 1H), 6.37 (dd, J = 1.3,
6.4 Hz, 1H), 7.27- 7.52 (m, 10H); 13C NMR (90 MHz, CDCl3) δ 62.8,
68.1, 73.1, 73.4, 74.2, 75.1, 102.8, 127.8 ꢀ 128.5, 137.7, 144.2.
DBU (0.2 mmol, 30 μL) was added to a solution of 23 (0.29 g,
0.68 mmol) and trichloroacetonitrile (0.7 mL, 6.8 mmol) in anhydrous
dichloromethane (10 mL) at 0 °C. The reaction was stirred at 0 °C for
1 h and then at room temperature for 2 h. It was evaporated and
purified by flash chromatography (5ꢀ20% EtOAc/hexanes) to give
compound 4 (0.27 g, 68% yield): Rf = 0.55 (1:4 EtOAc/hexanes); 1H
NMR (360 MHz, CDCl3) δ 2.09 (s, 3H), 3.57 ꢀ 3.63 (m, 1H), 3.67
(m, 1H), 4.20ꢀ4.27 (2H, m), 4.31 (m, 1H), 4.40ꢀ4.75 (m, 4H), 5.36
(dd, J = 3.0, 10.7 Hz, 1H), 6.48 (d, J = 3.8 Hz, 1H), 7.24ꢀ7.43
(m, 10H), 8.74 (s, 1H); 13C NMR (90 MHz, CDCl3) δ 20.7, 57.4, 67.4,
71.3, 71.4, 73.3, 73.9, 75.2, 90.8, 95.0, 127.7ꢀ128.4, 137.5, 137. 6,
160.7, 170.0; HRMS (ESI-TOF) [MHþ] calcd for C24H26Cl3N4O6
571.0912, found 571.0917.
4-O-Acetyl-2-azido-3,6-di-O-benzyl-2-deoxy-R-D-galactopyranose-
1-O-trichloroacetimidate (5) (Scheme 6). To a solution of the known
2454,55 (0.72 g, 1.8 mmol) and BnBr (0.5 mL, 3.6 mmol, 2 equiv) in
anhydrous DMF (10 mL) was added NaH (60% in mineral oil, 0.1 g, 3.6
mmol, 2 equiv) slowly at 0 °C. The reaction mixture was slowly warmed
to room temperature and stirred for 4 h. Aqueous workup was followed
as previously described. The mixture was purified by flash chromatog-
raphy (5ꢀ20% EtOAc/hexanes) to give 25 as a white powder (0.80 g,
91% yield): Rf = 0.4 (1:3 EtOAc/hexane); 1H NMR (360 MHz, CDCl3)
(β isomer) δ 2.30 (s, 3H), 3.36 (m, 1H), 3.43 (dd, J = 3.8, 9.4 Hz, 1H),
3.71 (t, J = 10.3 Hz, 1H), 3.95 (dd, J = 1.7, 12.4 Hz, 1H), 4.07 (m, 1H),
4.29ꢀ4.36 (m, 2H), 4.67 (s, 2H), 5.42 (s, 1H), 7.03 (d, J = 8.5 Hz, 2H),
7.25ꢀ7.45 (m, 10H), 7.59 (d, J = 9.0 Hz, 2H); 13C NMR (90 MHz,
CDCl3) δ 21.1, 59.4, 69.3, 69.7, 71.5, 72.0, 79.5, 85.0, 101.0, 125.9ꢀ
129.8, 134.7, 137.4, 137.6, 138.5.
To a solution of the 25 (0.6 g, 1.2 mmol), powdered molecular sieves
(0.6 g), and NaBH3CN (0.68 g, 10.4 mmol, 9 equiv) in anhydrous THF
(15 mL) was added 4 N HClꢀdioxane (4.0 mL, 16 mmol, 14 equiv)
dropwise at 0 °C under N2 atmosphere, and the mixture was stirred at
0 °C for 2 h. It was diluted with EtOAc (20 mL) and filtered through
Celite. The filtrate was washed with satd NaHCO3 (2 ꢁ 10 mL) and
brine (10 mL), dried over Na2SO4, and purified by flash column
chromatography (5ꢀ20%, EtOAc/hexanes to give 26 (0.5 g, 80% yield).
Compound 26 (0.35 g, 0.7 mmol) was dissolved in dichloromethane
(5 mL), and Et3N (0.2 mL, 1.4 mmol, 2 equiv) followed by Ac2O
(0.14 mL, 1.4 mmol, 2 equiv) were added. The reaction was stirred at
room temperature for 30 min, solvent was removed in vacuo, and the
resulting residue was purified by flash chromatography (5ꢀ20% EtOAc/
hexanes) to give 27 (0.38 g, 96% yield). Thioglycoside hydrolysis of 27
was carried out following the general procedure as outlined to give the
glycosyl hemiacetal:56 Rf = 0.36 (1:2 EtOAc/hexanes); 1H NMR (360
MHz, CDCl3) δ 2.06 (s, 3H), 2.08 (s, 3H), 3.36 (dd, J 2= 3.2, 10.4 Hz
1H), 3.67 (dd, J = 3.6, 10.4 Hz, 1H), 3.97 (dd, J = 3.6, 10.4 Hz, 1H), 4.33
(m, J = 1.0, 5.5 Hz, 1H), 4.48 (dd, J = 4.0, 7.8 Hz, 1H), 5.32 (t, J = 3.6 Hz,
1H), 5.48 (dd, J = 0.8, 3.2 Hz, 1H), 5.57 (dd, J = 1.0, 3.0 Hz, 1H), 7.30
(m, 10H). The resulting hemiacetal was converted to the R-trichlor-
oacetimidate 556 (80% yield over two steps): Rf = 0.55 (1:3 EtOAc/
hexanes),1H NMR (360 MHz, CDCl3) δ 2.07 (s, 3H), 3.47 (dd, J = 7.2,
12.0 Hz, 1H), 3.55 (dd, J = 5.50, 12.0 Hz, 1H), 3.82 (dd, J = 3.60,
A solution of 4,6-di-O-benzyl-D-galactal (800 mg, 2.45 mmol) in
anhydrous pyridine (10 mL) and acetic anhydride (5.0 mmol) was
stirred at room temperature for 2 h. The mixture was concentrated in
vacuo, and the residue was purified by flash chromatography (25%
EtOAc/hexanes) to yield 3-O-acetyl-4,6-di-O-benzyl-D-galactal (810
mg, 90% yield) as a colorless syrup: the NMR data were comparable to
1
literature data; TLC Rf = 0.45 (4:1 hexanes/EtOAc); H NMR (360
MHz, CDCl3) δ = 2.02 (s, 3H), 3.62 (dd, J = 5.4, 10.3 Hz, 1H), 3.76 (dd,
J = 7.4, 10.3 Hz, 1H), 4.00ꢀ4.03 (m, 1H), 4.22ꢀ4.27 (m, 1H),
4.42ꢀ4.55 (m, 2H), 4.70ꢀ4.75 (m, 2H), 5.44ꢀ5.48 (m, 1H), 6.43
(dd, J = 1.4, 6.2 Hz, 1H), 7.24ꢀ7.36 (m, 10H); 13C NMR (90 MHz,
CDCl3) δ 21.1, 65.4, 67.8, 70.7, 73.4, 73.5, 75.5, 98.5, 127.7ꢀ128.4,
137.8, 137.9, 145.6, 170.7.
3-O-Acetyl-4,6-di-O-benzyl-D-galactal (1.5 g, 4.32 mmol) was dis-
solved in CH3CN (50 mL) and cooled to ꢀ15 °C. CAN (7.0 g, 12.95
mmol, 3 equiv) and NaN3 (0.4 g, 6.47 mmol, 1.5 equiv) were added, and
mixture was stirred vigorously using a mechanical stirrer overnight. The
reaction mixture was diluted with ice cold Et2O (50 mL), washed with
water (2 ꢁ 40 mL), dried over anhydrous Na2SO4, and concentrated.
The crude residue was purified by flash chromatography (0ꢀ20%
EtOAc/hexanes) to afford the azido-nitrate product 22 (a 4:1 R/β
mixture, 0.6 g, 30% yield) as a colorless oil: 1H NMR (360 MHz, CDCl3,
selected peaks) δ 4.00 (dd, J = 8.8, 11.0 Hz, 1H), 4.07 (app d, J = 2.9 Hz,
1H), 4.18 (app d, J = 2.9 Hz, 1H), 4.29 (dd, J = 4.2, 11.3 Hz, 1H), 4.86
(dd, J = 3.0, 11.0 Hz, 1H), 5.19 (dd, J = 2.9, 11.3 Hz, 1H), 5.54 (d,
J = 8.8 Hz, 1H), 6.30 (d, J = 4.1 Hz, 1H); 13C NMR (90 MHz, CDCl3) δ
20.7, 56.4, 67.2, 71.2, 71.9, 73.5, 73.7, 75.4, 97.6, 127.8ꢀ128.5, 137.4,
137.5, 170.1.
To a solution of 22 (0.4 g, 0.88 mmol) in CH3CN (10 mL) were
added thiophenol (0.27 mL, 2.63 mmol) and DIPEA (0.15 mL,
0.88 mmol) at 0 °C. After 1 h, the reaction mixture was concentrated
in vacuo, and the crude residue was purified by flash chromatography
(15ꢀ60% EtOAc/hexanes) to give compound 23 as R/β mixture
1
(0.3 g, R:β = 2:1, 80% yield): H NMR (360 MHz, CDCl3, selec-
ted peaks) δ 2.05 (s, 3H), 3.07 (br s, 1H), 3.92 (dd, J = 3.5, 11.1 Hz,
1H), 3.94 (app d, J = 3.3 Hz, 1H), 4.06 (app d, J = 2.3 Hz, 1H), 4.74
(dd, J = 3.1, 10.8 Hz, 1H), 5.32 (dd, J = 2.9, 11.0 Hz, 1H), 5.38 (d, J =
3.4 Hz, 1H).
5214
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The Journal of Organic Chemistry
ARTICLE
Scheme 6. Synthesis of Donor 5
Scheme 7. Synthesis of Donor 6
10.4 Hz, 1H), 4.06 (dd, J 2,3 = 3.0, 10.6 Hz, 1H), 4.30 (m, 1H), 5.78
(dd, J = 1.0, 3.0 Hz, 1H), 6.40 (d, J = 3.60 Hz, 1H), 7.30 (m, 10H) 8.69
(s, 1H).
stirred for 15 min. It was concentrated and coevaporated with toluene to
remove traces of Et3N. A solution of the crude product in MeOH/H2O
(20 mL, 10:1) was boiled under reflux until TLC (1:1 hexanes/EtOAc)
showed complete disappearance of the starting material. It was coeva-
porated with toluene and purified by flash chromatography (10ꢀ50%
EtOAc/hexanes) to give 3,4-O-isopropylidene acetal 30 (0.72 g, 80%
yield). To a stirred solution of 30 (0.4 g, 1.14 mmol) and BnBr (0.3 mL,
2.28 mmol, 2 equiv) in anhydrous DMF (10 mL) at 0 °C was slowly
added NaH (60% in mineral oil, 0.06 g, 2.28 mmol, 2 equiv). The
reaction was warmed to room temperature and stirred for 4 h. It was
quenched with MeOH (15 mL) and extracted with dichloromethane
(3 ꢁ 10 mL). The organic layer was washed with water (3 ꢁ 10 mL) and
brine (2 ꢁ 10 mL). It was dried, concentrated, and purified by flash
chromatography (0ꢀ10% EtOAc/hexanes) to give 6-OBn derivative 31
(0.31 g, 62% yield). Compound 31 (0.3 g, 0.7 mmol) was dissolved in
TFA/H2O (10 mL, 9:1) and stirred at room temperature for 10 min. It
was coevaporated with toluene to give the 3,4-diol derivative (0.28 g,
98% yield), which was dissolved in dichloromethane (5 mL) and treated
with Et3N (0.2 mL, 1.39 mmol, 2 equiv), Ac2O (0.13 mL 1.39 mmol, 2
equiv), and DMAP (catalytic amount). After 30 min, it was concentrated
and purified by flash chromatography (0ꢀ30% EtOAc/hexanes) to give
the 3,4-di-O-acetyl derivative 32 (0.32 g, 94% yield). Thioglycoside
hydrolysis of 32 was carried following the general procedure to give the
hemiacetal which was converted to the R-trichloroacetimidate 7 (80%
yield over two steps): Rf = 0.4 (1:4 EtOAc/hexanes); [R]D = 81.3
(c = 1.00 in CHCl3); IR (thin film, CH2Cl2) 2116, 1755, 1677, 1234,
6-O-Acetyl-2-azido-3ꢀ4-di-O-benzyl-2-deoxy-R-D-galactopyranose-
1-O-trichloroacetimidate (6) (Scheme 7). To a solution of 25 (0.45 g,
0.9 mmol) in anhydrous dichloromethane (10 mL) were added a
solution of BH3.THF (1M, 1.8 mL, 1.8 mmol, 2 equiv) and TMSOTf
(17 μL, 0.1 mmol, 0.1 equiv), and the mixture was stirred under N2 at
room temperature for 3 h. Et3N (3 drops) was added followed by careful
addition of MeOH (5 mL) until H2 evolution ceased. It was concen-
trated, and the residue coevaporated with MeOH. The residue was
purified by flash column chromatography (0ꢀ35%, EtOAc/hexanes) to
give 28 (0.36 g, 80% yield). Compound 28 (0.35 g, 0.7 mmol) was
dissolved in CH2Cl2 (5 mL), and Et3N (0.2 mL, 1.4 mmol, 2 equiv)
followed by Ac2O (0.14 mL, 1.4 mmol, 2 equiv) were added. The
reaction was stirred at room temperature for 30 min. The solvent was
removed in vacuo, and the resulting residue was purified by flash
chromatography (0ꢀ25%, EtOAc/hexanes) to give 29 (0.33 g, 86%
yield). Thioglycoside hydrolysis of compound 29 was carried out
following the general procedure to give the hemiacetal which was
converted to the R-trichloroacetimidate 6 (66% yield over two steps): Rf
= 0.55 (1:3 EtOAc/hexanes), [R]D = 9.1 (c = 1.00 in CHCl3); IR (thin
film, CH2Cl2) 2117, 1734, 1422, 896 cmꢀ1 1H NMR (360 MHz,
;
CDCl3) δ 1.97 (s, 3H), 3.99ꢀ4.26 (m, 6H), 4.61, 4.96 (2d, J = 11.4 Hz,
each 1H) 4.78, 4.84 (2d, J = 11.6 Hz, each 1H), 6.45 (d, J = 3.4 Hz, 1H),
7.29ꢀ7.48 (m, 10H), 8.72 (s, 1H); 13C NMR (90 MHz, CDCl3) δ 20.7,
59.1, 63.0, 71.4, 72.4, 72.5, 74.6, 77.3, 90.9, 95.1, 127.7ꢀ128.8, 137.0,
137.5, 160.6, 170.5; HRMS (ESI-TOF) [MNaþ] calcd for C24H25Cl3-
N4O6Na 593.0732, found 593.0727.
3,4-Di-O-acetyl-2-azido-6-O-benzyl-2-deoxy-R-D-galactopyranose-
1-O-trichloroacetimidate (7) (Scheme 8). To a solution of 20 (0.8 g,
2.56 mmol) in 2,2-dimethoxypropane (20 mL) was added CSA
(catalytic amount), the mixture was stirred at room temperature for
24 h under N2, Et3N (0.5 mL) was then added, and the mixture was
1037 cmꢀ1 1H NMR (360 MHz, CDCl3) δ 2.06 (s, 3H), 2.07
;
(s, 3H), 3.41 ꢀ 3.55 (m, 2H), 4.00 (dd, J = 3.4, 10.0 Hz, 1H), 4.36
(m, H), 4.37, 4.52 (2d, J = 12.0 Hz, each 1H), 5.39 (dd, J = 3.0, 10.0 Hz,
1H), 5.62 (m, 1H), 6.48 (d, J = 3.4 Hz, 1H), 7.20 ꢀ 7.38 (m, 5H), 8.76
(s, 1H); 13C NMR (90 MHz, CDCl3) δ 20.5, 20.6, 57.2, 67.0, 67.3, 68.8,
70.1, 73.3, 90.7, 94.6, 127.8, 128.4, 137.3, 160.7, 169.6, 169.8; HRMS
(ESI-TOF) [MNaþ] calcd for C19H21Cl3N4O7Na 545.0368, found
545.0357.
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The Journal of Organic Chemistry
ARTICLE
Scheme 8. Synthesis of Donor 7
Scheme 9. Synthesis of Donor 8
Scheme 10. Synthesis of Donor 9
3,6-Di-O-acetyl-2-azido-4-O-benzyl-2-deoxy -R-D-galactopyranose-1-O
-trichloroacetimidate (8) (Scheme 9). To a solution of 24 (0.6 g, 1.48
4.05ꢀ4.28 (m, 5H), 4.56 (d, J = 11.1 Hz, 1H), 4.71 (d, J = 11.5, 1H),
5.32 (dd, J = 3.0, 11.4 Hz, 1H), 6.48 (d, J = 3.4 Hz, 1H), 7.29ꢀ7.40 (m,
5H), 8.76 (s, 1H); 13C NMR (90 MHz, CDCl3) δ 20.6, 20.8, 57.2, 62.1,
70.6, 71.5, 73.6, 75.3, 90.7, 94.7, 128.1, 128.2, 128.5, 137.0, 160.6, 170.0,
170.1; HRMS (ESI-TOF) [MNaþ] calcd for C19H21Cl3N4O7Na
545.0368, found 545.0343.
mmol) in anhydrous dichloromethane (8 mL)were added a BH3 THF
3
solution (1M, 3.0 mL, 2.95 mmol, 2 equiv) and TMSOTf (27 μL, 0.18
mmol, 1.2 equiv), and the mixture was stirred under N2 at room
temperature for 3 h. Et3N (3 drops) was added followed by careful
addition of MeOH (5 mL) until H2 evolution ceased. It was concen-
trated, and the residue was coevaporated with MeOH. The residue was
purified by flash column chromatography (10ꢀ50% EtOAc/hexanes) to
give the 4-OBn derivative 33 (0.51 g, 86% yield). Compound 33 (0.50 g,
1.25 mmol) was dissolved in dichloromethane (8 mL), and Et3N
(0.7 mL, 5.0 mmol, 4 equiv) followed by Ac2O (0.5 mL, 5.0 mmol, 4
equiv) were added together with DMAP (catalytic amount). The
reaction was stirred at room temperature for 30 min. The solvent was
removed in vacuo, and the resulting residue was purified by flash
chromatography (0ꢀ30% EtOAc/hexanes) to give the 3,6-di-OAc
derivative 34 (0.36 g, 80% yield). Thioglycoside hydrolysis of 34 was
carried out following the general procedure outlined above to give the
hemiacetal which was converted to the R-trichloroacetimidate 8 (74%
yield over two steps): Rf = 0.5 (1:3 EtOAc/hexanes); [R]D = 171.8 (c =
1.00 in CHCl3); IR (thin film, CH2Cl2) 2116, 1747, 1675, 1370, 1228,
1028 cmꢀ1; 1H NMR (360 MHz, CDCl3) δ 1.98 (s, 3H), 2.13 (s, 3H),
4,6-Di-O-acetyl-2-azido-3-O-benzyl-2-deoxy-R-D-galactopyranose-
1-O-trichloroacetimidate (9) (Scheme 10). CSA (catalytic amount)
was added to 25 (0.4 g, 0.82 mmol) in MeOH (8 mL). The reaction was
stirred at room temperature for 2 h. It was quenched with Et3N
(3 drops) and concentrated. Flash chromatography purification
(20ꢀ50%, EtOAc/hexanes) gave the 4,6-diol 35 (0.6 g, 90% yield).
Acetylation, thioglycoside hydrolysis, and conversion to the trichloror-
acetimidate were carried out following the general procedures outlined
above afford compound 9 (87% yield over three steps): Rf = 0.45 (1:3
EtOAc/hexanes); [R]D = 114.6 (c = 1.00 in CHCl3); IR (thin film,
1
CH2Cl2): 2116, 1747, 1677, 1225, 1064 cmꢀ1; H NMR (360 MHz,
CDCl3) δ 2.04 (s, 3H), 2.14 (s, 3H), 3.95 (dd, J = 3.4, 10.2 Hz, 1H),
4.02ꢀ4.09 (m, 2H), 4.21 (dd, J = 6.0, 11.2 Hz, 1H), 4.35 (t, J = 6.4 Hz,
1H), 4.53, 4.81 (2d, J = 10.7 Hz, each 1H), 5.70 (m, 1H), 6.44 (d, J = 3.4
Hz, 1H), 7.27ꢀ7.42 (m, 5H), 8.75 (s, 1H); 13C NMR (90 MHz, CDCl3)
δ 20.6, 20.7, 58.5, 61.8, 65.6, 69.5, 71.8, 74.1, 90.7, 94.7, 127.9ꢀ128.6,
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The Journal of Organic Chemistry
Table 3. Determination of r:β Ratios: Diagnostic Protons
diagnostic protons
ARTICLE
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: zli@binghamton.edu.
compd
δR (ppm)
δβ (ppm)
10
11
12
13
14
15
16
17
5.05 (d, J = 3.4 Hz, 1H, H-1’)
5.66 (t, J = 9.8 Hz, 1H, H-4)
5.56 (t, J = 9.8 Hz, 1H, H-4)
5.64 (t, J = 9.8 Hz, 1H, H-4)
5.65 (t, J = 9.8 Hz, 1H, H-4)
5.77 (t, J = 9.8 Hz, 1H, H-4)
5.04 (d, J = 3.8 Hz, 1H, H-1’)
4.98 (d, J = 3.4 Hz, 1H, H-1’)
4.47 (d, J = 7.7 Hz, 1H, H-1’)
5.49 (t, J = 9.8 Hz, 1H, H-4)
5.49 (t, J = 9.8 Hz, 1H, H-4)
5.52 (t, J = 9.8 Hz, 1H, H-4)
5.47 (t, J = 9.8 Hz, 1H, H-4)
5.66 (t, J = 9.8 Hz, 1H, H-4)
4.42 (d, J = 8.1 Hz, 1H, H-1’)
4.35 (d, J = 8.1 Hz, 1H, H-1’)
’ ACKNOWLEDGMENT
Financial support for the research was provided by Binghamton
University Research Foundation. We thank Dr. Venkata Subbarao
Kandula and Prof. Donald Dittmer of Syracuse University for
helping us determine the specific rotation value of compounds 6ꢀ9.
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’ ASSOCIATED CONTENT
1
Supporting Information. Selected H and 13C NMR
S
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and HSQC spectra. Cartesian coordinates and absolute energy of
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