Stereoselective 1,2-cis glycosylation of 2-O-Allyl protected thioglycosides

Article abstract of DOI:10.1002/1521-3765(20020603)8:11<2608::AID-CHEM2608>3.0.CO;2-4

The technique of intramolecular aglycon delivery (IAD), whereby a glycosyl acceptor is temporarily appended to a hydroxyl group of a glycosyl donor is an attractive method that can allow the synthesis of 1,2-cis glycosides in an entirely stereoselective f

Full text of DOI:10.1002/1521-3765(20020603)8:11<2608::AID-CHEM2608>3.0.CO;2-4

FULL PAPER
Stereoselective 1,2-cis Glycosylation of 2-O-Allyl Protected Thioglycosides
Mahmoud Aloui,[a] David J. Chambers,[a] Ian Cumpstey,[a] Antony J. Fairbanks,*[a]
Alison J. Redgrave,[b] and Christopher M. P. Seward[a]
Abstract: The technique of intramolec-
ular aglycon delivery (IAD), whereby a
glycosyl acceptor is temporarily append-
ed to a hydroxyl group of a glycosyl
donor is an attractive method that can
allow the synthesis of 1,2-cis glycosides
in an entirely stereoselective fashion.
2-O-Allyl protected thioglycoside do-
nors are excellent substrates for IAD,
and may be glycosylated stereoselective-
ly through a three-step reaction se-
quence. This sequence consists of quan-
titative yielding allyl bond isomerisa-
tion, to produce vinyl ethers that can
then undergo N-iodosuccinimide medi-
ated tethering of the desired glycosyl
acceptor, and subsequent intramolecu-
lar glycosylation, to yield either a-gluco-
sides or b-mannosides accordingly. Al-
though attempted one-pot tethering and
glycosylation is hampered by competi-
tive intermolecular reaction with excess
glycosyl acceptor, this problem can be
simply overcome by the use of excess
glycosyl donor. Allyl mediated IAD is a
widely applicable practical alternative to
other IAD approaches for the synthesis
of b-mannosides, that is equally appli-
cable for a-gluco linkages. It is advanta-
geous in terms of both simplicity of
application and yield, and in addition
has no requirement for cyclic 4,6-pro-
tection of the glycosyl donor.
Keywords:
glycosides
carbohydrates
¥ glycosylation
¥
¥
stereoselective synthesis
synthesis of b-mannosides.[3] Although several high yielding
intermolecular approaches have been developed which allow
the synthesis of b-mannosides,[4] most notably by Crich,[5]
interest in the further development of IAD has continued.[6, 7]
In particular a number of other methods have been developed
for the temporary linking of donor and acceptor prior to
glycosylation, the most successful of which involve modifica-
tion of the donor 2-hydroxyl protecting group to provide a
tethering site. The most notable of these is the Ogawa
approach[8] which employs oxidation of a p-methoxybenzyl
(PMB) protecting group allowing linking of donor and
acceptor as a mixed acetal. There have also been some very
successful attempts at more remote tethering and intra-
molecular glycosylation, whereby the glycosyl acceptor is
either appended to the anomeric leaving group, or to more
remote hydroxyl groups in particular as reported by the
groups of Schmidt,[9] Ziegler,[10] Valverde[11] and others.[12]
Following on from earlier studies[13] we report herein details
on the use of the 2-O-allyl protecting group for IAD which
allows entirely stereoselective access to both b-mannosides
and a-glucosides.[14] The strategy employed uses a reaction
sequence involving Wilkinson×s catalyst mediated isomerisa-
tion of 2-O-allyl ethers of thioglycosides to produce 2-O-vinyl
ethers, to which glycosyl acceptors may be tethered yielding
mixed acetals. These mixed acetals can then finally undergo
intramolecular glycosylation upon thioglycoside activation. In
particular a discussion of the scope and limitations of the allyl
mediated IAD is included.
Introduction
One of the major complications inherent in the construction
of an oligosaccharide is control of the stereochemistry of a
newly formed anomeric linkage. Although judicious choice of
solvent and protecting group pattern on the glycosyl donor
can in many cases allow high levels of stereoselectivity,
complete control of anomeric stereochemistry during the
glycosylation process is still difficult. This difficulty is
exacerbated when separation of mixtures of anomers be-
comes impossible. A logical partial solution to this problem is
to take advantage of neighbouring group participation,
whereby glycosyl donors possessing 2-O-ester protecting
groups are almost universally used in order to stereoselec-
tively synthesise 1,2-trans glycosidic linkages. The idea that
the configuration of the 2-hydroxyl of the glycosyl donor can
also be used to induce the formation of 1,2-cis linkages by the
technique of intramolecular aglycon delivery (IAD), was
originally introduced by Hindsgaul[1] and Stork[2] for the
[a] Dr. A. J. Fairbanks, Dr. M. Aloui, D. J. Chambers,
I. Cumpstey, C. M. P. Seward
Dyson Perrins Laboratory, Oxford University
South Parks Road, Oxford, OX13QY (UK)
Fax : (‡44)1865 275 674
E-mail: antony.fairbanks@chemistry.ox.ac.uk
[b] Dr. A. J. Redgrave
GlaxoSmithKline Research and Development
Medicines Research Centre, Gunnels Wood Road
Stevenage, SG12NY (UK)
2608
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Chem. Eur. J. 2002, 8, No. 1 1

2608 2621
ward method proceeded extremely efficiently in all cases to
yield the corresponding enol ethers 3, 6, 10 and 15 respec-
tively, in excellent yields (Scheme 1).
Results and Discussion
Synthesis of vinyl ethers
A selection of manno and gluco glycosyl donors with different
anomeric leaving groups bearing 2-O-allyl protection were
synthesised as substrates for isomerisation and subsequent
tethering and glycosylation experiments (Scheme 1). The
2-O-allyl protected manno thiophenyl glycoside 2 was ac-
cessed from the known acetate 1[15] by sodium methoxide
mediated deacetylation and immediate allylation with sodium
hydride and allyl bromide. The thiomethyl counterpart 5 was
likewise synthesised by standard allylation of the known
thiomethyl glycoside 4.[16] The required gluco thiomethyl
glycoside 9 was accessed by allylation of the alcohol 8.
Alcohol 8 was itself synthesised from the known orthoester
11,[17] through a two-step sequence involving initial conversion
of 11 to the glycosyl bromide 7[15] by treatment with either
HBr in acetic acid or acetyl bromide, and subsequent reaction
of 7 with lithium methyl thiolate, generated in situ by reaction
of dimethyl disulfide with n-butyllithium. The gluco 2-O-allyl
selenoglycoside 14 was also synthesised from the gluco
orthoester 11 by a reaction sequence involving mercury(ii)
promoted opening of 11 to yield the b-selenoglycoside 12,
subsequent sodium methoxide mediated deacetylation to
yield alcohol 13,[18] and finally allylation to yield 14.[19]
Tethering reactions
Tethering with N-iodosuccinimide: N-Iodosuccinimide (NIS)
mediated tethering was undertaken for the manno thiophenyl
donor 3 with a series of primary and secondary alcohols
(ROH, Table 1, Scheme 2) in the presence of 4 ä molecular
sieves. Exclusion of water from these reactions was important
in order to avoid competitive hydrolysis, and tethering yields
rose appreciably after the addition of sieves. In the vast
majority of cases tethering proceeded efficiently in either
THF or 1,2-dichloroethane (DCE) as solvent, to yield mixed
acetal intermediates 16a e. These mixed acetals are quite
robust[21] and much more stable than the Hindsgaul-type
acetals that we had previously worked with.[13] Pleasingly a
secondary carbohydrate alcohol was also successfully tethered
to yield mixed acetals 16g in an excellent 85% yield.
However, attempted tethering of the even more hindered
4-hydroxyl of a protected glucosamine derivative, required in
order to complete the b-manno linkage found in the N-glycan
core pentasaccharide, produced only an extremely disap-
pointing 9% yield of the tethered product 16h. The reason for
this extremely low yield became apparent after the isolation
of succinimide trapped material 22 in a total yield of 70% (as
a 6:1mixture of two diastereomers), together with approx-
imately 10% of recovered starting material. Succinimide
trapped material 22 was in fact also isolated in 10% yield
This selection of 2-O-allyl protected glycosyl donors 2, 5, 9
and 14 were then subjected to isomerisation using a combi-
nation of Wilkinson×s catalyst and n-butyllithium according to
the procedure recently reported by Boons.[20] This straightfor-
OAc
O
O
O
O
BnO
BnO
BnO
BnO
BnO
i), ii)
iii)
O
O
O
BnO
BnO
BnO
BnO
99%
99% over two steps
SPh
SMe
SPh
SPh
SMe
1
2
3
OH
O
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
ii)
iii)
O
91%
95%
4
5
6
SMe
BnO
BnO
BnO
BnO
O
BnO
BnO
BnO
ii)
iv)
iii)
O
O
O
O
O
BnO
BnO
SMe
SMe
SMe
BnO
BnO
BnO
OH
95%
68%
85%
AcO
Br
7
8
9
10
vi), iv)
61% over two steps
v) 73%
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
i)
ii)
O
vii)
O
O
O
O
SePh
SePh
SePh
BnO
OAc
BnO
91%
78%
92%
OH
O
O
12
13
14
iii)
OEt
92%
11
BnO
BnO
BnO
O
O
SePh
15
Scheme 1. i) Na, MeOH, RT; ii) NaH, allyl bromide, DMF, RT; iii) (Ph3P)3RhCl, nBuLi, THF, reflux; iv) BuLi, MeSSMe, THF, À788C; v) HBr, AcOH,
CH2Cl2, 08C; vi) AcBr, 08C; vii) PhSeH, HgBr2, MeCN, 508C.
Chem. Eur. J. 2002, 8, No. 11
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A. J. Fairbanks et al.
FULL PAPER
Table 1. Yields for tethering and glycosylation.
I
Entry Alcohol ROH
Product/
yield of
Product/
yield of
O
O
OR
BnO
BnO
BnO
BnO
i)
i)
i)
O
O
mixed acetals [%] glycosylation [%]
BnO
BnO
a)
b)
MeOH
16a/93
18a/98
20a/77
21a/65
SPh
SPh
16a-e,g,h
3
I
16b/95
18b/85
20b/81
21b/70
O
O
OR
BnO
BnO
BnO
BnO
O
O
BnO
BnO
SMe
SMe
17b (85%)
17c (80%)
17g (55%)
6
c)
16c/76
18c/80
20c/68
21c/77
BnO
O
BnO
BnO
BnO
O
O
BnO
SMe
SMe
OR
BnO
O
d)
16d/ > 99
18d/95
20d/76
21d/67
I
18a-g
10
e)
16e/90
18e/36
20e/65
21e/74
BnO
O
BnO
O
BnO
BnO
BnO
O
O
BnO
ii)
SePh
SePh
OMe
f)
18 f/63
21 f/72
20g/89
I
15
19a (36%)
Scheme 2. i) ROH (see Table 1), N-iodosuccinimide, 4 ä molecular sieves,
1,2-dichloroethane, À408C ! RT; ii) MeOH, N-iodosuccinimide, 4 ä mo-
lecular sieves, 1,2-dichloroethane, À408C ! RT, 36 %.
g)
16g/85
18g/22
h)
16h/9
see text
during the formation of 16g. Formation of 22 clearly occurs by
competitive nucleophilic attack by succinimide, and therefore
in the glucosamine case represents a limitation to the use of
NIS for tethering in the construction of the N-glycan core
pentasaccharide, an issue which was later addressed (see
below).
NIS-mediated tethering of the thiomethyl glycoside 6 with
diacetone galactose and cyclohexanol again produced the
corresponding mixed acetals 17b, c in good yield. However,
tethering of the secondary carbohydrate alcohol was less
efficient, providing 17g in 55% yield, and in this case the use
of protracted reaction times led to competitive activation of
the anomeric leaving group.
A similar series of tethering experiments were undertaken
in the gluco series with thiomethyl glycoside 10. For the
primary alcohols tethering was rapid and good yields of mixed
acetals 18a d were obtained. However, for the more
hindered alcohols yields of mixed acetals 18e g were much
lower. This reduction in yield was again in part due to
competitive activation of the anomeric thiomethyl group by
NIS during tethering, and as such could not be overcome by
the use of extended reaction times. A similar but more
extreme situation was observed for the selenoglycoside 15. In
this case NIS activation of the more reactive anomeric leaving
group was even competitive with tethering of methanol, and
the desired acetals 19a could only be isolated in 36% yield. It
can be concluded that fully armed selenoglycosides are
unsuitable substrates for NIS mediated tethering reactions.
Tethering with acid: The conclusion drawn from the above
experiments was that efficient NIS mediated tethering could
only be achieved for hindered alcohols with an unreactive
anomeric leaving group, particularly thiophenyl. For this
reason a series of acid-catalysed tethering reactions were also
attempted. An initial investigation involving reaction of
thiomethyl alcohol 4 with either ethyl or propyl vinyl ethers
catalysed by pyridinium p-toluene sulfonate (PPTS) produced
mixed acetals 23 and 24 in 91and 82% yield, respectively
(Scheme 3), and therefore revealed PPTS as a potential acid
catalyst. However, attempted PPTS-catalysed tethering of
thiomethyl vinyl ether 10 with diacetone galactose did not
result in the formation of any appreciable amount of mixed
acetal products; nor was PPTS capable of tethering diacetone
OH
O
O
OR
BnO
BnO
BnO
BnO
BnO
BnO
i) or ii)
O
4
SMe
SMe
23: R = Et (91%)
24: R = Pr (82%)
Scheme 3. i) ethyl vinyl ether, PPTS, CH2Cl2, RT; ii) propyl vinyl ether,
PPTS, CH2Cl2, RT.
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Chem. Eur. J. 2002, 8, No. 1 1

Stereoselective 1,2-cis Glycosylation
2608 2621
galactose and thiophenyl vinyl ether 3, with complete
recovery of starting material after reaction overnight at room
temperature. The use of other acids such as camphor sulfonic
acid and p-toluene sulfonic acid was similarly unsuccessful
and the attempted use of triflic acid (TfOH) caused complete
decomposition of the starting material.
a wide range of activation conditions were investigated using
NIS either alone, or with co-activators which included triflic
acid, silver triflate, tin(ii) triflate, triethylsilyl triflate (TE-
SOTf), and acetic acid. All reactions were performed in the
presence of di-tert-butyl methyl pyridine (DTBMP) as an
added base. Activation with NIS alone was much more
sluggish than had been previously experienced.[13] In general,
glycosylation was considerably slower than in the Hindsgaul-
type system and little glycosylation was observed upon
treatment with NIS alone at room temperature. Optimised
reaction conditions required the addition of silver triflate, and
more protracted reaction times at either room temperature or
higher. In all cases intramolecular glycosylation occurred in a
stereospecific fashion to furnish the corresponding b-manno-
sides 20a e,g in good yields.[22] However, the direct isolation
of the desired reaction product was sometimes complicated by
competitive trapping reactions whereby the oxonium ion
produced subsequent to intramolecular glycosylation was
trapped by a nucleophile. This nucleophile could either be
succinimide, to yield compounds such as 25, or any alcohol
present[23] to produce glycosylated mixed acetals of general
structure 26.[24] A large scale glycosylation of mixed acetals
16a without the addition of silver triflate in fact allowed the
isolation and characterisation of two diastereomers of the
succinimide trapped product 25a and b (see Scheme 5).
A variety of hydrolytic work-up procedures were inves-
tigated in order to overcome this problem. The most efficient
procedure involved treatment of the crude reaction mixture
with trifluoroacetic acid (TFA), in a 1:1:1 mixture of MeOH/
THF/water. In most cases this procedure efficiently converted
all trapped materials to the desired 1,2-cis glycoside. Care had
to be exercised for the cases involving glycosyl acceptors
which contained acid labile protecting groups, most notably
diacetone galactose (Table 1, entry b).
Glycosylation reactions
With a selection of mixed acetals in hand as a result of
successful NIS-mediated tethering, intramolecular glycosyla-
tion was then undertaken (Scheme 4). In the case of the less
reactive anomeric thiophenyl manno mixed acetals 16a e,g,
I
O
OR
OH
O
BnO
BnO
BnO
BnO
BnO
BnO
O
i)
OR
SPh
20a-e,g (65-89%)
16a-e,g
I
OH
O
BnO
BnO
BnO
O
O
O
O
O
O
O
O
O
BnO
BnO
BnO
O
O
ii)
O
O
O
SMe
20b (52%)
17b
18a-f
19a
BnO
BnO
BnO
BnO
BnO
BnO
O
O
SMe
OR
ii)
O
I
HO
OR
21a-f (65-77%)
A brief investigation into the role of the added DTBMP
was also undertaken for glycosylations of mixed acetals 16a.
Glycosylation was in fact much faster when DTBMP was
omitted and the methyl acetals 16a were glycosylated in
20 minutes, but the reactions were always less clean and
resulted in the formation of unidentified, undesired side
products, that were not trapped mixed acetals 25 or 26. The
use of alternative less hindered bases, such as collidine or
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
SePh
OMe
iii)
HO
OMe
I
21a (70%)
Scheme 4. i) N-Iodosuccinimide, AgOTf, DTBMP, 4 ä molecular sieves,
1,2-dichloroethane, RT! 508C; ii) MeOTf, DTBMP, 1,2-dichloroethane,
RT; iii) N-iodosuccinimide, CH2Cl2, À408C, 10 min.
O
I
I
I
O
N
O
N
O
OR
OR
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
BnO
O
OR
O
BnO
O
BnO
SPh
26
22
25
O
O
I
I
I
N
N
OH
O
O
O
O
OMe
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
OMe
O
OMe
i)
O
O
O
BnO
+
+
OMe
BnO
20a
(23%)
25a
25b
SPh
16a
(12%)
(15%)
Scheme 5. i) N-Iodosuccinimide, 4 ä molecular sieves, DTBMP, 1,2-dichloroethane, RT, 17 h, then 508C, 7 h.
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A. J. Fairbanks et al.
FULL PAPER
pyridine, slowed the rate of glycosylation so much that
effective reaction could not be achieved.
Mechanistic studies and one-pot reactions: With tethering and
glycosylation methodology successfully in hand attention next
turned to the potential one-pot reaction, whereby the two
steps are achieved in a single reaction vessel. Unlike our
previous results which were obtained with the Hindsgaul
mixed ketal system, attempted one-pot glycosylation of either
donors 3 or 6 with an excess of diacetone galactose or
cyclohexanol (1.4 to 3 equivalents) produced anomeric mix-
tures of products. A subsequent competition experiment
involving glycosylation of mixed acetals 16d in the presence
of methanol as an intermolecular nucleophile produced a
mixture of products containing the desired b-benzyl manno-
side 20d, together with both the a- and b-methyl mannosides
28 and 20a clearly indicating competitive intermolecular
reaction by the alcohol present in solution (Scheme 7).
Intramolecular glycosylation of the more reactive thio-
methyl manno mixed acetals 17b (derived from tethering 6
with diacetone galactose) was investigated under a number of
different activation conditions. These included the use of
dimethyl(methylthio)sulfonium triflate (DMTST), I2,
MeOTf, NIS/TESOTf, I2/TESOTf and PhSeOTf, in all cases
with DTBMP as an added base in DCE as solvent. Although
the thiomethyl glycoside was activated in all cases, the
reaction proceeded most cleanly when methyl triflate was
used as an activator alone. The thiomethyl gluco mixed acetals
18a f were very efficiently activated by the addition of
methyl triflate, yielding a-glucosides 21a f, again as single
anomers following work-up. Again the formation of mixed
acetals could complicate the
glycosylation reaction (as ob-
I
served by TLC) and the same
OH
O
OH
O
OH
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
OBn
general acid work-up proce-
dure was adopted to maximise
yields.
i)
BnO
BnO
BnO
OBn
OMe
+
O
+
BnO
BnO
OMe
20d
(31%)
28
(22%)
20a
(15%)
SPh
16d
Scheme 7. i) MeOH (1equiv), N-iodosuccinimide, AgOTf, DTBMP, 1,2-dichloroethane, 508C, 1.5 h.
Synthesis of Manb(1 ! 4)-
GlcNAc disaccharide
These results lead to the conclusion that any one-pot
reaction could only be successful with the use of an excess of
glycosyl donor rather than glycosyl acceptor which contrary to
the standard procedure up to this point. Gratifyingly the one-
pot reaction of donor 6 (2.0 equivalents) with either diacetone
galactose or cyclohexanol (in acetonitrile and DCE respec-
tively) produced the corresponding b-mannosides 20b and
20c as single anomers in 72% and 67% yields, respectively
(Scheme 8). Notably there was no product trapping in these
reactions and therefore they did not require an acidic work
up.
Due to the failure of NIS-mediated tethering with the most
hindered glucosamine acceptor detailed above (Table 1,
entry h), alternative reaction conditions were investigated
which would hopefully allow the allyl mediated IAD ap-
proach to be applicable for even more hindered secondary
alcohols. Clearly this was important in order to allow access to
the core N-glycan Manb(1 ! 4)GlcNAc disaccharide. Since
the major problem encountered with NIS tethering was
competitive nucleophilic attack by succinimide, which ap-
peared to be a better nucleophile than the 4-hydroxyl of the
protected glucosamine derivative 27,[25] it was thought that
‡
tethering may best be achieved by the use of a source of I in
the presence of a non-nucleophilic counterion. For this reason
the use of iodonium dicollidine triflate (IDCT), prepared in
situ from iodine, collidine and silver triflate, was investigated.
Pleasingly IDCT mediated tethering of vinyl ether 3 with
glucosamine acceptor 27 resulted in an 80% yield of mixed
acetals 16h (Scheme 6). Subsequent intramolecular glycosy-
lation mediated by iodine and silver triflate, successfully
yielded the key Manb(1 ! 4)GlcNAc disaccharide 20h in
66% yield. The results imply that by judicious choice of
tethering conditions that allyl mediated IAD may possibly be
used for the most hindered of glycosyl acceptors.
Conclusion
In summary we have demonstrated that 2-O-allyl protected
glycosyl donors may be employed for the efficient synthesis of
a variety of cis-1,2-glycosides by the technique of intra-
molecular aglycon delivery (IAD). Several points are worthy
of note. Firstly installation and isomerisation of the allyl group
is a very efficient process, and is superior to Tebbe approaches
to similar vinyl ethers. Secondly NIS is able to successfully
tether all but a very hindered glucosamine acceptor, whilst on
the other hand a variety of acids were unsuccessful. Moreover
O
BnO
O
BnO
I
BnO
BnO
OH
O
O
BnO
O
BnO
O
BnO
OPMP
NPhth
i)
ii)
SPh
BnO
BnO
O
3
O
OPMP
NPhth
BnO
BnO
BnO
BnO
O
+
BnO
16h
20h
O
HO
OPMP
SPh
BnO
NPhth
27
Scheme 6. i) I2, AgOTf, collidine, CH2Cl2, À788C to RT, 80%; ii) I2, AgOTf, DTBMP, 4 ä molecular sieves, 1,2-dichloroethane, RT, 66%.
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2612

Stereoselective 1,2-cis Glycosylation
2608 2621
0.22 0.25 mm thickness glass-backed sheets, pre-coated with 60F254 silica.
Plates were developed using 5% w/v ammonium molybdate in 2m sulfuric
acid. Flash column chromatography was carried out using Sorbsil C60 40/60
silica or basic alumina. Solvents and reagents were dried and purified
before use according to standard procedures; methanol was distilled from
calcium hydride, dichloromethane was distilled from calcium hydride, and
tetrahydrofuran was distilled from a solution of sodium/benzophenone
immediately before use. Petrol refers to the fraction of light petroleum
ether boiling in the range 40 608C. Ether refers to diethyl ether. All
procedures requiring anhydrous conditions were performed under an
atmosphere of argon in glassware which was flame-dried before use.
OH
O
BnO
BnO
O
BnO
O
O
O
BnO
BnO
BnO
i)
O
O
O
72%
O
SMe
6
20b
O
OH
O
BnO
BnO
BnO
BnO
BnO
BnO
ii)
O
O
Phenyl 2-O-allyl-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyranoside (2): Ace-
tate 1 (292 mg, 0.50 mmol) was dissolved in methanol (8 mL) under argon
and sodium (18 mg, 0.78 mmol) was added with stirring. The reaction
mixture was stirred at room temperature for 30 min, after which time TLC
(petrol/ethyl acetate 3:1) showed no remaining starting material (Rf ˆ 0.5)
and formation of a single product (Rf ˆ 0.2). The reaction mixture was co-
evaporated with toluene and subsequently exposed to high vacuum for two
hours. The resulting residue was taken up in DMF (3.5 mL) and NaH (60%
dispersion in mineral oil, 80 mg, 1.67 mmol) was added portionwise,
followed by allyl bromide (0.11 mL, 1.27 mmol). This solution was stirred
for 1.5 h, after which time TLC (petrol/ethyl acetate 3:1) showed no
remaining starting material (Rf ˆ 0.2) and the formation of a major product
(Rf ˆ 0.7). Methanol (5 mL) was added slowly and the mixture was
concentrated in vacuo. The residue was dissolved in ether (50 mL) and
washed with brine (2 Â 30 mL). The aqueous layers were re-extracted with
ether (30 mL) and the combined organic extracts were dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash column chroma-
tography (petrol/ether 3:1) gave the allylated thioglycoside 2 (289 mg,
99%) as a white solid. M.p. 60 628C (ether/petrol); [a]2D4 ˆ ‡132 (c ˆ 1.0
67%
SMe
20c
6
Scheme 8. i) Diacetone galactose, 4 ä molecular sieves, N-iodosuccini-
mide, DTBMP, 1,2-dichloroethane, À40 ! 08C, 1h then MeOTf, 0 8C !
RT, 24 h; ii) cyclohexanol, 4 ä molecular sieves, N-iodosuccinimide,
DTBMP, 1,2-dichloroethane, À30 ! 08C, 1h then MeOTf, 0 8C to RT, 1 8 h.
even the hindered glucosamine acceptor may be tethered by
the use of IDCTrather than NIS as coupling agent, ultimately
allowing access to the crucial Manb(1 ! 4)GlcNAc disacchar-
ide. A caveat to the tethering procedure is that yields for
glycosyl donors with very reactive anomeric leaving groups
(e.g. Se) may be lower due to competitive anomeric activa-
tion. Subsequent intramolecular glycosylation reactions are
slower than in the related Hindsgaul system, and in fact
intermolecular reaction can be competitive. However, the use
of an excess of glycosyl donor allows both tethering and
glycosylation to be performed in a single reaction vessel,
obviating the need for handling of sensitive mixed acetal
intermediates. By way of direct comparison with alternative
methods, allyl IAD is amenable in terms of both simplicity of
application, yield, and importantly is equally applicable for
the formation of b-manno and a-gluco linkages. In addition
there appears to be no requirement for cyclic 4,6-protection of
the glycosyl donor in order to produce good yields for the
glycosylation step. Further investigations into the use of allyl
derived vinyl ethers for 1,2-cis glycosylation procedures are
currently in progress, and the results will be reported in due
course.
1
in CHCl3); H NMR (400 MHz, CDCl3, 258C): d ˆ 7.52 7.49 (m, 2H; 2 Â
ˆ
Ar-H), 7.43 7.22 (m, 18H; 18 Â Ar-H), 5.99 5.90 (m, 1H; CH CH2), 5.62
(s, 1H; H-1), 5.31 (dd, 2J(H,H) ˆ 1.3 Hz, 3J(H,H) ˆ 17.2 Hz, 1H;
CH CHECHZ), 5.22 (dd, 2J(H,H) ˆ 1.3 Hz, 3J(H,H) ˆ 10.3 Hz, 1H;
ˆ
CH HEHZ), 4.93, 4.54 (ABq, 2J(H,H) ˆ 10.8 Hz, 2H; PhCH2), 4.74
ˆ
(ABq, 2J(H,H) ˆ 12.6 Hz, 2H; PhCH2), 4.67, 4.50 (ABq, 2J(H,H) ˆ
12.0 Hz, 2H; PhCH2), 4.30 (dd, 3J(H,H) ˆ 9.7 Hz, 9.5 Hz, 1H; H-5), 4.21
3
(dd, 2J(H,H) ˆ 13.1 Hz, J(H,H) ˆ 5.5 Hz, 1H; CHH'CH CH2), 4.12 (dd,
ˆ
2J(H,H) ˆ 13.1 Hz, 3J(H,H) ˆ 6.1Hz, 1H; C HH'CH CH2), 4.04 (at,
ˆ
3J(H,H) ˆ 9.5 Hz, 1H; H-4), 3.98 (dd, 3J(H,H) ˆ 1.6 Hz, 3.0 Hz, 1 H;
H-2), 3.89 (dd, 3J(H,H) ˆ 3.0 Hz, 9.4 Hz, 1H; H-3), 3.85 (dd, 2J(H,H) ˆ
10.8 Hz, 3J(H,H) ˆ 4.9 Hz, 1H; H-6'), 3.76 (dd, 2J(H,H) ˆ 10.8 Hz,
3J(H,H) ˆ 1.4 Hz, 1 H; H-6); 13C NMR (100.6 MHz, CDCl3): d ˆ 134.6 (d,
ˆ
CH CH2), 138.4, 138.3, 138.1, 134.4 (4 Â s, Ar-C), 131.4, 129.0, 128.4, 128.3,
128.2, 128.0, 127.9, 127.8, 127.6, 127.4, 127.3 (11 Â d, Ar-CH), 117.9 (t,
ˆ
CH CH2), 85.8, 80.1, 76.1, 74.9, 72.6 (5Â d, C-1, C-2, C-3, C-4, C-5), 75.2,
ˆ
73.2, 72.2, 71.4, 69.1 (5 t, C-6, 3  PhCH2, OCH2CH CH2); IR (KBr): nÄ ˆ
1643 cmÀ1 (C C); MS-APCI : m/z (%): 605 (21) [M‡Na] ; HRMS-ES:
‡
‡
ˆ
‡
calcd for C36H42NO5S [M‡NH4] : 600.2784, found: 600.2776).
Phenyl 2-O-(prop-1-enyl)-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyranoside
(3): n-Butyllithium (1.3m in hexanes, 250 mL) was added to a degassed
solution of Wilkinson×s catalyst (163 mg, 0.18 mmol) in THF (8 mL). This
mixture was stirred for 10 min before being added to a solution of the
allylated thioglycoside 2 (1.00 g, 1.72 mmol) in THF (5 mL) at reflux. After
10 min, TLC (petrol/ethyl acetate 5:1) showed no remaining starting
material (Rf ˆ 0.65) and the formation of a single product (Rf ˆ 0.75). The
solution was allowed to cool to room temperature before the addition of
dichloromethane (20 mL) and concentration in vacuo. Purification by flash
column chromatography (petrol/ether 7:1, with 1 % added triethylamine)
gave the vinyl ethers 3 (998 mg, >99%) as a clear, colourless oil, a partially
separable mixture of E and Z isomers. E isomer: 1H NMR (400 MHz,
Experimental Section
General methods: Melting points were recorded on a Kofler hot block and
are uncorrected. Proton NMR (dH) spectra were recorded on a Bruker
DPX400 (400 MHz) or on a Bruker AMX500 (500 MHz) spectrometer.
Carbon NMR (dC) spectra were recorded on a Bruker AC200 (50.3 MHz),
or on
a Bruker DPX400 (100.6 MHz), or on a Bruker AMX500
(125.7 MHz) spectrometer. Multiplicities were assigned using DEPT
sequence. All chemical shifts are quoted on the d scale in parts per million
(ppm). IR spectra were recorded on a Perkin Elmer 150 fourier transform
spectrophotometer. Low resolution mass spectra were recorded on a
Micromass Platform1APCI using atmospheric pressure chemical ionisa-
tion (APCI). High resolution mass spectra (electrospray) were performed
on a Waters 2790-Micromass LCT electrospray ionisation mass spectrom-
eter, or by the EPSRC Mass Spectrometry Service Centre, Department of
Chemistry, University of Wales, Swansea on a MAT900 XLT electrospray
ionisation mass spectrometer. Optical rotations were measured on a
Perkin Elmer 241polarimeter with a path length of 1dm. Concentrations
CDCl3, 258C): d ˆ 7.54 7.49 (m, 2H; 2  Ar-H), 7.44 7.23 (m, 18H; 18 Â
4
Ar-H), 6.11 (dd, 3J(H,H) ˆ 12.2 Hz, J(H,H) ˆ 1.1 Hz, 1 H; OCH CH),
ˆ
5.64 (s, 1H; H-1), 4.97 (m, 1H; CH 3CH), 4.75 (s, 2H; PhCH2), 4.93, 4.56
(ABq, 2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 4.68, 4.50 (ABq, 2J(H,H) ˆ
11.9 Hz, 2H; PhCH2), 4.34 4.30 (m, 1H; H-5), 4.23 (d, 3J(H,H) ˆ 2.9 Hz,
1H; H-2), 4.08 (at, 3J(H,H) ˆ 9.5 Hz, 9.3 Hz, 1H; H-4), 3.93 (dd, 3J(H,H) ˆ
2.9 Hz, 9.3 Hz, 1H; H-3), 3.87 (dd, 2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 4.9 Hz,
1H; H-6'), 3.76 (dd, 2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 1.3 Hz, 1 H; H-6), 1.56
(dd, 3J(H,H) ˆ 6.4 Hz, 4J(H,H) ˆ 1.1 Hz, 3H; CH3); 13C NMR (100.6 MHz,
are given in
g per 100 mL. Microanalyses were performed by the
microanalytical services of Elemental Microanalysis Ltd, Devon. Thin-
layer chromatography (TLC) was carried out on Merck Kieselgel
ˆ
CDCl3): d ˆ 144.8 (d, OCH CH), 138.4, 138.3, 137.9, 134.0 (4  s, Ar-C),
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2613 $ 20.00+.50/0
2613

A. J. Fairbanks et al.
FULL PAPER
131.5, 129.0, 128.9, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.7,
H-2), 2.13 (s, 3H; SCH3), 1.57 (dd, 3J(H,H) ˆ 6.8 Hz, 1.4 Hz, 3H;
OCH CHCH3); Z isomer: 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.40
ˆ
127.5, 127.5, 127.4 (15 Â d, Ar-CH), 102.6, 85.1, 79.3, 77.0, 74.8, 72.6 (6 Â d,
C-1, C-2, C-3, C-4, C-5, CHCH3), 75.1, 73.2, 72.2, 69.0 (4Â t, C-6, 3 Â
7.18 (m, 15H; Ar-H), 5.90 (dd, 3J(H,H) ˆ 6.1Hz, 4J(H,H) ˆ 1.8 Hz, 1 H;
‡
PhCH2), 12.4 (CH3); IR (thin film): nÄ ˆ 1675 cmÀ1 (C C); MS-APCI :
OCH CHCH3), 5.22 (d, 3J(H,H) ˆ 1.4 Hz, 1 H; H-1), 4.91 4.50 (m, 6H;
ˆ
ˆ
m/z (%): 606 (26) [M‡Na] ; Z isomer: 1H NMR (400 MHz, CDCl3, 258C):
3  PhCH2), 4.60 (dd, 3J(H,H) ˆ 6.8 Hz, 6.1Hz, 1H; OCH CHCH3),
‡
ˆ
d ˆ 7.71 7.00 (m, 20H; 20  Ar-H), 5.91(dd, 3J(H,H) ˆ 6.0 Hz, J(H,H) ˆ
4.14 3.69 (m, 6H; H-6', H-6, H-5, H-4, H-3, H-2), 2.13 (s, 3H; SCH3),
4
1.6 Hz, 1 H; OCH CH), 5.53 (d, 3J(H,H) ˆ 1.6 Hz, 1 H; H-1), 4.92 (d,
1.66 (dd, J(H,H) ˆ 6.8 Hz, J(H,H) ˆ 1.8 Hz, 3H; OCH CHCH3); MS-CI:
3
4
ˆ
ˆ
2J(H,H) ˆ 10.8 Hz, 1H; PhCHH'), 4.75 (s, 2H; PhCH2), 4.67, 4.50 (ABq,
2J(H,H) ˆ 12.0 Hz, 2H; PhCH2), 4.61 4.53 (m, 2H; CH 3CH, PhCHH'),
4.31(ddd, 3J(H,H) ˆ 9.7 Hz, 4.8 Hz, 1.7 Hz, 1 H; H-5), 4.11 (at, 3J(H,H) ˆ
9.5 Hz, 8.9 Hz, 1H; H-4), 4.11 (d, 3J(H,H) ˆ 3.1Hz, 1H; H-2), 3.92 (dd,
3J(H,H) ˆ 8.9 Hz, 3.1Hz, 1H; H-3), 3.87 (dd, 2J(H,H) ˆ 10.9 Hz,
3J(H,H) ˆ 4.8 Hz, 1H; H-6'), 3.77 (dd, 2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ
1.7 Hz, 1 H; H-6), 1.64 (dd, 4J(H,H) ˆ 1.6 Hz, 3J(H,H) ˆ 6.4 Hz, 3H;
CH3); 13C NMR (100.6 MHz, CDCl3): d ˆ 9.6 (q, CH3), 75.3, 73.1, 72.3,
69.0 (4 Â t, C-6, 3 Â PhCH2), 105.0, 86.1, 79.5, 78.8, 74.8, 72.7 (6 Â d, C-1,
C-2, C-3, C-4, C-5, CHCH3), 132.0, 131.7, 129.0, 128.5, 128.5, 128.4, 128.3,
128.2, 128.0, 128.0, 127.9, 127.6, 127.5, 127.5, 127.4 (15 Â d, Ar-CH), 138.4,
m/z (%): 521(100) [ M‡H] ; HRMS-ES: calcd for C31H40NO5S [M‡NH4] :
‡
‡
538.2627, found: 538.2635.
2-O-Acetyl-3,4,6-tri-O-benzyl-a-d-glucopyranosyl bromide (7): Orthoester
11[15] (400 mg, 0.77 mmol) was dissolved in dichloromethane (20 mL) and
cooled to 08C under Ar. HBr (33% in acetic acid, 0.7 mL) was added. After
3 min, TLC (ethyl acetate/petrol 1:3) indicated complete consumption of
starting material (Rf ˆ 0.6) and formation of a product (Rf ˆ 0.7). The
reaction was quenched with ice water (30 mL) then extracted with
dichloromethane (30 mL). The organic extracts were washed with satd aq
sodium bicarbonate (2 Â 20 mL), dried (MgSO4), filtered and concentrated
in vacuo. The residue was purified by flash column chromatography
(petrol/ethyl acetate 4:1with 1% added triethylamine) to afford the
bromide 7 (312 mg, 73%) as a colourless oil. [a]2D2 ˆ ‡150 (c ˆ 0.45 in
CHCl3); 1H NMR (200 MHz, CDCl3, 258C): d ˆ 7.38 7.16 (m, 15H; Ar-
H),6.67 (d, 3J(H,H) ˆ 4.0 Hz, 1H; H-1), 4.85, 4.80 (ABq, 3J(H,H) ˆ
11.3 Hz, 2H; PhCH2), 4.78 (dd, 3J(H,H) ˆ 9.8 Hz, 4.0 Hz, 1H; H-2), 4.83,
4.56 (ABq, 3J(H,H) ˆ 10.1 Hz, 2H; PhCH2), 4.62, 4.51(ABq, 3J(H,H) ˆ
12.2 Hz, 2H; PhCH2), 4.13 4.07 (m, 2H; H-3, H-5), 3.90 3.85 (m, 1H;
H-4), 3.83 (dd, 2J(H,H) ˆ 11.1 Hz, 3J(H,H) ˆ 3.2 Hz, 1H; H-6'), 3.69 (dd,
2J(H,H) ˆ 11.1 Hz, 3J(H,H) ˆ 1.8 Hz, 1 H; H-6), 2.06 (s, 3H; CH3). The
spectroscopic and analytical data were in agreement with those reported in
the literature.[15]
ˆ
138.3, 138.0, 134.0 (4  s, Ar-C), 143.9 (d, OCH CH); IR (thin film) nÄ ˆ
1670 cmÀ1 (C C); MS-APCI : m/z (%): 605 (100) [M‡Na] ; elemental
‡
‡
ˆ
analysis calcd (%) for C36H38O5S: C 74.20, H 6.57; found: C 74.44, H 6.58.
Methyl 2-O-allyl-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyranoside (5): So-
dium hydride (60% dispersion in mineral oil, 0.068 g, 1.716 mmol) was
added portionwise to a solution of alcohol 4[8] (0.55 g, 1.144 mmol) in dry
DMF (10 mL) at 08C. Allyl bromide (0.198 mL, 2.288 mmol) was then
added and the resulting solution was stirred at 08C for 30 min, after which
time TLC (ethyl acetate/petrol 1:4) indicated no remaining starting
material (Rf ˆ 0.1) and the formation of a major product (Rf ˆ 0.4).
Methanol (3 mL) was added carefully at 08C and the mixture was
concentrated in vacuo. The residue was dissolved in dichloromethane
(90 mL) and washed with brine (2 Â 40 mL) and then water (30 mL). The
aqueous layers were re-extracted with dichloromethane (40 mL) and the
combined organic extracts were dried with anhydrous sodium sulfate,
filtered and concentrated in vacuo. The crude residue was purified by flash
column chromatography (ethyl acetate/petrol 1:5) to give the allyl ether 5
(0.543 g, 91%) as a colourless oil. [a]2D1 ˆ ‡18.0 (c ˆ 1.5 in CHCl3); 1H NMR
Methyl 3,4,6-tri-O-benzyl-1-thio-b-d-glucopyranoside (8)
Method 1: n-Butyllithium (1.2m in hexanes, 1.6 mL, 1.92 mmol) and
dimethyl disulphide (0.17 mL, 1.92 mmol) were dissolved in THF (3 mL)
at À788C under argon and stirred for 10 min. Bromide 7 (305 mg, mmol)
was dissolved in THF (3 mL) and added to the reaction mixture by
cannular. The mixture was stirred at at À788C and after 80 min, TLC (ethyl
acetate/petrol 1:3) indicated formation of a product (Rf ˆ 0.3) and very
little remaining starting material (Rf ˆ 0.6). An aq satd ammonium chloride
solution (2 mL) was added and the mixture was partitioned between
dichloromethane (30 mL) and water (30 mL). The organic layer was dried
(MgSO4), filtered and concentrated in vacuo. The residue was recrystallised
from ether/petrol to afford methyl thioglycoside 8 (180 mg, 68%) as a
white, crystalline solid. M.p. 76 788C (ether/petrol); [a]2D2 ˆ ‡4.8 (c ˆ 0.25
in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.39 7.16 (m, 15H; Ar-
H), 4.93, 4.86 (ABq, 2J(H,H) ˆ 11.3 Hz, 2H; PhCH2), 4.83, 4.56 (ABq,
(400 MHz, CDCl3, 258C): d ˆ 7.40 7.17 (m, 15H, Ar-H), 5.95 (ddt,
3
ˆ
J(H,H) ˆ 17.3 Hz, 10.3 Hz, 5.6, Hz, 1H; OCH2CH CH2), 5.33 (dddd,
2J(H,H) ˆ 3.1Hz, 3J(H,H) ˆ 17.3 Hz, J(H,H) ˆ 1.3 Hz, 1 H; OCH2CH
4
ˆ
CHEHZ), 5.27 (d, 3J(H,H) ˆ 1.4 Hz, 1 H; H-1), 5.23 (dddd, 2J(H,H) ˆ
3.1Hz, 3J(H,H) ˆ 10.3 Hz, 4J(H,H) ˆ 1.3 Hz, 1 H; OCH2CH CHEHZ),
ˆ
4.89, 4.51(ABq, 2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 4.68 (s, 2H; PhCH2),
4.67, 4.53 (ABq, 2J(H,H) ˆ 11.7 Hz, 2H; PhCH2), 4.20 (ddat, 2J(H,H) ˆ
12.9 Hz, 3J(H,H) ˆ 5.4 Hz, 4J(H,H) ˆ 1.4 Hz, 1 H; OCHH'), 4.13 (ddat,
2J(H,H) ˆ 12.9 Hz, 3J(H,H) ˆ 5.8 Hz, 4J(H,H) ˆ 1.3 Hz, 1 H; OCHH'), 4.1
2
2J(H,H) ˆ 10.5 Hz, 2H; PhCH2), 4.60, 4.53 (ABq, J(H,H) ˆ 12.1 Hz, 2H;
(ddd, J(H,H) ˆ 4.9 Hz, 2.1Hz, 1H; H-5), 3.98 (at, 3J(H,H) ˆ 9.4 Hz, 1H;
3
3
PhCH2), 4.22 (d, J(H,H) ˆ 9.0 Hz, 1H; H-1), 3.75 (dd, 2J(H,H) ˆ 11.0 Hz,
H-4), 3.87 (dd, 3J(H,H) ˆ 9.3 Hz, 3.3 Hz, 1H; H-3), 3.83 3.79 (m, 2H;
H-6', H-2), 3.73 (dd, 2J(H,H) ˆ 11.1 Hz, 3J(H,H) ˆ 2.1Hz, 1H; H-6), 2.14
(s, 3H; SCH3); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.4, 138.3, 138.1 (3  s,
3J(H,H) ˆ 2.0 Hz, 1H; H-6'), 3.71(dd, 2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ
4.3 Hz, 1H; H-6), 3.64 (at, 3J(H,H) ˆ 9.0 Hz, 1H; H-4), 3.60 3.55 (m,
2H; H-2, H-3), 3.53 3.50 (m, 1H; H-5), 2.20 (s, 3H; SCH3); 13C NMR
(100.6 MHz, CDCl3): d ˆ 137.4, 137.0, 136.9 (3  s, Ar-C), 128.5, 128.4,
128.4, 128.3, 127.6, 128.1, 128.0, 127.9, 127.8, 127.7 (10 Â d, Ar-CH), 84.8,
84.5, 78.3, 76.2, 71.3 (5Â d, C-1, C-2, C-3, C-4, C-5), 74.1, 74.0, 72.3, 67.7
(4  t, C-6, 3  PhCH2), 10.4 (q, SCH3); IR (thin film): nÄ ˆ 3440 cmÀ1 (OH);
ˆ
Ar-C), 134.7 (d, OCH2CH CH2), 128.4, 128.3, 128.2, 127.9, 127.9, 127.7,
ˆ
127.7, 127.5, 127.4 (9 Â d, Ar-CH), 117.8 (t, OCH2CH CH2), 83.3, 80.1, 75.9,
75.0, 71.8 (5Â d, C-5, C-4, C-2, C-3, C-1), 75.1, 73.3, 72.2, 71.4, 69.1 (5 Â t,
ˆ
C-6, 3 Â PhCH2, OCH2CH CH2), 13.7 (q, SCH3); MS-CI: m/z (%): 473
‡
‡
(100) [M À SCH3] ; HRMS-ES: calcd for C31H40NO5S [M‡NH4] :
‡
‡
MS-APCI : m/z (%): 504 (100) [M‡Na] ; elemental analysis calcd (%) for
538.2627, found: 538.2643.
C28H32O5S: C 69.97, H 6.71; found: C 70.00, H 6.79.
Methyl 2-O-(prop-1-enyl)-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyranoside
(6): n-Butyllithium (1.2m in hexanes, 0.076 mL) was added to a degassed
solution of Wilkinson×s catalyst (0.061g, 0.062 mmol) in dry THF (90 mL).
The resulting mixture was stirred for 10 min, before being added to a
refluxing solution of the allyl ether 5 (0.345 g, 0.662 mmol) in THF (3 mL).
After 15 min, TLC (ethyl acetate/petrol 1:4) indicated complete consump-
tion of the starting material (Rf ˆ 0.45) and the formation of a single
product (Rf ˆ 0.6). The solution was allowed to cool to room temperature
then diluted with dichloromethane (20 mL) and concentrated in vacuo. The
residue was purified by flash column chromatography (ethyl acetate/petrol
1:8) to afford the desired vinyl ether 6 (0.326 g, 95%), as a clear colourless
oil, as an inseparable mixture of E and Z isomers (Z:E ratio 1.25:1). E
isomer: 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.40 7.18 (m, 15H; Ar-H),
Method 2: Acetyl bromide (10 mL) was added to the orthoester 11 (1.0 g,
1.92 mmol) at 08C under argon. After 15 min, TLC (ethyl acetate/petrol
1:2) indicated formation of a product (Rf ˆ 0.5) and complete consumption
of starting material (Rf ˆ 0.4). Toluene was added and the mixture
concentrated in vacuo to give bromide
7 which was used without
purification. n-Butyllithium (1.6m in hexanes, 3.0 mL, 4.81mmol) and
dimethyl disulphide (0.43 mL, 4.81mmol) were dissolved in THF (5 mL) at
À788C under argon and stirred for 15 min. The crude residue was dissolved
in THF (3 mL) and added to the reaction mixture by cannular under argon.
The mixture was stirred at À788C and after 1h, TLC (ethyl acetate/petrol
1:3) indicated formation of a product (Rf ˆ 0.2) and very little remaining
starting material (Rf ˆ 0.5). Aq satd ammonium chloride (30 mL) was
added and the mixture was partitioned between dichloromethane (2 Â
50 mL) and water (100 mL). The organic layer was dried (MgSO4), filtered
and concentrated in vacuo. The residue was purified by flash column
chromatography (petrol/ethyl acetate 4:1) to give a white solid which was
3
4
ˆ
6.1(dd, J(H,H) ˆ 12.5 Hz, J(H,H) ˆ 1.4 Hz, 1 H; OCH CHCH3), 5.29 (s,
3
ˆ
1H; H-1), 4.96 (dd, J(H,H) ˆ 12.5 Hz, 6.8 Hz, 1H; OCH CHCH3), 4.91
4.56 (m, 6H; 3 Â PhCH2), 4.14 3.69 (m, 6H; H-6', H-6, H-5, H-4, H-3,
2614
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2614 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 1 1

Stereoselective 1,2-cis Glycosylation
2608 2621
recrystallised from ether/petrol to afford methyl thioglycoside 8 (561mg,
61%) as a white, crystalline solid, identical to that previously described.
H-1), 4.82, 4.70 (ABq, 2J(H,H) ˆ 11.3 Hz, 2H; PhCH2), 4.81, 4.60 (ABq,
2J(H,H) ˆ 10.8 Hz, 2H; PhCH2), 4.61, 4.55 (ABq, 2J(H,H) ˆ 12.0 Hz, 2H;
PhCH2), 3.81(dd, 2J(H,H) ˆ 11.1 Hz, 3J(H,H) ˆ 1.9 Hz, 1 H; H-6'), 3.75 (dd,
2J(H,H) ˆ 11.1 Hz, 3J(H,H) ˆ 4.6 Hz, 1H; H-6), 3.72 3.67 (m, 2H; H-3,
H-4), 3.56 3.53 (m, 1H; H-5), 2.01 (s, 3H; CH 3); 13C NMR (100.6 MHz,
Methyl 2-O-allyl-3,4,6-tri-O-benzyl-1-thio-b-d-glucopyranoside (9): Alco-
hol 8 (2.74 g, 5.71mmol) was dissolved in anhydrous DMF (10 mL) and
cooled to 08C. Allyl bromide (1.0 mL, 11.42 mmol) was added and then
sodium hydride (60% dispersion in mineral oil, 457 mg, 11.42 mmol) was
added portionwise. After 30 min, TLC (ethyl acetate/petrol 1:3) indicated
formation of a single product (Rf ˆ 0.8) and complete consumption of
starting material (Rf ˆ 0.5). The reaction was quenched with methanol
(10 mL) the mixture adjusted to pH 7 with aqueous HCl (1m) and then
concentrated in vacuo. The residue was partitioned between dichloro-
methane (3 Â 100 mL) and water (200 mL). The combined organic layers
were washed with brine (50 mL), dried (MgSO4), filtered and concentrated
in vacuo. The residue was purified by flash column chromatography
(petrol/ethyl acetate 6:1) to afford allylated thioglycoside 9 (2.52 g, 85%)
ˆ
CDCl3): d ˆ 169.6 (s, C O),138.2, 138.0, 137.8 (3  s, Ar-C), 134.7, 128.9,
128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 127.6 (9 Â d, Ar-CH), 84.3, 81.7, 80.4,
77.7, 72.6 (5 Â d, C-1, C-2, C-3, C-4, C-5), 75.3, 75.1, 73.4, 68.8 (4Â t, C-6, 3 Â
‡
PhCH2), 21.1 (q, CH3); IR (thin film):nÄ ˆ 1737 cmÀ1 (C O); MS-APCI :
ˆ
‡
m/z (%): 655 (100) [M‡Na] ; elemental analysis calcd for C35H36O6Se: C
66.56, H 5.74; found: C 66.70, H 5.47.
Phenyl 3,4,6-tri-O-benzyl-1-seleno-b-d-glucopyranoside (13): The acetate
12 (7.34 g, 11.6 mmol) was suspended in methanol (900 mL). Sodium
(870 mg, 37.8 mmol) was added to methanol (100 mL), and this solution
was then added to the dissolved acetate. After 28 h, TLC (ethyl acetate/
petrol 1:3) indicated formation of a product (Rf ˆ 0.45) and complete
consumption of starting material (Rf ˆ 0.5). Aqueous HCl (1m) was added
until pH 7 was reached and the mixture was concentrated to ca. 150 mL in
vacuo. The solution was partitioned between ethyl acetate (400 mL) and
water (200 mL). The organic layer was dried (MgSO4), filtered and
concentrated in vacuo. The residue was recrystallised from ether/petrol to
afford the alcohol 13 (6.24 g, 91%) as a white, crystalline solid. M.p. 61
638C (ether/petrol); [a]D22 ˆ À1 2 (c ˆ 0.5 in CHCl3); 1H NMR (400 MHz,
CDCl3, 258C, TMS): d ˆ 7.68 7.19 (m, 20H; Ar-H),4.91, 4.84 (ABq,
1
as a pale yellow oil. [a]2D2 ˆ À11 (c ˆ 0.55 in CHCl3); H NMR (400 MHz,
CDCl3, 258C): d ˆ 7.41 7.15 (m, 15H; Ar-H); 6.01 (ddt, 3J(H,H) ˆ 17.1 Hz,
10.4 Hz, 6.0 Hz, 1H; OCH2CH CH2), 5.33 (dddd, 2J(H,H) ˆ 1.4 Hz,
ˆ
3J(H,H) ˆ 17.1 Hz, 4J(H,H) ˆ 1.3 Hz, 1.3 Hz, 1 H; OCH CH CHEHZ),
ˆ
2
5.21(dddd,
2J(H,H) ˆ 1.4 Hz, 3J(H,H) ˆ 10.4 Hz, 4J(H,H) ˆ 1.3 Hz,
2
ˆ
1.3 Hz, 1 H; OCH2CH CHEHZ), 4.95, 4.86 (ABq, J(H,H) ˆ 10.9 Hz, 2H;
PhCH2), 4.85, 4.58 (ABq, 2J(H,H) ˆ 10.8 Hz, 2H; PhCH2), 4.63, 4.57 (ABq,
2
3
2J(H,H) ˆ 12.0 Hz, 2H; PhCH2), 4.43 (ddat, J(H,H) ˆ 12.0 Hz, J(H,H) ˆ
5.8 Hz, 4J(H,H) ˆ 1.3 Hz, 1 H; OCHH'), 4.33 (d, 3J(H,H) ˆ 9.6 Hz, 1H;
H-1), 4.30 (ddat, 2J(H,H) ˆ 12.0 Hz, 3J(H,H) ˆ 6.0 Hz, 4J(H,H) ˆ 1.3 Hz,
1H; OCHH'), 3.78 (dd, 2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 1.9 Hz, 1 H; H-6'),
2
2J(H,H) ˆ 11.2 Hz, 2H; PhCH2), 4.82, 4.57 (ABq, J(H,H) ˆ 10.8 Hz, 2H;
PhCH2), 4.73 (d, 3J(H,H) ˆ 9.6 Hz, 1H; H-1), 4.61, 4.55 (ABq, 2J(H,H) ˆ
2
3
2
3
3.72 (dd, J(H,H) ˆ 10.9 Hz, J5,6 4.4 Hz, J(H,H) ˆ 10.9 Hz, 1H; H-6), 3.67
(at, 3J(H,H) ˆ 8.9 Hz, 1H; H-3), 3.62 (at, 3J(H,H) ˆ 9.2 Hz, 1H; H-4),
3.52 3.48 (m, 1H; H-5), 3.36 (dd, 3J(H,H) ˆ 9.6 Hz, 8.6 Hz, 1H; H-2), 2.26
(s, 3H; SCH3); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.4, 138.2, 138.0 (3  s,
12.0 Hz, 2H; PhCH2), 3.80 (dd, J(H,H) ˆ 11.1 Hz, J(H,H) ˆ 2.0 Hz, 1H;
2 3
H-6'), 3.76 (dd, J(H,H) ˆ 11.1 Hz, J(H,H) ˆ 4.0 Hz, 1H; H-6), 3.64 3.56
(m, 2H; H-3, H-4), 3.54 3.47 (m, 2H; H-2, H-5). The spectroscopic and
analytical data were in agreement with those reported in the literature.[18]
ˆ
Ar-C), 134.6 (d, OCH2CH CH2), 128.4, 128.4, 128.3, 128.0, 127.9, 127.8,
Phenyl 2-O-allyl-3,4,6-tri-O-benzyl-1-seleno-b-d-glucopyranoside (14):
The alcohol 13 (3.0 g, 5.09 mmol) was dissolved in anhydrous DMF
(10 mL) and cooled to 08C. Allyl bromide (0.88 mL, 10.18 mmol) was
added then sodium hydride (60% dispersion in mineral oil, 407 mg,
10.18 mmol) was added portionwise. After 30 min, TLC (ethyl acetate/
petrol 1:3) indicated formation of a single product (Rf ˆ 0.5) and complete
consumption of starting material (Rf ˆ 0.3). The reaction was quenched
with methanol (5 mL) then concentrated in vacuo. The residue was
partitioned between dichloromethane (100 mL) and water (100 mL). The
aqueous layer was extracted with dichloromethane (100 mL) and the
combined organic layers were washed with brine (30 mL), dried (MgSO4),
filtered and concentrated in vacuo. The residue was recrystallised from
ethanol to afford allylated selenoglycoside 14 (2.97 g, 92%) as a white,
crystalline solid. M.p. 61 628C (ethanol); [a]2D2 ˆ À7.6 (c ˆ 0.5 in CHCl3);
ˆ
127.7, 127.6 (8 Â d, Ar-CH), 117.5 (t, OCH2CH CH2), 86.5 (d, C-3), 85.3 (d,
ˆ
C-1), 80.8 (d, C-2), 79.1(d, C-5), 77.7 (d, C-4), 74.1(t, O CH2CH CH2), 75.8,
75.1, 73.4 (3Â t, 3 Â PhCH2), 68.9 (t, C-6), 13.0 (q, SCH3); IR (thin film):
‡
‡
nÄ ˆ 1647 cmÀ1 (C C); MS-APCI : m/z (%): 559 (42) [M‡K] , 543 (100)
ˆ
‡
[M‡Na] ; elemental analysis calcd (%) for C31H36O5S: C 71.51, H 6.97;
found: C 71.49, H 6.89.
Methyl 2-O-(prop-1-enyl)-3,4,6-tri-O-benzyl-1-thio-b-d-glucopyranoside
(10): Wilkinson×s catalyst (448 mg, 0.49 mmol) was dissolved in THF
(10 mL) and degassed. n-Butyllithium (1.6m in hexanes, 0.45 mL,
0.73 mmol) was added and the mixture stirred for 10 min. Thioglycoside
9 (2.52 g, 0.485 mmol) was dissolved in THF (10 mL) and heated to reflux.
The catalyst solution was added by cannular under argon. After 1h, TLC
(ethyl acetate/petrol 1:3) indicated formation of a single product (Rf ˆ 0.55)
and complete consumption of starting material (Rf ˆ 0.5). The reaction was
allowed to cool then diluted with dichloromethane (20 mL) and concen-
trated in vacuo. The residue was purified by flash column chromatography
(petrol/ethyl acetate 6:1with 1% added triethylamine) to afford the vinyl
ethers 10 (2.37 g, 94%) as a pale yellow oil, as a mixture of E and Z isomers,
E:Z ratio 2.7:1; partial data: E isomer: 1H NMR (200 MHz, CDCl3, 258C):
1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.69 7.17 (m, 20H; Ar-H), 5.97
3
ˆ
(ddat, J(H,H) ˆ 17.2 Hz, 10.7 Hz, 6.0 Hz, 1H; OCH2CH CH2), 5.28 (dd,
2J(H,H) ˆ 1.6 Hz, J(H,H) ˆ 17.2 Hz, 1H; OCH2CH CHEHZ), 5.18 (dd,
3
ˆ
2J(H,H) ˆ 1.6 Hz, J(H,H) ˆ 10.4 Hz, 1H; OCH2CH CHEHZ), 4.89, 4.83
3
ˆ
(ABq, 2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 4.80 (d, 3J(H,H) ˆ 9.8 Hz, 1H;
H-1), 4.81, 4.58 (ABq, 2J(H,H) ˆ 10.8 Hz, 2H; PhCH2), 4.59, 4.53 (ABq,
2J(H,H) ˆ 12.0 Hz, 2H; PhCH2), 4.34 (dd, 2J(H,H) ˆ 11.8 Hz, 3J(H,H) ˆ
d ˆ 6.23 (dd, 1H; OCH CHCH3), 5.05 (dd, 3J(H,H) ˆ 12.2 Hz, 1H;
ˆ
OCH CHCH3), 1.57 (dd, 3J(H,H) ˆ 6.9 Hz, 4J(H,H) ˆ 1.5 Hz, 3H;
5.6 Hz, 1H; OCHH'), 4.24 (dd, J(H,H) ˆ 11.8 Hz, J(H,H) ˆ 6.0 Hz, 1H;
OCHH'), 3.78 (dd, 2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 2.0 Hz, 1H; H-6'), 3.72
(dd, 2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 4.3 Hz, 1H; H-6), 3.64 3.62 (m, 2H;
H-3, H-4), 3.49 3.45 (m, 1H; H-5), 3.42 3.37 (m, 1H; H-2); 13C NMR
(100.6 MHz, CDCl3): d ˆ 138.8, 138.6 (2  s, Ar-C), 135.1, 134.9 (2  d, Ar-
2
3
ˆ
1
ˆ
OCH CHCH3); Z isomer: H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ
3
6.16 (dd, J(H,H) ˆ 6.2 Hz, 1H; OCH CHCH3), 1.64 (dd, 3J(H,H) ˆ
ˆ
4
‡
ˆ
6.9 Hz, J(H,H) ˆ 1.6 Hz, 3H; OCH CHCH3); MS-APCI : m/z (%): 543
‡
‡
(100) [M‡Na] ; HRMS-ES: calcd for C31H40NO5S [M‡NH4] : 538.2627,
ˆ
found: 538.2627.
CH, OCH2CH CH2), 129.5, 128.9, 128.8, 128.4, 128.4, 128.2, 128.1, 128.0
ˆ
(8 Â d, Ar-CH), 117.9 (t, OCH2CH CH2),87.2, 83.5, 81.6, 80.6, 78.2 (5Â d,
Phenyl 2-O-acetyl-3,4,6-tri-O-benzyl-1-seleno-b-d-glucopyranoside (12):
Orthoester 11[17] (8.3 g, 16.0 mmol) was dissolved in acetonitrile (60 mL).
Mercuric bromide (57.6 mg, 0.16 mmol) and then selenophenol (3.3 mL,
30.0 mmol) were added and the reaction mixture was stirred at 508C. After
C-1, C-2, C-3, C-4, C-5), 76.3, 75.6, 74.5, 73.9, 69.4 (5Â t, C-6, 3 Â PhCH2,
‡
‡
ˆ
OCH2CH CH2); MS-APCI : m/z (%): 653 (100) [M‡Na] ; elemental
analysis calcd for C36H38O5Se: C 68.67, H 6.08; found: C 68.77, H 6.09.
90 min, TLC (dichloromethane/ether 30:1) indicated formation of
a
Phenyl
2-O-(prop-1-enyl)-3,4,6-tri-O-benzyl-1-seleno-b-d-glucopyrano-
product (Rf ˆ 0.7) and complete consumption of starting material (Rf ˆ
0.3). The reaction was quenched with 5% aq sodium hydroxide (200 mL)
then extracted with dichloromethane (2 Â 200 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified by flash column chromatography (petrol/ethyl acetate
6:1) and recrystallised from ethanol to afford the selenoglycoside 5 (7.85 g,
78%) as a white, crystalline solid. M.p. 122 1258C (ethanol); [a]2D2 ˆ ‡2.7
(c ˆ 0.33 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.67 7.22 (m,
20H; Ar-H), 5.11 5.06 (m, 1H; H-2), 4.84 (d, 3J(H,H) ˆ 10.1 Hz, 1H;
side (15): Wilkinson×s catalyst (31mg, 0.033 mmol) was dissolved in THF
(3 mL) and degassed. n-Butyllithium (1.2m in hexanes, 0.04 mL,
0.049 mmol) was added and the mixture stirred for 15 min. Selenoglycoside
14 (205 mg, 0.326 mmol) was dissolved in THF (3 mL) and heated to reflux.
The catalyst solution was added by cannular under argon. After 140 min,
the reaction was allowed to cool then diluted with dichloromethane
(20 mL) and concentrated in vacuo. The residue was purified by flash
column chromatography (petrol/ethyl acetate 6:1) to give vinyl ethers 15
‡
(190 mg, 92%) as a pale yellow oil. MS-APCI : m/z (%): 653 (45)
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2615 $ 20.00+.50/0
2615

A. J. Fairbanks et al.
FULL PAPER
‡
‡
[M‡Na] ; HRMS: calcd for C36H42NO5Se [M‡NH4] : 648.2228, found:
74.9, 73.6, 73.4, 73.0, 72.7, 70.7, 70.3, 29.8, 28.8, 28.5, 28.3, 22.6, 21.9, 21.7, 19.5
(22 Â d/q, CHICH3, OCH(CH2)2, C-1, C-2, C-3, C-4, C-5, O2CH), 75.6, 75.5,
73.8, 72.6, 69.6, 69.3, 36.0, 33.7, 33.5, 33.3, 33.2, 26.1, 26.0, 25.9, 25.8, 24.6,
648.2234.
General procedure A: manno/S-phenyl NIS tethering: Vinyl ether 3
(typically 0.15 mmol), the alcohol (1.5 equiv) and powdered 4 ä molecular
sieves (ca. 500 mg) were stirred in dichloroethane (4 mL) under argon at
À408C. NIS (2.5 equiv) was added and the mixture was allowed to warm
slowly to room temperature overnight. After 16 h, dichloromethane was
added, the mixture was filtered through Celite washed with 10% aqueous
sodium thiosulfate, dried (MgSO4), filtered and concentrated in vacuo. The
resulting residue was purified by flash column chromatography to give the
mixed acetals 16a e,g,h.
‡
24.4, 24.3 (18 Â t, (CH2)5, C-6, 3 Â PhCH2); MS-APCI : m/z (%): 831(27)
‡
‡
[M‡Na] ; HRMS-CI: calcd for C42H53INO6S [M‡NH4] : 826.2638, found:
826.2635.
Phenyl
2-O-(1-benzyloxy-2-iodopropyl)-3,4,6-tri-O-benzyl-1-thio-a-d-
mannopyranoside (16d): Vinyl ether 3 (250 mg, 0.43 mmol) and benzyl
alcohol (0.11 mL, 1.06 mmol) gave mixed acetals 16d as a cloudy oil, an
inseparable mixture of diastereomers (341mg, 97%). 1H NMR (500 MHz,
CDCl3, 258C): d ˆ 7.75 7.14 (m, 25H; 25  Ar-H), 5.61, 5.60, 5.55, 5.44
(4  d, 3J(H,H) ˆ 2.0 Hz, 1H; H-1), 4.94 4.87, 4.78 4.50 (2  m, >9H;
4 Â PhCH2, O2CH, partial-CHI), 4.37 4.28 (m, <2H; partial-H-2, H-5,
partial-CHI), 4.25 (at, 3J(H,H) ˆ 2.0 Hz, <1H; partial-H-2), 4.13 4.04 (m,
>1H; partial-H-2, H-4), 3.95 3.82 (m, 2H; H-3, H-6'), 3.77 (dd, 2J(H,H) ˆ
11.0 Hz, 3J(H,H) ˆ 1.5 Hz, 1 H; H-6), 1.92, 1.90 (2 d, 3J(H,H) ˆ 7.0 Hz,
3H; CH3); 13C NMR (125.7 MHz, CDCl3): d ˆ 138.9, 138.7, 138.3, 134.0
(4 Â s, Ar-C), 132.4, 132.1, 129.4, 129.0, 128.9, 128.9, 128.8, 128.6, 128.5,
128.4, 128.4, 128.3, 128.3, 128.1, 128.0, 128.0, 127.8 (17 Â d, Ar-CH), 105.6,
105.1, 87.8, 87.5, 86.3, 81.1, 81.0, 76.5, 74.4, 75.2, 74.4, 73.5, 73.4 (13Â d, C-1,
C-2, C-3, C-4, C-5, O2CH), 75.7, 75.4, 73.7, 73.5, 73.2, 73.0, 69.5, 69.4, 67.8,
67.4 (10 Â t, C-6, 4 Â PhCH2), 26.7, 26.4, 23.9, 23.7, 21.6 (5Â d/q, CHICH3);
Phenyl 2-O-(2-iodo-1-methoxypropyl)-3,4,6-tri-O-benzyl-1-thio-a-d-man-
nopyranoside (16a): Vinyl ether 3 (254 mg, 0.49 mmol) gave mixed acetals
16a as a cloudy oil, an inseparable mixture of diastereomers (336 mg,
1
93%). H NMR (400 MHz, CDCl3, 258C): d ˆ 7.54 7.48 (m, 2H; 2  Ar-
H); 7.45 7.26 (m, 18H; 18 Â Ar-H), 5.63, 5.59, 5.57 (3 Â s, 1H; H-1), 4.93,
4.89 (ABq, 2J(H,H) ˆ 10.8 Hz, 1H; PhCHH), 4.83 4.51(m, 6H; 5
Â
PhCHH, O2CH), 4.36 4.17 (m, > 2H; partial-H-2, H-5, CHI), 4.15
(ad, 3J(H,H) ˆ 2.5 Hz, < 1H; partial-H-2), 4.10, 4.04 (2  at, 3J(H,H) ˆ
9.4 Hz, 9.5 Hz, 1H; H-4), 3.96 3.91 (m, 1H; H-3), 3.90 3.84 (m, 1H;
H-6'), 3.78 (d, 2J(H,H) ˆ 10.9 Hz, 1H; H-6), 3.43, 3.39, 3.33, 3.31 (4  s
[relative intensities: 1:1.4:1.7:2.3], 3H; OCH3), 1.91 1.85 (m, 3H;
CHCH3); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.4, 138.2, 137.9 (3  s,
Ar-C), 131.6, 129.1, 128.6, 128.5, 128.5, 128.2, 128.1, 127.9, 127.9, 127.8, 127.7,
127.7, 127.6, 127.4 (14 Â d, Ar-CH), 106.7, 106.5, 87.4, 87.2, 80.7, 80.7, 69.0,
77.4, 76.1, 75.9, 75.2, 75.1, 74.9, 74.8, 73.2, 73.2, 73.1, 73.0, 72.9, 72.9, 72.3
(21 Â d/t, C-1, C-2, C-3, C-4, C-5, C-6, 3Â PhCH2, O2CH), 54.6, 54.1, 52.4,
51.8 (4Â q, OCH3), 25.7, 25.5, 25.2, 23.7, 23.4, 21.5, 21.2 (7Â d/q, CHICH3);
‡
‡
MS-APCI : m/z (%): 839 (47) [M‡Na] ; HRMS-ES: calcd for C43H45I-
‡
NaO6S [M‡Na] : 839.1879, found: 839.1868.
Phenyl 2-O-(2-iodo-1-(methyl 2,3,4-tri-O-benzyl-a-d-glucopyranosid-6-O-
yl)propyl)-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyranoside (16e): Vinyl
ether 3 (100 mg, 0.17 mmol) and methyl 2,3,4-tri-O-benzyl-a-d-glucopyr-
anoside (213 mg, 0.46 mmol) gave mixed acetals 16e as a clear oil, an
inseparable mixture of diastereomers (181 mg, 90%). 1H NMR (400 MHz,
CDCl3, 258C): d ˆ 7.56 7.18 (m, 35H; 35  Ar-H), 5.83, 5.77, 5.73 (3  d,
3J(H,H) ˆ 1.4 Hz, 1.0 Hz, 1.0 Hz, 1 H; H-1man), 5.04 4.44 (m, >14H;
partial-H-1glc, H-2man, O2CHCHI, 6  PhCH2), 4.43 (d, 3J(H,H) ˆ 3.5 Hz,
‡
‡
MS-APCI : m/z (%): 764 (100) [M‡Na] ; elemental analysis for
C37H41IO6S: C 60.00, H 5.58; found: C 59.94, H 5.57.
Phenyl 2-O-(1-(1,2:3,4-di-O-isopropylidene-a-d-galactopyranos-6-O-yl)-2-
iodopropyl)-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyranoside (16b): Vinyl
ether 3 (185 mg, 0.32 mmol) and diacetone galactose (133 mg, 0.51 mmol),
gave mixed acetals 16b as a clear, colourless oil, an inseparable mixture of
diastereomers (293 mg, 95%). 1H NMR (400 MHz, CDCl3, 258C): d ˆ
7.53 7.19 (m, 20H; 20  Ar-H), 5.75, 5.73, 5.64 (3  d, 3J(H,H) ˆ 1.6 Hz,
1.4 Hz, 1.4 Hz, 1 H; H-1man), 5.58, 5.46, 5.39 (3  d, J1,2 ˆ 5.0 Hz, 1H, H-1gal),
<1H; partial-H-1glc), 4.38 4.34 (m, 1H; H-5man), 4.24 3.98 (m, 3H; H-3glc
,
,
H-4man, CHI), 3.96 3.56 (m, >6H; partial-H-2glc, partial-H-4glc, H-5glc
3
H-6glc, H-6'glc, H-3man, H-6man, H-6'man), 3.52 (dd, J(H,H) ˆ 9.6 Hz, 3.5 Hz,
<1H; partial-H-2glc), 3.44 (at, 3J(H,H) ˆ 9.4 Hz, <1H; partial-H-4glc), 3.38,
3.37, 3.35 (3 Â s [relative intensities: 2:1:9], 3H; OCH3), 1.95, 1.92, 1.89 (3Â
d, 3J(H,H) ˆ 7.0 Hz, 7.0 Hz, 6.9 Hz, 3H; CHCH3); 13C NMR (100.6 MHz,
CDCl3): d ˆ 138.8, 138.1, 138.0 (3  s, Ar-C), 135.0, 132.5, 130.4, 129.0,
128.5, 128.5, 128.4, 128.4, 128.4, 128.2, 128.1, 128.1, 128.0, 128.0, 127.8, 127.7,
127.7, 126.9 (18 Â d, Ar-CH), 106.5, 106.4, 103.6, 98.0, 97.8, 97.5, 87.1, 85.9,
4.93 4.48, 4.45 4.08, 4.02 3.68 (m, 20H; H-2man, H-3man, H-4man, H-5man
,
H-6man, H-6'man, H-2gal, H-3gal, H-4gal, H-5gal, H-6gal, H-6'gal, 3 Â PhCH2,
CHCHI, CHCHI), 1.84, 1.87 (2 d, 3J(H,H) ˆ 7.0 Hz, 6.9 Hz, 3H;
CHCH3), 1.56 1.30 (10Â s, 12 H; 2 Â C(CH3)2); 13C NMR (100.6 MHz,
CDCl3): d ˆ 138.4, 138.3, 138.0, 137.7, 137.5, 134.8, 134.5, 134.0, 132.1, 131.0,
130.8, 129.0, 128.8, 128.5, 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.8,
127.8, 127.7, 127.6, 127.3, 126.9 (18 Â d, Ar-CH; 9 Â s, Ar-C), 109.3, 109.2,
109.1, 108.7, 108.6, 108.4 (6 Â s, 2 Â C(CH3)2), 105.1, 102.9, 96.2, 87.2, 87.1,
85.3, 81.0, 81.0, 74.9, 74.7, 74.1, 72.7, 72.6, 71.3, 70.7, 70.6, 70.6, 70.5, 70.3, 67.5,
66.6, 26.7, 26.6, 26.4, 26.3, 26.2, 26.1, 26.0, 25.9, 24.9, 24.4, 24.3, 23.2, 23.1
82.0, 81.1, 80.4, 77.8, 74.9, 74.1, 72.9, 72.7, 70.2 (17Â d, C-1glc, C-2glc, C-3glc
C-4glc, C-5glc, C-1man, C-2man, C-3man, C-4man, C-5man, O2CH), 75.8, 75.3, 75.1,
75.0, 75.0, 73.4, 73.2, 73.1, 72.7, 72.6, 69.0, 66.0, 65.4, 64.3 (14Â t, C-6glc
,
,
C-6man, 6 Â PhCH2), 55.2, 55.2, 55.1(3 Â q, OCH3), 26.7, 26.3, 25.8, 23.1, 23.1,
‡
‡
22.0 (6  d/q, CHICH3); MS-APCI : m/z (%): 1195 (100) [M‡Na] ;
‡
HRMS-ES: calcd for C64H69INaO11S [M‡Na] : 1195.3503, found:
1195.3494.
(34  d‡q, C-1gal, C-2gal, C-3gal, C-4gal, C-5gal, C-1man, C-2man, C-3man, C-4man
,
C-5man, O2CHCHICH3, 2 Â C(CH3)2), 75.2, 73.2, 73.1, 72.5, 72.3, 71.8, 69.0,
Phenyl 2-O-(2-iodo-1-(methyl 2-O-benzyl-(R)-4,6-O-benzylidene-a-d-
mannopyranosid-6-O-yl)-propyl)-3,4,6-tri-O-benzyl-1-thio-a-d-mannopyr-
anoside (16g): Vinyl ether 3 (108 mg, 0.19 mmol) and methyl 2-O-benzyl-
(R)-4,6-benzylidene-a-d-mannopyranoside (175 mg, 0.47 mmol) gave
‡
65.4, 65.1, 63.8 (10Â t, C-6gal, C-6man, 3 Â PhCH2); MS-APCI : m/z (%): 991
‡
(100) [M‡Na] ; elemental analysis calcd for C48H57IO11S: C 59.23, H 5.83;
found: C 59.50, H 5.93.
Phenyl 2-O-(1-cyclohexyloxy-2-iodopropyl)-3,4,6-tri-O-benzyl-1-thio-a-d-
mannopyranoside (16c): Vinyl ether 3 (94 mg, 0.16 mmol) and cyclo-
hexanol (0.33 mL, 0.33 mmol) gave mixed acetals 16c as a clear oil, an
mixed acetals 16g as a clear oil, a partially separable mixture of
diastereomers (170 mg, 85%). Rf ˆ 0.55, 0.45 (petrol/ether 1:1). Data for
partially separated diastereomer at Rf ˆ 0.45: 1H NMR (400 MHz, CDCl3,
258C): d ˆ 7.56 (d, 3J(H,H) ˆ 6.9 Hz, 2H; 2  Ar-H), 7.43 (dd, 3J(H,H) ˆ
1.5 Hz, 8.0 Hz, 2H; 2Â Ar-H), 7.26 7.09 (m, 26H; 26 Â Ar-H), 5.86 (d,
3J(H,H) ˆ 0.9 Hz, 1H; H-1SPh), 5.62 (s, 1H; PhCHO2), 4.87 (d, 3J(H,H) ˆ
1
inseparable mixture of diastereomers (99 mg, 76%). H NMR (500 MHz,
CDCl3, 258C): d ˆ 7.67 7.25 (m, 20H; 20  Ar-H), 5.65, 5.62, 5.60, 5.57
(4  d, 3J(H,H) ˆ 2.0 Hz, 1.5 Hz, 1.5 Hz, 1.5 Hz, 1 H; H-1), 4.92 4.48 (m,
7H [incorporating: 4.91, 4.63 (ABq, 2J(H,H) ˆ 11.0 Hz, <2H; PhCH2),
4.88, 4.57 (ABq, 2J(H,H) ˆ 11.0 Hz, <2H; PhCH2), 4.86, 4.75 (ABq,
2J(H,H) ˆ 12.0 Hz, <2H; PhCH2), 4.75 (s, <2H; PhCH2)], 4.69, 4.53
(ABq, 2J(H,H) ˆ 12.0 Hz, <2H; PhCH2), 4.66, 4.50 (ABq, 3J(H,H) ˆ
12.0 Hz, <2H; 3 Â PhCH2, CHO2), 4.10 4.23 (m, >2H; partial-H-2,
partial-H-3, CHI), 4.37 4.27 (m, >1H; partial-H-2, H-5), 4.01 3.76 (m,
>2H; partial-H-3, H-4, partial-H-6, H-6'), 3.72 (dd, 2J(H,H) ˆ 11.0 Hz,
3J(H,H) ˆ 2.0 Hz, <1H; partial-H-6), 3.67 3.48, 3.40 3.30 (2  m, 1H;
3
3.6 Hz, 1H; O2CHCHI), 4.70 (d, J(H,H) ˆ 12.0 Hz, 1H; PhCHH'), 4.69,
4.41(ABq, 2J(H,H) ˆ 10.4 Hz, 2H; PhCH2), 4.59 4.55 (m, 6H; H-1OMe
,
H-2SPh, PhCH2, PhCHH', PhCHH'), 4.39 (d, 2J(H,H) ˆ 11.9 Hz, 1H;
PhCHH'), 4.16 4.08 (m, 2H; H-4OMe
, H-5SPh), 3.99 3.93 (m, 2H;
3
H-3OMe, CHI), 3.88 (at, J(H,H) ˆ 9.7 Hz, 1H; H-4SPh), 3.74 3.64 (m, 5H;
H-2OMe, H-5OMe, H-6'OMe, H-6SPh, H-6'SPh), 3.51(d, 2J(H,H) ˆ 11.3 Hz, 1H;
H-6OMe), 3.45 (dd, 3J(H,H) ˆ 3.1Hz, 9.4 Hz, 1H; H-3 SPh), 3.27 (s, 3H;
OCH3), 1.74 (3 d, 3J(H,H) ˆ 7.0 Hz, 3H; CHCH3); 13C NMR (100.6 MHz,
CDCl3): d ˆ 139.0, 139.0, 138.8, 138.4, 137.8, 134.7 (6  s, Ar-C),131.8, 130.0,
129.5, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 128.0,
127.9, 127.8, 127.7, 127.6, 127.5 (19 Â d, Ar-CH), 107.7, 103.1, 101.0, 88.3, 81.0,
3
OCH(CH2)2), 1.95, 1.90, 1.89, 1.86 (4 d, J(H,H) ˆ 7.0 Hz, 7.0 Hz, 7.0 Hz,
6.5 Hz, 3H; CH3), 1.94 1.13 (m, 10H, (CH2)5); 13C NMR (125.7 MHz,
CDCl3): d ˆ 138.9, 138.8, 138.6, 135.0, 134.5 (5  s, Ar-C), 132.4, 132.0,
129.4, 129.0, 128.9, 128.8, 128.8, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9 (17 Â d, Ar-CH), 104.7, 102.2, 102.0, 80.7, 81.4, 76.5, 75.7,
80.3, 78.6, 74.9, 74.9, 74.8, 72.9, 64.4 (12 Â d, C-1OMe, C-2OMe, C-3OMe
,
C-4OMe C-5OMe C-1SPh C-2SPh C-3SPh C-4SPh C-5SPh O2CHCHI,
,
,
,
,
,
,
,
2616
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2616 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 1 1

Stereoselective 1,2-cis Glycosylation
2608 2621
PhCHO2), 75.7, 74.7, 73.5, 71.1, 69.7, 69.4 (6Â t, C-6OMe, C-6SPh, 4 Â
and the mixture was allowed to warm slowly to room temperature. After
1h, the mixture was partitioned between dichloromethane and 10%
aqueous sodium thiosulfate. The organic phase was dried (MgSO4),
filtered, concentrated in vacuo and the resulting residue was purified by
flash column chromatography to give the mixed acetals 18a f as clear oils.
(Successful tethering to form 18 f required the addition of triethylamine
before work-up, presumably to stabilise the mixed acetal.)
‡
PhCH2), 55.3 (q, OCH3), 26.4, 21.5 (2Â d/q, CHICH3); MS-APCI : m/z
‡
‡
(%): 1098 (3) [M‡NH4] ; HRMS-ES: calcd for C57H65INO11S [M‡NH4] :
1098.3323, found: 1098.3308.
Selected data for mixture of diastereomers at Rf ˆ 0.55 and minor
component at Rf ˆ 0.45: 1H NMR (400 MHz, CDCl3, 258C): d ˆ 3.36,
3
3.17 (2  s, OCH3), 1.82, 1.66 (2 d, J(H,H) ˆ 6.9 Hz, 7.0 Hz, CHCH3). A
Methyl 2-O-(2-iodo-1-methoxypropyl)-3,4,6-tri-O-benzyl-1-thio-b-d-glu-
copyranoside (18a): Vinyl ether 10 (100 mg, 0.19 mmol) and methanol
side product was also isolated, a single diastereomer of succinimide trapped
thioglycoside 22 (22b), a clear oil (16 mg, 10%). Rf ˆ 0.3 (petrol/ether 1:1);
[a]2D5:5 ˆ ‡92.3 (c ˆ 0.57 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ
7.48 7.20 (m, 15H; 15  Ar-H), 5.63 (d, 1H; NCH), 5.30 (d, 3J(H,H) ˆ
1.7 Hz, 1H; H-1), 5.13 (dq, 3J(H,H) ˆ 10.2 Hz, 1H; CHI), 4.89, 4.68 (Abq,
(0.012 mL, 0.29 mmol) gave mixed acetals 18a (128 mg, 98%) as
colourless oil. MS-APCI : m/z (%): 701(100) [ M‡Na] .
a
‡
‡
Methyl 2-O-(1-(1,2:3,4-di-O-isopropylidene-a-d-galactopyranos-6-O-yl)-
2-iodopropyl)-3,4,6-tri-O-benzyl-1-thio-b-d-glucopyranoside (18b): Vinyl
ether 10 (100 mg, 0.19 mmol) and diacetone galactose (75 mg, 0.29 mmol)
2
2J(H,H) ˆ 10.9 Hz, 2H; PhCH2), 4.85, 4.54 (ABq, J(H,H) ˆ 10.9 Hz, 2H;
PhCH2), 4.60, 4.47 (ABq, 2J(H,H) ˆ 12.0 Hz, 2H; PhCH2), 4.20 4.16 (m,
1H; H-5), 4.10 (at, 3J(H,H) ˆ 2.0 Hz, 1H; H-2), 3.96 3.83 (m, 2H; H-3,
H-4), 3.75 (dd, 2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ 4.9 Hz, 1H; H-6'), 3.69 (dd,
2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ 1.9 Hz, 1 H; H-6), 2.60 2.54 (m, 4H;
(CH2)2), 2.00 (d, 3J(H,H) ˆ 6.9 Hz, 3H; CH3); 13C NMR (100.6 MHz,
CDCl3): d ˆ 138.3, 138.0, 137.6, 133.8 (4  s, Ar-C), 131.8, 129.1, 128.6, 128.5,
128.4, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5, 126.3, 125.5 (14 Â d, Ar-
CH), 86.6, 80.0, 76.2, 76.2, 74.6, 73.2 (6 Â d, C-1, C-2, C-3, C-4, C-5, NCH),
‡
gave mixed acetals 18b (147 mg, 84%) as a colourless oil. MS-APCI : m/z
‡
(%): 929 (100) [M‡Na] .
Methyl 2-O-(1-cyclohexyloxy-2-iodopropyl)-3,4,6-tri-O-benzyl-1-thio-b-d-
glucopyranoside (18c): Vinyl ether 10 (100 mg, 0.19 mmol) and cyclo-
hexanol (0.061mL, 0.577 mmol) gave mixed acetals 18c (115 mg, 80%) as
‡
‡
a colourless oil. MS-APCI : m/z (%): 769 (100) [M‡Na] .
Methyl 2-O-(1-benzyloxy-2-iodopropyl)-3,4,6-tri-O-benzyl-1-thio-b-d-glu-
copyranoside (18d): Vinyl ether 10 (80 mg, 0.15 mmol) and benzyl alcohol
(0.03 mL, 0.31mmol) gave mixed acetals 18d (110 mg, 95%) as a colour-
75.1, 73.2, 72.8, 69.0 (4Â t, C-6, 3 Â PhCH2), 27.8 (t, (CH2)2), 25.0, 23.8 (2 Â
‡
d/q, CHICH3); IR (thin film): nÄ ˆ 1715 cmÀ1 (C O); MS-APCI : m/z (%):
ˆ
‡
‡
825 (8) [M‡NH4] ; HRMS-ES: calcd for C40H46IN2O7S [M‡NH4] :
‡
‡
‡
less oil. MS-APCI : m/z (%): 793 (72) [M‡K] , 777 (100) [M‡Na] , 772
825.2071, found: 825.2078.
‡
(35) [M‡NH4] .
Phenyl
2-O-(2-iodo-1-(p-methoxyphenyl
3,6-di-O-benzyl-2-deoxy-2-
Methyl 2-O-(2-iodo-1-(methyl 2,3,4-tri-O-benzyl-a-d-glucopyranosid-6-O-
yl)propyl)-3,4,6-tri-O-benzyl-1-thio-b-d-glucopyranoside (18e): Vinyl
ether 10 (100 mg, 0.19 mmol) and methyl 2,3,4-tri-O-benzyl-a-d-glucopyr-
anoside (134 mg, 0.29 mmol) gave mixed acetals 18e (76 mg, 36%) as a
phthalimido-b-d-glucopyranosid-4-O-yl)-propyl)-3,4,6-tri-O-benzyl-1-
thio-a-d-mannopyranoside (16h): Vinyl ether 3 (94 mg, 0.16 mmol) and p-
methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-b-d-glucopyrano-
side (128 mg, 0.21 mmol) gave mixed acetals 16h as a clear oil, an
inseparable mixture of diastereomers (19 mg, 9%). Rf ˆ 0.15 (petrol/ethyl
acetate 4:1). 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.82 6.66 (m, 38H;
38  Ar-H), 6.43 (brs, 1H; H-1Man), 5.61(d, 3J(H,H) ˆ 8.2 Hz, 1H; H-1Glc),
5.11 (d, 2J(H,H) ˆ 13.0 Hz, 1H; PhCHH'), 4.81 3.66 (m, 23H;), 3.72 (s,
3H; OCH3), 1.60 (d, 3J(H,H) ˆ 7.1Hz, 3H; CHC H3); 13C NMR
‡
‡
colourless oil. MS-APCI : m/z (%): 1133 (100) [M‡Na] .
Methyl 2-O-(2-iodo-1-(methyl 2,3,4-tri-O-benzyl-a-d-mannopyranosid-6-
O-yl)propyl)-3,4,6-tri-O-benzyl-1-thio-b-d-glucopyranoside (18 f): Vinyl
ether 10 (40 mg, 0.077 mmol) and methyl 2,3,4-tri-O-benzyl-a-d-manno-
pyranoside (71mg, 0.15 mmol) gave mixed acetals 18 f (54 mg, 63%) as a
‡
‡
colourless oil. MS-APCI : m/z (%): 1133 (100) [M‡Na] .
ˆ
(100.6 MHz, CDCl3): d ˆ 155.3, 150.8 (2  s, C O), 138.9, 138.8, 138.3,
General procedure C: Intramolecular glycosylation with NIS/AgOTf: The
mixed acetals 16a e,g (typically ꢀ0.1mmol), NIS (5 equiv), silver triflate
(1equiv), 2,6-di- tert-butyl-4-methylpyridine (DTBMP) (5 equiv) and pow-
dered 4 ä molecular sieves (ca. 250 mg) were dissolved in dry dichloro-
ethane under argon. The solution was then stirred at room temperature (or
508C) until TLC indicated disappearance of the starting material.
Trifluoroacetic acid (10 mL), methanol (2 mL), THF (2 mL) and water
(2 mL) were added and the solution was stirred for a further 1 4 h.
Dichloromethane was added, the mixture filtered through Celite washed
with saturated aqueous sodium bicarbonate, and the aqueous layers were
re-extracted with dichloromethane. The combined organic extracts were
washed with 10% sodium thiosulfate, dried (MgSO4), filtered and
concentrated in vacuo. The resulting residue was purified by flash column
chromatography to give the pure b-mannoside 20a e,g.
137.9, 137.7 (5 Â s, Ar-C), 133.6, 133.2, 132.5, 129.3, 128.8, 128.7, 128.6, 128.4,
128.3, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5, 127.4,
127.3, 126.9, 126.7, 123.2, 118.8, 114.3 (26 Â d, Ar-CH), 104.5 (d, O2CCHI),
97.8 (d, C-1Glc), 86.1(d, C-1 Man), 80.8, 80.0, 77.5, 76.0, 75.6, 75.4, 73.7, 56.0
(8 Â d, C-2Man, C-3Man, C-4Man, C-5Man, C-2Glc, C-3Glc, C-4Glc, C-5Glc), 75.7,
75.1, 74.0, 73.0, 72.5, 69.3, 67.8 (7Â t, C-6Man, C-6Glc, 5 Â PhCH2), 55.6 (q,
OCH3), 29.7 (d, CHI), 23.7 (q, CHICH3); IR (thin film): nÄ ˆ 1716 cmÀ1
ˆ
(C O); elemental analysis calcd for C71H70INO13S: C 65.38, H 5.41, N 1.07;
found: C 65.36, H 5.44, N 1.10.
Two side products were also isolated, being two diastereomers of
succinimide trapped thioglycoside 22 as clear oils. Data for first diaster-
eomer of 22 (22a) (13 mg, 10%). Rf ˆ 0.35 (petrol/ethyl acetate 4:1);
1
[a]2D4 ˆ ‡22.4 (c ˆ 0.62 in CHCl3); H (500 MHz, CDCl3, 258C): d ˆ 7.55
7.21 (m, 15H; 15 Â Ar-H), 5.54 (d, 1H; H-1), 5.30 (d, 1H; NC H), 5.18 (dq,
3J(H,H) ˆ 10.1 Hz, 1H; CHI), 4.86, 4.59 (ABq, 2J(H,H) ˆ 10.9 Hz, 2H;
PhCH2), 4.73, 4.57 (ABq, 2J(H,H) ˆ 11.6 Hz, 2H; PhCH2), 4.61, 4.51 (ABq,
2J(H,H) ˆ 11.9 Hz, 2H; PhCH2), 4.32 (ddd, 3J(H,H) ˆ 8.1Hz, 3.5 Hz,
1.8 Hz, 1 H; H-5), 4.11 (dd, 3J(H,H) ˆ 2.5 Hz, 2.1Hz, 1H; H-2), 4.00 (at,
3J(H,H) ˆ 9.6 Hz, 1H; H-4), 3.83 3.79 (m, 2H; H-3, H-6'), 3.75 (dd,
2J(H,H) ˆ 10.9 Hz, 3J(H,H) ˆ 1.8 Hz, 1 H; H-6), 2.65 1.85 (br, 4H;
(CH2)2), 1.99 (d, 3J(H,H) ˆ 6.8 Hz, 3H; CH3); 13C NMR (125.7 MHz,
CDCl3): d ˆ 138.2, 138.0, 133.4 (3  s, Ar-C), 132.5, 129.0, 128.4, 128.3,
128.2, 127.8, 127.8, 127.8, 127.6, 127.6, 127.4, 127.3 (12 Â d, Ar-CH), 86.0, 85.9,
79.3, 78.2, 75.2, 72.9 (6 Â d, C-1, C-2, C-3, C-4, C-5, NCH), 75.1, 73.1, 73.0,
Methyl 3,4,6-tri-O-benzyl-b-d-mannopyranoside (20a): Mixed acetals 16a
(62 mg, 0.083 mmol) gave b-mannoside 20a as a clear, colourless oil (30 mg,
77%). [a]2D2 ˆ À16.6 (c ˆ 0.95 in CHCl3); 1H NMR (400 MHz, CDCl3,
258C): d ˆ 7.40 7.20 (m, 15H; 15  Ar-H), 4.90, 4.55 (ABq, 2J(H,H) ˆ
10.8 Hz, 2H; PhCH2), 4.78, 4.69 (ABq, 2J(H,H) ˆ 11.9 Hz, 2H; PhCH2),
4.65, 4.58 (ABq, 2J(H,H) ˆ 12.3 Hz, 2H; PhCH2), 4.35 (s, 1H; H-1), 4.11 (d,
3J(H,H) ˆ 3.0 Hz, 1H; H-2), 3.88 (at, 3J(H,H) ˆ 9.4 Hz, 1H; H-4), 3.80 (dd,
2J(H,H) ˆ 10.8 Hz, 3J(H,H) ˆ 2.1Hz, 1H; H-6 '), 3.74 (dd, 2J(H,H) ˆ
10.8 Hz, 3J(H,H) ˆ 5.1Hz, 1H; H-6), 3.57 (s, 3H; C H3), 3.60 3.52 (m,
1H; H-3), 3.45 (ddd, 3J(H,H) ˆ 9.7 Hz, 5.1Hz, 2.1Hz, 1H; H-5), 2.43 (brs,
1H; OH); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.2, 138.1, 137.8 (3  s, Ar-
C), 128.5, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6 (9 Â d, Ar-
CH),100.7 (d, 1J (C,H) ˆ 158 Hz, C-1), 81.5, 75.2, 74.2, 68.2 (4  d, C-2, C-3,
C-4, C-5), 75.2, 73.5, 71.4, 69.1 (4Â t, C-6, 3 Â PhCH2), 57.0 (q, CH3); MS-
68.8 (4 Â t, C-6, 3 Â PhCH2), 27.6 (t, (CH2)2), 24.9, 22.8 (2 Â d/q, CHICH3);
‡
IR (thin film): nÄ ˆ 1710 cmÀ1 (C O); MS-APCI : m/z (%): 825 (4)
ˆ
‡
‡
[M‡NH4] ; HRMS-ES: calcd for C40H46IN2O7S [M‡NH4] : 825.2071,
found: 825.2078.
‡
‡
APCI : m/z (%): 487 (27) [M‡Na] . The spectroscopic and analytical data
were in agreement with those reported in the literature.[26]
The second diastereomer of 22 (22b) (77 mg, 60%) was identical in all
respects to the material described previously.
3,4,6-Tri-O-benzyl-b-d-mannopyranosyl-(1 ! 6)-1,2:3,4-di-O-isopropyli-
dene-d-galactopyranose (20b): Mixed acetals 16b (62 mg, 0.064 mmol)
gave b-manno disaccharide 20b as a pale oil (28 mg, 63%). (Treatment of a
mixture of isolated side products with lithium hydroxide in a solution of
General procedure B: gluco/S-methyl NIS tethering: The alcohol
(1.5 equiv), NIS (3 equiv) and powdered 4 ä molecular sieves (ca.
250 mg) were stirred in dichloroethane (4 mL) under argon at À408C.
Vinyl ether 10 (typically ꢀ0.2 mmol) was added by cannula under argon
‡
methanol/water (4:1), followed by treatment with Dowex 50WX8 (H
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2617 $ 20.00+.50/0
2617

A. J. Fairbanks et al.
FULL PAPER
‡
‡
form) in a solution of methanol/water (4:1) led to the isolation of additional
product (8 mg, 63 ! 81%). [a]2D2 ˆ À50 (c ˆ 0.75 in CHCl3); 1H NMR
(400 MHz, CDCl3, 258C): d ˆ 7.39 7.19 (m, 15H; 15  Ar-H), 5.55 (d,
3J(H,H) ˆ 5.0 Hz, 1H; H-1a), 4.66, 4.78 (ABq, 2J(H,H) ˆ 11.9 Hz, 2H;
PhCH2), 4.60 (dd, 3J(H,H) ˆ 7.9 Hz, 2.4 Hz, 1H; H-3a), 4.64, 4.55 (ABq,
2J(H,H) ˆ 12.2 Hz, 2H; PhCH2), 4.91, 4.52 (ABq, 2J(H,H) ˆ 10.8 Hz, 2H;
PhCH2), 4.51(s, 1H; H-1 b), 4.32 (dd, 3J(H,H) ˆ 5.0 Hz, 2.4 Hz, 1H; H-2a),
4.23 4.21(m, 2H; H-4 a, H-2b), 4.14 (dd, 2J(H,H) ˆ 11.2 Hz, 3J(H,H) ˆ
2.9 Hz, 1H; H-6'a), 4.05 4.03 (m, 1H; H-5a), 3.92 (at, 3J(H,H) ˆ 9.4 Hz,
1H; H-4b), 3.79 3.71(m, 3H; H-6 a, H-6b, H-6'b), 3.56 (dd, 3J(H,H) ˆ
9.1Hz, 3.0 Hz, 1H; H-3 b), 3.42 (ddd, 3J(H,H) ˆ 9.7 Hz, 4.6 Hz, 2.1Hz,
1H; H-5b), 2.50 (brs, 1H; OH), 1.54, 1.44, 1.34, 1.32 (4Â s, 12 H; 4 Â CH3);
13C NMR (100.6 MHz, CDCl3): d ˆ 138.3, 138.2, 137.8 (3  s, Ar-C), 128.4,
128.3, 128.1, 128.0, 127.9, 127.9, 127.8, 127.6, 127.5 (9 Â d, Ar-CH), 109.3,
108.7 (2  s, 2  C(CH3)2), 100.2 (d, 1J (C,H) ˆ 158 Hz, C-1b), 96.3 (d, C-1a),
81.2, 77.0, 75.2, 75.1, 74.1, 73.5, 71.4, 71.1, 70.7, 70.2, 69.1, 67.9, 67.8 (13 d‡t,
C-2a, C-3a, C-4a, C-5a, C-6a, C-2b, C-3b, C-4b, C-5b, C-6b, 3 Â PhCH2), 26.1,
m/z (%): 919 (29) [M‡Na] ; HRMS-ES: calcd for C55H60O11Na [M‡Na] :
919.4033; found: 919.4052. The spectroscopic and analytical data were in
agreement with those reported in the literature.[2b]
Methyl 3,4,6-tri-O-benzyl-b-d-mannopyranosyl-(1 ! 6)-2-O-benzyl-(R)-
4,6-O-benzylidene-a-d-mannopyranoside (20g): Mixed acetals 16g
(86 mg, 0.08 mmol) gave the b-manno disaccharide 20g as a clear oil
(57 mg, 89%). Rf ˆ 0.25 (petrol/ethyl acetate 5:2); [a]2D5 ˆ ‡1.7 (c ˆ 0.46 in
1
CHCl3); H NMR (400 MHz, CDCl3, 258C): d ˆ 7.66 7.17 (m, 25H; 25 Â
2
Ar-H), 5.60 (s, 1H; PhCHO2), 4.86 (d, J(H,H) ˆ 10.8 Hz, 1H; PhCHH'),
4.77 (d, 3J(H,H) ˆ 1.7 Hz, 1 H; H-1a), 4.75 (d, 2J(H,H) ˆ 11.0 Hz, 1H;
2
PhCHH'), 4.72 (d, J(H,H) ˆ 12.3 Hz, 1H; PhCHH'), 4.64 4.47 (m, 6H;
2
3
H-3a, 3  PhCHH', PhCH2), 4.27 (dd, J(H,H) ˆ 9.7 Hz, J(H,H) ˆ 4.1Hz,
1H; H-6a'), 4.26 (d, 3J(H,H) ˆ 3.5 Hz, 1H; H-1b), 4.18 (at, 3J(H,H) ˆ
9.6 Hz, 1H; H-4a), 3.94 3.80 (m, 4H; H-2a, H-5a, H-6a, H-2b), 3.88 (at,
3J(H,H) ˆ 9.8 Hz, 1H; H-4b), 3.38 (dd, 3J(H,H) ˆ 3.5 Hz, 2H; H-6b, H-6b'),
3.32 (s, 3H; CH3), 3.28 3.24 (d(at), 3J(H,H) ˆ 9.5 Hz, 3.5 Hz, 3.5 Hz, 1H;
H-5b); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.5, 138.3, 138.1, 137.7, 137.3
(5 Â s, Ar-C), 129.2, 128.4, 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0,
127.8, 127.7, 127.7, 127.4, 126.1 (14 Â d, Ar-CH), 101.8 (d, PhCHO2), 99.7 (d,
‡
‡
25.9, 24.9, 24.3 (4  q, 4  CH3); MS-APCI : m/z (%): 715 (100) [M‡Na] .
The spectroscopic and analytical data were in agreement with those
reported in the literature.[13b]
1J (C,H) ˆ 169 Hz, C-1a), 96.4 (d, J (C,H) ˆ 159 Hz, C-1b), 80.9 (d, C-3b),
1
77.3 (d, C-4a), 75.9 (d, C-5b), 75.1(d, C-5 a), 74.0 (d, C-4b), 73.5, 73.0, 71.1
(3 Â t, 4 Â PhCH2), 71.9 (d, C-3a), 69.0, 68.8 (2 Â t, C-6a, C-6b), 68.4 (d, C-2a),
64.0 (d, C-2b), 54.9 (q, CH3); IR (thin film): nÄ ˆ 3480 cmÀ1 (OH); MS-
Cyclohexyl 3,4,6-tri-O-benzyl-b-d-mannopyranoside (20c): Mixed acetals
16c (89 mg, 0.11 mmol) gave b-mannoside 20c as a clear oil (40 mg, 68%).
[a]2D2 ˆ À23 (c ˆ 0.93 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ
‡
‡
2
APCI : m/z (%): 827 (11) [M‡Na] ; HRMS-ES: calcd for C48H56NO11
7.41 7.23 (m, 15H; 15  Ar-H), 4.91, 4.57 (ABq, J(H,H) ˆ 10.8 Hz, 2H;
‡
[M‡NH4] : 822.3853; found: 822.3845.
PhCH2), 4.80, 4.68 (ABq, 2J(H,H) ˆ 11.9 Hz, 2H; PhCH2), 4.63, 4.58 (ABq,
2J(H,H) ˆ 12.5 Hz, 2H; PhCH2), 4.56 (s, 1H; H-1), 4.08 (d, 3J(H,H) ˆ
2.9 Hz, 1H; H-2), 3.86 (at, 3J(H,H) ˆ 9.4 Hz, 1H; H-4), 3.80 (dd,
2J(H,H) ˆ 10.8 Hz, 3J(H,H) ˆ 2.0 Hz, 1H; H-6'), 3.77 3.68 (m, 2H; H-6,
OCH(CH2)2), 3.58 (dd, 3J(H,H) ˆ 9.1Hz, 2.9 Hz, 1H; H-3), 3.43 (ddd,
3J(H,H) ˆ 9.7 Hz, 5.6 Hz, 2.0 Hz, 1H; H-5), 2.49 (brs, 1H; O H), 2.06 1.16
(m, 10H; (CH2)5); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.3, 138.2, 137.9
(3 Â s, Ar-C), 128.4, 128.3, 128.3, 128.1, 127.9, 127.8, 127.7, 127.5 (8 Â d, Ar-
General procedure D: Intramolecular glycosylation with MeOTf: The
mixed acetals 18a
f (0.08 0.18 mmol) and DTBMP (3 equiv) were
dissolved in dry dichloroethane under argon. Methyl triflate (5 equiv)
was added and the solution was stirred at room temperature until TLC
indicated disappearance of the starting material. Trifluoroacetic acid
(2 mL) and water (1mL) were added and the solution was stirred until a
major product was detected (typically 1 4 h). The reaction mixture was
partitioned between dichloromethane and 10% aqueous sodium bicar-
bonate. The organic phase was dried (MgSO4), filtered and concentrated in
vacuo. The resulting residue was purified by flash column chromatography
to give the pure a-glucosides 21a f.
1
CH), 97.3 (d, J (C,H) ˆ 156 Hz, C-1), 81.7, 77.2, 75.2, 75.1, 74.3, 73.4, 71.3,
69.4, 68.9 (9 Â d/t, C-2, C-3, C-4, C-5, C-6, OCH(CH2)2, 3 Â PhCH2), 33.5,
‡
31.6, 25.5, 24.1, 24.0 (5Â t, (CH2)5); MS-APCI : m/z (%): 555 (53%)
‡
[M‡Na] . The spectroscopic and analytical data were in agreement with
those reported in the literature.[13b]
Methyl 3,4,6-tri-O-benzyl-a-d-glucopyranoside (21a): Mixed acetals 18a
(125 mg, 0.184 mmol) gave a-glucoside 21a (56 mg, 65%) as a white solid
which was recrystallised from ether/petrol. M.p. 78 818C (ether/petrol);
[a]2D2 ˆ ‡71( c ˆ 1.2 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ
7.36 7.11 (m, 15H; Ar-H), 4.88, 4.83 (ABq, 2J(H,H) ˆ 11.2 Hz, 2H;
PhCH2), 4.79, 4.47 (ABq, 2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 4.78 (d,
3J(H,H) ˆ 3.2 Hz, 1H; H-1), 4.62, 4.49 (ABq, 2J(H,H) ˆ 12.1 Hz, 2H;
PhCH2), 3.76 3.60 (m, 6H; H-2, H-3, H-4, H-5, H-6, H-6'), 3.40 (s, 3H;
OCH3), 2.11 (d, 3J(H,H) ˆ 7.4 Hz, 1H; OH-2). The spectroscopic and
analytical data were in agreement with those reported in the literature.[26]
Benzyl 3,4,6-tri-O-benzyl-b-d-mannopyranoside (20d): Mixed acetals 16d
gave b-mannoside 20d as a clear, transparent oil (45 mg, 76%). [a]2D2 ˆ À50
(c ˆ 1.3 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.39 7.13 (m,
20H; 20  Ar-H), 4.77, 4.68 (ABq, 2J(H,H) ˆ 11.9 Hz, 2H; PhCH2), 4.66,
4.60 (ABq, 2J(H,H) ˆ 10.8 Hz, 2H; PhCH2), 4.91, 4.56 (ABq, 2J(H,H) ˆ
10.8 Hz, 2H; PhCH2), 4.48 (s, 1H; H-1), 4.13 (d, 3J(H,H) ˆ 3.1Hz, 1H;
H-2), 3.90 (at, 3J(H,H) ˆ 9.3 Hz, 1H; H-4), 3.82 (dd, 2J(H,H) ˆ 10.7 Hz,
3J(H,H) ˆ 1.9 Hz, 1 H; H-6'), 3.76 (dd, 2J(H,H) ˆ 10.7 Hz, 3J(H,H) ˆ
5.2 Hz, 1H; H-6), 3.56 (dd, 3J(H,H) ˆ 9.0 Hz, 3.1Hz, 1H; H-3), 3.44
(ddd, 3J(H,H) ˆ 9.4 Hz, 5.2 Hz, 1.9 Hz, 1 H; H-5), 2.50 (brs, 1 H; OH);
13C NMR (100.6 MHz, CDCl3): d ˆ 138.2, 138.2, 137.8, 136.8 (4  s, Ar-C),
128.5, 128.4, 128.3, 128.2, 128.0, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6 (11 Â d,
Ar-CH), 98.1(d, 1J (C,H) ˆ 157 Hz, C-1), 81.5, 75.3, 74.2, 68.3 (4  d, C-2,
C-3, C-4, C-5), 75.1, 73.5, 71.4, 70.5, 69.2 (5Â t, C-6, 4 Â PhCH2); MS-
3,4,6-Tri-O-benzyl-a-d-glucopyranosyl-(1 ! 6)-1,2:3,4-di-O-isopropyli-
dene-d-galactopyranose (21b): Mixed acetals 18b (64 mg, 0.075 mmol)
gave a-gluco disaccharide 21b (34 mg, 70%) as a colourless oil. [a]2D2 ˆ ‡28
(c ˆ 0.35 in CHCl3): 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.41 7.12 (m,
15H; Ar-H),5.53 (d, 3J(H,H) ˆ 4.9 Hz, 1H; H-1a), 4.98, 4.82 (ABq,
2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 4.93 (d, 3J(H,H) ˆ 3.2 Hz, 1H; H-1b),
4.83, 4.49 (ABq, 2J(H,H) ˆ 10.3 Hz, 2H; PhCH2), 4.64, 4.50 (ABq,
3J(H,H) ˆ 11.7 Hz, 2H; PhCH2), 4.63 (dd, 3J(H,H) ˆ 7.8 Hz, 2.2 Hz, 1H;
H-3a), 4.34 (dd, 3J(H,H) ˆ 4.9 Hz, 2.2 Hz, 1H; H-2a), 4.25 (dd, 3J(H,H) ˆ
‡
‡
APCI : m/z (%): 558 (5) [M‡NH4] . The spectroscopic and analytical data
were in agreement with those reported in the literature.[27]
Methyl 3,4,6-tri-O-benzyl-b-d-mannopyranosyl-(1 ! 6)-2,3,4-tri-O-benzyl-
a-d-glucopyranoside (20e): Mixed acetals 16e (94 mg, 0.08 mmol) gave the
b-manno disaccharide 20e as a white solid (47 mg, 65%). M.p. 105 1088C
(ether/petrol); [a]2D2 ˆ ‡22 (c ˆ 0.9 in CHCl3); 1H NMR (400 MHz, CDCl3,
3
7.8 Hz, 1.9 Hz, 1 H; H-4a), 4.00 (dat, J(H,H) ˆ 6.7 Hz, 6.7 Hz, 1.9 Hz, 1 H;
H-5a), 3.91(dd, 2J(H,H) ˆ 10.2 Hz, 3J(H,H) ˆ 6.7 Hz, 1H; H-6'a), 3.85 (ddd,
3J(H,H) ˆ 9.9 Hz, 2.2 Hz, 3.0 Hz, 1H; H-5b), 3.79 3.63 (m, 6H; H-2b, H-3b,
H-4b, H-6b, H-6'b, H-6a), 1.54, 1.45, 1.35, 1.34 (4Â s, 12 H; 4 Â CH3). The
spectroscopic and analytical data were in agreement with those reported in
the literature.[26]
2
258C): d ˆ 7.41 7.14 (m, 30H; 30  Ar-H), 5.02 (ABq, J(H,H) ˆ 13.6 Hz,
1H; PhCHH'), 4.91 4.52 (m, 11H;
5
 PhCH2, PhCHH'), 4.58 (d,
3J(H,H) ˆ 2.7 Hz, 1H; H-1a), 4.14 (s, 1H; H-1b), 4.12 (d, 2J (H,H) ˆ
12.8 Hz, 1H; H-6'b), 4.02 (at, 3J(H,H) ˆ 8.9 Hz, 1H; H-4b), 3.94 (s, 1H;
H-2b), 3.82 (at, 3J(H,H) ˆ 9.6 Hz, 1H; H-4a), 3.81 3.78 (m, 1H; H-5 b),
3.76 3.70 (m, 2H; H-6a, H-6'a), 3.60 3.45 (m, 4H; H-2a, H-3a, H-3b, H-6b),
3.36 (m, 1H; H-5a), 3.36 (s, 3H; CH3), 2.41(brs, 1H; O H); 13C NMR
(100.6 MHz, CDCl3): d ˆ 138.7, 138.3, 138.2, 138.2, 138.0, 137.8 (6  s, Ar-
C), 128.5, 128.4, 128.4, 128.3, 128.1, 128.1, 127.9, 127.9, 127.9, 127.7, 127.6,
127.5, 125.5 (13  d, Ar-CH), 99.9 (d, 1J (C,H) ˆ 159 Hz, C-1b), 97.8 (d,
C-1a), 82.1(d, C-4 b), 81.2, 79.8, 77.4 (3Â d, C-2a, C-3a, C-3b), 75.3 (d, C-5a),
74.2 (d, C-4a), 75.7, 75.2, 74.7, 73.4, 73.4, 71.3 (6Â t, 6 Â PhCH2), 69.7 (d,
Cyclohexyl 3,4,6-tri-O-benzyl-a-d-glucopyranoside (21c): Mixed acetals
18c gave a-glucoside 21c (44 mg, 77%) as a white solid which was
recrystallised from ether/petrol. M.p. 92 948C (ether/petrol); [a]D22
ˆ
‡90.0 (c ˆ 0.3 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.42
7.14 (m, 15H; Ar-H), 5.03 (d, 3J(H,H) ˆ 3.5 Hz, 1H; H-1), 4.99, 4.84 (ABq,
2J(H,H) ˆ 11.0 Hz, 2H; PhCH2), 4.65, 4.51(ABq, 2J(H,H) ˆ 12.0 Hz, 2H;
PhCH2), 4.83, 4.49 (ABq, 2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 3.90 3.87 (m,
1H; H-5), 3.77 (dd, 2J(H,H) ˆ 10.7 Hz, 3J(H,H) ˆ 3.9 Hz, 1H; H-6'), 3.75
3.61(m, 5H; H-2, H-3, H-4, H-6, cyclohexyl OCH), 2.06 (d, 3J(H,H) ˆ
‡
C-5b), 69.2 (t, C-6a), 68.2 (d, C-2b), 68.0 (t, C-6b), 55.2 (q, CH3); MS-APCI :
2618
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2618 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 1 1

Stereoselective 1,2-cis Glycosylation
2608 2621
2.7 Hz, 1H; OH-2), 1.92 1.24 (m, 10H; cyclohexyl-H). The spectroscopic
and analytical data were in agreement with those reported in the
literature.[13b]
ature in dichloroethane (4 mL). Silver triflate (27.0 mg, 0.105 mmol), and
iodine (7.0 mg, 0.028 mmol) were then added. The resulting mixture was
stirred at room temperature for 20 min, after which time, TLC (petrol/ethyl
acetate 2:1) showed no remaining starting material (Rf ˆ 0.80) and the
formation of a major product (Rf ˆ 0.25). Dichloromethane (30 mL) was
added and the mixture was filtered through Celite, washed with 10% aq
sodium thiosulfate (20 mL) and the aqueous layers were re-extracted with
dichloromethane (15 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (petrol/ethyl acetate 2:1) to give disacchar-
ide 20h as a clear oil (6.4 mg, 66%). [a]2D5 ˆ ‡52 (c ˆ 0.59 in CHCl3);
1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.78 7.73 (brm, 4H; 4  Ar-H),
7.34 7.20 (m, 21H; 21 Â Ar-H), 7.02 7.00 (m, 2H; 2 Â Ar-H), 6.85 6.77
(m, 4H; 4  Ar-H), 6.72 6.68 (m, 2H; 2  Ar-H), 5.62 (d, 3J(H,H) ˆ
8.0 Hz, 1H; H-1a), 4.93 (d, 2J(H,H) ˆ 12.5 Hz, 1H; PhCHH'), 4.86 (d,
2J(H,H) ˆ 10.9 Hz, 1H; PhCHH'), 4.69 (s, 1H; H-1b), 4.68 (d, 2J(H,H) ˆ
12.0 Hz, 1H; PhCHH'), 4.64 (d, 2J(H,H) ˆ 11.5 Hz, 1H; PhCHH'), 4.54
(brm, 1H; H-2a), 4.57 4.43 (m, 6H; PhCH2, 4 Â PhCHH'), 4.17 (at,
3J(H,H) ˆ 8.9 Hz, 1H; H-3a), 4.05 (brd, 3J(H,H) ˆ 3.0 Hz, 1H; H-2b),
3.89 3.73 (m, 6H; H-4a, H-5a, H-6a, H-6a, H-4b, H-6'b), 3.71(s, 3H; C H3),
3.63 (dd, 2J(H,H) ˆ 10.8 Hz, 3J(H,H) ˆ 4.7 Hz, 1H; H-6b), 3.43 (dd,
3J(H,H) ˆ 9.2 Hz, 3.0 Hz, 1H; H-3b), 3.36 (ddd, 3J(H,H) ˆ 9.8 Hz, 4.7 Hz,
1.5 Hz, 1 H; H-5b), 2.56 (brs, 1H; OH); 13C NMR (125.7 MHz, CDCl3): d ˆ
138.3, 138.2, 138.1, 137.7 (4 Â s, Ar-C), 133.6, 128.4, 128.2, 128.2, 128.2, 127.9,
127.8, 127.8, 127.7, 127.7, 127.7, 127.6, 127.6, 127.3, 126.9, 123.2, 118.7, 114.2
(18  d, Ar-CH), 100.3 (d, 1J (C,H) ˆ 159 Hz, C-1b), 97.6 (d, 1J (C,H) ˆ
169 Hz, C-1a), 81.6 (d, C-3b), 78.1(d, C-3 a), 77.8 (d, C-5b), 75.3, 74.6, 73.8
(3 Â d, C-4a, C-5a, C-4b), 75.0, 74.8, 73.4, 73.2, 71.2 (5Â t, 5 Â PhCH2), 68.8,
Benzyl 3,4,6-tri-O-benzyl-a-d-glucopyranoside (21d): Mixed acetals 18d
(110 mg, 0.146 mmol) gave a-glucoside 21d (53 mg, 67%) as a colourless
oil. [a]2D2 ˆ ‡82 (c ˆ 0.5 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ
3
7.39 7.14 (m, 20H; Ar-H), 5.04 (d, J(H,H) ˆ 3.4 Hz, 1H; H-1), 4.95, 4.84
(ABq, 2J(H,H) ˆ 11.2 Hz, 2H; PhCH2), 4.76, 4.56 (ABq, 2J(H,H) ˆ
11.7 Hz, 2H; PhCH2), 4.65, 4.53 (ABq, 2J(H,H) ˆ 12.1 Hz, 2H; PhCH2),
4.83, 4.50 (ABq, 2J(H,H) ˆ 10.6 Hz, 2H; PhCH2), 3.85 3.81(m, 1H; H-5),
3.80 3.64 (m, 4H; H-2, H-3, H-4, H-6'), 3.63 (dd, 2J(H,H) ˆ 10.5 Hz,
3J(H,H) ˆ 1.9 Hz, 1 H; H-6). The spectroscopic and analytical data were in
agreement with those reported in the literature.[13b]
Methyl 3,4,6-tri-O-benzyl-a-d-glucopyranosyl-(1 ! 6)-2,3,4-tri-O-benzyl-
a-d-glucopyranoside (21e): Mixed acetals 18e (153 mg, 0.14 mmol) gave
a-gluco disaccharide 21e (81mg, 66%) as a colourless oil. [ a]2D2 ˆ ‡82 (c ˆ
0.85 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.39 7.13 (m, 30H;
Ar-H), 5.00, 4.81(ABq,
2J(H,H) ˆ 10.9 Hz, 2H; PhCH2), 4.93 (d,
3J(H,H) ˆ 3.4 Hz, 1H; H-1b), 4.93, 4.82 (ABq, 2J(H,H) ˆ 11.1 Hz, 2H;
PhCH2), 4.92, 4.58 (ABq, 2J(H,H) ˆ 10.7 Hz, 2H; PhCH2), 4.82, 4.47 (ABq,
2J(H,H) ˆ 10.9 Hz, 2H; PhCH2), 4.79, 4.68 (ABq, J(H,H) ˆ 12.2 Hz, 2H;
2
3
2
PhCH2), 4.60 (d, J(H,H) ˆ 3.4 Hz, 1H; H-1a), 4.58, 4.44 (ABq, J(H,H) ˆ
12.3 Hz, 2H; PhCH2), 4.00 (at, 3J(H,H) ˆ 9.3 Hz, 1H; H-3a), 3.93 (dd,
2J(H,H) ˆ 11.3 Hz, 3J(H,H) ˆ 4.5 Hz, 1H; H-6'a), 3.79 3.76 (m, 1H; H-5a),
3.75 3.61(m, 6H; H-2
, H-3b, H-4b, H-5b, H-6'b, H-6a), 3.54 (dd,
b
2J(H,H) ˆ 10.8 Hz, 3J(H,H) ˆ 1.9 Hz, 1 H; H-6b), 3.51(dd, 3J(H,H) ˆ
9.7 Hz, 3.4 Hz, 1H; H-2a), 3.48 (at, 3J(H,H) ˆ 9.7 Hz, 1H; H-4a), 3.36 (s,
3H; OCH3). The spectroscopic and analytical data were in agreement with
those reported in the literature.[28]
68.4 (2 Â t, C-6a, C-6b), 67.9 (d, C-2b), 55.6, 55.5 (2 Â d/q, C-2a, CH3); IR
‡
(thin film): nÄ ˆ 3500 (OH), 1714, 1776 cmÀ1 (imide O CNC O); MS-ES :
ˆ
ˆ
‡
‡
m/z (%): 1050.4 (100) [M‡Na] , 1066.3 (45) [M‡K] . MS-isotopic
Methyl 3,4,6-tri-O-benzyl-a-d-glucopyranosyl-(1 ! 6)-2,3,4-tri-O-benzyl-
a-d-mannopyranoside (21 f): Mixed acetals 18 f (91mg, 0.082 mmol) gave
a-gluco disaccharide 21 f (53 mg, 72%) as a colourless oil. [a]2D2 ˆ ‡66 (c ˆ
1.1 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.39 7.14 (m, 30H;
Ar-H), 5.00 (d, 3J(H,H) ˆ 2.9 Hz, 1H; H-1b), 4.98, 4.62 (ABq, 2J(H,H) ˆ
11.1 Hz, 2H; PhCH2), 4.92, 4.71(ABq, 2J(H,H) ˆ 11.1 Hz, 2H; PhCH2),
4.84, 4.47 (ABq, 2J(H,H) ˆ 10.8 Hz, 2H; PhCH2), 4.72 (s, 2H; PhCH2), 4.70
(d, 3J(H,H) ˆ 2.0 Hz, 1H; H-1a), 4.62 (s, 2H; PhCH2), 4.61, 4.48 (ABq,
2J(H,H) ˆ 12.2 Hz, 2H; PhCH2), 4.10 4.04 (m, 2H; H-4a, H-6'a), 3.91(dd,
3J(H,H) ˆ 9.4 Hz, 1H; H-3a), 3.80 3.59 (m, 8H; H-2b, H-3b, H-4b, H-5b,
H-6b, H-6'b, H-5a, H-6a), 3.79 (dd, 3J(H,H) ˆ 3.0 Hz, 2.0 Hz, 1H; H-2a), 3.30
(s, 3H; OCH3); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.9, 138.4, 138.3,
138.2, 138.0 (5 Â s, Ar-C), 128.4, 128.3, 128.3, 128.1, 128.0, 127.9, 127.9, 127.8,
127.8, 127.7, 127.6, 127.6, 127.4 (13 Â d, Ar-CH), 100.6, 98.9 (2 Â d, C-1b,
C-1a), 83.3, 79.9, 77.0, 74.2, 73.8, 71.3, 70.7, 74.1 (8Â d, C-2b, C-3b, C-4b, C-5b,
C-2a, C-3a, C-4a, C-5a), 75.2, 75.1, 75.0, 73.4, 72.8, 72.0, 68.4, 67.7 (8Â t, 6 Â
‡
distribution [M‡Na] : m/z (%): calcd for C62H61NO13Na: 1st peak
1050.40 (100), 2nd peak 1051.41 (71), 3rd peak 1052.41 (27%); found: 1st
peak 1050.38 (100), 2nd peak 1051.38 (74), 3rd peak 1052.37 (27%). The
spectroscopic and analytical data were in agreement with those reported in
the literature.[29]
General procedure E: One-pot tethering and glycosylation with MeOTf: A
solution of vinyl ether 6 (0.092 g, 0.176 mmol), the aglycon alcohol (either
cyclohexanol or diacetone galactose, 0.088 mmol) and powdered molecular
sieves 4 ä (ca. 200 mg) was stirred for 1h in dry acetonitrile (3 mL) at RT
under argon. The mixture was cooled to at À308C and then DTBMP
(0.036 g, 0.176 mmol) and NIS (0.0596 g, 0.265 mmol) were added. After
stirring at À308C for 2 h, TLC (ethyl acetate/petrol 1:2) indicated complete
consumption of the aglycon alcohol. Methyl triflate (0.05 mL, 0.441mmol)
was then added, and stirring continued for another 18 h at RT. The reaction
was then quenched by the addition of triethylamine (2 mL), and stirred for
a further 1h, before being diluted with dichloromethane (50 mL) and
filtered through Celite The organic extracts were washed with 10% aq
sodium thiosulfate (20 mL), saturated aqueous sodium bicarbonate
(20 mL), water (20 mL), dried (MgSO4), filtered and concentrated in
vacuo. The crude residue was purified by flash column chromatography
(ethyl acetate/petrol 1:1), to afford solely either the desired b-mannoside
20b (0.044 g, 72%) or b-mannoside 20c (0.045 g, 67%), respectively.
‡
PhCH2, C-6b, C-6a), 54.9 (q, CH3); MS-APCI : m/z (%): 919 (55)
‡
[M‡Na] ; MS-APCIÀ: m/z (%): 931(10) [ M‡Cl]À; HRMS-ES: calcd for
‡
C55H61O11 [M‡H] : 897.4214; found: 897.4229.
Synthesis of Manb(1 ! 4)GlcNAc disaccharide
Phenyl
2-O-(2-iodo-1-(p-methoxyphenyl
3,6-di-O-benzyl-2-deoxy-2-
phthalimido-b-d-glucopyranosid-4-O-yl)-propyl)-3,4,6-tri-O-benzyl-1-
thio-a-d-mannopyranoside (16h): Iodine (76 mg, 0.30 mmol), silver tri-
fluoromethane sulfonate (77 mg, 0.30 mmol) and 2,4,6-collidine (0.78 mL,
0.60 mmol) were dissolved in dichloromethane (1.5 mL) with molecular
sieves (powdered, 4 ä, ca. 250 mg). After stirring for 15 min this mixture
was cooled to À788C and a solution of vinyl ether 3 (86 mg, 0.15 mmol) and
glucosamine acceptor 27 (178 mg, 0.30 mmol) in dichloromethane (1.5 mL)
was added. The solution came to room temperature over 20 h, after which
time, TLC (petrol/ethyl acetate 3:1) showed no remaining starting vinyl
ether (Rf ˆ 0.9) and the formation of a major product (Rf ˆ 0.3). Dichloro-
methane (50 mL) was added and the solution was filtered through Celite,
washed with 10% aq sodium thiosulfate (30 mL), dried (MgSO4), filtered
and concentrated in vacuo. Purification by flash column chromatography
(petrol/ether 1:1) gave mixed acetals 16h as a white foam, an inseparable
mixture of diastereomers (113 mg, 80% over recovered starting vinyl
ether) identical to the material described previously.
Methyl 2-O-(1-ethoxyethyl)-1-thio-3,4,6-tri-O-benzyl-a-d-mannopyrano-
side (23): Alcohol 4 (182 mg, 0.38 mmol) and ethyl vinyl ether (0.10 mL,
0.95 mmol) were dissolved in dichloromethane (5 mL). Pyridinium p-
toluenesulfonate (10 mg, 0.04 mmol) was added, and the mixture was
stirred at room temperature under an atmosphere of argon. After 2 h
45 min, TLC (petrol/ethyl acetate 4:1) indicated the formation of a single
product (Rf ˆ 0.4) with no starting material remaining (Rf ˆ 0.1). The
reaction mixture was diluted with dichloromethane (20 mL) and washed
with aq satd sodium bicarbonate (2 Â 20 mL) and then aq satd brine (2 Â
20 mL). The organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. Purification by flash column chromatography (petrol/ethyl acetate
6:1) gave an inseparable diastereomeric mixture of mixed acetals 23
1
(190 mg, 91%) as a colourless oil (a:b 1.2:1). H NMR (400 MHz, CDCl3,
258C): d ˆ 7.38 7.20 (m, 15H; 15  Ar-H), 5.28 5.27 (m, 1H; H-1), 4.94
4.53 (m, 7H; 3 Â PhCH2, O2CH), 4.15 4.02 (m, 2H; H-2, H-4), 4.02 3.81
(m, 1H; H-5), 3.83 3.75 (m, 1H; H-3), 3.93 3.74 (m, 2H; H-6, H-6 '),
3.87 3.61(m, 1H; OCH aHbCH3), 3.59 3.48 (m, 1H; OCHaHbCH3), 2.16,
2.15 (2 Â s, 3H; SCH3), 1.43 1.39 (m, 3H; O2CHCH3), 1.21 1.16 (m, 3H;
p-Methoxyphenyl 3,4,6-tri-O-benzyl-b-d-mannopyranosyl-(1 ! 4)-3,6-di-
O-benzyl-2-deoxy-2-phthalimido-b-d-glucopyranoside (20h): Mixed ace-
tals 16h (12.2 mg, 0.009 mmol), molecular sieves (powdered, 4 ä, ca.
250 mg) and DTBMP (9.7 mg, 0.047 mmol) were stirred at room temper-
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2619 $ 20.00+.50/0
2619

A. J. Fairbanks et al.
FULL PAPER
OCH2CH3); 13C NMR (100.6 MHz, CDCl3): d ˆ 138.6 138.1 (5  s, 5  Ar-
C), 128.4 127.4 (15 Â d, Ar-CH), 101.0, 98.7 (2 Â d, O2CH), 85.2, 84.1(2 Â
d, C-1), 80.4, 79.5 (2 Â d, C-3), 75.0, 74.5 (2 Â d, C-4, C-5), 73.3, 73.2, 72.3,
72.3 (4 Â t, 2 Â PhCH2), 72.1, 72.0 (2Â d, C-2), 69.2 (t, C-6), 60.1, 60.0 (2Â t,
OCH2CH3), 20.2, 20.1(2 Â q, O2CHCH3), 15.3, 15.2 (2 Â q, OCH2CH3),
10.2 Hz, 6.9 Hz, 1H; CHI), 4.89, 4.61(ABq, 2J(H,H) ˆ 10.9 Hz, 2H;
PhCH2), 4.88, 4.73 (ABq, 2J(H,H) ˆ 11.1 Hz, 2H; PhCH2), 4.67, 4.62 (ABq,
2J(H,H) ˆ 12.0 Hz, 2H; PhCH2), 4.22 (s, 1H; H-1), 4.03 (d, 3J(H,H) ˆ
2.8 Hz, 1H; H-2), 3.82 3.73 (m, 3H; H-4, H-6, H-6'), 3.58 (dd,
3J(H,H) ˆ 9.3 Hz, 2.8 Hz, 1H; H-3), 3.46 (s, 3H; OCH3), 3.44 (ddd,
3J(H,H) ˆ 9.7 Hz, 6.0 Hz, 1.8 Hz, 1 H; H-5), 2.83 2.78, 2.75 2.69, 2.66
‡
13.8, 13.8 (2  q, SCH3); HRMS-ES: calcd for C32H40O6SNa [M‡Na] :
575.2443; found: 575.2441.
2.59 (3  m, 4H; (CH2)2), 2.04 (d, 3J(H,H) ˆ 6.9 Hz, 3H; CHCH3);
13
ˆ
C NMR (125.7 MHz, CDCl3): d ˆ 178.4, 176.3 (2  s, 2  C O), 138.9,
Methyl 2-O-(1-n-propoxyethyl)-1-thio-3,4,6-tri-O-benzyl-a-d-mannopyra-
noside (24): Alcohol 4 (156 mg, 0.33 mmol) and n-propyl vinyl ether
(0.10 mL, 0.81 mmol) were dissolved in dichloromethane (5 mL). Pyridi-
nium p-toluenesulfonate (8 mg, 0.03 mmol) was added, and the mixture
stirred at room temperature under an atmosphere of argon. After 50 min,
TLC (petrol/ethyl acetate 4:1) indicated the formation of two products
(Rf ˆ 0.4, 0.45) with no starting material remaining(Rf ˆ 0.1). The reaction
mixture was diluted with dichloromethane (20 mL) and washed with aq
satd sodium bicarbonate (2 Â 20 mL) and then aq satd brine (2 Â 20 mL).
The organic layer was dried (MgSO4), filtered, and concentrated in vacuo.
Purification by flash column chromatography (petrol/ethyl acetate 6:1)
gave a partially separable diastereomeric mixture of mixed acetals 24
138.4, 138.0 (3 Â s, Ar-C), 129.0, 128.8, 128.7, 128.6, 128.6, 128.4, 128.2, 127.9
(8 Â d, Ar-CH), 100.9 (d, C-1), 88.1 (d, NCH), 82.4 (d, C-3), 76.5 (d, C-2),
76.1(d, C-5), 75.5, 73.9, 72.8 (3 Â t, 3 Â PhCH2), 74.9 (d, C-4), 69.8 (t, C-6),
57.4 (q, OCH3), 28.4 (t, (CH2)2), 25.9 (q, CHCH3), 24.1(d, CHI); IR (thin
film): nÄ ˆ 1709 cmÀ1 (C O); MS-APCI : m/z (%): 752 (100) [M‡Na] ;
elemental analysis calcd (%): for C35H40INO8: C 57.62, H 5.53, N 1.92;
found: C 57.42, H 5.76, N 1.91.
‡
‡
ˆ
The remaining side products were not separated, although crude data
(NMR/MS) suggested that further diastereomers of 25 were produced,
along with material probably incorporating two units of the desired methyl
b-mannoside linked through the 2-iodopropyl tether.
1
(149 mg, 82%) as a colourless oil (a:b 1.3:1). H NMR (400 MHz, CDCl3,
Competition reaction: Methanol (0.006 mL, 0.15 mmol), NIS (167 mg,
0.74 mmol), silver triflate (41 mg, 0.16 mmol), DTBMP (151 mg,
0.74 mmol) and molecular sieves (powdered, 4 ä, ca. 250 mg) were added
to a solution of mixed acetals 16d (119 mg, 0.14 mmol) in 1,2-dichloro-
ethane (4 mL). This solution was heated to 508C and stirred for 1.5 h, after
which time, TLC (petrol/ethyl acetate 3:1) showed no remaining starting
material (Rf ˆ 0.7) and the formation of several more polar products. After
cooling to room temperature, dichloromethane (50 mL) was added and the
mixture was filtered through Celite washed with 10% aq sodium
thiosulfate (50 mL), dried (MgSO4), filtered and concentrated in vacuo.
Attempts to separate and analyse the product mixture using flash column
chromatography and NMR, respectively, were inconclusive. Therefore, the
combined products were treated with a mixture of TFA, THF, methanol
and water (5:2:2:1, 20 mL). After stirring at room temperature overnight,
the mixture was poured into saturated aqueous sodium bicarbonate
(100 mL). Dichloromethane (50 mL) was added, the organic layers
separated and washed with saturated aqueous sodium bicarbonate
(100 mL). The aqueous layers were re-extracted with dichloromethane
(50 mL) and the combined organic layers were dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column chromatography
(petrol/ethyl acetate 2:1 ! 1:1) gave benzyl 3,4,6-tri-O-benzyl-b-d-manno-
pyranoside (20d) as a clear, transparent oil (24 mg, 31%). Rf ˆ 0.6 (petrol/
ethyl acetate 1:1), data consistent with that reported above; methyl 3,4,6-
tri-O-benzyl-b-d-mannopyranoside (20a) as a clear, transparent oil (10 mg,
15%). Rf ˆ 0.25 (petrol/ethyl acetate 1:1), data consistent with that
reported above; and methyl 3,4,6-tri-O-benzyl-a-d-mannopyranoside
258C): d ˆ 7.42 7.21 (m, 15H; 15  Ar-H), 5.30 5.29 (m, 1H; H-1), 4.92
4.53 (m, 7H; 3 Â PhCH2, O2CH), 4.16 4.06 (m, 2H; H-2, H-4), 4.05 3.90
(m, 1H; H-5), 3.91 3.86 (m, 1H; H-3), 3.84 3.71 (m, 2H; H-6, H-6 '),
3.69 3.47 (m, 1H; OCHaHbCH2), 3.47 3.40 (m, 1H; OCHaHbCH2), 2.15,
2.14 (2 Â s, 3H; SCH3), 1.61 1.55 (m, 2H; OCH CH2CH3), 1.41 1.38 (m,
2
3H; O2CHCH3), 0.96 0.91(m, 3H; OCH 2CH2CH3); 13C NMR
(100.6 MHz, CDCl3): d ˆ 138.5 137.6 (6  s, 3  Ar-C), 128.6 127.4
(22 Â d, 15 Â Ar-CH), 101.2, 98.9 (2 Â d, O2CH), 85.3, 84.0 (2 Â d, C-1),
80.5, 79.5 (2 Â d, C-3), 75.1, 74.5 (2Â t, PhCH2), 75.0, 73.4 (2 Â d, C-5), 73.2,
72.4, 72.2, 72.2 (4 Â t, 2 Â PhCH2), 72.0, 71.4, 69.6 (3Â d C-2, C-4), 69.2, 68.9
(2 Â t, C-6), 67.3, 66.1(2 Â t, OCH2CH2), 23.1(t, OCH 2CH2), 23.0, 20.1(2 Â
q, O2CHCH3), 13.8, 13.8 (2 Â q, SCH3), 10.7, 10.6 (2 Â q, CH2CH3); HRMS-
‡
ES: calcd for C33H42O6SNa [M‡Na] : 589.2599; found: 589.2570.
Methyl 2-O-(2-iodo-1-succinimidopropyl)-3,4,6-tri-O-benzyl-b-d-manno-
pyranoside (25a and 25b): A solution of mixed acetals 16a (439 mg,
0.59 mmol) in 1,2,-dichloroethane (10 mL) was added to a mixure of NIS
(682 mg, 3.03 mmol), DTBMP (600 mg, 2.92 mmol) and molecular sieves
(powdered, 4 ä, ca. 450 mg). This solution was stirred at room temperature
for 70 h, and then subsequently at 508C for a further 7 h, after which time,
TLC (petrol/ethyl acetate 3:1) showed no remaining starting material (Rf ˆ
0.7) and the formation of several more polar products. After cooling to
room temperature, dichloromethane (200 mL) was added and the mixture
was filtered through Celite washed with 10% aq sodium thiosulfate (2 Â
50 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography (petrol/ethyl acetate
4:1 ! 1:2, with 1% added triethylamine) gave methyl b-mannoside 20a as a
clear, colourless oil (64 mg, 23%). Rf ˆ 0.2 (petrol/ethyl acetate 1:1),
identical to the material described previously. Further purification allowed
complete separation and isolation of two side products.
(28) as a clear, transparent oil (15 mg, 22%). Rf ˆ 0.4 (petrol/ethyl acetate
1
1:1); [a]2D2 ˆ ‡49 (c ˆ 0.61in CHCl ); H NMR (200 MHz, CDCl3, 258C):
3
d ˆ 7.22 6.99 (m, 15H; 15  Ar-H), 4.82 (d, 3J(H,H) ˆ 1.7 Hz, 1 H; H-1),
4.59 (s, 2H; PhCH2), 4.68, 4.55 (ABq, 2J(H,H) ˆ 12.2 Hz, 2H; PhCH2),
4.84, 4.51(ABq, 2J(H,H) ˆ 10.6 Hz, 2H; PhCH2), 4.05 (brs, 1H; H-2),
3.88 3.75 (m, 5H; H-3, H-4, H-5, H-6, H-6'), 3.38 (s, 3H; CH3), 2.50 (brd,
First diastereomer of succinimide trapped material, 25a, a clear oil (52 mg,
12%). Rf ˆ 0.3 (petrol/ethyl acetate 3:1); [a]2D3 ˆ ‡41( c ˆ 0.7 in CHCl3);
1H NMR (500 MHz, CDCl3, 258C): d ˆ 7.45 7.23 (m, 15H; 15  Ar-H),
5.58 (d, 3J(H,H) ˆ 10.2 Hz, 1H; NCH), 5.31(dq, 3J(H,H) ˆ 10.2 Hz, 6.9 Hz,
1H; CHI), 4.88, 4.64 (ABq, 2J(H,H) ˆ 10.9 Hz, 2H; PhCH2), 4.76, 4.59
(ABq, 2J(H,H) ˆ 12.0 Hz, 2H; PhCH2), 4.73, 4.65 (ABq, 2J(H,H) ˆ
12.3 Hz, 2H; PhCH2), 4.38 (s, 1H; H-1), 4.08 (d, 3J(H,H) ˆ 2.8 Hz, 1H;
‡
‡
1H; OH); MS-APCI : m/z (%): 487 (14) [M‡Na] . The spectroscopic and
analytical data were in agreement with those reported in the literature.[26]
3
H-2), 3.94 (at, J(H,H) ˆ 9.6 Hz, 1H; H-4), 3.86 3.79 (m, 2H; H-6, H-6'),
Acknowledgement
3.58 (s, 3H; OCH3), 3.48 3.44 (m, 2H; H-3, H-5), 2.81, 2.60 2.45, 2.40
2.03, 2.15 2.05 (4  br, 4H; (CH2)2), 2.17 (d, 3J(H,H) ˆ 6.9 Hz, 3H;
We gratefully acknowledge financial support from the Leverhulme Trust
(Postdoctoral Fellowship to M.A.), the EPSRC (Quota award to C.M.P.S.),
and GlaxoSmithkline (CASE award to I.C.), and also the use of the
Chemical Database Service (CDS) at Daresbury, UK and the EPSRC
National Mass Spectrometry Service at Swansea.
CHCH3); 13C NMR (125.7 MHz, CDCl3): d ˆ 178.1, 176.5 (2  s, 2  C O),
ˆ
138.9, 138.7, 138.5 (3 Â s, Ar-C), 129.0, 128.8, 128.8, 128.7, 128.4, 128.3, 128.2,
128.2, 128.0, 127.4 (10 Â d, Ar-CH), 101.9 (d, C-1), 88.2 (d, NCH), 81.8, 76.4
(2 Â d, C-3, C-5), 77.2 (d, C-2), 76.4, 73.8, 73.3 (3 Â t, 3 Â PhCH2), 75.7 (d,
C-4), 69.5 (t, C-6), 57.0 (q, OCH3), 28.1(brt, ( CH2)2), 25.9 (q, CHCH3), 25.4
‡
(d, CHI); IR (thin film): nÄ ˆ 1710 cmÀ1 (C O); MS-APCI : m/z (%): 753
ˆ
‡
‡
(100) [M‡Na] ; HRMS-ES: calcd for C35H44IN2O8 [M‡NH4] : 747.2142;
found: 747.2130.
[1] a) F. Barresi, O. Hindsgaul, Can. J. Chem. 1994, 72, 1447 1465; b) F.
Barresi, O. Hindsgaul, Synlett 1992, 759 761; c) F. Barresi, O.
Hindsgaul, J. Am. Chem. Soc. 1991, 113, 9376 9377.
[2] a) G. Stork, J. J. La Clair, J. Am. Chem. Soc. 1996, 118, 247 248; b) G.
Stork, G. Kim, J. Am. Chem. Soc. 1992, 114, 1087 1088.
Second diastereomer 25b (65 mg, 15%) a white solid. Rf ˆ 0.4 (petrol/ethyl
acetate 1:1); m.p. 120 1218C (ethyl acetate/petrol); [a]2D2:5 ˆ ‡3.0 (c ˆ 0.5
in CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d ˆ 7.50 7.24 (m, 15H;
15  Ar-H), 5.52 (d, 3J(H,H) ˆ 10.2 Hz, 1H; NCH), 5.34 (dq, 3J(H,H) ˆ
2620
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Chem. Eur. J. 2002, 8, No. 1 1

Stereoselective 1,2-cis Glycosylation
2608 2621
¬
b) S. Valverde, M. Garcia, A. M. Gomez, J. C. Lopez, Synlett 2000,
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¬
¬
22 26; c) S. Valverde, A. M. Gomez, J. C. Lopez, B. Herradon,
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[21] Although light sensitive they can be left on the bench at room
temperature in a foil coated flask for months with little degradation.
[22] The anomeric configurations of all b-mannosides were confirmed by
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[23] This alcohol is the 2-OH free glycoside (or disaccharide) 20, which is
formed by hydrolysis of the oxonium ion produced subsequent to
intramolecular glycosylation.
[24] Trapped species were identified by a combination of mass spectrom-
etry and HMQC/HMBC NMR analysis.
¬
[25] I. Robina, E. Lopez-Barba, J. Fuentes, Synth. Commun. 1996, 26,
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2847 2856.
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Received: August 16, 2001
Revised: February 25, 2002 [F3493]
[11] For leading references to the work of Valverde see: a) S. Valverde, M.
¬
Garcia, A. M. Gomez, J. C. Lopez, Chem. Commun. 2000, 813 814;
Chem. Eur. J. 2002, 8, No. 11
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