N-Iodosuccinimide-mediated intramolecular aglycon delivery

Article abstract of DOI:10.1016/S0040-4020(01)00308-8

Enol ethers may be accessed via Tebbe methylenation of either 2-O acetates or para-methoxybenzoates. N-Iodosuccinimide may then be employed to achieve both tethering and thioglycoside activation allowing the stereoselective synthesis of α-glucosides and β-mannosides, either in a one or two step procedure.

Full text of DOI:10.1016/S0040-4020(01)00308-8

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 4221±4230
N-Iodosuccinimide-mediated intramolecular aglycon delivery
S. C. Ennis, A. J. Fairbanks,p C. A. Slinn, R. J. Tennant-Eyles and H. S. Yeates
Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
Received 13 December 2000; revised 20 February 2001; accepted 8 March 2001
AbstractÐEnol ethers may be accessed via Tebbe methylenation of either 2-O acetates or para-methoxybenzoates. N-Iodosuccinimide
may then be employed to achieve both tethering and thioglycoside activation allowing the stereoselective synthesis of a-glucosides and
b-mannosides, either in a one or two step procedure. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
combination of the Ogawa PMB and the Hindsgaul mixed
ketal systems. In this paper we would like to give full details
of both of our investigations into NIS mediated variants of
the acetate derived enol ether system, and into a new hybrid
Ogawa/Hindsgaul system, which is derived via Tebbe
methylenation of a 2-O-para-methoxybenzoyl protected
glycosyl donor.
Glycosides may be subdivided into two categories depend-
ing on whether the 2-hydroxyl group is cis or trans to the
anomeric substituent. Whilst the use of participating
protecting groups on the 2-hydroxyl of the glycosyl donor
readily allows the formation of 1,2-trans linkages,1 the
stereoselective formation of 1,2-cis linkages is considerably
more dif®cult. Whilst there are several potential solutions to
this problem,2 one of the most ingenious is to temporarily
tether the glycosyl acceptor to the C-2hydroxyl of the
glycosyl donor. This process can then be followed by a
stereospeci®c intramolecular glycosylation, or intra-
molecular aglycon delivery 4IAD), wherein the aglycon is
delivered to the same face of the glycosyl donor as the C-2
hydroxyl, hence forming a 1,2-cis linkage. At least initially
the development of IAD was motivated by the ubiquity of
the b-manno linkage in the N-glycan core pentasaccharide.
The most notable applications of IAD of the synthesis of
b-mannosides have arisen from the laboratories of
Hindsgaul3, Stork,4 and Ogawa,5 whilst Bols extended
the Stork silicon tether approach to the synthesis of
a-glucosides.6
2. Results and discussion
2.1. Synthesis of glycosyl donors
Investigations focussed on the use of thiophenyl glycosides
as donors since it was envisaged that N-iodosuccinimide
could be used for both tethering and activation steps, allow-
ing the potential development of a one-pot approach which
would obviate the need for the handling of sensitive mixed
ketal intermediates. The required manno 18 and gluco 29
acetate substrates for Tebbe methylenation were readily
synthesised according to reported literature procedures
41: 4 steps from mannose a-pentaacetate, 33% overall
yield; 2: 4 steps from glucose b-pentacetate, 43% overall
yield). Tebbe methylenation then provided the correspond-
ing manno and gluco enol ethers 3 and 4 470% and 68%
yields respectively, Scheme 1). The corresponding 2-O-
para-methoxybenzoyl protected gluco thioglycoside 5 was
simply accessed by deacetylation of the gluco acetate 2, by
treatment with catalytic sodium methoxide in methanol to
yield the known10 alcohol 6 494% yield). Alcohol 6 was then
esteri®ed by treatment with p-anisic acid and dicyclohexyl-
carbodiimide to yield the gluco para-methoxy benzoate 5
452% yield). Tebbe methylenation of 5 then yielded the
required para-methoxyphenyl enol ether 7 466% yield).
We recently reported7 a modi®cation and extension of the
original Hindsgaul mixed ketal approach,3 which we
applied to the synthesis of a series of b-mannnosides and
a-glucosides. Whilst considering potential further modi®ca-
tions and improvements to the mixed ketal methodology, we
were mindful of the particular limitation observed in
Hindsgaul's initial investigations, namely the low yields
observed for glycosylations with bulky aglycons. In contrast
the Ogawa para-methoxybenzyl derived system5 does not
suffer from the same problem. It therefore seemed prudent
to additionally investigate a hybrid situation, involving a
2.2. Investigations of two step NIS mediated tethering
and glycosylation reactions
Keywords: carbohydrates; glycosidation; stereocontrol; thioglycosides.
Corresponding author. Tel.: 144-1865-275-647; fax: 144-1865-275-
674; e-mail: antony.fairbanks@chem.ox.ac.uk
p
gluco Donor: Initial attempts at tethering using catalytic
acid in the gluco series 4following the reported procedure3
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00308-8

4222
S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
O
BnO
O
O
BnO
(i)
O
O
BnO
BnO
BnO
BnO
3
4
1
SPh
SPh
OBn
O
OBn
O
(ii)
BnO
BnO
SPh
BnO
BnO
SPh
O
O
O
2
(iii)
OBn
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
SPh
SPh
(iv)
(v)
BnO
BnO
SPh
O
O
OH
O
6
5
7
MeO
MeO
Scheme 1. 4i) Tebbe reagent, pyridine, THF, 2408C to RT, 2h, 70%; 4ii) Tebbe reagent, pyridine, THF, 2408C to RT, 2h, 68%; 4iii) Na, MeOH, RT, 18 h,
94%; 4iv) p-anisic acid, DCCI, THF, DMAP, re¯ux, 18 h, 52%; 4v) Tebbe reagent, pyridine, THF, 2788C to RT, 18 h, 66%.
for the manno series) lead only to hydrolysis of the enol
ether. Therefore attention turned to the use of other electro-
philes for this initial step. Although it was found that iodine
could successfully tether methanol to enol ether 4 492%
yield), attention focussed on the use of N-iodosuccinimde
4NIS), driven by the prospect of the development of a one-
pot procedure, wherein tethering and glycosylation were
achieved sequentially in a single reaction vessel. Thus
treatment of the enol ether 4 with a variety of alcohols
and NIS in THF at low temperature, produced good to
excellent yields of mixed ketal intermediates 8%a±e)
which could each be isolated as an inseparable mixture
of diastereomers after ¯ash chromatography on silica
4Scheme 2, Table 1).
Subsequent attempted NIS mediated intramolecular
OBn
O
OBn
O
OBn
O
(i)
(ii)
BnO
BnO
SPh
OR
BnO
BnO
BnO
BnO
SPh
O
HO
O
OR
I
4
8(a-e)
9(a-e)
Scheme 2. 4i) ROH, NIS 43 equiv.), THF, 2788C to RT; 4ii) NIS 45 equiv.), DTBMP, CH2Cl2, 08C to RT.
Table 1. gluco Tethering and glycosidation
Entry
a)
Alcohol ROH
MeOH
Product /Yield of Mixed Ketals
Product /Yield of Glycosidation
8a / 96%
9a/ 75%
b)
8b/ 76%
8c/ 82 %
9b/ 75%
9c/ 86%
c)
d)
e)
8d/ 82 %
8e/ 56%
9d/ 65%
9e/ 55%

S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
4223
I
O
O
OR
OH
O
BnO
BnO
BnO
O
O
(i)
(ii)
BnO
BnO
BnO
BnO
BnO
BnO
OR
SPh
11(a-d)
SPh
3
12(a-d)
Scheme 3. 4i) ROH, NIS 43 equiv.), THF, 2788C to RT; 4ii) NIS 45 equiv.), DTBMP, CH2Cl2, 08C to RT.
Table 2. manno Tethering and glycosidation
Entry
a)
Alcohol ROH
MeOH
Product / Yield of Mixed Ketals
Product / Yield of Glycosidation
11a / 92 %
12a / 70%
b)
c)
d)
11b / 66%
11c / 95%
11d / 76%
12b / 88%
12c / 63%
12d / quantitative
glycosylation of these mixed ketals in THF as the solvent
gave only moderate yields of products. However glycosyl-
ation in dichloromethane at room temperature, with the
addition of 2,6-di-tert-butyl-4-methylpyridine 4DTBMP)
produced clean high yielding reactions 4Table 1). As can
be seen the yields for both tethering and glycosylation when
performed in these two different solvents are good with
primary alcohols, and in all cases only the a products
49a±e) were observed. Cyclohexanol also produced good
results 4entry d). Particularly noteworthy is the reaction of
4 with the protected serine derivative 10,11 which, after
sequential tethering and activation yielded the a-glycosyl
amino acid 9e.12 This approach may therefore be useful
for the stereoselective synthesis of a-O-linked glyco-
peptides.
p-Methoxybenzoyl derived donor. Initial tethering experi-
ments revealed that reaction of the PMBz derived enol
ether with NIS was extremely rapid at 2408C in dichloro-
ethane, but that yields were low. This lead to a change of
reaction solvent to dichloromethane, since tethering could
then be achieved at 2788C. Tethering experiments using the
PMBz derived enol ether 7 in dichloromethane quickly
revealed that the intermediate mixed ketals were much
more labile than in the acetate derived cases. For example
although reaction of enol ether 7 with methanol and NIS at
2788C in dichloromethane was complete by TLC after
10 minutes, attempted work-up produced large amounts of
hydrolysed material 6, together with a small amount of a
mixture of two compounds, the structures of which were
tentatively assigned14 as the mixed ketals 13 4Scheme 4).
Simple stirring of 13 with acidic ion exchange resin rapidly
resulted in the formation of the hydrolysed material 6 as the
sole isolable product. It was clear that the mixed ketal inter-
mediates in this PMBz derived system were extremely
sensitive and underwent hydrolysis very rapidly. Since in
this case a two-step procedure would probably not be either
high yielding or facile, attention turned to the development of
an operationally simple one-pot approach, which would avoid
the isolation or handling of these intermediates, along the lines
of that developed for the acetate derived system 4vide infra).
manno Donor. A similar set of reactions were performed in
the analogous mannoseries 4Scheme 3). NIS mediated
tethering in THF with a similar series of alcohols again
produced good yields of mixed ketals 11%a±d) and sub-
sequent NIS mediated glycosylation in dichloromethane
cleanly produced the corresponding glycosides 12%a±d)
4Table 2). Again yields for both tethering and glycosylation
were good, and in all cases only b-mannnoside products
were isolated.13
(ii)
OBn
O
OBn
O
OBn
O
BnO
BnO
SPh
(i)
BnO
BnO
SPh
BnO
BnO
+
SPh
O
O
OMe
OH
I
7
13
6
MeO
MeO
Scheme 4. 4i) MeOH, NIS 43 equiv.), DCM, 2788C, 10 min; 4ii) acidic ion exchange resin, MeOH, RT.

4224
S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
OBn
O
OBn
O
BnO
BnO
BnO
BnO
OBn
O
O
HO
O
(i)
O
(ii)
BnO
BnO
SPh
O
I
O
O
O
O
O
O
O
O
O
O
O
O
O
O
14
4
9c
O
O
OH
O
BnO
BnO
BnO
O
(iii)
O
BnO
BnO
BnO
O
O
O
O
SPh
O
O
3
12c
Scheme 5. 4i) diacetone galactose 43 equiv.), NIS 43 equiv.), DCE, 2408C to RT, 79%; 4ii) diacetone galactose, NIS, DTBMP, DCE, 2408C to RT, then
Dowex H1/MeOH, 68%; 4iii) diacetone galactose, NIS, DTBMP, DCE, 2408C to RT, then Dowex H1/MeOH, 84%.
2.3. One-Pot Approach
reaction, very small amounts of b-gluco products were
occasionally observed. A slight modi®cation of the experi-
mental procedure, involving the addition of the DTBMP and
further NIS immediately after tethering was complete
4,15 minutes at 2408C as monitored by TLC), together
the use of an acidic work-up procedure involving stirring
of the crude reaction product with acidic ion exchange resin
4Dowex 50WX8-100, H1) in methanol, allowed the forma-
tion of the a-disaccharide 9c in a single manipulation, in a
very satisfactory 68% yield 4Scheme 5). This completely
stereoselective glycosylation was in direct contrast with a
control reaction using phenyl 2,3,4,6 tetra-O-benzyl-1-thio-
a-d-glucopyranoside as the glycosyl donor, which under
similar reaction conditions produced a 1:1 mixture of the
a-and b-anomers. A similar one-pot transformation was
performed in the manno series, again with dichloroethane
as the solvent. In this case the reaction was even more
ef®cient, allowing the synthesis of the b-manno disaccharide
12c in a single operation in an excellent 84% yield
4Scheme 5).
The success of the tethering reactions in the acetate derived
series detailed above clearly demonstrated the order of
magnitude difference in reactivity between the enol ether
and the anomeric sulphur. Therefore in theory it should be
a simple matter to effect both tethering and glycosylation in
a single step, though early indications were that the choice
of reaction solvent was important. A screen to ®nd a solvent
which produced clean, high-yielding reactions for the
glycosylation step, led us to investigate the use dichloro-
ethane for the one-pot reaction.
Stirring the glucoacetate derived donor 4 with diacetone
galactose and 3 equivalents of NIS in dichloroethane
42408C to RT, overnight), produced an inseparable mixture
of products, which were identi®ed as the a-glucoside ketals
14, in a combined 79% yield 4Scheme 5). Production of 14
presumably occurred by trapping of the oxonium ion
produced subsequently to glycosylation by the excess of
glycosyl acceptor present in solution. Since in this case no
b-products were observed it can be concluded that the intra-
molecular process competed effectively with the possible
intermolecular reaction for this donor in this solvent. This
was con®rmed by a competitive control reaction, whereby
glycosylation of the diacetone galactose mixed ketals 8c
was undertaken in dichloroethane in the presence of
3 equivalents of methanol as intermolecular nucleophile;
no methyl glycoside products were observed. However it
is clear that the choice of reaction solvent is important to
ensure that intramolecular reaction is entirely competitive,
since when ether was used for the attempted one-pot
On the basis of these successful developments one-pot
tethering and glycosyation was attempted in the PMBz
derived system. Using the optimised reaction conditions
one-pot tethering and glycosylation of enol ether 7 was
undertaken in dichloromethane with both methanol and
diacetone galactose as glycosyl acceptors. In both cases
reaction was successful, though less ef®cient than in the
acetate derived case; the a-glycosides 9a and 9c were
obtained in 55% and 49% yields respectively. Again no
b-glucoside products were observed. However when one-
pot reaction of 7 was attempted with cyclohexanol in
OBn
O
OBn
O
OBn
O
BnO
BnO
SPh
(i) or (ii)
(iii)
BnO
BnO
BnO
BnO
O
O
OH
HO
OR
(i) R = Me, 9a
(ii) R = diacetone galactose, 9c
7
9d and 15
MeO
Scheme 6. 4i) MeOH, NIS, DTBMP, CH2Cl2, 2788C to RT, then Dowex H1/MeOH, 55%; 4ii) diacetone galactose, NIS, DTBMP, CH2Cl2, 2788C to RT, then
Dowex H1/MeOH, 49%; 4iii) cyclohexanol, NIS, DTBMP, CH2Cl2, 2788C to RT, then Dowex H1/MeOH, 51%, a:b 3:1.

S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
4225
dichloroethane surprisingly an a/b mixture of glycoside
products 9d and 15 was observed, in a combined 51%
yield 4Scheme 6). This was perplexing since all of the
previously investigated reactions in dichloroethane had
been completely stereoselective. In light of this result it
was concluded that in the case of the PMBz derived system
intermolecular reaction could occur competitively, limiting
the synthetic utility of this approach. This is probably due to
the inherent low stability of the para-methoxyphenyl mixed
ketal intermediates, which decompose during the reaction,
leaving intermolecular reaction as the only possibility.
Laboratory, Oxford. Thin layer chromatography 4TLC)
was carried out on Merck Kieselfel 0.220.25 mm thickness
glassbacked sheets, pre-coated with 60F254 silica. Plates
were developed using 0.2% w/v cerium 4IV) sulfate and
5% w/v ammonium molybdate in 2M sulphuric acid.
Flash column chromatography was carried out using Sorbsil
C60 40/60 silica or basic alumina. Solvents and reagents
were dried and puri®ed before use according to standard
procedures; methanol was distilled from sodium hydride,
dichloromethane 4DCM) was distilled from calcium
hydride, pyridine was distilled from calcium hydride and
stored over potassium hydroxide and tetrahydrofuran was
distilled from a solution of sodium benzophenone ketyl
immediately before use. Petrol was distilled between 40
and 608C before use to remove involatile fractions.
3. Summary and conclusion
In summary we have demonstrated that N-iodosuccinimide
can be used to effect both tethering and glycosylation steps
implicit in the Hindsgaul mixed ketal approach to 1,2-cis
glycosides, and that this methodology allows the stereo-
selective synthesis of a number of a-glucosides as well as
of b-mannosides. Moreover the use of dichloroethane as
solvent permits a one-pot approach, whereby both tethering
and glycosylation are achieved in a single manipulation.
However the PMBz derived system, which can be con-
sidered as a hybrid of the Hindsgaul and Ogawa approaches
has less synthetic utility. The mixed ketal intermediates in
this case are particularly unstable, and the utility of a one-
pot approach is diminished by the ®nding that intermolecu-
lar reaction can be competitive leading to the formation of
an a/b product mixture in the case of a secondary alcohol
acceptor.
4.1. Phenyl-3,4,6-tri-O-benzyl-2-O-%2-propenyl)-1-thio-
b-d-mannopyranoside 3
Acetate 18 4100 mg, 0.17 mmol) was dissolved in THF
44 ml) and pyridine 40.1 ml). Tebbe reagent 40.5 M in
toluene, 0.68 ml, 0.34 mmol) was added at 2408C, and
the reaction mixture was allowed to warm to 2108C.
After 2h, TLC 4petrol:ethyl acetate, 5:1) indicated the
consumption of starting material 4Rf 0.4) and the formation
of a major product 4Rf 0.6). The reaction was quenched by
the careful addition of ether 45 ml), and 1 M aqueous NaOH
40.1 ml), ®ltered through Celitew and washed with more
ether until the ®ltrate was colourless. The organic layer
was dried 4MgSO4), ®ltered, and concentrated in vacuo.
The deep red residue was puri®ed by column chromato-
graphy 4petrol:ethyl acetate, 5:1, 0.1% triethylamine) to
yield enol ether 3 470 mg, 70%) as a pale yellow crystalline
Further development and re®nement of the one-pot pro-
cedure, extensions to other enol ether systems, and investi-
gations into the applicability of this methodology to
hindered secondary carbohydrate alcohols are currently in
progress, and will be reported in due course.
24
solid; mp 63±658C 4ether/petrol); [a]D ˆ1106 4c, 0.95 in
CHCl3); nmax 4KBr disc) 1650 4CvC) cm21; dH 4400 MHz,
CDCl3) 1.90 43H, s, CH3), 3.77±3.74 42H, m, H-60,
CvCHH), 3.87 41H, dd, J5,6ˆ4.9 Hz, J6,6'ˆ10.9 Hz, H-6),
3.98±3.95 42H, m, H-3, CvCHH), 4.11 41H, a-t, J3,4ˆJ4,5ˆ
9.5 Hz, H-4), 4.31 41H, ddd, J4,5ˆ9.7 Hz, J5,6ˆ4.7 Hz,
J5,6'ˆ1.6 Hz, H-5), 4.49 41H, d, Jˆ11.9 Hz, PhCH2),
4.70±4.66 43H, m, PhCH2), 4.57±4.55 42H, m, PhCH2, H-
2), 4.95, 41H, d, Jˆ10.7 Hz, PhCH2), 5.76 41H, d,
J1,2ˆ0.8 Hz, H-1), 7.42±7.23 418H, m, ArH), 7.50±7.47
42H, m, ArH); dC 450.3 MHz, CDCl3) 21.1 4q, CH3), 69.1,
72.0, 73.3, 75.3 44£t, 3£PhCH2, C-6), 72.4, 75.4, 74.7, 79.0,
84.245 £d, C-1, C-2, C-3, C-4, C-5), 83.0 4t, CvCH2),
127.7, 127.9, 128.2, 128.5, 128.6, 128.7, 129.3, 129.6,
131.9 49£d, 20£ArCH), 134.2, 138.2, 138.5, 138.7 44£s,
4£ArC), 158.6 4s, CˆCH2); m/z 4APCI1) 604.8 4M1Na1,
17%), 583.0 4M1H1, 15), 638 418), 417.1 443), 341.1 484),
309.1 424), 120.8 4100), 106.7 421). 4Found: C, 74.25; H,
6.37. C36H38O5S requires: C, 74.20; H, 6.57%). 4HRMS
Calcd. For C36H39O5S 4M1H1) 583.2518. Found
583.2515).
4. Experimental
Melting points were recorded on a Ko¯er hot block and are
uncorrected. Proton nuclear magnetic resonance 4dH) spec-
tra were recorded on a Bruker DPX 400 4400 MHz) or on a
Bruker AMX 500 4500 MHz) spectrometer. Carbon nuclear
magnetic resonance 4dC) spectra were recorded on a Bruker
AC 200 450.3 MHz), or on a Bruker DPX 400 4100.6 MHz)
spectrometer. Multiplicities were assigned using DEPT
sequence. All chemical shifts are quoted on the d-scale in
parts per million 4ppm). Infrared spectra were recorded on a
Perkin±Elmer 150 Fourier Transform spectrophotometer.
Low resolution mass spectra were recorded a Micromass
Platform 1 APCI using atmospheric pressure chemical
ionisation 4APCI). High reolsution mass spectra 4electro-
spray) were performed on a Waters 2790-Micromass LCT
electrospray ionisation mass specrometer, or by the EPSRC
Mass Spectrometry Service Centre, Department of
Chemistry, University of Wales, Swansea on a MAT900
XLT electrospray ionisation mass specrometer. Optical
rotations were measured on a Perkin±Elmer 241 polari-
meter with a path length of 1 dm. Concentrations are
given in g/100 ml. Microanalyses were performed by
the microanalytical services of the Inorganic Chemistry
4.2. Phenyl 2,3,6-tri-O-benzyl-2-O-%2-propenyl)-1-thio-
b-d-glucopyranoside 4
To a stirred solution of acetate 29 43 g, 5.1 mmol) in THF
450 ml) and toluene 425 ml) was added pyridine 41 ml),
followed by Tebbe Reagent 40.5 M solution in toluene,
19 ml, 9.9 mmol) portionwise, at 2408C, under argon.
After the addition of Tebbe Reagent was completed, the

4226
S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
reaction was allowed to reach 2108C. After 1.5 h, TLC
4petrol:ethyl acetate, 3:1) indicated complete conversion
of starting material 4Rf 0.8) to a major product 4Rf 0.9).
1 M Aqueous NaOH 40.1 ml) was added carefully to the
reaction mixture 4vigorous methane evolution). After the
gas evolution subsided, the reaction mixture was allowed
to reach room temperature, followed by a further addition of
1M aqueous NaOH 40.5 ml). The deep red mixture was
®ltered through Celitew, the ®ltrate washed with ether
until colourless and concentrated in vacuo. The resulting
residue was puri®ed by column chromatography 4petro-
l:ethyl acetate, 7:1) to give enol ether 4 42.0 g, 68%) as a
pale yellow crystalline powder; mp 788C 4ether/petrol);
acetate, 2:1) indicated complete conversion of starting
material 4Rf 0.7) to a major product 4Rf 0.5). The reaction
mixture was ®ltered through Celitew, the ®ltrate was washed
with DCM 4150 ml), dried 4MgSO4), ®ltered, and concen-
trated in vacuo. The resulting residue was puri®ed by ¯ash
column chromatography 4petrol:ethyl acetate, 7:2) to give
ester 5 40.50 g, 52%) as a white crystalline solid; mp 110±
22
1118C 4ether/petrol); [a]D ˆ145 4c, 0.9 in CHCl3); nmax
4KBr disc) 17124C ˆO) cm21; dH 4400 MHz, CDCl3) 3.63±
3.67 41H, m, H-5), 3.76 41H, a-t, J3,4ˆJ4,5ˆ9.0 Hz, H-4),
0
3.78 41H, dd, J5,6ˆ4.7 Hz, J6,6 ˆ11.1 Hz, H-6), 3.86 41H,
0
0
dd, J5,6 ˆ1.6 Hz, H-6 ), 3.86±3.91 41H, m, H-3), 3.90 43H,
s, CH3), 4.59, 4.65 42H, ABq, Jˆ11.9 Hz, PhCH2), 4.62,
4.85 42H, ABq, Jˆ11.3 Hz, PhCH2), 4.69, 4.75 42H, ABq,
Jˆ10.9 Hz, PhCH2), 4.8241H, d, J1,2ˆ10.1 Hz, H-1), 5.32
41H, dd, J2,3ˆ9.2Hz, H-2), 6.95±6.98, 8.03±8.07 44H,
2£m, CH3OC6H4), 7.14±7.53 420H, m, ArH); dC
4100.6 MHz, CDCl3) 55.5 4q, CH3), 69.0, 73.5, 75.1, 75.3
44£t, C-6, PhCH2), 72.2, 77.7, 79.4, 84.4, 86.3 45£d, C1,
C-2, C-3, C4, C-5), 113.1 4d, ArCH), 122.2 4s, ArC), 127.6.
127.7, 127.9, 128.0, 128.1, 128.3, 128.4, 128.4, 128.8,
132.0, 132.4, 132.8, 133.1, 137.7, 137.9, 137.9, 138.2
417£d, 30£ArCH), 133.3, 137.7, 137.9, 138.244 £s,
4£ArC), 163.6, 164.9 42£s, ArC, CvO); m/z 4APCI1) 700
4M1Na1, 24%), 568 4M-SPh, 28), 135 4MeOC6H4CO,
100). 4Found: C, 72.90%; H, 5.99%. C41H40O7S requires:
C, 72.76%; H, 5.96%).
[a]D ˆ±30 4c, 1.2in CHCl ); nmax 4KBr disc) 1657 cm21
23
3
4CvC); dH 4400 MHz 1 COSY, CDCl3) 1.8243H, s, C H3),
0
3.46 41H, ddd, J4,5ˆ9.6 Hz, J5,6ˆ4.7 Hz, J5,6 ˆ1.8 Hz, H-5),
3.58 41H, a-t, J3,4ˆ4,5ˆ9.6 Hz, H-4), 3.63±3.70 42H, m, H-3,
0
0
H-6), 3.71 41H, dd, J6,6 ˆ10.9 Hz, H-6 ), 4.03 41H, d,
Jˆ1.4 Hz, CvCHH), 4.07 41H, a-t, J1,2ˆ2,3ˆ9.3 Hz, H-2),
4.1241H, d, C vCHH) 4.44 41H, d, Jˆ12.0 Hz, PhCH2),
4.48 41H, d, Jˆ10.3 Hz, PhCH2), 4.51 41H, d, PhCH2),
4.60 41H, d, J1,2ˆ9.7 Hz, H-1), 4.6241H, d, Jˆ10.7 Hz,
PhCH2), 4.74 41H, d, PhCH2), 4.76 41H, d, PhCH2),
7.11±7.57 420 H, m, ArH); dC 450.3 MHz 1 DEPT,
CDCl3): 21.3 4q, CH3), 69.1, 73.4, 75.1, 75.4, 85.1 45£t,
C-6, 3£PhCH2, CvCH2), 77.2, 77.4, 79.2, 86.1, 87.2
45£d, C-1, C-2, C-3, C-4, C-5), 127.6, 127.8, 127.9,
128.1, 128.5, 129.0, 132.2 47£d, ArCH), 134.0, 138.4,
138.5 43£s, ArC); m/z 4APCI 1ve) 605 4M1Na1, 20%),
525 4100). 4Found: C, 74.07; H, 6.52. C36H38O5S requires:
C, 74.20; H, 6.52%).
4.5. Phenyl 3,4,6-tri-O-benzyl-2-O-%1-para-methoxy-
phenyl-ethenyl)-1-thio-b-d-glucopyranoside 7
Tebbe reagent 40.5 M in toluene, 1.75 ml, 0.88 mmol) was
added to a stirred solution of the ester 5 4298 mg,
0.44 mmol) in anhydrous pyridine 40.4 ml), and anhydrous
THF 42ml) at 2788C under argon. The reaction was then
allowed to warm to room temperature and after 18 h, TLC
4petrol:ethyl acetate, 1:1) showed conversion of starting
material 4Rf 0.5) to a major product 4Rf 0.6). The reaction
mixture was diluted with ether 45 ml), cooled to 08C and
quenched by the addition of aqueous sodium hydroxide
41.0 M, 2ml) until vigorous gas evolution ceased. The
resulting residue was ®ltered though Celitew, washing
with ether 4250 ml). The ®ltrate was dried 4magnesium sul-
fate) and concentrated in vacuo. The resulting residue was
puri®ed by ¯ash column chromatography on basic alumina
4petrol:ethyl acetate, 5:1) to give the vinyl ether 7 4197 mg,
66%, 78% based on recovered starting material) as an
4.3. Phenyl 3,4,6-tri-O-benzyl-1-thio-b-d-glucopyrano-
side 610
A solution of sodium 4440 mg) in methanol 450 ml) was
added to a stirred solution of the acetate 29 42.02 g,
3.46 mmol) in methanol 4100 ml) under argon. After 18 h,
TLC 4petrol:ethyl acetate, 3:1) indicated complete conver-
sion of starting material 4Rf 0.5) to a major product 4Rf 0.4).
DCM 4100 ml) was added to the reaction mixture, which
was then washed with dilute aqueous HCl 41 M, 100 ml).
The organic phase was then dried 4MgSO4), ®ltered and
concentrated in vacuo. The resulting residue was puri®ed
by recrystallisation 4ether/petrol) to give the alcohol 6
41.77 g, 94%) as a white crystalline solid; mp 72±758C
4ether/petrol); [a]D ˆ211.24 c, 1.0 in CHCl3), [Lit.,10
22
mp 71±738C; [a]D25±11.5 4c, 1.4 in CHCl3)]; dH 4400
MHz, CDCl3) 2.42 41H, d, J2,OHˆ1.8 Hz, OH), 3.49±3.57
42H, m, H-2, H-5), 3.59±3.65 42H, m, H-3, H-4), 3.75 41H,
22
unstable brown syrup; [a]D 21.9 4c, 0.7 in CHCl3); nmax
4thin ®lm) 1684 4CvC) cm21; dH 4400 MHz, CDCl3) 3.62±
3.65 41H, m, H5), 3.7241H, a-t, J3,4ˆJ4,5 9.3 Hz, H-4), 3.78
0
0
0
dd, J5,6ˆ4.3 Hz, J6,6 ˆ11.0 Hz, H-6), 3.81 41H, dd, J5,6
41H, dd, J5,6 4.7 Hz, J6,6 10.8 Hz, H-6), 3.83±3.89 45H, m,
1.9 Hz, H-60), 4.5241H, d, J1,2ˆ9.6 Hz, H-1), 4.55±4.94
H3, H-60, CH3), 4.3241H, a-t, J1,2ˆJ2,3ˆ9.5 Hz, H-2) 4.48,
4.74 42H, 2£d, Jˆ2.8 Hz, CvCH2), 4.58, 4.64 42H, ABq,
Jˆ11.9 Hz, PhCH2), 4.60, 4.87 42H, ABq, Jˆ11.2Hz,
PhCH2), 4.67, 4.83 42H, ABq, Jˆ10.5 Hz, PhCH2), 4.83
41H, d, H-1), 6.87±6.97, 7.69±7.71 44H, m, CH3OC6H4),
7.20±7.38, 7.54±7.56 420H, m, ArH); dC 4100.6 MHz,
CDCl3) 55.5 4q, CH3), 69.0, 73.4, 75.1, 75.2, 84.4 45£t,
C-6, 3£PhCH2, CvCH2), 77.4, 77.6, 79.2, 86.2, 87.0
45£d, C-1, C-2, C-3, C-4, C-5), 113.4, 113.7, 113.7,
127.4, 127.5, 127.5, 127.6, 127.7, 127.8, 127.9, 127.9,
128.0, 128.3, 128.3, 128.3, 128.4, 128.4, 128.5, 128.7,
129.0, 132.5, 132.9 422£d, 24£ArCH), 130.6 4s, ArC),
46H, m, 3£PhCH2), 7.20±7.60 420H, m, ArH).
4.4. Phenyl 3,4,6-tri-O-benzyl-2-O-para-methoxy-
benzoyl-1-thio-b-d-glucopyranoside 5
Dicyclohexylcarbodiimide 41.19 g, 5.74 mmol) was added
to a stirred solution of the alcohol 6 4857 mg, 1.58 mmol) in
THF 415 ml) at room temperature. After 30 min., p-anisic
acid 41.21 g, 7.95 mmol) and then DMAP 451 mg,
0.42mmol) were added. The resulting reaction mixture
was re¯uxed under argon, and after 18 h, TLC 4petrol:ethyl

S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
4227
20
133.2, 4s, ArC) 138.1, 138.242 £s, ArC), 159.1, 160.0
[a]D ˆ12 6 c,4 0.5, CHCl3)]; dH 4400 MHz1COSY,
CDCl3) 1.34, 1.35, 1.45, 1.53 412H, 4£s, 4£CH3), 3.63±
3.78 46H, m, H-20, H-30, H-40, H-6a0, H-6b0, H-60), 3.85
1
42£s, ArC, CˆCH2); m/z 4APCI1) 692 4M1NH4
,
100%).
0
0
0
0
0
41H, ddd, J4 ,5 ˆ9.6 Hz, J5 , ˆ2.8 Hz, J5,6b ˆ1.9 Hz, H-
6a
50), 3.91 41H, dd, J5,6ˆ6.9 Hz, J6,6 ˆ10.3 Hz, H-6), 3.99
0
4.6. General procedure for two stage tethering and
glycosylation
0
41H, ddd, J4,5ˆ10.1 Hz, J5,6 ˆ1.9 Hz, H-5), 4.25 41H, dd,
H-4), 4.33 41H, dd, J1,2ˆ2.5 Hz, J2,3ˆ5.0 Hz, H-2), 4.47±
4.57 42H, 2£d, PhCH2), 4.61±4.65 42H, m, H-3, PhCH2),
A mixture of either the gluco 4 or manno 3 enol ether
4typically 100 mg, 0.17 mmol), the alcohol 43 equivalents)
Ê
and 4A molecular sieves 4200 mg, powdered) in THF 43 ml)
0
0
4.81±4.84 42H, 2£d, PhCH2), 4.93 41H, d, J1 ,2 ˆ3.4 Hz,
H-10), 4.98 41H, d, PhCH2), 5.5241H, d, J1,2ˆ5.0 Hz,
H-1), 7.13±7.53 415H, m, ArH).
was stirred at 2788C, under argon. N-Iodosuccinimide
4124 mg, 0.51 mmol) was added and the resulting reaction
mixture was allowed to reach 08C. After 18 h, DCM 450 ml)
was added to the reaction mixture, which was then ®ltered
through Celitew, the ®ltrate washed with 10% aq. sodium
thiosulfate 425 ml), the organic phase dried 4MgSO4),
®ltered and concentrated in vacuo. The resulting residue
was puri®ed by column chromatography 4petrol:ethyl
acetate, 4:1, 0.1% triethylamine) to give the mixed ketals,
as a colourless oil. A solution of this mixture 4typically
100 mg, 0.12mmol) and 2,6-di- tert-butyl-4-methyl pyri-
dine 45 equivalents) in DCM 45 ml) was stirred at 08C,
under argon. N-Iodosuccinimide 45 equivalents) was then
added and the resulting reaction mixture was allowed to
reach room temperature. After 18 h, TLC 4petrol:ethyl
acetate, 3:1) indicated complete conversion of starting
material to a major product. DCM 450 ml) was added to
the reaction mixture, which was then washed with dilute
aqueous HCl 41.0 M, 50 ml). The organic phase was further
washed with 10% aq. sodium thiosulfate 450 ml), dried
4MgSO4), ®ltered and concentrated in vacuo. The resulting
residue was puri®ed by column chromatography 4petrol:
ethyl acetate, 3:1) to give either the a-glucoside 9a±e or
b-mannoside 12a±d respectively.
4.10. Cyclohexyl 3,4,6-tri-O-benzyl-a-d-glucopyrano-
side 9d
The gluco enol ether 4 4100 mg, 0.17 mmol) and cyclo-
hexanol 40.1 ml, 0.85 mmol) gave the a-cyclohexyl gluco-
24
side 9d as a colourless oil; [a]D ˆ160 4c, 0.6 in CHCl3);
n
max 4thin ®lm) 3470 4br, OH) cm21; dH 4400 MHz1COSY,
CDCl3) 1.19±1.89 410H, m, OCH4CH2)5), 2.05 41H, d,
J2,OHˆ9.3 Hz, OH), 3.59±3.90 47H, m, H-2, H-3, H-4, H-
5, H-6, H-60,OCH4CH2)5), 4.45±5.00 46H, 6£d, 3£PhCH2),
5.03 41H, d, J1,2ˆ3.5 Hz, H-1), 7.14±7.42415H, m, Ar H);
dC 4125 MHz1DEPT, CDCl3) 23.9, 24.1, 25.3, 31.7, 33.4
45£t,OCH4CH2)5), 68.5, 73.4, 75.1, 75.3 44£t, C-6,
3£PhCH2), 70.4, 73.0, 76.1, 77.2, 83.8 45£d, C-2, C-3,
C-4, C-5,OCH4CH2)5), 96.8 4d, C-1), 127.6, 127.65, 127.7,
127.8, 128.0, 128.5, 128.6, 128.7 48£d, ArCH), 137.9,
138.1, 138.5 43£s, ArC); m/z 4APCI1ve) 555 4M1Na1,
1
25%). 4HRMS Calcd. For C33H44NO6 4M1NH4
550.3169. Found 550.3169).
)
4.11. N-%Phthaloyl)-O3-%3,4,6-tri-O-benzyl-a-d-gluco-
pyranosyl)-l-serine-tert butyl ester 9e
4.7. Methyl 3,4,6-tri-O-benzyl-a-d-glucopyranoside 9a
The gluco enol ether 4 480 mg, 0.14 mmol) and N-phtha-
loyl-l-serine-tert-butyl ester 1011 4122 mg, 0.42 mmol)
gave the a-glucosyl amino acid 9e as a colourless oil;
The gluco enol ether 4 4150 mg, 0.26 mmol), and methanol
40.03 ml, 0.78 mmol) gave the a-methyl glycoside 9a as a
colourless crystalline solid; m.p 89±908C 4petrol/ethyl
24
[a]D ˆ143 4c, 0.25 in CHCl3); nmax 4thin ®lm) 3480 4br,
OH), 1778 4CO2 Bu), 1716 4CˆO) cm21
;
dH
t
23
acetate); [a]D ˆ190 4c, 1.1 in CHCl3), [lit.15 mp 87±
4400 MHz1COSY, C6D6) 1.35 49H, s, C4CH3)3), 2.54
41H, d, JOH,2ˆ9.9 Hz, OH), 3.68 41H, dd, J5,6ˆ1.7 Hz,
J6,6ˆ10.8 Hz, H-6), 3.71±3.79 43H, m, H-2, H-4, H-60),
3.9241H, a-t, J2,3ˆ3,4ˆ9.1 Hz, H-3), 4.03 41H, m, H-5),
4.31±4.36 42H, m, H-2aa, H-20aa), 4.40 41H, d, J 12.2 Hz,
PhCH2), 4.50 41H, d, PhCH2), 4.63 41H, d, Jˆ11.3 Hz,
PhCH2), 4.87 41H, d, Jˆ11.4 Hz, PhCH2), 4.96 41H, d,
PhCH2), 4.97 41H, d, J1,2ˆ3.9 Hz, H-1), 5.07 41H, d,
20
888C; [a]D ˆ198 4c, 1.0 in CHCl3)]; dH 4400 MHz 1
COSY, CDCl3) 2.15 41H, d, J2,OHˆ7.5 Hz, OH), 3.43 43H,
s, OMe), 3.63±3.79 46H, m, H-2, H-3, H-4, H-5, H-6 and
H-60), 4.81 41H, d, J1,2ˆ3.3 Hz, H-1), 4.49±4.93 46H, 6£d,
3£PhCH2), 7.15±7.39 415H, m, ArH).
4.8. Benzyl 3,4,6-tri-O-benzyl-a-d-glucopyranoside 9b
0
PhCH2), 5.21 41H, dd, J1aa,2aaˆ5.0 Hz, J1aa,2 aaˆ6.5 Hz,
The gluco enol ether 4 4100 mg, 0.17 mmol) and benzyl
alcohol 40.05 ml, 0.51 mmol) gave the a-benzyl glucoside
H-1aa), 6.83±7.49 419 H, m, ArH); dC 4125 MHz1DEPT,
CDCl3) 27.8 4q, C4CH3)3), 53.2, 71.0, 73.2, 77.1, 83.3 45£d,
C-2, C-3, C-4, C-5, C-1aa), 66.3, 68.5, 73.5, 74.9, 75.2 45£t,
C-6, C-2aa, 3£PhCH2), 83.5 4s, C4CH3)3), 100.24d, C-1),
123.6, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.3,
128.4, 134.3 410£d, ArCH), 131.8, 138.1, 138, 3, 138.8
44£s, ArC), 165.7, 167.7 42£s, 2£CˆO); m/z 4APCI 1ve)
24
9b as a colourless oil; [a]D ˆ188 4c, 0.76 in CHCl3),
20
[lit.16 [a]D ˆ1105 4c, 1.8 in CHCl3)]; dH 4400 MHz1
COSY, CDCl3) 3.58±3.85 46H, m, H-2, H-3, H-4, H-5,
H-6 and H-60), 4.49±4.96 48H, 8£d, 4£PhCH2), 5.03 41H,
d, J1,2ˆ3.5 Hz, H-1), 7.13±7.54 420H, m, ArH).
747 4M1Na1, 50%), 488 415), 473 415), 209 4100), 181 450,
1
122 490). 4HRMS Calcd. For C42H49N2O10 4M1NH4
741.3387. Found 741.3386).
)
4.9. 3,4,6-Tri-O-benzyl-a-d-glucopyranosyl-%1!6)-
1,2:3,4-di-O-isopropylidene-a-d-galactopyranose 9c
The gluco enol ether 4 4100 mg, 0.17 mmol) and diacetone
galactose 4177 mg, 0.68 mmol) gave the a-disaccharide 9c
4.12. Methyl 3,4,6-Tri-O-benzyl-b-d-mannopyranoside 12a
The manno enol ether 3 4100 mg, 0.17 mmol) and anhydrous
as a colourless oil; [a]D ˆ12 9 c4, 0.9 in CHCl3), [lit.15
24

4228
S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
methanol 420.8 ml, 0.51 mmol) gave the b-methyl manno-
n
max 4thin ®lm) 3470 4br, OH) cm21; dH 4400 MHz1COSY,
CDCl3) 1.22±2.08 410H, m, OCH4CH2)5), 2.56 41H, s, OH),
24
side 12a as a colourless oil; [a]D ˆ213 4c, 1.0 in CHCl3)
[lit.15213 4c, 1.0 in CHCl3)]; dH 4400 MHz, CDCl3) 2.43
41H, s, OH), 3.44 41H, m, H-5), 3.57 43H, s,OCH3), 3.59
41H, dd, J2,3ˆ3.1 Hz, J3,4ˆ9.4 Hz, H-3), 3.73 41H, dd,
J5,6'ˆ5.2Hz, J6,6' 10.8 Hz, H-60), 3.80 41H, dd, J5,6ˆ
2.0 Hz, Hz, H-6), 3.87 41H, at, J3,4ˆJ4,5ˆ9.4 Hz, H-4),
4.10 41H, dd, J1,2ˆ0.8 Hz, H-2), 4.34 41H, d, H-1), 4.57,
4.64 42H, 2£d, Jˆ12.2 Hz, PhCH2), 4.69, 4.77 42H, 2£d,
Jˆ11.9 Hz, PhCH2), 4.54, 4.89 42H, 2£d, Jˆ10.8 Hz,
PhCH2), 7.18±7.41 415H, m, ArH).
3.48 41H, ddd, J4,5ˆ9.7 Hz, J5,6ˆ5.6 Hz, J5,6 ˆ1.9 Hz, H-5),
0
3.63 41H, dd, J2,3ˆ3.1 Hz, J3,4ˆ9.1 Hz, H-3), 3.74 41H, dd,
0
J6,6 ˆ 10.8 Hz, H-6), 3.78±3.8241H, m, OC H4CH2)5), 3.85
41H, dd, H-60), 3.90 41H, a-t, H-4), 4.1241H, d, H-2), 4.13±
4.98 46H, 6£d, 3£PhCH2), 4.61 41H, s, H-1), 7.28±7.46
415H, m, ArH); dC 4100.6 MHz 1 DEPT, CDCl3) 24.0,
24.1, 25.5, 31.6, 33.4 45£t, 5£OCH4CH2)5), 68.8, 74.3,
75.2, 76.6, 81.7 45£d, C-2, C-3, C-4, C-5,OCH4CH2)5),
69.4, 71.2, 73.4, 75.1 44£t, C-6, 3£PhCH2), 97.3 4d,
JC-1,H-1ˆ156.6 Hz, C-1), 127.5, 127.7, 127.8, 127.9, 128.1,
128.2, 128.3, 128.4 48£d, ArCH), 137.9, 138.2, 138.3 43£s,
ArC); m/z 4APCI 1ve) 555 4M1Na1, 50%). 4HRMS Calcd.
For C33H44NO6 4M1NH41) 550.3169. Found 550.3160).
4.13. Benzyl 3,4,6-tri-O-benzyl-b-d-mannopyranoside
12b
The manno enol ether 3 4100 mg, 0.17 mmol) and anhy-
drous benzyl alcohol 443 ml, 0.41 mmol) gave the b-benzyl
4.16. One-pot reactions
24
mannoside 12b as a colourless oil; [a]D ±40 4c, 0.4 in
CHCl3), [lit.17±43 4c, 1.3 in CHCl3); dH 4400 MHz,
CDCl3) 2.49 41H, s, OH), 3.43 41H, m, H-5), 3.56 41H,
dd, J2,3ˆ3.1 Hz, J3,4ˆ9.0 Hz, H-3), 3.75 41H, dd,
The following were prepared in one-pot reactions.
4.17. 3,4,6-Tri-O-benzyl-a-d-glucopyranosyl-%1!6)-
1,2:3,4-di-O-isopropylidene-a-d-galactopyranose 9c
J5,6 ˆ5.3 Hz, J6,6 ˆ10.7 Hz, H-60), 3.81 41H, dd,
J5,6ˆ2.1 Hz, H-6), 3.89 41H, a-t, J3,4ˆJ4,5ˆ9.4 Hz, H-4),
4.1241H, dd, J1,2ˆ0.6 Hz, J2,3ˆ2.8 Hz, H-2), 4.46 41H, d,
H-1), 4.55±4.96 48H, 8£d, 3£CH2Ph), 7.19±7.22 42H, m,
ArH), 7.38±7.27 418H, m, ArH).
0
0
The gluco enol ether 4 4278 mg, 0.48 mmol), diacetone
Ê
galactose 4373 mg, 1.43 mmol) and 4A molecular sieves
4200 mg, powdered) were stirred in dry DCE 43 ml) at
2408C under argon. N-Iodosuccinimide 4322 mg,
1.43 mmol) in dry DCE 41 ml) was then added. After
40 min. all the starting material had reacted, and further
N-iodosuccinimide 4215 mg, 0.95 mmol), together with
2,6-di-tert-butyl-4-methyl pyridine 4294 mg, 1.43 mmol)
were added in DCE 45 ml). The mixture was then allowed
to warm to room temperature. After approximately 22 h
glycosylation was complete 4as monitored by TLC in
hexane:ethyl acetate, 2:1). Dichloromethane 450 ml) was
added, the resulting mixture ®ltered through Celitew,
washed with 10% aqueous sodium thiosulfate 425 ml), the
organic phase dried 4MgSO4), ®ltered and concentrated in
vacuo. The residue was then dissolved in methanol 45 ml),
acidic ion exchange resin 4200 mg) added, and the
mixture stirred at room temperature overnight. Subsequent
®ltration and concentration in vacuo yielded a crude product
which was puri®ed by ¯ash column chromatography
4DCM:ether, 3:1) to yield the a-disaccharide 9c 4226 mg,
68%) as a colourless oil, identical to the material described
previously.
4.14. 3,4,6-Tri-O-benzyl-b-d-mannopyranosyl-%1!6)-
1,2,3,4-di-O-isopropylidene-d-galactopyranose 12c
The manno enol ether 3 4100 mg, 0.17 mmol) and diacetone
galactose 4134 mg, 0.52mmol) gave the b-disaccharide 12c
24
as a colourless oil; [a]D ˆ253 4c, 1.3 in CHCl3); nmax 4thin
®lm) 3584 4br, OH) cm21; dH 4400 MHz, CDCl3) 1.3243H,
s, CH3), 1.34 43H, s, CH3), 1.44 43H, s, CH3), 1.54 43H, s,
CH3), 2.57 41H, s, OH), 3.40±3.44 41H, ddd, J4',5'ˆ9.7 Hz,
J5',6'ˆ4.5 Hz, J5',6'aˆ2.2 Hz, H-50), 3.55±3.58 41H, dd,
J2',3'ˆ3.0 Hz, J3',4'ˆ9.1 Hz, H-30), 3.70±3.78 43H, m, H-
6a, H-60, H-60a), 3.89±3.94 41H, a-t, J3',4'ˆJ4',5'ˆ9.4 Hz,
H-40), 4.02±4.05 41H, m, H-5), 4.12±4.16 41H, dd,
J5,6ˆ2.9 Hz, J6,6aˆ11.2 Hz, H-6), 4.21±4.23 42H, m, H-20,
H-4), 4.32±4.33 41H, dd, J2,3ˆ2.4 Hz, J1,2ˆ5.0 Hz, H-2),
4.50±4.56 43H, m, H-10, PhCH2), 4.59±4.67 43H, m,
PhCH2, H-3), 4.80 41H, d, Jˆ11.9 Hz, PhCH2), 4.91 41H,
d, Jˆ10.8 Hz, PhCH2), 5.55 41H, J1,2ˆ5.0 Hz, H-1), 7.18±
7.39 415H, m, ArH); dC 450.3 MHz, CDCl3) 24.3, 24.9,
25.9, 26.1 44£q, CH3), 69.0, 69.1, 71.1, 75.1 44£t,
3£PhCH2, C-6, C-60), 67.7, 67.9, 70.3, 70.7, 71.4, 74.1,
75.2, 81.2 48£d, C-2, C-3, C-4, C-5, C-20, C-30, C-40,
C-50), 96.3 4d, C-1), 100.24d, JC-1',H-1'ˆ157.8 Hz, C-10),
108.7, 109.4 42£s, 2£ C4CH3)2), 127.6, 127.7, 127.8,
127.9, 127.9, 128.0, 128.3, 128.4 48£d, 15£ArCH), 137.8,
138.2, 137.8 43£s, ArC); m/z 4APCI1) 715.6 4M1Na1,
15%). 4Found: C, 67.10; H, 7.35. C39H48O11 requires: C,
67.61; H, 7.35%). 4HRMS Calcd. For C39H52NO11
4M1NH41) 710.3540. Found 710.3552).
4.18. 3,4,6-Tri-O-benzyl-b-d-mannopyranosyl-%1!6)-
1,2,3,4-di-O-isopropylidene-d-galactopyranose 12c
The manno enol ether 3 4138 mg, 0.24 mmol), diacetone
Ê
galactose 4186 mg, 0.72mmol) and 4A molecular sieves
4200 mg, powdered) were stirred in dry DCE 41 ml) at
±408C under argon. N-Iodosuccinimide 4161 mg, 0.72
mmol) in dry DCE 41 ml) was then added. After 15 min.
all the starting material had reacted, and further N-iodosuc-
cinimide 4107 mg, 0.48 mmol), together with 2,6-di-tert-
butyl-4-methyl pyridine 4147 mg, 0.72mmol) were added
in DCE 44 ml). The mixture was then allowed to warm to
room temperature. After 48 h glycosylation was complete
4as monitored by TLC in hexane:ethyl acetate, 2:1).
Dichloromethane 450 ml) was added, the resulting mixture
®ltered through Celitew, washed with 10% aqueous sodium
4.15. Cyclohexyl 3,4,6-tri-O-benzyl-b-d-manno-
pyranoside 12d
The manno enol ether 3 4100 mg, 0.17 mmol) and cyclo-
hexanol 40.1 ml, 0.85 mmol) gave the b-cyclohexyl manno-
side 12d as a colourless oil; [a]D24±19 4c, 1.6 in CHCl3);

S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
4229
thiosulfate 425 ml), the organic phase dried 4MgSO4),
®ltered and concentrated in vacuo. The residue was then
dissolved in methanol 45 ml), acidic ion exchange resin
4200 mg) added, and the mixture stirred at room temperature
overnight. Subsequent ®ltration and concentration in vacuo
yielded a crude product which was puri®ed by ¯ash column
chromatography 4DCM:ether, 2:1) to yield the b-disacchar-
ide 12c 4138 mg, 84%) as a colourless oil, identical to the
material described previously.
yield the a-disaccharide 9c 432mg, 49%), as a colourless oil
identical to the material described previously.
4.21. Cyclohexyl 3,4,6-tri-O-benzyl-a-d-glucopyrano-
side 9d and cyclohexyl 3,4,6-tri-O-benzyl-b-d-gluco-
pyranoside 1518
A solution of enol ether 7 4191 mg, 0.28 mmol) in anhy-
drous 1,2-dichloroethane 41.5 ml), was added to a stirred
solution of cyclohexanol 490 ml, 0.85 mmol), N-iodosucci-
nimide 4192mg, 0.85 mmol) and powdered molecular
4.19. Methyl 3,4,6-tri-O-benzyl-a-d-glucopyranoside 9a
Ê
sieves 44A, 200 mg) in anhydrous dichloroethane 42 ml) at
±408C under argon. After 30 min, TLC 4DCM:ether, 20:1)
indicated complete consumption of starting material
4Rf 0.6). A solution of N-iodosuccinimide 4127 mg, 0.56
mmol) and 2,6-di-tert-butyl-4-methyl pyridine 4174 mg,
0.85 mmol) in anhydrous 1,2-dichloroethane 41 ml) was
added under argon, and the reaction mixture was allowed
to warm to room temperature. After 18 h, TLC 4DCM:ether,
20:1) indicated formation of a major product 4Rf 0.2) and a
minor product 4Rf 0.5). The reaction mixture was diluted
with DCM 4150 ml), ®ltered through Celitew, washed with
aqueous sodium thiosulfate 410% w/v, 50 ml), and aqueous
hydrochloric acid 41.0 M, 50 ml). The organic layer was
dried 4MgSO4), ®ltered and concentrated in vacuo. The
resulting residue was stirred in a mixture of tri¯uoroacetic
acid 41 ml), distilled water 41 ml) and methanol 48 ml) at
room temperature. After 1 h, TLC 4DCM:ether, 20:1)
showed conversion of the minor product 4Rf 0.5) to a
product 4Rf 0.3). Ether 4150 ml) was added and the mixture
was washed with saturated sodium bicarbonate solution
44£150 ml). The organic phase was dried 4magnesium
sulfate), ®ltered and concentrated in vacuo. The resulting
residue was puri®ed by ¯ash column chromatography
4DCM:diethyl ether, 50:1) to give ®rstly the b-glucoside
N-Iodosuccinimide 498 mg, 0.44 mmol) was added to a
stirred solution of enol ether 7 498 mg, 0.15 mmol),
Ê
powdered molecular sieves 44 A, 100 mg) and anhydrous
methanol 40.018 ml, 0.44 mmol), in anhydrous DCM
42.5 ml), at 788C under argon. After 15 min, a solution of
N-iodosuccinimide 464 mg, 0.28 mmol) and 2,6-di-tert-
butyl-4-methyl pyridine 488 mg, 0.43 mmol) in anhydrous
DCM 41.5 ml) was added. The reaction mixture was allowed
to warm to room temperature. After 18 h the reaction
mixture was diluted with DCM 4200 ml), ®ltered through
Celitew, washed with aqueous sodium thiosulfate solution
410% w/v, 2£70 ml), dried 4MgSO4), ®ltered and concen-
trated in vacuo. The resulting residue was taken up in 1,4-
dioxan 45 ml) and stirred with acidic ion exchange resin
4Dowexw 50WX8-100, 200 mg) at room temperature.
After 4 h, TLC 4petrol:ethyl acetate, 2:1) showed complete
conversion of starting material 4Rf 0.4) to a major product
4Rf 0.1). The reaction mixture was ®ltered, concentrated in
vacuo and puri®ed by ¯ash column chromatography
4petrol:ethyl acetate, 4:1) and recrystallised 4ethanol) to
give the a-methyl glycoside 9a 434 mg, 55%) as a white
crystalline solid, identical to the material described
previously.
22
15 418 mg, 12%) as a clear oil; [a]D ˆ24.4 4c, 0.25 in
CHCl3); nmax 4thin ®lm) 3584 4br, OH) cm21
;
4.20. 3,4,6-Tri-O-benzyl-a-d-glucopyranosyl-%1!6)-
1,2:3,4-di-O-isopropylidene-a-d-galactopyranose 9c
dH 4500 MHz, CDCl3) 1.21±1.77 and 2.00±2.02 410H,
2£m, 10£4CH2)5), 1.93 41H, d, J2,OHˆ11.0 Hz, OH),
3.54±3.75 47H, m, H2, H3, H4, H5, H6, H60,
4CH2)2CHO), 4.37 41H, d, J1,2ˆ7.6 Hz, H1), 4.56, 4.85
42H, ABq, Jˆ10.7 Hz, PhCH2), 4.57, 4.624H2, ABq,
Jˆ12.3 Hz, PhCH2), 4.84, 4.96 42H, ABq, Jˆ11.3 Hz,
PhCH2), 7.20±7.39 415H, m, 15£ArH); dC 4100.6 MHz,
CDCl3) 24.5, 24.7, 26.0, 32.5, 34.1 45£t, 4CH2)5) 69.5,
72.7, 75.5 43£t, C6, 3£PhCH2), 75.2, 75.5, 78.1, 85.0
44£d, C2, C3, C4, C5, OCH4CH2)5), 101.5 4d, C1), 124.7,
128.0, 128.1, 128.2, 128.4, 128.4, 128.6, 128.8, 128.8,
128.9, 128.9, 129.0, 129.0, 131.4 414£d, 15£ArCH),
138.5, 138.6, 139.1 43£s, 3£ArC); m/z 4APCI1) 555
4M1Na1). Further elution and recrystallisation 4ethanol),
gave the a-glucoside 9d, as a white crystalline solid
459 mg, 39%), identical to the material described
previously.
A solution of enol ether 7 464 mg, 0.09 mmol) in anhydrous
DCM 41 ml), was added to a stirred solution of diacetone
galactose 480 mg, 0.31 mmol), N-iodosuccinimide 463 mg,
Ê
0.28 mmol) and powdered molecular sieves 44A, 100 mg),
in anhydrous DCM 41 ml) at 2788C under argon. After
20 min, TLC 4petrol:ethyl acetate, 2:1) indicated complete
conversion of starting material 4Rf 0.5) to a major product
4Rf 0.4).
A
solution of N-iodosuccinimide 443 mg,
0.19 mmol) and 2,6-di-tert-butyl-4-methyl pyridine
460 mg, 0.29 mmol) in anhydrous DCM 41.5 ml) was then
added, at 2788C under argon. The resulting reaction
mixture was allowed to warm to room temperature. After
18 h the reaction mixture was diluted with DCM 4100 ml),
®ltered through Celitew, washed with aqueous sodium thio-
sulphate solution 410% w/v, 2£50 ml), dried 4MgSO4),
®ltered and concentrated in vacuo. The resulting brown
residue was taken up in methanol 45 ml) and stirred with
acidi®ed ion exchange resin 4Dowexw 50WX8-100,
100 mg) at room temperature. After 4 h, TLC 4petrol:ethyl
acetate, 2:1) showed complete conversion of the starting
material 4Rf 0.8) to a major product 4Rf 0.4). The reaction
mixture was ®ltered, concentrated in vacuo and puri®ed by
¯ash column chromatography 4petrol:ethyl acetate, 4:1) to
Acknowledgements
We gratefully acknowledge the EPSRC 4Quota Awards to
S. C. E. and R. J. T.-E.) and the Royal Society for ®nancial
support. We also gratefully acknowledge the use of the
EPSRC Mass Spectrometry Service 4Swansea, UK) and
the Chemical Database Service 4CDS) at Daresbury, UK.

4230
S. C. Ennis et al. / Tetrahedron 57 02001) 4221±4230
8. Zhang, Y.-M.; Mallet, J.-M.; SinayÈ, P. Carbohydr. Res. 1992,
236, 73.
 Â
9. de Pouilly, P.; Chenede, A.; Mallet, J.-M.; SinayÈ, P. Bull.
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