4,6-O-benzylidene directed β-mannosylation without intermediate triflate formation? Comparison of trichloroacetimidate and disal donors in microwave-promoted glycosylations under neutral conditions

Article abstract of DOI:10.1080/07328300701634762

4,6-Benzylidene-protected mannosyl donors have emerged as efficient tools for the formation of 1,2-cis β-mannosides, which otherwise are difficult to access. Previously studied sulfoxide and trichloroacetimidate mannosyl donors were activated with strong

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4,6‐O‐Benzylidene Directed β‐Mannosylation
Without Intermediate Triflate Formation?
Comparison of Trichloroacetimidate and
DISAL Donors in Microwave‐Promoted
Glycosylations under Neutral Conditions
Kasper Worm‐Leonhard a , Kim Larsen a & Knud J. Jensen a
a Department of Natural Sciences, Section for Bioorganic Chemistry , Royal
Veterinary and Agricultural University , Frederiksberg, Denmark
Published online: 07 Nov 2007.
To cite this article: Kasper Worm‐Leonhard , Kim Larsen & Knud J. Jensen (2007) 4,6‐O‐Benzylidene Directed
β‐Mannosylation Without Intermediate Triflate Formation? Comparison of Trichloroacetimidate and DISAL
Donors in Microwave‐Promoted Glycosylations under Neutral Conditions, Journal of Carbohydrate Chemistry,
26:7, 349-368, DOI: 10.1080/07328300701634762
To link to this article: http://dx.doi.org/10.1080/07328300701634762
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Journal of Carbohydrate Chemistry, 26:349–368, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300701634762
4,6-O-Benzylidene Directed
b-Mannosylation Without
Intermediate Triflate
Formation? Comparison of
Trichloroacetimidate and
DISAL Donors in Microwave-
Promoted Glycosylations
under Neutral Conditions
Kasper Worm-Leonhard, Kim Larsen, and Knud J. Jensen
Department of Natural Sciences, Section for Bioorganic Chemistry, Royal Veterinary
and Agricultural University, Frederiksberg, Denmark
4,6-Benzylidene-protected mannosyl donors have emerged as efficient tools for the for-
mation of 1,2-cis b-mannosides, which otherwise are difficult to access. Previously
studied sulfoxide and trichloroacetimidate mannosyl donors were activated with
strong Lewis acids at low temperature and the glycosylations are believed to proceed
through intermediate formation of an a-triflate. This paper describes the synthesis of
new benzylidene-protected glucosyl and mannosyl methyl 3,5-dinitrosalicylate
(DISAL) donors, their application in O-glycosylations, and comparison with a
mannosyl trichloroacetimidate donor. In contrast to previous reports on torsionally
“disarmed” donors, these glycosylations were performed in the absence of strong
Lewis acids, but in the presence of lithium perchlorate or triflate, using either conven-
tional heating to 40 to 608C or precise microwave heating to 100 to 1508C. This approach
aimed at addressing the question of whether mannosyl triflate intermediates are essen-
tial for high b-selectivity in 4,6-O-benzylidene directed mannosylations. We find, again,
that precise microwave heating promoted glycosylations under very mild conditions.
Received January 5, 2006; accepted June 19, 2006.
The two first authors contributed equally.
Address correspondence to Knud J. Jensen, Faculty of Life Sciences, Department of
Natural Sciences, Section for Bioorganic Chemistry, University of Copenhagen,
Thorvaldsensvej 40, DK-1871, Frederiksberg, Denmark. E-mail: kjj@life.ku.dk
349

K. Worm-Leonhard et al.
350
While a DISAL mannosyl donor gave higher b-selectivity in the presence of LiOTf than
with LiClO4, the corresponding trichloroacetimidate did not give any b-selectivity with
LiOTf. Thus, under these conditions, the nature of the original leaving group, trichlor-
oacetimidate vs. DISAL, still is important. However, our results point to the possibility
of intermediate formation of a mannosyl triflate from a DISAL donor.
Keywords Mannosides, Microwave promotion, Glycosylations, Stereo-control
INTRODUCTION
Glycoconjugates play crucial roles in the development, growth, and proper
function of an organism.[1] Mannose is found in many biologically important
poly- and oligosaccharides (e.g., in glycans of O- and N-glycopeptides and
proteins) and tumor-associated antigens. The synthesis of oligosaccharides of
these glycoconjugates provides important tools for glycobiology (e.g. in neuro-
glycobiology).[2] Establishing the b-mannosidic linkage has for a long time
been one of the major problems in glycosylation chemistry. One recent
solution to this problem has been the use of torsionally deactivated 4,6-benzy-
lidene mannosyl donors. Crich[3] and later Schmidt[4] showed that activation of,
respectively, sulfoxide and trichloroacetimidate donors with strong Lewis acids
form b-mannosides with good b-selectivity. Crich has ascribed this to inter-
mediate formation of an a-configured glycosyl triflate, which as a contact ion
pair gives preferred displacement from the b-face, as the 4,6-benzylidene
moiety opposes rehybridization of the anomeric carbon.[3e] Schmidt has
hypothesized that the 4,6-benzylidene moiety favors formation of a twist-
boat-type intermediate, which is preferably attacked from the b-face, and
thus it would be a conformational effect and not the displacement of an a-con-
figured triflate that gives rise to the remarkable b-selectivity.[4] Bols and co-
workers have indicated that the deactivating effect of a 4,6-benzylidene is
due to not only “torsional disarmament” but also an electronic effect associated
with locking the 6-OH in the tg conformation; their conclusion was based on a
study of the hydrolysis of dinitrophenyl b-glucoside derivatives.[17] Thus, the
question arose as to whether 4,6-O-benzylidene-directed b-mannosylation
can occur without intermediate formation of a mannosyl triflate. Toshima
and coworkers have very recently reported b-selective mannosylation with
2,3-di-O-benzyl-4,6-benzylidene mannosyl phosphite in the presence of the
solid promoter montmorillonite K-10 without formation of a mannosyl
triflate intermediate.[5]
Novel methods for glycosylation in the absence of strong Lewis acids (i.e.,
under mild conditions) hold great promise (e.g., for combinatorial chemistry
and solid-phase synthesis applications).[6] We have recently described a new,
efficient method for glycosylation under strictly neutral, mildly basic, or very
mildly acidic (LiClO4) conditions.[7] In this glycosylation technique, the

Benzylidene b-Mannosylation Without Triflate?
351
anomeric leaving group on benzyl or benzoyl protected donors is methyl 3,5-
dinitrosalicylate (DISAL) or its para regioisomer. The potential of DISAL
glycosyl donors was demonstrated in their successful application to solution-
d[7a,d] and solid-phase[7b] oligosaccharide synthesis, as well as intramolecular
glycosylation via a novel 1,9-glycosyl shift.[7c]
DISAL glycosyl donors were prepared by a convenient and robust nucleo-
philic aromatic substitution protocol. DMAP-catalyzed formation of DISAL gly-
cosides predominantly gave a-anomers, while dimethylpiperazine (DMP)
predominantly gave b-anomers. Whereas O-benzyl (Bn)-protected DISAL
donors could O-glycosylate simply by dissolution in N-methylpyrrolidinone
(NMP) at 40 to 608C with a-selectivity, the less reactive benzoyl (Bz) donors
became efficient donors in CH3NO2 or (CH2Cl)2 in the presence of LiClO4 pro-
viding 1,2-trans b-selectivity. Also, b-selective glycosylations with glucosamine
donors have been achieved.[7f] These glycosylations are operationally simple
and can be carried out in standard plastic vials.
We have previously shown that a per-O-benzyl-protected mannosyl DISAL
donor can glycosylate in good yields and with a slight preference for formation
of a-linkages (Sch. 1).[7a]
Here we describe the synthesis of three new, benzylidene-protected
glucose and mannose DISAL donors, their use in O-glycosylations, and com-
parison with a trichloroacetimidate 4,6-benzylidene mannosyl donor. These
glycosylations were performed with a-configured DISAL donors either (1) in
the absence of added Lewis acids or (2) in the presence of LiClO4, both thus
proceeding without intermediate formation of glycosyl triflates, or (3) in the
presence of LiOTf or TMSOTf, which could give rise to an intermediate
glycosyl triflate. The question was whether b-selectivity could be achieved
without the intermediate formation of a configurationally locked triflate.[3,4]
In addition, we applied our new protocol for the precise microwave heating
in O-glycosylations.[7g]
Scheme 1: Disaccharide synthesis with per-O-benzyl protected mannosyl DISAL donor.[7a]

K. Worm-Leonhard et al.
352
RESULTS AND DISCUSSION
First, the 4,6-O-benzylidene glucose derivative 1[8] was converted into DISAL
donor 3. Reaction of lactol 1 (a/b 1:1) with aryl fluoride 2 in the presence of
DMAP gave DISAL donor 3 in 94% yield (a/b 1:2.7), while DMP catalysis
gave 91% with good b-selectivity (a/b 1:14.3). Glycosylations of MeOH were
solvolytic, while glycosylations of cyclohexanol were performed with 5 equiv.
relative to donor 3. The temperature was increased from 40 to 608C to acceler-
ate the reaction and to prevent hydrolysis of 3, which was seen with prolonged
reaction times. The 4,6-O-benzylidene-protected glucose donor 3 gave stereo-
specific glycosylation of the very reactive acceptor MeOH and a-selectivity in
glycosylation of secondary alcohol cyclohexanol (Sch. 2, Table 1), and thus
behaved similarly to the corresponding tetra-O-benzyl glucose DISAL donor.
This is in accordance with previous findings on per-O-benzylated glucose
DISAL donors.[7a] As the benzylidene di-O-benzyl-protected donor in our
initial screen provided stereoselectivities similar to the tetra-O-benzyl-pro-
tected donor, we did not glycosylate more challenging acceptors.
The 4,6-O-benzylidene mannose lactol proved somewhat difficult to access,
as benzylidenation of 4-methoxyphenyl[9] mannoside gave both the mono- and
dibenzylidenated derivatives. However, with the 2,3:4,6-di-O-benzylidene-pro-
tected 4-methylphenyl derivative 6 at hand, it was converted to first the hemi-
acetal and then further to the DISAL donor 8, the latter by DMAP catalysis,
which gave the pure a-anomer in 91% yield (Sch. 3). Dibenzylidene derivative
8 was unreactive under our standard, very mild glycosylation conditions (solvo-
lysis with MeOH, no added additive or activator). Most likely, this donor is too
conformationally locked and was not chosen for further studies.
The (mono-) 4,6-benzylidenated mannose lactol 12 (Sch. 4) was accessed
after some optimization, as changing the anomeric protection group from
4-methoxyphenyl to 4-methylphenylthio together with other changes in the
protocol provided the mono-benzylidene thioglycoside derivative 11. The
Scheme 2: Synthesis of benzylidene glucosyl DISAL donor 3 and its use in O-glycosylations.

Benzylidene b-Mannosylation Without Triflate?
Table 1: Glycosylation with glucose DISAL donor 3.
353
DISAL
donor
(a/b)
Product,
yield
(a/b ratio)
Temp.a
[8C]
Entry
ROH (solvent)
Time
1
2
3
3 (1:0)
3 (0:1)
3 (1:0)
MeOH
MeOH
Cyclohexanol
(NMP)
40
40
60
4d
20 h
27 h
4b 90% (0:1)
4a 95% (1:0)
5 53% (1.7:1)
4
3 (1:14.3)
Cyclohexanol
(NMP)
60
24 h
5 63% (1.9:1)
a
Heating by heater shaker.
4-methylphenylthio moiety was introduced via either the nucleophilic reaction
of thiocresol with per-acetylated mannose[10] or via phase-transfer catalyzed
thiophenolysis[11] of a tetra-O-acetyl-mannosyl bromide.[12] The 4,6-O-benzyli-
dene group was introduced using the method of Oshitari et al.,[13] which
provided the 4,6-O-benzylidene derivative 10, without formation of the analo-
gous dibenzylidene derivative. Finally, 10 was benzylated followed by removal
of the 4-methylphenylthiol group using NBS as described by Motawia et al.,[14]
which easily led to the required lactol 12.[13]
Mannose lactol 12 was converted to the DISAL donor 13 with DMAP cata-
lysis, which gave the a-anomer in 92% yield. Initial studies of glycosylations
with DISAL donor 13 under mild conditions revealed that it was relatively
Scheme 3: Synthesis of 2,3:4,6-di-O-benzylidene-protected mannosyl DISAL derivative.

K. Worm-Leonhard et al.
354
Scheme 4: Synthesis of lactol 12.
stable and less reactive; thus, we applied our previously described protocol[7g]
for precise microwave heating to accelerate glycosylations. Microwave
irradiation is an efficient source of energy, leading to a rapid rise in reaction
temperature without heating the reaction vessel first. This in turn can lead
to faster and cleaner reactions with precise temperature control.[15]
Solvolytic glycosylation of MeOH with DISAL donor 13 proceeded in
20 min at 1308C (Table 2, entry 1), giving the methyl mannoside in 80%
yield with predominant b-configuration. Glycosylation of cyclohexanol (5
equiv.) with conventional heating in CH3NO2 required 42 h at 708C
(Table 2, entry 2) and provided no stereoselectivity. The same reaction but
with microwave heating at 1308C took only 10 min (2 ꢀ 5 min) and had the
added benefit of improved stereoselectivity (a/b 1:6). Increasing the
reaction time to 60 min did increase the yield from the previous 50% to 67%
Table 2: Initial glycosylations with DISAL donor 13 (pure a-anomer); see Scheme 5.
Product,
Solvent
(additive)
Time
yield (a/b
Entry
Acceptor
MeOH
temp.a
ratio)
1
2
3
4
5
MeOH
(none)
20 min
1308C#
14
80% (1:5)
15
Cyclohexanol
Cyclohexanol
Cyclohexanol
Cyclohexanol
CH3NO2
(LiClO4)
CH3NO2
(LiClO4)
CH3NO2
(LiClO4)
(CH2Cl)2
(LiClO4)
42 h 708Cꢁ
50% (1:1)
2 ꢀ 5 min
1308C#
60 min
1308C#
15 min
1508C
15
50% (1:6)
15
67% (1:1)
15
44% (1:2)
a
Symbol indicates means of heating. ꢁHeater shaker. #Microwave heating.

Benzylidene b-Mannosylation Without Triflate?
355
but with the loss of stereoselectivity (Table 2, entry 3). Changing the solvent
to the more apolar (CH2Cl)2 and increasing the reaction temperature to 1508C
did not improve the yield (44%) or stereoselectivity (a/b 1:2) much (Table 2,
entry 5). Though we have not previously observed trans-O-glycosylation of
the product formed in glycosylations with microwave heating to 100 to
1508C, this possibility cannot be ruled out as the cause for the loss of stereo-
selectivity in the case of prolonged reaction times with excess of the acceptor
(entry 3 vs. 4). Nishimura and coworkers have described transglycosylation of
methyl 2,3,4,6-tetra-O-benzyl-b-D-glucopyranoside with 1-octanol with
microwave heating to 1208C in the presence of Yb(TfO)3 to give the octyl
glucoside.[16]
Next, we tested glycosylations with DISAL donor 13 of the galactose
acceptor 16 (Sch. 5, Table 3). Initial glycosylation of acceptor 16 with
donor 13 in nitromethane and with LiClO4 as additive and at 1308C did
not produce any satisfactory results (not shown). A change of solvent to
(CH2Cl)2 and an increase in glycosylation temperature to 1508C led to a
yield of 74% but with the desired 1,2-cis b-mannoside as the minor
anomer (Table 3, entry 1). Substituting LiClO4 for LiOTf could give inter-
mediate formation of the a-mannosyl triflate, which according to Crich’s
model should lead to preferred formation of the b-mannoside. Thus, would
the addition of a very weak Lewis acid to a triflate counter-ion improve
the b-selectivity? Indeed, LiOTf as additive gave the pure b-mannoside
Scheme 5: Synthesis of donors 13 and 18; O-glycosylations of methanol and cyclohexanol
with DISAL donor 13.

K. Worm-Leonhard et al.
356
Table 3: Glycosylation of acceptor 16 with DISAL mannosyl donor 13 (a-anomer);
see Scheme 5.
Product
17, yield
(a/b ratio)
Entry
Solvent (additive)
(CH2Cl)2 (LiClO4)
(CH2Cl)2 (LiOTf)
(CH2Cl)2 (LiOTf)
Time temp.a
1
2
3
4
2 ꢀ 30 min 1508C
30 min 1508C
74% (2:1)
38% (0:1)
35% (1:3)
26% (1:1)
2 ꢀ 30 min 1508C
(CH2Cl)2 (TMSOTf, 0.3eq to 13)
10 min 1008C
a
All reactions were heated using microwave irradiation.
but in a low, 38% yield (Table 3, entry 2). Increasing the reaction time from
30 min to 60 min did not improve the yield, but lowered the perfect b-selec-
tivity into a 1:3 a/b ratio (Table 3, entry 3). Somewhat surprisingly, a change
to the strong Lewis acid, TMSOTf (Table 3, entry 4), at 1008C, gave poor
yield and a/b ratio.
Weingart and Schmidt[4] have reported the b-selective mannosylation with
4,6-O-benzylidene-protected mannosyl trichloroacetimidate 18. We have pre-
viously shown that glycosylation with trichloroacetimidates can be promoted
by microwave heating in the presence of lithium salts.[7g]
The aim here was to investigate mannosylations with the trichloroacetimi-
date donor 18 in the presence of lithium perchlorate or triflate and with micro-
wave heating. We now find that mannosylation with trichloroacetimidate donor
18 in the presence of lithium salts can be accelerated by microwave heating.
Thus, mannosylation at 1308C for 25 min in (CH2Cl)2 (Table 4, entry 1)
produced disaccharide 17 in 88% yield, unfortunately only with a a/b-ratio of
1:1. Changing the activator from LiClO4 to LiOTf did not improve the a/b
ratio or the yields (Table 4, entry 2). Glycosylation of acceptor 19 gave a yield
of 44% with an a/b ratio of 1.3:1 (Table 4, entry 3).
In conclusion, we have prepared three new benzylidene-protected
mannose and glucose DISAL donors, and compared their glycosylating
ability with that of a 4,6-O-benzylidene mannosyl trichloroacetimidate in
O-glycosylations in the absence of a strong Lewis acid but in the presence
of lithium perchlorate or triflate and with microwave heating. All benzyli-
dene-protected donors in this study were found to be less reactive than com-
parable benzyl-protected donors. Microwave heating to 100 to 1508C again
proved efficient for promoting sluggish glycosylations under mild conditions.
The stereoselectivity provided by 4,6-benzylidene-protected DISAL glucosyl
donor 3 was comparable to that of the corresponding benzyl-protected donor,
even providing the same stereospecific glycosylation of methanol. That 4,6-
O-benzylidene-protected glucose donors react similar to their benzyl-
protected analogs has been shown previously for trichloroacetimidate and

Benzylidene b-Mannosylation Without Triflate?
357
Table 4: Initial glycosylations with trichloroacetimidate donor 18 (a/b 5:1); see
Scheme 6.
Product,
Solvent
(additive)
yield
(a/b ratio)
Entry
Acceptor
Time temp.a
1
2
3
16
16
19
(CH2Cl)2 (LiClO4)
(CH2Cl)2 (LiOTf)
(CH2Cl)2 (LiClO4)
25 min 1308C
25 min 1308C
25 min 1308C
17 88% (1:1)
17 48% (1.6:1)
20 44% (1.3:1)
aAll reactions were heated using microwave irradiation; solvent (CH2Cl)2.
sulfoxide donors. The 4,6-benzylidene-protected mannosyl donor 13 glyco-
sylated methanol with high b-selectivity, whereas mannosylation of cyclo-
hexanol in the presence of LiClO4 did proceed with some b-selectivity,
albeit with low reactivity. Interestingly, mannosylation of monosaccharide
16 with DISAL donor 13 in the presence of LiClO4 gave some a-selectivity,
whereas LiOTf as additive gave b-selectivity. This could indicate that
these relatively slow glycosylations to some extent can proceed through a
a-mannosyl triflate contact ion pair. The analogous trichloroacetimidate
mannosyl donor was able to glycosylate at 130 to 1508C in the presence of
LiClO4 or LiOTf, unfortunately without any b-selectivity but with
somewhat improved yields. Thus, under these conditions, the nature of the
original leaving group, trichloroacetimidate vs. DISAL, still is important.
However, our results point to the possibility of intermediate formation of a
mannosyl triflate from a DISAL donor. There are three scenarios for these
particular mannosylations: (1) the reactive acceptor MeOH provides SN2-
type reactions with DISAL donors in the absence of additives, (2) the
DISAL donor gives improved b-selectivity with LiOTf rather than LiClO4
as additive, whereas (3) for the trichloroacetimidate donor the b-selectivity
does not improve in the presence of LiOTf.
Scheme 6: O-Glycosylations with trichloroacetimidate donor 18.

K. Worm-Leonhard et al.
358
EXPERIMENTAL
General Methods
˚
˚
Molecular sieves (3 A and 4 A) were activated under high vacuum at
1508C for 24 h. Water contents (,20 ppm) were measured by Karl-
˚
Fischer titration. All other solvents were distilled and/or stored over 3 A
˚
or 4 A molecular sieves as appropriate. Analytical HPLC was performed
on a Waters 600 system with a 996 diode array detector and a 717 Auto-
˚
sampler equipped with a 3.9 ꢀ 50 mm Nova-Pak C18 4 mm 60 A column.
The following solvents were used: 0.1% TFA/H2O (A); 0.1% TFA/CH3CN
(B); H2O (C); and CH3CN (D). Analytical HPLC was performed on micro
filtered or centrifuged 0.1% solutions in MeCN (for more hydrophilic com-
pounds, solubility was improved by addition of water). The following
programs were used:
Program A; 0.00 min: 1.00 mL/min, 95.0% C, 5.0% D; 7.00 min: 1.00 mL/
min, 5.0% C, 95.0% D; 8.50 min: 1.00 mL/min, 5.0% C, 95.0% D; 9.00 min:
1.00 mL/min, 95.0% C, 5.0% D; 15.00 min: 1.00 mL/min, 95.0% C, 5.0% D.
Characteristic absorption maxima were: Bn: 256 to 257 nm, DISAL-OH:
220 nm and 286 nm.
Preparative HPLC was performed on a Waters 600 system with Waters 996
diode array detector and three consecutive columns (40 ꢀ 100 mm prep. NOVA
˚
Pak HR C18 6 mm 60 A units). Linear gradients of CH3CN (D) and water
(MilliQ) (C) were used.
Program A; 0.00 min: 0.00 mL/min, 95.0% C, 5.0% D; 1.00 min: 20.00 mL/
min, 95.0% C, 5.0% D; 20.00 min: 20.00 mL/min, 50.0% C, 50.0% D; 60.00 min:
20.00 mL/min, 5.0% C, 95.0% D; 75.00 min: 20.00 mL/min, 0.0% C, 100.0% D;
81.00 min: 0.00 mL/min, 0.0% C, 100.0% D.
1H, 13C, gHSQC, HMBC, and H,H-COSY NMR spectra were recorded on
Varian Mercury 300, Bruker Avance 300, or Varian Unity Inova 500 spec-
trometers. The chemical shifts are referred to the residual solvent signal.
Chemical shift (d) values are in ppm; coupling constants (J) are in Hz. Mass
determination (high-resolution MS, HR-MS) was performed on a Micromass
LCT instrument with an ESI probe. For TLC Merck TLC Aluminium Sheets
Silica Gel 60 F254 were used. Compounds containing UV-absorbing groups
were visualized under UV light (254 nm), and carbohydrates were developed
with 2M H2SO4 followed by charring with a heat gun. Vacuum liquid chromato-
graphy (VLC) was performed on columns of Merck 60H silica packed under
vacuum. The crude product was dissolved in CH2Cl2 and the equivalent
amount of silica added, concentrated, placed on column, and finally covered
with acid-rinsed sea sand. Chromatography was hereafter run with the appro-
priate eluents until product was collected. Microwave experiments were
carried out in a Biotage Initiator (Biotage, Sweden). The reaction times are

Benzylidene b-Mannosylation Without Triflate?
359
specified as ramp time and hold time at the final temperature. Temperatures
were measured by IR and pressure via the septum. The new compounds
described in this paper are all fully characterized. All known compounds
have been verified by NMR and ESI-MS.
2,4-Dinitro-6-(methoxycarbonyl)phenyl 2,3-Di-O-benzyl-
4,6-O-benzylidene-D-glucopyranoside (3)
DMAP procedure: To a stirred suspension of 2,3-di-O-benzyl-4,6-O-benzy-
lidene-D-glucopyranose 1[8] (75 mg, 0.17 mmol) and Li2CO3 (25 mg,
0.33 mmol) in dry DCM (0.5 mL) was added DISAL-F 2 (49 mg, 0.2 mmol).
DMAP (5.6 mg, 0.05 mmol) was dissolved in DCM (0.5 mL) and added in
five portions over 20 min. Upon addition of DMAP the solution changed
from colorless to orange. After 45 min the reaction mixture was purified by
VLC (DCM) to give the title compound as a yellow foam (106 mg, 94%, a/b
1:2.7).
DMP procedure: The glucose derivative 1[8] (100 mg, 0.22 mmol) and
Li2CO3 (33 mg, 0.45 mmol) was suspended in dry DCM (0.8 mL) in a 10-mL
flask. To this suspension was added DISAL-F 2 (65 mg, 0.27 mmol) and DMP
(15 mL, 0.11 mmol). After 3(1/2) h a solution of DMAP (7.5 mg, 0.07 mmol) in
DCM was added and after another 15 min the reaction mixture was purified
by VLC (DCM) to give the title compound as a yellow foam (137 mg, 91%, a/
b 1:14.3). 1H NMR 3a (300 MHz, CDCl3): d 8.68 (d, 1H, J ¼ 2.9 Hz), 8.51
(d, 1H, J ¼ 2.9 Hz), 7.52–6.93 (m, 15H, ArH), 5.57 (s, 1H, PhCHO2), 5.43
(d, 1H, J ¼ 3.5 Hz, H-1a), 4.96–4.34 (m, 4H, Ph-CH), 4.33 (dd, 1H,
J ¼ 9.6 Hz, J ¼ 5.0 Hz, H-6), 4.16 (dd, 1H, J ¼ 9.6 Hz, J ¼ 9.4 Hz, H-60), 4.12
(ddd, 1H, J ¼ 10.1 Hz, J ¼ 9.4 Hz, J ¼ 5.0 Hz, H-5), 3.92 (s, 3H, OMe), 3.73
(dd, 1H, J ¼ 10.1 Hz, J ¼ 9.6 Hz, H-4), 3.67 (dd, 1H, J ¼ 9.6 Hz, J ¼ 9.6 Hz,
H-3), 3.64 (dd, 1H, J ¼ 9.6 Hz, J ¼ 3.5 Hz, H-2). 13C NMR (126 MHz, CDCl3):
d 163.6, 154.3, 144.8, 141.4, 138.5, 137.2, 137.0, 129.7, 126.7, (m, Ar), 123.5,
104.3, 101.6 (C-1), 81.2, 80.6, 78.4, 75.6, 75.0, 68.7, 65.7, 53.5 (OMe). 1H
NMR 3b (500 MHz, CDCl3): d 8.83 (d, 1H, J ¼ 3.0 Hz), 8.72 (d, 1H,
J ¼ 3.0 Hz), 7.48–7.25 (m, 15H, ArH), 5.57 (s, 1H, PhCHO2), 5.31 (d, 1H,
J ¼ 7.7 Hz, H-1b), 4.97–4.81 (m, 4H, Ph-CH), 4.18 (dd, 1H, J ¼ 10.2 Hz,
J ¼ 4.9 Hz, H-6), 3.90 (s, 3H, OMe), 3.86–3.82 (m, 2H, H-2, H-3), 3.77–3.73
(m, 1H, H-4), 3.69 (t, 1H, J ¼ 10.2 Hz, H-60), 3.39 (ddd, 1H, J ¼ 9.8 Hz,
J ¼ 9.8 Hz, J ¼ 4.9 Hz, H-5). 13C NMR (126 MHz, CDCl3): d 163.3, 151.3,
146.9, 143.3, 138.4, 138.1, 137.1, 130.0-126.1 (m, Ar), 122.9, 104.7, 101.4 (C-
1), 82.0, 80.9, 80.5, 75.5, 75.2, 68.2, 66.6, 53.5 (OMe). ES-HR-MS: m/z calcd
for C35H32N2O12 672.1955; [M þ Na]þ 695.1853; found: 695.1731.

K. Worm-Leonhard et al.
360
Methyl 2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-
glucopyranoside (4a)
The DISAL donor 3b (20 mg, 0.03 mmol) and MeOH (700 mL) were placed
in an Eppendorf tube and heated to 408C on an Eppendorf Thermomixer 5436.
After 20 h the solvent was evaporated and the reaction mixture purified by
VLC (toluene-EtOAc 5:1) to give the title compound as white crystals (13 mg,
95%), mp 89–918C (crystallized from toluene and EtOAc; lit. 938C[18]). The
observed NMR data were identical with literature values.[19]
Methyl 2,3-Di-O-benzyl-4,6-O-benzylidene-b-D-
glucopyranoside (4b)
The donor 3a (20 mg, 0.03 mmol) and MeOH (700 mL) were placed in an
Eppendorf tube and heated to 408C on an Eppendorf Thermomixer 5436.
After 96 h the solvent was evaporated and the reaction mixture was purified
by VLC (toluene-EtOAc 5:1) to give the title compound as white crystals
(12.4 mg, 90%, a/b 0:1), mp 116–1188C (crystallized from toluene and
EtOAc; lit. 118–1208C[20]). The observed NMR data were identical with litera-
ture values.[21]
Cyclohexyl 2,3-di-O-Benzyl-4,6-O-benzylidene-D-
glucopyranoside (5)
The donor 3b (20 mg, 0.03 mmol, a/b 1:14.3), cyclohexanol (16 mL,
0.15 mmol), and NMP (900 mL) were placed in an Eppendorf tube and heated
to 608C on an Eppendorf Thermomixer 5436. After 24 h EtOAc (30 mL) was
added and the reaction mixture was washed with brine (2 ꢀ 20 mL), NaOH
(0.5 M, 2 ꢀ 20 mL), and again with brine (2 ꢀ 20 mL). The organic phase was
dried with Na2SO4, evaporated, and purified by VLC (EtOAc-toluene
1:60 ! 1:5) to give the title compound as an off-white powder (10 mg, 63%,
1
a/b 1.9:1). H NMR 5a (500 MHz, CDCl3): d 7.51–7.27 (m, 15H, ArH), 5.56
(s, 1H, PhCHO2), 4.95–4.68 (m, 4H, Ph-CH), 4.93 (d, 1H, J ¼ 3.8 Hz, H-1),
4.26 (dd, 1H, J ¼ 10.3 Hz, J ¼ 5.4 Hz, H-6), 4.07 (t, 1H, J ¼ 9.4 Hz, H-3), 3.96
(ddd, 1H, J ¼ 10.3 Hz, J ¼ 9.9 Hz, J ¼ 5.4 Hz, H-5), 3.70–3.67 (m, 1H, H-60),
3.61 (t, 1H, J ¼ 9.4 Hz, H-4), 3.57–3.52 (m, 1H, CH-OGlc, cyclohexyl), 3.55
1
(dd, 1H, J ¼ 9.4 Hz, J ¼ 3.8 Hz, H-2), 1.2–2.0 (m, 10H, CH2, cyclohexyl). H
NMR 5b (500 MHz, CDCl3): d 7.51–7.27 (m, 15H, ArH), 5.56 (s, 1H,
PhCHO2), 4.95–4.78 (m, 4H, Ph-CH), 4.62 (d, 1H, J ¼ 7.6 Hz, H-1), 4.34 (dd,
1H, J ¼ 10.3 Hz, J ¼ 4.9 Hz, H-6), 3.79 (t, 1H, J ¼ 10.3 Hz, H-60), 3.75–3.79
(m, 1H, H-3), 3.70–3.67 (m, 1H, H-4), 3.57–3.52 (m, 1H, CH-OGlc, cyclohexyl),
3.46 (t, 1H, J ¼ 8.2 Hz, H-2), 3.39 (ddd, 1H, J ¼ 10.3 Hz, J ¼ 9.6 Hz,
J ¼ 4.9 Hz, H-5), 1.2–2.0 (m, 10H, CH2, cyclohexyl). 13C NMR 5a/b

Benzylidene b-Mannosylation Without Triflate?
361
(126 MHz, CDCl3): d 139.2, 138.6, 137.7, 129.0–127.6 (m, Ar), 126.2, 101.3, 96.3
(C-1), 82.6, 82.4, 81.7, 81.3, 79.6, 78.9, 76.2, 75.5, 75.4, 73.5, 69.3, 69.1, 66.2,
62.6, 33.9, 33.6, 32.1, 31.7, 25.8, 24.5, 24.3, 24.2.
The donor 3a (12 mg, 18 mmol), cyclohexanol (9.4 mL, 89 mmol), and NMP
(600 mL) were placed in an Eppendorf tube and heated to 608C on an Eppendorf
Thermomixer 5436. After 27 h EtOAc (20 mL) was added, and the reaction
mixture was washed with brine (2 ꢀ 20 mL), NaOH (0.5 M, 2 ꢀ 20 mL), and
again with brine (2 ꢀ 20 mL). The organic phase was dried with Na2SO4, evap-
orated, and purified by VLC (EtOAc-toluene 1:60 ! 1:5) to give the title
compound as an off-white powder (5.0 mg, 53%, a/b 1.7:1).
4-Methoxyphenyl 2,3:4,6-Di-O-benzylidene-a-D-
mannopyranoside (6)
In a 50-mL flask 4-methoxyphenyl mannoside (synthesized from mannose
according to[4,22,23]
) (230 mg, 0.80 mmol), benzaldehyde dimethylacetal
(600 mL, 4.0 mmol) and camphorsulfonic acid (CSA, 19 mg, 0.08 mmol) were
dissolved in CH3CN (20 mL). A part (15 mL) of the reaction mixture was
removed by distillation and Et3N (five drops) were added followed by evapor-
ation. MeOH (10 mL) was added and heated to boiling where a white solid
(6-exo) precipitated from the solution and was filtered off. When the mother
liquor was left to cool down the corresponding endo-isomer precipitated out
and was filtered off as a white powder (308 mg, 83%, endo/exo 1:3.3).
Data of 6-endo: mp (endo) 131–1328C; [a]D ¼ 36.0 (c 8.83 ꢀ 1023 CHCl3). 1H
NMR (300 MHz, CDCl3): d 7.60–7.34 (m, 10H, ArH), 7.03–7.00 (m, 2H, ArH),
6.88–6.85 (m, 2H, ArH), 6.05 (s, 1H, PhCHO2), 5.82 (s, 1H, H-1), 5.54 (s, 1H,
PhCHO2), 4.65 (dd, 1H, J ¼ 7.5 Hz, J ¼ 6.2 Hz, H-3), 4.55 (d, 1H, J ¼ 6.2 Hz,
H-2), 4.23 (dd, 1H, J ¼ 10.2 Hz, J ¼ 5.1 Hz, H-6), 4.01 (ddd, 1H, J ¼ 10.2 Hz,
J ¼ 9.8 Hz, J ¼ 5.1 Hz, H-5), 3.82 (dd, 1H, J ¼ 9.8 Hz, J ¼ 7.5 Hz, H-4), 3.79
(s, 3H, OMe), 3.72 (t, 1H, J ¼ 10.2 Hz, H-60). 13C NMR (75 MHz, CDCl3): d
155.4, 149.9, 137.3, 137.1, 129.6–126.2 (m, benzylidene), 2 ꢀ 118.1, 2 ꢀ 114.9,
104.4, 102.0, 97.0 (C-1), 80.5, 78.5, 74.3, 68.9, 61.4, 55.8. ES-HR-MS: m/z calcd
for C27H26O7 462.1679; [M þ H]þ: 463.1757; found: 463.1755.
Data of 6-exo: mp (exo) 189–1928C; 1H NMR (300 MHz, CDCl3): d 7.57–7.35
(m, 10H, ArH), 7.00–6.97 (m, 2H, ArH), 6.86–6.83 (m, 2H, ArH), 6.35 (s, 1H,
PhCHO2), 5.75 (s, 1H, H-1), 5.66 (s, 1H, PhCHO2), 4.81 (dd, 1H, J ¼ 7.7 Hz,
J ¼ 5.6 Hz, H-3), 4.39 (d, 1H, J ¼ 5.6 Hz, H-2), 4.29 (dd, 1H, J ¼ 10.4 Hz,
J ¼ 4.5 Hz, H-6), 4.04 (ddd, 1H, J ¼ 10.4 Hz, J ¼ 9.7 Hz, J ¼ 4.5 Hz Hz, H-5),
3.97 (dd, 1H, J ¼ 9.7 Hz, J ¼ 7.7 Hz, H-4), 3.81 (t, 1H, J ¼ 10.4 Hz, H-60), 3.78
(s, 3H, OMe). 13C NMR (75 MHz, CDCl3): d 155.4, 150.0, 138.6, 137.2, 129.6–
126.2 (m, benzylidene), 2 ꢀ 118.1, 2 ꢀ 114.9, 103.3, 102.2, 97.1 (C-1), 77.6,
75.8, 75.6, 68.9, 61.3, 55.8. ES-HR-MS: m/z calcd for C27H26O7: 462.1679;

K. Worm-Leonhard et al.
362
[M þ H]þ: 463.1757; found: 463.1805. Anal. Calcd. for C27H26O7: C, 70.12; H,
5.67. Found: C, 70.10; H, 5.64.
2,3:4,6-Di-O-benzylidene-D-mannopyranose (7-exo)
In a 25-mL flask the mannoside 6-exo (360 mg, 0.78 mmol) was dissolved in
CH3CN (10 mL) and a solution of Ce(NH4)2(NO3)6 (CAN, 1.92 g, 3.5 mol) in
H2O (2.5 mL) was added. The orange solution was stirred for 20 min followed
by addition of EtOAc (20 mL), washed with brine (3 ꢀ 20 mL), and dried with
solid MgSO4. The crude compound was purified by preparative HPLC to give
the title compound as an off-white powder (113 mg, 41%, a/b 3.2:1; ratio
1
obtained by integration of the benzylidene peaks around 5.65 ppm). H NMR
(a-anomer; 300 MHz, CDCl3): d 7.57–7.35 (m, 10H, ArH), 6.30 (s, 1H,
PhCHO2), 5.65 (s, 1H, PhCHO2), 5.54 (s, 1H, H-1), 4.69 (dd, 1H, J ¼ 8.1 Hz,
J ¼ 5.5 Hz, H-3), 4.34 (dd, 1H, J ¼ 10.4 Hz, J ¼ 5.0 Hz, H-6), 4.20 (d, 1H,
J ¼ 5.5 Hz, H-2), 4.06 (ddd, 1H, J ¼ 10.1 Hz, J ¼ 9.9 Hz, J ¼ 5.0 Hz, H-5),
3.91 (dd, 1H, J ¼ 9.9 Hz, J ¼ 8.3 Hz, H-4), 3.81 (dd, 1H, J ¼ 10.4 Hz,
J ¼ 10.1 Hz, H-60), 2.68 (broad s, 1H, OH). 13C NMR (75 MHz, CDCl3): d
138.7, 137.2, 129.6–126.2 (m, benzylidene), 103.2, 102.2, 92.9, 77.5, 75.6,
75.5, 69.0, 60.8. ES-HR-MS: m/z calcd for C20H20O6: 356.1260; [M þ H]þ:
357.1338; found: 357.1539.
2,4-Dinitro-6-(methoxycarbonyl)phenyl 2,3:4,6-Di-O-
benzylidene-a-D-mannopyranoside (8-exo)
In a 10-mL flask the dibenzylidene-protected mannose 7-exo (35 mg,
98 mmol) and Li2CO3 (15 mg, 0.20 mmol) were suspended in dry DCM.
DISAL-F 2 (29 mg, 0.12 mmol) was added followed by a solution of DMAP
(3.5 mg, 31 mmol) dissolved in DCM (0.3 mL) added in five portions over
20 min. The solution gradually changed from colorless to strong orange.
After 1 h the reaction mixture was purified by VLC (DCM) to give the title
1
compound as yellow foam (52 mg, 91%). H NMR (300 MHz, CDCl3): d 8.90
(d, 1H, J ¼ 3.0 Hz), 8.72 (d, 1H, J ¼ 3.0 Hz), 7.55–7.36 (m, 10H, ArH), 6.30
(s, 1H, PhCHO2), 5.76 (s, 1H, H-1), 5.61 (s, 1H, PhCHO2), 4.81 (dd, 1H,
J ¼ 8.2 Hz, J ¼ 5.8 Hz, H-3), 4.69 (d, 1H, J ¼ 5.8 Hz, H-2), 4.27 (dd, 1H,
J ¼ 9.3 Hz, J ¼ 4.4 Hz, H-6), 3.91 (dd, 1H, J ¼ 9.3 Hz, J ¼ 8.2 Hz, H-4), 3.89
(s, 3H, OMe), 3.76 (ddd, 1H, J ¼ 9.8 Hz, J ¼ 9.3 Hz, J ¼ 4.4 Hz, H-5), 3.68
(dd, 1H, J ¼ 9.8 Hz, J ¼ 9.3 Hz, H-60). 13C NMR (75 MHz, CDCl3): d 162.9,
153.0, 146.0, 143.0, 138.2, 136.9, 130.1–123.4 (m, ArH), 104.5, 103.3, 102.0
(C-1), 76.4, 75.4, 75.3, 68.3, 63.8, 53.7. Hetero-nuclear coupling constant
1JC1,H1 ¼ 180.6 (a). ES-HR-MS: m/z calcd for C28H24N2O12: 580.1329;
[M þ H]þ: 581.1408; found: 581.1420.

Benzylidene b-Mannosylation Without Triflate?
363
4-Methylphenyl 4,6-O-Benzylidene-1-thio-a-D-
mannopyranoside (10)
4-Methylphenyl 2,3,4,6-tetra-O-acetyl-1-thio-a-D-mannopyranoside (9)[10]
(4.4 g, 9.7 mmol) was dissolved in dry MeOH (35 mL) and treated with
NaOMe in dry MeOH (33% w/v, 4.6 mL) for 2.5 h. The solution was neutralized
with Dowex 50W-X8 (Hþ-form, 200–400 mesh) ion-exchange resin, filtered,
and passed through a layer of sand and silica gel, which after evaporation
yielded crude 4-methylphenyl 1-thio-a-D-mannopyranoside. The crude
4-methylphenyl 1-thio-a-D-mannopyranoside (1.67 g, 5.8 mmol) was dissolved
in DMF (7 mL) and cooled to 08C. Benzaldehyde dimethylacetal (879 mL,
.
5.8 mmol) and HBF4 OEt2 (54% Et2O solution, 640 mL, 4.7 mmol) were
added at 08C, and the solution were stirred at rt overnight. Et3N (1 mL) was
added, and the mixture was poured into water (10 mL) and the formed precipi-
tate was filtered, washed with cold Et2O, and purified by VLC (DCM-MeOH
1:0 ! 9:1) to give 10 as fine white crystals (1.44 g, 79%), mp 213–2148C (crys-
tallized from MeOH). [a]D ¼ –54.6 (c 8.08 ꢀ 1023 CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.45–7.13 (m, 10H, ArH), 5.59 (s, 1H, PhCHO2), 5.37 (d, 1H,
J ¼ 5.1 Hz, H-1), 5.18 (m, 2H, 2 ꢀ OH), 4.16 (dd, 1H, J ¼ 4.6 Hz, J ¼ 9.9 Hz,
H-6), 3.95 (m, 1H, H-2), 3.82–3.69 (m, 3H, H-3, H-4, H-6), 3.43 (m, 1H, H-5),
2.27 (s, 3H, Ph-CH3). 13C NMR (75 MHz, CDCl3): d 137.9, 135.8, 132.2, 129.8-
126.2 (m, ArC), 101.0, 87.6 (C-1), 78.1, 72.7, 70.4, 67.8, 20.5. ES-HR-MS: m/z
calcd for C20H22O5S: 374.1188; [M þ H]þ: 375.1266; found: 375.1246.
p-Methylphenyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1-thio-
a-D-mannopyranoside (11)
NaH (ca 60% in mineral oil, 500 mg) in DMF (6 mL) was added to a 08C
cold solution of 10 (1.6 g, 4.3 mmol) in DMF (20 mL) and the mixture was
stirred for 30 min. To the mixture was added benzyl bromide (1.4 mL,
11.8 mmol), and the reaction was stirred for 19 h. MeOH (5 mL) was added,
and the reaction mixture was concentrated at reduced pressure, poured
into H2O, and extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated at reduced pressure.
The residue was purified by column chromatography (EtOAc/hexane ¼ 1/9)
to give 11 (1.6 g, 67%) as colorless crystals. mp 153–1598C (crystallized
from hexane and EtOAc). [a]D ¼ –39.3 (c 7.83 ꢀ 1023 CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.54–7.11 (m, 20H, ArH), 5.65 (s, 1H, PhCHO2), 5.13–
4.73 (m, 4H, Ph-CH), 4.81 (d, 1H, J ¼ 1.1 Hz, H-1), 4.36–4.29 (m, 2H, H-4,
H-6), 4.20 (dd, 1H, J ¼ 3.0 Hz, J ¼ 1.1 Hz, H-2), 3.96 (dd, 1H, J ¼ 10.4 Hz,
H-6), 3.75 (dd, 1H, J ¼ 9.8 Hz, J ¼ 3.1 Hz, H-3), 3.41 (ddd, 1H, J ¼ 14.4 Hz,
J ¼ 5.0 Hz, J ¼ 5.0 Hz, H-5), 2.35 (s, 3H, Ph-CH3). 13C NMR (75 MHz,
CDCl3): d 138.5–137.0 (m, ArC), 132.3–126.1 (m, ArC), 101.4, 89.6 (C-1),

K. Worm-Leonhard et al.
364
79.9, 79.0, 78.8, 75.9, 73.2, 71.7, 69.0, 68.5, 21.1. ES-MS: m/z calcd for
C34H34O5S: 554.21; [M þ H]þ: 555.22; found: 555.25. [M þ Na]þ: 577.20;
found: 577.22. Anal. Calcd. for C34H34O5: C, 73.62; H, 6.18. Found: C, 73.24;
H, 6.12.
2,3-Di-O-benzyl-4,6-O-benzylidene-a/b-D-mannopyranose
(12)
N-Bromosuccinimide (0.61 g, 3.4 mmol) was added at rt to a stirred solution
of 11 (0.5 g, 0.9 mmol) in 9:1 acetone:water (22 mL). Stirring was continued for
20 min after which the solvent was concentrated until turbidity arose. The
residue was dissolved in EtOAc (30 mL), washed with a saturated solution of
Na2CO3 (3 ꢀ 10 mL) and water (3 ꢀ 10 mL), dried over anhydrous Na2SO4,
and concentrated to dryness. The residue was purified by column chromato-
graphy (EtOAc/hexane ¼ 3:2), yielding 12 (330 mg, 82%) as colorless syrup.
ES-HR-MS: m/z calcd for C27H28O6: 448.1886; [M þ H]þ: 448.1964; found:
448.1989. The observed NMR data were identical with literature values.[13b]
2,4-Dinitro-6-(methoxycarbonyl)phenyl 2,3-Di-O-benzyl-4,6-
O-benzylidene-a-D-mannopyranoside (13)
To a stirred suspension of 12 (300 mg, 0.67 mmol) and Li2CO3 (100 mg,
1.35 mmol) in dry DCM (10 mL) was added DISAL-F 2 (197 mg, 0.81 mmol).
DMAP (25 mg, 0.2 mmol) was dissolved in DCM (2 mL) and added in five
portions over 20 min. Upon addition of DMAP the solution changed from color-
less to orange. After 40 min the reaction mixture was purified by VLC (DCM) to
give the title compound as yellow foam (417 mg, 93%,). [a]D ¼ –11.0 (c
1
8.25 ꢀ 1023 CHCl3). H NMR (300 MHz, CDCl3): d 8.84 (d, 1H, J ¼ 2.7 Hz),
8.72 (d, 1H, J ¼ 2.9 Hz), 7.54–7.28 (m, 15H, ArH), 5.63 (s, 1H, PhCHO2),
5.52 (d, 1H, J ¼ 1.3 Hz, H-1a), 4.93–4.66 (m, 4H, Ph-CH), 4.42 (dd, 1H,
J ¼ 3.2 Hz, J ¼ 1.3 Hz, H-2), 4.32 (dd, 1H, J ¼ 9.5 Hz, H-6), 4.18–4.09
(m, 2H, H-3, H-60), 3.97 (s, 3H, OMe), 3.82 (m, 2H, H-4, H-5). 13C NMR
(75 MHz, CDCl3): d 162.9 153.0, 145.4, 142.4, 138.4, 137.8, 137.3, 129.4–
123.1 (m, Ar), 105.5, 101.5 (C-1), 77.6, 76.3, 75.7, 74.1, 73.4, 68.2, 67.3, 53.5
(OMe). ES-MS: m/z calcd for C35H32N2O12: 672.20; [M þ H]þ: 673.20; found:
673.24. [M þ Na]þ: 695.19; found: 695.20. Anal. Calcd. for C35H32N2O12: C,
62.50; H, 4.80. Found: C, 61.44; H, 4.61.
Optimization of glycosylation conditions (Table 2)
Conventional heating: The glycosyl donor (0.027 to 0.05 mmol) was dis-
solved in dry NMP (1 mL) in a micro centrifuge tube (Plasticbrand), and

Benzylidene b-Mannosylation Without Triflate?
365
˚
crushed 3 A molecular sieves and cyclohexanol (5 eq.) were added. The tube
was stirred at 708C during, and the progress of the reactions was moni-
tored by HPLC and TLC (30% EtOAc in hexane). Evaporation of the
solvent was followed by purification by either VLC chromatography (hexa-
ne:EtOAc 18:1 ! 1:1) or preparative HPLC to give product indicated by
Table 2.
Microwave heating: Glycosyl donor (typically 0.05 mmol) was dissolved in
either dry methanol or NMP (500 mL), and in the case of NMP, cyclohexanol
(0.25 mmol) was added followed by mixing. The reaction mixture was subjected
to microwave radiation (reaction time and temperature, see Table 2); a sample
(12 mL) was diluted in acetonitrile (0.7 mL) and analyzed by analytical HPLC.
From a series of test reactions, the product was purified by preparative HPLC
and characterized by NMR and ES-MS.
Methyl 2,3-Di-O-benzyl-4,6-O-benzylidene-a/b-D-
mannopyranoside (14)
The observed NMR data were identical with literature values.[24]
Cyclohexyl 2,3-Di-O-benzyl-4,6-O-benzylidene-a/b-D-
mannopyranoside (15)
The observed NMR data were identical with literature values.[3c]
General procedure for the microwave-assisted
glycosylation reactions (Tables 3 and 4)
Glycosyl donor (0.075 mmol, 1,5 equiv.); glycosyl acceptor (0.05 mmol, 1
˚
equiv.); activators and additives if required (see Tables); crushed 3 A molecu-
lar sieves; and a magnet were placed in a 5-mL microwave reaction vial and
fitted with a septum, which was then pierced with a needle. The closed vial
was then evacuated under high vacuum; Ar was let in followed by re-evacua-
tion. This cycle was repeated twice and then left to dry for 1 to 2 h. Ar was let
in, the needle was removed, and dry solvent (500 mL) was added under
argon. The reaction mixture was subjected to microwave radiation for
5 min at 1008C (unless stated otherwise), transferred to a 15-mL Falcon
plastic tube, and centrifuged for 3 min at 4000 rpm, and the supernatant
was transferred to a new 15-mL Falcon plastic tube and concentrated to
dryness under a stream of air. The residue was loaded onto a preparative
HPLC column with 2 mL of CH3CN and purified, followed by evaporation
of appropriate fractions.

K. Worm-Leonhard et al.
366
1,2;3,4-Di-O-isopropylidene-6-O-(2,3-di-O-benzyl-4,6-O-
benzylidene-a/b-D-mannopyranosyl)-a-D-
galactopyranoside (17)
The observed NMR data were identical with literature values.[3c]
2,3-Di-O-benzyl-4,6-O-benzylidene-a/b-D-mannopyranosyl
trichloroacetimidate (18)
A solution of 12 (336 mg; 0.75 mmol) and trichloroacetonitrile (1 mL) in dry
CH2Cl2 (10 mL) was stirred vigorously with anhydrous K2CO3 (0.5 g) overnight
at rt under Ar atmosphere. The mixture was diluted with dry Et2O (10 mL) and
filtered through a layer of sand and silica gel. The silica gel layer was washed
several times with Et2O and the combined filtrates were evaporated to give the
trichloroacetimidate 18 (330 mg, 75%, a/b 5:1) in a chromatographically pure
form as colorless syrup. Observed NMR data were identical with literature
values.[4]
1,2;5,6-DI-O-ISOPROPYLIDENE-3-O-(2,3-DI-O-BENZYL-4,6-O-
BENZYLIDENE-a/b-D-MANNOPYRANOSYL)-a-D-
GLUCOFURANOSIDE (20)
The observed NMR data were identical with literature values.[3c]
ACKNOWLEDGMENTS
Financial support from the Lundbeck Foundation, the Torkil Holm’s Foun-
dation, and the Hede-Nielsen Foundation is acknowledged.
REFERENCES
[1] Varki, A. Biological roles of oligosaccharides–all of the theories are correct.
Glycobiology 1993, 3, 97–130.
[2] Dembitsky, V.M. Chemistry and biodiversity of the biologically active natural
glycosides. Chem. Biodiv. 2004, 1, 673–781.
[3] (a) Crich, D.; Sun, S.X. Formation of beta-mannopyranosides of primary alcohols
using the sulfoxide method. J. Org. Chem. 1996, 61, 4506–4507; (b) Crich, D.;
Sun, S.X. Direct synthesis of beta-mannopyranosides by the sulfoxide method.
J. Org. Chem. 1997, 62, 1198–1199; (c) Crich, D.; Sun, S. Direct chemical synthesis
of b-mannopyranosides and other glycosides via glycosyl triflates. Tetrahedron
1998, 54, 8321–8348; (d) Crich, D.; Cai, W. Chemistry of 4,6-O-benzylidene-D-gly-
copyranosyl triflates: contrasting behavior between the gluco and manno series.
J. Org. Chem. 1997, 64, 4926–4930; (e) Crich, D.; Chandrasekera, N.S. Mechanism
of 4,6-0-benzylidene-directed beta-mannosylation as determined by alpha-deuter-
ium kinetic isotope effects. Angew. Chem. Int. Ed. 2004, 43, 5386–5389.

Benzylidene b-Mannosylation Without Triflate?
367
[4] Weingart, R.; Schmidt, R.R. Can preferential b-mannopyranoside formation with
4,6-O-benzylidene protected mannopyranosyl sulfoxides be reached with trichlor-
oacetimidates. Tetrahedron Lett. 2000, 41, 8753–8758.
[5] Nagai, H.; Sasaki, K.; Matsumura, S.; Toshima, K. Environmentally benign beta-
stereoselective glycosidations of glycosyl phosphites using a reusable hetero-
geneous solid acid, montmorillonite K-10. Carb. Res. 2005, 340, 337–353.
[6] Jensen, K.J. O-Glycosylations under neutral or basic conditions. J. Chem. Soc.
Perkin Trans. 1 2002, 2219–2233.
[7] (a) Petersen, L.; Jensen, K.J. A new, efficient glycosylation method for oligosacchar-
ide synthesis under neutral conditions: preparation and use of new DISAL donors.
J. Org. Chem. 2001, 66, 6268–6275; (b) Petersen, L.; Jensen, K.J. DISAL glycosyl
donors for efficient glycosylations under acidic conditions: application to solid-
phase oligosaccharide synthesis. J. Chem. Soc. Perkin Trans. 1 2001, 2175–2182;
(c) Laursen, J.B.; Petersen, L.; Jensen, K.J. Intramolecular glycosylation under
neutral conditions for synthesis of 1,4-linked disaccharides. Org. Lett. 2001, 3,
687–690; (d) Petersen, L.; Laursen, J.B.; Larsen, K.; Motawia, M.S.; Jensen, K.J.
DISAL glycosyl donors for the synthesis of a linear hexasaccharide under mild con-
ditions. Org. Lett. 2003, 5, 1309–1312; (e) Laursen, J.B.; Petersen, L.; Jensen, K.J.;
Nielsen, J. Efficient synthesis of glycosylated phenazine natural products and
analogs with DISAL (methyl 3,5-dinitrosalisylate) glycosyl donors. Org. Biomol.
Chem. 2003, 1, 3147–3153; (f) Grathe, S.; Thygesen, M.B.; Larsen, K.;
Petersen, L.; Jensen, K.J. Glucosamine derived DISAL donors for stereoselective
glycosylations under neutral conditions. Tetrahedron Asymm. 2005, 16,
1439–1448; (g) Larsen, K.; Worm-Leonhard, K.; Olsen, P.; Hoel, A.; Jensen, K.J.
Reconsidering glycosylations at high temperature: precise microwave heating.
Org. Biomol. Chem. 2005, 3, 3966–3970.
´
´ ´
[8] Liptak, A.; Imre, J.; Harangi, J.; Nanasi, P. Hydrogenolysis of the isomeric 1,2-4,6-
di-O-benzylidene-a-D-glucopyranose derivatives with the LiAlH4-AlCl3 reagent.
Carb. Res. 1983, 116, 217–225.
[9] Classon, B.; Garegg, P.J.; Samuelsson, B. The p-methoxybenzyl group as protective
group of the anomeric centre. Selective conversions of hydroxy groups into bromo
groups in p-methoxybenzyl 2-deoxy-2-phthalimido-b-D-glycopyranoside. Acta
Chem. Scand. B. 1984, 38, 419–422.
[10] Zhang, Z.Y.; Ollmann, I.R.; Ye, X.S.; Wischnat, R.; Baasov, T.; Wong, C.H. Program-
mable one-pot oligosaccharide synthesis. J. Am. Chem. Soc. 1999, 121, 734–753.
[11] (a) Bogusiak, J.; Szeja, W. Synthesis of 1-thioglycosides in a catalytic two-phase
system. Pol. J. Chem. 1985, 59, 293–298; (b) Tropper, F.D.; Anderson, F.O.;
ˆ
Grand-Maıtre, C.; Roy, R. Stereospecific synthesis of 1,2-trans-1-phenylthio-b-D-
disaccharides under phase transfer catalysis. Synthesis 1991, 734–736;
(c) Larsen, K.; Olsen, C.E.; Motawia, M.S. A facile protocol for direct conversion
of unprotected sugars into phenyl 4,6-O-benzylidene-per-O-acetylated-1,2-trans-
thioglycosides. Carbohydr. Res. 2003, 338, 199–202.
[12] Kartha, K.P.R.; Jennings, H.J. A simplified, one-pot preparation of acetobromosu-
gars from reducing sugars. J. Carbohydr. Chem. 1990, 9, 777–781.
[13] (a) Oshitari, T.; Tomita, M.; Kobayashi, S. New method for the preparation of
L-gulose from D-mannose - synthetic study on the sugar moiety of bleomycin. Tet-
rahedron Lett. 1994, 35, 6493–6494; (b) Oshitari, T.; Shibasaki, M.; Yoshizawa, T.;
Tomita, M.; Takao, K.; Kobayashi, S. Synthesis of 2-O-(3-O-carbamoyl-alpha-D-
mannopyranosyl)-L-gulopyranose: sugar moiety of antitumor antibiotic bleomycin.
Tetrahedron 1997, 53, 10993–11006.

K. Worm-Leonhard et al.
368
[14] Motawia, M.S.; Marcussen, J.; Møller, B.L. A general method based on the use of
N-bromosuccinimde for removal of the thiophenol group at the anomeric position
to generate a reducing sugar with the original protecting groups still present.
J. Carbohydr. Chem. 1995, 14, 1279–1294.
[15] (a) Kappe, C.O. Controlled microwave heating in modern organic synthesis.
Angew. Chem. Int. Ed. 2004, 43, 6250–6284; (b) Hayes, B.L. Recent advances in
microwave-assisted synthesis. Aldrichimica Acta 2004, 37, 66–76.
[16] Yoshimura, Y.; Shimizu, H.; Hinou, H.; Nishimura, S.I. A novel glycosylation
concept; microwave-assisted acetal-exchange type glycosylations from methyl gly-
cosides as donors. Tetrahedron Lett. 2005, 46, 4701–4705.
[17] Jensen, H.H.; Nordstrom, L.U.; Bols, M. The disarming effect of the 4,6-acetal
group on glycoside reactivity: torsional or electronic? J. Am. Chem. Soc. 2004,
126, 9205–9213.
[18] Bell, D.J.; Lorber, J. Use of the benzyl radical in syntheses of methylated sugars.
Part I. 4:6-Dimethyl glucose. J. Chem. Soc. 1940, 453–455.
[19] Madsen, J.; Viuf, C.; Bols, M. A new method for the deprotection of benzyl ethers or
the selective protection of alcohols. Chem. Eur. J. 2000, 6, 1140–1146.
[20] Ishikawa, T.; Shimizu, Y.; Kudoh, T.; Saito, S. Conversion of D-glucose to cyclitol
with hydroxymethyl substituent via intramolecular silyl nitronate cycloaddition
reaction: application to total synthesis of (þ)-cyclophellitol. Org. Lett. 2003, 5,
3879–3882.
[21] Garegg, P.J.; Iversen, T.; Oscarson, S. Monobenzylation of diols using phase-
transfer catalysis. Carbohydr. Res. 1976, 50, C12–C14.
[22] Bonner, W.A. Isomers of tetra-O-acetyl-D-mannopyranose. J. Am. Chem. Soc. 1958,
80, 3372–3379.
[23] Mori, M.; Ito, Y.; Ogawa, T. Total synthesis of the mollu-series glycosyl ceramides:
a-D-ManP-(1 ! 3)-b-D-ManP-(1 ! 4)-b-D-GlcP-(1 ! 1)-Cer
and
a-D-ManP-
(1 ! 3)-[b-D-XylP-(1 ! 2)]-b-D-ManP-(1 ! 4)-b-D-GlcP-(1 ! 1)-Cer. Carbohydr.
Res. 1990, 195, 199–224.
[24] Crich, D.; Banerjee, A.; Yao, Q.J. Direct chemical synthesis of the b-D-mannans: the
b-(1 ! 2) and b-(1 ! 4) series. J. Am. Chem. Soc. 2004, 126, 14930–14934.