On the mechanism of p-methoxybenzylidene assisted intramolecular aglycon delivery

Article abstract of DOI:10.1016/S0040-4020(01)00300-3

p-Methoxybenzylidene-assisted intramolecular aglycon delivery was developed in this laboratory and has been demonstrated to be highly efficient and versatile particularly for the synthesis of complex glycoprotein-related glycans. It was revealed that the reaction course of IAD can be clearly monitored by performing the reaction in an NMR tube. Our results suggest that the nonhydrolytic pathway that converts metastable intermediate 3 to the product is functional. Comparative experiments in the presence and absence of water in the reaction media afforded supporting evidence eliminating the possibility of fortuitous contamination of water under standard IAD conditions.

Full text of DOI:10.1016/S0040-4020(01)00300-3

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 4123±4132
On the mechanism of p-methoxybenzylidene assisted
intramolecular aglycon delivery
Yukishige Ito,p Hiromune Ando, Megumi Wada, Tsubasa Kawai, Yuki Ohnish
²
and Yoshiaki Nakahara
RIKEN ꢀThe Institute of Physical and Chemical Research) and CREST, Japan Science and Technology Corporation ꢀJST), 2-1 Hirosawa,
Wako-shi, Saitama 351-0198, Japan
Received 31 January 2001; accepted 12 March 2001
AbstractÐp-Methoxybenzylidene-assisted intramolecular aglycon delivery was developed in this laboratory and has been demonstrated to
be highly ef®cient and versatile particularly for the synthesis of complex glycoprotein-related glycans. It was revealed that the reaction
course of IAD can be clearly monitored by performing the reaction in an NMR tube. Our results suggest that the nonhydrolytic pathway that
converts metastable intermediate 3 to the product is functional. Comparative experiments in the presence and absence of water in the reaction
media afforded supporting evidence eliminating the possibility of fortuitous contamination of water under standard IAD conditions. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
be expected.2±4 In this approach, aglycon is ®rst connected
to the axially oriented C-2 hydroxy group of the mannosyl
donor, by a certain type of tether.
Among various approaches to achieve the stereocontrolled
formation of b-manno glycoside,1 the one called intra-
molecular aglycon delivery 5IAD) is particularly attractive,
because exclusive formation of the correct stereoisomer can
p-Methoxybenzylidene-assisted IAD using donor
5Scheme 1) was developed in this laboratory4±6 and has
1
Scheme 1. Presumed reaction pathway of p-methoxybenzylidene-assisted intramolecular aglycon delivery.
Keywords: intramolecular aglycon delivery; glycoprotein; oligosaccharides; stereoselective; glycosylation.
Corresponding author. Tel.: 181-48-467-9430; fax 181-48-462-4680; e-mail: yukito@postman.riken.go.jp
p
²
Alternative address: Department of Industrial Chemistry, Tokai University, Hiratsuka-shi, Kanagawa 259-1292, Japan
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00300-3

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Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
been demonstrated to be highly ef®cient and versatile par-
ticularly for the synthesis of complex glycoprotein-related
oligosaccharides. This reaction takes advantage of the facile
formation of mixed acetal 2 under oxidative conditions.7
Subsequent activation of the mannose anomeric position
triggers IAD to give b-glycoside 4.
groups would be a subject of concern. In order to see if 3
is actually produced in substantial concentration during the
course of IAD, the progress of the reaction was monitored
1
by H-NMR. For this purpose, fructose-derived 9a10 and
4,6-O-cyclohexylidene-protected thiomannoside 5a were
used as glycosyl acceptor 5aglycon) and donor, respectively
5Scheme 3). Since 9a is devoid of the anomeric proton,
analysis of 1H-NMR was expected to be greatly simpli®ed.
This method has several attractive features; 51) various
methods for the introduction of O-p-methoxybenzyl
5PMB) group have been established, 52) the conditions
required for the formation of the mixed acetal are mild
and near neutral, which may well be compatible with the
presence of various types of protecting groups, and 53)
compared to other IAD systems developed previously,
more ef®cient charge delocalization and therefore clean
IAD by a mesomerically stabilized transition state can be
expected in this system, due to the assistance of an electron
donating p-methoxyphenyl group.
2. Results and discussion
Previously reported 5a6 was prepared in a modi®ed manner
as depicted in Scheme 4. Thus, methyl 1-thio-a-d-manno-
pyranoside 514) was treated with cyclohexanone dimethyl-
acetal and camphorsulfonic acid 5CSA) to provide 4,6-O-
cyclohexylidene-protected 15. Subsequent transformation
to bis-acetal 16 was effected by p-anisaldehyde dimethyl-
acetal and pyridinium p-toluenesulfonate 5PPTS), which
was followed by chemo- and regioselective ring opening
with diisobutyl aluminum hydride 5DIBAL-H)11 in toluene
to afford 2-O-PMB derivative 17 as the major product,12
together with a small amount of corresponding regioisomer
in a ratio of 20:1. Subsequent silylation under standard
conditions gave 5a.
In particular, IAD using 4,6-O-cyclohexylidene-protected
thioglycoside 5a proved to be a highly ef®cient donor. For
instance, reaction with glucosamine-derived acceptor 6
afforded 83% yield of 7 which corresponds to the core
disaccharide 5Manb1!4GlcNAc) of an Asn-linked glycan
chain6 5Scheme 2). The synthesis of complex-type undeca-
saccharide 8 was achieved using this reaction.8 Quite
interestingly, the formation of the mixed acetal 2 was
revealed to be a remarkably stereoselective process and
the absolute con®guration of the acetalic carbon was
assigned S 5Scheme 1).9
The formation of the mixed acetal 10a from 5a and 9a
51.3equiv.) was performed under our standard conditions
51.25 equiv. DDQ, MS 4 A, CH2Cl2, r.t., 130 min). After
reductive work-up13 and puri®cation by size exclusion
chromatography on Bio Beads SX-35Bio Rad) eluted with
toluene, mixed acetal 10a [dH 5.85 5acetal CH), 5.44
5H-1Man) was obtained in a quantitative yield 5Scheme 3).
Subsequent IAD was performed in an NMR tube in the
presence of MeOTf14 and 2,6-di-tert-butyl-4-methylpyri-
dine 53.3 equiv. each) and powdered molecular sieves 4 A
in CDCl3 at 358C. As seen from Fig. 1, the progress of the
On the other hand, analysis of the assumed reaction pathway
5Scheme 1) gave rise to a simple question. Immediate
product after successful glycoside bond formation would
most likely be a quinonemethide 5or benzyl cation) like
species 3, which eventually collapses to the end-product 4
and p-anisaldehyde most understandably after aqueous
work-up.
1
reaction can be clearly monitored by H-NMR. The most
diagnostic was the decrease of the signals of mixed acetal
CH 5d 5.85) and H-1Man 5d 5.44).
Such an assumption seems to be potentially hazardous. With
the accumulation of a highly reactive species like 3, stability
of an oligosaccharide that includes various functional
A new set of signals 5d 5.77 and 5.40) was observed at the
Scheme 2. Typical results of b-mannosylation.

Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
4125
Scheme 3. Formation of Manb1!3Fru 513) by intramolecular aglycon delivery.
Scheme 4. Preparation of the mannosyl donor.

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Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
Figure 1. Starting from 10a, the reaction course of IAD was followed by 1H-NMR 5CDCl3, 270 MHz, 358C): 5a), 5 min; 5b), 10 min; 5c), 20 min.
early stage of the reaction 5see asterisks). The transient
species observed here may be assignable as either cationic
intermediate 11 or b-thioglycoside 10c derived from
anomerization of 10a, possibly via 11. Since the anomeric
proton of pyranosides carrying a positively charged sub-
stituent at C-1 is expected to appear at lower ®eld compared
to the parent neutral species,15 the latter possibility would be
more likely. The stereochemical scrambling of the acetalic
carbon was initially conceived. However, this possibility
was excluded by a comparative experiment using diastereo-
meric acetal 10b 5vide infra).
10a 5Fig. 1) and 10b 5Fig. 3) were clearly distinct from 10b
and 10a, respectively. Therefore, the possibility of the inter-
conversion between two diastereomers, 10a and 10b,
during IAD can be excluded. Secondly, the reaction of
R-con®gured 10b turned out to be less ef®cient, in terms
of both reaction kinetics and ef®ciency. Namely, IAD of
10b was ca. 50% completion after 220 min, while 10a
was completely consumed after 160 min 5Fig. 3). After
24 h, product 13 was isolated in 32% yield which was
substantially lower than that obtained from 10a 576%).
Since it was previously observed that 3-O-TMS-protected
donor 18 gave cyclic acetal 21 as the b-mannoside product
5Scheme 5), it is quite probable that IAD of mixed acetal 19
®rst gives metastable cationic product 20, which is
immediately quenched intramolecularly to give 21 5instead
of 22). On the other hand, in the case of reaction using 5a,
C-3oxygen of 12 is probably not competent for intra-
molecular participation, because of the steric hindrance of
the TBDPS group.
After 160 min, it was observed that the product 13 having
liberated 2-OH was produced quite cleanly together with an
equimolar amount of p-anisaldehyde 5Fig. 2). Therefore, the
formation of the end-product 13 does not seem to require
aqueous work-up. With a closer look at the NMR spectrum,
it was noticed that H-2Man 5d 3.58) of 13 present in the
reaction mixture had a signal broadening, compared to the
same signal of the puri®ed material. It probably means that
the product 13 had a C-2 hydroxy group deuterated 5at least
partially), suggesting the intermediacy of an oxy-radical-
like species which abstracts deuterium from the solvent
CDCl3. The same reaction was performed in a preparative
scale 578 mmol) in CH2Cl2 57 ml) to afford 13 in 76% yield
based on 5a.
Of course the possibility of the contamination of water in
the reaction mixture cannot be readily excluded. In fact,
addition of base 52,6-di-tert-butyl-4-methylpyridine) seem
to be an absolute requirement for successful IAD. Its
absence resulted in the rapid decomposition of the mixed
acetal to afford a complex mixture. Therefore, under our
experimental conditions, a trace amount of water may be
present and generates acidic species 5e.g. trifric acid).
Compared to conventional glycosylation, IAD might well
be more resistant to moisture because of its intramolecular
nature. It can be argued that contamination of water may
simply help quenching the initial product 3 into 4 without
affecting the ef®ciency of the aglycon transfer step.
However, in a separate experiment using glucosamine-
derived 6 as an acceptor, it was demonstrated that the
ef®ciency of IAD is not totally insensitive to the presence
of water 5Scheme 6). The presence of 1.6 and 10 equiv. of
In contrast, the DDQ-mediated reaction of 2-O-unprotected
thiomannoside 5b 5prepared from 15, see Scheme 4) and
3-O-PMB-protected fructose derivative 9b afforded dia-
stereomeric mixed acetal 10b [dH 5.90 5acetal CH), 4.66
5H-1Man)] as the major isomer 5,10:1). NMR experiment
5see Fig. 1 and 3) as well as preparative scale reaction
revealed several interesting aspects of IAD. Firstly, con-
®gurational rigidity of the acetal carbon was retained with
no indication of the stereochemical scrambling between
10a,b throughout the course of IAD. It is to be noted that
the transiently observed species 5see asterisks) derived from

Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
4127
Figure 2. IAD was nearly complete after 160 min at 358C. Comparison of 1H-NMR 5CDCl3, 270 MHz): 5a), reaction mixture 5358C); 5b), puri®ed product 13
5room temperature).

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Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
Figure 3. 1H-NMR pro®le of IAD starting from diastereomeric mixed acetal 10b 5358C, 220 min).
Scheme 5. Formation of cyclic acetal containing b-mannoside from the 3-O-TMS-protected donor 18.

Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
4129
Scheme 6. Intramolecular aglycon delivery under water containing conditions.
H2O results in the formation of the IAD product 7 in 54%
and 17% yield, respectively, while the same product was
obtained in 83% yield under anhydrous conditions. It is
highly unlikely that a stoichiometric amount 5but less than
1.6 equiv.) of water constantly exists in the reaction mixture
of IAD. NMR analysis 5Fig. 3) suggested the intermediacy
of an oxy-radical species 5vide supra). The initial formation
of quinonemethide-like 12 may well be a reasonable
premise. However, its lifetime seems to be rather short,
being undetectable by NMR, and the subsequent pathway
is triggered immediately.16
26.1 mmol) was dissolved in MeCN±DMF 51:2, 150 ml)
containing camphorsulfonic acid 50.303 g, 1.3 mmol),
cyclohexanone dimethylacetal 57.8 ml, 52 mmol) and
Drierite 55 g) and the mixture stirred for 1.5 h and
exposed to vacuum 5,10 mmHg) to remove methanol.
After being stirred for an additional 0.5 h, the reaction
was quenched with triethylamine and ®ltered through
Celite. The ®ltrate was evaporated in vacuo and the residue
was chromatographed over silica gel 5hexane±AcOEt 3:1)
to afford 6.01 g 579%) of the title compound as a crystalline
solid; mp 98±1008C; [a]Dˆ1182.6 5c 1.0, CHCl3);
1H-NMR 5CD3OD, 400 MHz) d 5.11 51 H, s, H-1),
4.04 51 H, t, Jˆ9.5 Hz, H-6), 3.94 51 H, d, Jˆ3.9 Hz),
3.90 51 H, d, Jˆ9.5 and 4.4 Hz, H-60), 3.84 51 H, t,
Jˆ10.1 Hz, H-4), 3.75±3.68 52 H, m, H-3,5), 2.10 53 H, s,
SMe); 13C-NMR 5CD3OD, 100 MHz) d 101.2 5cyclo-
hexylidene), 88.8 5C-1), 74.0, 71.7, 70.4, 66.6. 62.5, 39.2,
29.0, 23.8, 23.6, 13.8 5MeS). Anal. Calcd for C13H22O5S:
C, 53.77; H, 7.64; S, 11.04. Found: C, 53.44; H, 7.44; S,
10.61.
Taken together, results presented here suggest that a non-
hydrolytic pathway, which leads 3 to 4, is functional in IAD,
although its precise nature is not clear at this moment.
3. Experimental
3.1. General methods
3.1.2. Methyl 4,6-O-cyclohexylidene-2,3-O-p-methoxy-
benzylidene-1-thio-a-d-mannopyranoside -16). A solu-
tion of compound 15 55.00 g, 17.2 mmol), p-anisaldehyde
dimethylacetal 53.8 ml, 22 mmol) and PPTS 50.28 g,
1.1 mmol) in MeCN 545 ml) was stirred at room tempera-
ture for 40 min. The mixture was quenched with Et3N and
evaporated in vacuo. The residue was coevaporated with
toluene and chormatographed over silica gel 5hexane±
AcOEt 15:1) to afford 5.13g 581%) of the title compound
Starting materials and reagents were purchased from
standard vendors and used without puri®cation unless other-
wise noted. All reactions sensitive to air or moisture were
carried out under nitrogen or argon atmosphere with
anhydrous solvents. Anhydrous solvents were purchased
from Kanto Chemical Co. 5Tokyo, Japan). Molecular sieves
were purchased from Nacalai Tesque 5Kyoto, Japan) and
activated by heating at 1808C under vacuum prior to use.
Analytical thin-layer chromatography 5TLC) was developed
on E. Merck Silica Gel 60 F256 plates 50.25 mm thickness).
Column chromatography was performed on E. Merck Silica
Gel 60 560±230 mesh or 130±400 mesh). Melting points
were determined with a BuÈchi 510 melting point apparatus
and uncorrected. Optical rotations were measured with a
JASCO DIP 370 polarimeter at ambient temperature
520^38C). NMR spectra were obtained on a JEOL
EX-270, EX-400, or a-400 spectrometer at ambient
1
as a mixture 5ca. 6:5) of diastereomers; H-NMR 5CDCl3,
400 MHz) 7.44 5d, Jˆ8.8 Hz), 7.36 5d, Jˆ8.8 Hz), 6.91 5d,
Jˆ8.8 Hz), 6.89 5d, Jˆ8.8 Hz), 6.18, 5.91, 5.52 and 5.46 5s,
acetal CH and H-1), 4.5±3.7 5m, 6 H), 3.82 and 3.81 5s,
OMe), 2.13and 2.11 5s, SMe), 2.0±1.35m, 10 H, cyclo-
hexylidene). Anal. Calcd for C21H28O6S: C, 61.74; H, 6.91.
Found: C, 61.62; H, 6.94.
1
3.1.3. Methyl 4,6-O-cyclohexylidene-2-O-p-methoxy-
benzyl-1-thio-a-d-mannopyranoside -17). To a stirred
solution of compound 16 5280 mg, 0.685 mmol) in toluene
56 ml) was added DIBAL 51.01 M toluene solution, 2.0 ml,
2.0 mmol) at 2408C. The mixture was stirred at the same
temperature for 30 min and quenched with an aqueous solu-
tion of Rochelle salt 56 ml). The mixture was stirred at room
temperature unless otherwise noted. H chemical shifts are
in parts per million 5d) adjusted to Me4Si at 0 ppm as an
internal reference. 13C chemical shifts were referenced with
CDCl3 at 77.0 ppm or with CD3OD at 49.0 ppm.
3.1.1. Methyl 4,6-O-cyclohexylidene-1-thio-a-d-manno-
pyranoside -15). Methyl 1-thiomannoside 14 55.481 g,

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Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
temperature for 1 h and extracted with AcOEt. The organic
layer was successively washed with water and brine, dried
over MgSO4 and evaporated in vacuo. Puri®cation by silica
gel column chromatography 5hexane±AcOEt 10:1) afforded
224 mg 580%) of 17.
3.1.6. 1,2;4,5-Di-O-isopropylidene-3-O-p-methoxybenzyl-
a-d-fructopyranose -9b). To a solution of compound 9a
5602 mg, 2.31 mmol) in DMF 510 ml) was added NaH
560%, 130 mg, 3.3 mmol) under ice-water cooling and stir-
red for 10 min. p-Methoxybenzyl chloride 50.44 ml,
3.0 mmol) was added dropwise and the mixture was stirred
at 08C to room temperature for 2 h. The reaction was
quenched with MeOH 5,0.1 ml), diluted with ether, washed
with water and brine, successively, dried over MgSO4 and
evaporated in vacuo. The residue was chromatographed
over silica gel 5hexane±AcOEt 3:1) to afford 858 mg
598%) of the title compound; [a]Dˆ282.35c, 0.2,
CHCl3); 1H-NMR 5CDCl3, 400 MHz) d 7.28 and 6.80
5each 2 H, d, Jˆ8.8 Hz, Ar), 4.88 and 4.60 5each 1H, d,
Jˆ11.6 Hz, CH2Ar), 4.37 51 H, dd, Jˆ7.1 and 5.6 Hz,
H-4), 4.21 51 H, dd, Jˆ5.6 and 2.7 Hz, H-5), 4.1351 H,
dd, Jˆ13.4 and 2.7 Hz, H-6), 4.02 51 H, d, Jˆ8.4 Hz,
H-1), 3.99 51 H, d, Jˆ13.4 Hz, H-60), 3.85 51 H, d,
Jˆ8.4 Hz, H-10), 3.80 53 H, s, OMe), 3.48 51 H, d,
Jˆ7.1 Hz, H-3), 1.55, 1.49, 1.40, and 1.39 5each 3 H, s,
isopropylidene); 13C-NMR 5CDCl3, 100 MHz) d 158.9,
130.1, 129.2, 113.5, 112.0, 108.9, 104.3, 77.8, 74.5, 73.8,
72.7, 71.8, 60.2, 55.2, 28.3, 27.0, 26.3, 26.1. Anal. Calcd for
C20H28O7: C, 63.14; H, 7.42. Found: C, 63.07; H, 7.47.
[a]Dˆ188.1 5c 0.96, CHCl3); 1H-NMR 5CDCl3, 400 MHz)
d 7.26 52 H, d, Jˆ8.3Hz, Ar), 6.88 52 H, d, Jˆ8.3Hz, Ar),
5.18 51 H, s, H-1), 4.64 and 4.50 5each 1H, d, Jˆ11.5 Hz),
3.79 53 H, s, OMe), 4.00±3.70 56 H, m), 2.06 53 H, s, SMe);
13C-NMR 5CDCl3, 100 MHz) d 159.5, 129.7, 129.3, 113.9,
100.0 5cyclohexylidene), 83.7, 79.4, 72.7, 71.4, 69.3, 64.9,
61.4, 55.3, 38.0, 28.0, 25.6, 22.8, 22.6, 13.7. Anal. Calcd for
C21H30O6S: C, 61.44; H, 7.37; S, 7.81. Found: C, 60.97; H,
7.07; S, 7.78.
3.1.4. Methyl 4,6-O-cyclohexylidene-2-O-p-methoxy-
benzyl-3-O-tert-butyldiphenylsilyl-1-thio-a-d-manno-
pyranoside -5a). To a solution of compound 17 50.52 g,
1.27 mmol) in acetonitrile containing imidazole 5256 mg,
3.76 mmol) was added t-BuPh2SiCl 50.66 ml, 2.5 mmol) at
08C. After being stirred at room temperature for 2 h, the
reaction was cooled down to 08C and quenched with
MeOH. The mixture was diluted with AcOEt, washed
successively with water and brine, dried 5Na2SO4) and
evaporated in vacuo. The residue was chromatographed
over silica gel 5hexane±AcOEt 10:1) to afford 0.75 g
591%) of the title compound; [a]Dˆ15.8 5c 1.1, CHCl3);
1H-NMR 5CDCl3, 400 MHz) d 7.78 54 H, m, Ar), 7.37 56 H,
m, Ar), 7.3±7.5 56 H, Ar), 7.10 52 H, d, Jˆ8.5 Hz, Ar), 6.79
52 H, d, Jˆ8.5 Hz, Ar) 4.82 51 H, s, H-1), 4.45 51 H, d,
Jˆ11.5 Hz, ArCH2), 4.22 51 H, d, Jˆ11.5 Hz, ArCH2),
4.20 52 H, bs), 4.19 51 H, d, Jˆ11.6 Hz, ArCH2), 3.9±3.7
53H, m), 3.77 53H, s, OMe), 3.22 51 H, bs), 1.88 53H, s,
SMe), 1.12 59 H, s, t-Bu); 13C-NMR 5CDCl3, 100 MHz) d
158.9, 136.4, 136.1, 135.8, 134.5, 133.3, 130.2, 129.6,
129.4, 129.2, 127.8, 127.6, 127.4, 127.2, 113.5, 99.8 5cyclo-
hexylidene), 84.7 5C-1), 79.8, 72.9, 71.5, 70.6, 65.8, 61.5
5CH2), 55.2, 38.1 5CH2), 28.0 5CH2), 27.0 5Me3C), 25.7
5CH2), 22.7 5CH2), 22.5 5CH2), 19.4 5Me3C), 13.7 5MeS).
Anal. Calcd for C37H48O6SSi: C, 68.48; H, 7.46. Found: C,
68.14; H, 7.50.
3.1.7. Formation of mixed acetal -10a). A mixture of
compounds 5a 5156 mg, 0.24 mmol) and 9a 581 mg,
0.31 mmol) and molecular sieves 4 A 50.25 g) in CH2Cl2
55 ml) was stirred at ice-water temperature. To the mixture
was added DDQ 568 mg, 0.30 mmol) with a positive ¯ush of
nitrogen and stirring continued at 08C for 5 min and at room
temperature for 130 min. The reaction was quenched with
an aqueous solution of ascorbic acid 50.7%)±citric acid
51.3%)±NaOH 50.9%) 510 ml). The resulting lemon-yellow
mixture was diluted with AcOEt and ®ltered through Celite.
The ®ltrate was washed successively with aqueous NaHCO3
and brine, and combined organic layers were dried over
Na2SO4 and evaporated in vacuo. The residue was puri®ed
by size exclusion chromatography with Bio Beads S-X3
5toluene) to afford 220 mg 5quantitative) of compound
1
10a; H-NMR 5CDCl3, 270 MHz) d 7.85±7.65 54 H, m,
Ar), 7.50±7.10 58 H, m, Ar), 6.90 52 H, m, Jˆ8.6 Hz, Ar),
5.85 51 H, s, acetal CH), 5.44 51 H, d, Jˆ1.0 Hz, H-1), 3.84
53 H, s, OMe), 3.67 and 3.52 5each 1 H, d, Jˆ8.6 Hz,
H-1Fru), 3.13 51 H, d, Jˆ6.6 Hz, H-3Fru), 1.95 53H, s,
SMe), 1.42, 1.37, 1.33 and 1.31 5each 3 H, s, isopropyli-
dene), 1.07 59 H, s, t-Bu); 13C-NMR 5CDCl3, 67.8 MHz) d
160.2, 136.3, 136.1, 134.3, 134.1, 130.5, 129.4, 129.0,
128.9, 127.6, 127.2, 125.3, 113.4, 111.8, 109.0, 104.8,
104.1, 99.8, 87.0, 80.4, 78.1, 73.7, 71.4 5CH2), 71.3, 70.3,
65.8, 61.5 5CH2), 60.0 5CH2), 55.3, 37.8 5CH2), 28.0, 27.6
5CH2), 27.0, 26.7, 26.4, 26.1 5CH2), 25.6, 22.5, 22.4, 21.4
5Me3C), 19.6, 13.4 5SMe).
3.1.5. Methyl 4,6-O-cyclohexylidene-3-O-tert-butyl-
diphenylsilyl-1-thio-a-d-mannopyranoside -5b). Com-
pound 15 5111 mg, 0.385 mmol) was dissolved in
DMF 52 ml) containing imidazole 550 mg, 0.73mmol).
t-BuPh2SiCl 50.16 ml, 0.62 mmol) was added and the
mixture was stirred at room temperature for 20 h. Resulting
mixture was diluted with ether, washed with water and
brine, successively, dried over MgSO4 and evaporated in
vacuo. The residue was puri®ed by silica gel column chro-
matography 5hexane±AcOEt 8:1) to afford 165 mg 581%) of
1
the title compound; [a]Dˆ112.1 5c 0.2, CHCl3); H-NMR
5CDCl3, 270 MHz) d 5.04 51 H, s, H-1), 4.18±4.02 52 H, m),
3.95±3.68 53 H, m), 3.43 51 H, d, Jˆ2.6 Hz, H-2), 1.96 53H,
s, SMe), 1.11 59 H, s, t-Bu); 13C-NMR 5CDCl3, 67.8 MHz) d
136.1, 135.7, 133.5, 132.6, 130.1, 129.8, 127.9, 127.7 and
127.5 5Ar), 99.9 5cyclohexylidene), 85.1 5C-1), 72.4, 71.4,
3.2. O--4,6-O-Cyclohexylidene-2-O-p-methoxybenzyl-3-
O-tert-butyldiphenylsilyl-b-d-mannopyranosyl)--1!3)-
1,2;4,5-di-O-isopropylidene-a-d-fructopyranose -13)
3.2.1. Preparative reaction. A mixture of mixed acetal 10a
570.5 mg, 0.0777 mmol), 2,6-di-tert-butyl-4-methylpyridine
555 mg, 0.27 mmol) and molecular sieves 4 A 50.2 g) in 1,2-
dichloroethane 57 ml) was stirred at 08C. A solution of
methyl tri¯uoromethanesulfonate 51 M in CCl4, 0.27 ml,
70.5, 64.9, 61.35C-6), 38.0 5CH ), 27.7 5CH2), 26.9 5Me3C),
2
25.6 5CH2), 22.5 5CH2), 22.35CH ), 19.2 5Me3C), 13.3
2
5SMe). Anal. Calcd for C29H40O5SSi: C, 65.87; H, 7.62.
Found: C, 65.95; H, 7.62.

Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
4131
0.27 mmol) was added and stirring continued at 358C. After
18 h, the mixture was diluted with AcOEt±ice water,
quenched with Et3N 5,50 ml), and ®ltered through Celite.
The ®ltrate was washed with aqueous NaHCO3 and brine,
successively, dried over MgSO4 and evaporated in vacuo.
The residue was chromatographed over silica gel 5hexane±
AcOEt 3:1) to afford 43.3 mg 576%) of the title compound;
[a]Dˆ246.7 5c 1.02, CHCl3); 1H-NMR 5CDCl3, 400 MHz)
d 7.7±7.8 54 H, m, Ar), 7.3±7.5 56 H, m, Ar), 4.36 51 H, s,
H-1Man), 4.34 51 H, t, Jˆ6 Hz, H-4Fru), 4.19 51 H, dd, Jˆ6.3
and 1.9 Hz, H-5Fru), 4.06 51 H, dd, Jˆ13.2 and 2.2 Hz,
H-6Fru), 3.70 51 H, d, Jˆ6.4 Hz, H-3Fru), 3.58 51 H, d,
Jˆ2.9 Hz, H-2Man), 3.03 51 H, ddd, Jˆ10.0, 10.0 and
5.4 Hz, H-5Man), 1.45, 1.41, 1.30 and 1.24 5each 3 H, s,
isopropylidene), 1.09 59 H, s, t-Bu); 13C-NMR 5CDCl3,
100 MHz) d 136.1, 135.8, 133.7, 132.9, 129.8, 129.6,
A 50.2 g) in CH2Cl2 51 ml) was added a solution of
compounds 5a 5120.8 mg, 0.186 mmol) and 6 581.6 mg,
0.137 mmol) as a solution in CH2Cl2 53ml in total). The
mixture was stirred at 08C 515 min) and at room temperature
for 130 min and worked up as described for 10a. The
organic layer was dried over MgSO4, evaporated in vacuo
and exposed to high vacuum for 2 h to afford crudely mixed
acetal 23, which was used directly for IAD. To a ¯ask
containing molecular sieves 4 A 50.4 g), was added a
mixture of 23 and 2,6-di-tert-butyl-4-methylpyridine 598
mg, 0.48 mmol) as a solution in ClCH2CH2Cl 58 ml in
total) and then cooled to ice-water temperature. A solution
of MeOTf in CCl4 51 M, 0.48 ml, 0.48 mmol) was added and
the mixture was stirred at 08C to room temperature for 1 h
and at 458C for 20 h. The reaction was quenched under ice-
water cooling with Et3N 5,100 ml) and diluted with AcOEt.
Aqueous NaHCO3 was added and the two-phase mixture
was ®ltered through Celite. The ®ltrate was washed with
water and brine, successively, dried over MgSO4 and evapo-
rated in vacuo. The residue was chromatographed over
silica gel 5hexane±AcOEt 5:2) to afford 122.0 mg 583%)
of the title compound; [a]Dˆ140.7 5c 1.8, CHCl3);
1H-NMR 5CDCl3, 400 MHz) d 7.9±6.6 528 H, Ar), 5.55
51 H, d, Jˆ8.3Hz, H-1 GN), 4.82, 4.56, 4.45 and 4.25 5each
1 H, d, Jˆ12 Hz, benzyl), 4.36 51 H, s, H-1Man), 4.0351 H,
m), 4.35 51 H, d, Jˆ3.9 Hz, H-2Man), 3.98 51 H, t, Jˆ9.3Hz),
3.76 51 H, dd, Jˆ10.7, 5.4 Hz), 3.68 53 H, s, OMe), 3.68 51
H, m), 3.64±3.52 53 H, m), 3.43±3.38 52 H, m), 2.87 51 H,
dd, Jˆ10, 10, 5 Hz, H-5Man), 2.61 51 H, br, OH), 2.0±1.3510
H, m, cyclohexyl), 1.11 59 H, s, t-Bu); 13C-NMR 5CDCl3,
67.8 MHz) d 100.2 5cyclohexylidene), 99.8 51JCHˆ159 Hz),
97.7 51JCHˆ165 Hz), 78.7, 74.6, 73.4 5CH2), 73.1, 71.3,
127.6, 127.3, 111.2, 109.1, 103.6, 101.1 5C-1Man
,
1JCZHˆ160 Hz), 99.9, 76.4, 74.9, 73.3, 73.1, 72.6 5CH2),
71.0, 69.7, 68.3, 61.3 5CH2), 61.2 5CH2), 38.0 5CH2), 27.8
5CH2), 27.3, 26.9 5Me3C), 26.4, 26.2, 25.7, 25.6 5CH2), 22.6
5CH2), 22.4 5CH2), 19.35Me 3C). Anal. Calcd for
C40H56O11Si: C, 64.84; H, 7.62. Found: C, 64.64; H, 7.64.
3.2.2. NMR experiment. Mixed acetal 10a 510.8 mg,
0.012 mmol) and 2,6-di-tert-butyl-4-methylpyridine 59
mg, 0.04 mmol) was dissolved in CDCl3 5ca. 0.6 ml,
contains TMS) and transferred to an NMR tube. Pre-
activated molecular sieves 4 A 520 mg) were added
followed by MeOTf 51 M in CCl4, 40 ml, 0.04 mmol). The
mixture was shaken for 10 min and left at 358C. The
1
progress of the reaction was followed by H-NMR 5JEOL
EX-270, Figs. 1 and 2).
69.8, 67.9 5CH2), 67.7, 61.2 5CH2), 60.35CH ), 55.5, 37.9
2
3.2.3. From 5b and 9b: via diastereomeric mixed acetal
10b. A mixture of DDQ 539 mg, 0.17 mmol) and molecular
sieves 4 A 50.15 g) in CH2Cl2 51 ml) was stirred under ice-
water cooling. Compounds 5b 560.3mg, 0.114 mmol) and
9b 558.0 mg, 0.152 mmol) were added as a solution in
CH2Cl2 51.5 ml) and the whole was stirred at room tempera-
ture for 70 min. The mixture was worked up as described for
10a and puri®ed by a column of Bio Beads S-X35toluene)
to afford the mixed acetal 574.0 mg, 71%), which consists of
10b as the major diastereomer 5,10:1). The mixed acetal
574.0 mg, 0.0816 mmol) was dissolved in CDCl3 50.37 ml),
50 ml of which was transferred to an NMR tube and diluted
with CDCl3 into ca. 0.6 ml. The solution was treated with
MeOTf 51 M, 40 ml, 0.04 mmol) and 2,6-di-tert-butyl-4-
methylpyridine 59 mg, 0.04 mmol) at 358C 5Fig. 3). The
rest of the mixed acetal was subjected to IAD 5358C, 24 h)
in a standard manner using MeOTf 51 M, 0.26 ml,
0.26 mmol) and 2,6-di-tert-butyl-4-methylpyridine 559
mg, 0.29 mmol). After 24 h, both mixtures were combined
and worked up as described above. Successive puri®cation
by Bio Beads SX-35toluene) and preparative TLC 5hexane±
AcOEt 2:1) afforded 19.1 mg 532 %) of compound 13.
5CH2), 27.7 5CH2), 26.8 5Me3C), 25.6 5CH2), 22.6 5CH2),
22.35CH 2), 19.2 5Me3C). Anal. Calcd for C63H69NO13Si: C,
70.30; H, 6.46; N, 1.30. Found: C, 70.06; H, 6.54; N, 1.31.
3.3.2. In the presence of water. Mixed acetal 23 was
prepared from 29.6 mg 50.046 mmol) of 5a and 20.5 mg
50.034 mmol) of 6 using 12 mg 50.053mmol) of DDQ and
molecular sieves 4 A 50.15 g) as described above and
dissolved in ClCH2CH2Cl 53ml) containing 2,6-di- tert-
butyl-4-methylpyridine 524 mg, 0.12 mmol). MeOTf
50.12 mmol) and H2O 51.0 ml, 0.06 mmol) was added and
the mixture was stirred at 458C for 20 h. Subsequent work-
up and puri®cation by silica gel column chromatography
afforded 20.1 mg 554%) of compound 7 together with 6.8
mg 533%) of recovered 6.
The same reaction was performed using 47.9 mg
50.074 mmol) of 5a, 32.3 mg 50.054 mmol) of 6, 19 mg
50.084 mmol) of DDQ, 0.19 mmol of MeOTf and 39 mg
50.19 mmol) of 2,6-di-tert-butyl-4-methylpyridine in the
presence of 10 equiv. 510 ml, 0.55 mmol) of H2O to give
9.8 mg 517%) of compound 7.
3.3. p-Methoxyphenyl O--4,6-O-cyclohexylidene-2-O-p-
methoxybenzyl-3-O-tert-butyldiphenylsilyl-b-d-manno-
pyranosyl)--1!4)-3,6-di-O-benzyl-2-deoxy-2-phthal-
imido-b-d-glucopyranoside -7)
Acknowledgements
This work was partly supported by a Grant-in-Aid for
Scienti®c Research from the Ministry of Education,
Science, Sports and Culture. We are grateful to Dr Hiroyuki
Koshino and his staff for NMR measurements and Dr Teiji
3.3.1. Under anhydrous conditions. To an ice-water cold
mixture of DDQ 548 mg, 0.21 mmol) and molecular sieves 4

4132
Y. Ito et al. / Tetrahedron 57 ꢀ2001) 4123±4132
9. LergenmuÈller, M.; Nukada, T.; Kuramochi, K.; Dan, A.;
Ogawa, T.; Ito, Y. Eur. J. Org. Chem. 1999, 1367.
10. Schmidt, O. Th. Methods in Carbohydr. Chem. 1962, 2, 191.
11. Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 1593.
Chihara and his staff for elemental analysis. We thank Ms.
A. Takahashi for her technical assistance.
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