Propargyl mediated intramolecular aglycon delivery (IAD): applications to the synthesis of core N-glycan oligosaccharides

Article abstract of DOI:10.1016/j.tetasy.2007.06.026

The use of propargyl mediated intramolecular aglycon delivery (IAD) for the synthesis of the key Manβ(1→4)GlcNAc linkage of N-glycan oligosaccharides, including the core N-glycan pentasaccharide, is investigated. Isomerisation of a 2-O-progargyl group of

Full text of DOI:10.1016/j.tetasy.2007.06.026

Tetrahedron: Asymmetry 18 (2007) 1721–1734
Propargyl mediated intramolecular aglycon delivery (IAD):
applications to the synthesis of core N-glycan oligosaccharides
Emanuele Attolino, Thomas W. D. F. Rising, Christoph D. Heidecke
and Antony J. Fairbanks*
Chemistry Research Laboratory, Oxford University, Mansfield Road, Oxford OX1 3TA, UK
Received 19 June 2007; accepted 28 June 2007
Available online 25 July 2007
Abstract—The use of propargyl mediated intramolecular aglycon delivery (IAD) for the synthesis of the key Manb(1!4)GlcNAc linkage
of N-glycan oligosaccharides, including the core N-glycan pentasaccharide, is investigated. Isomerisation of a 2-O-progargyl group of
manno thioglycoside donors to an allene is followed by iodonium ion mediated mixed acetal formation with the 4-OH of protected Glc-
NAc acceptors, and subsequent intramolecular glycosylation occurs with complete control of anomeric stereochemistry to form the
Manb(1!4)GlcNAc linkage. A variety of linear and convergent approaches (1+2, 3+1, 3+2) to the core pentasaccharide are investigated
as means of probing the generality and limitations of this type of intramolecular aglycon delivery for the formation of b-mannoside link-
ages in complex oligosaccharides.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the formation of b-mannosides and cannot be applied sim-
ilarly for the synthesis of other 1,2-cis glycosidic linkages.
The current situation is therefore one in which there is still
no generally applicable method available for the formation
of all 1,2-cis glycosidic bonds.3
The control of anomeric stereochemistry during the course
of a glycosylation reaction is a key consideration during the
synthesis of any oligosaccharide. Whilst much work has
been done to facilitate the speed of assembly of oligosac-
charide structures, the issue of absolute control of ano-
meric stereochemistry still remains unanswered. Whilst
1,2-trans glycosidic linkages can usually be synthesised
with high levels of stereocontrol by taking advantage of
the neighbouring group participation of 2-O-acyl pro-
tected glycosyl donors,1 the synthesis of 1,2-cis glycosidic
linkages is considerably more difficult. One of the early
focuses for synthetic development was construction of the
difficult to synthesise b-mannoside linkage, which appears
in all N-glycan oligosaccharides as the somewhat notorious
Manb(1!4)GlcAc disaccharide. Considerable effort has
since led to the development of several elegant approaches
to the construction of b-mannosides,2 and a selection of
these methods have been applied to the synthesis of the
Manb(1!4)GlcAc disaccharide and larger N-glycan oligo-
saccharides, which are generally the most difficult b-
mannosides to make. However, the majority of these
approaches, efficient as some of them are, are limited to
Conceptually a potentially elegant solution to this ongoing
‘1,2-cis glycoside problem’ is to apply the technique of
intramolecular aglycon delivery, or IAD, which is a partic-
ular type of intramolecular glycosylation strategy,4
wherein the glycosyl acceptor is temporarily appended to
the 2-hydroxyl group of a glycosyl donor through a short
linker. The first so-called ‘tethering’ step, that is, the linking
of donor and acceptor, is followed by the activation of the
glycosyl donor, which subsequently furnishes the 1,2-cis
glycoside in a completely stereoselective fashion. The two
key advantages of the IAD approach over other intra-
molecular glycosylation reactions in which the donor and
acceptor are either connected by other hydroxyl groups,
through longer linkers, or other remote positions, are the
predictability and strict control of the anomeric stereo-
chemistry of the product. However, even when using the
IAD approach, one has to be careful to avoid problems
of regiochemical control, that is, to ensure that only the de-
sired hydroxyl is glycosylated,5 and also to avoid the use of
slightly longer linkers, which can lead to undesired non-
stereoselective reactions.6
*
Corresponding author. E-mail: antony.fairbanks@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.026

1722
E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
Amongst several of the IAD methodologies that have been
reported,7–9 the approach developed by Ogawa, based on
the use of 2-O-para-methoxybenzyl (PMB) protected glycos-
yl donors,10 is the only methodology that has been really
successfully applied to the synthesis of complex targets,
such as the core N-glycan pentasaccharide. This pentasac-
charide, which contains the crucial Manb(1!4)GlcNAc
linkage, can be considered a benchmark test for potential
widespread utility of any 1,2-cis glycosylation procedure.
Although the Ogawa approach has also been applied to
the synthesis of a selection of other 1,2-cis glycosides, with
varying degrees of success11 it is notable that for whatever
reason, it has not yet found routine applicability.
mixed acetal formation with an acceptor alcohol, and sub-
sequent intramolecular glycosylation with complete control
of stereochemistry. An envisaged advantage of the propar-
gyl based approach over the allyl based methodology was
that the oxonium ion produced subsequent to glycosylation
would be stabilised by conjugation with the side chain
alkene; a factor which may facilitate aglycon delivery,
which had been the least efficient step in the allyl approach
particularly when using disarmed glycosyl donors.
In order to demonstrate the applicability of this approach
propargyl ether 3 was synthesised by the regioselective
silylation of the known diol 110b to yield alcohol 2, which
then underwent subsequent etherification using propargyl
bromide and sodium hydride in DMF to give propargyl
ether 3. Isomerisation by treatment with tert-butoxide19 in
ether then yielded the desired intermediate allene 4. Iodo-
nium ion mediated mixed acetal formation with the known
glucosamine acceptor 510d gave mixed acetals 6 in an excel-
lent 88% yield. Subsequent intramolecular glycosylation,
using a Me2S2/Tf2O mixture, as reported originally by
We recently reported the development of an allyl protect-
ing group mediated IAD approach (allyl IAD),12 based
on either thioglycoside13 or glycosyl fluoride donors.14 This
methodology relied on iodonium ion mediated formation
of a mixed acetal between a glycosyl acceptor alcohol
and an enol ether, itself derived from a 2-O-allyl protected
glycosyl donor by Wilkinson’s catalyst mediated isomerisa-
tion15 of the double bond. However the attempted applica-
tion of this methodology to the synthesis of complex
oligosaccharides, such as the core N-glycan pentasaccha-
ride, met with frustration. With the reasoning that an
increase in stability of the oxonium ion produced subse-
quent to the intramolecular glycosylation step would facil-
itate the glycosylation process the use of 2-O-propargyl
ethers for a similar intramolecular glycosylation strategy
was therefore investigated, and this applied to the synthesis
of the key Manb(1!4)GlcNAc disaccharide.16 Following
on from these initial studies, it was decided to investigate
the potential scope of the propargyl IAD methodology
by attempting the synthesis of core N-glycan oligosaccha-
rides in a more convergent manner, using di- and tri-sac-
charides as the donor and acceptor components for the
IAD reaction sequence. In this respect previous reports
from Hindsgaul7c have highlighted the potential limitations
of IAD reactions using donors and acceptors, which are
larger than monosaccharides, whilst in contrast the PMB
based approach of Ogawa has been reported10 to be appli-
cable to more convergent oligosaccharide syntheses, and
our own previous studies17 on allyl IAD had demonstrated
the iterative use of IAD sequences for the construction
of tri- and tetrasaccharides in which the acceptors were
di- or tri-saccharides. Herein we report full details of inves-
tigations into the use of propargyl IAD for the synthesis of
N-glycan oligosaccharides, including the core N-glycan
pentasaccharide, both by linear and convergent approaches
and highlights potential limitations of the use of IAD for
such highly convergent syntheses.
Fugedi,20 together with added di-tert butylmethylpyridine
¨
(DTBMP) which was found to further improve efficiency
of glycosylation, proceeded smoothly to give the desired
Manb(1!4)GlcNAc disaccharide 7a10d in an excellent
81% yield, with complete stereocontrol (Scheme 1). Depro-
tection of the silyl group of 7a with TBAF gave diol 7b,
which was then glycosylated regioselectively at the 3-posi-
tion with the known trichloroacetimidate donor 8,21 to give
a trisaccharide, which was immediately acetylated to give
9a. Removal of the 4,6-benzylidene protection to yield tri-
saccharide diol 9b proved problematic. Simple treatment
with aqueous acetic acid invariably resulted in formation
of small quantities of the 6-O-acetate as a side product.
An optimised procedure was therefore developed involving
treatment with trifluoroacetic acid in aqueous acetonitrile.
In this case although some of the corresponding 6-O-triflu-
oroacetate was formed initially; this material was readily
hydrolysed upon work-up, yielding diol 9b in 90% yield.
A second regioselective glycosylation reaction with donor
821 then smoothly gave tetrasaccharide 10a. Removal of
the acetates from 10a with anhydrous potassium carbonate
in methanol also unfortunately resulted in partial cleavage
of the phthalamido protection, and necessitated a re-closure
procedure involving treatment of the crude reaction prod-
uct, firstly with acetic anhydride in methanol and, following
concentration, with tosic acid in DMF to yield triol 10b.
Benzylation of 10b was achieved with sodium hydride and
benzyl bromide to produce fully protected tetrasaccharide
10c. Removal of the anomeric PMP protecting group with
ceric ammonium nitrate gave hemiacetals 10d, which were
then converted to the corresponding trichloroacetimidate
10e, before final glycosylation with acceptor 5 to yield the
desired pentasaccharide 11 (Scheme 1).
2. Results and discussion
As reported previously, the propargyl IAD approach firstly
requires the synthesis of glycosyl donors bearing a propar-
gyl ether at the 2-position, which can then undergo base-
mediated isomerisation to allow access to 2-O-allenyl
protected carbohydrates.18 Such allenes can then undergo
a similar sequence as had previously been applied as the
basis of the allyl IAD—namely, iodonium ion catalysed
This sequence represents a completely linear approach to
the core N-glycan pentasaccharide in which the IAD reac-
tion is performed as the first glycosylation reaction.
Clearly, a more convergent synthesis would be consider-
ably more efficient, and such possibilities were investigated
next. The most convergent reaction sequence would be a
[3+2] approach in which the difficult b-manno linkage

E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
1723
C
O
OH
O
OH
O
O
Ph
O
Ph
O
Ph
O
Ph
O
a)
b)
c)
O
O
O
O
O
O
TBDPSO
HO
TBDPSO
TBDPSO
SMe
4
1
2
3
SMe
SMe
SMe
d)
+
I
OBn
O
OBn
O
OBn
O
HO
BnO
OH
Ph
O
O
O
OPMP
PhthN
O
Ph
O
O
e)
O
OPMP
BnO
O
O
RO
OPMP
BnO
TBDPSO
PhthN
5
PhthN
SMe
6
7a R=TBDPS
7b R=H
f)
OBn
BnO
BnO
BnO
OAc
O
O
BnO
BnO
BnO
OBn
O
NH
CCl3
O
BnO
O
OR1
O
BnO
BnO
O
PhthN
g),h)
BnO
BnO
O
8
O
5, o)
O
O
OPMP
BnO
BnO
BnO
OBn
OBn
OR1
O
PhthN
O
O
BnO
O
R2O
OR2
O
R1O
8, j)
OR3
OBn
O
BnO
O
R1O
BnO
OBn
OBn
11
O
O
PhthN
OPMP
O
BnO
OBn
OBn
O
OBn
PhthN
O
OBn
OR1
OBn
OAc
10a R1= Ac, R2=H, R3=PMP
10b R1= H, R2=H, R3=PMP
10c R1= R2=Bn, R3=PMP
10d R1= R2=Bn, R3=OH
k)
l)
9a R1= benzylidene, R2=Ac
9b R1= H, R2=Ac
i)
m)
n)
10e R1= R2=Bn, R3=OC(NH)CCl3
Scheme 1. Reagents and conditions: (a) tBuPh2SiCl, imidazole, CH2Cl2, rt, 84%; (b) propargyl bromide, NaH, DMF, rt, 72%; (c) tBuOK, Et2O, 66%; (d)
5, I2, AgOTf, DTBMP, CH2Cl2, ꢀ78 ꢁC to rt, 88%; (e) Me2S2, Tf2O, DTBMP, CH2Cl2, 0 ꢁC to rt, 81%; (f) TBAF, THF, rt, 60%; (g) 8, TMSOTf, CH2Cl2,
ꢀ78 ꢁC to rt; (h) Ac2O, pyridine, rt, 86% over two steps; (i) 10% TFA in 10:1 MeCN–H2O, 90%; (j) 8, TMSOTf, CH2Cl2, ꢀ78 ꢁC to rt, 76%; (k) K2CO3,
MeOH, rt; (l) NaH, BnBr, DMF, rt, 77% over two steps; (m) (NH4)2Ce(NO3)6, toluene, MeCN, H2O, rt, 77%; (n) Cl3CCN, DBU, CH2Cl2, rt, 96%; (o) 5,
TMSOTf, CH2Cl2, ꢀ78 ꢁC to rt, 85%.
was made as the final step by glycosylation of a tri-man-
nose donor with a chitobiose acceptor. The synthesis of
the required tri-mannose donor was therefore undertaken
as shown in Scheme 2. Regioselective propargylation of
diol 1 was achieved using phase transfer conditions to give
propargyl ether 12, which was then glycosylated with
trichloroacetimidate donor 821 to yield disaccharide 13a.
Removal of the 4,6-benzylidene protection then yielded
diol 13b, which was regioselectively glycosylated22 at the
6-position using the same donor 8, to give trisaccharide
14a. A protecting group exchange then allowed formation
of the perbenzylated donor 14b, which was finally isomer-
ised to the required allene 15 by treatment with potassium
tert-butoxide in DMSO (Scheme 2).
in good yield to provide intermediates 18a (Table 1, entry
2). However, the intramolecular glycosylation step did not
work well at all and resulted in the formation of a complex
mixture of products, from which the desired trisaccharide
18b could only be isolated in pure form in a very poor yield
(<10%). Finally, the most ambitious and most convergent
[3+2] approach was attempted (Table 1, entry 3). Once
O
RO
O
O
RO
OH
O
8, b)
Ph
O
a)
Ph
O
O
O
O
O
HO
HO
SMe
BnO
BnO
12
SMe
1
O
OAc
SMe
BnO
13a R=benzylidene
13b R=H
c)
With trisaccharide allene 15 in hand, the efficiency of
various possible convergent approaches was investigated
(Table 1). Firstly a [1+2] IAD sequence was investigated
using the monosaccharide allene 4 as donor, and the known
chitobiose derivative 16 as acceptor. Iodonium ion medi-
ated mixed acetal formation proceeded to give mixed acetals
17a in good yield (Table 1, entry 1). However intramolecu-
lar glycosylation using the Fugedi conditions did not work
¨
as well as for the previous glycosylation of 6, while trisac-
charide 17b was only produced in a modest 32% yield.
8, d)
OR1
O
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
g)
O
O
O
C
O
O
O
R2O
BnO
O
O
SMe
SMe
BnO
BnO
BnO
BnO
BnO
BnO
O
O
OBn
OR1
14a R1=Ac, R2=H
14b R1=R2=Bn
15
e), f)
Scheme 2. Reagents and conditions: (a) Bu4NHSO4, propargyl bromide,
CH2Cl2, 5% aqueous NaOH, rt, 60%; (b) 8, TMSOTf, CH2Cl2, ꢀ78 ꢁC to
rt; (c) CF3CO2H, CH3CN–H2O, 10:1, 78% over two steps; (d) 8, TMSOTf,
CH2Cl2, ꢀ78 ꢁC to rt, 77%; (e) K2CO3, MeOH, rt; (f) NaH, BnBr, DMF,
The next sequence investigated was a [3+1] IAD approach
using trisaccharide allene 15 as the donor, and monosaccha-
ride 5 as acceptor. Again mixed acetal formation proceeded
t
rt, 91% over two steps; (g) BuOK, DMSO, 65 ꢁC, 77%.

Table 1. Convergent approaches to N-glycan oligosaccharides using propargyl IAD
Entry
Allene donor
Acceptor
Mixed acetals/yield
Glycosylation product/yield
I
OBn
O
OH
O
OBn
O
Ph
OBn
O
OBn
O
C
O
OBn
O
OBn
O
O
O
HO
O
O
O
TBDPSO
BnO
OPMP
O
Ph
O
O
BnO
BnO
O
BnO
OPMP
O
1
OPMP
Ph
O
BnO
PhthN
17b
BnO
O
PhthN
O
PhthN
PhthN
O
PhthN
TBDPSO
PhthN
TBDPSO
16
SMe
17a
SMe
4
32%
70%
OBn
O
I
OBn
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
O
OBn
O
BnO
BnO
BnO
O
O
OH
O
OBn
O
O
O
C
O
OBn
O
OPMP
BnO
O
O
O
BnO
BnO
HO
PhthN
BnO
O
O
OPMP
OPMP
O
BnO
O
BnO
2
SMe
18a
BnO
BnO
BnO
PhthN
PhthN
BnO
BnO
BnO
SMe
BnO
BnO
BnO
O
OBn
O
OBn
5
O
OBn
18b
15
<5%
64%
OBn
O
I
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
OBn
O
BnO
OBn
O
BnO
BnO
O
O
OH
O
O
O
C
OBn
O
O
O
OBn
O
OBn
O
O
BnO
O
OBn
O
O
OPMP
BnO
BnO
BnO
BnO
HO
PhthN
O
O
O
PhthN
O
O
O
BnO
3
BnO
OPMP
OPMP
BnO
BnO
SMe
PhthN
BnO
BnO
BnO
PhthN
SMe
PhthN
BnO
BnO
BnO
BnO
BnO
BnO
PhthN
O
OBn
16
O
OBn
O
OBn
19b
19a
15
<5%
64%

E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
1725
again mixed acetal formation proceeded as expected to pro-
duce 19a (64% yield), but again the intramolecular glycosyl-
ation step failed to cleanly produce the desired
pentasaccharide; indeed in this case it was not possible to
isolate 19b from the complex reaction mixture, although
its presence was confirmed by mass spectrometric analysis.
meter. High resolution mass spectra were recorded on a
Walters 2790-Micromass LCT electrospray ionisation mass
spectrometer using either electrospray ionisation tech-
niques as stated. m/z values are reported in Daltons and
are followed by their percentage abundance in parentheses.
Optical rotations were measured on a Perkin–Elmer 241
polarimeter with a path length of 1 dm. Concentrations
are given in g/100 ml. Microanalyses were performed by
the Inorganic Chemistry Laboratory Elemental Analysis
service. Thin-layer chromatography (TLC) was carried
out on Merck Kieselgel 60F254 pre-coated glass-backed
plates. Visualisation of the plates was achieved using a
UV lamp (kmax = 254 or 365 nm), and/or ammonium
molybdate (5% in 2 M sulfuric acid), or sulfuric acid (5%
in ethanol). Flash column chromatography was carried
out using Sorbsil C60 40/60 silica. DCM was distilled from
calcium hydride or dried via Alumina column (post Janu-
ary 2004). Anhydrous THF, DMF, pyridine, methanol
and toluene were purchased from Fluka over molecular
sieves. Petrol refers to the fraction of light petroleum ether
boiling in the range of 40–60 ꢁC.
These somewhat disappointing results are in line with the
original findings of Hindsgaul,7c that is, that the intra-
molecular aglycon delivery approach only works well for
the construction of the Manb(1!4)GlcNAc linkage really
with monosaccharide donors and acceptors. However these
findings are in contrast with the reports of Ogawa,23 and
unfortunately it appears that, at least in our case, the use
of IAD for the synthesis of N-glycan oligosaccharides is
limited to a linear approach in which the b-mannose link-
age is formed during the first glycosylation reaction.
3. Conclusions
In conclusion, the development of propargyl mediated IAD
appears to represent a considerable improvement over the
allyl IAD approach in terms of efficiency of the intramole-
cular glycosylation step for disarmed monosaccharide
donors, and allows completion of the total synthesis of
the core N-glycan pentasaccharide, which had not been
achieved using the allyl approach. However, limitations
of the use of this methodology become apparent when
more convergent approaches to the N-glycan oligosaccha-
rides are attempted and efficient sequences are only really
achievable for the synthesis of N-glycan disaccharides.
4.2. General procedure for mixed acetal formation
˚
Molecular sieves (4 A) were suspended in freshly distilled
DCM (1 ml) in a flame-dried flask under Ar. 2,6-Di-tert-
butyl-4-methylpyridine (3 equiv), iodine (1.2 equiv) and sil-
ver triflate (1.2 equiv) were added. The mixture was stirred
for 20 min at room temperature and then cooled to
ꢀ78 ꢁC. Allenyl donor (typically ꢁ100 mg, 1 equiv) and
the acceptor alcohol (1.1 equiv) were dissolved in freshly
distilled DCM (2 ml) and were then added to the reaction
vessel by cannula under Ar. The reaction was stirred for
2 h at ꢀ78 ꢁC and then allowed to warm to room temper-
ature. After 17 h, TLC (typically petrol–ethyl acetate, 2:1)
indicated complete consumption of starting allenyl ether
and the formation of a major product. The reaction was
quenched with sodium thiosulfate (typically 5 ml of a
10% aqueous solution) and then filtered. The aqueous layer
was washed with DCM (2 · 10 ml) and the combined
organic extracts dried over MgSO4, filtered and concen-
trated in vacuo. The residue could be purified by flash
column chromatography if desired (typically petrol–ethyl
acetate, 4:1) to afford a pure sample of the mixed acetals,
in which one diastereomer was predominant and could
often be separately isolated.
4. Experimental
4.1. General
Melting points were recorded on a Kofler hot block. Pro-
ton and carbon nuclear magnetic resonance (dH, dC) spec-
tra were recorded on Bruker DPX250 (250 MHz), Bruker
DPX400 (400 MHz), Bruker AV400 (400 MHz), Bruker
AV500 (500 MHz) or Bruker DRX500 (500 MHz) spec-
trometers. All chemical shifts are quoted on the d-scale in
parts per million using a residual solvent as an internal
standard. 1H and 13C spectra were assigned using 2D
NMR experiments including COSY, NOESY, ROESY,
HSQC, HSQC ‘non-decoupled’, HSQC–TOCSY, TOCSY,
HMBC, DEPT and APT. Identical proton coupling con-
stants are averaged in each spectra and reported to the
nearest 0.1 Hz. It should be noted that measured J values
are limited by the digital resolution of 0.3 Hz per point.
Carbohydrates and derivatives have been named in accor-
dance with IUPAC recommendations and numbered
according to the carbohydrate convention. The two pro-
tons on C-6 are labelled H-6 and H-60. The individual com-
ponents of oligosaccharides are distinguished by the
assignment of a lowercase letter, given alphabetically start-
ing from the reducing terminus. Low resolution mass spec-
tra were recorded on a Micromass Platform 1 spectrometer
using electrospray ionisation in either positive or negative
polarity (ES+ or ESꢀ), or using a VG Micromass spectro-
4.3. General procedure for intramolecular glycosylation
˚
Molecular sieves (4 A) were suspended in freshly distilled
DCM (typically 1 ml) in a flame-dried flask under Ar and
2,6-di-tert-butyl-4-methylpyridine (6 equiv), dimethyldisul-
fide (5 equiv) and triflic anhydride (5 equiv) were added.
The mixture was stirred for 5 min at room temperature
and then cooled at 0 ꢁC. Mixed acetals (typically 30 mg,
1 equiv) were dissolved in freshly distilled DCM (typically
1 ml) and added to the reaction vessel by cannula under
Ar. The stirred reaction was allowed to warm to room tem-
perature. After 1 h, TLC (typically petrol–ethyl acetate,
2:1) indicated complete consumption of the starting mate-
rial and formation of a major product (typically slightly
more polar). The reaction was diluted with DCM (5 ml),

1726
E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
0
quenched with sodium bicarbonate (2 ml of a saturated
aqueous solution) and then filtered. The aqueous layer
was washed with DCM (2 · 10 ml) and the combined
organic extracts dried over MgSO4, filtered and concentrated
in vacuo. The residue was then purified by flash column
chromatography (typically petrol–ethyl acetate, 2:1).
4.12 (1H, at, J 9.7 Hz, H-4), 4.16 (1H, dd, J5,6 4.6 Hz,
J6,6 10.0 Hz, H-60), 4.26–4.30 (2H, m, H-3, CHH0C„CH),
0
4.38 (1H, dd, J 2.3 Hz, Jgem 15.8 Hz, CHH0C„CH), 5.02
(1H, s, H-1), 5.41 (1H, s, PhCH), 7.23–7.46 (11H, m,
11 · Ar-H), 7.67–7.70 (4H, m, 4 · Ar-H); dC (100.6 MHz,
CDCl3) 13.8 (q, SCH3), 19.4 (s, C(CH3)3), 26.9 (q,
C(CH3)3), 59.0 (t, CH2C„CH), 64.5 (d, C-5), 68.6 (t, C-
6), 71.0 (d, C-3), 74.9 (s, CH2C„CH), 79.0 (d, C-4), 79.5
(s, CH2C„CH), 79.9 (d, C-2), 84.9 (d, C-1), 101.8 (d,
PhCH), 126.3, 127.4, 127.7, 128.0, 128.7, 129.5, 129.8,
136.0 (8 · d, 15 · Ar-CH), 133.5, 133.6, 137.4 (3 · s,
3 · Ar-C); m/z (ES+) 664 (95), 649 (87), 575 (M+H+,
100). HRMS (ES+) calcd for C33H39O5SSi (M+H+)
575.287. Found 575.286.
4.4. Methyl 4,6-O-benzylidene-3-O-tert-butyldiphenylsilyl-1-
thio-a-D-mannopyranoside 2
Diol 110b (2.0 g, 6.70 mmol), imidazole (912 mg,
13.4 mmol) and tert-butyl (chloro)diphenylsilane (2.6 ml,
10.05 mmol) were dissolved in anhydrous DMF (30 ml).
The reaction mixture was stirred under Ar at room temper-
ature. After 14 h, TLC (petrol–ethyl acetate, 1:1) indicated
the formation of a major product (Rf 0.92) and complete
consumption of starting material (Rf 0.21). The reaction
was concentrated in vacuo, and the residue was diluted
with DCM and then washed with NaHCO3 (150 ml of a
saturated aqueous solution). The combined organic
extracts were dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by flash column chroma-
4.6. Methyl 4,6-O-benzylidene-2-O-(allenyl)-3-O-tert-butyl-
diphenylsilyl-1-thio-a-D-mannopyranoside 4
Propargyl ether 3 (878 mg, 1.53 mmol) was dissolved in
anhydrous ether (15 ml). KOtBu (515 mg, 4.59 mmol) was
added and the reaction mixture stirred at room tempera-
ture. After 3.5 h, TLC (petrol–ethyl acetate, 9:1) indicated
formation of a major product (Rf 0.40) and complete con-
sumption of starting material (Rf 0.30). The reaction was
diluted with ether (50 ml) and quenched with water
(20 ml). The two phases were separated and the organic
one washed with water (2 · 20 ml). The combined organic
extracts were dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by flash column chroma-
tography (petrol–ethyl acetate, 9:1, with 2% added triethyl-
tography (petrol–ethyl acetate, 85:15) to afford alcohol 2
17
(3.02 g, 84%) as a white amorphous foam. ½aꢂD ¼ þ115 (c
1.0, CHCl3); dH (400 MHz, CDCl3) 1.07 (9H, s,
C(CH3)3), 2.03 (3H, s, SCH3), 2.97 (1H, br s, OH), 3.65
(1H, d, J2,3 2.6 Hz, H-2), 3.84 (1H, at, J 9.6 Hz, H-6),
4.01–4.10 (2H, m, H-4, H-5), 4.14–4.21 (2H, m, H-3, H-
60), 5.16 (1H, s, H-1), 5.47 (1H, s, PhCH), 7.21–7.44
(11H, m, 11 · Ar-H), 7.62–7.67 (4H, m, 4 · Ar-H); dC
(100.6 MHz, CDCl3) 13.4 (q, SCH3), 19.2 (s, C(CH3)3),
27.0 (q, C(CH3)3), 63.7 (d, C-5), 68.6 (t, C-6), 70.9 (d, C-
3), 72.6 (d, C-2), 79.0 (d, C-4), 85.2 (d, C-1), 101.9 (d,
PhCH), 126.3, 127.5, 127.9, 128.0, 128.9, 129.7, 130.1,
135.8, 135.9 (9 · d, 15 · Ar-CH), 132.8, 132.9, 137.3
(3 · s, 3 · Ar-C); m/z (ES+) 626 (100), 554 (M+NHþ4 ,
92), 537 (M+H+, 65). HRMS (ES+) calcd for C30H37O5SSi
(M+H+) 537.2131. Found 537.2130.
amine) to afford allene 4 (577 mg, 66%) as a colourless
20
syrup. ½aꢂD ¼ þ67 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
1.05 (9H, s, C(CH3)3), 2.00 (3H, s, SCH3), 3.69 (1H, d,
J2,3 3.4 Hz, H-2), 3.82 (1H, at, J 10.1 Hz, H-6), 4.00 (1H,
adt, J 4.7 Hz, J 9.7 Hz, H-5), 4.13 (1H, at, J 9.7 Hz, H-
4), 4.16 (1H, dd, J5,6 4.7 Hz, J6,6 10.1 Hz, H-60), 4.23
(1H, dd, J3,4 9.7 Hz, H-3), 5.08 (1H, s, H-1), 5.31 (1H,
dd, J 5.9 Hz, Jgem 8.2 Hz, CH@C@CHH0), 5.42 (1H, dd,
J 6.0 Hz, CH@C@CHH0), 5.50 (1H, s, PhCH), 6.77 (1H,
0
0
4.5. Methyl 4,6-O-benzylidene-2-O-(prop-2-ynyl)-3-O-tert-
butyldiphenylsilyl-1-thio-a-D-mannopyranoside 3
at, J
5.9 Hz, CH@C@CHH0), 7.20–7.45 (11H, m,
11 · Ar-H), 7.67–7.70 (4H, m, 4 · Ar-H); dC (100.6 MHz,
CDCl3) 13.9 (q, SCH3), 19.2 (s, C(CH3)3), 26.8 (q,
C(CH3)3), 64.4 (d, C-5), 68.6 (t, C-6), 69.9 (d, C-3), 78.6
(d, C-2), 78.9 (d, C-4), 83.1 (d, C-1), 91.8 (t, CH@C@CH2),
101.8 (d, PhCH), 120.9 (d, CH@C@CH), 126.3, 127.3,
127.7, 128.0, 128.8, 129.5, 129.7, 136.0 (8 · d, 15 · Ar-
CH), 133.4, 133.7, 137.5 (3 · s, 3 · Ar-C), 200.4 (s,
CH2@C@CH); m/z (ES+) 575 (M+H+, 100). HRMS
(ES+) calcd for C33H38O5NaSSi (M+H+) 597.2107. Found
597.2115.
Alcohol 2 (2.04 g, 3.80 mmol) was dissolved in anhydrous
DMF (5 ml) and cooled to 0 ꢁC. Sodium hydride (60% in
mineral oil) (167 mg, 4.18 mmol) and propargyl bromide
(80% in toluene) (1.70 g, 11.4 mmol) were added and the
reaction mixture stirred at 0 ꢁC. After 10 min, TLC (pet-
rol–ethyl acetate, 85:15) indicated formation of a major
product (Rf 0.50) and complete consumption of starting
material (Rf 0.23). The reaction was diluted with ether
(100 ml) and quenched with NH4Cl (50 ml of a saturated
aqueous solution). The two phases were separated and
the organic one washed with water (2 · 50 ml). The com-
bined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo. The residue was purified by
flash column chromatography (petrol–ethyl acetate, 9:1)
4.7. Methyl 4,6-O-benzylidene-3-O-tert-butyldiphenylsilyl-2-
O-(2-iodo-1-(para-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-
2-phthalimido-b-D-glucopyranosid-4-O-yl)prop-2-enyl)-1-
thio-a-D-mannopyranoside 6
to afford propargyl ether 3 (1.58 g, 72%) as a white amor-
General procedure for mixed acetal formation using mole-
cular sieves (4 A), DCM (2 ml), 2,6-di-tert-butyl-4-methyl-
pyridine (89 mg, 0.435 mmol), iodine (43 mg, 0.171 mmol),
silver triflate (45 mg, 0.174 mmol), allenyl donor 4 (83 mg,
0.145 mmol) and para-methoxyphenyl 3,6-di-O-benzyl-2-
17
˚
phous foam. ½aꢂD ¼ þ122 (c 0.9, CHCl3); 3278 (stretching
C–H, C„CH). dH (400 MHz, CDCl3) 1.07 (9H, s,
C(CH3)3), 2.05 (3H, s, SCH3), 2.42 (1H, at, J 2.1 Hz,
C„CH), 3.59 (1H, d, J2,3 3.2 Hz, H-2), 3.83 (1H, at, J
10.0 Hz, H-6), 4.01 (1H, adt, J 4.8 Hz, J 9.7 Hz, H-5),
deoxy-2-phthalimido-b-D-glucopyranoside
5
(95 mg,

E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
1727
0.159), after purification by flash column chromatography
(petrol–ethyl acetate, 8:2 to 1:1), afforded a pure sample of
the major diastereomer of 6 (74 mg, 51%) and a mixture of
H); dC (125.8 MHz, CDCl3) 19.3 (s, C(CH3)3), 26.8 (q,
C(CH3)3), 55.5 (OCH3, C-2a), 66.5 (d, C-5b), 68.0 (t, C-
6b), 68.5 (t, C-6a), 71.4 (d, C-2b), 72.6 (d, C-3b), 73.4
(2 · t, 2 · PhCH2), 74.7 (C-5a, PhCH2), 78.3 (d, C-4b),
78.7 (d, C-4a), 97.7 (d, C-1a), 100.3 (d, C-1b), 101.8 (d,
PhCH), 114.3, 118.8, 123.3, 126.2, 127.1, 127.4, 127.7,
127.8, 127.9, 128.0, 128.4, 128.8, 129.7, 130.0, 132.8,
133.7, 135.6, 135.9 (33 · Ar-CH), 133.4, 134.0, 137.3,
137.7, 138.4, 150.8, 155.4 (7 · s, 9 · Ar-C), 168.9
(2 · C@O). m/z (ES+) 1354 (30), 1313 (M+NHþ4 , 100).
HRMS (ES+) calcd for C64H65NO13NaSi (M+Na+)
1106.4117. Found 1106.4118.
both diastereomers of 6 (54 mg, 37%) as white amorphous
20
foams. Data for major diastereomer: ½aꢂD ¼ þ79 (c 0.8,
CHCl3); dH (400 MHz, CDCl3) 0.98 (9H, s, C(CH3)3),
1.99 (3H, s, SCH3), 3.63–3.78 (3H, m, H-5a, H-6a, H-2b),
3.73 (3H, s, OCH3), 3.88–3.99 (3H, m, H-60a, H-5b, H-
6b), 4.17 (1H, dd, J5b,6 b 2.8 Hz, J6b,6 b 8.4 Hz, H-60b),
4.22–4.28 (2H, m, H-4a, H-4b), 4.32 (1H, dd, J2b,3b
2.7 Hz, J3b,4b 9.9 Hz, H-3b), 4.42 (1H, at, J 9.4 Hz, H-
3a), 4.48 (1H, dd, J1a,2a 8.1 Hz, J2a,3a 10.7 Hz, H-2a),
4.58, 5.40 (2H, ABq, J 12.2 Hz, PhCH2), 4.62, 4.75 (2H,
ABq, J 12.6 Hz, PhCH2), 4.66 (1H, s, CHCI@CH2), 4.73
(1H, s, PhCH), 5.64 (1H, s, H-1b), 5.65 (1H, d, H-1a),
5.78 (1H, d, J 1.5 Hz, CI@CHH0), 6.19 (1H, d, CI@CHH0),
6.71–6.73 (2H, m, 2 · Ar-H), 6.84–6.88 (5H, m, 5 · Ar-H),
7.10–7.39 (18H, m, 18 · Ar-H), 7.58–7.62 (4H, m, 4 · Ar-
H), 7.79–7.81 (4H, m, 4 · Ar-H); dC (100.6 MHz, CDCl3)
13.6 (q, SCH3), 19.3 (s, C(CH3)3), 27.2 (q, C(CH3)3),
55.6, 55.8 (OCH3, C-2a), 65.3 (C-5b), 67.7, 68.5 (C-6a, C-
6b), 70.6 (d, C-3b), 73.8, 75.8 (2 · t, 2 · PhCH2), 74.9,
75.1 (2 · d, C-4a, C-5a), 78.0, 78.2, 78.3 (3 · d, C-3a, C-
2b, C-4b), 82.6 (d, C-1b), 98.0 (d, C-1a), 101.5, 101.7
(2 · d, PhCH, CH(O)), 107.5 (s, CI@CH2), 114.3, 118.8,
126.5, 127.2, 127.3, 127.4, 127.6, 127.9, 128.0, 128.3,
128.4, 128.6, 129.4, 129.5, 133.9, 136.1, 136.3 (33 · Ar-
CH, CI@CH2), 133.4, 134.0, 137.6, 137.8, 138.9, 150.9,
155.4 (7 · s, 9 · Ar-C), 168.9 (2 · C@O). m/z (ES+) 1354
(30), 1313 (M+NHþ4 , 100). HRMS (ES+) calcd
for C68H70INO13NaSSi (M+Na+) 1318.3274. Found
1318.3267. Selected signals for the minor diastereomer:
dH (400 MHz, CDCl3) 0.98 (9H, s, C(CH3)3), 2.04 (3H, s,
SCH3), 3.71 (3H, s, OCH3), 5.01 (1H, s, H-1b), 5.40 (1H,
s, CI@CHH0), 5.78 (1H, s, CI@CHH0), 6.14 (1H, s,
CI@CHH0).
0
0
4.9. p-Methoxyphenyl-4,6-O-benzylidene-b-D-mannopyranos-
yl-(1!4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-b-D-gluco-
pyranoside 7b
Disaccharide 7a (400 mg, 0.37 mmol) was dissolved in dry
DMF (5 ml) and treated with TBAF (0.74 ml of 1 M solu-
tion in THF). The reaction mixture was stirred overnight at
room temperature under Ar. TLC (petrol–ethyl acetate,
1:1) indicated complete consumption of starting material
(Rf 0.71) and formation of a major product (Rf 0.08).
The reaction mixture was diluted with ethyl acetate
(50 ml) and Et2O (50 ml) and washed with water (20 ml).
The organic phase was dried over MgSO4, filtered and con-
centrated in vacuo. The residue was purified by flash col-
umn chromatography (petrol–ethyl acetate, 4:6) to afford
17
alcohol 7b (190 mg, 60%) as white foam. ½aꢂD ¼ þ41 (c
0.8, CHCl3), mmax (KBr disc) 1775, 1713 (s, C@O) cmꢀ1
;
dH (500 MHz, CDCl3) 2.58 (1H, d, J3b,OH 6.6 Hz, OH),
2.76 (1H, s, OH), 3.18 (1H, adt, J 5.0 Hz, J 9.7 Hz, H-
5b), 3.59 (1H, at, J 10.2 Hz, H-6b), 3.63 (1H, ddd, J2b,3b
3.4 Hz, J3b,4b 9.5 Hz, H-3b), 3.72 (3H, s, OCH3), 3.73
(1H, m, H-5a), 3.78 (1H, at, J 9.4 Hz, H-4b), 3.79 (1H,
0
dd, J5a,6a 2.2 Hz, J6a,6 a 11.3 Hz, H-6a), 3.84 (1H, dd,
J5a,6 a 3.4 Hz, H-60a), 3.96 (1H, br s, H-2b), 4.18–4.21
0
4.8. p-Methoxyphenyl-4,6-O-benzylidene-3-O-tert-butyldi-
phenylsilyl-b-D-mannopyranosyl-(1!4)-3,6-di-O-benzyl-2-
deoxy-2-phthalimido-b-D-glucopyranoside 7a10d
(2H, m, H-4a, H-6b), 4.45 (2H, m, H-2a, H-3a), 4.47,
4.84 (2H, ABq, J 12.1 Hz, PhCH2), 4.53, 4.76 (2H, ABq,
J 11.9 Hz, PhCH2), 4.77 (1H, s, H-1b), 5.48 (1H, s, PhCH),
5.63 (1H, m, H-1a), 6.70–6.73 (2H, m, 2 · Ar-H), 6.81–6.84
(2H, m, 2 · Ar-H), 6.89–6.97 (3H, m, 3 · Ar-H), 7.05 (2H,
m, 2 · Ar-H), 7.34–7.41 (8H, m, 8 · Ar-H), 7.47–7.49 (2H,
m, 2 · Ar-H) 7.64–7.86 (4H, m, 4 · Ar-H); dC (125.8 MHz,
CDCl3) 55.6 (OCH3), 55.7 (d, C-2a), 66.6 (C-5b), 68.4 (C-
6a), 68.5 (C-6b), 70.6 (d, C-3b), 70.7 (d, C-2b), 73.8, 74.8
(2 · t, 2 · PhCH2), 74.6 (d, C-5a), 77.7 (d, C-3a), 78.4 (d,
C-4b), 78.6 (d, C-4a), 97.8 (d, C-1a), 100.5 (d, C-1b),
102.1 (d, PhCH), 114.4, 118.8, 123.4, 126.2, 127.3, 128.0,
128.1, 128.3, 128.6, 129.2, 133.8 (33 · Ar-CH), 131.5,
137.1, 137.5, 138.1, 150.8, 155.4 (9 · Ar-C), 168.9
(2 · C@O). m/z (ES+) 868 (M+Na+, 10), 904 (M+59,
100), 1749 (2M+59, 100), HRMS (ES+) calcd for
C48H47NO13Na (M+Na+) 868.2940. Found 868.2940.
General procedure for intramolecular glycosylation using
˚
molecular sieves (4 A), DCM (2 ml), 2,6-di-tert-butyl-4-
methylpyridine (19 mg, 0.092 mmol), dimethyldisulfide
(7 ll, 0.077 mmol) and triflic anhydride (7 ll, 0.077 mmol),
and mixed acetals 6 (20 mg, 0.0154 mmol) afforded a pure
sample of disaccharide 7a (13.5 mg, 81%) as white powder.
21
21
½aꢂD ¼ þ49 (c 1.0, CHCl3), lit.10d ½aꢂD ¼ þ51:1 (c 1.0,
CHCl3); dH (500 MHz, CDCl3) 1.06 (9H, s, C(CH3)3),
2.99 (1H, adt, J 4.9 Hz, J 9.7 Hz, H-5b), 3.53 (1H, dd,
0
J5a,6a 3.5 Hz, J6a,6 a 11.3 Hz, H-6a), 3.58 (1H, at, J
10.2 Hz, H-6b), 3.64–3.69 (3H, m, H-5a, H-60a, H-2b),
3.71 (3H, s, OCH3), 3.78 (1H, dd, J2b,3b 3.2 Hz, J3b,4b
9.3 Hz, H-3b), 3.93 (1H, at, J 9.3 Hz, H-4b), 4.09 (1H,
0
0
at, J 9.2 Hz, H-4a), 4.17 (1H, dd, J5b,6 b 4.9 Hz, J6b,6 b
10.4 Hz, H-60b), 4.32, 4.61 (2H, ABq, J 11.9 Hz, PhCH2),
4.39 (2H, m, H-2a, H-3a), 4.48 (1H, s, H-1b), 4.49, 4.85
(2H, ABq, J 12.3 Hz, PhCH2), 5.38 (1H, s, PhCH), 5.58
(1H, d, J1a,2a 7.8 Hz, H-1a), 6.69 (2H, d, J 9.0 Hz,
2 · Ar-H), 6.80 (2H, d, J 9.0 Hz, 2 · Ar-H), 6.86–6.90
(3H, m, 3 · Ar-H), 7.03 (2H, d, J 6.8 Hz, 2 · Ar-H),
7.14–7.46 (10H, m, 10 · Ar-H), 7.67–7.71 (4H, m, 4 · Ar-
4.10. p-Methoxyphenyl 2-O-acetyl-3,4,6-tri-O-benzyl-a-D-
mannopyranosyl-(1!3)-2-O-acetyl-4,6-O-benzylidene-b-D-
mannopyranosyl-(1!4)-3,6-di-O-benzyl-2-deoxy-2-phthal-
amido-b-D-glucopyranoside 9a
Disaccharide 7b (65 mg, 0.077 mmol) and trichloroacetim-
idate 8 (54 mg, 0.085 mmol) were dissolved in dry DCM

1728
E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
(8 ml) and transferred via cannula to a flame-dried flask
containing powdered molecular sieves (4 A, 100 mg). The
The reaction mixture was stirred for 2 h at room tempera-
ture and TLC (petrol–ethyl acetate, 1:2) indicated the for-
mation of a major product (Rf 0.2) and full consumption of
starting material (Rf 0.75). The reaction mixture was con-
centrated in vacuo after which the crude was dissolved in
DCM (50 ml) and washed with sodium hydrogen carbon-
ate (4 · 20 ml of a saturated solution). The organic phase
was dried over MgSO4, filtered and concentrated at
reduced pressure and the residue was purified by flash
column chromatography (petrol–ethyl acetate, 3:7) to give
˚
solution was stirred for 30 min at room temperature, then
cooled to ꢀ78 ꢁC and stirred under an atmosphere of ar-
gon. TMSOTf (2.8 ll, 15.4 lmol) was added and the mix-
ture was stirred at ꢀ78 ꢁC for 1 h, after which the
temperature was allowed to rise to room temperature over-
night. TLC (petrol–ethyl acetate, 3:2) indicated the forma-
tion of
a major product (Rf 0.32) and complete
consumption of acceptor (Rf 0). Triethylamine (50 ll)
was added and the solution stirred for a further 10 min.
The reaction mixture was then filtered, diluted with
DCM (50 ml), washed with sodium hydrogen carbonate
(50 ml of a saturated solution), dried over MgSO4, filtered
and concentrated in vacuo. The residue was directly acety-
lated using standard conditions (Ac2O, pyridine, DMAP)
and after evaporation of solvent, the crude residue was
purified by flash column chromatography (petrol–ethyl
acetate, 7:3!6:4) to give trisaccharide 9a (90 mg, 86%) as
trisaccharide diol 9b (76 mg, 91%) as a white foam.
23
½aꢂD ¼ þ40 (c 0.5, CHCl3); mmax (KBr disc) 3476 (br,
OH), 1777, 1747, 1716 (s, C@O); dH (500 MHz, CDCl3)
2.11, 2.20 (6H, 2 · s, 2 · OC(O)CH3), 2.92 (2H, br s,
2 · OH), 3.09–3.11 (1H, m, H-5b), 3.56–3.60 (2H, m, H-
3b, H-6b), 3.67–3.68 (1H, m, H-5a), 3.73–3.83 (5H, m,
H-6a, H-6c, H-60a H-60b H-60c), 3.77 (3H, s, PhOCH3),
3.83–3.89 (2H, m, H-4b, H-4c), 3.91–3.93 (1H, m, H-3c),
3.99–4.01 (1H, m, H-5c), 4.18 (1H, at, J 9.3 Hz, H-4a),
4.33 (1H, at, J 9.6 Hz, H-3a), 4.43–4.46 (2H, m, H-2a,
PhCH), 4.50, 4.77 (2H, ABq, J12.3 Hz, PhCH2), 4.54–
4.56 (2H, m, 2 · PhCH), 4.60, 4.73 (2H, ABq, J 11.5 Hz,
PhCH2), 4.66–4.70 (2H, m, H-1b, PhCH), 4.89–4.92 (2H,
m, 2 · PhCH), 5.29 (2H, m, H-1c, H-2c), 5.37 (1H, d,
J1b,2b 2.7 Hz, H-2b), 5.64 (1H, d, J1a,2a 8.8 Hz, H-1a),
6.74–6.76 (2H, m, 2 · Ar-H), 6.84–6.86 (2H, m, 2 · Ar-
H), 7.00–7.03 (3H, m, 3 · Ar-H), 7.06–7.24 (2H, m,
2 · Ar-H), 7.24–7.26 (2H, m, 2 · Ar-H), 7.32–7.42 (18H,
m, 18 · Ar-H), 7.67–7.87 (4H, m, 4 · Ar-H); dC
(125.8 MHz, CDCl3) 21.1, 21.8 (2 · q, 2 · OC(O)CH3),
55.6 (d, C-2a), 55.6 (OCH3), 62.3 (t, C-6b), 66.9 (d, C-
4b), 68.0 (t, C-6c), 69.1 (t, C-6a), 69.3 (d, C-2c), 71.1 (d,
C-2b), 71.8 (d, C-5c), 71.9, 73.5, 73.6, 74.5, 74.9 (5 · t,
5 · PhCH2), 74.3 (d, C-4c), 74.7 (d, C-5a), 75.4 (d, C-5b),
76.8 (d, C-3a), 77.4 (d, C-3c), 78.2 (d, C-4a), 78.8 (d, C-
3b), 97.6 (d, C-1a), 98.0 (d, C-1c), 98.4 (d, C-1b), 114.4,
118.6, 127.4, 127.7, 127.8, 127.9, 127.9, 128.0, 128.0,
128.1, 128.2, 128.4, 128.4, 128.5, 128.6, 128.7, 133.9
(17 · d, 33 · Ar-C), 137.8, 137.8, 137.9, 138.3, 138.4,
150.8, 155.4 (7 · s, 9 · Ar-C), 169.9, 170.6 (2 · s,
4 · C@O); JC-1a/H-1a 166 Hz (b), JC-1b/H-1b 160 Hz (b),
JC-1c/H-1c 172 Hz (a); m/z (ESI+) species observed
(M+NHþ4 ) (major), (M+Na+); (M+NHþ4 ) peaks observed:
1291.3 (100%), 1292.3 (70%), 1293.3 (15%), peaks calcul-
ated: 1291.5 (100%), 1292.5 (80%), 1293.5 (35%). Anal.
Calcd for C72H75NO20: C, 67.86; N, 1.10; H, 5.93. Found:
C, 67.55; N, 1.01; H, 6.02.
a
white foam. Rf 0.43 (petrol–ethyl acetate, 3:2);
23
½aꢂD ¼ þ20 (c 1.0, CHCl3); mmax (KBr disc) 1749, 1716 (s,
C@O) cmꢀ1; dH (500 MHz, CDCl3) 2.10, 2.15 (6H, 2 · s,
2 · OC(O)CH3), 3.12–3.15 (1H, m, H-5b), 3.60 (1H, at, J
10.0 Hz, H-6b), 3.64–3.66 (1H, m, H-5a), 3.72–3.78 (3H,
m, H-6a, H-6c, H-60c), 3.76 (3H, s, PhOCH3), 3.81–3.83
(1H, m, H-60a), 3.85–3.94 (5H, m, H-3b, H-3c, H-4b, H-
4c, H-5c), 4.17–4.25 (2H, m, H-4a, H-60b), 4.34 (1H, at, J
9.8 Hz, H-3a), 4.42–4.46 (1H, m, H-2a), 4.45–4.56 (5H,
m, 5 · PhCH), 4.69–4.77 (4H, m, H-1b, 3 · PhCH), 4.87–
4.92 (2H, m, 2 · PhCH), 5.28 (1H, s, H-1c), 5.42 (1H, s,
H-2b), 5.52 (1H, s, H-2c), 5.55 (1H, s, PhCH(O)), 5.63
(1H, d, J1a,2a 7.9 Hz, H-1a), 6.74–6.76 (2H, m, 2 · Ar-H),
6.81–6.86 (2H, m, 2 · Ar-H), 6.94–7.00 (3H, m, 3 · Ar-
H), 7.06–7.10 (2H, m, 2 · Ar-H), 7.24–7.26 (2H, m,
2 · Ar-H), 7.32–7.52 (23H, m, 23 · Ar-H), 7.69–7.86 (4H,
m, 4 · Ar-H); dC (125.8 MHz, CDCl3) 20.9, 21.1 (2 · q,
2 · OC(O)CH3), 55.6 (d, C-2a), 55.6 (PhOCH3), 66.5 (d,
C-5b), 68.0 (t, C-6c), 68.4 (t, C-6b), 68.5 (d, C-2c), 68.9
(t, C-6a), 70.7 (d, C-2b), 71.8 (t, PhCH2), 72.1 (d, C-5c),
72.7 (d, C-4c), 73.5, 73.5 (2 · t, 2 · PhCH2), 74.1 (d, C-
4b), 74.7 (t, PhCH2), 74.7 (d, C-5a), 74.8 (t, PhCH2), 76.8
(d, C-3a), 77.6 (d, C-3c), 78.6 (d, C-4a), 78.7 (d, C-3b),
97.7 (d, C-1a), 98.7 (d, C-1c), 99.2 (d, C-1b), 101.2 (d,
PhCH), 114.4, 118.7, 126.0, 127.3, 127.5, 127.7, 127.7,
127.8, 127.8, 127.9, 128.0, 128.0, 128.1, 128.1, 128.2,
128.3, 128.4, 128.4, 128.7, 128.9 (20 · d, 38 · Ar-C),
137.1, 137.9, 138.0, 138.2, 138.5, 138.6, 150.8, 155.4
(8 · s, 10 · Ar-C), 169.8, 170.2 (2 · s, 4 · C@O); JC-1a/H-1a
167 Hz (b), JC-1b/H-1b 164 Hz (b), JC-1c/H-1c 177 Hz (a); m/z
(ESI+) species observed (M+NHþ4 ) (major), (M+Na+);
(M+NHþ4 ) peaks observed: 1379.5 (100%), 1380.5 (80%),
1381.5 (30%), peaks calculated: 1379.6 (100%), 1380.6
(90%), 1381.5 (45%). Anal. Calcd for C79H79NO20: C,
69.64; N, 1.03; H, 5.84. Found: C, 69.45; N, 1.03; H, 5.85.
4.12. p-Methoxyphenyl 2-O-acetyl-3,4,6-tri-O-benzyl-a-D-
mannopyranosyl-(1!6)-[2-O-acetyl-3,4,6-tri-O-benzyl-a-D-
mannopyranosyl-(1!3)]-2-O-acetyl-b-D-mannopyranosyl-
(1!4)-3,6-di-O-benzyl-2-deoxy-2-phthalamido-b-D-gluco-
pyranoside 10a
Trisaccharide diol 9b (233 mg, 183 lmol) and trichloroace-
timidate 8 (128 mg, 201 lmol) were dissolved in dry DCM
(10 ml) and transferred via cannula to a flame-dried flask
4.11. p-Methoxyphenyl 2-O-acetyl-3,4,6-tri-O-benzyl-a-D-
mannopyranosyl-(1!3)-2-O-acetyl-b-D-mannopyranosyl-
(1!4)-3,6-di-O-benzyl-2-deoxy-2-phthalamido-b-D-gluco-
pyranoside 9b
˚
containing molecular sieves (4 A, 200 mg). The solution
was cooled to ꢀ78 ꢁC and stirred under an atmosphere of
argon. TMSOTf (3.31 ll, 18.3 lmol) was added and the
temperature allowed to rise to 0 ꢁC after 3 h. After 5 h,
TLC (petrol–ethyl acetate, 1:1) indicated the formation of
Benzylidene acetal 9a (90 mg, 0.066 mmol) was dissolved in
DCM (8 ml) and trifluoroacetic acid (0.5 ml) was added.

E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
1729
a major product (Rf 0.3) and complete consumption of
acceptor (Rf 0.05). Triethylamine (100 ll) was added and
the solution stirred for a further 10 min. The reaction mix-
ture was diluted with DCM (100 ml) washed with sodium
hydrogen carbonate (50 ml of a saturated solution), dried
over MgSO4, filtered and concentrated in vacuo. The resi-
due was purified by flash column chromatography (petrol–
was heated at 45 ꢁC and stirred at room temperature over-
night. The solution was concentrated and the residue was
dissolved in dry MeOH (3 ml) and treated with Ac2O
(1 ml). The mixture was stirred for 3 h, then concentrated
in vacuo and repeatedly co-evaporated with toluene. The
residue was dissolved in DMF (3 ml), treated with TsOH
(4 mg, 0.021 mmol) and stirred at room temperature for
5 h at reduced pressure (40 mbar). The reaction mixture
was quenched by the addition of Et3N (200 ll) and evapo-
rated in vacuo. The crude residue containing 10b was then
dissolved in dry DMF (3 ml) and treated with BnBr
(142 ll, 1.2 mmol) and sodium hydride (32 mg of a 60%
mineral oil dispersion, 0.8 mmol). The mixture was stirred
for 2 h at room temperature and a TLC (petrol–ethyl ace-
tate, 3:2) revealed complete consumption of starting mate-
rial (Rf 0) and formation of a major product (Rf 0.56). The
reaction was quenched by adding MeOH and then diluted
with ether (50 ml) and washed with water (50 ml). The
organic phase was dried over MgSO4, filtered and concen-
trated in vacuo. The residue was purified by flash column
chromatography (petrol–ethyl acetate, 7:3) to afford perb-
ethyl acetate, 1:1) to give tetrasaccharide 10a (243 mg,
22
76%) as a white foam. ½aꢂD ¼ þ39 (c 0.25, CHCl3); mmax
(KBr disc) 3459 (br, OH), 1777, 1746, 1716 (s, C@O); dH
(500 MHz, CDCl3) 2.00, 2.06, 2.12 (9H, 3 · s,
3 · OC(O)CH3), 3.07 (1H, dat, J4b,5b 9.6 Hz, J 2.7 Hz, H-
5b), 3.50 (1H, br s, OH), 3.56 (1H, dd, J2b,3b 3.2 Hz,
J3b,4b 9.7 Hz, H-3b), 3.58–3.60 (1H, m, H-5a), 3.65–3.78
(11H, m, H-5d, H-6a, H-6b, H-6c, H-6d, H-60a, H-60c,
H-60d, OCH3), 3.82 (1H, at, J 9.5 Hz, H-4d), 3.82 (1H,
dd, J2d,3d 2.3 Hz, J3d,4d 9.3 Hz, H-3d), 3.86–3.87 (2H, m,
H-3c, H-5c), 3.91–3.98 (3H, m, H-4b, H-4c, H-60b), 4.10
(1H, at, J 9.4 Hz, H-4a), 4.20, 4.41 (2H, ABq, J 11.1 Hz,
PhCH2), 4.25 (1H, dd, J2a,3a 10.6 Hz, J3a,4a 8.5 Hz, H-
3a), 4.34 (1H, dd, J1a,2a 8.5 Hz, H-2a), 4.44, 4.77 (2H,
ABq, J 10.6 Hz, PhCH2), 4.45–4.53 (6H, m, 6 · PhCH),
4.64–4.69 (5H, m, H-1b, 4 · PhCH), 4.83 (1H, d, J1d,2d
1.7 Hz, H-1d), 4.85 (1H, d, J 11.2 Hz, PhCH), 4.86 (1H,
d, J 12.8 Hz, PhCH), 5.20 (1H, d, J1c,2c 1.2 Hz, H-1c),
5.30 (1H, dd, H-2d), 5.35 (1H, br d, H-2b), 5.41 (1H, m,
H-2c), 5.56 (1H, d, H-1a), 6.67–6.69 (2H, m, 2 · Ar-H),
6.74–6.79 (5H, m, 5 · Ar-H), 6.97–6.98 (2H, m, 2 · Ar-
H), 7.10–7.11 (2H, m, 2 · Ar-H), 7.14–7.16 (2H, m,
2 · Ar-H), 7.19–7.36 (31H, m, 31 · Ar-H), 7.64–7.81 (4H,
m, 4 · Ar-H); dC (125.8 MHz, CDCl3) 20.9, 21.0, 21.1
(3 · q, 3 · OC(O)CH3), 55.5 (q, OCH3), 55.6 (d, C-2a),
66.1 (t, C-6b), 66.8 (d, C-4b), 68.1, 68.7, 68.9 (3 · t,
C-6a, C-6c, C-6d), 68.4 (d, C-2d), 68.9 (d, C-2c), 71.0 (d,
C-2b), 71.5, 71.8, 73.3, 73.3, 73.4, 74.5, 74.7, 75.3 (8 · t,
PhCH2), 71.8 (d, C-4d), 71.9 (d, C-4c), 74.1 (d, H-5c),
74.3 (d, H-5d), 74.6 (2 · d, C-5a, C-5b), 76.8 (d, C-3a),
77.7 (d, C-3c), 77.9 (d, C-3b), 78.2 (d, C-3d), 78.8 (d, C-
4a), 97.5 (d, C-1a), 97.9 (d, C-1d), 99.1 (d, C-1b), 99.3 (d,
C-1c), 114.3, 118.5, 123.2, 127.2, 127.4, 127.6, 127.6,
127.7, 127.8, 127.8, 127.9, 128.0, 128.0, 128.0, 128.1,
128.2, 128.2, 128.3, 128.3, 128.4, 128.5 (21 · d, 46 · Ar-
C), 131.6 (s, 2 · Ar-C), 133.6 (d, 2 · Ar-C), 137.8, 137.8,
137.9, 138.0, 138.0, 138.2, 138.5, 138.5, 150.8, 155.3
(10 · s, 10 · Ar-C), 170.0, 170.4, 170.5 (3 · s, 5 · C@O);
JC-1a/H-1a 167 Hz (b), JC-1b/H-1b 160 Hz (b), JC-1c/H-1c
174 Hz (a), JC-1d/H-1d 173 Hz (a); m/z (ESI+) species
observed (M+NHþ4 ), (M+Na+) (major); (M+Na+) peaks
observed: 1770.7 (84%), 1771.7 (100%), 1772.7 (51%),
1773.7 (16%), 1774.7 (5%), 1775.7 (1%), peaks calculated:
1770.7 (89%), 1771.7 (100%), 1772.7 (60%), 1773.7 (26%),
1774.7 (9%), 1775.7 (2%).
enzylated tetrasaccharide 10c (153 mg, 77%) as a white
17
amorphous foam; ½aꢂD ¼ þ42 (c 0.50, CHCl3); dH
(500 MHz, CDCl3) 3.21 (1H, dat, J4b,5b 9.2 Hz, J 2.7 Hz,
H-5b), 3.40 (1H, dat, J4a,5a 9.8 Hz, J 2.5 Hz, H-5a), 3.49–
3.64 (6H, H-3b, H-5d, H-6a, H-6d, H-60a, H-60d), 3.67–
3.74 (4H, m, H-2d, H-6b, H-6c, H-60c), 3.71 (3H, s,
OCH3), 3.75 (1H, at, J 2.2 Hz, H-2c), 3.82 (1H, dd, J2d,3d
0
3.0 Hz, J3d,4d 9.5 Hz, H-3d), 3.87 (1H, dd, J5b,6 b 3.9 Hz,
J6b,6 b 12.1 Hz, H-60b), 3.91–3.99 (6H, m, H-2b, H-3c, H-
0
4b, H-4c, H-4d, H-5c), 4.06 (1H, dd, J3a,4a 8.5 Hz, H-4a),
4.22 (1H, dd, J2a,3a 10.6 Hz, H-3a), 4.30–4.37 (5H, m, H-
2a, 4 · PhCH), 4.44–4.62 (14H, m, 14 · PhCH), 4.63 (1H,
s, H-1b), 4.82 (1H, d, J 10.9 Hz, PhCH), 4.86 (2H, d, J
12.6 Hz, 2 · PhCH), 4.90 (1H, d, J 11.1 Hz, PhCH), 5.01
(1H, d, J1d,2d 1.5 Hz, H-1d), 5.04 (1H, d, J 12.0 Hz, PhCH),
5.19 (1H, d, J1c,2c 1.5 Hz, H-1c), 5.55 (1H, d, J1a,2a 8.5 Hz,
H-1a), 6.60–6.71 (5H, m, 5 · Ar-H), 6.79–6.85 (4H, m,
4 · Ar-H), 7.07–7.35 (55H, m, 55 · Ar-H), 7.43–7.81 (4H,
m, 4 · Ar-H); dC (125.8 MHz, CDCl3) 55.5 (d, C-2a),
55.6 (q, OCH3), 66.3 (t, C-6b), 68.1 (t, C-6a), 69.0 (t, C-
6d), 70.0 (t, C-6c), 71.2 (t, PhCH2), 72.2 (t, PhCH2), 72.2
(d, C-5d), 72.4 (t, PhCH2), 72.8 (d, C-5c), 73.2, 73.3,
73.4, 74.3, 74.3, 74.5 (6 · t, 7 · PhCH2), 74.5, 74.6 (2 · d,
C-4b, C-4c, C-4d, C-5b), 74.8 (t, PhCH2), 74.8 (d, C-2d),
74.9 (d, C-5a), 75.0 (t, PhCH2), 75.5 (d, C-2c), 76.8 (d, C-
3a), 78.5 (d, C-2b), 79.5 (d, C-3d), 79.5 (d, C-4a), 80.0 (d,
C-3c), 81.5 (d, C-3b), 97.6 (d, C-1a), 98.1 (d, C-1d), 100.3
(d, C-1c), 102.0 (d, C-1b), 114.3, 118.7, 123.2, 126.5,
127.0, 127.1, 127.2, 127.3, 127.3, 127.4, 127.5, 127.6,
127.7, 127.7, 127.8, 127.9, 127.9, 128.0, 128.1, 128.2,
128.2, 128.3, 128.3, 128.4, 128.4 (25 · d, 66 · Ar-C), 131.7
(s, 2 · Ar-C), 133.5 (d, 2 · Ar-C), 138.0, 138.2, 138.3,
138.3, 138.4, 138.5, 138.6, 138.6, 138.7, 139.0, 150.9,
155.3 (12 · s, 14 · Ar-C), 167.4, 167.9 (2 · s, 2 · C@O);
JC-1a/H-1a 166 Hz (b), JC-1b/H-1b 158 Hz (b), JC-1c/H-1c
172 Hz (a), JC-1d/H-1d 170 Hz (a); m/z (ESI+) species
observed (M+NHþ4 ), (M+Na+) (major); (M+Na+) peaks
observed: 2004.8 (66%), 2005.8 (100%), 2006.8 (61%),
2007.8 (23%), 2008.8 (6%), 2009.8 (2%), peaks calculated:
2004.8 (74%), 2005.8 (100%), 2006.8 (71%), 2007.8 (35%),
2008.9 (13%), 2009.9 (4%).
4.13. p-Methoxyphenyl 2,3,4,6-tetra-O-benzyl-a-D-manno-
pyranosyl-(1!6)-[2,3,4,6-tetra-O-benzyl-a-D-mannopyran-
osyl-(1!3)]-2,4-di-O-benzyl-b-D-mannopyranosyl-(1!4)-
3,6-di-O-benzyl-2-deoxy-2-phthalamido-b-D-glucopyran-
oside 10c
Tetrasaccharide 10a (175 mg, 0.10 mmol) was dissolved in
dry MeOH (5 ml) and anhydrous K2CO3 (28 mg,
0.20 mmol) was added at room temperature. The mixture

1730
E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
4.14. 2,3,4,6-Tetra-O-benzyl-a-D-mannopyranosyl-(1!6)-
[2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-(1!3)]-2,4-di-
O-benzyl-b-D-mannopyranosyl-(1!4)-3,6-di-O-benzyl-2-
deoxy-2-phthalamido-b-D-glucopyranose 10d
100 mg). The mixture was stirred for 30 min at room tem-
perature, then cooled to ꢀ78 ꢁC and stirred under an atmo-
sphere of Ar. TMSOTf (2 ll, 11 lmol) was added after
which the mixture was stirred at ꢀ78 ꢁC for 1 h, then the
temperature was allowed to rise to room temperature over-
night. TLC (petrol–ethyl acetate, 1:1) revealed the forma-
Tetrasaccharide 10c (160 mg, 80 lmol) was dissolved in a
mixture of toluene, acetonitrile and water 1:4:2 (3 ml). Ce-
ric ammonium nitrate (222 mg, 0.40 mmol) was added and
the solution stirred at room temperature overnight. TLC
(petrol–ethyl acetate, 6:4) indicated the formation of a
major product (Rf 0.20) and complete consumption of
the starting material (Rf 0.56). The reaction mixture was
diluted with DCM (20 ml) and washed with brine (10 ml),
sodium hydrogen carbonate (2 · 10 ml of a saturated
solution), water (10 ml) and finally dried over MgSO4,
filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (petrol–ethyl acetate,
6:4) to give hemiacetals 10d as a white amorphous foam
(116 mg, 77%). m/z (ESI+) species observed (M+NHþ4 ),
(M+Na+) (major); (M+Na+) peaks observed: 1898.78
(73%), 1899.79 (100%), 1900.79 (57%), 1901.79 (17%),
1902.79 (4%), 1903.80 (1%), peaks calculated: 1898.79
(78%), 1899.80 (100%), 1900.80 (67%), 1901.81 (31%),
1902.81 (11%), 1903.81 (3%). dH (400 MHz, CDCl3,
significant peaks only) 5.00 (1H, br s, H-1d), 5.19 (1H, d,
J1c,2c 1.3 Hz, H-1c), 5.56 (1H, d, J1a,2a 8.5 Hz, H-1a);
dC (100.6 MHz, CDCl3, significant peaks only) 93.2
(d, C-1a), 98.5 (d, C-1d), 100.0 (d, C-1c), 100.7
(d, C-1b).
tion of
a major product (Rf 0.75) and complete
consumption of trichloroacetimidate (Rf 0.90). Triethyl-
amine (50 ll) was added and the solution stirred for a fur-
ther 10 min. The reaction mixture was then diluted with
DCM (20 ml), filtered, washed with sodium hydrogen car-
bonate (20 ml of a saturated solution), dried over MgSO4,
filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (petrol–ethyl acetate,
17
3:2) to give pentasaccharide 11 (103 mg, 85%). ½aꢂD ¼ þ30
(c 0.9, CHCl3); dH (500 MHz, CDCl3) 3.17–3.21 (2H, m, H-
5b, H-5c), 3.37–3.41 (2H, m, H-5a, H-6a), 3.44 (1H, dd,
J5b,6b 2.7 Hz, J6b,6 b 11.5 Hz, H-6b), 3.47–3.51 (2H, m, H-
0
6e, H-60a), 3.57–3.60 (2H, m, H-5e, H-60e), 3.62–3.74
(6H, H-2e, H-3c, H-6c, H-6d, H-60b, H-60d), 3.65 (3H, s,
OCH3), 3.76 (1H, m, H-2d), 3.81 (1H, dd, J2e,3e 3.1 Hz,
J3e,4e 9.5 Hz, H-3e), 3.85–3.86 (1H, m, H-60c), 3.90–3.97
(6H, m, H-2c, H-3d, H-4c, H-4d, H-4e, H-5d), 4.07 (1H,
dd, J3b,4b 7.9 Hz, J4b,5b 9.8 Hz, H-4b), 4.15–4.20 (4H, m,
H-2b, H-3a, H-3b, H-4a), 4.25–4.35 (5H, m, H-2a,
4 · PhCH), 4.39–4.62 (18H, m, 18 · PhCH), 4.65 (1H, d,
J 11.9 Hz, PhCH), 4.65 (1H, s, H-1c), 4.81 (1H, d, J
10.3 Hz, PhCH), 4.85 (1H, d, J 11.1 Hz, PhCH), 4.85
(1H, d, J 12.9 Hz, PhCH), 4.87 (1H, d, J 12.2 Hz, PhCH),
4.90 (1H, d, J 11.1 Hz, PhCH), 4.97 (1H, d, J1e,2e 1.1 Hz,
H-1e), 5.03 (1H, d, J 12.0 Hz, PhCH), 5.21 (1H, d, J1d,2d
1.3 Hz, H-1d), 5.23 (1H, d, J1b,2b 7.8 Hz, H-1b), 5.44
(1H, d, J1a,2a 8.5 Hz, H-1a), 6.58–6.6.84 (12H, m,
12 · Ar-H), 6.94–7.39 (54H, m, 54 · Ar-H), 7.43–7.90
(16H, m, 16 · Ar-H); dC (125.8 MHz, CDCl3) 55.5 (d, C-
2a), 55.6 (q, OCH3), 56.5 (d, C-2b), 66.3 (t, C-6c), 67.6 (t,
C-6b), 68.0 (t, C-6a), 69.0 (t, C-6e), 69.6 (t, C-6d), 71.2
(t, PhCH2), 72.2 (2 · t, 2 · PhCH2), 72.2 (d, C-5e), 72.4
(t, PhCH2), 72.6 (t, PhCH2), 72.9 (d, C-5d), 73.0, 73.2,
73.4, 74.3 (4 · t, 4 · PhCH2), 74.3 (d, C-4d), 74.4 (t,
PhCH2), 74.5 (2 · d, C-4c, C-5c), 74.6, 74.6 (2 · t,
2 · PhCH2), 74.6 (d, C-5a), 74.7 (d, C-5b), 74.8 (t, PhCH2),
74.8 (2 · d, C-2e, C-4e), 75.0 (t, PhCH2), 75.5 (d, C-2d),
76.0, 76.7, 76.9 (3 · d, C-3a, C-3b, C-4a), 78.6 (d, C-2c),
79.4 (d, C-3e), 79.7 (d, C-4b), 80.0 (d, C-3d), 81.4 (d, C-
3c), 97.1 (d, C-1b), 97.4 (d, C-1a), 98.1 (d, C-1e), 100.2
(d, C-1d), 102.0 (d, C-1c), 114.2, 118.5, 123.0, 123.2,
126.5, 126.9, 127.0, 127.1, 127.2, 127.2, 127.3, 127.4,
127.5, 127.5, 127.6, 127.6, 127.7, 127.8, 127.8, 127.9,
128.0, 128.1, 128.2, 128.2, 128.3, 128.3, 128.4, 128.5,
128.5 (29 · d, 78 · Ar-C), 131.4, 131.8 (2 · s, 4 · Ar-C),
133.6, 133.9 (2 · d, 4 · Ar-C), 137.6, 138.0, 138.1, 138.2,
138.3, 138.3, 138.4, 138.4, 138.5, 138.6, 138.7, 138.8,
139.0, 150.8, 155.2 (15 · s, 16 · Ar-C), 167.4, 168.1 (2 · s,
4 · C@O); JC-1a/H-1a 167 Hz (b), JC-1b/H-1b 167 Hz (b),
JC-1c/H-1c 158 Hz (b), JC-1d/H-1d 171 Hz (a), JC-1e/H-1e
171 Hz (a); m/z (ESI+) species observed (M+NHþ4 ),
(M+Na+) (major); (M+Na+) peaks observed: 2476.0
(49%), 2477.0 (100%), 2478.0 (79%), 2479.0 (36%), 2480.0
(10%), 2481.0 (3%), peaks calculated: 2476.0 (60%),
2477.0 (100%), 2478.0 (87%), 2479.0 (52%), 2480.0 (24%),
2481.0 (9%).
4.15. 2,3,4,6-Tetra-O-benzyl-a-D-mannopyranosyl-(1!6)-
[2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-(1!3)]-2,4-di-
O-benzyl-b-D-mannopyranosyl-(1!4)-3,6-di-O-benzyl-2-
deoxy-2-phthalamido-b-D-glucopyranosyl trichloroacet-
imidate 10e
Trichloroacetonitrile (53 ll, 0.53 mmol) was added to a
solution of hemiacetals 10d (100 mg, 53 lmol) in freshly
distilled DCM (2 ml). DBU was added (2 ll,13 lmol) and
the mixture stirred at room temperature overnight. TLC
(petrol–ethyl acetate, 6:4) indicated the formation of a
major product (Rf 0.38) and complete consumption of
the starting material (Rf 0.20). The solution was concen-
trated at a reduced pressure and the residue purified on a
plug of silica gel eluting with petrol–ethyl acetate 1:1 to
afford pure trichloroacetimidate 10e (103 mg, 96%), which
was used directly in the next step. dH (400 MHz, CDCl3,
significant peaks only) 5.00 (1H, br s, H-1d), 5.19 (1H, br
s, H-1c), 6.34 (1H, d, J1a,2a 8.9 Hz, H-1a), 8.53 (s, 1H,
C@NH).
4.16. p-Methoxyphenyl 2,3,4,6-tetra-O-benzyl-a-D-manno-
pyranosyl-(1!6)-[2,3,4,6-tetra-O-benzyl-a-D-mannopyran-
osyl-(1!3)]-2,4-di-O-benzyl-b-D-mannopyranosyl-(1!4)-
3,6-di-O-benzyl-2-deoxy-2-phthalamido-b-D-glucopyranosyl-
(1!4)-3,6-di-O-benzyl-2-deoxy-2-phthalamido-b-D-gluco-
pyranoside 11
Glycosyl acceptor 5 (59 mg, 99 lmol) and trichloroacetim-
idate 10e (100 mg, 49 lmol) were dissolved in freshly dis-
tilled DCM (2 ml) and transferred via cannula to a flame-
˚
dried flask containing powdered molecular sieves (4 A,

E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
1731
4.17. Methyl 4,6-O-benzylidene-2-O-(prop-2-ynyl)-1-thio-
a-D-mannopyranoside 12
and then dissolved in MeOH (10 ml), and treated at room
temperature with Et3N (1 ml). After 30 min the solution
was concentrated in vacuo and the residue purified by flash
Diol 1 (5.0 g, 16.7 mmol) was dissolved in DCM (150 ml)
and propargyl bromide (80% in toluene) (3.7 g,
25.05 mmol), Bu4NHSO4 (1.13 g, 3.34 mmol) and 5% aq
NaOH (23 ml) were added. The mixture was stirred for
2 days at room temperature after which TLC (petrol–ethyl
acetate, 7:3) revealed complete consumption of starting
material (Rf 0.09) and formation of several products, the
major one with Rf 0.39. The two phases were separated
and the organic one was washed with water (100 ml) and
brine (100 ml) and successively dried over MgSO4, filtered
and concentrated in vacuo. After recrystallisation (isopro-
column chromatography (petrol–ethyl acetate, 3:2) to give
19
disaccharide 13b (1.84 g, 78% over two steps). ½aꢂD ¼ þ35
(c 0.8, CHCl3); mmax (KBr disc) 1777 (C@O) cmꢀ1. dH
(400 MHz, CDCl3) 2.12 (3H, s, SCH3), 2.14 (3H, s,
OC(O)CH3), 2.41 (1H, at, J 2.3 Hz, C„CH), 3.68 (1H,
0
dd, J5b,6b 6.1 Hz, J6b,6 b 10.3 Hz, H-6b), 3.74–3.78 (2H,
m, H-4b, H-60b), 3.82–3.83 (2H, m, H-6a, H-60a), 3.92
(1H, m, H-5a), 3.99 (1H, dd, J2a,3a 3.2 Hz, J3a,4a 9.8 Hz,
H-3a), 4.04 (1H, dd, J2b,3b 3.3 Hz, J3b,4b 9.3 Hz, H-3b),
4.06–4.12 (3H, m, H-2a, H-4a, H-5b), 4.22 (1H, dd, J
2.3 Hz, Jgem 16.2 Hz, CHH0C„CH), 4.28 (1H, dd,
CHH0C„CH), 4.49, 4.87 (2H, ABq, J 11.0 Hz, PhCH2),
4.53, 4.64 (2H, ABq, J 12.0 Hz, PhCH2), 4.56, 4.71 (2H,
ABq, J 11.3 Hz, PhCH2), 5.25 (1H, d, J1a,2a 0.7 Hz, H-
1a), 5.40 (1H, d, J1b,2b 1.5 Hz, H-1b), 5.42 (1H, dd, H-
2b), 7.16–7.19 (2H, m, 2 · Ar-H), 7.27–7.37 (13H, m,
13 · Ar-H); dC (100.6 MHz, CDCl3) 13.9 (q, SCH3), 21.1
(q, OC(O)CH3), 57.5 (t, CH2C„CH), 62.6 (t, C-6a), 67.0
(d, C-4a), 69.1 (d, C-2b), 69.2 (t, C-6b), 71.7 (d, C-5b),
71.9, 73.5, 75.0 (3 · t, 3 · PhCH2), 72.5 (d, C-5a), 74.6
(C-4b), 75.7 (s, CH2C„CH), 77.8, 77.9 (2 · d, C-3a, C-
3b), 78.9 (d, C-2a), 79.4 (s, CH2C„CH), 83.2 (d, C-1a),
97.9 (d, C-1b), 127.6, 127.7, 127.8, 127.9, 128.1, 128.3,
128.4 (7 · d, 15 · Ar-CH), 137.9, 138.4 (2 · s, 3 · Ar-C),
170.5 (s, C@O); m/z (ES+) 745 (M+Na+, 100), 781 (82).
HRMS (ES+) calcd for C39H46NaO11S (M+Na+)
745.2653. Found 745.2646.
panol), a pure sample of propargyl ether 12 was obtained
20
(2.8 g, 50%); mp 175–177 ꢁC (isopropanol); ½aꢂD ¼ þ122
(c 0.8, CHCl3); mmax (KBr disc) 3274 (stretching C–H,
C„CH) cmꢀ1; dH (400 MHz, CDCl3) 2.18 (3H, s, SCH3),
2.41 (1H, at, J 2.4 Hz, C„CH), 3.86 (1H, at, J 10.0 Hz,
H-6), 3.92 (1H, at, J 9.4 Hz, H-4), 4.08–4.09 (2H, m, H-
2, H-3), 4.18 (1H, adt, J 4.8 Hz, J 9.6 Hz, H-5), 4.25 (1H,
dd, J5,6 4.9 Hz, J6,6 10.0 Hz, H-60), 4.36 (1H, dd, J
2.4 Hz, Jgem 16.1 Hz, CHH0C„CH), 4.43 (1H, dd,
CHH0C„CH), 5.35 (1H, s, H-1), 5.58 (1H, s, PhCH),
7.36–7.52 (5H, m, 5 · Ar-H); dC (100.6 MHz, CDCl3)
13.9 (q, SCH3), 58.5 (t, CH2C„CH), 63.9 (d, C-5), 68.6
(t, C-6), 68.9 (d, C-3), 75.6 (s, CH2C„CH), 79.0 (s,
CH2C„CH), 79.1 (d, C-2), 79.6 (d, C-4), 84.1 (d, C-1),
102.2 (d, PhCH), 126.3, 128.3, 129.2 (3 · d, 5 · Ar-CH),
137.4 (s, Ar-C); m/z (ES+) 395 (95), 337 (M+H+, 90).
HRMS (ES+) calcd for C17H20NaO5S (M+Na+)
359.0924. Found 359.0924.
0
0
4.19. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-a-D-manno-
pyranosyl-(1!3)-[2-O-acetyl-3,4,6-tri-O-benzyl-a-D-
mannopyranosyl-(1!6)]-2-O-(prop-2-ynyl)-1-thio-
a-D-mannopyranoside 14a
4.18. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-a-D-mannopyr-
anosyl-(1!3)-2-O-(prop-2-ynyl)-1-thio-a-D-mannopyran-
oside 13b
Disaccharide diol 13b (148 mg, 0.20 mmol) and trichloro-
acetimidate 8 (143 mg, 0.22 mmol) were dissolved in dry
DCM (10 ml) and transferred via cannula to a flame-dried
Alcohol 12 (1.10 g, 3.27 mmol) and trichloroacetimidate 8
(2.29 g, 3.60 mmol) were dissolved in dry DCM (120 ml)
and transferred via cannula to a flame-dried flask contain-
˚
flask containing powdered molecular sieves (4 A, 100 mg).
˚
ing powdered molecular sieves (4 A, 5.0 g). The mixture
The mixture was stirred for 30 min at room temperature,
then cooled to ꢀ78 ꢁC and stirred under an atmosphere
of argon. TMSOTf (3.7 ll, 0.02 mmol) was added and
the mixture was stirred at ꢀ78 ꢁC for 4 h, then the temper-
ature was allowed to rise to room temperature overnight.
TLC (petrol–ethyl acetate, 1:1) revealed formation of a ma-
jor product (Rf 0.57) and complete consumption of accep-
tor (Rf 0.1). Triethylamine (100 ll) was added and the
solution stirred for a further 10 min. The reaction mixture
was then filtered, diluted with DCM (40 ml) washed with
sodium hydrogen carbonate (20 ml of a saturated solu-
tion), dried over MgSO4, filtered and concentrated in va-
cuo. The residue was purified by flash column
was stirred for 30 min at room temperature, then cooled
to ꢀ78 ꢁC and stirred under an atmosphere of argon.
TMSOTf (118 ll, 0.65 mmol) was added and the mixture
stirred at ꢀ78 ꢁC for 1 h, then the temperature was allowed
to rise to room temperature overnight. TLC (petrol–ethyl
acetate, 2:1) revealed the formation of a major product
(Rf 0.50) and complete consumption of acceptor (Rf
0.43). Triethylamine (0.5 ml) was added and the solution
stirred for a further 10 min. The reaction mixture was then
filtered, diluted with DCM (150 ml), washed with sodium
hydrogen carbonate (200 ml of a saturated solution), dried
over MgSO4, filtered and concentrated in vacuo. The resi-
due was partially purified by flash column chromatography
(petrol–ethyl acetate, 4:1) to give disaccharide 13a which
was then directly dissolved in a 10:1 CH3CN–H2O mixture
(100 ml) and treated with trifluoroacetic acid (10 ml). The
mixture was stirred at room temperature overnight and
TLC (petrol–ethyl acetate, 2:1) revealed formation of a
major product (Rf 0) and complete consumption of starting
material (Rf 0.50). The mixture was concentrated under
reduced pressure, repeatedly co-evaporated with toluene,
chromatography (petrol–ethyl acetate, 3:2) to give trisac-
17
charide 14a (185 mg, 77%). ½aꢂD ¼ þ58 (c 1.0, CHCl3); mmax
(KBr disc) 1743 (C@O) cmꢀ1; dH (400 MHz, CDCl3) 2.07
(3H, s, SCH3), 2.12, 2.15 (6H, 2 · s, OC(O)CH3), 2.37
(1H, at, J 2.3 Hz, C„CH), 3.70–3.75 (5H, m, H-6a, H-
6b, H-60b, H-6c, H-60c), 3.80, 3.82 (2H, 2 · at, J 9.0 Hz,
J 9.6 Hz, H-4b, H-4c), 3.88–4.13 (9H, m, H-2a, H-3a, H-
3b, H-3c, H-4a, H-5a, H-5b, H-5c, H-60a), 4.18 (1H, dd,
Jgem 16.2 Hz, CHH0C„CH), 4.30 (1H, dd, CHH0C„CH),

1732
E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
4.47, 4.85 (2H, ABq, J 10.7 Hz, PhCH2), 4.48, 4.86 (2H,
ABq, J 11.0 Hz, PhCH2), 4.51–4.56 (4H, m, PhCH2),
4.65–4.73 (4H, m, PhCH2), 4.89 (1H, d, J1c,2c 1.8 Hz, H-
1c), 5.25 (1H, d, J1a,2a 0.9 Hz, H-1a), 5.35 (1H, d, J1b,2b
1.6 Hz, H-1b), 5.48 (1H, dd, J2b,3b 3.2 Hz, H-2b), 5.49
(1H, dd, J2c,3c 3.3 Hz, H-2c), 7.14–7.17 (4H, m, 4 · Ar-
H), 7.26–7.38 (26H, m, 26 · Ar-H); dC (100.6 MHz,
CDCl3) 13.7 (q, SCH3), 21.1 (2 · q, 2 · OC(O)CH3), 57.1
(t, CH2C„CH), 66.4 (t, C-6a), 66.5 (d, C-4a), 68.7, 68.9
(2 · d, C-2b, C-2c), 68.7, 69.1 (2 · t, C-6b, C-6c), 71.6,
71.8, 71.9 (3 · d, C-5a, C-5b, C-5c), 71.7, 71.9, 73.4, 73.5,
74.9, 75.3 (6 · t, 6 · PhCH2), 74.4, 74.5 (C-4b, C-4c), 75.7
(s, CH2C„CH), 77.7, 77.9, 78.1, 78.4 (4 · d, C-2a, C-3a,
C-3b, C-3c), 79.5 (s, CH2C„CH), 82.8 (d, C-1a), 98.0 (d,
C-1c), 98.6 (d, C-1b), 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.1, 128.2, 128.3, 128.4 (10 · d, 30 · Ar-CH),
137.9, 138.1, 138.2, 138.5 (4 · s, 6 · Ar-C), 170.3 (s,
2 · C@O); m/z (ESI+) species observed (M+NHþ4 ),
(M+Na+) (major); (M+Na+) peaks observed: 1219.47
(100%), 1220.47 (74%), 1221.47 (27%), 1222.48 (4%),
1223.48 (0.3%), peaks calculated: 1219.47 (100%), 1220.47
(76%), 1221.47 (36%), 1222.48 (13%), 1223.48 (4%).
9 · PhCH2), 71.8, 71.9 (2 · d, C-4b, C-5b), 72.6 (C-4c),
74.7, 74.8, 75.0 (3 · d, C-5a, C-2b, C-3b, C-5b, C-2c),
75.2 (s, CH2C„CH), 76.0, 77.3 (2 · d, C-4a, C-3c), 78.6
(d, C-2a), 79.4 (d, C-5c), 79.7 (d, C-3a), 79.9 (s,
CH2C„CH), 82.6 (d, C-1a), 98.2 (d, C-1c), 99.7 (d, C-
1b), 126.7, 127.1, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7,
129.0, 129.8 (18 · d, 45 · Ar-CH), 138.2, 138.3, 138.4,
138.6, 138.7, 140.9 (6 · s, 9 · Ar-C); m/z (ESI+) species
observed (M+Na+); (M+Na+) peaks observed: 1405.59
(100%), 1406.60 (91%), 1407.59 (44%), 1408.59 (8%),
1409.59 (1%), peaks calculated: 1405.59 (100%), 1406.59
(94%), 1407.59 (52%), 1408.60 (21%), 1409.60 (7%),
1410.60 (2%).
4.21. Methyl 2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-
(1!3)-[2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-(1!6)]-
4-O-benzyl-2-O-(allenyl)-1-thio-a-D-mannopyranoside 15
Propargylated trisaccharide 14b (165 mg, 0.119 mmol) was
dissolved in dry DMSO (1 ml). tBuOK (7 mg, 62 lmol) was
added and the reaction mixture stirred at 65 ꢁC overnight.
TLC (petrol–ethyl acetate, 7:3) indicated the formation of a
major product (Rf 0.45) and complete consumption of a
starting material (Rf 0.39). The reaction was diluted with
ether (10 ml) and quenched with water (5 ml). The two
phases were separated and the organic one washed with
water (2 · 5 ml). The combined organic extracts were dried
over MgSO4, filtered and concentrated in vacuo. The resi-
due was purified by column chromatography (petrol–ethyl
4.20. Methyl 2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-
(1!3)-[2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-(1!6)]-
4-O-benzyl-2-O-(prop-2-ynyl)-1-thio-a-D-mannopyranoside
14b
Diacetate 14a (300 mg, 0.25 mmol) was dissolved in dry
MeOH (5 ml) and anhydrous K2CO3 (7.0 mg, 0.050 mmol)
was added. The mixture was stirred at room temperature
overnight. TLC (petrol–ethyl acetate, 1:1) revealed com-
plete consumption of starting material (Rf 0.57) and forma-
tion of a major product (Rf 0). The solution was
evaporated in vacuo and the residue dissolved in dry
DMF (10 ml) and treated with sodium hydride (45 mg of
a 60% mineral oil dispersion, 1.125 mmol). The mixture
was stirred for 30 min, then BnBr was added (178 ll,
1.5 mmol) and, after 1 h stirring, TLC (petrol–ethyl ace-
tate, 4:1) revealed complete consumption of the starting
material (Rf 0) and formation of a major product (Rf
0.13). The reaction was quenched by adding MeOH and
then diluted with ether (50 ml) and washed with water
(50 ml). The organic phase was dried (MgSO4), filtered
and concentrated in vacuo. The residue was purified by
flash column chromatography (petrol–ethyl acetate,
acetate, 7:3, with 2% added triethylamine) to afford allene
17
15 (128 mg, 77%) as a colourless syrup. ½aꢂD ¼ þ52 (c
0.6, CHCl3); dH (400 MHz, CDCl3, significant peaks only)
2.00 (3H, s, SCH3), 5.08 (1H, s, H-1), 5.07 (1H, d, J1c,2c
1.2 Hz, H-1c), 5.17 (2H, br s, H-1a, H-1b), 5.34 (1H, dd,
J 6.0 Hz, Jgem 8.6 Hz, CH@C@CHH0), 5.43 (1H, dd, J
6.0 Hz, CH@C@CHH0), 6.77 (1H, at,
CH@C@CHH0).
J
6.0 Hz,
4.22. p-Methoxyphenyl 4,6-O-benzylidene-3-O-tert-butyldi-
phenylsilyl-b-D-mannopyranosyl-(1!4)-3,6-di-O-benzyl-2-
deoxy-2-phthalimido-b-D-glucopyranosyl-(1!4)-3,6-di-O-
benzyl-2-deoxy-2-phthalimido-b-D-glucopyranoside 17b10d
General procedure for mixed acetal formation using mole-
˚
cular sieves (4 A), DCM (3 ml), 2,6-di-tert-butyl-4-methyl-
4:1!3:1) to afford fully protected trisaccharide 14b
pyridine (38 mg, 0.186 mmol), iodine (25 mg, 0.10 mmol),
silver triflate (26 mg, 0.101 mmol), allene donor 4 (49 mg,
84 lmol) and chitobiose acceptor16 (70 mg, 65 lmol) affor-
ded mixed acetals 17a as a mixture of diastereoisomers
(81 mg, 70%) as a white amorphous foam. dH (400 MHz,
CDCl3) major diastereoisomer 0.98 (9H, s, C(CH3)3),
1.99 (3H, s, SCH3), 3.67 (3H, s, OCH3), 5.35 (1H, d,
J1b,2b 8.2 Hz, H-1b), 5.49 (1H, d, J1a,2a 8.5 Hz, H-1a),
5.65 (1H, s, H-1c), 5.79 (1H, s, CI@CHH0), 6.27 (1H,þs,
CI@CHH0). m/z (ESI+) species observed (M+NH4 ),
(M+Na+) (major); (M+Na+) peaks observed: 1789.48
(78%), 1790.48 (100%), 1791.48 (60%), 1792.49 (19%),
1793.48 (6%), 1794.51 (2%), peaks calculated: 1789.50
(89%), 1790.50 (100%), 1791.50 (67%), 1792.50 (32%),
1793.50 (13%), 1794.51 (5%). The general procedure for
17
(316 mg, 91%) as a white amorphous foam. ½aꢂD ¼ þ50 (c
1.0, CHCl3); dH (500 MHz, CDCl3) 2.03 (3H, s, SCH3),
2.36 (1H, at, J 2.3 Hz, C„CH), 3.60–3.63 (2H, m, H-6a,
H-6c), 3.67–3.73 (2H, m, H-5b, H-60c), 3.76–3.86 (5H, m,
H-5a, H-60a, H-2b, H-6b, H-60b), 3.87–3.92 (3H, m, H-
2c, H-3c, H-5c), 3.98–4.06 (6H, m, H-2a, H-3a, H-3b, H-
4b, H-5b, H-4c), 4.11–4.17 (2H, m, H-4a, CHH0C„CH),
4.22 (1H, dd, Jgem 16.1 Hz, CHH0C„CH), 4.39, 4.70
(14H, m, PhCH2), 4.75 (2H, s, PhCH2), 4.87 (1H, d, JAB
10.9 Hz, PhCH2), 4.90 (1H, d, JAB 10.7 Hz, PhCH2), 5.07
(1H, d, J1c,2c 1.5 Hz, H-1c), 5.17 (1H, s, H-1a), 5.27 (1H,
d, J1b,2b 1.1 Hz, H-1b), 7.13–7.41 (45H, m, 45 · Ar-H);
dC (125.8 MHz, CDCl3) 13.8 (q, SCH3), 57.3 (t,
CH2C„CH), 65.5 (t, C-6a), 69.1, 69.2 (2 · t, C-6b, C-6c),
71.6, 72.2, 72.4, 73.3, 73.5, 74.4, 75.1, 75.2 (8 · t,
˚
intramolecular glycosylation using molecular sieves (4 A),

E. Attolino et al. / Tetrahedron: Asymmetry 18 (2007) 1721–1734
1733
DCM (3 ml), 2,6-di-tert-butyl-4-methylpyridine (12.5 mg,
61 lmol), dimethyldisulfide (4.6 ll, 51 lmol), triflic anhy-
dride (8.6 ll, 51 lmol) and mixed acetals 17a (18 mg,
acceptor 16 (66 mg, 61.7 lmol), afforded mixed acetals
19a (100 mg, 63%) as white amorphous foams. m/z
(ESI+) species observed (M+NHþ4 ), (M+Na+) (major);
(M+Na+) peaks observed: 2597.51 (55%), 2598.51
(100%), 2599.51 (86%), 2600.51 (47%), 2601.52 (19%),
2602.51 (5%), peaks calculated: 2597.87 (61%), 2598.88
(100%), 2599.88 (89%), 2600.88 (55%), 2601.89 (28%),
2602.89 (11%). The general procedure for intramolecular
glycosylation afforded an inseparable complex mixture of
products. Mass spectrometry revealed the presence of the
desired pentasaccharide 19b as a minor component of this
mixture of products. m/z (ESI+) species observed:
(M+NHþ4 ) 2381.94 (M+Na+) 2386.89.
10 lmol) then afforded trisaccharide 17b10d (5 mg, 32%);
22
½aꢂD ¼ þ44 (c 1.0, CHCl3), lit.10d [a]D = +45.1 (c 1.0,
CHCl3); mmax (KBr disc) 3474 (br, OH), 1777, 1716 (s,
C@O); dH (500 MHz, CDCl3) 1.06 (9H, s, C(CH3)3), 2.72
(1H, br s, OH), 2.96 (1H, adt, J 4.9 Hz, J 9.6 Hz, H-5c),
0
3.29 (1H, dd, J5b,6b 2.6 Hz, J6b,6 b 11.3 Hz, H-6b), 3.33
(1H, m, H-5b), 3.38–3.44 (2H, m, H-5a, H-6a), 3.51–3.56
(2H, m, H-60a, H-6c), 3.59 (1H, d, J2c,3c 3.4 Hz, H-2c),
3.64 (1H, m, H-60b), 3.66 (3H, s, OCH3), 3.77 (1H, dd,
J3c,4c 9.4 Hz, H-3c), 3.92 (1H, at, J 9.4 Hz, H-4c), 4.08–
4.30 (6H, m, H-3a, H-4a, H-2b, H-4b, H-60c, PhCH2),
4.36 (1H, dd, J1a,2a 8.6 Hz, J2a,3a 10.7 Hz, H-2a), 4.37
(1H, dd, J2b,3b 10.7 Hz, J3b,4b 8.6 Hz, H-3b), 4.43–4.56
(6H, m, PhCH2), 4.47 (1H, s, H-1c), 4.85 (1H, d, J
12.6 Hz, PhCH2), 5.25 (1H, d, J1b,2b 8.4 Hz, H-1b), 5.39
(1H, s, PhCH), 5.44 (1H, d, J1a,2a 8.6 Hz, H-1a), 6.59–
6.61 (2H, m, 2 · Ar-H), 6.70–6.77 (5H, m, 5 · Ar-H),
6.85–7.03 (9H, m, 9 · Ar-H), 7.14–7.39 (13H, m, 13 · Ar-
H), 7.41–7.93 (18H, m, 18 · Ar-H); dC (125.8 MHz,
CDCl3) 19.3 (s, C(CH3)3), 26.9 (q, C(CH3)3), 55.5
(OCH3, C-2a), 56.5 (d, C-2b), 66.4 (d, C-5c), 67.3 (t, C-
6b), 67.9 (t, C-6a), 68.5 (C-6c), 71.5 (d, C-2c), 72.5, 73.0,
74.4, 74.7 (4 · t, 4 · PhCH2), 72.6 (d, C-3c), 74.5, 74.6
(2 · d, C-5a, C-5b), 75.5 (d, C-4a), 76.4, 76.7 (2 · d, C-
3a, C-3b), 78.3 (d, C-4c), 78.9 (d, C-4b), 96.9 (d, C-1b),
97.4 (d, C-1a), 100.1 (d, C-1c), 101.7 (d, PhCH), 114.2,
118.5, 123.2, 123.3, 123.6, 126.1, 126.3, 126.9, 127.1,
127.2 127.4, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1,
128.2, 128.4, 128.8, 129.8, 130.1, 132.7, 133.3, 133.7,
133.8, 134.0, 135.8, 136.0 (47 · Ar-CH), 131.4, 131.7,
134.0, 137.3, 137.7, 138.4, 150.8, 155.1 (13 · Ar-C), 167.6,
168.2 (4 · C@O). JC-1c/H-1c 161 Hz (b).
Acknowledgement
The authors gratefully acknowledge the European Union
(Marie Curie Intra-EU Fellowship to E.A.) for financial
support.
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