Allyl protecting group mediated intramolecular aglycon delivery: Optimisation of mixed acetal formation and mechanistic investigation

Article abstract of DOI:10.1016/j.tetasy.2004.09.003

An efficient protocol for the formation of α-iodo mixed acetals, the first step of allyl-mediated IAD, by reaction of allyl-derived enol ethers and alcohols, using I₂, AgOTf and di-tert-butyl methylpyridine as a novel source of I⁺, i

Full text of DOI:10.1016/j.tetasy.2004.09.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3207–3221
Allyl protecting group mediated intramolecular aglycon delivery:
optimisation of mixed acetal formation and
mechanistic investigation
Ian Cumpstey,a Kampanart Chayajarus,a Antony J. Fairbanks,a,* Alison J. Redgraveb and
Christopher M. P. Sewarda
aChemistry Research Laboratory, Oxford University, Mansfield Road, Oxford OX1 3TA, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 7 July 2004; accepted 6 September 2004
Available online 2 October 2004
Abstract—An efficient protocol for the formation of a-iodo mixed acetals, the first step of allyl-mediated IAD, by reaction of allyl-
derived enol ethers and alcohols, using I2, AgOTf and di-tert-butyl methylpyridine as a novel source of I+, is reported. This reagent
combination is capable of tethering glycosyl donors to the secondary alcohol groups of a variety of glycosyl acceptors including
mono-, di- and trisaccharides. Mechanistic studies confirm the intramolecular nature of the glycosylation reaction, whilst the
attempted use of diol glycosyl acceptors reveals limitations of both regio- and stereoselectivity in the glycosylation step.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
activation of the glycosyl donor, which subsequently
furnishes the 1,2-cis glycoside in a completely stereo-
selective fashion via an intramolecular glycosyl-
ation reaction.
Control of anomeric stereochemistry during the course
of a glycosylation reaction is a key consideration when
undertaking the synthesis of any glycoside or oligosac-
charide. In the majority of cases, 1,2-trans glycosidic
linkages, wherein the anomeric substituent is formally
trans to the 2-hydroxyl of the glycosyl donor, may be
synthesised with high levels of stereocontrol by taking
advantage of classical neighbouring group participation
of 2-O-acyl protected glycosyl donors.1 However, the
synthesis of 1,2-cis glycosidic linkages is considerably
more difficult.2 Several research groups have sought to
solve the perennial problem of stereochemical control
of glycosylation by investigating the use of intramolecu-
lar glycosylation reactions.3 Intramolecular aglycon
delivery or IAD, is a particular intramolecular glycosyl-
ation strategy aimed at the stereospecific synthesis of
1,2-cis glycosides wherein the glycosyl acceptor is tem-
porarily appended to the 2-hydroxyl group of a glycosyl
donor.4 This first so-called ÔtetheringÕ step, that is,
the linking of donor and acceptor, is then followed by
The IAD approach was originally conceived by Barresi
and Hindsgaul,5 and Stork and co-workers6 for the syn-
thesis of the b-mannosyl linkage, which is notoriously
difficult to synthesise.7 Following on from these initial
reports, Ogawa and co-workers reported the develop-
ment of a considerably more efficient and reliable IAD
approach for the synthesis of b-mannosides based on
the use of 2-O-para-methoxybenzyl (PMB) protected
glycosyl donors.8 This approach has also been applied
to the syntheses of other 1,2-cis glycosides with varying
degrees of success.9 As part of our own programme10
into the development of a reliable and widely applicable
synthetic methodology that will allow the formation of
1,2-cis glycosidic linkages with complete stereocontrol,
we recently reported the development of an allyl protect-
ing group mediated IAD approach (allyl IAD)11 based
on either thioglycoside12 or glycosyl fluoride donors.13
This methodology relies on tethering of an aglycon alco-
hol to an enol ether at the 2-position of a glycosyl
donor, itself derived from a 2-O-allyl protected donor
by WilkinsonÕs catalyst mediated isomerisation14 of the
*
Corresponding author. Tel.: +44 186 5275647; fax: +44 186
5275674; e-mail: antony.fairbanks@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.003

3208
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
double bond. Previous studies have focused on the use
of N-iodosuccinimide (NIS) as an iodonium ion source
to form a-iodo mixed acetals such as 1 in the tethering
step. Subsequent activation of the glycosyl donor by
the addition of an appropriate promoter then furnishes
the 1,2-cis glycoside 2 with complete control of anomeric
stereochemistry (Fig. 1).
proposed16 as an alternative to the more commonly
used17 iodonium di-sym-collidine perchlorate (IDCP),18
was therefore deemed a potential source of I+. In this
case, the counter ion is triflate, and it was postulated
that even if the ionic intermediate 4 (either the cyclic
iodonium ion or the non-bridged oxonium ion) was
attacked competitively by the triflate in preference to
the aglycon alcohol, then the resultant acetal triflate 5
would itself be sufficiently labile to eventually lead to
the formation of the desired mixed acetal product 1
(Fig. 2).
isomerise
O
O
O
O
RO
RO
X
X
I
2-O-allyl protected
I
donor
ROH
source of I+
'tethering'
I+
O
O
O
O
O
O
RO
RO
RO
RO
I
4
X
X
X
OH
O
glycosylate
OR
RO
O
OR
ROH
O
RO
-OTf
1,2-cis glycoside
X
I
I
2
1
O
OR
O
OTf
ROH
O
O
I
RO
O
X
1
X
N
5
O
O
RO
O
Figure 2.
X
3
As a test reaction, IDCT-mediated mixed acetal forma-
tion from the manno enol ethers 613 and the hindered
glucosamine alcohol 719 was investigated as a possible
Ôworst-caseÕ scenario, since previous attempts at NIS-
mediated tethering of acceptors such as 7 with enol
ethers derived from 2-O-allyl donors had only produced
a very low yield of the desired mixed acetals.12b IDCT is
most readily generated in situ by reaction of iodine, sil-
ver triflate and collidine and it was found that when
manno enol ethers 6 and aglycon alcohol 7 were added
to such a mixture, tethering did take place to give an
acceptable 60% yield of 8;12b a significant improvement
on the previous NIS-mediated reaction. However, mon-
itoring of this IDCT-mediated reaction revealed that
after initial rapid formation of some of the desired teth-
ered material 8, the reaction seemed to stop rather than
proceed to completion, despite the use of excess rea-
gents. Interestingly, attempted mixed acetal formation
using iodine and collidine alone produced no reaction.
In addition, it was also found that NIS-mediated tether-
ing reactions did not work at all in the presence of
pyridine and other unhindered amine bases instead
of collidine, but that they did proceed in the presence
of the hindered base di-tert-butyl methylpyridine
(DTBMP). Consequently, it was proposed that a better
source of I+ to be used in a tethering reaction could be
generated in situ from I2, AgOTf and DTBMP, a previ-
ously unused combination of reagents. Indeed, when a
tethering reaction of 6 and 7 was carried out under these
conditions, using only 1equiv of all reagents, the desired
mixed acetals 8 were formed in 75% yield. Intramolecu-
lar glycosylation of mixed acetals 8, mediated by tin(II)
chloride and AgOTf in the presence of DTBMP, then
produced the Manb(1!4)GlcNAc disaccharide 9, which
forms part of the core N-glycan pentasaccharide, in a
Figure 1.
However, the formation of mixed acetals 1 was found to
be quite inefficient for more hindered aglycon alcohols,
and in particular, succinimide-trapped acetals such as
3 were sometimes formed as the major products, a result
which precludes the use of this methodology more gen-
erally for oligosaccharide synthesis. Indeed nucleophilic
trapping by succinimide has been reported in other sys-
tems where NIS is employed as an iodonium ion
source.15 Herein we report the use of a novel source of
I+ that allows greatly increased efficiency of tethering
of glycosyl donor and acceptor and the formation of
mixed acetals 1 in high yield. In addition, crossover
experiments are detailed, which confirm the intramolec-
ular nature of the subsequent glycosylation reaction.
Finally, some unexpected limitations are revealed, which
highlight the important problems of regio- and stereo-
control that must be considered when designing any
intramolecular glycosylation strategy.
2. Results and discussion
2.1. Optimisation of mixed acetal formation
The formation of succinimide-trapped species, such as 3,
indicated a fundamental limitation in the use of NIS as a
source of iodonium ions for the efficient formation of
mixed acetals from hindered secondary carbohydrate
alcohols. It was postulated that increased yields of
mixed acetals could be achieved by the use of an iodo-
nium source with a non-nucleophilic counter ion. Iodo-
nium di-sym-collidine triflate (IDCT), which has been

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3209
respectable 54% yield as the sole glycosylated reaction
Me
OMe
O
BnO
BnO
OAc
O
BnO
BnO
product (Scheme 1). It seemed therefore that this new
reagent combination was optimal for mixed acetal for-
mation,20 and represented a marked improvement on
both the NIS- and IDCT-mediated versions. A series
of tethering reactions under these new conditions (I2,
AgOTf and DTBMP) was therefore attempted for a
variety of different donors 10, 11, 1213 and 6. New glyc-
osyl donors were synthesised as follows (Scheme 2).
Donor 10 was synthesised from the known orthoester
1321 by treatment with para-thiocresol to give thioglyco-
side 14, which was then converted into 2-O-allyl thiogly-
coside 15 by sequential deprotection with sodium
methoxide and methanol, and then treatment with allyl
bromide and sodium hydride. Isomerisation of the allyl
group using WilkinsonÕs catalyst then yielded enol ethers
10. Donor 11 was synthesised from tetraacetate 1622 by
sequential deacetylation and immediate benzylidenation
to yield predominantly the monobenzylidene derivative
17. Selective pivaloylation of the 3-hydroxyl yielded
alcohol 18, was then treated with allyl bromide and
sodium hydride to yield allyl ether 19. Finally,
WilkinsonÕs catalyst mediated isomerisation yielded enol
ethers 11 (Scheme 2).
O
O
(i)
BnO
BnO
STol
14
13
(ii),(iii)
(iv)
BnO
BnO
BnO
BnO
O
O
O
O
BnO
BnO
STol
STol
10
15
AcO
OAc
O
OH
Ph
Ph
O
O
(v),(vi)
(viii)
O
AcO
AcO
HO
STol
STol
17
(vii)
16
OH
O
O
O
Ph
Ph
O
O
O
O
PivO
PivO
19
STol
STol
18
(ix)
O
O
O
O
PivO
11
STol
OBn
BnO
O
O
O
HO
BnO
+
Scheme 2. Reagents and conditions: (i) TolSH, DCE, reflux, 65%;
(ii) Na, MeOH; (iii) allyl bromide, NaH, DMF, 95% over two steps;
(iv) (Ph3P)3RhCl, n-BuLi, THF, reflux, 94%; (v) Na, MeOH;
(vi) PhCH(OMe)2, camphor sulfonic acid, DMF, 38% over two steps;
(vii) PivCl, pyridine, 0ꢁC, 76%; (viii) allyl bromide, NaH, DMF, 74%;
(ix) (Ph3P)3RhCl, n-BuLi, THF, reflux, 95%.
OPMP
BnO
BnO
NPhth
F
6
7
(i)
I
OBn
O
BnO
BnO
O
O
OPMP
NPhth
BnO
O
BnO
yields. In contrast, with the I2/AgOTf/DTBMPreagent
combination, only virtually equimolar quantities of enol
ether and aglycon alcohol were required to give good
yields of the mixed acetals. This represents an important
advantage, particularly in the cases of more precious
aglycon alcohols, such as di- or trisaccharides.
F
8
(ii)
OBn
O
BnO
BnO
OH
O
O
OPMP
BnO
BnO
NPhth
2.2. Mechanistic investigations
9
2.2.1. Tethering reactions. In certain cases, integration
of the carbohydrate H-1 signals in the 1H NMR spectra
of the mixed acetals obtained by treatment of an allyl
derived 2-O-vinyl ether with an iodonium ion source
and an aglycon alcohol allows measurement of the dia-
stereomeric ratios of the mixed acetal products. More-
over, correlation of these values with the Z:E
diastereomeric ratios of the vinyl ether starting materials
gives an insight into the precise mechanism of the teth-
ering reaction. For example, an N-iodosuccinimide
mediated tethering reaction of methanol to the rhamno
vinyl ethers 27E/Z,26 gave the mixed acetals 28a–d.26
Assignment of each diastereomer was arbitrarily
based on the chemical shift of H-1, given in brackets
(Table 2). The product distribution of the four diastereo-
meric mixed acetals varied with the ratio of Z- and E-
vinyl ether starting materials as detailed in Table 2. Two
points are worthy of note. First, in this particular case,
Scheme 1. Reagents and conditions: (i) I2, AgOTf, DTBMP, CH2Cl2,
˚
4A molecular sieves, À78ꢁC to room temperature, 75%; (ii) SnCl2,
˚
AgOTf, DTBMP, DCE, 4A molecular sieves, 50ꢁC, 54%.
A selection of aglycons, including mono- 7,19 22,23 di-
2024 and trisaccharide 2125 alcohols, were used as
coupling partners, and using the I2, AgOTf, DTBMP
reagent combination produced good yields of mixed ace-
tals 23, 26, 24 and 25, respectively (Table 1).
Besides the marked improvement of reaction yields, a
further advantage of the I2/AgOTf/DTBMPsystem over
alternative sources of I+ was demonstrated by the quan-
tity of reagents needed for complete reaction. In previ-
ous studies, typically 3equiv of the I+ source (e.g.,
NIS), and a 2- to 3-fold excess of the aglycon alcohol
were required in order to obtain satisfactory tethering

3210
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
Table 1. Synthesis of mixed acetals mediated by I2, AgOTf and DTBMP
Enol ethers
Aglycon
Mixed acetals
Yield (%)
I
OBn
O
OBn
O
BnO
O
BnO
O
O
HO
O
OPMP
77
BnO
BnO
O
OPMP
BnO
BnO
BnO
NPhth
BnO
NPhth
STol
STol
7
10
23
I
OBn
O
OBn
O
OBn
O
OBn
O
O
O
Ph
O
O
O
O
HO
75
O
Ph
O
O
BnO
O
OPMP
BnO
BnO
OPMP
O
BnO
PivO
NPhth
PivO
NPhth
NPhth
NPhth
STol
SPh
24
11
20
BnO
BnO
BnO
O
OBn
F
BnO
BnO
O
BnO
OBn
O
O
O
I
O
F
HO
OBn
O
BnO
BnO
78
Ph
O
BnO
O
BnO
BnO
O
O
O
O
OBn
O
OBn
Ph
O
BnO
BnO
BnO
O
O
O
O
OBn
25
OMe
12
OMe
21
I
BnO
BnO
OBn
O
OBn
O
BnO
BnO
BnO
BnO
O
O
HO
O
55
O
BnO
BnO
O
BnO
BnO
OMe
OMe
F
F
6
22
26
Table 2. Variation of diastereomeric ratios of mixed acetals formed
with vinyl ether configuration
that a cyclic iodonium ion mechanism may predominate
in this case, but there is some degree of leakage, which
allows the formation of small amounts of diastereomeric
products which can only arise from a non-bridged inter-
mediate wherein C–C bond rotation occurs before
nucleophilic trapping by the algycon alcohol. In other
cases, particularly with more hindered aglycon alcohols,
the diastereomeric ratio of the mixed acetals was ob-
served to vary markedly depending on the identity of
the algycon alcohol, presumably indicating reversibility
of iodination and the intermediacy of non-bridged
intermediates.
OMe
OMe
O
O
O
STol
O
STol
O
NIS, MeOH
DCE, -40oC to RT
O
O
MeO
MeO
MeO
O
I
27E/Z
28a-d
Entry
27E/Z
28a
(5.46)a
28b
(5.43)a
28c
(5.41)a
28d
(5.36)a
1
2
3
4
33:67
68:32
0:100
100:0
6
17
3
17
8
60
25
71
4
17
50
3
2.2.2. Glycosylation reactions. The question as to
whether the glycosylation step of allyl IAD, which fol-
lows on from activation of the anomeric leaving group
of mixed acetals such as 1, is entirely intramolecular or
is not an important one. Previous studies of competition
reactions of allyl-derived mixed acetals 1 in the presence
of added external nucleophiles, such as methanol, have
revealed that intermolecular glycosylation does compete
with glycosylation of the tethered aglycon in the allyl sys-
tem. Here, a diastereomeric mixture of methyl glycosides
arising from a nonstereoselective intermolecular glycosyl-
ation reaction was produced as well as the desired 1,2-cis
glycoside product.12b This result was in contrast to ear-
lier studies on the Hindsgaul IAD system, in which inter-
nal delivery of the tethered nucleophile competed over
23
4
22
70
a Chemical shift of H-1 of each diastereomer given in brackets.
all four diastereomeric products were formed in all four
cases, even when either pure Z- or pure E-vinyl ether
was used as a starting material. Secondly the diastereo-
meric ratio of products is strongly dependent on the
ratio of vinyl ethers used: the use of pure Z-vinyl ether
27Z as staring material resulted in the formation of pre-
dominantly 28b and 28c, whereas the use of pure E-vinyl
ether 27E resulted in the formation of predominantly
28a and 28d. These two points taken together suggest

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3211
any intermolecular process.5a,10 Although the formation
of only the 1,2-cis glycoside in any of the glycosylation
reactions previously performed in the allyl IAD system
implied that glycosylation was entirely intramolecular,
a more definitive investigation involving crossover reac-
tions was undertaken. Such crossover reactions have pre-
viously revealed the intermolecular nature of a series of
glycosylation reactions that were initially thought to be
intramolecular,27 though the lack of total stereocontrol
in these latter reactions also pointed to non-intramole-
cularity. To this end, two crossover reactions were de-
signed. The first required the synthesis of the gluco mixed
acetal 32 derived from reaction of enol ethers 31 with
methanol (Scheme 3). Enol ethers 31 were themselves ac-
cessed from the known alcohol 2928 by a sequence of
allylation, to give allyl ether 30 and then WilkinsonÕs cat-
alyst mediated allyl isomerisation, which led to enol
ethers 31. NIS-mediated mixed acetal formation with
methanol then resulted in the formation of the required
mixed acetal 32. Glycosylation of an equimolar mixture
of this mixed acetal 32 and the known benzyl manno
mixed acetal 3312b produced only the b-manno benzyl
glycoside 34 and the a-gluco methyl glycoside 35 (Scheme
3). No crossover products, that is, benzyl glucosides or
methyl mannosides, were produced in detectable
amounts during this reaction.
ucts. Benzyl manno mixed acetal 36 was synthesised
from enol ethers 6 by treatment with NIS and benzyl
alcohol (Scheme 4). A similar mixed glycosylation reac-
tion of this manno mixed acetal 36 and known gluco
mixed acetal 37,13 mediated by tin(II) chloride and
AgOTf in the presence of DTBMP, again produced only
the b-manno benzyl glycoside 34 and the a-gluco methyl
glycoside 35 (Scheme 4). No crossover products were
observed. These results strongly indicate that, at least
in the cases of thioglycosides and glycosyl fluorides,
the glycosylation reaction step of allyl IAD is almost
certainly entirely intramolecular in nature.
I
BnO
BnO
(i)
O
O
OBn
OBn
O
O
BnO
BnO
BnO
BnO
F
6
36 F
I
BnO
BnO
OH
O
O
OBn
BnO
O
BnO
BnO
BnO
36
F
34
(ii)
+
O
+
O
BnO
BnO
BnO
BnO
BnO
BnO
F
HO
O
OMe
Bn
BnO
O
OMe
(i)
35
37
I
O
O
O
30
BnO
BnO
SPh
SPh
SPh
BnO
BnO
OH
˚
29
32
Scheme 4. Reagents and conditions: (i) BnOH, NIS, 4A molecular
sieves, DCE, À40ꢁC to room temperature, 88%; (ii) SnCl2, AgOTf,
(ii)
˚
DTBMP, 4A molecular sieves, DCE, 50ꢁC; 32, 60%; 33, 59%.
BnO
BnO
BnO
BnO
BnO
O
O
O
O
(iii)
SPh
BnO
OMe
2.3. Attempted synthesis of b-1,4-linked disaccharides
31
I
The efficiency of the formation of mixed acetals in the
first tethering step of the IAD process is dependent
on the steric bulk of the aglycon alcohol. In particular,
the 4-hydroxyl of a carbohydrate aglycon is generally
the most hindered and therefore the most difficult to gly-
cosylate. Indeed, previous experience indicated that
tethering reactions of the 4-hydroxyl of carbohydrate
aglycons were consistently less efficient than for the
other hydroxyl groups, hence the choice of aglycon 7
as a worst case scenario (vide supra). In an attempt to
circumvent this problem, it was envisaged that the steric
differentiation between the 4-hydroxyl and the primary
6-hydroxyl of a hexose glycosyl acceptor could in fact
be used advantageously in the allyl IAD approach.
The principle was that selective tethering of a glycosyl
acceptor, in which both the 4- and 6-hydroxyls were
unprotected, would occur regioselectively through the
less hindered primary hydroxyl, leaving the 4-hydroxyl
free to participate in the subsequent intramolecular gly-
cosylation reaction. This intramolecular glycosylation
reaction would be similar in nature to the approaches
previously published by Shiba and co-workers,29
Schmidt and co-workers,30 Ziegler and co-workers,31
Fukase and co-workers,32 Takahsahi and co-
workers33 and Valverde and co-workers.34
I
BnO
BnO
O
OBn
OH
O
O
BnO
BnO
OBn
BnO
BnO
SPh
33
34
(iv)
+
+
O
BnO
BnO
BnO
BnO
O
BnO
SPh
OMe
BnO
HO
35
O
32
OMe
I
Scheme 3. Reagents and conditions: (i) allyl bromide, NaH, DMF,
˚
75%; (ii) (Ph3P)3RhCl, n-BuLi, THF, reflux, 96%; (iii) MeOH, NIS, 4A
molecular sieves, DCE, À78ꢁC to room temperature, 96%; (iv) NIS,
˚
AgOTf, DTBMP, 4A molecular sieves, DCE, 50ꢁC; 32, 56%; 33, 52%.
Since the activation conditions for glycosyl fluorides are
markedly different to those used for thioglycoside acti-
vation, a similar crossover reaction was undertaken for
glycosyl fluoride donors. In particular, in this case,
Lewis acid catalysed scrambling of mixed acetal starting
materials was considered to be a potential side reaction
that could also lead to the formation of crossover prod-

3212
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
BnO
OH
O
I
BnO
O
BnO
HO
HO
BnO
BnO
BnO
O
O
42
O
HO
BnO
BnO
O
O
O
(i)
O
Bn
(ii),(iii)
+
O
O
HO
BnO
BnO
BnO
OMe
BnO
BnO
BnO
OMe
F
BnO
OH
O
+
OMe
F
6
38
Bn
O
OH
O
BnO
39
43
O
BnO
BnO
OMe
BnO
OH
O
I
BnO
O
BnO
O
O
HO
44
BnO
BnO
BnO
BnO
Bn
HO
HO
BnO
O
O
OPMP
NPhth
(iv)
(v),(vi)
O
O
O
O
HO
O
+
OPMP
OPMP
BnO
BnO
BnO
Bn
O
+
NPhth
NPhth
OH
O
STol
STol
41
BnO
10
40
OH
O
Bn
O
O
45
OPMP
BnO
NPhth
˚
˚
Scheme 5. Reagents and conditions: (i) NIS, 4A molecular sieves, DCE, À40ꢁC to room temperature, 73%; (ii) SnCl2, AgOTf, DTBMP, 4A
˚
molecular sieves, DCE, 50ꢁC; (iii) THF, TFA, MeOH, H2O; 41, 12% over two steps; 40, 29% over two steps; (iv) NIS, 4A molecular sieves, DCE,
À78ꢁC to room temperature, 60%; (v) NIS, AgOTf, DTBMP, 4A molecular sieves, DCE, 50ꢁC; (vi) THF, TFA, MeOH, H2O; 42, 16% over two
˚
steps; 43, 30% over two steps.
In order to investigate the feasibility of such an approach,
the known diol 3835 and enol ethers 6 were tethered selec-
tively through the 6-hydroxyl of 38 by treatment with
NIS in DCE at low temperature, to give the mixed acetals
39 (Scheme 5). However, subsequent intramolecular gly-
cosylation of mixed acetals 37 did not produce the ex-
pected b(1!4) linked products. Glycosylation of 39,
mediated by tin(II) chloride and AgOTf in the presence
of DTBMP, produced a mixture of tricyclic products,
which were then treated with a mixture of trifluoroacetic
acid/methanol/THF/water (5:2:2:1) to yield the b(1!6)
linked disaccharide 426b and the a(1!4) linked disacchar-
ide 43 as the major reaction products. None of the
hoped for b(1!4) linked product was observed.
and therefore less useful results. Secondly, in the mixed
acetal IAD approach, the formation of the b(1!6)
linked products 42 and 44 demonstrates that free hyd-
roxyl groups are not necessarily glycosylated in prefer-
ence to those involved in forming the tether. These
observations taken together strengthen the case for
the development of an intramolecular glycosylation
strategy based on as short a tether as possible, and
one in which the hydroxyl of the acetal is the one
that is delivered in the intramolecular glycosylation
reaction.
3. Conclusions
To corroborate this unexpected result, a similar investi-
gation was undertaken with thioglycoside donors Thus,
reaction of enol ethers 10 and the known diol 40,36 again
mediated by NIS, produced mixed acetal 41, in which
tethering had again selectively occurred through the pri-
mary hydroxyl group of 38. However subsequent glyco-
sylation, on this occasion mediated by NIS and AgOTf in
DCE, again produced a complex mixture of tricyclic
products, which were then treated directly with trifluoro-
acetic acid/methanol/THF/water (5:2:2:1) to yield the
b(1!6) linked disaccharide 44 and the a(1!4) linked
disaccharide 45 as the major reaction products. Again,
none of the anticipated b(1!4) linked product was ob-
served (Scheme 5).
Allyl IAD is a useful technique that allows the synthesis
of a variety of 1,2-cis glycosides and disaccharides with
complete stereocontrol. The optimisation of the first step
of mixed acetal formation, using the I2, AgOTf and
DTBMPreagent combination, represents a significant
improvement over previous procedures, and now permits
the formation of mixed acetals derived from secondary
alcohols of mono-, di- and trisaccharides in high yield,
importantly, using only 1equiv of all reagents. Crossover
glycosylation reactions provide substantial supporting
evidence that the glycosylation step of allyl IAD is indeed
entirely intramolecular in nature for both thioglycosides
and glycosyl fluorides. Finally, the failure of the
attempted synthesis of b(1!4) disaccharides highlights
the potential problems of regio- and stereoselectivity
inherent in an intramolecular glycosylation strategy in
which the donor and acceptor, which themselves possess
a free hydroxyl group, are linked by a longer mixed acet-
al tether. Glycosylation of the free hydroxyl of the accep-
tor may not necessarily occur in preference to the
hydroxyl forming the mixed acetal, and the use of a
longer tether may result in loss of the desired 1,2-cis
stereocontrol. Further investigations into the develop-
The failure of these two glycosylation reactions to give
the desired b(1!4) product highlights two potential
problems when designing an intramolecular glycosyla-
tion strategy. Firstly, it is clear that the use of a longer
tether can lead to the formation of the undesired ano-
mer of the product, as demonstrated by the formation
of the a(1!4) linked products 43 and 45. This implies
that longer tethers may lead to rather unpredictable

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3213
ment of allyl IAD for the stereospecific synthesis of a
variety of oligosaccharides containing 1,2-cis linkages
are currently in progress and the results will be reported
in due course.
by flash column chromatography (petrol–ethyl acetate,
7:1 ! 3:1) to afford the mixed acetals as a colourless oil.
4.3. 3,4,6-Tri-O-benzyl-2-O-(2-iodo-1-(para-methoxy-
phenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-b-D-gluco-
pyranosid-4-O-yl)propyl)-a-D-mannopyranosyl fluoride 8
4. Experimental
4.1. General
General procedure A: Alcohol 7 (102mg, 0.17mmol) and
enol ethers 6 (80mg, 0.16mmol) gave mixed acetals 8
(147mg, 75%) as a colourless oil; m/z (ES+) 1252
(M + K+, 7), 1236 (M + Na+, 100), 1231 (M + NH4
41).
,
+
Melting points were recorded on a Kofler hot block.
Proton nuclear magnetic resonance (dH) spectra were
recorded on Varian Gemini 200 (200MHz), Bruker
AC 200 (200MHz), Bruker DPX 400 (400MHz),
Bruker AV 400 (400MHz), or Bruker AMX 500
(500MHz) spectrometers. Carbon nuclear magnetic
resonance (dC) spectra were recorded on a Bruker
DPX 400 (100.6MHz) or a Bruker AMX 500 (125.75
MHz) spectrometer. Multiplicities were assigned using
APT or DEPT sequence. All chemical shifts are quoted
on the d scale. Infrared spectra were recorded on a
Perkin–Elmer 150 Fourier Transform spectrophoto-
meter. Mass spectra were recorded on VG Micromass
30F, ZAB 1F, Masslab20-250, Micromass Platform 1
APCI or Trio-1 GCMS (DB-5 column) spectrometers,
using desorption chemical ionisation (NH3 DCI),
electron impact (EI), electron spray ionisation (ESI),
chemical ionisation (NH3 CI), atmospheric pressure
chemical ionisation (APCI) and fast atom bombard-
ment (FAB) techniques as stated. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter
with a path length of 1dm. Concentrations are given in
g/100mL. Microanalyses were performed by the micro-
analytical services of the Inorganic Chemistry Labora-
tory, Oxford. Thin layer chromatography (TLC) was
carried out on Merck glass backed sheets, pre-coated
coated with 60F254 silica. Plates were developed using
0.2% w/v cerium(IV) sulfate and 5% ammonium moly-
bdate in 2M sulfuric acid. Flash chromatography was
carried out using Sorbsil C60 40/60 silica. Solvents
and available reagents were dried and purified before
use according to standard procedures; dichlorometh-
ane was distilled from calcium hydride immediately
before use.
4.4. para-Methoxyphenyl 3,4,6-tri-O-benzyl-b-D-manno-
pyranosyl-(1!4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-
b-D-glucopyranoside 9
˚
Molecular sieves (4A) were suspended in anhydrous
dichloroethane (1mL) in a flame-dried flask under Ar.
2,6-Di-tert-butyl-4-methylpyridine (50mg, 0.25mmol),
silver trifluoromethanesulfonate (63mg, 0.25mmol)
and anhydrous tin(II) chloride (47mg, 0.25mmol) were
added. Mixed acetals 8 (147mg, 0.12mmol) were dis-
solved in anhydrous dichloroethane (6mL) and added
by cannula under Ar. The reaction mixture was stirred
at 50ꢁC. After 7.5h, TLC (petrol–ethyl acetate, 3:1)
indicated the absence of any starting material (Rf 0.5)
and the formation of a major (Rf 0.1) and minor (Rf
0.2) product. The reaction was quenched with NaHCO3
(15mL of a saturated aqueous solution) and the mixture
stirred for a further 20min. The mixture was diluted
with ethyl acetate (150mL), filtered through Celite and
washed with brine (50mL). The organic layer was dried
over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography
(petrol–ethyl acetate, 3:1 ! 1:1) to afford b-manno
disaccharide 9 (67mg, 54%) as a colourless oil;
25
½aŠ ¼ þ44:5 (c 1.5, CHCl3) [lit. +52 (c 0.59, CHCl3)];12b
D
dH (400MHz, CDCl3) 3.35 (1H, ddd, J4,5 9.6Hz, J5,6
0
4.5Hz, J5,6 1.4Hz, H-5b), 3.44 (1H, dd, J2,3 3.3Hz,
0
J3,4 9.2Hz, H-3b), 3.64 (1H, dd, J6,6 10.7Hz, H-6b),
3.72 (3H, s, OCH3), 3.74–3.77 (2H, m, H-5a, H-60b),
0
3.79 (1H, dd, J5,6 1.9Hz, J6,6 11.2Hz, H-6a), 3.84 (1H,
0
dd, J5,6 3.9Hz, H-60a), 3.87 (1H, at, J 9.2Hz, H-4b),
4.05 (1H, d, H-2b), 4.18 (1H, at, J 8.6Hz, H-3a), 4.42–
4.47 (2H, m, H-2a, H-4a), 4.48 (2H, s, PhCH2), 4.52,
4.69 (2H, ABq, JAB 12.0Hz, PhCH2), 4.54, 4.86 (2H,
ABq, JAB 10.8Hz, PhCH2), 4.55, 4.94 (2H, ABq, JAB
12.4Hz, PhCH2), 4.56, 4.64 (2H, ABq, JAB 11.8Hz,
PhCH2), 4.70 (1H, s, H-1b), 5.63 (1H, d, J1,2 7.9Hz,
H-1a), 6.69–6.73 (2H, m, Ar-H), 6.79–6.85 (4H, m, Ar-
H), 7.01–7.03 (2H, m, Ar-H), 7.19–7.63 (21H, m, Ar-
H), 7.68–7.80 (4H, m, Ar-H); dC (125.7MHz, CDCl3)
55.4, 55.6 (d, q, C-2a, OCH3), 67.9 (d, C-2b), 68.4, 68.8
(2 · t, C-6a, C-6b), 71.2, 73.2, 73.4, 74.7, 75.0 (5 · t,
5 · PhCH2), 73.8 (d, C-4b), 74.6 (d, C-5a), 75.4 (d, C-
5b), 77.8, 78.0 (2 · d, C-3a, C-4a), 81.6 (d, C-3b), 97.6
(d, JC-1, H-1 166.0Hz, C-1a), 100.3 (d, JC-1, H-1
158.1Hz, C-1b), 114.2, 118.7, 123.2, 126.9, 127.3,
127.5, 127.6, 127.7, 127.7, 127.7, 127.8, 127.8, 127.9,
128.0, 128.2, 128.2, 128.4, 128.4, 128.4, 133.6 (20 · d,
Ar-CH), 137.8, 138.1, 138.2, 138.3, 150.7, 155.3 (6 · s,
Ar-C).
4.2. General procedure A: tethering with I2, AgOTf and
DTBMP
Iodine (55mg, 0.22mmol), silver triflate (56mg,
0.22mmol), 2,6-di-tert-butyl-4-methylpyridine (116mg,
˚
0.57mmol) and 4A molecular sieves were added to
freshly distilled CH2Cl2 (1mL) and cooled to À78ꢁC
under Ar. The aglycon alcohol (65mg, 0.18mmol) was
dissolved in freshly distilled CH2Cl2 (2mL) and added
by cannula under Ar. The enol ethers (100mg,
0.17mmol) were dissolved in freshly distilled CH2Cl2
(2mL) and added to the reaction vessel by cannula
under Ar. The reaction was allowed to warm to room
temperature. After 17h, the reaction was quenched with
sodium thiosulfate (40mL of a 10% aqueous solution)
and then extracted with CH2Cl2 (2 · 40mL). The com-
bined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo. The residue was purified
1
1

3214
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
0
0
4.5. para-Tolyl 2-O-acetyl-3,4,6-tri-O-benzyl-1-thio-a-D-
mannopyranoside 14
J5,6 1.5Hz, J6,6 11.0Hz, H-6), 3.84 (1H, dd, J5,6
5.0Hz, H-60), 3.88 (1H, dd, J2,3 3.0Hz, J3,4 9.5Hz, H-
3), 3.96 (1H, d, H-2), 4.01 (1H, at, J 9.5Hz, H-4), 4.10
(1H, dd, Jgem 13.0Hz, J 6.0Hz, CHH0CH@CH2), 4.19
(1H, dd, J 5.5Hz, CHH0CH@CH2), 4.30 (1H, ddd, H-
5), 4.48, 4.65 (2H, ABq, JAB 12.0Hz, PhCH2), 4.53,
4.92 (2H, ABq, JAB 11.0Hz, PhCH2), 4.70, 4.74 (2H,
ABq, JAB 12.0Hz, PhCH2), 5.20 (1H, d, JZ 10.5Hz,
CH@CHEHZ), 5.31 (1H, d, JE 17.0Hz, CH@CHEHZ),
5.53 (1H, s, H-1), 5.88–5.98 (1H, m, CH@CH2), 7.05–
7.07 (2H, m, 2 · Ar-H), 7.21–7.42 (17H, m, 17 · Ar-
H); dC (100.6MHz, CDCl3) 21.0 (q, ArCH3), 69.2,
71.3, 72.2, 73.2, 75.2 (5 · t, C-6, 3 · PhCH2,
CH2CH@CH2), 75.6, 75.0, 76.1, 76.7 (4 · d, C-2, C-3,
C-4, C-5), 86.0 (d, C-1), 117.9 (t, CH@CH2), 127.4,
127.6, 127.8, 127.9, 128.0, 128.2, 128.3, 128.4, 129.7,
132.0 (10 · d, Ar-CH), 130.6, 137.5, 138.1, 138.3, 138.4
(5 · s, Ar-C), 134.6 (d, CH@CH2); m/z (ES+) 620 (37),
619 (M + Na+, 100), 615 (36), 614 (M + NH4+, 93);
(HRMS (ES+) Calcd for C37H40O5SNa (MNa+)
619.2494. Found 619.2485). (Found: C, 74.76; H, 6.66.
C37H40O5S requires: C, 74.47; H, 6.76).
Orthoester 1321 (2.0g, 3.85mmol) and para-thiocresol
(717mg, 5.78mmol) were dissolved in DCE (20mL)
and the solution heated to reflux under argon. After
72h, TLC (petrol–ethyl acetate, 3:1) indicated no
remaining starting material (Rf 0.35) and the formation
of a major product (Rf 0.45). The reaction mixture was
allowed to cool to room temperature and then concen-
trated in vacuo. Purification by flash column chroma-
tography (petrol–ethyl acetate, 5:1) gave thioglycoside
14 as a white solid (1.87g, 65%), which was recrystallised
25
D
from ethyl acetate/petrol; mp 78–79ꢁC; ½aŠ ¼ þ125 (c
1.08, CHCl3); mmax (KBr) 1750 (C@O) cmÀ1; dH
(400MHz, CDCl3) 2.17 (3H, s, CO2CH3), 2.33 (3H, s,
0
ArCH3), 3.75 (1H, dd, J5,6 2.0Hz, J6,6 11.0Hz, H-6),
0
3.88 (1H, dd, J5,6 4.5Hz, H-60), 3.96–4.01 (2H, m, H-
3, H-4), 4.37 (1H, ddd, J4,5 9.0Hz, H-5), 4.49, 4.69
(2H, ABq, JAB 12.0Hz, PhCH2), 4.53, 4.91 (2H, ABq,
JAB 10.5Hz, PhCH2), 4.59, 4.75 (2H, ABq, JAB
11.0Hz, PhCH2), 5.49 (1H, d, J1,2 1.5Hz, H-1), 5.63
(1H, dd, J2,3 2.0Hz, H-2), 7.07–7.09 (2H, m, 2 · Ar-
H), 7.20–7.40 (17H, m, 17 · Ar-H); dC (100.6MHz,
CDCl3) 21.1 (q, CO2CH3, ArCH3), 68.8, 71.9, 73.3,
75.3 (4 · t, C-6, 3 · PhCH2), 70.3, 72.4, 74.5, 78.5, 86.5
(5 · d, C-1, C-2, C-3, C-4, C-5), 127.6, 127.7, 127.8,
127.9, 128.2, 128.3, 128.4, 128.5, 129.8, 132.3 (10 · d,
Ar-CH), 137.6, 137.9, 138.2, 138.3 (4 · s, Ar-C), 170.4
4.7. para-Tolyl 3,4,6-tri-O-benzyl-2-O-(prop-1-enyl)-1-
thio-a-D-mannopyranoside 10
n-Butyllithium (1.6M in hexanes, 193lL) was added to
a degassed solution of WilkinsonÕs catalyst (162mg,
0.18mmol) in tetrahydrofuran (7mL). This mixture
was stirred for 10min before being added to a refluxing
solution of allyl ether 15 (1.024g, 1.72mmol) in tetra-
hydrofuran (6mL). After 10min, TLC (petrol–ethyl ace-
tate, 5:1) showed no remaining starting material (Rf 0.5)
and the formation of a single product (Rf 0.6). The solu-
tion was allowed to cool to room temperature before the
addition of dichloromethane (50mL) and concentration
in vacuo. Purification by flash column chromatography
(petrol–ether, 7:1, with 1% added triethylamine) gave
enol ethers 10, a clear, colourless oil, as a partially sep-
arable mixture of E- and Z-isomers (959mg, 94%); mmax
(thin film) 1668 (m, C@C) cmÀ1; NMR data for E-iso-
mer: dH (400MHz, CDCl3) 1.54 (3H, dd, J 1.5Hz, J
7.0Hz, CHCH3), 2.31 (3H, s, ArCH3), 3.75 (1H, dd,
(d, C@O); m/z (ES+) 622 (39), 621 (M + Na+, 100),
+
616 (M + NH4
,
40); (HRMS (ES+) Calcd for
C36H38O6SNa (MNa+) 621.2287. Found 621.2288).
(Found: C, 72.23; H, 6.37. C36H38O6S requires: C,
72.22; H, 6.40).
4.6. para-Tolyl 2-O-allyl-3,4,6-tri-O-benzyl-1-thio-a-D-
mannopyranoside 15
Acetate 14 1.626g, 2.7mmol) was dissolved in methanol
(40mL) and a solution of sodium (53mg, 2.3mmol) in
methanol (1mL) added. The reaction mixture was stir-
red at room temperature for 3h, after which time,
TLC (petrol–ethyl acetate, 3:1) showed no remaining
starting material (Rf 0.85) and the formation of a single
product (Rf 0.45). The reaction mixture was co-evapo-
rated with toluene and subsequently exposed to high
vacuum for 2h. The resulting residue was taken up in
DMF (25mL) and allyl bromide (0.58mL, 6.7mmol)
added, followed by sodium hydride (60% dispersion in
mineral oil, 324mg, 8.1mmol). This solution was stirred
for 3h, after which time TLC (petrol–ethyl acetate, 3:1)
showed no remaining starting material (Rf 0.5) and the
formation of a major product (Rf 0.7). Methanol
(5mL) was added slowly and the mixture concentrated
in vacuo (at 60ꢁC). The residue was taken up in ether
(200mL) and washed with brine (2 · 100mL). The aque-
ous layers were re-extracted with ether (100mL) and the
combined organic extracts dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash column
0
0
J5,6 2.0Hz, J6,6 11.0Hz, H-6), 3.84 (1H, dd, J5,6
5.0Hz, H-60), 3.91 (1H, dd, J2,3 3.0Hz, J3,4 9.5Hz, H-
3), 4.02 (1H, at, J 9.5Hz, H-4), 4.20 (1H, d, J1,2
1.5Hz, H-2), 4.31 (1H, ddd, H-5), 4.48, 4.65 (2H,
ABq, JAB 12.0Hz, PhCH2), 4.54 (1H, d, J 11.0Hz,
PhCHH0), 4.72 (2H, s, PhCH2), 4.90–4.98 (2H, m,
PhCHH0, CH3CH), 5.54 (1H, d, H-1), 6.08 (1H, dd, J
12.5Hz, OCH@CH), 7.05–7.07 (2H, m, 2 · Ar-H),
7.21–7.42 (17H, m, 17 · Ar-H); dC (100.6MHz, CDCl3)
12.4 (q, CHCH3), 21.1 (q, ArCH3), 69.1, 72.2, 73.3, 75.3
(4 · t, C-6, 3 · PhCH2), 72.5, 74.8, 76.7, 79.2, (4 · d, C-
2, C-3, C-4, C-5), 85.4 (d, C-1), 102.5 (d, CHCH3),
127.4, 127.5, 127.6, 127.7, 127.8, 128.0, 128.0, 128.0,
128.1, 128.2, 128.2, 128.3, 128.5, 129.5, 132.0, 132.3,
(16 · d, Ar-CH), 130.2, 137.6, 137.9, 138.3, 138.4
(5 · s, Ar-C), 144.8 (d, OCH@CH); NMR data for Z-
isomer: dH (400MHz, CDCl3) 1.67 (3H, dd, J 1.5Hz, J
7.0Hz, CHCH3), 2.32 (3H, s, ArCH3), 3.79 (1H, dd,
chromatography (petrol–ether, 4:1) gave allyl ether
25
D
15 (1.536g, 95%) as a clear oil; ½aŠ ¼ þ137:1 (c
0.96, CHCl3); mmax (thin film) 1645 (w, C@C) cmÀ1; dH
(400MHz, CDCl3) 2.32 (3H, s, CH3), 3.75 (1H, dd,
J5,6 2.0Hz, J6,6 11.0Hz, H-6), 3.88 (1H, dd, J5,6
0
0
5.0Hz, H-60), 3.94 (1H, dd, J2,3 3.0Hz, J3,4 9.5Hz, H-

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3215
3), 4.10 (1H, at, J 9.5Hz, H-4), 4.12 (1H, d, J1,2 2.0Hz,
H-2), 4.34 (1H, ddd, H-5), 4.51, 4.67 (2H, ABq, JAB
12.0Hz, PhCH2), 4.55–4.61 (1H, m, CHCH3), 4.58,
4.94 (2H, ABq, JAB 11.0Hz, PhCH2), 4.76 (2H, s,
PhCH2), 5.47 (1H, d, H-1), 5.90–5.92 (1H, m,
OCH@CH), 7.06–7.08 (2H, m, 2 · Ar-H), 7.24–7.44
(17H, m, 17 · Ar-H); dC (100.6MHz, CDCl3) 9.6 (q,
CH3), 21.1 (q, ArCH3), 69.1, 72.3, 73.2, 75.3 (4 · t, C-
6, 3 · PhCH2), 72.7 (d, C-5), 74.9, 78.8 (2 · d, C-2, C-
4), 79.5 (d, C-3), 86.5 (d, C-1), 105.0 (d, CHCH3),
127.4, 127.6, 127.7, 127.9, 128.0, 128.0, 128.2, 128.4,
128.5, 129.8, 132.3 (11 · d, Ar-CH), 137.8, 138.0,
130.0, 132.4 (5 · d, Ar-CH), 137.1, 138.1 (2 · s, Ar-C);
m/z (ES+) 398 (21), 397 (M + Na+, 100), 375 (M + H+,
44). (HRMS (ES+) Calcd for C20H22NaO5S (MNa+)
397.1086. Found 397.1090). (Found: C, 64.01; H, 5.92.
C20H22O5S requires: C, 64.15; H, 5.92).
4.9. para-Tolyl (R)-4,6-O-benzylidene-3-O-pivaloyl-1-
thio-a-D-mannopyranoside 18
Diol 17 (673mg, 1.8mmol) was dissolved in pyridine
(10mL) and cooled to 0ꢁC. Pivaloyl chloride (0.32mL,
2.6mmol) was then added dropwise. After stirring for
an hour, additional pivaloyl chloride (0.12mL, 1mmol)
was added. After a further 1h, TLC (petrol–ethyl ace-
tate, 1:1) showed no remaining starting material (Rf
0.3) and the formation of a single product (Rf 0.9). Ethyl
acetate (100mL) was added and the mixture washed
with hydrochloric acid (100mL of a 1M aqueous solu-
tion), sodium bicarbonate (100mL of a saturated aque-
ous solution) and brine (100mL), dried over MgSO4,
filtered and concentrated in vacuo. Recrystallisation
from ethyl acetate/petrol yielded pivolate ester 18
(623mg, 76%) as white needles. Purification of the
recrystallisation residues by flash column chromatogra-
phy (petrol–ethyl acetate, 7:2) gave further product
138.4, 138.4 (4 · s, Ar-C), 143.9 (d, OCH@CH); m/z
(ES+) 620 (37), 619 (M + Na+, 100), 614 (M + NH4
,
+
70). (HRMS (ES+) Calcd for C37H40NaO5S (MNa+)
619.2494. Found 619.2491). (Found: C, 74.54; H, 6.75.
C37H40O5S requires: C, 74.47; H, 6.76).
4.8. para-Tolyl (R)-4,6-O-benzylidene-1-thio-a-D-manno-
pyranoside 17
Tetraacetate 1622 (8.39g, 18.4mmol) was dissolved in
methanol (140mL) and a solution of sodium (40mg,
1.7mmol) in methanol (2mL) added. The reaction mix-
ture was stirred at room temperature for 3h, after which
time, TLC (petrol–ethyl acetate, 1:4) showed no remain-
ing starting material (Rf 0.8) and the formation of a sin-
gle product (Rf 0.0). A small quantity of Dowexꢂ
50WX8 acidic ion exchange resin was added, and after
30min, the solution became pH neutral. The ion ex-
change resin was removed by filtration and the reaction
mixture co-evaporated twice with toluene and subse-
quently exposed to high vacuum for 2h. This crude
intermediate was dissolved in DMF (60mL) and benzal-
dehyde dimethyl acetal (3mL, 20.0mmol) and camphor
sulfonic acid (128mg, 0.6mmol) added. The reaction
mixture was subjected to reduced pressure (ca. 10mbar)
at room temperature on a rotary evaporator for 5h,
after which time additional benzaldehyde dimethyl acetal
(0.5mL, 3.3mmol) was added. After a further 4h under
reduced pressure, TLC (ethyl acetate) showed little
remaining starting material (Rf 0.05) and the formation
of a major product (Rf 0.70). Triethylamine (5mL) and
then ethyl acetate (400mL) were added and the mixture
washed with brine (3 · 150mL). The aqueous washes
were re-extracted with ethyl acetate (150mL), and the
combined organic extracts dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash column
chromatography (petrol–ethyl acetate, 1:1 ! 0:1) gave
(146mg, 76% ! 94%); mp 178–181ꢁC (ethyl acetate/
25
petrol); ½aŠ ¼ þ217:1 (c 1.0, CHCl3); mmax (KBr) 1719
D
(s, C@O), 3508 (br, OH) cmÀ1; dH (400MHz, CDCl3)
1.26 (9H, s, C(CH3)3), 2.34 (3H, s, ArCH3), 3.87 (1H,
0
at, J5,6 = J6,6 10.5Hz, H-6), 4.20 (1H, at, J3,4 = J4,5
0
10.0Hz, H-4), 4.26 (1H, dd, J5,6 5.0Hz, H-60), 4.42–
4.48 (2H, m, H-2, H-5), 5.38 (1H, dd, J2,3 3.5Hz, H-
3), 5.49 (1H, d, J1,2 1.0Hz, H-1), 5.60 (1H, s, PhCH),
7.13–7.15 (2H, m, 2 · Ar-H), 7.35–7.39 (5H, m,
5 · Ar-H), 7.45–7.47 (2H, m, 2 · Ar-H); dC
(100.6MHz, CDCl3) 21.1 (q, ArCH3), 27.1 (q,
C(CH3)3), 39.1 (s, C(CH3)3), 64.9 (d, C-5), 68.5 (t, C-
6), 70.5, 71.2 (d, C-2, C-3), 76.3 (d, C-4), 88.7 (d, C-1),
101.4 (d, PhCH), 125.9, 128.2, 129.9, 132.5 (4 · d, Ar-
CH), 137.2, 138.1 (2 · s, Ar-C), 177.2 (s, C@O); m/z
(ES+) 482 (28), 481 (M + Na+, 100), 459 (M + H+, 18).
(HRMS (ES+) Calcd for C25H30NaO6S (MNa+)
481.1661. Found 481.1668). (Found: C, 65.34; H, 6.64.
C25H30O6S requires: C, 65.48; H, 6.59).
4.10. para-Tolyl 2-O-allyl-(R)-4,6-O-benzylidene-3-O-
pivaloyl-1-thio-a-D-mannopyranoside 19
Ester 18 (140mg, 0.30mmol) and allyl bromide
(0.079mL, 0.91mmol) were dissolved in DMF (0.4mL)
and the solution cooled to 0ꢁC. Sodium hydride (60%
dispersion in mineral oil, 15mg, 0.38mmol) was added
under argon. After 10min, TLC (petrol–ethyl acetate,
5:1) showed no remaining starting material (Rf 0.15)
and the formation of a major product (Rf 0.55) as well
as some minor products. Ether (5mL) was added, fol-
lowed by ammonium chloride (5mL of a saturated
aqueous solution). The mixture was then diluted with
further ether (45mL) and washed with brine
(3 · 20mL), dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash column chroma-
tography (petrol–ether, 6:1) gave allyl ether 19 as a
clear oil (112mg, 74%); Rf 0.20 (petrol–ether, 6:1);
diol 17 as a white powder (2.41g, 38% over two steps);
25
mp 206–208ꢁC (ethyl acetate); ½aŠ ¼ þ201:7 (c 0.58,
D
Me2SO); mmax (KBr) 3226 (br, OH) cmÀ1
(400MHz, CDCl3) 2.35 (3H, s, CH3), 2.70 (1H, d,
J3,OH 3.5Hz, OH-3), 2.79 (1H, d, J2,OH 2.0Hz, OH-2),
; dH
0
3.84 (1H, at, J5,6 = J6,6 10.5Hz, H-6), 4.01 (1H, at,
J3,4 = J4,5 9.5Hz, H-4), 4.13–4.17 (1H, m, H-3), 4.24
(1H, dd, J5,6 5.0Hz, H-60), 4.32–4.33 (1H, m, H-2),
0
4.37 (1H, ddd, H-5), 5.53 (1H, s, H-1), 5.59 (1H, s,
PhCH), 7.14–7.16 (2H, m, 2 · Ar-H), 7.36–7.43 (5H,
m, 5 · Ar-H), 7.50–7.55 (2H, m, 2 · Ar-H); dC
(100.6MHz, CDCl3) 21.1 (q, CH3), 64.1, 69.1 (2 · d,
C-3, C-5), 68.5 (t, C-6), 72.2 (d, C-2), 79.0 (d, C-4),
88.3 (d, C-1), 102.3 (d, PhCH), 126.3, 128.4, 129.3,

3216
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
24:5
½aŠ ¼ þ119:5 (c 1.0, CHCl3); mmax (thin film) 1647 (w,
(2 · d, OCHE@CH, OCHZ@CH), 177.8 (s, C@O); m/z
(ES+) 523 (27), 522 (M + Na+, 76), 517 (20), 476 (28),
475 (30), 474 (100), 459 (28), 434 (37), 353 (100).
(Found: C, 67.64; H, 6.89. C28H34O6S requires: C,
67.45; H, 6.87).
D
C@C), 1733 (s, C@O) cmÀ1; dH (400MHz, CDCl3) 1.26
(9H, s, C(CH3)3), 2.35 (3H, s, ArCH3), 3.89 (1H, at,
0
J5,6 = J6,6
10.5Hz, H-6), 4.07–4.12 (2H, m,
CH2CH@CH2), 4.16 (1H, dd, J1,2 1.5Hz, J2,3 3.5Hz,
H-2), 4.24 (1H, at, J3,4 = J4,5 10.0Hz, H-4), 4.25 (1H,
dd, J5,6 4.5Hz, H-60), 4.42 (2H, ddd, H-5), 5.21 (1H,
0
4.12. para-Tolyl 2-O-(2-iodo-1-(para-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-mannopyr-
anoside 23
dd, JZ 10.5Hz, Jgem 1.5Hz, CH@CHEHZ), 5.29
(1H, dd, JE 15.5Hz, CH@CHEHZ), 5.31 (1H, dd, H-
3), 5.49 (1H, d, H-1), 5.62 (1H, s, PhCH), 5.84–5.94
(1H, m, CH@CH2), 7.14–7.16 (2H, m, 2 · Ar-H),
7.35–7.39 (5H, m, 5 · Ar-H), 7.46–7.48 (2H, m,
2 · Ar-H); dC (100.6MHz, CDCl3) 21.1 (q, ArCH3),
27.1 (q, C(CH3)3), 39.0 (s, C(CH3)3), 65.4 (d, C-5),
68.5 (t, C-6), 70.4 (d, C-3), 72.4 (t, CH2CH@CH2),
76.4 (d, C-4), 77.8 (d, C-2), 87.1 (d, C-1), 101.2 (d,
PhCH), 118.2 (t, CH@CH2), 125.9, 128.1, 129.8, 129.9,
129.9, 132.3 (6 · d, Ar-CH), 133.9 (d, CH@CH2),
137.3, 139.0 (2 · s, Ar-C), 177.8 (s, C@O); m/z (ES+)
522 (33), 521 (M + Na+, 100), 516 (M + NH4+, 36),
500 (22), 499 (M + H+, 70), 393 (37). (HRMS (ES+)
Calcd for C28H34O6SNa (MNa+) 521.1974. Found
521.1970). (Found: C, 67.30; H, 6.83. C28H34O6S
requires: C, 67.45; H, 6.87).
General procedure A: Enol ethers 10 and alcohol 7 gave
mixed acetals 23, a partially separable mixture of dia-
stereomers, as a clear foam (292mg, 77%); mmax (thin
film) 1715 and 1777 (s and w, 2 · imide C@O) cmÀ1
;
NMR data for major diastereomer: dH (500MHz,
CDCl3) 1.60 (3H, d, J 7.3Hz, CHCH3), 2.37 (3H, s,
ArCH3), 3.64–3.97 (11H, m, H-4Glc, H-5Glc, H-6Glc
,
H-60Glc, H-3Man, H-4Man, H-6Man, H-60Man, OCH3), 4.11
(1H, d, J 2.1Hz, O2CHCHI), 4.34–4.48 (8H, m, H-
2Glc, H-3Glc, H-2Man, H-5Man, P hCH2, P hCHH0, CHI),
4.52, 4.67 (2H, ABq, JAB 11.9Hz, PhCH2), 4.53 (1H,
d, J 12.2Hz, PhCHH0), 4.59, 4.79 (2H, ABq, JAB
10.9Hz, PhCH2), 4.72, 5.08 (2H, ABq, JAB 13.1Hz,
PhCH2), 5.59 (1H, d, J1,2 8.3Hz, H-1Glc), 6.29 (1H, s,
H-1Man), 6.64–6.72 (5H, m, 5 · Ar-H), 6.81–7.05 (6H,
m, 6 · Ar-H), 7.20–7.90 (26H, m, 26 · Ar-H); partial
NMR data for minor diastereomers: dH (500MHz,
CDCl3) 1.76, 1.86 (2 · d, J 7.0 and 7.1Hz, CHCH3),
2.30, 2.34 (2 · s, ArCH3), 5.38, 6.20 (2 · s, H-1Man),
5.64 (d, J1,2 8.3Hz, H-1Glc); dC (125.7MHz, CDCl3)
21.2 (q, ArCH3), 23.6 (q, CHCH3), 29.6 (d, CHI),
55.5, 55.8 (d, q, C-2Glc, OCH3), 65.7, 67.6, 69.2, 72.5,
73.0, 73.8, 75.0, 75.5 (8 · t, C-6Glc, C-6Man, 5 · PhCH2),
73.8, 75.3, 75.5, 75.9, 77.2, 79.8, 80.6 (7 · d, C-3Glc, C-
4Glc, C-5Glc, C-2Man, C-3Man, C-4Man, C-5Man), 86.5 (d,
C-1Man), 97.6 (d, C-1Glc), 104.3 (d, O2CHCHI), 114.2,
118.1, 118.6, 123.1, 126.6, 126.8, 127.1, 127.2, 127.3,
127.3, 127.5, 127.6, 127.7, 127.8, 127.8, 128.0, 128.1,
128.1, 128.2, 128.2, 128.3, 128.3, 128.5, 128.6, 128.7,
129.3, 130.1, 132.7, 133.2, 133.5 (30 · d, Ar-CH),
129.7, 137.6, 137.6, 137.9, 138.3, 138.7, 138.8 (7 · s,
Ar-C), 150.7, 155.2 (2 · s, 2 · C@O); m/z (ES+) 1343
(18), 1342 (35), 1341 (77), 1340 (M + Na+, 100), 1337
(27), 1336 (62), 1335 (M + NH4+, 80). (Found: C,
66.02; H, 5.34; N, 1.30. C72H72INO13S requires: C,
65.60; H, 5.50; N, 1.06).
4.11. para-Tolyl 4,6-O-benzylidene-3-O-pivaloyl-2-O-
(prop-1-enyl)-1-thio-a-D-mannopyranoside 11
n-Butyllithium (1.6M in hexanes, 100lL) was added to
a degassed solution of WilkinsonÕs catalyst (80mg,
0.08mmol) in tetrahydrofuran (3mL). This mixture
was stirred for 10min before being added to a refluxing
solution of allyl ether 19 (440mg, 0.88mmol) in tetra-
hydrofuran (4mL). After 10min, TLC (petrol–ether,
6:1) showed no remaining starting material (Rf 0.35)
and the formation of a single product (Rf 0.50). The
solution was allowed to cool to room temperature be-
fore the addition of dichloromethane (50mL) and con-
centration in vacuo. Purification by flash column
chromatography (petrol–ether, 9:1, with 1% added tri-
ethylamine) gave enol ethers 11, as a white foam, an
inseparable mixture of E- and Z-isomers (416mg, 95%;
E:Z, 1:2.5); mmax (thin film) 1731 (m, C@O) cmÀ1; dH
(400MHz, CDCl3) 1.23 (9H, s, C(CH3)3), 1.52 (<3H,
dd, J 1.5Hz, J 7.0Hz, CH3E), 1.64 (<3H, dd, J 1.5Hz,
J 7.0Hz, CH3Z), 2.35 (3H, s, ArCH3), 3.90 (1H, at,
0
J5,6 = J6,6 10.5Hz, H-6), 4.23–4.29 (2H, m, H-4, H-5),
4.39 (<1H, dd, J1,2 1.5Hz, J2,3 3.5Hz, H-2Z), 4.42–
4.52 (>2H, m, H-2E, H-60, CHECH3, CHZCH3), 5.30
(1H, dd, J3,4 10.5Hz, H-3), 5.45 (<1H, d, H-1Z), 5.49
(<1H, d, J1,2 1.0Hz, H-1E), 5.53 (<1H, s, PhCHE),
5.62 (<1H, s, PhCHZ), 5.88 (<1H, dd, J 6.0Hz,
OCHZ@CH), 6.01–6.05 (<1H, m, OCHE@CH), 7.13–
7.15 (2H, m, 2 · Ar-H), 7.35–7.39 (5H, m, 5 · Ar-H),
7.46–7.49 (2H, m, 2 · Ar-H); dC (100.6MHz, CDCl3)
9.4, 12.3 (2 · q, CHCH3E, CHCH3Z), 21.1 (q, ArCH3),
27.0 (q, C(CH3)3), 39.0 (s, C(CH3)3), 65.0, 65.0, 69.9,
70.1, 76.2, 76.4, 77.2, 78.0, 79.6 (9 · d, C-2E, C-3E, C-
4E, C-5E, C-2Z, C-3Z, C-4Z, C-5Z), 68.4, 68.5 (2 · t, C-
6E, C-6Z), 86.6, 87.3 (2 · d, C-1E, C-1Z), 101.3 (d,
CHECH3, CHZCH3), 102.6, 103.7 (2 · d, PhCHE,
PhCHZ), 125.9, 128.2, 128.9, 129.9, 132.3, 132.5 (6 · d,
Ar-CH), 129.4, 137.2, 138.2 (3 · s, Ar-C), 144.5, 145.3
4.13. para-Tolyl 4,6-O-benzylidene-2-O-(2-iodo-1-(para-
methoxyphenyl 30,60-di-O-benzyl-20-deoxy-20-phthalim-
ido-b-D-glucopyranosyl-(1!4)-3,6-di-O-benzyl-2-deoxy-
2-phthalimido-b-D-glucopyranosid-40-O-yl)-propyl)-3-O-
pivaloyl-1-thio-a-D-mannopyranoside 24
General procedure A: Enol ethers 11 and alcohol 20 gave
mixed acetals 24, an inseparable mixture of diastereo-
mers, as a white foam, (102mg, 75); mmax (thin film)
1717 and 1775 (s and w, 2 · imide C@O, pivaloyl
C@O) cmÀ1
; NMR data (diagnostic peaks): dH
(400MHz, CDCl3) 1.26, 1.27 (9H, 2 · s, C(CH3)3),
1.67, 1.77 (3H, 2 · d, J 7.5Hz, J 7.0Hz, CHCH3), 5.30
(1H, s, PhCHO2), 5.43, 5.47 (2 · d, J1,2 8.0Hz,

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3217
H-1Glc), 5.69, 6.19 (1H, 2 · d, J1,2 1.0Hz, 1.5Hz, H-
1Man); m/z (ES+) 1715 (64), 1714 (M + Na+, 86), 1285
(100). (Found: C, 64.61; H, 5.30; N, 1.60. C91H91INO20S
requires: C, 64.61; H, 5.42; N, 1.66).
Ar-C), 134.6 (d, CH@CH2); m/z (APCI+) 605
(M + Na+, 27), 181 (52), 173 (21), 155 (15), 145 (24),
143 (29), 131 (100), 129 (75), 121 (57), 111 (36). (Found:
C, 74.46; H, 6.54. C36H38O5S requires: C, 74.20; H,
6.57).
4.14. Methyl 3,4,6-tri-O-benzyl-2-O-(2-iodo-1-(3,4,6-tri-
O-benzyl-1-deoxy-1-fluoro-b-D-glucopyranos-2-O-yl)prop-
yl)-a-D-glucopyranosyl-(1!3)-2,4,6-tri-O-benzyl-a-D-
glucopyranosyl-(1!3)-2-O-benzyl-4,6-O-benzylidene-a-
D-mannopyranoside 25
4.17. Phenyl 3,4,6-tri-O-benzyl-2-O-(prop-1-enyl)-1-thio-
b-D-glucopyranoside 31
n-Butyllithium (1.6M in hexanes, 0.05mL) was added to
a degassed solution of WilkinsonÕs catalyst (43mg,
0.046mmol) in tetrahydrofuran (3mL). This mixture
was stirred for 10min before being added to a refluxing
solution of allyl ether 30 (269mg, 0.46mmol) in tetra-
hydrofuran (2mL). After 1h, TLC (petrol–ethyl acetate,
5:1) showed no remaining starting material (Rf 0.45) and
the formation of a single product (Rf 0.55). The solution
was allowed to cool to room temperature before the
addition of dichloromethane (50mL) and concentration
in vacuo. Purification by flash column chromatography
(petrol–ethyl acetate, 10:1, with 1% added triethylamine)
gave enol ethers 31, a semi-crystalline solid, as an insep-
arable mixture of E- and Z-isomers (257mg, 96%, ca.
1:2, E:Z). mmax (thin film) 1671 (m, C@C) cmÀ1; dH
(400MHz, CDCl3) 1.57 (ca. 1H, dd, J 1.5Hz, J 7.0Hz,
CH3E), 1.66 (ca. 2H, dd, J 1.5Hz, J 7.0Hz, CH3Z),
3.51–3.82 (6H, m, H-2, H-3, H-4, H-5, H-6, H-60),
4.46 (<1H, dq, J 6.0Hz, CH3CHZ), 4.54–4.68 (4H, m,
H-1, PhCH2, P hCHH0), 4.73, 4.83 (2H, ABq, JAB
10.0Hz, PhCH2), 4.84 (1H, d, J 11.0Hz, PhCHH0),
5.02 (<1H, dq, J 12.0Hz, CH3CHE), 6.03 (<1H, dd, J
General procedure A: Enol ethers 12 and alcohol 21 gave
mixed acetals 25, an inseparable mixture of diastereo-
mers, as a colourless oil (83mg, 78) m/z (ES+) 1878
(M + Na+, 100).
4.15. 3,4,6-Tri-O-benzyl-2-O-(2-iodo-1-(methyl 2,3,6-
tri-O-benzyl-a-D-mannopyranosid-4-O-yl)propyl)-a-D-
mannopyranosyl fluoride 26
General procedure A: Enol ethers 6 and alcohol 22 gave
mixed acetals 26, an inseparable mixture of diastereo-
mers, (139mg, 55) as a colourless oil; m/z (APCIÀ)
1117 (M + ClÀ, 8).
4.16. Phenyl 2-O-allyl-3,4,6-tri-O-benzyl-1-thio-b-D-
glucopyranoside 30
Alcohol 2928 (700mg, 1.29mmol) was dissolved in DMF
(6mL) and the solution cooled to 0ꢁC. Sodium hydride
(60% in mineral oil, 105mg, 2.63mmol) was added
portionwise, followed by allyl bromide (0.22mL,
2.54mmol) and the reaction mixture allowed to return
to room temperature. The solution was stirred for 2h,
after which time TLC (petrol–ethyl acetate, 5:1) showed
no remaining starting material (Rf 0.25) and the forma-
tion of a major product (Rf 0.55). Methanol (5mL) was
slowly added and the mixture concentrated in vacuo.
The residue was taken up in ether (50mL), washed with
brine (4 · 30mL), dried over MgSO4, filtered and con-
centrated in vacuo. Purification by flash column chro-
matography (petrol–ethyl acetate, 8:1) gave allyl ether
1.5Hz, OCHZ@CH), 6.09 (<1H, dd,
J
1.5Hz,
OCHE@CH), 7.12–7.36 (18H, m, 18 · Ar-H), 7.57–
7.60 (2H, m, 2 · Ar-H); dC (100.6MHz, CDCl3) 9.4
(CH3Z), 12.2 (CH3E), 68.9 (t, C-6), 73.4, 75.1, 75.7
(3 · t, 3 · PhCH2), 77.2, 79.2, 81.5, 82.4, 86.0, 86.2
(6 · d, C-1, C-2, C-3, C-4, C-5), 100.3, 100.9 (2 · d,
CH3CHE, CH3CHZ), 127.5, 127.6, 127.8, 127.8, 127.9,
127.9, 128.3, 128.4, 128.8, 132.9, 132.9 (11 · d, Ar-
CH), 132.6, 138.0, 138.3 (3 · s, Ar-C), 146.5, 147.4
(2 · d, OCHE@CH, OCHZ@CH); m/z (ES+) 606 (31),
605 (M + Na+, 100), 600 (M + NH4+, 40). (HRMS
(ES+) Calcd for C36H38NO5SNa (MNa+) 605.2338.
Found 600.2330). (Found: C, 74.26; H, 6.49.
C36H38O5S requires: C, 74.20; H, 6.57).
30 (566mg, 75%) as a white solid; mp 58–59ꢁC (ether/
24:5
petrol); ½aŠ ¼ À21:1 (c 1.04, CHCl3); mmax (KBr)
D
1587 (w, C@C) cmÀ1; dH (400MHz, CDCl3) 3.41 (1H,
dd, J1,2 9.5Hz, J2,3 8.5Hz, H-2), 3.52 (1H, ddd, J4,5
4.18. Phenyl 3,4,6-tri-O-benzyl-2-O-(2-iodo-1-methoxy-
propyl)-1-thio-b-D-glucopyranoside 32
0
9.0Hz, J5,6 1.5Hz, J5,6 4.5Hz, H-5), 3.61–3.71 (2H, m,
0
H-3, H-4), 3.73 (1H, dd, J6,6 11.0Hz, H-6), 3.80 (1H,
dd, H-60), 4.27 (1H, dd, Jgem 12.0Hz, J 6.0Hz,
Methanol (0.07mL, 1.73mmol) was added to 1,2-dichlo-
˚
roethane (2mL) with molecular sieves (powdered, 4A,
CHH0CH@CH2),
4.40
(1H,
dd,
J
5.5Hz,
CHH0CH@CH2), 4.54–4.64 (4H, m, H-1 and
3 · PhCHH0), 4.85 (1H, d, J 11.0Hz, PhCHH0), 4.86
(1H, d, J 11.0Hz, PhCHH0), 4.93 (1H, d, J 11.0Hz,
PhCHH0), 5.21 (1H, d, JZ 10.5Hz, CH@HEHZ), 5.31
(1H, dd, JE 15.5Hz, Jgem 1.5Hz, CH@CHEHZ), 5.95–
6.05 (1H, m, CH@CH2), 7.21–7.36 (18H, m, 18 · Ar-
H), 7.56–7.62 (2H, m, 2 · Ar-H); dC (100.6MHz) 69.0,
73.4, 74.2, 75.0, 75.8 (5 · t, C-6, 3 · PhCH2,
OCH2CH@CH2), 77.6, 79.0, 80.5, 86.7, 87.4 (5 · d, C-
1, C-2, C-3, C-4, C-5), 117.4 (CH@CH2), 127.3, 127.5,
127.6, 127.7, 127.8, 127.9, 128.3, 128.4, 128.4, 128.8,
131.8 (11 · d, Ar-CH), 133.8, 138.0, 138.2, 138.3 (4 · s,
ca. 250mg) and stirred for 1h. After this time, enol
ethers 31 (103mg, 0.18mmol), dissolved in 1,2-dichloro-
ethane (2mL), were added. N-Iodosuccinimide (100mg,
0.44mmol) was added and the solution immediately
cooled to À78ꢁC. The solution was then allowed to
return to room temperature over 14h, after which time,
TLC (petrol–ethyl acetate, 7:1) showed no remaining
starting material (Rf 0.45) and the formation of a single
product (Rf 0.40). Dichloromethane (50mL) was added
and the solution was filtered through Celiteꢂ, washed
with sodium thiosulfate (25mL of a 10% aqueous solu-
tion), dried over MgSO4, filtered and concentrated

3218
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
0
in vacuo. Purification by flash column chromatography
(petrol–ethyl acetate, 7:1, with 1% added triethylamine)
gave mixed acetals 32 as a clear oil, an inseparable mix-
ture of diastereomers (126mg, 96%); mmax (thin film) no
significant peaks; dH (400MHz, CDCl3) 1.72, 1.80, 1.93,
1.97 (3H, 3 · d, J 7.0Hz, CHCH3), 3.37, 3.42, 3.49 and
3.60 (3H, 4 · s [relative intensities: 2:6:1.5:1], OCH3),
3.52–3.88 (6H, m, H-2, H-3, H-4, H-5, H-6, H-60),
4.08–4.40 (1H, m, CHI), 4.45 (<1H, d, J 3.5Hz, par-
tial-O2CH), 4.52–5.21 (>7H, m, H-1, 3 · PhCH2, par-
tial-O2CH), 7.20–7.45 (18H, m, 18 · Ar-H), 7.57–7.60
(2H, m, 2 · Ar-H); dC (100.6MHz, CDCl3) 21.5, 21.9,
23.2 (3 · q, CHCH3), 27.2, 28.2 (2 · d, CHI), 57.5,
58.0, 58.1 (3 · q, OCH3), 69.0 (t, C-6), 73.3, 73.5, 74.6,
74.8, 75.1, 76.1, 76.2 (7 · t, 3 · PhCH2), 77.2, 77.3,
78.7, 78.8, 79.0, 85.6 (6 · d, C-2, C-3, C-4, C-5), 87.5,
87.7 (2 · d, C-1), 106.3, 106.4 (2 · d, O2CH), 127.1,
127.3, 127.6, 127.6, 127.7, 127.8, 128.3, 128.3, 128.4,
128.5, 128.6, 128.6, 128.7, 129.1, 131.4, 131.5, 131.7
H-3), 3.75 (1H, dd, J5,6 5.3Hz, J6,6 10.7Hz, H-6), 3.80
(1H, at, J 10.4Hz, H-60), 3.89 (1H, at, J 9.3Hz, H-4),
4.12 (1H, d, H-2), 4.46 (1H, s, H-1), 4.55, 4.90 (2H,
ABq, JAB 11.0Hz, PhCH2), 4.59, 4.66 (2H, ABq, JAB
11.9Hz, PhCH2), 4.66, 4.76 (2H, ABq, JAB 11.9Hz,
PhCH2), 4.67, 4.96 (2H, ABq, JAB 11.7Hz, PhCH2),
7.20–7.38 (20H, m, Ar-H); HSQC (400MHz, CDCl3)
1JC-1,H-1 157Hz; and methyl a-glucoside 35 as white
crystals (19mg, 52%); mp 87–89ꢁC (ether/petrol) [lit.10b
24:5
mp 89–90ꢁC]; ½aŠ ¼ þ89:0 (c 1.01, CHCl3)
D
23
D
[lit.10b ½aŠ ¼ þ90 (c 1.1, CHCl3)]; dH (400MHz,
CDCl3) 2.11 (1H, d, J2,OH 8.0Hz, OH), 3.43 (3H, s,
OCH3), 3.61–3.79 (6H, m, H-2, H-3, H-4, H-5, H-6,
H-60), 4.51, 4.83 (2H, ABq, JAB 11.0Hz, PhCH2), 4.53,
4.66 (2H, ABq, JAB 12.0Hz, PhCH2), 4.82 (1H, d, J1,2
3.0Hz, H-1), 4.86, 4.92 (2H, ABq, JAB 11.0Hz, PhCH2),
7.15–7.48 (15H, m, 15 · Ar-H). No trace of crossover
1
products was observed by H NMR or TLC.
(17 · d, Ar-CH), 138.2, 138.2, 138.5 (3 · s, Ar-C); m/z
4.20. 2-O-(2-Iodo-1-benzyloxy-propyl)-3,4,6-tri-O-benz-
yl-a-D-glucopyranosyl fluoride 36
(ES+) 764 (22), 763 (M + Na+, 47), 758 (M + NH4+
100). (HRMS (ES+) Calcd for C37H45INO6S (MNH4
758.2012. Found 758.2003).
,
+
)
Benzyl alcohol (29lL, 0.28mmol) was dissolved in 1,2-
dichloroethane (1mL) with molecular sieves (powdered,
˚
4A, ca. 100mg) and stirred for 1h. After this time, enol
4.19. Crossover experiment 1. Benzyl 3,4,6-tri-O-benzyl-
b-D-mannopyranoside 34and methyl 3,4,6-tri- O-benzyl-a-
D-glucopyranoside 35
ethers 6 (70mg, 0.14mmol), dissolved in 1,2-dichloro-
ethane (1mL), were added. N-Iodosuccinimide (96mg,
0.43mmol) was added and the solution immediately
cooled to À40ꢁC. The solution was warmed to room
temperature over 3h, after which time dichloromethane
(20mL) was added, the solution filtered through Celiteꢂ,
washed with sodium thiosulfate (10mL of a 10% aque-
ous solution), dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash column
chromatography (petrol–ethyl acetate, 5:1, with 1%
added triethylamine) gave mixed acetals 36 as a
clear oil, an inseparable mixture of diastereomers
N-Iodosuccinimide (170mg, 0.76mmol), silver trifluoro-
methanesulfonate (39mg, 0.15mmol) and 2,6-di-tert-
butyl-4-methyl-pyridine (112mg, 0.55mmol) were added
to benzyl manno mixed acetal 33 (62mg, 0.08mmol),
methyl gluco mixed acetal 32 (57mg, 0.08mmol) and
˚
molecular sieves (powdered, 4A, ca. 500mg) in 1,2-
dichloroethane (10mL). This mixture was stirred at
50ꢁC for 2h, after which time, TLC (petrol–ethyl ace-
tate, 5:1) showed no remaining starting materials (Rf
0.85 and 0.75) and the formation of several more polar
products. The mixture was allowed to cool to room tem-
perature before the addition of dichloromethane
(100mL) and filtration through Celiteꢂ. The mixture
was washed with sodium thiosulfate (50mL of a 10%
aqueous solution), dried over MgSO4, filtered and con-
centrated in vacuo. A mixture of trifluoroacetic acid
(4mL), methanol (2mL), tetrahydrofuran (2mL),
dichloromethane (4mL) and water (1mL) was added.
After stirring at room temperature for 2h, dichloro-
methane (20mL) and sodium bicarbonate (50mL of a
saturated aqueous solution) were added and the mixture
stirred for 30min before the addition of additional
dichloromethane (40mL) and separation. The organic
phase was washed with sodium bicarbonate (100mL of
a saturated aqueous solution) and the combined aque-
ous layers re-extracted with dichloromethane (50mL).
The combined organic extracts were washed with so-
dium thiosulfate (50mL of a 10% aqueous solution),
dried over MgSO4, filtered and concentrated in vacuo.
Partial purification by flash column chromatography
(petrol–ethyl acetate, 5:2 ! 2:1) gave benzyl b-manno-
(91mg, 88%); m/z (ES+) 749 (M + Na+, 35), 748 (100),
+
747 (80), 743 (M + NH4
,
30). (HRMS (ES+)
Calcd for C37H44FINO6 (MNH4+) 744.2197. Found
744.2195).
4.21. Crossover experiment 2. Benzyl 3,4,6-tri-O-benzyl-
b-D-mannopyranoside 34and methyl 3,4,6-tri- O-benzyl-a-
D-glucopyranoside 35
˚
Molecular sieves (4A) were suspended in anhydrous
dichloroethane (1mL) in a flame-dried flask under Ar.
2,6-Di-tert-butyl-4-methylpyridine (55mg, 0.27mmol),
silver trifluoromethanesulfonate (69mg, 0.27mmol)
and anhydrous tin(II) chloride (51mg, 0.27mmol) were
added. Methyl gluco mixed acetal 37 (45mg,
0.069mmol) and benzyl manno mixed acetal 36 (47mg,
0.065mmol) were dissolved in anhydrous dichloro-
ethane (7mL) and added via cannula under Ar. The
reaction mixture was then stirred at 50ꢁC. After 5h,
TLC (petrol–ethyl acetate, 2:1) indicated the absence
of any starting materials (Rf 0.7 and 0.6) and the forma-
tion of two major products (Rf 0.2 and 0.3). The reac-
side 34 as a clear, colourless oil (23mg, 56%);
tion was quenched with NaHCO3 (10mL of a
25
½aŠ ¼ À40:7 (c 0.7, CHCl3) [lit.12b À50 (c 1.3, CHCl3)];
saturated aqueous solution) and stirred for a further
10min. The mixture was filtered through Celiteꢂ, diluted
with CH2Cl2 (100mL) and washed with brine (50mL).
D
dH (500MHz, CDCl3) 2.48 (1H, br s, OH-2), 3.42–3.45
(1H, m, H-5), 3.55 (1H, dd, J2,3 2.9Hz, J3,4 8.9Hz,

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3219
The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash
3.69, 3.71 (3H, 3 · s, OCH3), 3.68–3.75 (1H, m, H-
6Man), 3.78–3.94, 4.00–4.34 (10H, 2 · m, H-2Man, H-
column
chromatography
(petrol–ethyl
acetate,
3Man, H-4Man, H-60Man, H-3Glc, H-4Glc, H-5Glc, H-6Glc
,
5:2 ! 2:1) to afford benzyl b-mannoside 34 (21mg,
60%) as a colourless oil and methyl a-glucoside 35
(19mg, 59%) as white crystals, both identical to those
described above. No trace of crossover products was ob-
H-60Glc, CHI), 4.40–4.96 (10H, m, H-2Glc, CHCHICH3,
4 · PhCH2), 5.55, 5.74, 5.80 (1H, 3 · d, J1,2 1.5, 1.0,
1.0Hz, H-1Man), 5.57, 5.62, 5.69 (1H, 3 · d, J1,2 8.5Hz,
H-1Glc), 6.67–6.99 (4H, m, 4 · Ar-H), 7.06–7.10 (6H,
m, 6 · Ar-H), 7.20–7.42 (18H, m, 18 · Ar-H), 7.70–
8.00 (4H, br, 4 · Ar-H); dC (100.6MHz, CDCl3) 21.0,
21.1, 21.1 (3 · q, ArCH3), 22.2, 23.8, 23.9 (3 · q,
CHCH3), 25.0, 26.0 (2 · d, CHI), 55.3, 55.5, 55.5
(3 · d/q, C-2Glc, OCH3), 61.9 (t, C-6Glc), 68.8 (t, C-
6Man), 71.5, 73.3, 74.0, 74.3, 75.2, 75.3 (5 · t,
4 · PhCH2), 72.3, 72.3, 72.6, 72.8, 74.5, 74.7, 76.7,
1
served by H NMR or TLC.
4.22. 3,4,6-Tri-O-benzyl-2-O-(2-iodo-1-(methyl 2,3-di-O-
benzyl-a-D-glucopyranosid-6-O-yl)propyl)-a-D-mannopy-
ranosyl fluoride 39
˚
N-Iodosuccinimide (206mg, 0.92mmol) and 4A molecu-
lar sieves were added to anhydrous dichloroethane
(2mL) and cooled to À40ꢁC under Ar. Diol 3835
(228mg, 0.61mmol) was dissolved in anhydrous dichlo-
roethane (2mL) and added to the reaction vessel by
cannula under Ar. Enol ethers 6 (150mg, 0.30mmol)
were dissolved in anhydrous dichloroethane (2mL)
and added to the reaction vessel by cannula under Ar.
The reaction was stirred in the dark and allowed to
warm to room temperature. After 19h, TLC (petrol–
ethyl acetate, 2:1) indicated the formation of a product
(Rf 0.5) and the complete consumption of the enol ether
(Rf 0.8). The reaction was quenched with 10% aqueous
sodium thiosulfate (30mL) and then extracted with
CH2Cl2 (2 · 30mL). The combined organic extracts
were dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by flash column chro-
matography (petrol–ethyl acetate, 3:1) to afford mixed
acetals 39 (220mg, 73%) as a colourless oil; m/z (APCI+)
77.0, 77.2, 77.3, 78.1, 78.6, 80.0, 80.3 (14 · d, C-2Man
,
C-3Man, C-4Man, C-5Man, C-3Glc, C-4Glc, C-5Glc), 87.2,
87.8 (2 · d, C-1Man), 97.8, 98.0 (2 · d, C-1Glc), 105.5,
105.9 (2 · d, CHCHICH3), 114.3, 114.3, 114.3, 118.9,
119.1, 119.2, 123.4, 127.3, 127.3, 127.5, 127.7, 127.8,
127.8, 127.9, 127.9, 127.9, 128.0, 128.0, 128.1, 128.1,
128.1, 128.2, 128.2, 128.3, 128.4, 128.4, 128.5, 129.9,
130.0, 130.1, 130.1, 131.4, 131.8, 132.8, 133.8 (35 · d,
Ar-CH), 137.7, 137.8, 137.9, 138.2, 138.3, 138.4 (6 · s,
Ar-C), 150.8, 155.3, 155.4 (3 · s, C@O); m/z (ES+)
1251 (50), 1250 (M + Na+, 62), 1247 (35), 1246 (68),
+
1245
(M + NH4
,
100).
(Isotope
distribution
M + NH4+: first isotopic peak m/z 1245.42 (100), second
isotopic peak m/z 1246.44 (81), third isotopic peak m/z
1247.44 (35), fourth isotopic peak m/z 1248.44 (13).
Calcd for C65H70IN2O13S: first isotopic peak m/z
1245.36 (100), second isotopic peak m/z 1246.37 (68),
third isotopic peak m/z 1247.37 (35), fourth isotopic
peak m/z 1248.37 (12)). Other products (63mg,
39%) were identified as succinimide-containing mixed
acetals.
1048 (M+56, 60), 1010 (M + NH4+, 22). (HRMS Calcd
+
for C51H62NO11IF (MNH4
1010.3362).
)
1010.3352. Found
4.23. para-Tolyl 3,4,6-tri-O-benzyl-2-O-(2-iodo-1-(para-
methoxyphenyl 3-O-benzyl-2-deoxy-2-phthalimido-b-D-
glucopyranosid-6-O-yl)-propyl)-1-thio-a-D-mannopyrano-
side 41
4.24. Methyl 3,4,6-tri-O-benzyl-b-D-mannopyranosyl-
(1!6)-2,3-di-O-benzyl-a-D-glucopyranoside 42 and
methyl 3,4,6-tri-O-benzyl-a-D-mannopyranosyl-(1!4)-
2,3-di-O-benzyl-a-D-glucopyranoside 43
˚
Molecular sieves (4A) were suspended in anhydrous
Diol 40 (101mg, 0.20mmol) and enol ethers 10 (116mg,
0.19mmol) were dissolved in 1,2-dichloroethane (5mL)
dichloroethane (1mL) in a flame-dried flask under Ar.
2,6-Di-tert-butyl-4-methylpyridine (67mg, 0.33mmol),
silver trifluoromethanesulfonate (84mg, 0.33mmol)
and anhydrous tin(II) chloride (62mg, 0.33mmol) were
added. Mixed acetals 39 (162mg, 0.16mmol) were dis-
solved in anhydrous dichloroethane (4mL) and added
by cannula under Ar and the reaction mixture stirred
at 50ꢁC. After 22h, TLC (petrol–ethyl acetate, 3:1)
showed the absence of any starting material (Rf 0.2)
and the formation of two major products (Rf 0.3 and
0.1). The reaction mixture was diluted with ether
(50mL), filtered through Celite and washed with NaH-
CO3 (30mL of a saturated aqueous solution). The
organic layer was dried over MgSO4, filtered and con-
centrated in vacuo. The residue was then dissolved in
THF/TFA/methanol/water (2:5:1:2, 2.5mL) and stirred
at room temperature. After 72h, TLC (petrol–ethyl ace-
tate, 1:2) indicated the formation of two products (Rf
0.6, 0.7) and little remaining starting material (Rf 0.8).
The reaction mixture was concentrated in vacuo. The
residue was purified by flash column chromatography
˚
with molecular sieves (powdered, 4A, ca. 250mg). N-
Iodosuccinimide (110mg, 0.49mmol) was added and
the resulting mixture cooled immediately to À78ꢁC.
The solution was allowed to return to room temperature
over 17h, after which time, TLC (petrol–ethyl acetate,
3:1) showed no remaining starting material (Rf 0.8)
and the formation of several products. Dichloromethane
(50mL) was added and the solution filtered through Cel-
iteꢂ, washed with sodium thiosulfate (50mL of a 10%
aqueous solution), dried over MgSO4, filtered and con-
centrated in vacuo. Purification by flash column chro-
matography (petrol–ethyl acetate, 4:1 ! 3:1) gave
mixed acetals 41 as a clear oil, an inseparable mixture
of diastereomers (143mg, 60%; three major diastereo-
mers, ratio 1:1.5:5); Rf 0.35 (petrol–ethyl acetate, 2:1);
mmax (thin film) 1714 and 1776 (s and w, 2 · imide
C@O) cmÀ1; dH (400MHz, CDCl3) 1.83, 1.87, 1.90
(3H, 3 · d, J 7.0Hz, CHCH3), 2.24, 2.28, 2.33 (3H,
3 · s, ArCH3), 3.22, 3.32, 3.37 (1H, 3 · d, J4,OH 4.5Hz,
4.0Hz, 3.0Hz, OH), 3.53–3.58 (1H, m, H-5Man), 3.62,

3220
I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
(petrol–ethyl acetate, 1:1) to afford a(1!4) disaccharide
(c 0.45, CHCl3); mmax 3451 (br, OH) cmÀ1; dH (500MHz,
CDCl3) 2.09 (1H, br s, OH-2), 3.37 (1H, br s, OH-6),
(Rf 0.55, 0.45). The mixture was allowed to cool to room
temperature and then dichloromethane (50mL) added
and the solution filtered through Celiteꢂ, washed with
sodium thiosulfate (50mL of a 10% aqueous solution),
dried over MgSO4, filtered and concentrated in vacuo.
The crude mixture was treated with trifluoroacetic acid,
tetrahydrofuran, methanol and water (5:2:2:1, 6mL)
for 5days. After this time, sodium bicarbonate (20mL
of a saturated aqueous solution) was added and the mix-
ture extracted with dichloromethane (50mL). The organ-
ic layer was washed with sodium bicarbonate (50mL of a
saturated aqueous solution) and brine (50mL), dried
over MgSO4, filtered and concentrated in vacuo. Purifi-
cation by flash column chromatography (petrol–ethyl
acetate, 2:3) gave b(1!6) disaccharide 44 as a clear oil
24
43 (13mg, 12%) as a colourless oil; ½aŠ ¼ þ33:1
D
0
3.38 (3H, s, OCH3), 3.48 (1H, dd, J5,6 8.1Hz, J6,6
9.9Hz, H-6b), 3.52–3.57 (2H, m, H-2a, H-5a), 3.57
(1H, dd, J3,4 8.7Hz, J4,5 9.5Hz, H-4b), 3.65–3.70 (2H,
m, H-6a, H-60b), 3.75 (1H, dd, J2,3 3.2Hz, H-3b), 3.77–
3.78 (1H, m, H-2b), 3.80–3.85 (1H, m, H-5b), 3.87–3.92
(3H, m, H-3a, H-4a, H-60a), 4.45, 4.78 (2H, ABq, JAB
11.0Hz, PhCH2), 4.54 (2H, s, PhCH2), 4.58 (1H, d,
J1,2 3.7Hz, H-1a), 4.59, 4.63 (2H, ABq, JAB 11.7Hz,
PhCH2), 4.63, 4.75 (2H, ABq, JAB 12.2Hz, PhCH2),
4.63, 5.01 (2H, ABq, JAB 11.0Hz, PhCH2), 5.37 (1H,
d, J1,2 1.5Hz, H-1b), 7.14–7.38 (25H, m, Ar-H); dC
(125.7MHz, CDCl3) 55.1 (q, OCH3), 60.2 (t, C-6a),
68.6 (d, C-2b), 69.1 (t, C-6b), 70.4 (d, C-5a), 72.0, 73.2,
73.4, 74.9, 75.5 (5 · t, 5 · PhCH2), 72.2 (d, C-5b), 74.3
(d, C-4b), 74.8 (d, C-4a), 79.8, 79.9 (2 · d, C-2a, C-3b),
(16mg, 16%); Rf 0.1 (petrol–ethyl acetate, 1:1);
22
½aŠ ¼ þ21:2 (c 0.33, CHCl3); mmax (thin film) 1714 and
D
1774 (s and w, 2 · imide C@O), 3433 (br, OH) cmÀ1
;
dH (500MHz, CDCl3) 3.18 (1H, d, J4,OH 6.5Hz, OH),
1
0
3.48 (1H, ddd, J4,5 9.5Hz, J5,6 5.0Hz, J5,6 2.0Hz, H-
5Man), 3.54 (1H, dd, J2,3 3.0Hz, J3,4 9.0Hz, H-3Man),
81.9 (d, C-3a), 97.9 (d, JC-1, H-1 166.4Hz, C-1a), 101.1
1
(d, JC-1, H-1 172.5Hz, C-1b), 127.5, 127.7, 127.7, 127.8,
127.9, 128.0, 128.0, 128.1, 128.3, 128.3, 128.4 (11 · d,
Ar-CH), 137.2, 137.7, 137.7, 137.8, 138.4 (5 · s, Ar-C);
m/z (ES+) 829 (M + Na+, 70), 824 (M + NH4+, 100)
(HRMS Calcd for C48H58NO11 (MNH4+) 824.4010.
3.70 (3H, s, OCH3), 3.72–3.88 (5H, m, H-6ManH-6M0 an
,
H-4Glc, H-5Glc, H-6Glc), 3.91 (1H, at, H-4Man), 3.99
0
0
0
(1H, dd, J5,6 6.0Hz, J6,6 11.0Hz, H-6Glc), 4.15 (1H, d,
H-2Man), 4.26–4.38 (2H, m, H-2Glc, H-3Glc), 4.43–4.68
(6H, m, H-1Man, P hCH2, 3 · PhCHH0), 4.77 (1H, d, J
12.0Hz, PhCHH0), 4.80 (1H, d, J 12.0Hz, PhCHH0),
4.90 (1H, d, J 11.0Hz, PhCHH0), 5.75 (1H, d, J1,2
8.5Hz, H-1Glc), 6.70–8.00 (28H, m, 28 · Ar-H); dC
(125.7MHz, CDCl3) 55.2, 55.4 (d, q, C-2Glc, OCH3),
Found 824.4016) and b(1!6) disaccharide 426b (36mg,
24
D
29%) as
a
colourless oil; ½aŠ ¼ À3:2 (c 0.25,
CHCl3); dH (500MHz, CDCl3) 2.43 (2H, br s,
2 · OH), 3.37 (3H, s, OCH3), 3.41–3.52 (3H, m, H-2a,
H-4a, H-5b), 3.54 (1H, dd, J2,3 3.0Hz, J3,4 8.9Hz, H-
3b), 3.68–3.77 (4H, m, H-5a, H-6a, H-6b, H-60b), 3.79
(1H, at, J 9.1Hz, H-3a), 3.87 (1H, at, J 9.3Hz, H-4b),
4.11 (1H, d, H-2b), 4.13–4.16 (1H, m, H-60a), 4.48 (1H,
s, H-1b), 4.53, 4.89 (2H, ABq, JAB 10.8Hz, PhCH2),
4.55, 4.61 (2H, ABq, JAB 12.2Hz, PhCH2), 4.60 (1H,
d, J1,2 3.6Hz, H-1a), 4.66, 4.77 (2H, ABq, JAB 11.9Hz,
PhCH2), 4.67, 4.78 (2H, ABq, JAB 12.2Hz, PhCH2),
4.74, 5.02 (2H, ABq, JAB 11.4Hz, PhCH2), 7.20–7.40
(25H, m, Ar-H); dC (100.6MHz, CDCl3) 55.2 (q,
OCH3), 68.1 (d, C-2b), 68.7 (t, C-6a), 69.1 (t, C-6b),
70.0 (d, C-5a), 70.6 (d, C-4a), 71.3, 73.1, 73.4, 75.2,
75.1 (5 · t, 5 · PhCH2), 74.1 (d, C-4b), 75.1 (d, C-5b),
79.5 (d, C-2a), 81.3, 81.3 (2 · d, C-3a, C-3b), 98.0 (d,
69.3, 71.4, 73.9, 74.6, 74.9 (5 · t, C-6Glc, C-6Man
,
4 · PhCH2), 67.9, 68.9, 73.4, 74.4, 74.9, 78.7, 81.3
(7 · d, C-2Man, C-3Man, C-4Man, C-5Man, C-3Glc, C-4Glc
,
C-5Glc), 97.0 (d, 1JC1-H1 169Hz, C-1Glc), 99.9 (d, 1JC1-H1
160Hz, C-1Man), 114.3, 118.2, 123.3, 127.4, 127.6,
127.6, 127.8, 127.8, 128.0, 128.1, 128.2, 128.3, 128.4,
131.4, 133.8 (15 · d, Ar-CH), 137.6, 137.9, 137.9, 138.0
(4 · s, Ar-C), 150.5, 155.2 (2 · s, C@O); m/z (ES+) 961
+
(32), 960 (M + Na+, 51), 956 (57), 955 (M + NH4+
,
100) (HRMS (ES+) Calcd for C55H59N2O13 (MNH4
)
955.4017. Found 955.4019) and a(1!4) disaccharide 45
22
as a clear oil, (29mg, 30%); Rf 0.55 (ethyl acetate–petrol,
3:2); ½aŠ ¼ þ73:9 (c 0.7, CHCl3); mmax (thin film) 1714
D
1
1JC-1, H-1 168.9Hz, C-1a), 100.0 (d, JC-1, H-1 157.5Hz,
and 1774 (s and w, 2 · imide C@O), 3474 (br, OH)
cmÀ1; dH (400MHz, CDCl3) 3.12 (1H, at, J 6.5Hz,
OH), 3.52–3.55 (1H, m, H-4Glc), 3.60 (1H, dd, J5,6
6.5Hz, J06;6 10.0Hz, H-6Man), 3.68–3.98 (8H, m, H-
C-1b), 127.5, 127.7, 127.8, 127.8, 127.9, 128.0, 128.0,
128.1, 128.3, 128.3, 128.4, 128.5, 128.6 (13 · d, Ar-
CH), 137.8, 137.9, 138.1, 138.7 (4 · s, Ar-C).
2Man, H-3Man, H-4Man, H-5Man, H-60Man, H-5Glc, H-6Glc
,
4.25. para-Methoxyphenyl 3,4,6-tri-O-benzyl-a-D-manno-
pyranosyl-(1!4)-3-O-benzyl-2-deoxy-2-phthalimido-b-D-
glucopyranoside 45 and para-methoxyphenyl 3,4,6-tri-O-
benzyl-b-D-mannopyranosyl-(1!6)-3-O-benzyl-2-deoxy-
2-phthalimido-b-D-glucopyranoside 44
H-60Glc), 3.71 (3H, s, OCH3), 4.09–4.13 (1H, m, H-3Glc),
4.30, 4.69 (2H, ABq, JAB 12.0Hz, PhCH2), 4.45–4.46
(1H, m, H-2Glc), 4.48, 4.80 (2H, ABq, JAB 11.0Hz,
PhCH2), 4.56, 4.61 (2H, ABq, JAB 12.0Hz, PhCH2),
4.63, 4.69 (2H, ABq, JAB 11.5Hz, PhCH2), 5.37 (1H, d,
J1,2 2.0Hz, H-1Man), 5.61 (1H, d, J1,2 8.5Hz, H-1Glc),
6.68–7.90 (28H, m, 28 · Ar-H); dC (100.6MHz, CDCl3)
55.6, 55.7 (d, q, C-2Glc, OCH3), 68.5, 72.3, 73.5, 75.4
(4 · t, C-6Glc, C-6Man, 4 · PhCH2), 69.0, 72.5, 75.1,
79.8, 80.9 (5 · d, C-2Man, C-3Man, C-4Man, C-5Man, C-
Mixed acetals 41 (127mg, 0.10mmol) were dissolved in
1,2-dichloroethane (10mL) with molecular sieves (pow-
˚
dered, 4A, ca. 500mg). 2,6-Di-tert-butyl-4-methylpyr-
idine (54mg, 0.26mmol), N-iodosuccinimide (58mg,
0.25mmol) and silver trifluoromethanesulfonate (29mg,
0.11mmol) were added and the resulting mixture heated
to 50ꢁC. After 2days, TLC (petrol–ethyl acetate, 1:1)
showed material coincident with the starting material
(Rf 0.65) and the formation of two other major products
1
3Glc, C-4Glc, C-5Glc), 97.5 (d, JC1-H1 167Hz, C-1Glc),
1
101.2 (d, JC1-H1 173Hz, C-1Man), 114.4, 118.8,
127.5, 127.6, 127.8, 127.9, 128.1, 128.2, 128.4, 128.6,
137.6 (11 · d, Ar-CH) 150.8 (s, C@O). (HRMS (ES+)
C55H59N2O13 (MNH4+) 955.4017. Found 955.4025).

I. Cumpstey et al. / Tetrahedron: Asymmetry 15 (2004) 3207–3221
3221
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We gratefully acknowledge financial support from the
EPSRC (Quota Awards to I.C. and C.M.P.S.) and from
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