The methylsulfonylethoxymethyl (Msem) as a hydroxyl protecting group in oligosaccharide synthesis

Article abstract of DOI:10.1016/j.tet.2010.06.007

The methylsulfonylethoxymethyl (Msem) is introduced as a base-labile, non-participating protecting group in carbohydrate chemistry. Conditions to introduce the Msem on primary and secondary alcohols are described. Removal of the Msem is best achieved using a catalytic amount of tetrabutylammonium fluoride (TBAF), with or without a nucleophilic scavenger. Applicability of the Msem group is illustrated in the assembly of an all 1,3-cis-linked mannotrioside.

Full text of DOI:10.1016/j.tet.2010.06.007

Tetrahedron 66 (2010) 6121e6132
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The methylsulfonylethoxymethyl (Msem) as a hydroxyl protecting group in
oligosaccharide synthesis
*
Asghar Ali, Richard J.B.H.N. van den Berg, Herman S. Overkleeft, Gijsbert A. van der Marel ,
*
Jeroen D.C. Codée
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The methylsulfonylethoxymethyl (Msem) is introduced as a base-labile, non-participating protecting
group in carbohydrate chemistry. Conditions to introduce the Msem on primary and secondary alcohols
are described. Removal of the Msem is best achieved using a catalytic amount of tetrabutylammonium
fluoride (TBAF), with or without a nucleophilic scavenger. Applicability of the Msem group is illustrated
in the assembly of an all 1,3-cis-linked mannotrioside.
Received 15 March 2010
Received in revised form 11 May 2010
Accepted 1 June 2010
Available online 9 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Protecting groups
Carbohydrates
Stereoselectivity
1. Introduction
donors5 proved to be effective to obtain
nosylations, the nature of protective groups at the 3-OH position
has also been shown to have a major effect on the
-ratio.6,7 For
instance, it has become clear that the bulky 3-O-tert-butyldime-
thylsilyl ether reduces the -selectivity by a steric interaction with
the C-2 hydroxyl protecting group,6 while 3-O-carboxylate esters
give essentially pure -mannosides, presumably via neighboring
group participation.3b,7
b-selective man-
The development of new protective group strategies remains
a major research objective in synthetic carbohydrate chemistry.1
The ideal protective group for any given carbohydrate functional-
ity is orthogonal with respect to all other protective groups present
in the donor and acceptor glycosides that partake in a glycosylation
event. In recent years it has become increasingly clear that pro-
tective groups are not necessarily innocent bystanders in a glyco-
sylation event but can influence both reactivity of the donor/
acceptor glycoside2 and the stereochemical outcome and yield of
a glycosylation reaction.3 By carefully selecting the appropriate
protective group scheme one can take advantage of this by steering
the glycosylation toward the desired interglycosidic linkage. The
use of participating groups at the 2-position of donor glycosides is
a well-established procedure to obtain 1,2-trans glycosidic linkages
with high anomeric purity.1a Of a more recent date is the discovery
that protective groups at positions more distal from the anomeric
centre of the donor can also exert remarkable stereochemical
control on specific glycosylations.3 A striking example of the in-
fluence of a remote protecting group is represented by 4,6-O-ben-
zylidene protected mannopyranose donors, which allow the easy
introduction of 1,2-cis-mannosidic linkages.4 Although the pres-
ence of 4,6-O-benzylidene acetal in several types of mannose
a/b
b
a
We recently reported on the development of the methyl-
sulfonylethoxycarbonyl (Msc, 1, Fig. 1) functionality as a new or-
thogonal protective group in the synthesis of glucose containing
O
O
O
O
O
O
O
S
S
O
O
O
O
1
2
, Msc
, Msem
Figure 1. The methylsulfonylethoxycarbonyl (Msc, 1) and methylsulfonylethoxymethyl
(Msem, 2) protecting groups.
oligosaccharides.8 In this work we demonstrated, amongst others,
that the Msc group is orthogonal with the levulinoyl (Lev) group
and can be easily removed using a catalytic amount of 1,8-dia-
zabicyclo[5.4.0]undec-7-ene (DBU) in DMF. At the onset of the here
presented work and based on literature precedence7 we reasoned
that the carbonyl character of 1 when introduced onto C-3-OH of
4,6-O-benzylidene protected mannopyranose donors would steer
* Corresponding authors. E-mail addresses: marel_g@chem.leidenuniv.nl (G.A.
van der Marel), jcodee@chem.leidenuniv.nl (J.D.C. Codée).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.007

6122
A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
a mannosylation event toward the 1,2-trans-linked product. With
the aim to install 1,2-cis-mannosidic linkages we considered
methylsulfonylethoxymethyl (Msem, 2) as a useful addition to the
carbohydrate chemistry protective group palette. In principle, it can
N-iodosuccinimide (NIS) and trimethylsilyltriflate (TMSOTf)11 pro-
duced Msem-protected 8 in 74% yield (Scheme 1). The preparation
of Msem-protected 10 from methyl 2,3,6-tri-O-benzyl-a-D-gluco-
pyranoside 9 using reagent 4 and the same activator system dem-
onstrate that this procedure is also suitable to protect secondary
hydroxyl functions with the Msem group. Using the milder iodo-
nium di-sym-collidine perchlorate (IDCP) as iodonium source,12 the
condensation of methyl glycoside 7 and thiomethyl ether 4 led to
the isolation of Msem-protected 8 in 63% yield, whereas activation
of 4 with diphenylsulfoxide (Ph2SO) in combination with tri-
fluoromethanesulfonic anhydride (Tf2O)13 and an excess tri-tert-
butylpyrimidine (TTBP)14 as a proton scavenger provided 8 in 79%
yield.
be removed by b-elimination in a fashion similar to the removal of
Msc 1. It however lacks the carbonyl and is relatively small and thus
we expected little to no interference with the 1,2-cis directing effect
of the 4,6-O-benzylidene moiety in mannoside synthesis. The re-
alization that related alkoxymethyl protective groups such as the
cyanoethoxymethyl have proven useful protective groups in RNA
oligomer synthesis9 further strengthened us in our resolve to ex-
plore the merits of the Msem functionality as a carbohydrate pro-
tective group. We here present our results on the introduction and
removal of the Msem group and its use in the construction of a
1,3-mannan trisaccharide.
b
-
To investigate whether the Msem group can be introduced un-
der basic conditions methylsulfonylethoxymethyl chloride 5 was
prepared by treatment of thiomethyl ether 4 with sulfuryl chloride
in DCM. Although it is known that alkyloxymethyl chlorides can be
introduced with the aid of tin ketals15 (vide infra) attention was
directed to more stringent conditions. Unfortunately, attempts to
introduce the Msem group to the primary hydroxyl in compound 7
with methylsulfonylethoxymethyl chloride 5, employing either
sodium hydride, diisopropylethylamine (DIPEA), 2,6-lutidine or
2,4,6-syn-collidine as a base failed and resulted only in the recovery
of starting compound 7. Apparently, chloride 5 is not stable under
the applied conditions. The possibility to introduce the Msem un-
der acidic conditions was explored with acetyl acetal 6, which was
produced by reaction of thioether 4 with AcOH under the influence
of NIS in 95% yield. Unfortunately the reaction of (2-(methyl-
2. Results and discussion
The most efficient way to introduce various alkoxymethyl pro-
tecting groups is based on the use of thiomethyl intermediates.9,10
We therefore decided to explore two complementary strategies to
introduce the methylsulfonylethoxymethyl (Msem) group on a hy-
droxyl function. In the first approach, an alkoxymethyl thiomethyl
ether reagent is prepared while in the second procedure, the
hydroxyl function to be protected is converted into the corre-
sponding thiomethyl ether. First attention was focused on the
former approach and to this end commercially available methyl-
sulfonylethanol 3 was converted to thiomethyl ether 4 in 57% yield
by treatment with dimethylsulfoxide (DMSO) and acetic anhydride
(Ac2O) in acetic acid (Scheme 1). Condensation of methyl 2,3,4-tri-
sulfonyl)ethoxy)methyl acetate 6 and methyl 2,3,6-tri-O-benzyl-
-glucopyranoside 9 under influence of TfOH or SnCl4 mainly led to
the formation of the methylene acetal 11 instead of the desired
a-
D
O-benzyl-a-D-glucopyranoside 7 with 4 under the influence of
b
c
O
O
O
S
S
O
O
Cl
O
O
5
a
O
O
S
S
OH
O
S
3
4
O
OAc
6
d (74%)
e (63%)
HO
MsemO
or f (79%)
O
O
BnO
BnO
BnO
BnO
4
BnO
BnO
OMe
OMe
OMe
7
8
O
O
O
BnO
BnO
11
BnO
BnO
OMe
d (70%)
O
O
HO
MsemO
BnO
BnO
4
BnO
BnO
OMe
9
10
3
g
d (32%)
or e (64%)
BnO
O
S
O
BnO
BnO
OMe
12
Scheme 1. Introduction of the Msem group on glucosyl hydroxyls. Reagents and conditions; (a) AcOH, Ac2O, DMSO, rt, 48 h, 57%; (b) SO2Cl2, DCM, rt, 2 h, 100%; (c) NIS, AcOH, DCM,
ꢀ20 ꢁC to rt, 2 h, 95%; (d) NIS, TMSOTf, DCM, ꢀ20 ꢁC to rt, 24 h; (e) IDCP, DCM, rt, 2 h; (f) DPS, TTBP, Tf2O, DCM, ꢀ60 ꢁC, 2 h; (g) NaH, MTM-Cl, DMF, 1 h, 73%.

A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
6123
Msem-protected 10, indicating that the Msem can be introduced
using acidic conditions, but that the intermediate ketal is sensitive
toward these conditions.
tetrabutylammonium fluoride (TBAF, 0.1 equiv) led to the com-
plete cleavage of the Msem group after 24 h at room temperature
(Table 1, entry 4).
The second approach, in which a hydroxyl function in a mono-
saccharide is firstly transformed into the methylthiomethyl ether
and subsequently into the Msem ether was pursued next. 2,3,4-Tri-
The feasibility of the Msem acetal as hydroxyl protecting group
in oligosaccharide synthesis was investigated in the context of the
stereoselective construction of mannosidic bonds. In this respect,
the comparison of the here presented Msem group and the meth-
ylsulfonylethoxycarbonyl (Msc) group, both relatively small pro-
tecting groups and having the methylsulfonylethoxy moiety in
common, is relevant (vide supra). To directly compare the influence
of the Msem acetal with the Msc carbonate, thiomannosides 16 and
17 were prepared. Benzylation of mannoside 13 under phase
transfer conditions16 provided a separable mixture of the mono
benzylated mannosides 14a and 14b, and dibenzylated 14c in
a 1.5:4:1 ratio. Mono benzyl ether 14b was treated with Msc-Cl and
pyridine to provide the fully protected MSc-mannoside 16. Guided
by ample literature precedent describing the use of tin ketals to
introduce alkoxymethyl ethers,9a,15 the regioselective alkylation of
the 2,3-O-dibutylstannylidene of diol 13 with methyl-
sulfonylethoxymethyl chloride 5 was undertaken. A mixture of 13
and dibutyltin oxide in toluene was heated for 2 h and after evap-
oration of the solvents, the crude product was treated with Msem-
Cl 5 in presence of cesium fluoride and tetrabutylammonium bro-
mide (TBABr) in toluene. 3-O-Msem protected mannopyranoside
15 was obtained in high yield as the sole regioisomer. Benzylation
of this Msem-mannoside could be efficiently effected by treatment
of 15 with NaH in the presence of BnBr to give mannoside 17 in 75%
yield.
O-benzyl-a-D-glucopyranoside 9 was converted into fully protected
12 by treatment with sodium hydride and methylthiomethyl
chloride (MTM-Cl) in DMF (Scheme 1). Condensation of thiomethyl
ether 12 with 2-(methylsulfonyl)ethanol 3 using the NIS/TMSOTf
combination
gave
methyl
2,3,6-tri-O-benzyl-4-O-methyl-
sulfonylethoxymethyl-a-D-glucopyranoside 10 in 20% yield. The
low yield can be explained by the predominant formation of
methylene acetal 11. Employing IDCP (4 equiv) as a milder acti-
vating system gave 10 in 64% yield but a small amount of side
product 11 was also formed in this case.
With two methods at hand for the introduction of the Msem
group, we set out to identify the most favorable conditions for
cleavage of the Msem group. Therefore, 2,3,4-tri-O-benzyl-6-O-
methylsulfonylethoxymethyl-
a-
D-glucopyranoside
8
was sub-
jected to conditions that normally effect
b
-elimination. As sum-
marized in Table 1, the Msem group is reasonably stable under
basic conditions, and significantly more robust than its carbonate
counterpart (Msc, 1). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
(2 equiv) and reaction for 3 h at elevated temperature (100 ꢁC)
Table 1
Conditions for cleavage of the Msem group
MsemO
HO
BnO
BnO
The Ph2SO/Tf2O-mediated condensation of 3-O-Msc donor 16
with acceptor 18 led to the predominant formation of the a-man-
O
O
BnO
BnO
BnO
8
BnO
nopyranoside linkage in 19 (Scheme 2). This result underlines that,
not only carboxylate esters3b,7 but also carbonates such as the Msc-
group at the C-3-hydroxyl of benzylidene mannosides, direct
OMe
OMe
7
Entry
Conditions
Temperature
100 ꢁ
Time (h)
Yield
mannosylation reactions toward the a-products. The condensation
1
2
3
4
DBU (2 equiv), DMF
C
3
20
24
24
91
93
89
94
of 3-O-Msem donor 17 with acceptor 18 on the other hand, pro-
vided the 1,2-cis-linked dimannoside 20 as the major product
(Scheme 2). The outcome of this glycosylation indicates that the
Msem group does not act as a remote participating group and is
DBU (2 equiv), DMF, PhSH
KOtBu (5 equiv), MeOH
TBAF (0.1 equiv), THF
100 ꢁC
40 ꢁ
rt
C
OR1
O
OBn
O
OH
O
Ph
O
Ph
O
R2O
Ph
O
a or b
c or d
O
O
O
SPh
SPh
SPh
HO
RO
16 R = Msc
14a R1 = Bn, R2 = H
13
17
R = Msem
e
1
2
14b
R = H, R = Bn
14c R1 = R2 = Bn
OBn
O
1
2
Ph
O
15
R = H, R = Msem
O
HO
18
OMe
OBn
O
OBn
O
Ph
O
Ph
O
O
O
RO
O
OMe
19
R = Msc α/β = >10:1
R = Msem α/β = 1:5
20
Scheme 2. Coupling of both Msc-protected 16 and Msem-protected 17 with acceptor 18. Reagents and conditions: (a) BnBr, Bu4NSO4, NaOH, DCM, H2O (14a: 17%, 14b: 44%, 14c:
11%); (b) (i). Bu2SnO, toluene, reflux, 2 h: (ii). Msem-Cl, CsF, TBABr, toluene, 18 h, 15: 81%; (c) Msc-Cl, pyridine, DCM, 16: 97%; (d) BnBr, TBAI, NaH, DMF, 0 ꢁC, 15 min, 17: 75%; (e)
Ph2SO, Tf2O, TTBP, DCM, ꢀ78 ꢁC to rt, 2 h, 19: 78%, 20: 84%.
were required to completely remove the Msem group (Table 1,
entry 1). Addition of thiophenol as the scavenger retarded the
time for cleavage considerably (Table 1, entry 2). Complete
deblocking of the Msem group with the aid of 5 equiv of potas-
sium tert-butoxide (KOtBu) was achieved after 24 h at 40 ꢁC (Table
1, entry 3). Gratifyingly, treatment of 8 with a catalytic amount of
sterically minimally intrusive, allowing the selective formation of
the b
-mannosidic bond in line with recent results from the Crich17
and Seeberger laboratories.5e
The glycosylating properties of 3-O-Msem protected mannopyr-
anose 17 were further examined in a set of Ph2SO/Tf2O-mediated
condensations with a range of different nucleophiles (Table 2).

6124
A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
Table 2
Surprisingly, condensation with primary acceptor 7 furnished the
and -isomers of disaccharide 24 in almost equal amounts (Table 2,
entry 1).18 Secondary alcohol 9, which has previously been shown to
be a relatively challenging substrate to -mannosylate, reacted with
donor 17 to provide the -disaccharide 25 in a 1:3 ratio (Table 2,
entry 2).3b,5e,19 When glucosamine acceptor 21, also a notoriously
difficult substrate for the -mannosylation reaction, was employed,
equal amounts of and products (26) were obtained (Table 2, entry
3).17,20 Condensation of donor 17 with methyl 4,6-O-benzylidine-3-
O-benzyl- -mannopyranoside 22 on the other hand gave di-
saccharide 27 with good -selectivity (
a-
Glycosylation of donor 17 with various acceptorsa
b
OBn
O
OBn
O
Ph
O
Ph
O
O
b
O
+ ROH
SPh
MsemO
MsemO
OR
a/b
17
24 R = 7
25 R = 9
26 R = 21
27 R = 22
28 R = 23
b
a
b
a-D
Entry
Acceptor (ROH)
Time (h) Temp.
Yield
a
/b
b
a/b
¼1:5, Table 1, entry 4). The
HO
O
same result, in terms of stereoselectivity and yield was obtained
earlier with the corresponding 2-O-benzyl acceptor 18 (see Scheme
BnO
ꢀ78 ꢁC to ꢀ72 ꢁ
C
74
4:5
1:3
1:1
1:5
BnO
1
2
3
4
2
BnO
2). Finally, the use of 1,2:5,6-di-O-isopropylidene-3-O-
a-D-glucofur-
OMe
7
anose 23 led to the formation of disaccharide 28 in 1:10
a/b
ratio
BnO
(Table 2, entry 6). These experiments show that the glycosylations of
17 can proceed with good to moderate 1,2-cis selectivity. It should be
noted that the reactivity of the hydroxyl function in the acceptor
glycoside plays an important role. Although poor selectivities for
acceptors 93b,19 and 215e have been reported before, the outcome of
the mannosylation of primary alcohol 7 stands in sharp contrast to
O
HO
ꢀ78 ꢁC to 0 ꢁ
ꢀ78 ꢁC to 0 ꢁ
ꢀ78 ꢁC to 0 ꢁ
C
C
C
72
78
72
BnO
4
4
4
BnO
OMe
9
BnO
O
HO
BnO
ZHN
21
the b-selective mannosylations commonly reported for this accep-
OMe
tor.4,18 At this moment we cannot offer a conclusive explanation for
this unexpected result, but do wish to point out that this result
highlights how minor changes in a glycosylation system can result in
major changes in the outcome of the reaction.
OH
O
Ph
O
O
BnO
OMe
22
Finally the assembly of
depicted in Scheme 3. To this end, the
pound 20 were separated by silica gel column chromatography and
the Msem group in -dimer 20 was cleaved by treatment with TBAF
b
-1,3-mannotriose 32 was undertaken as
a
- and -anomers of com-
b
O
H
O
b
O
ꢀ78 ꢁC to ꢀ60 ꢁ
C
75
1:10
O
5
2
to give disaccharide 29 in 60% yield (Scheme 3). Apart from target
29, a substantial amount of side product 30 was isolated, the for-
mation of which can be explained by Michael addition of the re-
leased (methylsulfonyl)ethene to the free C-3-hydroxyl in 29.
Notably this side reaction has not been observed for any other
Msem substrate investigated so far. To circumvent the formation of
O
HO
23
a
Reagents: TTBP, Ph2SO, Tf2O, DCM.
OBn
O
Ph
OBn
Ph
O
O
O
O
O
O
MsemO
20β
OMe
a
OBn
O
OBn
O
Ph
O
Ph
O
OBn
OBn
O
Ph
O
Ph
S
O
O
O
O
O
O
O
O
HO
O
29
30
OMe
OMe
O
O
17
b
OBn
OBn
a, c
OBnPh
O
O
Ph
O
O
Ph
O
O
O
O
O
O
MsemO
O
31
OMe
OH
O
OH
O
HO
OH
HO
HO
HO
HO
HO
HO
O
O
O
32
OMe
Scheme 3. The synthesis of
Pd(OH)2/C, H2, 24 h, 32: 60% over two steps.
b
-1,3-mannan 32. Reagents and conditions; (a) TBAF, piperidine, THF, 24 h, 29: 88%; (b) TTBP, Ph2SO, Tf2O, DCM, ꢀ78 ꢁC to rt, 2 h, 31: 83% (
a
/b¼1:5); (c)

A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
6125
side product 30, piperidine was added to the reaction mixture to
scavenge the released vinyl sulfone. In this case disaccharide 29
was obtained in 88% yield. Elongation of 29 by pre-activation of
2 equiv of thioglycoside 17 with Ph2SO/Tf2O in the presence of an
excess of TTBP furnished trisaccharide 31 in 83% yield, as an
(MeSO2CH2CH2OCH2SCH3), 74.7 (MeSO2(CH2)2OCH2SCH3); HRMS
[MþNH4]þ calculated for C5H16O3S2N 202.0566, found 202.0566.
4.1.2. Methylsulfonylethoxymethyl chloride (5). To
a solution of
((methylsulfonylethoxy)methyl)methylsulfane 4 (1.39 g, 7.55 mmol)
in DCM (25 mL, 0.3 M) was added sulfuryl chloride (0.6 mL,
7.6 mmol, 1 equiv) and the mixture was stirred for 2 h. The solvents
were removed in vacuo to give 5; IR (neat, cmꢀ1): 643, 944, 1112,
anomeric mixture (
a
/b¼1:5). Also in this case, the
a- and b-
anomers could be separated by silica gel chromatography. Anom-
erically pure 31 was then deprotected in two steps. First, the Msem
group in 30 was removed by treatment with TBAF in the presence
of piperidine. Subsequent hydrogenolysis of the remaining benzy-
lidene and benzyl groups using palladium hydroxide on charcoal
and hydrogen gas led to the isolation of trisaccharide 32 in 60%
yield over two steps.
1288; 1H NMR (400 MHz, CDCl3)
d
¼2.92 (s, 3H, CH3SO2e), 3.27 (t,
2H, J¼5.2 Hz, MeSO2CH2CH2OCH2Cl), 4.07 (t, 2H, J¼5.6 Hz, MeSO2
-
CH2CH2OCH2Cl), 5.46 (s, 2H, MeSO2(CH2)2OCH2Cl); 13C NMR
(100 MHz, CDCl3)
d
¼42.5 (CH3SO2e), 53.9 (MeSO2CH2CH2OCH2Cl),
63.6 (MeSO2CH2CH2OCH2Cl), 81.9 (MeSO2(CH2)2OCH2Cl); HRMS
[MþNH4]þ calculated for C4H13ClO3S2N 190.0299, found 190.0288.
3. Conclusion
4.1.3. Methylsulfonylethoxymethylacetate (6). To a solution of
((methylsulfonylethoxy)methyl)methylsulfane 4 (1.05 g, 5.7 mmol)
in DCM (29 mL, 0.2 M) was added N-iodosuccinimide (1.52 g,
6.83 mmol, 1.2 equiv). The mixture was cooled to ꢀ20 ꢁC followed
by the addition of acetic acid (0.65 mL, 11.4 mmol, 2 equiv). The
mixture was allowed to warm to rt and was stirred for 2 h. The
reaction mixture was quenched with triethylamine (5 equiv), fil-
tered, diluted with DCM, and washed with Na2S2O3(aq). The aque-
ous layer was extracted with DCM thrice and the combined organic
layers were dried over MgSO4, filtered, concentrated, and purified
by silica gel column chromatography to afford 6 (1.06 g, 5.41 mmol,
95%). TLC (66% EtOAc in PE): Rf¼0.6; IR (neat, cmꢀ1): 489, 961, 1124,
We have reported the development of the methyl-
sulfonylethoxymethyl (Msem) group as a new hydroxyl protecting
group that meets the requirements for productive oligosaccharide
synthesis. The Msem group can be conveniently introduced at
primary and secondary hydroxyl functions of O-glycosides with
thiomethyl ether reagent 4 and a thiophilic activator. For the in-
stallation of the Msem group at the hydroxyl functions of thio-
glycosides, the conversion of the hydroxyl functions into
dibutylstannylidene acetals followed by reaction with Msem-Cl 5 is
the method of choice. The methylsulfonylethoxymethyl ether is
sterically unbiased, does not provide remote neighboring group
participation and is easily removed by a catalytic amount of TBAF in
the presence of piperidine as scavenger. The usefulness of the
Msem group is illustrated by the synthesis of an all 1,3-cis-linked
mannotrioside.
1285, 1740; 1H NMR (400 MHz, CDCl3)
d
¼2.12 (s, 3H, CH3 OAc), 2.98
(s, 3H, CH3SO2e), 3.26 (t, 2H, J¼5.2 Hz, MeSO2CH2CH2OCH2OAc),
4.09 (t, 2H, J¼5.6 Hz, MeSO2CH2CH2OCH2OAc), 5.27 (s, 2H, MeS-
O2(CH2)2OCH2OAc); 13C NMR (100 MHz, CDCl3)
d
¼20.7 (CH3 OAc),
42.8 (CH3 CH3SO2e), 54.7 (CH2 MeSO2CH2CH2OCH2OAc), 63.5 (CH2
MeSO2CH2CH2OCH2OAc), 88.0 (CH2 MeSO2(CH2)2OCH2OAc); HRMS
[MþNa]þ calculated for C6H12O5S1Na 219.0298, found 219.0298.
4. Experimental
4.1.4. Methyl 2,3,4-tri-O-benzyl-6-O-methylsulfonylethoxymethyl-
-glucopyranoside (8). Method I: A solution of methyl 2,3,4-tri-O-
benzyl- -glucopyranoside 7 (0.525 g, 1.14 mmol) and ((methyl-
sulfonylethoxy)methyl)methylsulfane (0.314 g, 1.70 mmol,
a-
4.1. General method for glycosylations using Ph2SO/Tf2O
D
a-D
A solution of the mannopyranosyl donor, diphenylsulfoxide
(1.3 equiv) and tri-tert-butylpyrimidine (3 equiv) in DCM
(0.05 M) was stirred over activated MS 3 Å for 30 min. The
mixture was brought to ꢀ78 ꢁC before triflic acid anhydride
(1.3 equiv) was added. The mixture was allowed to warm to
ꢀ60 ꢁC in 15 min followed by the addition of the acceptor
(1.5 equiv). The reaction mixture was stirred at the temperature
described in Table 2. The reaction mixture was quenched with
triethylamine (5 equiv), filtered, diluted with DCM and washed
with water. The aqueous layer was extracted with DCM thrice,
the combined organic layers were dried over MgSO4, filtered,
concentrated and purified by size exclusion and silica gel column
chromatography.
4
1.5 equiv) in DCM (23 mL, 0.05 M) was stirred over activated MS 3 Å
for 30 min before N-iodosuccinimide (0.304 g, 1.36 mmol,
1.2 equiv) was added. The mixture was cooled to ꢀ20 ꢁC followed
by the addition of trimethylsilyltrifluoromethanesulfonate (10% in
DCM, 0.41 mL, 0.23 mmol, 0.2 equiv). The reaction mixture was
stirred for 1.5 h. The reaction mixture was quenched with trie-
thylamine (5 equiv), filtered, diluted with DCM, and washed with
Na2S2O3(aq). The aqueous layer was extracted with DCM thrice, the
combined organic layers were dried over MgSO4, filtered, concen-
trated, and purified by silica gel column chromatography to provide
8 (0.570 g, 0.949 mmol, 84%).
Method II: A solution of methyl 2,3,4-tri-O-benzyl-a-D-gluco-
pyranoside 7 (0.102 g, 0.22 mmol) and ((methylsulfonylethoxy)
methyl)methylsulfane 4 (0.061 g, 0.33 mmol, 1.5 equiv) in DCM
(4.5 mL, 0.05 M) was stirred over activated MS 3 Å for 30 min before
iodonium di-sym-collidine perchlorate (IDCP, 0.412 g, 0.88 mmol,
8 equiv) was added in the dark. The reaction mixture was stirred in
the dark for 24 h. The reaction mixture was quenched with
4.1.1. ((Methylsulfonylethoxy)methyl)methylsulfane (4). To a solution
of methylsulfonylethanol 3 (6.55 g, 52.8 mmol) in DMSO (15 mL,
211 mmol, 4 equiv) was added acetic acid (6 mL, 106 mmol, 2 equiv)
and acetic anhydride (9.9 mL, 106 mmol, 2 equiv). The reaction
mixture was stirred for 48 h. The mixture was neutralized by careful
addition of NaHCO3(s), extracted using a large excess of EtOAc, dried
over MgSO4, filtered, concentrated, and purified by silica gel column
chromatography to afford 4 (5.54 g, 30.0 mmol, 57%) as a yellow oil.
TLC (75% EtOAc in toluene): Rf¼0.75; IR (neat, cmꢀ1): 730, 1129,
NH4Cl(aq), filtered, diluted with DCM, and washed with Na2S2O3(aq)
.
The aqueous layer was extracted with DCM thrice, the combined
organic layers were washed with NH4Cl(aq), NaHCO3(aq) and brine,
dried over MgSO4, filtered, concentrated, and purified by silica gel
column chromatography to provide 8 (0.070 g, 0.12 mmol, 63%).
Method III: A solution of ((methylsulfonylethoxy)methyl)meth-
1286; 1H NMR (400 MHz, CDCl3)
d¼2.15 (s, 3H, eCH2SCH3), 2.99 (s,
3H, CH3SO2e), 3.31 (t, 2H, J¼5.2 Hz, MeSO2CH2CH2OCH2SCH3), 3.95
(t, 2H, J¼5.6 Hz, MeSO2CH2CH2OCH2SCH3), 4.68 (s, 2H, MeSO2(-
ylsulfane
4 (0.058 g, 0.31 mmol, 1.5 equiv), diphenylsulfoxide
CH2)2OCH2SCH3); 13C NMR (100 MHz, CDCl3)
d
¼13.3 (eCH2SCH3),
(0.083 g, 0.41 mmol, 1.3 equiv), and tri-tert-butylpyrimidine
(0.234 g, 0.942 mmol, 3 equiv) in DCM (6.3 mL, 0.05 M) was stirred
42.0
(CH3SO2e),
53.9
(MeSO2CH2CH2OCH2SCH3),
60.9

6126
A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
over activated MS 3 Å for 30 min. The mixture was brought to
filtered, concentrated, and purified by silica gel column chroma-
tography to provide 10 (0.146 g, 0.24 mmol, 64%) and 11 (0.024 g,
0.06 mmol, 16%). Compound 10: TLC (50% EtOAc in PE): Rf¼0.4;
ꢀ60 ꢁC before triflic acid anhydride (69
ml, 0.41 mmol, 1.3 equiv)
was added. The mixture was allowed to warm to ꢀ40 ꢁC in 15 min
followed by the addition of methyl 2,3,4-tri-O-benzyl-
a
-D
-gluco-
[a
]
22 þ70.4 (c 1.0, DCM); IR (neat, cmꢀ1): 524, 1027, 1311; 1H NMR
D
pyranoside 7 (0.097 g, 0.21 mmol, 1 equiv). The reaction mixture
was stirred for 1 h. The reaction mixture was quenched with trie-
thylamine (5 equiv), filtered, diluted with DCM, and washed with
water. The aqueous layer was extracted with DCM thrice, the
combined organic layers were dried over MgSO4, filtered, concen-
trated, and purified by silica gel column chromatography to afford 8
(0.099 g, 0.165 mmol, 79%).
(400 MHz, CDCl3)
d
¼2.75 (s, 3H, CH3 Msem), 2.78e2.90 (m, 2H,
MeSO2CH2CH2OCH2e), 3.39 (s, 3H, OMe), 3.54 (dd, 1H, J¼3.6,
9.6 Hz, H-2), 3.60e3.67 (m, 3H, H-4, and 2ꢂH-6), 3.71 (m, 1H, H-5),
3.75 (m, 2H, MeSO2CH2CH2OCH2e), 3.88 (t, 1H, J¼9.6 Hz, H-3), 4.50
(d, 1H, J¼12.0 Hz, CHH Bn), 4.59e4.68 (m, 5H, H-1, MeSO2(CH2)2
-
OCHHe, and 3ꢂCHH Bn), 4.73e4.78 (m, 2H, MeSO2(CH2)2OCHHe,
and CHH Bn), 5.02 (d, 1H, J¼10.8 Hz, CHH Bn), 7.23e7.35 (m, 15H, H
TLC (50% EtOAc in PE): Rf¼0.4; [
a]
22 þ43.0 (c 1.0, DCM); IR (neat,
arom); 13C NMR (100 MHz, CDCl3)
d
¼42.6 (CH3 Msem), 54.6
D
cmꢀ1): 696, 1026, 1717; 1H NMR (400 MHz, CDCl3)
d
¼2.91 (s, 3H,
(MeSO2CH2CH2OCH2e), 55.1 (CH3 OMe), 62.3 (MeSO2
-
CH3 Msem), 3.15 (t, 2H, J¼5.2 Hz, MeSO2CH2CH2OCH2e), 3.38 (s,
3H, OMe), 3.50e3.55 (m, 2H, H-2, and H-4), 3.73e3.77 (m, 3H, H-5,
and 2ꢂH-6), 3.88e4.03 (m, 3H, H-3, and MeSO2CH2CH2OCH2e),
4.57e4.63 (m, 3H, H-1, MeSO2(CH2)2OCHHe, and CHH Bn),
4.65e4.70 (m, 2H, MeSO2(CH2)2OCHHe, and CHH Bn), 4.78e4.82
(m, 2H, 2ꢂCHH Bn), 4.92 (d, 1H, J¼11.2 Hz, CHH Bn), 4.99 (d, 1H,
J¼10.8 Hz, CHH Bn), 7.26e7.37 (m, 15H, H arom); 13C NMR
CH2CH2OCH2e), 68.4 (C-6), 69.6 (C-5), 72.9 (CH2 Bn), 73.2 (CH2 Bn),
75.1 (C-4), 75.3 (CH2 Bn), 79.8 (C-2), 81.0 (C-3), 96.2 (MeSO2-
(CH2)2OCH2e), 97.6 (C-1), 127.5e128.3 (CH arom), 137.7 (Cq Bn),
138.3 (Cq Bn); HRMS [MþNa]þ calculated for C32H40O9S1Na
623.2285, found 623.2283.
4.1.6. Methyl 2,3-di-O-benzyl-4,6-O-methylidine-a-D-glucopyrano-
(100 MHz, CDCl3)
d
¼42.8 (CH3 Msem), 55.0 (MeSO2CH2CH2OCH2e),
side (11). Rf¼0.7; [
a]
D
þ57.8 (c 1.0, DCM); IR (neat, cmꢀ1): 696,
22
55.2 (CH3 OMe), 61.8 (MeSO2CH2CH2OCH2e), 66.8 (C-6), 69.7 (C-5),
73.3 (CH2 Bn), 74.9 (CH2 Bn), 75.7 (CH2 Bn), 77.5, 79.8 (C-2 and C-4),
82.0 (C-3), 95.8 (MeSO2(CH2)2OCH2e), 98.1 (C-1), 127.6e128.4 (CH
arom), 138.0 (Cq Bn), 138.2 (Cq Bn), 138.6 (Cq Bn); HRMS [MþNa]þ
calculated for C32H40O9S1Na 623.2285, found 623.2283.
1049; 1H NMR (400 MHz, CDCl3)
d
¼3.31 (t, 1H, J¼9.6 Hz, H-4),
3.38e3.44 (m, 4H, H-6, and CH3 OMe), 3.50 (dd, 1H, J¼3.6, 9.2 Hz,
H-2), 3.72 (m, 1H, H-5), 3.96 (t,1H, J¼9.2 Hz, H-3), 4.11 (dd, 1H,
J¼4.8, 10.0 Hz, H-6), 4.55 (d, 1H, J¼4.0 Hz, H-1), 4.60 (d, 1H,
J¼6.0 Hz, CHH methylene), 4.65 (d, 1H, J¼12.0 Hz, CHH Bn),
4.80e4.89 (m, 2H, 2ꢂCHH Bn), 4.87 (d, 1H, J¼11.2 Hz, CHH Bn), 5.07
(d, 1H, J¼6.4 Hz, CHH methylene), 7.24e7.35 (m, 10H, H arom); 13C
4.1.5. Methyl
-glucopyranoside (10). Method I: A solution of methyl 2,3,6-tri-
O-benzyl- -glucopyranoside 9 (0.553 g, 1.2 mmol) and ((meth-
ylsulfonylethoxy)methyl)methylsulfane (0.330 g, 1.8 mmol,
2,3,6-tri-O-benzyl-4-O-methylsulfonylethoxymethyl-
a-D
NMR (100 MHz, CDCl3)
d
¼55.3 (CH3 OMe), 62.4 (C-5), 68.8 (C-6),
a
-D
73.6 (CH2 Bn), 75.2 (CH2 Bn), 78.5 (C-3), 79.3 (C-2), 82.0 (C-4), 93.7
(CH2 methylene), 99.1 (C-1), 125.8e130.2 (CH arom), 138.0 (Cq Bn),
138.7 (Cq Bn); HRMS [MþNH4]þ calculated for C22H30O6N
404.2068, found 404.2067.
4
1.5 equiv) in DCM (24 mL, 0.05 M) was stirred over activated MS 3 Å
for 30 min before N-iodosuccinimide (0.320 g, 1.435 mmol,
1.2 equiv) was added. The mixture was cooled to ꢀ20 ꢁC followed
by the addition of trimethylsilyltrifluoromethanesulfonate (10% in
DCM, 0.43 mL, 0.239 mmol, 0.2 equiv). The mixture was stirred for
2 h. The reaction mixture was quenched with triethylamine
4.1.7. Methyl
2,3,6-tri-O-benzyl-4-O-methylthiomethyl-a-D-gluco-
pyranoside (12). To a solution of methyl 2,3,6-tri-O-benzyl-
a-D-
glucopyranoside 9 (0.907 g, 2.1 mmol) in DMF (4.2 mL, 0.05 M) was
added methylthiomethyl chloride (0.43 mL, 5.2 mmol, 2.5 equiv).
The reaction mixture was brought to 0 ꢁC before sodium hydride
(60% in oil, 0.150 g, 3.75 mmol, 1.8 equiv) was added in small por-
tions and the stirring was continued for 1 h. The reaction mixture
was diluted with diethyl ether and washed with NH4Cl(aq), NaHCO3
(aq) and brine, dried over MgSO4, filtered, concentrated, and purified
by silica gel chromatography to provide compound 12 (0.802 g,
(5 equiv), filtered, diluted with DCM, and washed with Na2S2O3(aq)
.
The aqueous layer was extracted with DCM thrice, the combined
organic layers were dried over MgSO4, filtered, concentrated, and
purified by silica gel column chromatography to afford 10 (0.530 g,
0.74 mmol, 70%).
Method II: A solution of methyl 2,3,6-tri-O-benzyl-4-O-methyl-
thiomethyl-a-D-glucopyranoside 12 (0.160 g, 0.31 mmol) and
methylsulfonylethanol (0.095 g, 0.77 mmol, 2.5 equiv) in DCM
(3 mL, 0.1 M) was stirred over activated MS 3 Å for 30 min before N-
iodosuccinimide (0.102 g, 0.48 mmol, 1.5 equiv) was added. The
mixture was cooled to ꢀ20 ꢁC followed by the addition of triflic acid
(1% in DCM, 0.4 mL, 0.045 mmol, 0.14 equiv). The mixture was
allowed to warm to room temperature. The reaction mixture was
quenched with triethylamine (5 equiv), filtered, diluted with DCM,
and washed with Na2S2O3(aq). The aqueous layer was extracted with
DCM thrice, the combined organic layers were dried over MgSO4,
filtered, concentrated, and purified by silica gel column chroma-
tography to provide 10 (0.062 g, 0.10 mmol, 32%) and 11 (0.029 g,
0.08 mmol, 25%).
1.5 mmol, 73%). TLC (50% toluene in EtOAc): Rf¼0.8; [
a
]
22 þ178.0 (c
D
0.3, DCM); IR (neat, cmꢀ1): 530, 1049; 1H NMR (400 MHz, CDCl3)
d
¼1.99 (s, 3H, CH3 MTM), 3.38 (s, 3H, CH3 OMe), 3.52 (dd, 1H, J¼3.6,
9.6 Hz, H-2), 3.57 (t, 1H, J¼10.0 Hz, H-4), 3.64e3.74 (m, 3H, H-5, and
2ꢂH-6), 3.94 (t, 1H, J¼9.2 Hz, H-3), 4.56 (m, 2H, 2ꢂCHH Bn),
4.60e4.62 (m, 2H, H-1, and CHH Bn), 4.68 (d, 1H, J¼10.8 Hz, CHH
MeSCHHe), 4.74e4.78 (m, 3H, CHH MeSCHHe, and 2ꢂCHH Bn),
4.97 (d, 1H, J¼10.8 Hz, CHH Bn), 7.24e7.37 (m, 15H, H arom); 13C
NMR (100 MHz, CDCl3)
d
¼14.7 (CH3 MTM), 55.2 (CH3 OMe), 68.8
(C-6), 69.7 (C-5), 73.3 (CH2 Bn), 73.4 (CH2 Bn), 75.6 (CH2 Bn), 76.1
(C-4), 76.7 (CH2 MeSCH2e), 79.9 (C-2), 81.8 (C-3), 97.9 (C-1),
127.6e128.4 (CH arom), 138.0 (Cq Bn), 138.0 (Cq Bn), 138.5 (Cq Bn);
HRMS [MþNa]þ calculated for C30H36O6S1Na 574.2125, found
574.2120.
Method III: A solution of methyl 2,3,6-tri-O-benzyl-4-O-methy-
lthiomethyl-a-D-glucopyranoside 12 (0.200 g, 0.381 mmol) and
methylsulfonylethanol (0.118 g, 0.95 mmol, 2.5 equiv) in DCM
(7.6 mL, 0.1 M) was stirred over activated MS 3 Å for 30 min before
iodonium di-sym-collidine perchlorate (IDCP, 0.712 g, 1.524 mmol,
4 equiv) was added in dark. The mixture was stirred in the dark for
24 h. The reaction mixture was quenched with NH4Cl (aq), filtered,
diluted with DCM, and washed with Na2S2O3(aq). The aqueous layer
was extracted with DCM thrice, the combined organic layers were
washed with NH4Cl(aq), NaHCO3(aq) and brine, dried over MgSO4,
4.1.8. Methyl 2,3,4-tri-O-benzyl-
Msem from 8). Method I: To a solution of 8 (24 mg, 40
(0.8 mL, 0.05 M) was added DBU (1 M in DMF, 80
a
-
D
-glucopyranoside (7) (cleavage of
mol) in DMF
l, 80 mol,
m
m
m
2 equiv) and the reaction mixture was heated at 100 ꢁC for 3 h. The
reaction mixture was neutralized with NH4Cl(aq), diluted with
EtOAc, washed with NH4Cl(aq), NaHCO3(aq) and brine, dried over
MgSO4, filtered, and concentrated. The crude product was purified

A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
6127
by silica gel column chromatography to afford methyl 2,3,6-tri-O-
benzyl- -glucopyranoside 7 (17 mg, 36 mol, 91%).
Method II: To a solution of 8 (35 mg, 58 mol) in DMF (1.2 mL,
0.05 M) was added thiophenol (0.2 M in DMF, 0.32 mL, 64 mol,
1.1 equiv) and DBU (1 M in DMF, 116 l, 116 mol, 2 equiv) and the
1134, 1267, 1752; 1H NMR (400 MHz, CDCl3)
d
¼2.75 (s, 3H, CH3
a
-
D
m
Msc), 3.15e3.20 (m, 1H, CHH MeSO2CHHCH2e), 3.24e3.31 (m, 1H,
CHH MeSO2CHHCH2Oe), 3.48 (m, 1H, H-5), 3.90 (t, 1H, J¼10.4 Hz,
H-6), 4.24 (t, 1H, J¼9.6 Hz, H-4), 4.30 (dd, 1H, J¼4.8, 10.4 Hz, H-6),
m
m
m
m
4.36 (d, 1H, J¼2.8 Hz, H-2), 4.48 (t, 2H, J¼6.4 Hz, CH2 MeSO2
-
reaction mixture was heated at 100 ꢁC for 20 h. The reaction mix-
ture was neutralized with NH4Cl(aq), diluted with EtOAc, washed
with NH4Cl(aq), NaHCO3(aq) and brine, dried over MgSO4, filtered,
and concentrated. The crude product was purified by silica gel
CH2CH2e), 4.79 (d, 1H, J¼11.2 Hz, CHH Bn), 4.85 (d, 1H, J¼11.2 Hz,
CHH Bn), 4.93e4.97 (m, 2H, H-1, and H-3), 5.53 (s, 1H, CH benzy-
lidene), 7.24e7.42 (m, 15H, H arom); 13C NMR (100 MHz, CDCl3)
d
¼42.3 (CH3 Msc), 53.4 (CH2 MeSO2CH2CH2Oe), 61.5 (CH2 MeSO2
-
column chromatography to afford methyl 2,3,6-tri-O-benzyl-
glucopyranoside 7 (25 mg, 54 mol, 93%).
Method III: To a solution of 8 (24 mg, 40
a-
D-
CH2CH2Oe), 68.2 (C-6), 71.3 (C-5), 75.2 (C-4), 76.4 (CH2 Bn), 77.7 (C-
3), 78.1 (C-2), 88.6 (C-1), 101.7 (CH benzylidene), 126e134.0 (CH
arom), 134.0 (Cq SPh), 136.9, 137.1 (Cq benzylidene and Cq Bn); CH
m
mmol) in MeOH (0.8 mL,
0.05 M) was added KOtBu (23 mg, 0.2 mmol, 5 equiv) and the re-
action mixture was heated at 40 ꢁC for 24 h. The reaction mixture
was neutralized with NH4Cl(aq), diluted with EtOAc, washed with
NH4Cl(aq), NaHCO3(aq) and brine, dried over MgSO4, filtered, and
concentrated. The crude product was purified by silica gel column
Gated NMR (100 MHz, CDCl3)
d
¼88.6 (J¼154 Hz, C-1); HRMS
[MþNa]þ calculated for C30H32O9S2Na 623.1380, found 623.1378.
4.1.11. Phenyl 4,6-O-benzylidene-3-O-methylsulfonylethoxymethyl-
1-thio-b-
D-mannopyranoside (15). To a solution of phenyl 4,6-O-
chromatography to afford methyl 2,3,6-tri-O-benzyl-
anoside 7 (16 mg, 35 mol, 89%).
Method IV: To a solution of 8 (34 mg, 57
0.05 M) was added TBAF (0.1 M in THF, 57
and the reaction mixture was stirred for 24 h. The reaction mixture
was neutralized with NH4Cl(aq), diluted with EtOAc, washed with
NH4Cl(aq), NaHCO3(aq) and brine, dried over MgSO4, filtered, and
concentrated. The crude product was purified by silica gel column
a
-
D
-glucopyr-
benzylidene-1-thio-b-D
-mannopyranoside (13) (3.0 g, 8.3 mmol) in
m
toluene (55 mL, 0.15 M) was added dibutyltin oxide (2.18 g,
8.77 mmol, 1.05 equiv) and the reaction mixture was refluxed for
2 h. The solvents were evaporated and the residue was co-evapo-
rated with toluene. The mixture was re-dissolved in toluene
(55 mL) followed by the addition of tetrabutylammonium bromide
(3.23 g, 10 mmol, 1.2 equiv), cesium fluoride (1.51 g, 10 mmol,
1.2 equiv), and methylsulfonylethoxymethyl chloride (1.86 g,
10.8 mmol, 1.3 equiv) and stirring was continued for 18 h. The re-
m
m
mol) in THF (1.1 mL,
l, 5.7 mol, 0.1 equiv)
m
chromatography to afford methyl 2,3,6-tri-O-benzyl-a-D-glucopyr-
anoside 7 (25 mg, 53 mol, 94%).
m
action mixture was diluted with EtOAc, washed with NaHCO3(aq),
and extracted thrice with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered, concentrated, and
purified by silica gel chromatography to provide 15 (3.48 g,
4.1.9. Phenyl 2-O-benzyl-4,6-O-benzylidene-1-thio-
anoside (14a). To a solution of phenyl 4,6-O-benzylidene-1-thio-
-mannopyranoside (13) (0.355 g, 1.0 mmol) in DCM (13 mL,
b-D-mannopyr-
b
-
D
6.85 mmol, 82%); TLC (66% EtOAc in PE): Rf¼0.4; [
a
]
22 ꢀ225.0 (c 1,
D
0.08 M) was added benzyl bromide (0.14 mL, 1.18 mmol, 1.2 equiv),
tetrabutylammonium sulfonate (0.067 g, 0.20 mmol, 0.2 equiv),
and NaOH(aq) (1 M, 5 mL, 5.0 mmol, 5 equiv). The reaction mixture
was refluxed at 40 ꢁC for 18 h. The reaction mixture was quenched
with NH4Cl(aq), diluted with EtOAc, and extracted thrice with EtOAc.
The combined organic layers were washed with NH4Cl(aq), NaHCO3
(aq) and brine, dried over MgSO4, filtered, concentrated, and purified
by silica gel chromatography to provide 14a (0.196 g, 0.44 mmol,
44%), 14b (0.071 g, 0.16 mmol, 16%), and 14c (0.058 g, 0.11 mmol,
DCM); IR (neat, cmꢀ1): 696, 732, 1020, 1310; 1H NMR (400 MHz,
CDCl3)
d
¼2.83 (s, 3H, CH3 Msem), 2.95e3.01 (m, 1H, CHH MeSO2
-
CHHCH2OCH2e), 3.10e3.17 (m, 1H, CHH MeSO2CHHCH2OCH2e),
3.32 (d,1H, J¼2.8 Hz, 2-OH), 3.45 (m,1H, H-5), 3.85e3.93 (m, 3H, H-
3, H-6, and CHH MeSO2CH2CHHOCH2e), 3.98e4.04 (m, 1H, CHH
MeSO2CH2CHHOCH2e), 4.10 (t, 1H, J¼9.6 Hz, H-4), 4.29 (dd, 1H,
J¼4.8, 10.4 Hz, H-6), 4.34 (br s, 1H, H-2), 4.80 (d, 1H, J¼7.2 Hz, CHH
MeSO2(CH2)2CHHOe), 4.86 (d, 1H, J¼7.2 Hz, CHH MeSO2(-
CH2)2CHHOe), 4.95 (s, 1H, H-1), 5.53 (s, 1H, CH benzylidene),
11%); compound 14a: TLC (33% Et2O in PE): Rf¼0.25; [
a]
22 ꢀ21.2 (c 1,
7.22e7.42 (m, 10H, H arom); 13C NMR (100 MHz, CDCl3)
(CH3 Msem), 54.5 (CH2 MeSO2CH2CH2OCH2e), 61.5 (CH2 MeSO2
d
¼42.6
D
DCM); IR (neat, cmꢀ1): 695, 731, 1047, 1089, 2360; 1H NMR
-
(400 MHz, CDCl3)
d
¼2.56 (s,1H, OH-3), 3.37 (m,1H, H-5), 3.82e3.90
CH2CH2OCH2e), 68.2 (C-6), 71.1 (C-5), 71.3 (C-2), 76.0 (C-3), 77.0
(C-4), 87.8 (C-1), 94.5 (CH2 MeSO2(CH2)2OCH2e), 101.6 (CH benzy-
lidene), 125.9e130.9 (CH arom), 134.2 (Cq SPh), 137.1 (Cq benzyli-
(m, H-3, and H-6), 3.97 (t, 1H, J¼9.6 Hz, H-4), 4.08 (d, 1H, J¼2.4 Hz,
H-2), 4.29 (dd, 1H, J¼5.2, 10.8 Hz, H-6), 4.85 (d, 1H, J¼1.2 Hz, H-1),
4.85e4.97 (m, 2H, 2ꢂCHH Bn), 5.53 (s, 1H, CH benzylidene),
dene); CH Gated NMR (100 MHz, CDCl3)
d
¼87.8 (J¼152 Hz, C-1);
7.24e7.37 (m, 15H, H arom); 13C NMR (100 MHz, CDCl3)
d¼68.3 (C-
HRMS [MþNa]þ calculated for C23H28O8S2Na 519.1118, found
6), 71.2 (C-5), 72.8 (C-3), 76.6 (CH2 Bn), 78.6 (C-4), 80.5 (C-2), 88.8
(C-1), 102.0 (CH benzylidene), 126.1e131.1 (CH arom), 134.7 (Cq
SPh), 137.1, 137.8 (Cq CHPh and Cq Bn); CH Gated NMR (100 MHz,
519.1114.
4.1.12. Phenyl
thoxymethyl-1-thio-
phenyl 4,6-O-benzylidene-3-methylsulfonylethoxymethyl-1-thio-
-mannopyranoside (15) (3.3 g, 6.65 mmol) in DMF (33 mL,
2-O-benzyl-4,6-O-benzylidene-3-O-methylsulfonyle
CDCl3)
d
¼88.8 (J¼153 Hz, C-1); HRMS [MþNa]þ calculated for
b-
D
-mannopyranoside (17). To solution of
a
C26H26O5S1Na 473.1393, found 473.1390.
b-D
4.1.10. Phenyl 2-O-benzyl-4,6-O-benzylidene-3-O-methylsulfonyleth
0.2 M) was added benzyl bromide (2 mL, 17.0 mmol, 2.5 equiv)
and tetrabutylammonium iodide (2.46 g, 6.65 mmol, 1 equiv). The
reaction mixture was brought to 0 ꢁC and sodium hydride (60%,
0.266 g, 6.65 mmol, 1 equiv) was subsequently added in small
portions. The reaction mixture was allowed to warm to rt and
stirring was continued for 2 h. The reaction mixture was
oxycarbonyl-1-thio-
2-O-benzyl-4,6-O-benzylidene-1-thio-
(0.140 g, 0.31 mmol) in DCM (1.5 mL, 0.2 M) was cooled to 0 ꢁC
before pyridine (75 l, 0.93 mmol, 3 equiv) was added. Methyl-
b
-D-mannopyranoside (16). A solution of phenyl
b-D-mannopyranoside 14a
m
sulfonylethoxycarbonyl chloride (Msc-Cl, in 0.5 mL DCM, 0.116 g,
0.62 mmol, 2 equiv) was added drop wise at 0 ꢁC over the span of
30 min. The mixture was allowed to warm to room temperature.
The reaction mixture was quenched with methanol, diluted with
DCM, washed with NaHCO3(aq) and brine, dried over MgSO4, fil-
tered, concentrated, and purified by silica gel column chromatog-
raphy to afford 16 (0.182 g, 0.303 mmol, 97%); TLC (50% EtOAc in
quenched with NH4Cl(aq)
, diluted with EtOAc, washed with
NH4Cl(aq), NaHCO3(aq),brine, dried over MgSO4, filtered, concen-
trated and purified by silica gel chromatography to provide 17
22
(2.91 g, 4.97 mmol, 75%); TLC (50% EtOAc in PE): Rf¼0.6; [
a]
D
ꢀ30.2 (c 1, DCM); IR (neat, cmꢀ1): 738, 1089, 1282; 1H NMR
(400 MHz, CDCl3)
d
¼2.76 (s, 3H, CH3 Msem), 2.83e2.89 (m, 1H,
PE): Rf¼0.2; [
a
]
22 ꢀ42.2 (c 1, DCM); IR (neat, cmꢀ1): 523, 630, 699,
CHH
MeSO2CHHCH2OCH2e),
3.02e3.09
(m, 1H,
CHH
D

6128
A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
MeSO2CHHCH2OCH2e), 3.42 (m, 1H, H-5), 3.80e3.96 (m, 4H, H-3,
H-6, and CH2 MeSO2CH2CH2OCH2e), 4.16e4.20 (m, 2H, H-2, and
H-4), 4.27 (dd, 1H, J¼4.8, 10.4 Hz, H-6), 4.71 (d, 1H, J¼6.8 Hz, CHH
(100 MHz, CDCl3)
d
¼99.69 (J¼173 Hz), 99.71 (J¼177 Hz); HRMS
[MþNa]þ calculated for C45H52O14SNa 871.2970, found 871.2954.
22
MeSO2(CH2)2OCHHe), 4.79 (d, 1H, J¼6.8 Hz, CHH MeSO2(CH2)2
4.1.14.2.
b
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.4; [
a]
D
-
OCHHe), 4.82 (d, 1H, J¼11.2 Hz, CHH Bn), 4.91 (s, 1H, H-1), 4.99 (d,
1H, J¼10.8 Hz, CHH Bn), 5.53 (s, 1H, CH benzylidene), 7.22e7.50
ꢀ68.4 (c 1.0, DCM); IR (neat, cmꢀ1): 750, 1088; 1H NMR (400 MHz,
CDCl3)
d
¼2.74 (s, 3H, CH3 Msem), 2.82 (dt, 1H, J¼4.8, 15.2 Hz,
(m, 15H, H arom); 13C NMR (100 MHz, CDCl3)
d
¼42.5 (CH3 Msem),
MeSO2CHHCH2OCH2e), 3.01e3.08 (m, 1H, MeSO2CHHCH2OCH2e),
3.14 (m, 1H, H-50), 3.38 (CH3 OMe), 3.61 (dd, 1H, J¼3.2, 9.6 Hz, H-30),
54.4 (CH2 MeSO2CH2CH2OCH2e), 61.4 (CH2 MeSO2CH2CH2OCH2e),
68.1 (C-6), 71.4 (C-5), 75.8 (CH2 Bn), 76.4 (C-3), 77.5, 78.7 (C-2 and
C-4), 88.7 (C-1), 94.0 (CH2 MeSO2(CH2)2OCH2e), 101.4 (CH ben-
zylidene), 125.9e131.1 (CH arom), 134.5 (Cq SPh), 137.2, 137.5 (Cq
3.69e3.92 (m, 7H, H-2, H-20, H-5, H-6, H-60, and MeSO2
-
CH2CH2OCH2e), 4.05 (t, 1H, J¼9.6 Hz, H-40), 4.17e4.22 (m, 2H, H-4,
and H-60), 4.27 (dd, 1H, J¼4.4, 9.6 Hz, H-6), 4.33 (dd, 1H, J¼3.2,
10.4 Hz, H-3), 4.47 (s, 1H, H-10), 4.56 (d, 1H, J¼7.2 Hz,
MeSO2(CH2)2OCHHe), 4.66e4.76 (m, 4H, 3ꢂCHH Bn, and
MeSO2(CH2)2OCHHe), 4.80 (s, 1H, H-1), 4.96 (d, 1H, J¼12.0 Hz, CHH
Bn), 5.46 (s, 1H, CH benzylidene), 5.63 (s, 1H, CH benzylidene),
benzylidene and Cq Bn); CH Gated NMR (100 MHz, CDCl3)
d¼88.7
(J¼153 Hz, C-1); HRMS [MþNa]þ calculated for C30H34O8S2Na
609.1587, found 609.1585.
4.1.13. Methyl 2-O-benzyl-4,6-O-benzylidene-3-O-(2-O-benzyl-4,6-
7.19e7.51 (m, 20H, H arom); 13C NMR (100 MHz, CDCl3)
d¼42.6
O-benzylidene-3-O-methylsulfonylethoxy
carbonyl-
D
-mannopyr-
(CH3 Msem), 54.7 (MeSO2CH2CH2OCH2e), 54.9 (CH3 OMe), 61.2
(MeSO2CH2CH2OCH2e), 64.0 (C-2, C-20 or C-5), 67.6 (C-50), 68.5 (C-
60), 68.8 (C-6), 73.1 (CH2 Bn), 73.6 (C-3), 74.6 (CH2 Bn), 74.8 (C-30),
75.2 (C-2, C-20 or C-5) 76.0 (C-2, C-20 or C-5), 77.4 (C-40), 77.6(C-4),
93.9 (MeSO2(CH2)2OCH2e), 99.1 (C-10), 99.5 (C-1), 101.6 (CH ben-
zylidene), 101.6 (CH benzylidene), 126.0e129.1 (CH arom), 137.4,
137.5, 137.8, 138.4 (2ꢂCq benzylidene and 2ꢂCq Bn); CH Gated NMR
anosyl)- -mannopyranoside (19). Disaccharide 19 (0.178 g,
a-D
0.21 mmol) was prepared in 78% yield from donor 16 (0.160 g,
0.27 mmol, 1 equiv) and acceptor 18 (148 g, 40 mmol, 1.5 equiv)
according to the general procedure for glycosylations described
22
above. TLC (33% toluene in EtOAc): Rf¼0.6; [
a
]
ꢀ8.0 (c 0.5); IR
(neat, cmꢀ1): 697, 734, 1020, 1066, 1108, 1829; 1DH NMR (500 MHz,
CDCl3)
d
¼2.79 (s, 3H, CH3 Msem), 3.18e3.22 (m, 1H, MeSO2
(100 MHz, CDCl3)
d
¼99.1 (J¼155 Hz, C-10), 99.5 (J¼172 Hz, C-1);
-
CHHCH2Oe), 3.27e3.33 (m,1H, MeSO2CHHCH2Oe), 3.38 (s, 3H, CH3
OMe), 3.80e3.90 (m, 5H, H-2, H-5, H-50, H-6, and H-60), 4.05 (m, 1H,
H-20), 4.08e4.16 (m, 2H, H-40, CHH Bn), 4.20e4.29 (m, 5H, H-3, H-4,
H-6, H-60, and CHH Bn), 4.37 (d, 1H, J¼12.0 Hz, CHH Bn), 4.48 (m,
2H, MeSO2CH2 CH2Oe), 4.76 (d, 1H, J¼1.5 Hz, H-1), 4.79 (s, 2H, H-10,
CHH Bn), 5.17 (dd, 1H, J¼3.5, 10.5 Hz, H-30), 5.53 (s, 1H, CH benzy-
lidene), 5.61 (s, 1H, CH benzylidene), 7.0e7.5 (m, 20H, H arom); 13C
HRMS [MþNa]þ calculated for C45H52O14SNa 871.2970, found
871.2967.
4.1.15. Methyl
dene-3-O-methylsulfonylethoxymethyl-
copyranoside (24). Disaccharide 24 (0.171 g, 0.18 mmol,
2,3,4-tri-O-benzyl-6-O-(2-O-benzyl-4,6-O-benzyli-
-mannopyranosyl)- -glu-
¼4:5)
D
a-D
a/b
was prepared in 74% yield from donor 17 (0.147 g, 0.25 mmol,
1 equiv) and acceptor 7 (0.174 g, 0.38 mmol, 1.5 equiv) according to
the general procedure for glycosylations described above.
NMR (125 MHz, CDCl3)
d
¼42.4 (CH3 Msem), 53.7 (MeSO2
-
CH2CH2Oe), 55.0 (CH3 OMe), 61.4 (MeSO2CH2CH2Oe), 63.8, 64.4,
77.3 (C-2, C-5, and C-50), 68.7, 68.9 (C-6 and C-60), 72.6 (CH2 Bn),
73.5 (CH2 Bn), 73.8, 79.3 (C-3 and C-4), 75.4 (C-30), 75.7 (C-20), 76.0
(C-40), 99.2, (C-10), 100.1, (C-1), 101.9 (CH benzylidene), 102.1 (CH
benzylidene), 126.2e129.7 (CH arom), 137.2, 137.3, 137.5 (2ꢂCq
benzylidene, and 2ꢂCq Bn), 153.5 (C]O Msc); CH Gated NMR
22
4.1.15.1.
a
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.65; [
a]
D
þ52.2 (c 0.5, DCM); IR (neat, cmꢀ1): 697, 1027; 1H NMR (400 MHz,
CDCl3)
d
¼2.74 (s, 3H, CH3 Msem), 2.77e2.83 (m, 1H, MeSO2
-
CHHCH2OCH2e), 2.98e3.05 (m, 1H, MeSO2CHHCH2OCH2e), 3.36 (s,
3H, CH3 OMe), 3.48 (t, 1H, J¼9.2 Hz, H-4), 3.51 (dd, 1H, J¼3.6,
10.0 Hz, H-2), 3.65 (dd, 1H, J¼1.6, 11.2 Hz, H-6), 3.71 (m, 1H, H-5),
(125 MHz, CDCl3)
d
¼99.2 (J¼170 Hz, C-10), 100.1 (J¼182 Hz, C-1).
HRMS [MþNa]þ calculated for C45H50O15SNa 885.2763, found
885.2768.
3.80e3.90 (m, 6H, H-6, H-20, H-50, H-60, and MeSO2
-
CH2CH2OCH2Oe), 3.98e4.04 (m, 2H, H-3, and H-40), 4.10e4.16 (m,
2H, H-6, and H-30), 4.57 (d,1H, J¼3.6 Hz, H-1), 4.60 (d,1H, J¼11.2 Hz,
CHH Bn), 4.68e4.72 (m, 4H, 3ꢂCHH Bn, and MeSO2(CH2)2OCHHe),
4.75e4.82 (m, 3H, 2ꢂCHH Bn, and MeSO2(CH2)2OCHHe), 4.90 (d,
1H, J¼1.2 Hz, H-10), 4.93 (d, 1H, J¼11.2 Hz, CHH Bn), 5.00 (d, 1H,
J¼10.4 Hz, CHH Bn), 5.55 (s, 1H, CH benzylidene), 7.25e7.42 (m,
4.1.14. Methyl 2-O-benzyl-4,6-O-benzylidene-3-O-(2-O-benzyl-4,6-
O-benzylidene-3-O-methylsulfonylethoxymethyl-
anosyl)- -mannopyranoside (20). Disaccharide 20 (0.317 g,
0.37 mmol,
D-mannopyr-
a-D
a
/
b
¼1:5) was prepared in 84% yield from donor 17
(0.26 g, 0.44 mmol, 1 equiv) and acceptor 18 (0.248 g, 0.67 mmol,
1.5 equiv) according to the general procedure for glycosylations
described above.
25H, H arom); 13C NMR (100 MHz, CDCl3)
d
¼42.8 (CH3 Msem), 54.8
(MeSO2CH2CH2OCH2e), 55.2 (CH3 OMe), 61.6 (MeSO2
-
CH2CH2OCH2e), 64.3 (C-5), 66.2 (C-60), 68.7 (C-6), 69.7 (C-20or C-
50), 73.3 (CH2 Bn), 73.4 (CH2 Bn), 73.6 (C-3 or C-40), 74.9 (CH2 Bn),
75.9 (CH2 Bn), 76.6 (C-20 or C-50), 77.4 (C-4), 78.1 (C-30), 80.0 (C-2),
82.0 (C-3 or C-40), 94.7 (MeSO2(CH2)2OCH2e), 98.0 (C-1), 99.2 (C-
10), 100.8 (CH benzylidene), 126.1e129.1 (CH arom), 137.5, 137.8,
138.0, 138.1, 138.4 (Cq benzylidene and 4ꢂCq Bn); CH Gated NMR
22
4.1.14.1.
a
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.66; [
a]
D
ꢀ2.5 (c 0.4, DCM); IR (neat, cmꢀ1): 698, 1067; 1H NMR (400 MHz,
CDCl3)
d
¼2.64 (s, 3H, CH3 Msem), 2.70e2.77 (m, 1H, MeSO2
-
CHHCH2OCH2e), 2.95 (m, 1H, MeSO2CHHCH2OCH2e), 3.38 (s, 3H,
CH3 OMe), 3.78e3.89 (m, 8H), 4.05e4.16 (m, 3H) 4.18e4.29 (m, 4H),
4.42 (d, 1H, J¼12.4 Hz, CHH Bn), 4.59 (d, 1H, J¼7.2 Hz,
MeSO2(CH2)2OCHHe), 4.70e4.77 (m, 4H, H-10, 2ꢂCHH Bn, and
MeSO2(CH2)2OCHHe), 5.34 (s, 1H, H-1), 5.57 (s, 1H, CH benzyli-
dene), 5.64 (s,1H, CH benzylidene), 7.02e7.53 (m, 20H, H arom); 13C
(100 MHz, CDCl3)
d
¼97.9 (J¼166 Hz, C-1), 99.2 (J¼170 Hz, C-10);
HRMS [MþNa]þ calculated for C52H60O14SNa 963.3596, found
963.3595.
22
NMR (100 MHz, CDCl3)
d
¼42.7 (CH3 Msem), 54.8 (MeSO2
4.1.15.2.
b
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.4; [
a]
D
-
CH2CH2OCH2e), 55.0 (CH3 OMe), 61.6 (MeSO2CH2CH2OCH2e), 63.9,
64.8, 72.9, 73.9, 76.3, 77.7, 78.1, 79.2 (C-2, C-3, C-4, C-5, C-20, C-30, C-
40, and C-50), 68.8, 68.9 (C-6 and C-60), 72.5 (CH2 Bn), 73.2 (CH2 Bn),
94.6 (MeSO2(CH2)2OCH2e), 99.69 (C-1 and C-10), 101.8 (CH benzy-
lidene), 102.2 (CH benzylidene), 125.3e129.3 (CH arom), 137.5,
137.6, 137.6 (2ꢂCq benzylidene and 2ꢂCq Bn); CH Gated NMR
þ1.5 (c 0.5, DCM); IR (neat, cmꢀ1): 696, 1026; 1H NMR (400 MHz,
CDCl3)
d
¼2.73 (s, 3H, CH3 Msem), 2.79e2.85 (m, 1H, MeSO2
-
CHHCH2OCH2e), 3.01e3.08 (m, 1H, MeSO2CHHCH2OCH2e), 3.29
(m, 1H, H-50), 3.36 (s, 3H, CH3 OMe), 3.45 (t, 1H, J¼9.6 Hz, H-4),
3.50 (dd, 1H, J¼3.6, 9.6 Hz, H-2), 3.55 (dd, 1H, J¼5.2, 10.4 Hz, H-6),
3.70 (dd, 1H, J¼3.2, 10.0 Hz, H-30), 3.74e3.87 (m, 4H, H-5, H-20,

A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
6129
and MeSO2CH2CH2OCH2e), 3.90 (t, 1H, J¼10.0 Hz, H-60), 4.01e4.10
(m, 2H, H-3, and H-40), 4.14 (dd, 1H, J¼1.6, 10.4 Hz, H-6), 4.28 (dd,
1H, J¼4.8, 10.4 Hz, H-6), 4.31 (s, 1H, H-10), 4.51 (d, 1H, J¼7.2 Hz,
MeSO2(CH2)2OCHHOe) 4.54e4.60 (m, 2H, H-1, CHH Bn),
4.64e4.69 (m, 2H, CHH Bn, and MeSO2(CH2)2OCHHOe), 4.73 (d,
1H, J¼12.4 Hz, CHH Bn), 4.79 (d, 1H, J¼12.4 Hz, CHH Bn), 4.83
(d, 1H, J¼11.2 Hz, CHH Bn), 4.87 (d, 1H, J¼11.6 Hz, CHH Bn), 4.92
(d, 1H, J¼12.0 Hz, CHH Bn), 5.01 (d, 1H, J¼10.8 Hz, CHH Bn), 5.53
(s, 1H, CH benzylidene), 7.23e7.44 (m, 25H, H arom); 13C NMR
4.1.17. Methyl 2-deoxy-3,6-di-O-benzyl-2-(N-carboxybenzyl)-amino-
4-O-(2-O-benzyl-4,6-O-benzylidene-3-O-methylsulfonylethox-
ymethyl-
D-mannopyranosyl)-a-D-glucopyranoside (26). Disacchar-
ide 26 (0.177 g, 0.19 mmol,
a
/
b
¼1:1) was prepared in 78% yield
from donor 17 (0.142 g, 0.24 mmol, 1 equiv) and acceptor 21
(0.168 g, 0.36 mmol, 1.5 equiv) according to the general procedure
for glycosylations described above.
22
4.1.17.1.
a
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.5; [
a]
D
(100 MHz, CDCl3)
d
¼42.6 (CH3 Msem), 54.7 (MeSO2
þ58.4 (c 0.5, DCM); IR (neat, cmꢀ1): 733, 1311, 1717; 1H NMR
-
CH2CH2OCH2e), 55.1 (CH3 OMe), 61.2 (MeSO2CH2CH2OCH2e), 67.6
(C-50), 68.5 (C-60), 68.6 (C-6), 69.6 (C-20), 73.3 (CH2 Bn), 74.7 (CH2
Bn), 74.7 (C-30), 74.7 (CH2 Bn), 75.1 (C-5), 75.7 (CH2 Bn), 77.6 (C-4),
77.6 (C-40), 79.8 (C-2), 82.0 (C-3), 93.8 (MeSO2(CH2)2OCH2e), 97.8
(C-1), 101.7 (CH benzylidene), 102.2 (C-10), 126.0e129.2 (CH arom),
137.4, 138.0, 138.2, 138.3, 138.7 (Cq benzylidene and 4ꢂCq Bn); CH
(400 MHz, CDCl3)
d
¼2.78e2.85 (m, 4H, CH3 Msem, and MeSO2
-
CHHCH2OCH2e), 3.03e3.10 (m, 1H, MeSO2CHHCH2OCH2e), 3.37 (s,
3H, CH3 OMe), 3.70e3.83 (m, 6H, H-2, H-4, H-5, H-6, H-60, and (H-6
or H-60)), 3.84e3.89 (m, 3H, H-50, and MeSO2CH2CH2OCH2e), 3.95
(t, 1H, J¼9.2 Hz, H-40), 4.01 (dd, 1H, J¼2.8, 10.0 Hz, H-30), 4.08e4.15
(m, 3H, H-3, H-20, and (H-6 or H-60)), 4.21e4.32 (m, 2H, 2ꢂCHH Bn),
4.55e4.78 (m, 7H, H-1, 4ꢂCHH Bn, and MeSO2(CH2)2OCH2e), 4.92
(d, 1H, J¼10.0 Hz, NH), 4.98e5.05 (m, 2H, 2ꢂCHH Cbz), 5.36 (s, 1H,
H-10), 5.55 (s, 1H, CH benzylidene), 7.12e7.54 (m, 25H, H arom); 13C
Gated NMR (100 MHz, CDCl3)
d
¼97.8 (J¼168 Hz, C-1), 102.2
(J¼156 Hz, C-10); HRMS [MþNa]þ calculated for C52H60O14SNa
963.3596, found 963.3603.
NMR (100 MHz, CDCl3)
(MeSO2CH2CH2OCH2e), 55.3 (CH3 OMe), 61.6 (MeSO2
d
¼42.8 (CH3 Msem), 54.4 (C-20 or C-3), 54.8
4.1.16. Methyl
dene-3-O-methylsulfonylethoxymethyl-
copyranoside (25). Disaccharide 25 (0.135 g, 0.14 mmol,
was prepared in 72% yield from donor 17 (0.117 g, 0.2 mmol,
1 equiv) and acceptor 9 (0.138 g, 0.3 mmol, 1.5 equiv) according to
the general procedure for glycosylations described above.
2,3,6-tri-O-benzyl-4-O-(2-O-benzyl-4,6-O-benzyli-
-mannopyranosyl)- -glu-
¼1:3)
-
D
a
-
D
CH2CH2OCH2e), 67.0 (CH2 Cbz), 68.6, 69.2 (C-6 and C-60), 73.0 (CH2
Bn), 73.6 (CH2 Bn), 73.8 (CH2 Bn), 65.3, 70.5, 73.3, 76.0, 77.4, 78.0,
81.1 (C-2, C-3, C-4, C-5, C-20, C-30, C-40, C-5-) 94.5 (MeSO2(-
CH2)2OCH2e), 99.0 (C-1), 100.4 (C-10), 101.8 (CH benzylidene),
126.2e129.2 (CH arom), 137.6, 137.9, 137.9 (Cq benzylidene and
2ꢂCq Bn), 155.8 (C]O Cbz); CH Gated NMR (100 MHz, CDCl3)
a/b
4.1.16.1.
NMR (400 MHz, CDCl3)
a
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.45; 1H
d
¼99.0 (J¼169 Hz, C-1), 100.4 (J¼174 Hz, C-10); HRMS [MþH]þ
d
¼2.80 (m, 4H, CH3 Msem, and MeSO2
calculated for C53H62NO15S 984.38347, found 984.38438, [MþNa]þ
-
CHHCH2OCH2e), 3.00e3.13 (m, 1H, MeSO2CHHCH2OCH2e), 3.41 (s,
3H, CH3 OMe), 3.55 (m, 1H) 3.76 (m, 6H) 3.84 (m, 4H), 3.98 (m, 2H),
4.09 (m, 1H), 4.20 (d, 1H, J¼12.0 Hz, CHH Bn), 4.25 (d, 1H, J¼12.0 Hz,
CHH Bn), 4.68 (m, 8H, H-1, 5ꢂCHH Bn, and MeSO2(CH2)2OCH2e),
5.17 (d, 1H, J¼12.0 Hz, CHH Bn), 5.41 (s, 1H, H-10), 5.54 (s, 1H, CH
benzylidene), 7.23e7.43 (m, 25H, H arom); 13C NMR (100 MHz,
calculated for C53H61NO15SNa 1006.3654, found 1006.3659.
22
4.1.17.2.
b
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.35; [
a]
D
þ16.4 (c 0.5, DCM); IR (neat, cmꢀ1): 522, 1028, 1717; 1H NMR
(400 MHz, CDCl3)
d
¼2.76 (s, 3H, CH3 Msem), 2.78e2.85 (m, 1H,
MeSO2CHHCH2OCH2e), 3.06e3.15 (m, 2H, MeSO2CHHCH2OCH2e,
and H-50), 3.36 (s, 3H, CH3 OMe), 3.46 (t,1H, J¼10.0 Hz, H-60), 3.53 (t,
1H, J¼9.6 Hz, H-4), 3.59 (dd, 1H, J¼2.8, 10.0 Hz, H-30), 3.65e3.68 (m,
2H, 2ꢂH-6), 3.83 (m, 4H, H-20, H-3, and MeSO2CH2CH2OCH2e),
3.95e4.03 (m, 2H, H-2, and H-40), 4.04e4.12 (m, 2H, H-5, H-60),
4.50e4.59 (m, 4H, H-1, 2ꢂCHH Bn, and MeSO2(CH2)2OCHHe),
4.71e4.74 (m, 3H, H-10, and CHH Bn and MeSO2(CH2)2OCHHe), 4.80
(m, 2H, NH, and CHH Bn), 4.87 (d, 1H, J¼12.0 Hz, CHH Bn), 5.00e5.12
(m, 3H, CHH Bn, and 2ꢂCHH Cbz), 5.45 (s, 1H, CH benzylidene),
CDCl3)
d
¼42.7 (CH3 Msem), 54.8 (MeSO2CH2CH2OCH2e), 55.4 (CH3
OMe), 61.5 (MeSO2CH2CH2OCH2e), 68.6, 69.1 (C-6 and C-60), 73.0
(CH2 Bn), 73.1 (CH2 Bn), 73.6 (CH2 Bn), 74.8 (CH2 Bn), 65.1, 69.6, 73.4,
76.2, 77.5, 77.8, 79.9, 81.6 (C-2, C-3, C-4, C-5, C-20, C-30, C-40, C-50),
94.4 (MeSO2(CH2)2OCH2e), 97.7 (C-1), 100.5 (C-10), 101.8 (CH ben-
zylidene), 126.0e129.1 (CH arom), 137.5, 138.0, 138.3, 138.3, 139.4
(Cq benzylidene and 4ꢂCq Bn); HRMS [MþNa]þ calculated for
C52H60O14SNa 963.3596, found 963.3603.
7.23e7.43 (m, 25H, H arom); 13C NMR (100 MHz, CDCl3)
Msem), 54.6 (MeSO2CH2CH2OCH2e), 55.3 (CH3 OMe), 61.1 (MeSO2
d
¼42.9 (CH3
22
4.1.16.2.
b
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.35; [
a]
D
-
þ7.2 (c 0.5, DCM); IR (neat, cmꢀ1): 696, 1026; 1H NMR (400 MHz,
CH2CH2OCH2e), 66.8 (CH2 Cbz), 67.2 (C-50), 68.5 (C-6 and C-60), 70.5
(C-3), 73.5 (CH2 Bn), 74.3 (CH2 Bn), 75.0 (C-3), 75.1 (CH2 Bn), 75.3
(CH2 Bn), 76.7 (C-20), 77.8 (C-40), 77.9 (C-2 and C-5), 78.5 (C-4), 94.0
(MeSO2(CH2)2OCH2e), 98.9 (C-1), 101.6 (CH benzylidene), 101.8 (C-
10), 126.0e129.2 (CH arom), 137.5, 138.0, 138.3, 138.3, 139.4 (Cq ben-
zylidene and 4ꢂCq Bn), 155.9 (C]O Cbz); CH Gated NMR (100 MHz,
CDCl3)
d
¼2.76 (s, 3H, CH3 Msem), 2.80e2.83 (m, 1H, MeSO2
-
CHHCH2OCH2e), 3.05e3.13 (m, 2H, H-50, and MeSO2
-
CHHCH2OCH2e), 3.41 (s, 3H, CH3 OMe), 3.48e3.58 (m, 3H, H-2, H-
3 and H-60), 3.61e3.68 (m, 3H, H-5, H-6, and H-6), 3.75e3.83 (m,
3H, H-20, and MeSO2CH2CH2OCH2e), 3.87 (t, 1H, J¼9.2 Hz, H-30),
3.94e4.02 (m, 2H, H-4, and H-40), 4.09 (dd, 1H, J¼5.2, 10.8 Hz, H-
60), 4.46 (d, 1H, J¼12.0 Hz, CHH Bn), 4.53e4.57 (m, 2H, H-10, and
MeSO2(CH2)2OCHHe), 4.60e4.85 (m, 8H, H-1, and 6ꢂCHH Bn and
MeSO2(CH2)2OCHHe), 5.05 (d, 1H, J¼10.8 Hz, CHH Bn), 5.46 (s, 1H,
CH benzylidene), 7.23e7.43 (m, 25H, H arom); 13C NMR (100 MHz,
CDCl3)
d
¼98.9 (J¼173 Hz, C-1),101.6 (J¼157 Hz, C-10); HRMS [MþH]þ
calculated for C53H62NO15S 984.3835, found 984.3846; [MþNa]þ
calculated for C53H61NO15SNa 1006.3654, found 1006.3661.
4.1.18. Methyl 3-O-benzyl-4,6-O-benzylidene-2-O-(2-O-benzyl-4,6-
CDCl3)
d
¼42.8 (CH3 Msem), 54.6 (MeSO2CH2CH2OCH2e), 55.4
O-benzylidene-3-O-methylsulfonylethoxymethyl-
anosyl)- -mannopyranoside (27). Disaccharide 27 (0.117 g,
0.14 mmol,
0.19 mmol, 1 equiv) and acceptor 22 (0.107 g, 0.29 mmol, 1.5 equiv)
accordingtothegeneral procedureforglycosylations describedabove.
D-mannopyr-
(CH3 OMe), 61.1 (MeSO2CH2CH2OCH2e), 67.3 (C-50), 68.5, 68.6 (C-6
and C-60), 69.7 (C-5), 73.4 (CH2 Bn), 73.6 (CH2 Bn), 75.0 (C-3), 75.1
(CH2 Bn), 75.3 (CH2 Bn), 76.7 (C-20), 77.4, 77.9 (C-4 and C-40), 79.0
(C-2), 80.3 (C-30), 94.0 (MeSO2(CH2)2OCH2e), 98.4 (C-1), 101.4 (C-
10), 101.6 (CH benzylidene), 126.1e129.2 (CH arom), 137.5, 138.0,
138.3, 138.3, 139.4 (Cq benzylidene and 4ꢂCq Bn); CH Gated NMR
a-D
a
/b
¼1:5)waspreparedin72%yieldfromdonor 17 (0.112 g,
22
4.1.18.1.
a
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.6; [
a]
D
(100 MHz, CDCl3)
d
¼98.4 (J¼170 Hz, C-1), 101.4 (J¼156 Hz, C-10);
ꢀ8.5 (c 0.3, DCM); IR (neat, cmꢀ1): 696, 1040, 1312; 1H NMR
HRMS [MþNa]þ calculated for C52H60O14SNa 963.3596, found
(400 MHz, CDCl3)
d
¼2.81.2.87 (m, 4H, CH3 Msem, and MeSO2
-
963.3603.
CHHCH2OCH2e), 3.04e3.11 (m, 1H, MeSO2CHHCH2OCH2e), 3.37 (s,

6130
A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
3H, CH3 OMe), 3.77e3.94 (m, 7H), 3.98 (dd, 1H, J¼3.2, 10.0 Hz),
4.00e4.17 (m, 4H), 4.27 (m, 2H), 4.42 (d, 1H, J¼12.0 Hz, CHH Bn),
4.51 (d, 1H, J¼12.0 Hz, CHH Bn), 4.67e4.69 (m, 3H, H-1 or H-10, CHH
Bn, and MeSO2(CH2)2OCHHe), 4.81e4.85 (m, 2H, CHH Bn, and
MeSO2(CH2)2OCHHe), 5.33 (d, 1H, J¼0.8 Hz, H-1 or H-10), 5.58 (s,
1H, CH benzylidene), 5.69 (s, 1H, CH benzylidene), 7.23e7.54 (m,
99.4 (C-10), 101.7 (CH benzylidene), 105.2 (C-1), 109.5 (Cq iso-
propylidene), 112.2 (Cq isopropylidene), 125.9e129.2 (CH arom),
137.3, 137.6 (Cq benzylidene and Cq Bn); CH Gated NMR (100 MHz,
CDCl3)
d
¼99.4 (J¼172 Hz, C-10), 105.2 (J¼181 Hz, C-1); HRMS
[MþNa]þ calculated for C36H48O14SNa 759.2657, found 759.2660.
22
20H, H arom); 13C NMR (100 MHz, CDCl3)
(CH3 OMe), 54.9 (MeSO2CH2CH2OCH2e), 61.5 (MeSO2
d
¼42.9 (CH3 Msem), 54.8
4.1.19.2.
b
-Anomer. TLC (50% toluene in EtOAc): Rf¼0.4; [
a]
D
ꢀ43.0 (c 0.5, DCM); IR (neat, cmꢀ1): 697, 733, 1025; 1H NMR
-
CH2CH2OCH2e), 68.6, 68.7 (C-6 and C-60), 63.9, 64.6, 72.6, 75.4,
76.3, 76.5, 78.3, 79.0 (C-2, C-3, C-4, C-5, C-20, C-30, C-40, C-50), 73.0
(CH2 Bn), 73.7 (CH2 Bn), 94.5 (MeSO2(CH2)2OCH2e), 100.3, 101.1 (C-
1 and C-10), 101.4 (CH benzylidene), 101.8 (CH benzylidene),
126.0e129.2 (CH arom), 137.4, 137.5, 137.8, 138.3 (2ꢂCq benzylidene
(400 MHz, CDCl3)
d
¼1.33 (s, 3H, CH3 isopropylidene), 1.34 (s, 3H,
CH3 isopropylidene), 1.44 (s, 3H, CH3 isopropylidene), 1.51 (s, 3H,
CH3 isopropylidene), 2.80 (s, 3H, CH3 Msem), 2.82e2.88 (m, 1H,
MeSO2CHHCH2OCH2e), 3.08e3.15 (m, 1H, MeSO2CHHCH2OCH2e),
3.35 (m, 1H, H-50), 3.73e3.85 (m, 3H, H-30, and MeSO2
-
and 2ꢂCq Bn); CH Gated NMR (100 MHz, CDCl3)
d¼100.3
CH2CH2OCH2e), 3.90e3.96 (m, 2H, H-20, and C-60), 4.05e415 (m,
3H, 2ꢂH-6, and H-40), 4.30e4.32 (m, 3H, H-3, H-4, and H-60), 4.42
(m, 1H, H-5), 4.51 (d, 1H, J¼4.0 Hz, H-2), 4.55 (d, 1H, J¼6.8 Hz,
MeSO2(CH2)2OCHHe), 4.64 (s, 1H, H-10), 4.70e4.74 (m, 2H, CHH Bn,
and MeSO2(CH2)2OCHHe), 4.88 (d, 1H, J¼12.0 Hz, CHH Bn), 5.56 (s,
1H, CH benzylidene), 5.93 (d, 1H, J¼3.6 Hz, H-1), 7.15e7.45 (m, 10H,
(J¼170 Hz), 101.1 (J¼171 Hz); HRMS [MþNa]þ calculated for
C45H52O14SNa 871.2971, found 871.2967.
22
4.1.18.2.
b
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.35; [
a]
D
ꢀ61.8 (c 1.0, DCM); IR (neat, cmꢀ1): 696, 1084, 1312; 1H NMR
(400 MHz, CDCl3)
d
¼2.77 (s, 3H, CH3 Msem), 2.84 (dt, 1H, J¼3.6,
H arom); 13C NMR (100 MHz, CDCl3)
d
¼25.4 (CH3 isopropylidene),
16.4 Hz, MeSO2CHHCH2OCH2e), 3.04e3.11 (m, 1H, MeSO2
26.2 (CH3 isopropylidene), 26.5 (CH3 isopropylidene), 26.6 (CH3
isopropylidene), 42.8 (CH3 Msem), 54.5 (MeSO2CH2CH2OCH2e),
61.0 (MeSO2CH2CH2OCH2e), 66.0 (C-6), 67.7 (C-50), 68.3 (C-60), 72.9
(C-5), 74.4 (C-30), 74.8 (CH2 Bn), 75.9 (C-20), 77.6 (C-40), 80.3, 80.9 (C-
3 and C-4), 82.6 (C-2), 93.9 (MeSO2(CH2)2OCH2e), 100.2 (C-10),
101.5 (CH benzylidene), 104.8 (C-1), 108.6 (Cq isopropylidene), 111.9
(Cq isopropylidene), 125.2e129.1 (CH arom), 137.2, 137.8 (Cq ben-
-
CHHCH2OCH2e), 3.30e3.38 (m, 4H, CH3 OMe, and H-50), 3.71e3.82
(m, 5H, H-3, H-5, H-6, and MeSO2CH2CH2OCH2e), 3.88 (t, 1H,
J¼10.4 Hz, H-60), 3.94e3.98 (m, 2H, H-3, and H-20), 4.09e4.18 (m,
2H, H-4, and H-40), 4.23 (m, 1H, H-2), 4.27e4.30 (m, 2H, H-6, and H-
60), 4.53 (d, 1H, J¼6.8 Hz, MeSO2(CH2)2OCHHe), 4.69 (s, 1H, H-10),
4.72e4.79 (m, 4H, H-1, 2ꢂCHH Bn, and MeSO2(CH2)2OCHHe), 4.93
(d, 1H, J¼12.0 Hz, CHH Bn), 5.06 (d, 1H, J¼12.4 Hz, CHH Bn), 5.51 (s,
1H, CH benzylidene), 5.55 (s, 1H, CH benzylidene), 7.23e7.39 (m,
zylidene and Cq Bn); CH Gated NMR (100 MHz, CDCl3)
d
¼100.2
(J¼154 Hz, C-10), 104.8 (J¼181 Hz, C-1); HRMS [MþNa]þ calculated
20H, H arom); 13C NMR (100 MHz, CDCl3)
(MeSO2CH2CH2OCH2e), 54.9 (CH3 OMe), 61.1 (MeSO2
d
¼42.7 (CH3 Msem), 54.7
for C36H48O14SNa 759.2657, found 759.2659.
-
CH2CH2OCH2e), 64.0 (C-30 or C-5), 67.8 (C-50), 68.5 (C-60), 68.9 (C-
6), 71.4 (CH2 Bn), 74.0 (C-3 or C-20), 74.3 (C-30 or C-5), 74.5 (CH2 Bn),
75.4 (C-3 or C-20), 75.8 (C-2), 77.5 (C-40), 78.7 (C-4), 93.8 (MeS-
O2(CH2)2OCH2e), 99.5 (C-1), 101.2 (C-10), 101.6 (CH benzylidene),
101.6 (CH benzylidene), 126.0e129.1 (CH arom), 137.3, 137.5, 138.2,
138.8 (2ꢂCq benzylidene and 2ꢂCq Bn); CH Gated NMR (100 MHz,
4.1.20. Methyl 2-O-benzyl-4,6-O-benzylidene-3-O-(2-O-benzyl-4,6-
O-benzylidene-
a solution of methyl 2-O-benzyl-4,6-O-benzylidene-3-O-(2-O-ben-
zyl-4,6-O-benzylidene-3-O-methysulfonylethoxymethyl- -man-
nopyranosyl)- -mannopyranoside (20 ) (0.148 g, 0.17 mmol) in
THF (3.5 mL, 0.05 M) was added piperidine (35 l, 0.35 mmol,
b-D-mannopyranosyl)-a-D-mannopyranoside (29). To
b-D
a-D
b
m
CDCl3)
d
¼99.5 (J¼167 Hz, C-1), 101.2 (J¼153 Hz, C-10); HRMS
2 equiv) followed by the addition of tetrabutylammonium fluoride
(0.01 M in THF, 1.74 mL, 0.1 equiv). The reaction mixture was stirred
for 24 h. The reaction mixture was quenched with NH4Cl(aq), diluted
with EtOAc, washed with NH4Cl(aq), NaHCO3(aq), brine, dried over
MgSO4, filtered, concentrated, and purified by silica gel chromatog-
raphy to give 29 (0.114 g, 0.160 mmol, 92%). TLC (50% EtOAc in PE):
[MþNa]þ calculated for C45H52O14SNa 871.2970, found 871.2969.
4.1.19. 1,2:5,6-Di-O-isopropylidene-3-O-(2-O-benzyl-4,6-O-benzyli-
dene-3-O-methylsulfonylethoxymethyl-
D
-mannopyranosyl)-
a
-
D
-glu-
cofuranoside (28). Disaccharide 28 (0.139 g, 0.187 mmol,
a/b
¼1:10)
was prepared in 75% yield from donor 17b (0.147 g, 0.25 mmol,
1 equiv) and acceptor 23 (0.098 g, 0.38 mmol, 1.5 equiv) according
to the general procedure for glycosylations described above.
Rf¼0.8; [
a
]
22 ꢀ48.0 (c 0.6, DCM); IR (neat, cmꢀ1): 535, 698, 1093; 1H
D
NMR (500 MHz, CDCl3)
d
¼2.59 (br s, 1H, OH-30), 3.12 (m, 1H, H-50),
3.35 (CH3 OMe), 3.63e3.71 (m, 2H, H-50, and H-60), 3.71 (d, 1H,
J¼4.0 Hz, H-20), 3.79e3.88 (m, 4H, H-2, H-5, H-6, H-40), 4.11e4.15 (m,
2H, H-4, andH-60), 4.25(dd,1H, J¼4.0,9.5 Hz,H-6), 4.30(dd,1H, J¼3.5,
10.0 Hz, H-3), 4.44(s,1H, H-10), 4.58e4.62(m, 2H, 2ꢂCHH Bn), 4.70(d,
1H, J¼12.0 Hz, CHH Bn), 4.79 (s, 1H, H-1), 4.97 (d, 1H, J¼11.0 Hz, CHH
Bn), 5.20 (br s, 1H, CH benzylidene), 5.57 (s, 1H, CH benzylidene),
22
4.1.19.1.
a
-Anomer. TLC (50% toluene in EtOAc): Rf¼0.6; [
a]
D
þ50.0 (c 0.5, DCM); IR (neat, cmꢀ1): 697, 1026; 1H NMR (400 MHz,
CDCl3)
d
¼1.33 (s, 3H, CH3 isopropylidene), 1.36 (s, 3H, CH3 iso-
propylidene), 1.43 (s, 3H, CH3 isopropylidene), 1.51 (s, 3H, CH3
isopropylidene), 2.84e2.88 (m, 4H, CH3 Msem, and MeSO2
7.16e7.49 (m, 20H, H arom); 13C NMR (125 MHz, CDCl3)
d¼54.8 (CH3
-
CHHCH2OCH2e), 3.07e3.10 (m, 1H, MeSO2CHHCH2OCH2e),
3.79e3.92 (m, 5H, H-20, H-50, H-60, and MeSO2CH2CH2OCH2e), 4.00
(dd, 1H, J¼3.2, 10.0 Hz, H-30), 4.05e4.08 (m, 2H, H-4, and H-6),
4.15e4.20 (m, 2H, H-40, and H-6), 4.23 (m, 1H, H-5), 4.31e4.35 (m,
2H, H-30, and H-6), 4.57 (d, 1H, J¼3.6 Hz, H-2), 4.62 (d, 1H, J¼7.2 Hz,
MeSO2(CH2)2OCHHe), 4.66 (d, 1H, J¼12.4 Hz, CHH Bn), 4.76e4.79
(m, 2H, CHH Bn, and MeSO2(CH2)2OCHHe), 5.30 (s, 1H, H-10), 5.61
(s, 1H, CH benzylidene), 5.84 (d, 1H, J¼3.6 Hz, H-1), 7.17e7.47 (m,
OMe), 64.0 (C-2 or C-5), 66.6 (C-50), 68.5 (C-60), 68.7 (C-6), 70.0 (C-30),
72.6 (C-3), 72.9 (CH2 Bn), 74.3 (C-2 or C-5), 74.5 (CH2 Bn), 77.1 (C-4 and
C-20), 79.7 (C-40), 98.0 (C-10), 99.4 (C-1),101.4 (CH benzylidene),101.8
(CH benzylidene), 126.1e128.9 (CH arom), 137.2, 137.4, 137.5, 138.0
(2ꢂCq benzylidene and 2ꢂCq Bn); CH Gated NMR (100 MHz, CDCl3)
d
¼98.0 (J¼158 Hz, C-10), 99.4 (J¼168 Hz, C-1); HRMS [MþH]þ calcu-
lated for C41H45O11 713.29564, found 713.29657; [MþNa]þ calculated
for C41H44O11Na 735.2776, found 735.2778.
10H, H arom); 13C NMR (100 MHz, CDCl3)
propylidene), 26.2 (CH3 isopropylidene), 26.8 (CH3 isopropylidene),
d
¼25.4 (CH3 iso-
4.1.21. Methyl 2-O-benzyl-4,6-O-benzylidene-3-O-(2-O-benzyl-4,6-
26.9 (CH3 isopropylidene), 42.8 (CH3 Msem), 54.8 (MeSO2
O-benzylidene-3-O-methylsulfonylethyl-
mannopyranoside (30). The title compound was obtained as a side
D-mannopyranosyl)-a-D-
-
CH2CH2OCH2e), 61.6 (MeSO2CH2CH2OCH2e), 65.0 (C-50), 67.8 (C-6),
68.7 (C-60), 72.4 (C-5), 73.0 (C-30), 73.0 (CH2 Bn), 75.9 (C-20), 78.0 (C-
40), 80.1 (C-3), 81.4 (C-4), 84.0 (C-2), 94.7 (MeSO2(CH2)2OCH2e),
product in the reaction of 20b with TBAF without piperidine as
a scavenger. TLC (50% EtOAc in PE): Rf¼0.6; [
a]
22 ꢀ33.4 (c 1.0, DCM);
D

A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
6131
IR (neat, cmꢀ1): 730, 1061; 1H NMR (400 MHz, CDCl3)
d
¼2.79 (s, 3H,
54.7 (MeSO2CH2CH2OCH2e), 55.0 (CH3 OMe), 61.3 (MeSO2
-
CH3 Mse), 3.01e3.16 (m, 2H, MeSO2CH2CH2e), 3.36 (m, 1H, H-50),
CH2CH2OCH2e), 64.0, 74.2, 74.2, 74.4 (C-2, C-3 C-20, and C-5), 67.5,
67.8 (C-50 and C-500), 68.5, 68.6 (C-60 and C-600), 68.8 (C-6), 72.7 (CH2
Bn), 72.8 (C-3), 74.3 (CH2 Bn), 74.5 (CH2 Bn), 74.6 (C-200), 75.2 (C-300),
77.0, (C-400), 77.3 (C-4), 77.4 (C-40), 93.7 (MeSO2(CH2)2OCH2e), 98.1,
98.4 (C-10 and C-100), 99.2 (C-1), 101.5 (CH benzylidene), 101.7 (CH
benzylidene), 101.7 (CH benzylidene), 125.3e129.7 (CH arom),
137.3, 137.4, 137.5, 137.5, 138.3, 138.6 (3ꢂCq benzylidene and 3ꢂCq
3.39 (CH3 OMe), 3.70e3.80 (m, 3H, H-20, H-60, and MeSO2
CH2CHH2e), 3.80e3.93 (m, 4H, H-2, H-5, H-6, and MeSO2
-
-
CH2CHH2e), 4.04 (t, 1H, J¼8.8 Hz, H-40), 4.08e4.20 (m, 2H, H-4, and
H-60), 4.29 (dd, 1H, J¼4.4, 10.0 Hz, H-6), 4.32 (dd, 1H, J¼3.2, 10.0 Hz,
H-3), 4.39 (s, 1H, H-10), 4.58 (d, 1H, J¼12.4 Hz, CHH Bn), 4.63 (d, 1H,
J¼11.6 Hz, CHH Bn), 4.74 (d, 1H, J¼12.4 Hz, CHH Bn), 4.82 (s, 1H, H-
1), 4.96 (d, 1H, J¼11.6 Hz, CHH Bn), 5.26 (br s, 1H, CH benzylidene),
5.63 (s, 1H, CH benzylidene), 7.19e7.50 (m, 20H, H arom); 13C NMR
Bn); CH Gated NMR (100 MHz, CDCl3)
d
¼98.1 (J¼153 Hz, C-10 or C-
100), 98.1 (J¼155 Hz, C-10 or C-100), 99.2 (J¼167 Hz, C-1); HRMS
(100 MHz, CDCl3)
d
¼43.1 (CH3 Mse), 54.9 (CH3 OMe), 55.3 (MeS-
[MþNa]þ calculated for C65H72O19SNa 1211.4281, found 1211.4284.
O2CH2CH2e), 63.8 (MeSO2CH2CH2e), 64.0 (C-2 or C-5), 67.0 (C-50),
68.6 (C-60), 68.8 (C-6), 72.6 (C-3), 72.9 (CH2 Bn), 74.2 (CH2 Bn), 74.4
(C-2 or C-5), 74.9 (C-20), 77.2 (C-4), 77.3 (C-40), 77.7 (C-30), 99.1 (C-
10), 99.4 (C-1), 101.2 (CH benzylidene), 101.8 (CH benzylidene),
126.0e129.0 (CH arom), 137.2, 137.5, 137.6, 138.2 (2ꢂCq benzylidene
4.1.23. Methyl
3-O-[3-O-(b-D-mannopyranosyl)-b-D-mannopyr-
anosyl]- -mannopyranoside (31). To a solution of methyl 2-O-
a-D
benzyl-4,6-O-benzylidene-3-O-[2-O-benzyl-4,6-O-benzylidene-3-
O-(2-O-benzyl-4,6-O-benzylidene3-O-methysulfonylethoxymethyl
and 2ꢂCq Bn); CH Gated NMR (100 MHz, CDCl3)
d¼99.1 (J¼160 Hz,
-
b
-
D
-mannopyranosyl)-
side 31 (40 mg, 35 mol) in THF (0.7 mL, 0.05 M) were added pi-
peridine (7 l, 70 mol, 2 equiv) and tetrabutylammonium fluoride
(0.01 M in THF, 0.35 mL, 3.5 mol, 0.1 equiv). The reaction mixture
was stirred for 24 h. The reaction mixture was quenched with
NH4Cl(aq), diluted with EtOAc, washed with NH4Cl(aq), NaHCO3(aq)
b
-
D
-mannopyranosyl]
a-D-mannopyrano-
C-10), 99.5 (J¼167 Hz, C-1); HRMS [MþNa]þ calculated for
b
m
C44H50O13SNa 841.2864, found 841.2868.
m
m
m
4.1.22. Methyl 2-O-benzyl-4,6-O-benzylidene-3-O-[2-O-benzyl-4,6-
O-benzylidene-3-O-(2-O-benzyl-4,6-O-benzylidene-3-O-methyl-
,
sulfonylethoxymethyl-
D
-mannopyranosyl)-
b
-
D
-mannopyranosyl]-
a
-
brine, dried over MgSO4, filtered, concentrated, and purified by
silica gel chromatography to provide methyl 2-O-benzyl-4,6-O-
benzylidene-3-O-[2-O-benzyl-4,6-O-benzylidene-3-O-(2-O-ben-
D-mannopyranoside (31). Trisaccharide 31(0.199 g, 0.17 mmol,
a/
b
¼1:5) was prepared in 83% yield fromdonor 17 (0.172 g, 0.30 mmol,
1.5 equiv) and acceptor 29 (0.144 g, 0.20 mmol,1 equiv) according to
zyl-4,6-O-benzylidene-b-D-mannopyranosyl)-b-D-mannopyranosyl
the general procedure for glycosylations described above.
]-a-D-mannopyranoside. This trimer was dissolved in MeOH (1 mL)
and H2O (0.7 mL) before the addition of catalytic amount of Pd
(OH)2 on charcoal. The mixture was stirred for 24 h under an H2-
atmosphere, filtered, and purified by gel filtration (HW-40), to af-
22
4.1.22.1.
a
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.66; [
a]
D
ꢀ2.5 (c 0.4, DCM); IR (neat, cmꢀ1): 698, 1067; 1H NMR (400 MHz,
CDCl3)
d
¼2.59 (s, 3H, CH3 Msem), 2.72e2.76 (m, 1H, MeSO2
ford trisaccharide 32 (11 mg, 21
CDCl3)
m
mol, 60%); 1H NMR (600 MHz,
-
CHHCH2OCH2e), 2.91e2.98 (m, 1H, MeSO2CHHCH2OCH2e),
3.05e3.10 (m, 1H, H-50) 3.36 (s, 3H, CH3 OMe), 3.68 (dd, 1H, J¼3.2,
10.0 Hz, H-30), 3.75e3.92 (m, 10H) 4.01e4.36 (m, 10H), 4.39 (d, 1H,
J¼12.0 Hz, CHH Bn), 4.56e4.60 (m, 2H, CHH Bn, and MeSO2(-
CH2)2OCHHe), 4.73e4.79 (m, 3H, 2ꢂCHH Bn, and MeSO2(-
CH2)2OCHHe), 4.85 (s, 1H), 4.97 (d, 1H, J¼12.0 Hz, CHH Bn), 5.27 (s,
1H), 5.55 (s,1H, CH benzylidene), 5.59 (s,1H, CH benzylidene), 5.63 (s,
1H, CH benzylidene), 7.03e7.51 (m, 30H, H arom); 13C NMR
d
¼3.30e3.37 (m, 5H) 3.49 (t, 1H, J¼9.6 Hz), 3.58e3.61 (m,
2H), 3.63e3.67 (m, 5H), 3.83e3.88 (m, 3H), 3.91 (dd, 1H, J¼2.4,
9.6 Hz), 3.95 (dd, 1H, J¼3.0, 9.6 Hz), 3.98 (d, 1H, J¼2.4 Hz), 4.06 (s,
1H), 4.19 (s, 1H), 4.73 (s, 1H), 4.74 (s, 1H), 4.79 (s, 1H); 13C NMR
(150 MHz, CDCl3)
d
¼53.7 (CH3 OMe), 61.8, 61.9 (C-6, C-60, and C-600),
66.1, 66.2, 67.8, 67.9, 68.7, 71.7, 73.3, 73.8, 77.0, 77.3, 78.2, 79.8 (C-2,
C-3, C-4, C-5, C-20, C-30, C-40, C-50, C-200, C-300, C-400, C-500), 97.6, 97.7,
101.6 (C-1, C-10, and C-100); HRMS [MþNa]þ calculated for
C19H34O16Na 541.1739, found 541.1736.
(100 MHz, CDCl3)
d
¼42.8 (CH3 Msem), 54.8 (MeSO2CH2CH2OCH2e),
55.0 (CH3 OMe), 61.5 (MeSO2CH2CH2OCH2e), 64.0, 64.8, 67.4, 72.9,
72.9, 74.2, 76.2, 76.5, 78.0, 78.2, 78.2, 78.6(C-2, C-3, C-4, C-5, C-20, C-30,
C-40, C-50, C-200, C-300, C-400, and C-500), 68.6, 68.8 (C-6, C-60, and C-600),
72.6 (CH2 Bn), 72.7 (CH2 Bn), 75.0 (CH2 Bn), 94.8 (MeSO2(-
CH2)2OCH2e), 98.7, 99.1, 99.8 (C-1, C-10, and C-100), 101.7 (CH benzy-
lidene), 101.8 (CH benzylidene), 102.0 (CH benzylidene), 126.1e129.3
(CH arom),137.5,137.6,137.6 (3ꢂCq benzylidene and 3ꢂCq Bn); HRMS
[MþNa]þ calculated for C65H72O19SNa 1211.4281, found 1211.4285.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.007. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
22
References and notes
4.1.22.2.
b
-Anomer. TLC (33% toluene in EtOAc): Rf¼0.45; [
a]
D
ꢀ136.4 (c 1.0, DCM); IR (neat, cmꢀ1): 698, 1092; 1H NMR (400 MHz,
1. (a) The Organic Chemistry of Sugars; Levy, D. E., Fügedi, P., Eds.; CRC: Boca Raton,
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Kocienski, P. J. Chem. Soc., Perkin Trans. 1 2001, 2109e2135 For some recent
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CDCl3)
d
¼2.72 (s, 3H, CH3 Msem), 2.72e2.82 (m, 1H, MeSO2
-
CHHCH2OCH2e), 2.99e3.00 (m, 1H, MeSO2CHHCH2OCH2e),
3.10e3.15 (m, 2H, H-50, and H-500), 3.40 (CH3 OMe), 3.52 (dd, 1H,
J¼3.2, 10.0 Hz, H-30 or H-300), 3.71 (m, 1H, H-20 or H-200), 3.75 (m, 1H,
MeSO2CH2CHHOCH2e), 3.82e3.95 (m, 8H, H-2, H-5, H-6, H-20 or H-
200), (H-30 or H-300), H-60, H-600, and MeSO2CH2CHHOCH2e), 4.01 (m,
1H, H-40 or H-400), 4.08 (m, 1H, H-40 or H-400), 4.15e4.22 (m, 3H, H-4,
H-60, and H-600), 4.28 (dd, 1H, J¼3.6, 9.2 Hz, H-6), 4.34e4.38 (m, 2H,
H-3, and (H-10 or H-100), 4.43 (s, 1H, H-10 or H-100), 4.49 (d, 1H,
J¼6.8 Hz, MeSO2(CH2)2OCHHe), 4.64 (d, 1H, J¼7.2 Hz, MeSO2(-
CH2)2OCHHe), 4.66e4.75 (m, 3H, 3ꢂCHH Bn), 4.78 (d, 1H,
J¼12.0 Hz, CHH Bn), 4.85 (s, 1H, H-1), 4.96 (d, 1H, J¼12.0 Hz, CHH
Bn), 5.04 (d, 1H, J¼12.0 Hz, CHH Bn), 5.46 (s, 1H, CH benzylidene),
5.48 (s, 1H, CH benzylidene), 5.58 (s, 1H, CH benzylidene), 7.15e7.48
(m, 30H, H arom); 13C NMR (100 MHz, CDCl3)
d
¼42.5 (CH3 Msem),

6132
A. Ali et al. / Tetrahedron 66 (2010) 6121e6132
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