An approach to the synthesis of α-(1-6)-C-disaccharides by tandem Tebbe methylenation and Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2005.05.032

Uronic acids, most efficiently synthesised from the corresponding alcohols by two step Dess-Martin and sodium chlorite mediated oxidation, may be used as coupling partners for esterification with an allo glycal as substrates for the tandem Tebbe/Claisen a

Full text of DOI:10.1016/j.tet.2005.05.032

Tetrahedron 61 (2005) 7184–7192
An approach to the synthesis of a-(1-6)-C-disaccharides by
tandem Tebbe methylenation and Claisen rearrangement
David J. Chambers,a Graham R. Evansb and Antony J. Fairbanksa,
*
aChemistry Research Laboratory, Oxford University, Mansfield Road, Oxford OX1 3TA, UK
bCelltech R & D, Granta Park, Great Abington, Cambridge CB1 6GS, UK
Received 18 March 2005; revised 25 April 2005; accepted 13 May 2005
Available online 13 June 2005
Abstract—Uronic acids, most efficiently synthesised from the corresponding alcohols by two step Dess-Martin and sodium chlorite
mediated oxidation, may be used as coupling partners for esterification with an allo glycal as substrates for the tandem Tebbe/Claisen
approach to the synthesis of 1-6 linked C-disaccharides. Whilst esters of glucuronic and mannuronic acids successfully undergo Tebbe
methylenation, esters derived from galacturonic acids are unreactive under these conditions. Thermal Claisen rearrangement of vinyl ethers
produced by methylenation yields a-C-disaccharides with complete control of anomeric stereochemistry.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
glycal possessing a free 3-hydroxyl group with a carboxylic
acid. Tebbe methylenation7 of the resultant ester can then be
followed by [3,3] sigmatropic rearrangement8,9 yielding the
C-glycoside product in a predictable and entirely stereo-
selective fashion. One particular attraction of this approach
is that carbohydrate-derived carboxylic acids may be used
for the esterification step. In particular, selective oxidation
of the primary hydroxyl of any one of the hexoses would
readily provide access to suitable coupling partners. Tebbe
methylenation of the resultant esters could then be followed
It is now well established that oligosaccharides play a huge
number of crucially important roles in an enormously wide
variety of fundamentally important biological systems.1 It
has also been long-proposed that carbohydrate mimetics2
may be expected to display interesting biological activity
either as enzyme inhibitors, for example, by inhibition of
glycosidases or glycosyl tranferases, or as inhibitors or
mediators of carbohydrate recognition events. Although the
number of currently administered glycomimetic drugs is
small, such molecules are expected to provide the basis of
several new therapeutic strategies against a variety of
disease states and infective agents in the future.3
Significant interest has recently, arisen in the synthesis of
C-disaccharides,4 in which the interglycosidic oxygen atom
of a natural O-linked disaccharide is replaced by a
methylene unit. These materials have been proposed as
non-hydrolysable disaccharide mimetics, which may dis-
play interesting biological activity,5 and therefore, perhaps
therapeutic potential.
In principle the Tebbe/Claisen approach which, as recently,
reported, allows stereospecific access to a wide range of
C-glycoside materials,6 could be advantageously applied to
the synthesis of a variety of (1-6) linked C-disaccharides.
This tandem approach initially involves esterification of a
*
Corresponding author. Tel.: C44 1865 275 647; fax: C44 1865 275 674;
e-mail: antony.fairbanks@chem.ox.ac.uk
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.032

D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
7185
by Claisen rearrangement to yield 1-6-linked disaccharides,
with complete control of anomeric stereochemistry
(Scheme 1). This paper gives full details of investigations
into the applicability of the tandem Tebbe/Claisen
approach for the synthesis of a series of a-(1-6)-linked
C-disaccharides.10
several reagent combinations were investigated for effecting
the one-pot oxidation directly to the carboxylic acid.
Unfortunately the ruthenium trichloride/sodium periodate
system,13 which had proven to be an excellent method for
oxidation of diacetone galactose to the corresponding
galacturonic acid6a proved to be incompatible with the
benzyl protection of the other hydroxyls of 2. In addition,
although a TEMPO14 mediated oxidation with trichloro-
cyanuric acid as co-oxidant did on one occasion provide the
desired product 3 in 64% yield, the reaction proved
unreliable and was unrepeatable. It was finally, concluded
that in fact a two-step oxidation was the most efficient route
to the desired product; sequential oxidation of alcohol 2
firstly by treatment with the Dess–Martin periodinane15 and
then immediate oxidation of the crude aldehyde product by
treatment with sodium chlorite in the presence of 2-methyl-
2-butene as a ClC scavenger16 yielded the desired acid 317
in quantitative yield over two steps (Scheme 2).
2. Results and discussion
2.1. Synthesis of uronic acid substrates and esterification
allo Glycal 1, accessed using published synthetic routes,11
was selected for esterification reactions, since sigmatropic
rearrangement of a 3-O vinyl ether derived from 1 would
produce a C-glycoside with the desired a-anomeric
stereochemistry. It was envisaged that a series of uronic
acids could be accessed via simple oxidation of the
corresponding selectively protected alcohols in which only
the primary OH-6 hydroxyl was free. The gluco alcohol 2
was synthesised using standard procedures12 in order to
provide a substrate for investigation of the most efficient and
reliable method of achieving such an oxidation. Firstly
With this optimised oxidation protocol in hand, further
uronic acids were synthesised. The known manno alcohol
418 was accessed by literature procedures. The correspond-
ing galacto alcohol 8 was accessed from methyl
Scheme 2. Reagents and conditions: (i) Dess–Martin periodinane, DCM; (ii) NaClO2, NaH2PO4, ButOH, THF, H2O, 2-methyl-2-butene, quantitative over two
steps; (iii) DCC, DMAP, DCM; 11, 83%; 12, 76%; 13 87%; (iv) TBDMSCl, imidazole, DMF, 0 8C, 92%; (v) BnBr, NaH, DMF, 84%; (vi) TsOH, MeCN, H2O,
90%.

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D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
galactopyranoside 5 via a three-step reaction sequence.
Thus, regioselective silylation of 5 with tert-butyldimethy-
silylchloride and imidazole in DMF at 0 8C yielded the
known silyl ether 619 (92% yield). Benzylation of the
remaining free hydroxyl groups by treatment of 6 with
benzyl bromide and sodium hydride in DMF yielded
completely protected galactoside 7 (84% yield). Finally,
de-silylation by treatment of 7 with toluenesulfonic acid in
aqueous acetonitrile20 yielded the desired alcohol 8 (90%
yield). Both manno and galacto alcohols were then oxidised
smoothly to the desired carboxylic acids 9 and 10 by the
two-step Dess–Martin/sodium chlorite procedure (both in
quantitative yield over two steps). Finally, all three acids 3,
9 and 10 were esterified by treatment with glycal 1 in the
presence of dicyclohexylcarbodiimide (DCC) and dimethyl-
amino pyridine (DMAP), in dichloromethane (DCM), to
yield the corresponding gluco, manno and galacto esters 11,
12 and 13 in 83, 76, and 87% yields, respectively,
(Scheme 2).
With two substrates in hand Claisen rearrangement of both
vinyl ethers 14 and 15 was undertaken. Mindful of previous
studies22 which had clearly demonstrated that in the case of
a-C-glycosides the stereochemical purity of the product was
dependent on the precise reaction conditions, thermal
rearrangement of both substrates was undertaken in xylene
in a sealed tube at 185 8C. Pleasingly under these conditions
vinyl ethers 14 and 15 both underwent smooth stereo-
controlled rearrangement to yield only the desired a-C-
glycoside products 16 and 17 in 66 and 83% yields,
respectively, (Scheme 3).
3. Conclusions
These studies demonstrate that the use of uronic acids,
together with glycals in which the 3-hydroxyl group is not
protected, allows access to (1-6)-linked C-disaccharide
materials via the tandem Tebbe/Claisen approach. Uronic
acid substrates for this reaction sequence were most
efficiently obtained from selectively protected hexoses by
a two-step oxidation process involving treatment of the
alcohol firstly with the Dess–Martin periodinane and then
immediate further, oxidation with sodium chlorite. The
product carboxylic acids were readily esterified with the
3-hydroxyl group of the glycal. The efficiency of the Tebbe
methylenation step was actually dependent on the stereo-
chemistry of the uronic acid; whilst both gluco and manno
esters readily underwent methylenation the galacto counter-
part was resistant to reaction. Both gluco and manno vinyl
ethers then underwent smooth thermal Claisen reaction to
yield the desired a-C-disaccharide products with complete
2.2. Tebbe methylenation and Claisen rearrangement
Methylenation reactions by the Tebbe reagent were
attempted on the three esters 11–13. Both gluco and
manno esters 11 and 12 were smoothly methylenated by
the Tebbe reagent to yield the desired enol ethers 14 and 15
in 82 and 76% yields, respectively, (Scheme 2). However,
the corresponding galacto ester 13 was inert to methyl-
enation under these conditions. Indeed despite protracted
reaction times, and performing the reaction at room
temperature the starting material was recovered in this
case.21
Scheme 3. Reagents and conditions: (i) Tebbe reagent, THF, pyridine, K40 8C to rt, 16 h; 14, 82%; 15, 76%; (ii) 185 8C, xylene, sealed tube, 12 h; 16, 66%; 17,
83%.

D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
7187
control of stereochemistry. Further studies on the use of this
tandem approach to C-disaccharide synthesis and in
particular iteration of the process to allow access to (1-6)-
linked C-oligosaccharides are currently in progress, and the
results will be reported in due course.
cooled to K40 8C under an atmosphere of argon. Tebbe
reagent (0.5 M in toluene, 2.0–4.0 equiv depending on age
and quality) was added drop-wise, and the reaction mixture
allowed to warm to room temperature with stirring. After
16 h, when TLC indicated complete consumption of starting
material, the reaction mixture was cooled to 0 8C and
quenched by drop-wise addition of sodium hydroxide
(0.5 M aqueous solution) until effervescence ceased. The
mixture was diluted with petrol, stirred for 30 min, and
sonicated for a further, 10 min. The mixture was poured
onto a short column of silica and eluted (petrol and ether
with 2% triethylamine), concentrated in vacuo and purified
by flash column chromatography (silica; petrol and ether
with 2% triethylamine).
4. Experimental
4.1. General
Melting points were recorded on a Kofler hot block and are
uncorrected. Proton nuclear magnetic resonance (dH)
spectra were recorded on a Bruker DPX 400 (400 MHz),
or on a Bruker DQX 400 (400 MHz) spectrometer, and
spectra were assigned using COSY and HMQC experi-
ments. Carbon nuclear magnetic resonance (dC) spectra
were recorded on a Bruker DPX 400 (100.6 MHz), or on a
Bruker DQX 400 (100.6 MHz) and were assigned using
HMQC experiments. Multiplicities were assigned using
DEPT or APT sequences. All chemical shifts are quoted on
the d-scale in parts per million (ppm) using residual solvent
as internal standard. Infrared spectra were recorded on a
Perkin-Elmer 150 Fourier Transform spectrophotometer.
Mass spectra were recorded on VG Micromass 30F, ZAB
1F, Masslab20-250, Micromass Platform 1 APCI, or Trio-1
GCMS (DB-5 column) spectrometers, using desorption
chemical ionization (NH3 DCI), electron impact (EI),
electron spray ionisation (ESI), chemical ionization (NH3
CI), atmospheric pressure chemical ionization (APCI), and
fast atom bombardment (FAB) techniques as stated. 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 micro-
analytical services of the Inorganic Chemistry Laboratory,
Oxford. Thin layer chromatography (TLC) was carried out
on Merck glass backed sheets, pre-coated coated with
60F254 silica. Plates were developed using 5% ammonium
molybdate in 2 M sulfuric acid. Flash chromatography was
carried out using Sorbsil C60 40/60 silica. Solvents and
available reagents were dried and purified before use
according to standard procedures; dichloromethane
(DCM) was distilled from calcium hydride immediately
before use. 4,6-O-Benzylidene-D-allal 1 was synthesised
following literature procedures.11
4.3.1. Methyl 2,3,4-tri-O-benzyl-a-D-glucuronic acid 3.
Alcohol 2 (256 mg, 0.55 mmol) was dissolved in anhydrous
DCM (15 ml) and Dess–Martin periodinane (350 mg,
0.83 mmol) was added. The mixture was stirred under an
atmosphere of argon for 1 h, when TLC (petrol/ethyl
acetate, 1:1) indicated consumption of starting material
(Rf 0.4) and formation of a single product (Rf 0.3). The
mixture was diluted with ether (12 ml) and sodium
bicarbonate (12 ml) and sodium thiosulphate (2 g) was
added. The mixture was stirred for 1 h, and was then diluted
with ether (50 ml) and the layers separated. The aqueous
phase was extracted with ether (4!25 ml) and the
combined organic layers were washed with saturated
aqueous sodium bicarbonate (50 ml) and water (50 ml),
dried (MgSO4), filtered and concentrated in vacuo to give
crude aldehyde as a colourless oil; dH (400 MHz, CDCl3)23
3.41 (3H, s, OCH3), 3.53 (1H, dd, J1,2Z3.4 Hz, J2,3
Z
9.7 Hz, H-2), 3.60 (1H, at, JZ9.6 Hz, H-4), 4.11 (1H, at,
JZ9.1 Hz, H-3), 4.19 (1H, d, J4,5Z10.6 Hz, H-5), 4.64–
4.68 (3H, m, H-1, 2!PhCH), 4.81–4.85 (2H, m, 2!PhCH),
4.89 (1H, d, JZ10.6 Hz, PhCH), 5.03 (1H, d, JZ10.6 Hz,
PhCH), 7.28–7.38 (15H, m, 15!Ar-H), 9.67 (1H, s, H-6).
The crude aldehyde was dissolved in a mixture of tert-
butanol (7 ml), THF (3 ml), water (3 ml) and 2-methyl-2-
butene (2 ml). Sodium dihydrogenphosphate (0.4 g) and
then sodium chlorite (80%, 62 mg, 0.55 mmol) were added,
and the mixture stirred under an atmosphere of argon for
16 h. After this time, TLC (petrol/ethyl acetate, 1:1)
indicated complete consumption of starting material (Rf
0.5) and formation of a major product (Rf 0.1). The mixture
was quenched by addition of hydrochloric acid (10 ml of a
1 M aqueous solution). The organic layer was separated, and
the aqueous layer extracted with ethyl acetate (4!25 ml).
The combined organic layers were washed with water
(50 ml), dried (MgSO4), filtered and concentrated in vacuo
to give the gluco acid 3 (319 mg, quant.) as a colourless oil;
[a]D22 C28.9 (c, 1.2 in CHCl3) [lit. [a]2D0 C3 (c, in
CHCl3)];17 dH (400 MHz, CDCl3) 3.40 (3H, s, OCH3),
3.57 (1H, dd, J1,2Z3.4 Hz, J2,3Z9.9 Hz, H-2), 3.70 (1H, dd,
J3,4Z9.1 Hz, J4,5Z10.2 Hz, H-4), 4.01 (1H, at, JZ9.4 Hz,
H-3), 4.22 (1H, d, H-5), 4.60–4.66, 4.79–4.83 (6H, m, 5!
PhCH, H-1), 4.97 (1H, d, JZ10.7 Hz, PhCH), 7.20–7.36
(15H, m, 15!Ar-H).
4.2. General procedure A: esterification
Glycal (1.0 equiv) and carboxylic acid (1.2–1.5 equiv) were
dissolved in anhydrous DCM, and N,N0-dimethyl-4-amino
pyridine (0.2 equiv) and then dicyclohexylcarbodiimide
(2.0 equiv) were added. The reaction mixture was stirred
under an atmosphere of argon until TLC indicated the
complete consumption of starting material. The reaction
mixture was concentrated in vacuo, the residue taken up in
ethyl acetate, and the suspension filtered through Celitew.
The solution was concentrated in vacuo, and the residue
purified by flash column chromatography.
4.3. General procedure B: Tebbe methylenation
4.3.2. Methyl 6-O-tert-butyldimethylsilyl-a-D-galacto-
pyranoside 6. Methyl a-D-galactopyranoside 5 (5.07 g,
26.1 mmol) was dissolved in anhydrous DMF (60 ml) and
The enol ether (1.0 equiv) was dissolved in a 4:1 mixture of
anhydrous THF and anhydrous pyridine and the solution

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D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
cooled to 0 8C. Imidazole (4.44 g, 65 mmol) and then tert-
butyldimethylsilyl chloride (4.72 g, 31 mmol) were added
to the solution, and the mixture was stirred for 19 h, when
TLC (ethyl acetate) indicated complete consumption of
starting material (Rf 0) and formation of a single product (Rf
0.3). The mixture was concentrated in vacuo and the residue
taken up in ethyl acetate (400 ml). The solution was washed
with water (2!200 ml) and brine (2!200 ml), dried
(MgSO4), filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (ethyl
acetate) to afford silyl ether 6 (7.41 g, 92%) as an
amorphous white solid; [a]2D1 C102 (c, 1.0 in CHCl3); dH
(400 MHz, CDCl3)19 0.09 (6H, s, 2!SiCH3), 0.90 (9H, s,
SiC(CH3)3), 3.41 (3H, s, OCH3), 3.73–3.78 (2H, m, H-3,
H-5), 3.80–3.90 (3H, m, H-2, H-6, H-60), 4.04 (1H, br d, JZ
2.9 Hz, H-4), 4.80 (1H, d, J1,2Z3.8 Hz, H-1).
bicarbonate (2!150 ml) and brine (150 ml), dried
(MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (petrol/ethyl
acetate, 2:1) to afford alcohol 8 (6.20 g, 90%) as an
amorphous white solid; [a]2D1 C7.01 (c, 1.0 in CHCl3); nmax
(KBr disc) 3482 (br, OH) cmK1; dH (400 MHz, CDCl3) 3.38
(3H, s, OCH3), 3.49–3.52 (1H, m, H-6), 3.70–3.76 (2H, m,
H-5, H-60), 3.89 (1H, d, J3,4Z2.8 Hz, H-4), 3.96 (1H, dd,
J2,3Z10.1 Hz, H-3), 4.07 (1H, dd, J1,2Z3.6 Hz, H-2), 4.66,
4.99 (2H, 2!d, JZ11.6 Hz, PhCH2), 4.72, 4.87 (2H, 2!d,
JZ11.9 Hz, PhCH2), 4.73 (1H, d, H-1), 4.77, 4.92 (2H, 2!
d, JZ11.7 Hz, PhCH2), 7.28–7.44 (15H, m, 15!Ar-H); dC
(100.6 MHz, CDCl3) 55.4 (q, OCH3), 60.4 (t, C-6), 70.2 (d,
C-5), 73.6, 73.6, 74.4 (3!t, 3!PhCH2), 75.0 (d, C-4), 76.5
(d, C-2), 79.1 (d, C-3), 98.8 (d, C-1), 127.6, 127.6, 127.8,
128.0, 128.1, 128.4, 128.4, 128.5, 128.6 (9!d, 15!Ar-C),
138.1, 138.4, 138.7 (3!s, 3!Ar-C); m/z (ESC) 951 (2MC
NaC, 3), 523 (MCNH4CCCH3CN, 100), 487 (MCNaC,
5%). (HRMS (ESC) Calcd for C28H32O6Na (MCNaC)
487.2097. Found, 487.2087).
4.3.3. Methyl 2,3,4-tetra-O-benzyl-6-O-tert-butyl-
dimethylsilyl-a-D-galactopyranoside 7. Alcohol
6
(7.00 g, 23 mmol) was dissolved in anhydrous DMF
(100 ml) and cooled to 0 8C. Benzyl bromide (12.2 ml,
102 mmol) and then sodium hydride (3.27 g, 82 mmol)
were added and the reaction mixture stirred under an
atmosphere of argon for 16 h, when TLC (petrol/ethyl
acetate, 9:1) indicated consumption of starting material (Rf
0) and formation of a major product (Rf 0.3). The reaction
mixture was quenched by drop-wise addition of methanol
(10 ml), poured into water (500 ml) and extracted with ether
(5!100 ml). The combined organic phases were washed
with water (2!200 ml) and brine (2!200 ml), dried
(MgSO4), filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (petrol/ethyl
acetate, 19:1) to afford benzyl ether 7 (11.0 g, 84%) as a
colourless oil; [a]D21 C19.6 (c, 0.9 in CHCl3); nmax (thin
film) no significant peak s; dH (400 MHz, CDCl3) 0.08 (6H,
s, 2!SiCH3), 0.93 (9H, s, SiC(CH3)3), 3.42 (3H, s, OCH3),
3.61–3.70 (2H, m, H-6, H-60), 3.74–3.78 (1H, m, H-5),
3.96–4.00 (2H, m, H-3, H-4), 4.09 (1H, dd, J1,2Z3.5 Hz,
J2,3Z9.8 Hz, H-2), 4.65, 5.02 (2H, 2!d, JZ11.3 Hz,
PhCH2), 4.73 (1H, d, H-1), 4.75, 4.88 (2H, 2!d, JZ
12.0 Hz, PhCH2), 4.79, 4.93 (2H, 2!d, JZ12.0 Hz,
PhCH2), 7.27–7.46 (15H, m, 15!Ar-H); dC (100.6 MHz,
CDCl3) K5.4, K5.4 (2!q, 2!SiCH3), 18.2 (s,
SiC(CH3)3), 25.9 (q, SiC(CH3)3), 55.2 (q, OCH3), 62.0 (t,
C-6), 71.1 (d, C-5), 73.3, 73.6, 74.8 (3!t, 3!PhCH2), 75.2
(d, C-4), 76.5 (d, C-2), 79.2 (d, C-3), 98.8 (d, C-1), 127.5,
127.7, 127.9, 128.1, 128.2, 128.2, 128.3, 128.4 (8!d, 15!
Ar-C), 138.6, 138.9, 138.9 (3!s, 3!Ar-C); m/z (ESC) 637
(MCNHC4 CCH3CN, 100), 601 (MCNaC, 3%). (HRMS
(ESC) Calcd for C34H50NO6Si (MCNHC4 ) 596.3407.
Found, 596.3408). (Found: C, 70.21; H, 8.33. C34H46O6Si
requires C, 70.55; H, 8.01%).
4.3.5. Methyl 2,3,4-tri-O-benzyl-a-D-mannuronic acid 9.
Methyl 2,3,4-tri-O-benzyl-a-D-mannopyranoside
4
(435 mg, 0.81 mmol) was dissolved in anhydrous DCM
(15 ml) and Dess–Martin periodinane (514 mg, 1.21 mmol)
was added. The mixture was stirred under an atmosphere of
argon for 3 h, when TLC (petrol/ethyl acetate, 1:1) indicated
consumption of starting material (Rf 0.6) and formation of a
single product (Rf 0.8). The mixture was diluted with ether
(20 ml) and saturated aqueous sodium bicarbonate (20 ml)
and sodium thiosulphate (2 g) were added. The mixture was
stirred for 1 h, and was then diluted with ether (50 ml) and
the layers separated. The aqueous phase was extracted with
ether (4!25 ml) and the combined organic layers were
washed with saturated aqueous sodium bicarbonate (2!
50 ml), dried (MgSO4), filtered and concentrated in vacuo to
give crude aldehyde as a colourless oil; dH (400 MHz,
CDCl3)24 3.40 (3H, s, OCH3), 3.78 (1H, at, JZ2.7 Hz, H-2),
3.96 (1H, dd, J2,3Z2.8 Hz, J3,4Z8.0 Hz, H-3), 4.05–4.12
(2H, m, H-4, H-5), 4.63 (2H, s, PhCH2), 4.67 (1H, d, JZ
11.2 Hz, PhCH), 4.73 (2H, s, PhCH2), 4.84–4.87 (2H, m,
H-1, PhCH), 7.22–7.51 (15H, m, 15!Ar-H), 9.75 (1H, s,
H-6). The crude residue was dissolved in a mixture of tert-
butanol (9 ml), THF (3 ml), water (3 ml) and 2-methyl-2-
butene (2 ml). Sodium dihydrogenphosphate (0.4 g) and
then sodium chlorite (80%, 91 mg, 0.81 mmol) were added,
and the mixture was stirred under an atmosphere of argon
for 16 h. After this time, TLC (petrol/ethyl acetate, 1:1)
indicated complete consumption of starting material (Rf 0.8)
and formation of a major product (Rf 0.5). The mixture was
quenched by addition of hydrochloric acid (30 ml of a 1 M
aqueous solution). The organic layer was separated, and the
aqueous layer extracted with ethyl acetate (4!25 ml). The
combined organic layers were washed with saturated
aqueous sodium bicarbonate (4!30 ml), dried (MgSO4),
filtered and concentrated in vacuo to give the manno
carboxylic acid 9 (488 mg, quant.) as a colourless oil; [a]D23
C15.0 (c, 1.2 in CHCl3); nmax (thin film) 3386 (br, OH),
1725 (s, C]O) cmK1; dH (400 MHz, CDCl3) 3.46 (3H, s,
4.3.4. Methyl 2,3,4-tetra-O-benzyl-a-D-galactopyrano-
side 8. Silyl ether 7 (8.57 g, 14.8 mmol) was dissolved in
acetonitrile (100 ml). Water (20 ml) was added, and the pH
of the solution adjusted to pH 3 by the addition of toluene
sulphonic acid. The reaction mixture was stirred for 19 h,
until TLC (petrol/ethyl acetate, 4:1) indicated consumption
of starting material (Rf 0.7) and formation of a major
product (Rf 0.1). The reaction mixture was concentrated in
vacuo and the residue taken up in ethyl acetate (300 ml).
The solution was washed with saturated aqueous sodium
OCH3), 3.79 (1H, at, JZ3.2 Hz, H-2), 3.92 (1H, dd, J2,3
Z
3.1 Hz, J3,4Z7.8 Hz, H-3), 4.23 (1H, at, JZ7.8 Hz, H-4),
4.32 (1H, d, JZ7.7 Hz, H-5), 4.61, 4.65 (2H, 2!d, JZ
11.9 Hz, PhCH2), 4.70–4.82 (4H, m, 4!PhCH), 4.97 (1H,

D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
7189
d, J1,2Z3.1 Hz, H-1), 7.18–7.64 (15H, m, 15!Ar-H), 8.72
(1H, br s, OH); dC (100.6 MHz, CDCl3) 55.7 (q, OCH3),
71.4 (d, C-5), 72.4, 73.0, 74.4 (3!t, 3!PhCH2), 74.5 (d,
C-2), 75.6 (d, C-4), 78.5 (d, C-3), 99.6 (d, C-1), 127.7,
127.7, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5 (8!d, 15!
Ar-C), 137.8, 138.0, 138.2 (3!s, 3!Ar-C), 174.0 (s, C-6);
m/z (ESC) 537 (MCNH4CCCH3CN, 100), 501 (MCNaC,
20%). (HRMS (ESC) Calcd for C28H34NO7 (MCNHC4 )
496.2335. Found, 496.2328).
138.2, 138.2 (3!s, 3!Ar-C), 171.2 (s, C-6); m/z (ESC) 537
(MCNHC4 CCH3CN, 100), 501 (MCNaC, 5%). (HRMS
(ESC) Calcd for C28H34NO7 (MCNHC4 ) 496.2335. Found,
496.2328).
4.3.7. Methyl 6-O-(40,60-O-benzylidene-30-O-yl-D-allal)-
2,3,4-tri-O-benzyl-a-D-glucuronic ester 11. General
procedure A. 4,6-O-Benzylidene-D-allal 111 (158 mg,
0.67 mmol), gluco acid 3 (558 mg, 1.0 mmol), N,N-
dimethyl-4-amino pyridine (16 mg, 0.14 mmol), dicyclo-
hexylcarbodiimide (278 mg, 1.4 mmol) in DCM (30 ml)
gave ester 11 (388 mg, 83%) as a colourless oil; [a]2D1 C119
(c, 1.0 in CHCl3); nmax (thin film) 1746 (s, C]O), 1636 (m,
C]C–O) cmK1; dH (400 MHz, CDCl3) 3.45 (3H, s, OCH3),
3.60 (1H, dd, J1,2Z3.5 Hz, J2,3Z9.9 Hz, H-2 Glc), 3.80–
3.87 (2H, m, H-4 Glc, H-6 All), 4.00–4.05 (2H, m, H-4 All,
4.3.6. Methyl 2,3,4-tri-O-benzyl-a-D-galacturonic acid
10. Galacto alcohol 8 (1.75 g, 3.8 mmol) was dissolved in
anhydrous DCM (40 ml) and Dess–Martin periodinane
(2.39 g, 5.6 mmol) was added. The mixture was stirred
under an atmosphere of argon for 3 h, when TLC (petrol/
ethyl acetate, 1:1) indicated consumption of starting
material (Rf 0.4) and formation of a single product (Rf
0.5). The mixture was diluted with ether (75 ml) and
saturated aqueous sodium bicarbonate (75 ml) and sodium
thiosulphate (3 g) were added. The mixture was stirred for
1 h, and the layers separated. The aqueous phase was
extracted with ether (3!25 ml) and the combined organic
layers were washed with brine (3!75 ml), dried (MgSO4),
filtered and concentrated in vacuo to give crude aldehyde as
a colourless oil; dH (400 MHz, CDCl3) 3.42 (3H, s, OCH3),
3.98 (1H, dd, J3,4Z2.7 Hz, J4,5Z10.0 Hz, H-4), 4.10–4.14
(2H, m, H-2, H-5), 4.32 (1H, at, JZ2.2 Hz, H-3), 4.57, 4.93
(2H, 2!d, JZ11.1 Hz, PhCH2), 4.72, 4.88 (2H, 2!d, JZ
11.9 Hz, PhCH2), 4.77, 4.89 (2H, 2!d, JZ11.7 Hz,
PhCH2), 4.83 (1H, d, J1,2Z3.5 Hz, H-1), 7.24–7.43 (15H,
m, 15!Ar-H), 9.54 (1H, d, J5,6Z1.5 Hz, H-6); dC
(100.6 MHz, CDCl3) 55.9 (q, OCH3), 73.5, 73.8, 74.9
(3!t, 3!PhCH2), 75.6, 76.0, 76.1 (3!d, C-2, C-3, C-5),
78.1 (d, C-4), 99.3 (d, C-1), 127.5, 127.7, 127.8, 127.9,
128.1, 128.2, 128.3, 128.4, 128.5 (9!d, 15!Ar-C), 137.9,
138.3, 138.4 (3!s, 3!Ar-C), 200.5 (d, C-6). The residue
was dissolved in a mixture of tert-butanol (32 ml), THF
(14 ml), water (14 ml) and 2-methyl-2-butene (9 ml).
Sodium dihydrogenphosphate (1.8 g) and then sodium
chlorite (80%, 425 mg, 3.8 mmol) were added, and the
mixture stirred under an atmosphere of argon for 16 h. After
this time, TLC (petrol/ethyl acetate, 1:1) indicated complete
consumption of starting material (Rf 0.6) and formation of a
major product (Rf 0.1). The mixture was quenched by
addition of hydrochloric acid (100 ml of a 1 M aqueous
solution). The organic layer was separated, and the aqueous
layer extracted with ethyl acetate (5!30 ml). The combined
organic layers were washed with water (3!75 ml), dried
(MgSO4), filtered and concentrated in vacuo to give the
galacto acid 10 (1.82 g, quant.) as a white crystalline solid,
mp 126–130 8C (ether/petrol); [a]2D1 C38.2 (c, 1.0 in
CHCl3); nmax (KBr disc) 3220 (br, OH), 1775 (s,
C]O) cmK1; dH (400 MHz, CDCl3) 3.41 (3H, s, OCH3),
4.01 (1H, dd, J2,3Z10.1 Hz, J3,4Z2.8 Hz, H-3), 4.08 (1H,
dd, J1,2Z3.4 Hz, H-2), 4.34 (1H, at, JZ2.1 Hz, H-4), 4.39
(1H, d, J4,5Z1.4 Hz, H-5), 4.62, 4.95 (2H, 2!d, JZ
11.0 Hz, PhCH2), 4.68 (1H, d, JZ12.3 Hz, PhCH), 4.77
(1H, d, JZ11.5 Hz, PhCH), 4.78 (1H, d, H-1), 4.87 (2H, d,
JZ11.4 Hz, 2!PhCH), 7.24, 7.42 (15H, m, 15!Ar-H); dC
(100.6 MHz, CDCl3) 56.2 (q, OCH3), 70.4 (d, C-5), 73.4,
73.8, 75.2 (3!t, 3!PhCH2), 75.5 (d, C-2), 76.4 (d, C-4),
77.9 (d, C-3), 99.4 (d, C-1), 127.5, 127.7, 127.7, 127.9,
128.1, 128.1, 128.2, 128.4, 128.5 (9!d, 15!Ar-C), 138.0,
H-3 Glc), 4.13–4.22 (1H, m, H-5 All), 4.27 (1H, d, J4,5
Z
0
0
9.8 Hz, H-5 Glc), 4.41 (1H, dd, J5,6 Z5.0 Hz, J6,6
Z
10.6 Hz, H-60 All), 4.67 (1H, d, J1,2Z3.4 Hz, H-1 Glc),
4.68 (1H, d, JZ12.0 Hz, PhCH), 4.72, 4.76 (2H, 2!d, JZ
11.0 Hz, PhCH2), 4.80 (1H, d, JZ10.8 Hz, PhCH), 4.83
(1H, d, JZ12.1 Hz, PhCH), 4.95 (1H, d, JZ11.0 Hz,
PhCH), 5.03 (1H, at, JZ5.9 Hz, H-2 All), 5.46 (1H, dd,
J2,3Z5.8 Hz, J3,4Z3.9 Hz, H-3 All), 5.62 (1H, s, PhCHO2),
6.49 (1H, d, J1,2Z6.0 Hz, H-1 All), 7.21–7.54 (20H, m,
20!Ar-H); dC (100.6 MHz, CDCl3) 55.5 (q, OCH3), 63.6
(d, C-3 All), 64.9 (d, C-5 All), 68.5 (t, C-6 All), 70.5 (d, C-5
Glc), 73.6, 74.7, 75.8 (3!t, 3!PhCH2), 75.8, 81.5 (2!d,
C-4 All, C-3 Glc), 79.2, 79.4 (2!d, C-4 Glc, C-2 Glc), 97.8
(d, C-2 All), 98.6 (d, C-1 Glc), 101.6 (d, PhCHO2), 126.2,
126.2, 127.4, 127.6, 127.6, 127.9, 128.0, 128.1, 128.2,
128.2, 128.3, 128.5, 129.1, 129.3 (14!d, 20!Ar-C), 137.0,
138.1, 138.2, 138.6 (4!s, 4!Ar-C), 147.8 (d, C-1 All),
168.9 (s, C-6 Glc); m/z (ESC) 1447 (2MCNH4CCCH3CN,
3), 753 (MCNHC4 CCH3CN, 100%). (HRMS (ESC) Calcd
for C41H46NO10 (MCNHC4 ) 712.3122. Found, 712.3112).
4.3.8. Methyl 6-O-(40,60-O-benzylidene-30-O-yl-D-allal)-
2,3,4-tri-O-benzyl-a-D-mannuronic ester 12. General
procedure A. 4,6-O-Benzylidene-D-allal 111 (408 mg,
1.74 mmol), manno acid 9 (1.25 g, 2.6 mmol), N,N-
dimethyl-4-amino pyridine (43 mg, 0.35 mmol), dicyclo-
hexylcarbodiimide (719 mg, 3.5 mmol) in DCM (30 ml)
gave recovered 4,6-O-benzylidene-D-allal 1 (60 mg) and
ester 12 (919 mg, 76%, 89% based on recovered starting
material) as a colourless oil; [a]2D2 C147 (c, 1.0 in CHCl3);
nmax (thin film) 1748 (s, C];O), 1636 (w, C]C–O) cmK1
;
dH (400 MHz, CDCl3) 3.52 (3H, s, OCH3), 3.72 (1H, dd,
J1,2Z4.9 Hz, J2,3Z3.0 Hz, H-2 Man), 3.81–3.87 (2H, m,
H-3 Man, H-6 All), 4.00 (1H, dd, J3,4Z4.1 Hz, J4,5
Z
10.4 Hz, H-4 All), 4.20 (1H, dat, JZ5.2, 10.3, 10.3 Hz, H-5
All), 4.27 (1H, at, JZ6.3 Hz, H-4 Man), 4.38–4.46 (3H, m,
PhCH, H-5 Man, H-60 All), 4.52 (1H, d, JZ11.7 Hz,
PhCH), 4.62–4.72 (2H, m, 2!PhCH), 4.71 (1H, d, JZ
11.2 Hz, PhCH), 4.76 (1H, d, JZ12.3 Hz, PhCH), 4.94 (1H,
at, JZ5.9 Hz, H-2 All), 5.06 (1H, d, H-1 Man), 5.30 (1H,
dd, J2,3Z6.1 Hz, H-3 All), 5.60 (1H, s, PhCHO2), 6.40 (1H,
d, J1,2Z6.0 Hz, H-1 All), 7.19–7.48 (20H, m, 20!Ar-H);
dC (100.6 MHz, CDCl3) 56.0 (q, OCH3), 63.5 (d, C-3 All),
64.9 (d, C-5 All), 68.6 (t, C-6 All), 72.2, 72.8 (2!t, 3!
PhCH2), 72.5 (d, C-5 Man), 74.8 (d, C-2 Man), 75.7, 75.8
(2!d, C-4 All, C-4 Man), 76.7 (d, C-3 Man), 98.1 (d, C-2
All), 99.4 (d, C-1 Man), 101.9 (d, PhCHO2), 126.3, 127.5,

7190
D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
127.5, 127.6, 127.7, 127.8, 128.2, 128.3, 129.2 (9!d, 20!
Ar-C), 137.0, 138.0, 138.1, 138.4 (4!s, 4!Ar-C), 147.4 (d,
C-1 All), 169.1 (s, C-6 Man); m/z (ESC) 712 (MCNH4C,
100%). (HRMS (ESC) Calcd for C41H46NO10 (MCNHC4 )
712.3122. Found, 712.3132). (Found: C, 70.51; H, 6.14.
C41H42O10 requires C, 70.88; H, 6.09%).
C-1 Glc, C-2 All), 101.9 (d, PhCHO2), 127.1, 127.5, 127.6,
127.7, 127.9, 127.9, 128.1, 128.3, 128.4, 128.4, 128.5,
128.6, 129.1 (13!d, 20!Ar-C), 138.5, 139.5, 140.0, 140.0
(4!s, 4!Ar-C), 146.7 (d, C-1 All), 158.5 (s, C-6 Glc); m/z
(ESC) 751 (MCNHC4 CCH3CN, 100%). (HRMS (ESC)
Calcd for C42H48NO9 (MCNHC4 ) 710.3329. Found,
710.3338).
4.3.9. Methyl 6-O-(40,60-O-benzylidene-30-O-yl-D-allal)-
2,3,4-tri-O-benzyl-a-D-galacturonic ester 13. General
procedure A. 4,6-O-Benzylidene-D-allal 111 (168 mg,
0.72 mmol), galacto acid 10 (595 mg, 1.1 mmol), N,N-
dimethyl-4-amino pyridine (18 mg, 0.14 mmol), dicyclo-
hexylcarbodiimide (296 mg, 1.4 mmol) in DCM (30 ml)
gave ester 13 (433 mg, 87%) as a white crystalline solid, mp
149–152 8C (ethyl acetate / petrol); [a]2D1 C140 (c, 1.2 in
CHCl3); nmax (KBr disc) 1771 (s, C]O), 1637 (m, C]C–
O) cmK1; dH (400 MHz, CDCl3) 3.41 (3H, s, OCH3), 3.85
(1H, at, JZ10.5 Hz, H-6 All), 4.00–4.04 (2H, m, H-3 Gal,
H-4 All), 4.08 (1H, dd, J1,2Z3.0 Hz, J2,3Z10.1 Hz, H-2
Gal), 4.27 (1H, dat, JZ5.4, 10.4, 10.4 Hz, H-5 All), 4.34
(1H, d, J3,4Z1.4 Hz, H-4 Gal), 4.41, 4.64 (2H, 2!d, JZ
4.3.11. Methyl 1,5-anhydro-2,3,4-tri-O-benzyl-6-O-
(40,60-O-benzylidene-30-yl-D-allal)-7-deoxy-a-D-manno-
hept-6-enopyranoside 15. General procedure B. Ester 12
(Rf 0.2 (petrol/ethyl acetate, 4:1), 331 mg, 0.48 mmol),
Tebbe reagent (0.5 M, 3.8 ml, 1.9 mmol) in THF (12 ml)
and pyridine (3 ml) gave enol ether 15 (252 mg, 76%) as a
pale yellow oil; (Rf 0.25, petrol/ethyl acetate, 4:1). This
unstable compound was used in the next step without
further, purification; nmax (thin film) 1634 (m, C]C–O)
cmK1; dH (400 MHz, C6D6) 3.22 (3H, s, OCH3), 3.59 (1H,
at, JZ10.5 Hz, H-6 All), 3.64 (1H, dd, J3,4Z3.7 Hz, J4,5
Z
10.5 Hz, H-4 All), 3.93 (1H, at, JZ2.5 Hz, H-2 Man), 4.15
(1H, dd, J2,3Z3.0 Hz, J3,4Z9.3 Hz, H-3 Man), 4.30 (1H,
0
0
0
11.0 Hz, PhCH2), 4.43 (1H, s, H-5 Gal), 4.51 (1H, dd,
dd, J5,6 Z5.3 Hz, J6,6 Z10.3 Hz, H-6 All), 4.36 (1H, d,
J4,5Z9.5 Hz, H-5 Man), 4.42 (1H, d, JZ1.7 Hz,
C]CHH0), 4.54 (1H, dat, JZ5.3, 10.4, 10.4 Hz, H-5 All),
4.57–4.70 (6H, m, H-3 All, H-4 Man, C]CHH0, 3!
0
0
0
J5,6 Z5.0 Hz, J6,6 Z10.6 Hz, H-6 All), 4.66 (1H, d, JZ
12.2 Hz, PhCH), 4.73 (1H, d, JZ12.1 Hz, PhCH), 4.80–
4.84 (3H, m, 2!PhCH, H-1 Gal), 5.15 (1H, at, JZ5.9 Hz,
H-2 All), 5.31 (1H, at, JZ4.8 Hz, H-3 All), 5.60 (1H, s,
PhCHO2), 6.49 (1H, d, J1,2Z6.1 Hz, H-1 All), 7.07–7.45
(20H, m, 20!Ar-H); dC (100.6 MHz, CDCl3) 56.0 (q,
OCH3), 63.8 (d, C-3 All), 65.0 (d, C-5 All), 68.6 (t, C-6 All),
70.4 (d, C-5 Gal), 72.8, 73.7, 74.9 (3!t, 3!PhCH2), 75.5,
75.6, 78.1 (3!d, C-2 Gal, C-3 Gal, C-4 All), 77.5 (d, C-4
Gal), 98.3 (d, C-2 All), 99.2 (d, C-1 Gal), 101.9 (d,
PhCHO2), 126.2, 127.0, 127.3, 127.4, 127.5, 127.8, 128.2,
128.2, 128.4, 129.2 (10!d, 20!Ar-C), 137.0, 138.3, 138.6,
138.8 (4!s, 4!Ar-C), 147.6 (d, C-1 All), 168.3 (s, C-6
Gal); m/z 1447 (2MCNHC4 CCH3CN, 7), 753 (MCNH4CC
CH3CN, 100%). (ESC) Calcd for C41H46NO10 (MCNHC4 )
712.3122. Found, 712.3132).
PhCH), 4.78 (1H, d, JZ12.3 Hz, PhCH), 4.88 (1H, d, J1,2
Z
1.6 Hz, H-1 Man), 4.91 (1H, at, JZ6.0 Hz, H-2 All), 5.01
(2H, s, PhCH2), 5.40 (1H, s, PhCHO2), 6.16 (1H, d, H-1
All), 7.14–7.80 (20H, m, 20!Ar-H); dC (100.6 MHz, C6D6)
54.7 (q, OCH3), 65.2 (d, C-5 All), 66.0 (d, C-3 All), 69.0 (t,
C-6 All), 72.8, 73.1, 75.0 (3!t, 3!PhCH2), 75.5 (d, C-5
Man), 76.2 (d, C-2 Man), 77.3 (d, C-4 Man), 77.6 (d, C-4
All), 80.5 (d, C-3 Man), 89.1 (t, C]CH2), 99.0 (d, C-2 All),
100.0 (d, C-1 Man), 102.1 (d, PhCHO2), 127.3, 127.5,
127.7, 127.7, 128.1, 128.4, 128.6, 128.7, 129.1 (9!d, 20!
Ar-C), 138.6, 139.5, 139.7, 140.3 (4!s, 4!Ar-C), 146.6 (d,
C-1 All), 159.1 (s, C]CH2); m/z (ESC) 710 (MCNH4C,
100%). (HRMS (ESC) Calcd for C42H48NO9 (MCNHC4 )
710.3329. Found, 710.3329).
4.3.10. Methyl 1,5-anhydro-6-O-(40,60-O-benzylidene-30-
yl-D-allal)-7-deoxy-2,3,4-tri-O-benzyl-a-D-gluco-hept-6-
enopyranose 14. General procedure B. Ester 11 (Rf 0.2
(petrol/ethyl acetate, 4:1), 170 mg, 0.24 mmol), Tebbe
reagent (0.5 M, 2.0 ml, 0.98 mmol) in THF (8 ml) and
pyridine (2 ml) gave enol ether 14 (138 mg, 82%) as a pale
yellow foam; (Rf 0.2 petrol/ethyl acetate, 4:1). This unstable
compound was used in the next step without further,
purification; nmax (thin film) 1634 (sh, C]C–O) cmK1; dH
(400 MHz, C6D6) 3.16 (3H, s, OCH3), 3.44–3.52 (2H, m,
H-5 All, H-6 All), 3.58 (1H, dd, J1,2Z3.5 Hz, J2,3Z9.5 Hz,
4.3.12. Methyl 8,12-anhydro-2,3,4-tri-O-benzyl-11,13-O-
benzylidene-9,10-didehydro-6-oxo-7,9,10-trideoxy-a-D-
glycero-D-ido-a-D-glucopyranoside 16. Enol ether 14
(125 mg, 0.18 mmol) was dissolved in xylene (3 ml) and
stirred at 185 8C in a sealed tube under an atmosphere of
argon. After 12 h, TLC (petrol/ethyl acetate, 4:1) indicated
consumption of starting material (Rf 0.25) and formation of
a major product (Rf 0.20). The solution was concentrated in
vacuo, and the residue was purified by flash column
chromatography (petrol/ethyl acetate, 4:1) to afford a-C-
disaccharide 16 (83 mg, 66%) as a white foam; [a]2D1 C18.7
(c, 1.0 in CHCl3); nmax (thin film) 1728 (s, C]O) cmK1; dH
0
H-2 Glc), 4.08 (1H, at, JZ9.3 Hz, H-4 Glc), 4.19 (1H, dd,
0
0
0
J5,6 Z5.4 Hz, J6,6 Z10.5 Hz, H-6 All), 4.22–4.27 (2H, m,
H-3 Glc, C]CHH0), 4.31 (1H, d, J4,5Z9.9 Hz, H-5 Glc),
4.36, 4.48 (2H, 2!d, JZ11.8 Hz, PhCH2), 4.38–4.44 (3H,
m, H-3 All, H-4 All, C]CHH0), 4.65 (1H, d, H-1 Glc), 4.74
(1H, at, JZ5.9 Hz, H-2 All), 4.87, 4.98 (2H, 2!d, JZ
11.2 Hz, PhCH2), 4.92, 4.95 (2H, 2!d, JZ11.3 Hz,
PhCH2), 5.28 (1H, s, PhCHO2), 6.04 (1H, d, J1,2Z5.9 Hz,
H-1 All), 7.03–7.65 (20H, m, 20!Ar-H); dC (100.6 MHz,
C6D6) 55.1 (q, OCH3), 65.3, 65.9 (2!d, C-3 All, C-4 All),
68.8 (t, C-6 All), 73.1, 74.9, 75.9 (3!t, 3!PhCH2), 74.1 (d,
C-5 Glc), 77.3 (d, C-5 All), 80.1 (d, C-4 Glc), 81.3 (d, C-2
Glc), 82.2 (d, C-3 Glc), 89.1 (t, C]CH2), 98.8, 98.8 (2!d,
(400 MHz, CDCl3) 2.66 (1H, dd, J7,7 Z17.2 Hz, J7,8
Z
4.9 Hz, H-7), 3.14 (1H, dd, J7 ,8Z8.2 Hz, H-70), 3.43 (3H, s,
OCH3), 3.51–3.57 (2H, m, H-2, H-12), 3.67 (1H, at, JZ
9.3 Hz, H-4), 3.75 (1H, at, JZ10.4 Hz, H-13), 4.04 (1H, at,
JZ9.4 Hz, H-3), 4.12–4.17 (1H, m, H-11), 4.17 (1H, d,
0
0
0
J4,5Z10.0 Hz, H-5), 4.21 (1H, dd, J12,13 Z4.6 Hz, J13,13
Z
10.4 Hz, H-130), 4.63 (1H, d, J1,2Z3.3 Hz, H-1), 4.64 (1H,
d, JZ10.6 Hz, PhCH), 4.68 (1H, d, JZ12.1 Hz, PhCH),
4.82–4.87 (4H, m, H-8, 3!PhCH), 5.00 (1H, d, JZ10.9 Hz,
PhCH), 5.59 (1H, s, PhCHO2), 5.70 (1H, dat, JZ2.6,
2.6, 10.5 Hz, H-10), 6.03 (1H, d, J9,10Z10.4 Hz, H-9),

D. J. Chambers et al. / Tetrahedron 61 (2005) 7184–7192
7191
2. For a review see: Sears, P.; Wong, C.-H. Angew. Chem., Int.
Ed. 1999, 38, 2300–2324.
7.25–7.53 (20H, m, 20!Ar-H); dC (100.6 MHz, CDCl3)
43.8 (t, C-7), 55.8 (q, OCH3), 65.7 (d, C-12), 69.5 (t, C-13),
69.9 (d, C-8), 73.6, 75.1, 75.9 (3!t, 3!PhCH2), 74.2, 75.0
(2!d, C-5, C-11), 78.7 (d, C-4), 79.4 (d, C-2), 81.7 (d, C-3),
98.7 (d, C-1), 101.9 (d, PhCHO2), 126.2, 127.5, 127.7,
127.9, 127.9, 128.1, 128.1, 128.2, 128.3, 128.4, 128.5, 129.1
(12!d, C-9, 20!Ar-C), 129.6 (d, C-10), 137.4, 137.8,
137.9, 138.5 (4!s, 4!Ar-C), 203.8 (s, C-6); m/z (ESC) 751
(MCNHC4 CCH3CN, 100%). (HRMS (ESC) Calcd for
C42H48NO9 (MCNHC4 ) 710.3329. Found, 710.3328).
3. (a) Witczak, Z. J. Curr. Med. Chem. 1995, 1, 392–405. (b)
Mulvey, G.; Kitov, P. I.; Marcato, P.; Bundle, D. R.;
Armstrong, G. D. Biochimie 2001, 83, 841–847. (c) Drinnan,
N. B.; Vari, F. Mini Rev. Med. Chem. 2003, 3, 633–649.
4. For a selection of approaches to C-disaccharide synthesis see:
(a) Rouzaud, D.; Sinay¨, P. J. Chem. Soc., Chem. Commun.
1983, 1353–1354. (b) Dawson, I. M.; Johnson, T.; Paton,
R. M.; Rennie, R. A. C. J. Chem. Soc., Chem. Commun. 1988,
1339–1340. (c) Lay, L.; Nicotra, F.; Panza, L.; Russo, G.;
´ ´
Caneva, E. J. Org. Chem. 1992, 57, 1304–1306. (d) Chenede,
A.; Perrin, E.; Rekai, E. D.; Sinay¨, P. Synlett 1994, 420–422.
´
(e) Mazeas, D.; Skrydstrup, T.; Doumeix, O.; Beau, J.-M.
4.3.13. Methyl 8,12-anhydro-2,3,4-tri-O-benzyl-11,13-O-
benzylidene-9,10-didehydro-6-oxo-7,9,10-trideoxy-a-D-
glycero-D-ido-a-D-mannopyranoside 17. Enol ether 15
(151 mg, 0.22 mmol) was dissolved in xylene (3 ml) and
stirred at 185 8C in a sealed tube under an atmosphere of
argon. After 12 h, TLC (petrol/ethyl acetate, 2:1) indicated
no change (Rf 0.5), but crude NMR indicated complete
consumption of starting material and formation of a major
product. The solution was concentrated in vacuo, and the
residue was purified by flash column chromatography
(toluene/ether, 19:1) to afford a-C-disaccharide 17
(125 mg, 83%) as a colourless oil; [a]2D1 C41.5 (c, 1.0 in
CHCl3); nmax (thin film) 1730 (s, C]O) cmK1; dH
0
Angew. Chem., Int. Ed. Engl. 1994, 33, 1383–1386. (f) Khan,
A. T.; Sharma, P.; Schmidt, R. R. J. Carbohydr. Chem. 1995,
14, 1353–1367. (g) Dondoni, A.; Boscarato, A.; Zuurmond, H.
Tetrahedron Lett. 1996, 37, 7587–7590. (h) Lei, L.; McKee,
M.; Postema, M. H. D. Curr. Org. Chem. 2001, 1133–1167.
5. Reports of biological activity of C-disaccharides and C-oligo-
saccharides have been scarce. See: (a) Wei, A.; Boy, K. M.;
Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9432–9436. (b)
Helmboldt, A.; Mallet, J.-M.; Petitou, M.; Sinay¨, P. Bull Soc.
Chim. Fr. 1997, 134, 1057–1067. (c) Xin, Y.-C.; Zhang,
Y.-M.; Mallet, J.-M.; Glaudemans, C. P. J.; Sinay¨, P. Eur.
J. Org. Chem. 1999, 471–476.
(400 MHz, CDCl3) 2.73 (1H, dd, J7,7 Z17.2 Hz, J7,8
Z
5.0 Hz, H-7), 3.26 (1H, dd, J7 ,8Z8.6 Hz, H-70), 3.38 (3H, s,
OCH3), 3.56–3.62 (1H, m, H-12), 3.76 (1H, at, JZ10.4 Hz,
0
6. (a) Godage, H. Y.; Fairbanks, A. J. Tetrahedron Lett. 2000, 41,
7589–7593. (b) Godage, H. Y.; Fairbanks, A. J. Tetrahedron
Lett. 2003, 44, 3631–3635. (c) Godage, H. Y.; Chambers, D. J.;
Evans, G. R.; Fairbanks, A. J. Org. Biomol. Chem. 2003, 1,
3772–3786. (d) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J.
Tetrahedron: Asymmetry 2005, 16, 45–55.
H-13), 3.79 (1H, at, JZ2.7 Hz, H-2), 3.92 (1H, dd, J2,3
Z
3.1 Hz, J3,4Z8.5 Hz, H-3), 4.05–4.18 (3H, m, H-4, H-5,
0
0
H-11), 4.27 (1H, dd, J12,13 Z4.7 Hz, J13,13 Z10.2 Hz,
H-130), 4.62, 4.66 (2H, 2!d, JZ11.9 Hz, PhCH2), 4.68,
4.81 (2H, 2!d, JZ9.9 Hz, PhCH2), 4.73, 4.79 (2H, 2!d,
JZ12.0 Hz, PhCH2), 4.81 (1H, d, J1,2Z2.3 Hz, H-1), 4.89–
4.93 (1H, m, H-8), 5.60 (1H, s, PhCHO2), 5.75 (1H, dat, JZ
2.4, 2.4, 10.4 Hz, H-10), 6.03 (1H, d, J9,10Z10.4 Hz, H-9),
7.18–7.53 (20H, m, 20!Ar-H); dC (100.6 MHz, CDCl3)
42.8 (t, C-7), 55.5 (q, OCH3), 65.8 (d, C-12), 69.7 (t, C-13),
70.1 (d, C-8), 72.5, 73.0, 74.9 (3!t, 3!PhCH2), 74.5 (d,
C-2), 75.1, 75.1, 76.8 (3!d, C-4, C-5, C-11), 79.4 (d, C-3),
99.8 (d, C-1), 102.0 (d, PhCHO2), 125.4, 126.4, 127.4,
127.7, 127.8, 127.9, 127.9, 128.3, 128.4, 128.4, 128.5,
128.5, 128.5, 129.2 (14!d, C-9, 20!Ar-C), 129.2 (d,
C-10), 137.6, 138.2, 138.2, 138.4 (4!s, 4!Ar-C), 204.4 (s,
C-6); m/z (ESC) 1443 (2MCNH4CCCH3CN, 3), 751 (MC
NHC4 CCH3CN, 100%). (HRMS (ESC) Calcd for
C42H48NO9 (MCNHC4 ) 710.3329. Found, 710.3315).
7. (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem.
Soc. 1978, 100, 3611–3613. (b) Hartley, R. C.; McKiernan,
G. J. J. Chem. Soc., Perkin Trans. 1 2002, 2763–2793.
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ments in carbohydrate chemistry see: (a) Corey, E. J.;
Shibasaki, M.; Knolle, J. Tetrahedron Lett. 1977, 18,
1625–1626. (b) Fleet, G. W. J.; Spensley, C. R. C. Tetrahedron
Lett. 1982, 23, 109–112. (c) Fleet, G. W. J.; Gough, M. J.
Tetrahedron Lett. 1982, 23, 4509–4512. (d) Fleet, G. W. J.;
Gough, M. J.; Shing, T. K. M. Tetrahedron Lett. 1983, 24,
3661–3664.
9. For approaches to C-glycosides by Claisen rearrangement see:
(a) Ireland, R. E.; Wilcox, C. S.; Thaisrivongs, S.; Vanier, R.
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Dawe, R. D.; Tulshian, D. B. Can. J. Chem. 1979, 57,
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Chem. Soc. 1981, 103, 3205–3207. (d) Ireland, R. E.;
Anderson, R. C.; Badoub, R.; Fitzsimmons, B. J.; McGarvey,
G.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,
105, 1988–2006. (e) Tulshian, D. B.; Fraser-Reid, B. J. Org.
Chem. 1984, 49, 518–522. (f) Curran, D. P.; Suh, Y. G.
Carbohydr. Res. 1987, 111, 161–191. (g) Colombo, L.;
Casiraghi, G.; Pittalis, A.; Rassu, G. J. Org. Chem. 1991, 56,
3897–3900. (h) Vidal, T.; Haudrechy, A.; Langlois, Y.
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4145–4152.
Acknowledgements
We gratefully acknowledge financial support from the
EPSRC (Project Studentship to D.J.C.) and from Celltech
(CASE award to D.J.C). We also acknowledge the use of the
Chemical Database Service (CDS) at Daresbury, UK.
References and notes
10. The products of the Tebbe/Claisen approach detailed here,
actually require ketone reduction and alkene dihydroxylation
in order to be formally classified as C-disaccharides. These
functional group transformations have been achieved on a
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model a-C-glycoside (derived from esterification of allal 1
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with benzoic acid and then Tebbe methylenation and Claisen
rearrangement) as follows. Complete ketone reduction was
achieved via a three step reaction sequence involving; (a)
reduction with sodium borohydride in ethanol to give a
diastereomeric mixture of alcohols; (b) formation of a
diastereomeric mixture of imidazole xanthates by subsequent
reaction with thiocarbonyldiimidazole; (c) free radical
reduction with triphenyltin hydride and AIBN in toluene at
80 8C. Diastereoselective cis dihydroxylation to give the
manno configured product was then achieved by treatment
with catalytic K2OsO4$2H2O in an acetone/water mixture in
the presence of quinuclidine, and methyl sulphonamide, with
N-methyl morpholine N-oxide as stoichiometric oxidant.
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¨
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4-substituent in the case of the galacto ester means that the
ester is simply too hindered for reaction to occur.
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