The synthesis of an O,C-trisaccharide: The O,C-analog of methyl 4'-O-β- D-glucopyranosylgentiobioside

Article abstract of DOI:10.1016/S0040-4020(99)00923-0

The synthesis of an O,C-trisaccharide, namely methyl O-β-D- glucopyranosyl-(1→4)-C-β-D-glucopyranosyl-(1→6)-α-D-glucopyranoside, was achieved in 14 steps by way of the nitro-aldol coupling of hepta-O-acetyl-β- cellobiosylnitromethane and methyl 6-aldehydo-2,3,4-tri-O-benzyl-α-D-gluco- hexodialdo-1,5-pyranoside, followed by the elaboration of the coupling product. The resulting O,C-trisaccharide constitutes a potential inhibitor of the β-glucanases of the cellulase family. The perbenzylated derivative of cellobiosylnitromethane was also prepared. Both disaccharide-C-glycosides constitute useful starting materials for the preparation of higher mixed O,C- oligosaccharides.

Full text of DOI:10.1016/S0040-4020(99)00923-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 217–224
The Synthesis of an O,C-Trisaccharide: The O,C-Analog of Methyl
40-O-b-d-glucopyranosylgentiobioside
,†
*
Stephen J. Spak and Olivier R. Martin
Department of Chemistry, State University of New York at Binghamton, Binghamton, NY 13902-6016, USA
This article is dedicated to Professeur Pierre Sinay¨ on the occasion of his 62nd birthday
Received 6 September 1999; accepted 14 October 1999
Abstract—The synthesis of an O,C-trisaccharide, namely methyl O-b-d-glucopyranosyl-(1!4)-C-b-d-glucopyranosyl-(1!6)-a-d-
glucopyranoside, was achieved in 14 steps by way of the nitro–aldol coupling of hepta-O-acetyl-b-cellobiosylnitromethane and methyl
6-aldehydo-2,3,4-tri-O-benzyl-a-d-gluco-hexodialdo-1,5-pyranoside, followed by the elaboration of the coupling product. The resulting
O,C-trisaccharide constitutes a potential inhibitor of the b-glucanases of the cellulase family. The perbenzylated derivative of cellobiosyl-
nitromethane was also prepared. Both disaccharide-C-glycosides constitute useful starting materials for the preparation of higher mixed
O,C-oligosaccharides. ᭧ 1999 Elsevier Science Ltd. All rights reserved.
Introduction
compounds were prepared by iterative Wittig olefination
(Dondoni et al.8) and by iterative lactoneϩacetylide
couplings (Sinay¨ et al.9); the latter procedure was in fact
the one that had been used by its authors to obtain the
very first example of a C-disaccharide.10 In comparison,
few examples of mixed O,C-oligosaccharides have been
described: a C-analog of the pentasaccharide corresponding
to the antithrombin III binding domain of heparin,3 and an
O,C-analog of the Lewisx trisaccharide.11 Both of
these compounds were generated by the glycosylation of a
C-disaccharide.
The C-analogs of disaccharides and higher oligosaccharides,
i.e. analogs in which one or more interglycosidic oxygen
atom is replaced by a methylene group, form a class of
carbohydate mimics1 of increasing importance: such
compounds constitute useful glycosidase-resistant probes
for the study, at the molecular level, of carbohydrate–
protein interactions in lectins, antibodies and, possibly,
enzymes. Of particular significance are the recent findings
that methylene-bridged analogs retain the same affinity as
the substrates for their macromolecular receptor in a number
of cases: the C,C-analog of the H-type II human blood group
antigenic trisaccharide for the lectin from Ulex europaeus,2
a C-analog of a heparin-derived pentasaccharide for the
antithrombin III protein,3 and C-oligogalactosides of the
[–(1!6)-C-b-Gal–]n type for three monoclonal antigalac-
tan antibodies.4 In all cases, these results suggested that the
interglycosidic oxygen atom(s) of the natural substrate
is (are) not involved in an essential interaction with the
receptor such as hydrogen bonding.
We had reported12 the synthesis of (1!1)- and (1!6)-
linked C-disaccharides by way of the nitroaldol coupling
of a glycosylnitromethane with a sugar aldehyde. This
method remains one of the simplest and shortest procedures
for the preparation of unbranched C-disaccharides and the
modification recently proposed by Bednarski13 should
extend its scope. Since hexobiosylnitromethane derivatives
had been reported to be readily available from the
corresponding disaccharides,14 we considered that such
C-glycosyl compounds could serve as the precursors of
O,C-trisaccharides using our methodology. We report in
this article a new synthesis of cellobiosylnitromethane
derivatives and an investigation of their utility in the
synthesis of O,C-trisaccharides.
The synthesis of C-disaccharides has been the topic of
intense research activity and several methods have been
developed.5 Examples of even more challenging higher
C-oligosaccharides (C,C-trisaccharides) have also been
reported,6,7 in particular by Kishi and coworkers. The
largest, fully methylene-bridged oligosaccharide analogs
reported so far are C,C,C-tetrasaccharides: these remarkable
Results and Discussion
Keywords: nitroaldol; C-glycosides; cellobiosylnitromethane.
14
ˇ
According to Petrus and coworkers, hexobiosylnitro-
* Corresponding author. e-mail: olivier.martin@univ-orleans.fr
†
methanes can be generated from free disaccharides under
´
´
New address: I.C.O.A., Faculte des Sciences, BP 6759, 45067 Orleans,
the same conditions as b-d-glucopyranosylnitromethane
France.
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00923-0

218
S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
Scheme 1. (a) CO, HSiEt2Me, cat Co2(CO)8; (b) THF/aq. HOAc; (c) Ph3P, imidazole, I2; (d) NaNO2, DMSO/DMF.
from d-glucose. However, in our hands, the base-catalyzed
reaction of cellobiose with nitromethane followed by the
dehydration and cyclization of the resulting nitroalditols
did not afford more than traces of the desired b-cellobiosyl-
nitromethane. This approach was therefore abandoned and
an alternative method sought. As shown by Murai et al.,15
glycosyl acetates are converted into the silyl ether of the
corresponding glycosylmethanol derivatives in good yield
and with a high degree of (b)-stereoselectivity in the gluco
and galacto series, on treatment with CO and a trialkylsilane
in the presence of cobalt octacarbonyl. As the hydroxy-
methyl group constitutes a convenient precursor of the nitro-
methyl group as well as of other functionalized C1 units, we
decided to investigate the siloxymethylation of cellobiose
peracetate 1. The reaction of 1 with HSiMe2Et/CO/
Co2(CO)8 was found to provide b-cellobiosylmethanol deri-
vative 2 in good yield (66% isolated product on 10 g scale),
and no a-epimer could be detected (Scheme 1). The best
results were obtained using a recrystallized catalyst and
taking the precaution of refilling the reaction flask with
fresh CO every day (reaction time: 10–12 days). The
intermediate,15,16 thus provides a convenient method for
the direct C-glycosylation of disaccharide derivatives.
Compound 2 was then converted into b-cellobiosylnitro-
methane peracetate 5 in three steps and 58% overall yield:
desilylation of 2 under mildly acidic conditions, to give 3,
replacement of the OH group of 3 by an iodine atom17 (!4),
and substitution of the iodide in 4 by the nitrite ion.18 The
b-configuration of the C-glycosidic linkage was clearly
established by the NMR parameters of compounds 3, 4,
and 5 (J2,3ˆ9.5–9.7 Hz).
The condensation of compound 5 with 6-aldehydo-gluco-
pyranoside 619 in the presence of KF in an aprotic medium
afforded the desired pseudotrisaccharide 7 in 44% yield
(Scheme 2). Some starting material (5) could be recovered
and the yield of 7 based on consumed nitrosugar reached
73%. The coupling reaction is highly stereoselective: only
one product could be isolated and the NMR analysis of this
product revealed the presence of a single stereoisomer.
Murai procedure, which involves
a
glycosylcobalt
The coupling constants between the protons at positions 5,
Scheme 2. (a) KF, 18-crown-6, CH3CN, r.t.; (b) Ac2O, py, 54 h; (c) NaBH4, EtOH, 0ЊC; (d) Bu3SnH, AIBN, toluene, refl., 30 min; (e) H2/Pd(OH)2, 1 atm.,
EtOH; (f) MeOH/MeONa.

S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
219
Scheme 3. (a) CH3OCH2OCH3, P2O5; (b) MeONa/MeOH; (c) NaH, BnBr, DMF; (d) 6M HCl, THF, D; (e) I2, Ph3P, imidazole; (f) NaNO2, DMSO/DMF.
6, 7 and 8 in compound 7 indicate a gauche relationship
between H-5 and H-6, anti between H-6 and H-7 and gauche
between H-7 and H-8. On the basis of an analysis of the
steric interactions in the conformations compatible with
these relationships and of the fact that the carbon chain
tends to preferentially adopt a zigzag arrangement in such
systems,20 we tentatively propose that the configuration at
C-6 and C-7 in compound 7 is S and R, respectively. This
structure is free of 1,3-diaxial-like interactions between
substituents at C-5–C-8 and should be particularly
favorable.
to use more vigorous coupling conditions, the perbenzylated
derivative of cellobiosylnitromethane, compound 18, was
prepared (Scheme 3). For this purpose, compound 3 was
converted into the MOM ether derivative 13 and the acetyl
groups of 13 were replaced by benzyl groups under conven-
tional conditions to give compound 15. The MOM ether of
15 was then cleaved under acidic conditions and the OH
group thus freed (compound 16) was replaced by a nitro
group by way of iodomethyl intermediate 17, as described
above for the synthesis of 5. This sequence of reactions
provided compound 18 in 26% overall yield from 3 (not
optimized).
The coupling of the nitronate ion derived from 18 with keto
sugar 19, under various conditions, was unsuccessful;
attempts to use the dianionic species generated by the treat-
ment of 18 with 2 equiv. of BuLi, under the conditions
described by Seebach,21 also remained fruitless.
Compound 7 was further elaborated into a pseudotrisacchar-
ide as follows: the nitroaldol product was dehydrated by
acetylation and spontaneous elimination of acetic acid to
afford a mixture of E and Z isomers of nitro alkene 8.
These sensitive compounds were rapidly treated with
NaBH4 to reduce the double bond, thus providing the 11-
O-glucosylated 7-nitro-6,7-dideoxy-tridecose derivative 9
in 45% yield (ϳ2:1 mixture of stereoisomers at C-7). The
nitro group of 9 was then removed under radical conditions
to give protected pseudotrisaccharide 10. Deprotection of 10
by catalytic hydrogenation followed by deacetylation gave
the free pseudotrisaccharide 12, the methylene analog of
methyl 40-O-b-d-glucopyranosyl-a-gentiobioside. This
compound constitutes a novel example of mixed O,C-oligo-
saccharide and the first one to have been made using as
precursor a disaccharide C-glycoside. It is a potential
inhibitor of the enzymes that cleave cellobiose and higher
b-(1!4)-glucose oligomers (b-glucanases).
In spite of these results, compounds 5 and 18 themselves, as
well as their precursors carrying a hydroxymethyl or an
iodomethyl substituent, constitute very useful synthetic
intermediates in the field of carbohydrate mimics: they
should readily give access to C-analogs of disaccharide-
derived glycoconjugates, a class of compound for which
few direct synthetic routes are available.
Conclusion
The synthesis of the O,C-analog of methyl b-d-glucopyran-
osyl-(1!4)-b-d-glucopyranosyl-(1!6)-a-d-glucopyran-
oside was achieved in 14 steps from simple sugars by the
nitroaldol coupling methodology using a cellobiosylnitro-
methane derivative as the key precursor. This is the first
synthesis of a mixed O,C-oligosaccharide in which the
C-glycosidic linkage is already built into a disaccharide
precursor. The cellobiosylnitromethane derivatives pre-
pared, and their synthetic precursors, provide useful inter-
mediates for the synthesis of other pseudo-oligosaccharides
The possibility of using cellobiosylnitromethane for the
synthesis of an O,C-analog of cellotriose was also investi-
gated. However, attempts to couple 5 with a ‘4-ketoglucose’
derivative (methyl 2,3,6-tri-O-benzyl-a-d-xylo-hexopyra-
nosid-4-ulose, 19) were not successful. In order to be able

220
S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
as well as of C-glycosidic analogs of disaccharide glyco-
conjugates.
after 11 days of stirring at room temperature. The cobalt
complex was precipitated by the dropwise addition of
pyridine (2 mL) and then bubbling air through the solution
for 15 min. The content of the flask was filtered through
5 cm of silica gel that was eluted with chloroform. The
filtrate was evaporated and the residue subjected to flash
chromatography (EtOAc/hexanes 1:2) that afforded 7.62 g
(10.12 mmol; 66%) of white solid product 2. [a]2D0 Ϫ10.3 (c
1.07, CHCl3); mp 148.0–149.0ЊC; Rf 0.37 (EtOAc/hexanes
5:6); IR (film, cmϪ1) 1748.6 (CyO); 13C NMR: d 170.39,
170.24, 170.11, 169.94, 169.60, 169.21, 168.96 (acetate
COs), 100.72 (C-10), 78.49 (C-2), 76.65 (C-5), 76.39
(C-6), 74.16 (C-4), 72.94 (C-30), 71.88 (C-50), 71.61
(C-20), 69.03 (C-3), 67.84 (C-40), 62.26 (C-1,7), 61.56
(C-60), 20.69, 20.62, 20.54, 20.44 (acetate CH3s), 6.54,
6.13, 6.10, Ϫ5.08 (silyl CHs); FABMS (3-NBA): m/z 773
[MϩNa]ϩ; HR-FABMS: calcd for C32H50NaO18Si m/z
773.2664; found 773.2635.
Experimental
General methods
Melting points were obtained using a Fisher–Johns melting
point apparatus and are uncorrected. Thin-layer chromato-
graphy was performed on 0.25 mm Merck silica gel plates
(60F254). The determination of spots was conducted by
inspection under UV light (254 nm), as well as by spraying
the developed plates with a solution of ammonium
phosphomolybdate
(H2SO4ˆ100 mL/H3PO4ˆ100 mL/
H2Oˆ3.8 L/(NH4)6Mo7O24ˆ100 g) and charring on a hot
plate. Flash column chromatography was performed on
silica gel 60 (230–400 mesh) from Merck. Optical rotations
were measured with a Perkin–Elmer 243B polarimeter for
solutions in a 0.1 dm cell at room temperature (20^3ЊC). 1H
and 13C NMR spectra were recorded on a Bruker AM-360
spectrometer at 360 and 90 MHz, respectively. CDCl3 was
used as the solvent unless otherwise noted; chemical shifts
are in ppm (d) relative to tetramethylsilane (TMS) with
TMS (dˆ0:00 ppm) as the internal reference, unless indi-
cated otherwise. Chemical shifts and coupling constants
were obtained from the direct examination of spectra for
all first-order spectra and all assignments of signals were
verified by 2D correlation spectra. IR spectra were obtained
using a Perkin–Elmer 1600 FT-IR instrument. Mass spec-
tral analyses were carried out by Midwest Center for Mass
Spectrometry, University of Nebraska, Lincoln, NE 68588.
Elemental analyses were carried out by Atlantic Microlab,
Inc., Norcross, GA 30091.
(Hepta-O-acetyl-b-d-cellobiosyl)methanol (3). To a solu-
tion of compound 2 (1.62 g; 2.16 mmol) in THF (5.5 mL) at
0ЊC, HOAc (2.5 mL) and water (1.5 mL) were added. The
reaction mixture was stirred for 9 h. The THF was then
evaporated and the remaining suspension was diluted with
CH2Cl2 (large excess). The solution was washed succes-
sively with saturated aqueous sodium bicarbonate and
with a phosphate buffer (pHˆ7). The organic layer was
then separated, dried over MgSO4 and the solvent
evaporated. The resultant compound was purified by flash
chromatography (EtOAc/hexanes 1:1) to furnish 3 as a
beige-white solid (1.29 g; 1.98 mmol, 92%). [a]2D0 Ϫ13.6
(c 0.96, CHCl3); mp 198.0–198.5ЊC; Rf 0.15 (EtOAc/
hexanes 2:1), 0.54 (EtOAc); IR (film, cmϪ1) 3495.1
(O–H), 1748.6 (CyO); 13C NMR d 170.39, 170.32,
170.26, 170.11, 169.81, 169.21, 168.96 (acetate COs),
100.69 (C-10), 77.87 (C-2), 76.64 (C-6), 76.49 (C-5),
73.54 (C-4), 72.87 (C-30), 71.89 (C-50), 71.56 (C-20),
68.75 (C-3), 67.77 (C-40), 62.15 (C-7), 61.53 (C-60), 61.28
(C-1), 20.76, 20.55, 20.47, 20.42 (acetate CH3s);1H NMR: d
(Hepta-O-acetyl-b-d-cellobiosyl)methanol methyldiethyl-
silyl ether (2). For general procedure: see Ref. 16. The
following precautions were followed: a-d-cellobiosyl
octaacetate was dried at 100ЊC for 8 h under high vacuum.
Et2MeSiH was used straight from an ampoule or from
reagent that was stored at 0ЊC under CO atmosphere in a
desiccator. Co2(CO)8 (Strem Chemicals Co.) was recrystal-
lized from hexane (room temperature to Ϫ25ЊC) and
collected under CO atmosphere. The recrystallized
Co2(CO)8 was stored under CO at 0ЊC in a desiccator.
Caution: the purified crystals ignite spontaneously on expo-
sure to air. The CO gas used (99.99% purity) was passed
through an on-line desiccant. CO gas was stored in a
helium-quality balloon that was connected to a three-neck
reaction flask by a glass stopcock. The vessel was evacuated
daily and refilled with CO in the course of the reaction.
0
0
5.23 (t, 1H, J4,3ˆJ4,5ˆ9.3 Hz, H-4), 5.15 (t, 1H, J3 ,2
ˆ
0
0
0
0
0
0
J3 ,4 ˆ9.3 Hz, H-3 ), 5.07 (t, 1H, J4 ,5 ˆ9.7 Hz, H-4 ), 4.96
(t, 1H, J3,2ˆ9.7 Hz, H-3), 4.93 (t, 1H, H-20), 4.52 (d, 1H,
0
0
0
J1 ,2 ˆ8.0 Hz, H-1 ), 4.51 (dd, 1H, J7b,6ˆ1.8 Hz, H-7b), 4.38
0
0
0
0
0
(dd, 1H, J6 a,6 bˆ12.5 Hz, J6 b,5 ˆ4.3 Hz, H-6 b), 4.09 (dd,
1H, J7a,7bˆ12.1, J7a,6ˆ5.3 Hz, H-7a), 4.05 (dd, 1H,
0
0
0
J6 a,5 ˆ2.2 Hz, H-6 a), 3.75 (t, 1H, J5,6ˆ9.7 Hz, H-5), 3.71
(dd, 1H, J1a,1bˆ12.4 Hz, J1b,2ˆ1.9 Hz, H-1b), 3.67 (ddd, 1H,
H-50), 3.61 (ddd, 1H, H-6), 3.54 (dd, 1H, J1a,2ˆ4.9 Hz,
H-1a), 3.50 (ddd, 1H, H-2), 2.33 (s, broad, 1H, O–H),
2.15–1.90 (7s, 21H, acetate CH3s). Anal. calcd for
C27H38O18: C, 49.85; H, 5.89; found: C, 50.42; H, 5.99.
(Hepta-O-acetyl-b-d-cellobiosyl)iodomethane (4).
A
Actual procedure
mixture of compound 3 (1.33 g; 2.04 mmol), triphenylphos-
phine (0.83 g; 3.2 mmol), imidazole (0.45 g; 6.6 mmol) and
iodine (0.78 g; 3.1 mmol) in THF (35 mL) was stirred under
reflux for 3.5 h. THF was then evaporated, the crude product
was dissolved in CH2Cl2 (100 mL) and solids were removed
by filtration. An equal volume of saturated aqueous sodium
bicarbonate was added and the mixture was stirred for
10 min. Iodine was added in portions and when the organic
phase remained iodine-colored, the mixture was stirred for
an additional 10 min. Excess iodine was destroyed by the
Co2(CO)8 (0.25 g; 0.73 mmol) was added to a three-neck
flask under CO atmosphere. Et2MeSiH (12.0 mL; 8.46 g;
82.7 mmol; 5.4 eq.) was then added and the mixture was
stirred for 5 min. A solution of a-d-cellobiosyl octaacetate
1 (10.41 g; 15.34 mmol) in anhydrous CH2Cl2 (85 mL) was
degassed (freeze–pump–thaw procedure) and then added
using a syringe. After complete addition, the flask was evac-
uated and refilled (3×) with CO gas. The gas was added
under the level of the solution. The reaction was stopped

S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
221
addition of saturated aqueous sodium thiosulfate. The
organic layer was diluted with CH2Cl2 (100 mL), separated,
washed with water (100 mL), dried over MgSO4, and
concentrated to afford a solid residue. The product was
purified by flash chromatography (EtOAc/hexanes,
1:3!1:1 gradient), thus affording compound 4 (1.38 g,
1.82 mmol, 89%). [a]2D0Ϫ32.5 (c 0.94, CHCl3); mp 211.0–
212.0ЊC; Rf 0.40 (EtOAc/hexanes 1:1); 13C NMR d 170.44,
170.29, 170.16, 169.83, 169.62, 169.25, 169.00 (acetate
COs), 100.79 (C-10), 76.69 (C-5), 76.65 (C-6), 76.60
(C-2), 73.34 (C-4), 72.90 (C-30), 72.32 (C-3), 71.97
(C-50), 71.58 (C-20), 67.78 (C-40), 61.88 (C-7), 61.55
(C-60), 20.90, 20.68, 20.63, 20.50 (acetate CH3s), 3.54
were added nitro sugar 5 (1.99 g; 2.93 mmol), KF (0.26 g;
4.82 mmol; 1.7 eq.) and 18-crown-6 ether (0.14 g;
0.05 mmol). The mixture was stirred for 6 h at r.t. The solu-
tion was then concentrated to dryness and the residue
dissolved in CH2Cl2 (100 mL). The solution was then
washed with water (2 × 40 mL), dried over Na2SO4, and
concentrated. The residual product was submitted to flash
chromatography (EtOAc/hexanes 5:6) which afforded
compound 7 (1.46 g, 1.28 mmol; 44% yield) as a white
solid (single stereoisomer). Some starting material (5)
could be recovered (yield based on nitro sugar consumed:
73%). [a]2D0 Ϫ3.2 (c 4.0, CHCl3); mp 237.0–238.0ЊC; Rf
0.18 (EtOAc/hexanes 1:1); IR (film, cmϪ1) 3483.3 (OH),
1754.5 (CO), 1552.8 and 1367.2 (NO2); 13C NMR: d
170.44, 170.18, 170.12, 170.02, 169.24, 168.99, 168.86
(acetate COs), 138.54, 137.99 (2)(ArCs), 128.77, 128.49,
128.39, 128.05, 128.00, 127.95, 127.66 (ArCHs), 100.80
(C-10), 98.86 (C-1), 84.32 (C-7), 81.51 (C-3), 79.49 (C-2),
77.19 (C-12), 76.34 (C-4), 76.05 (C-11), 75.79, 74.79, 73.48
(3 benzyl CH2s), 74.13 (C-30), 74.13 (C-8), 72.87 (C-10),
72.03 (C-50), 71.59 (C-9), 69.38 (C-5), 68.56 (C-20), 67.76
(C-40), 66.18 (C-6), 61.51 (C-60), 61.30 (C-13), 55.83
(CH3), 20.59, 20.51, 20.46, 20.25 (acetates CH3s); 1H
NMR: d 7.22–7.45 (m, 15H, ArHs), 5.15, 5.14 (2t, 2H,
1
(C-1); H NMR: d 5.18 (t, 1H, J4,3ˆJ4,5ˆ9.2 Hz, H-4),
0
0
0
0
00
0
5.15 (t, 1H, J3 ,2 ˆJ3 ,4 ˆ9.3 Hz, H-3 ), 5.07 (t, 1H,
0
0
J4 ,5 ˆ9.5 Hz, H-4 ), 4.93 (t, 1H, H-2 ), 4.85 (t, 1H,
J3,2ˆ9.50 Hz, H-3), 4.52 (dd, 1H, J7b,7aˆ12.0 Hz,
0
0
0
J7b,6ˆ2.0 Hz, H-7b), 4.50 (d, 1H, J1 ,2 ˆ7.9 Hz, H-1 ),
0
0
0
0
0
4.39 (dd, 1H, J6 a,6 bˆ12.5 Hz, J6 b,5 ˆ4.3 Hz, H-6 b), 4.12
0
0
(dd, 1H, J7a,6ˆ5.4 Hz, H-7a), 4.04 (dd, 1H, J6 a,5 ˆ2.3 Hz,
H-60a), 3.75 (t, 1H, J5,6ˆ9.3 Hz, H-5), 3.66 (ddd, 1H, H-50),
3.63 (ddd, 1H, H-6), 3.37 (ddd, 1H, J2,1aˆ7.1 Hz,
J2,1bˆ2.7 Hz, H-2), 3.29 (dd, 1H, J1b,1aˆ11.1 Hz, H-1b),
3.10 (dd, 1H, H-1a), 2.15–1.95 (7s, 21H, acetate CH3s).
Anal. Calcd for C27H37O17I: C, 42.64; H, 4.90; I, 16.69;
found: C, 42.94; H, 5.07; I, 16.48.
Jˆ9.4, 9.0 Hz, H-30,10), 5.09 (t, 1H, J3 ,4 ˆJ4 ,5 ˆ9.7 Hz,
H-40), 4.97 (d, 1H, Jˆ10.4 Hz), 4.88 (d, 1H, Jˆ11.1 Hz),
4.81 (d, 1H, Jˆ12.5 Hz), 4.81 (d, 1H, Jˆ10.4 Hz), 4.71 (d,
1H, Jˆ11.4 Hz) and 4.62 (d, 1H, Jˆ12.7 Hz) (3AB, 3
CH2Ph), 4.95 (t, 1H, H-9), 4.92 (t, 1H, H-20), 4.70 (dd,
0
0
0
0
(Hepta-O-acetyl-b-d-cellobiosyl)nitromethane
(5).
Compound 4 (0.65 g; 0.86 mmol) was dissolved in a
mixture of DMSO (2 mL) and DMF (6 mL). Phloroglucinol
dihydrate (0.08 g; 0.49 mmol) and sodium nitrite (0.26 g;
3.8 mmol) were added and the mixture was stirred for
3 days at r.t. The solution was then poured onto ice (50 g)
and the mixture was stored in a freezer for 10 min. The
suspension was allowed to warm up slightly, the precipitate
was filtered (Bu¨chner) and washed with ice–water until the
filtrate remained clear. The precipitate was dried and
submitted to flash chromatography (EtOAc/hexanes 1:1)
to furnish white solid 5 (0.41 g; 0.60 mmol; 71% yield).
[a]2D0 Ϫ26.2 (c 1.09, CHCl3); mp 215.0–216.0ЊC; Rf 0.24
(EtOAc/hexanes 1:1); IR (film, cmϪ1) 1560.6, 1369.7
(NO2); 13C NMR: d 170.32, 170.06, 169.76, 169.57,
169.18, 168.89 (acetate COs), 100.61 (C-10), 76.81 (C-50),
76.10 (C-5), 75.62 (C-1), 74.08 (C-2), 73.17 (C-4), 72.80
(C-30), 71.96 (C-6), 71.51 (C-20), 69.42 (C-3), 67.87 (C-40),
61.67 (C-60), 61.60 (C-7), 20.55, 20.51, 20.37 (acetate
1H, J7,8ˆ2.3, J7,6ˆ8.9 Hz, H-7), 4.65 (dd, 1H, J13b,13a
ˆ
12.1, J13b,12ˆ2.3 Hz, H-13b), 4.59 (broad m, 1H, H-6),
0
0
4.55 (d, 1H, J1,2ˆ3.5 Hz, H-1), 4.51 (d, 1H, J1 ,2 ˆ7.9 Hz,
0
H-10), 4.36 (dd, 1H, J6 a,6 bˆ12.6, J6 b,5 ˆ4.3 Hz, H-6 b),
0
0
0
0
4.12 (dd, 1H, J8,9ˆ10.3 Hz, H-8), 4.03 (dd, 1H,
0
0
0
J6 a,5 ˆ2.2 Hz, H-6 a), 3.98 (2dd, 2H, J13a,12ˆ5, J3,4ˆ8 Hz,
H-3,13a), 3.74 (t, 1H, J10,11ˆ J11,12ˆ9.6 Hz, H-11), 3.65
(ddd, 1H, H-50), 3.62 (distorted dd, 1H, J3,4ˆ8.1,
J4,5ˆ10 Hz, H-4), 3.58 (br distorted d, J5,6Յ1 Hz, H-5),
3.57 (ddd, 1H, H-12), 3.45 (dd, 1H, J2,3ˆ9.7 Hz, H-2),
3.27 (s, 3H, OCH3), 1.90–2.20 (several s, 21H, acetate
CH3s); FABMS (3-NBAϩNaϩ): m/z 1164 [MϩNa]ϩ; HR-
FABMS: calcd for C55H67NNaO25 m/z 1164.3900; found
1164.3867.
Z- and E-Methyl 9,10,13-tri-O-acetyl-11-O-(tetra-O-
acetyl-b-d-glucopyranosyl)-8,12-anhydro-2,3,4-tri-O-
benzyl-6,7-dideoxy-7-nitro-a-d-glycero-d-gulo-d-gluco-
1
CH3s); H NMR: d 5.23 (t, 1H, J4,3ˆJ4,5ˆ9.1 Hz, H-4),
0
0
0
0
00
0
5.14 (t, 1H, J3 ,2 ˆJ3 ,4 ˆ9.3 Hz, H-3 ), 5.06 (t, 1H,
tridec-6-eno-1,5-pyranoside (8). To
a
solution of
0
0
J4 ,5 ˆ9.4 Hz, H-4 ), 4.92 (t, 1H, H-2 ), 4.87 (t, 1H,
compound 7 (780.0 mg; 0.683 mmol) in CH2Cl2 (5 mL) at
0ЊC was added freshly distilled Ac2O (1.2 mL; 13 mmol)
and pyridine (0.75 mL; 9.3 mmol). The mixture was
allowed to warm up to r.t. and maintained in absence of
light for 54 h. The reaction mixture was then diluted with
CH2Cl2 (100 mL) and washed successively with 1M aq HCl
(2×10 mL), aq NaHCO3 (5% w/v; 2×20 mL) and water
(2×20 mL). The solution was then dried over Na2SO4 and
concentrated. Flash chromatography (EtOAc/hexanes 2:3)
of the residue afforded 99.1 mg of E-8, 104.4 mg of Z-8, and
442.7 mg of a mixture of E-8 and Z-8; total yield: 86%. Z-8:
mp 174.5–175.5ЊC, light yellow solid; Rf 0.29 (EtOAc/
hexanes 2:3); 1H NMR: d 6.15 (dd, 1H, J6,5ˆ9.7 Hz,
4J6,8ˆ1.4 Hz, H-6), 3.87 (dd, 1H, J8,9ˆ9.8 Hz, H-8);
FABMS (3-NBAϩNaϩ): m/z 1146 [MϩNa]ϩ, also
0
0
0
J3,2ˆ9.5 Hz, H-3), 4.50 (d, 1H, J1 ,2 ˆ7.9 Hz, H-1 ), 4.50–
4.34 (overlapping dd, 4H, H-1a,1b,60b,7b), 4.22 (qd, 1H,
J2,1a
ˆ2.9 Hz, J2,1b
ˆ9 Hz, H-2), 4.12 (dd, 1H,
or 1b
or 1a
0 0
J7a,7bˆ12.1, J7b,6ˆ5.3 Hz, H-7a), 4.05 (dd, 1H, J6 a,6 b
ˆ
0
0
0
12.4, J6 a,5 ˆ2.1 Hz, H-6 a), 3.77 (t, 1H, J5,6ˆ9.5 Hz, H-5),
3.66 (m, 1H, H-6), 3.65 (m, 1H, H-50), 1.9–2.2 (7s, 21H,
acetate CH3s). Anal. calcd for C27H37NO19: C, 47.72; H,
5.49; N, 2.06; found: C, 47.94; H, 5.63; N, 2.00.
Methyl 9,10,13-tri-O-acetyl-11-O-(tetra-O-acetyl-b-d-
glucopyranosyl)-8,12-anhydro-2,3,4-tri-O-benzyl-7-
deoxy-7-nitro-a-d-arabino-d-manno-d-gluco-trideco-
1,5-pyranoside (7). To a solution of aldehydo-sugar 6 (Ref.
19) (2.03 g; 4.34 mmol; 1.5 eq.) in dry CH3CN (30 mL)

222
S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
observed: 1206 [MϩHOAcϩNa]ϩ; HR-FABMS: calcd for
C55H65NNaO24 m/z 1146.3794; found 1146.3824. E-8:
[a]2D0ϩ15.0 (c 1.8, CHCl3); mp 80.5–81.5ЊC, white solid;
Rf 0.37 (EtOAc/hexanes 2:3); IR (film, cmϪ1) 1538 and
1367 (NO2); 13C NMR: d 171.0–169.0 (acetate COs),
148.56 (C-7), 137.90, 137.80, 137.05 (ArCs), 136.60
(C-6), 128.5–127.0 (ArCHs), 100.88 (C-14), 98.84 (C-1),
81.32, 80.01, 79.54, 77.04, 75.95, 75.78, 75.06, 73.69,
73.50, 72.93, 72.21, 72.00, 71.62, 70.33, 67.71, 65.91,
(C-40), 62.43 (C-13), 61.59 (C-60), 54.93 (OCH3), 27.77
(C-6), 27.17 (C-7), 20.67, 20.61, 20.55, 20.46 (acetate
CH3s); H NMR: d 7.43–7.22 (m, 15H, ArH’s), 5.14 (t,
1
1H, J3 ,2 ˆJ3 ,4 ˆ9.3 Hz, H-30), 5.12 (t, 1H, J10,9
ˆ
0
0
0
0
0
0
0
J10,11ˆ9.3 Hz, H-10), 5.06 (t, 1H, J4 ,5 ˆ9.6 Hz, H-4 ),
4.96 (d, 1H, Jˆ10.9 Hz), 4.87 (d, 1H, Jˆ10.9 Hz), 4.79
(d, 1H, Jˆ10.7 Hz), 4.78 (d, 1H, Jˆ12 Hz), 4.65 (d, 1H,
Jˆ12.1 Hz) and 4.59 (d, 1H, Jˆ10.8 Hz) (3 AB, 3
0
0
0
0
0
OCH2Ph), 4.92 (dd, 1H, J1 ,2 ˆ8.2, J2 ,3 ˆ9 Hz, H-2 ), 4.76
1
61.48, 61.37, 56.49 (OCH3), 20.9–20.1 (acetate CH3s); H
(t, 1H, J9,8ˆ9.5 Hz, H-9), 4.51 (d, 1H, J1,2ˆ4.1 Hz, H-1),
0
0
0
NMR: d 6.86 (d, 1H, J6,5ˆ6.5 Hz, H-6); FABMS
(3-NBAϩNaϩ): m/z 1146 [MϩNa]ϩ; HR-FABMS: calcd
for C55H65NNaO24 m/z 1146.3794; found 1146.3805.
4.49 (d, 1H, J1 ,2 ˆ8.3 Hz, H-1 ), 4.43 (dd, 1H, J13b,13aˆ11.9,
0
0
J13b,12ˆ1.7 Hz, H-13b), 4.37 (dd, 1H, J6 b,6 aˆ12.5 Hz,
0
0
0
0
J6 b,5 ˆ4.3 Hz, H-6 b), 4.04 (m, 2H, H-6 a,13a), 3.93 (t,
1H, J3,2ˆJ3,4ˆ9.2 Hz, H-3), 3.71 (t, 1H, J11,12ˆ9.6 Hz,
H-11), 3.64 (ddd, 1H, J5 ,6 aˆ2.4 Hz, H-50), 3.55 (m, 1H,
H-5), 3.51 (m, 1H, H-12), 3.48 (dd, 1H, H-2), 3.34 (m,
1H, H-8), 3.315 (s, 3H, OCH3), 3.13 (t, 1H, J4,5ˆ9.2 Hz,
H-4), 2.1–1.9 (several s, 21H, acetate CH3s), 2.08 (m, 1H,
H-6b), 1.72 (m, 1H, H-7b), 1.36 (m, 1H, H-7a), 1.30 (m, 1H,
H-6a); FABMS (3-NBAϩNaϩ): m/z 1103 [MϩNa]ϩ; HR-
FABMS: calcd for C55H68NaO22 m/z 1103.4100; found
1103.4067. Anal. calcd for C55H68O22: C, 61.10; H, 6.34;
found: C, 60.91; H, 6.27.
0
0
Methyl 9,10,13-tri-O-acetyl-11-O-(tetra-O-acetyl-b-d-
glucopyranosyl)-8,12-anhydro-2,3,4-tri-O-benzyl-6,7-
dideoxy-7-nitro-a-d-erythro-(l-talo and l-galacto)-d-
gluco-trideco-1,5-pyranoside (9). To
a solution of
compound 8 (E,Z mixture; 442.7 mg; 0.403 mmol) in
CH2Cl2 (2 mL) at 0ЊC was added a solution of NaBH4
(0.07 g; 1.9 mmol; 4.7 eq.) in EtOH (10 mL). The mixture
was stirred for 13 h. The solution was then diluted with
EtOAc (100 mL), washed with water (2×25 mL), dried
over Na2SO4 and concentrated. Flash chromatography of
the residue (EtOAc/hexanes 5:6) furnished a homogeneous
mixture of 7(R) and 7(S) epimers (white solid; 199 mg; 45%
yield). Rf 0.42 (EtOAc/hexanes 1:1); IR (film, cmϪ1) 1560
and 1368.5 (NO2);13C NMR (mixture of epimers, all signals
are given): d 170.4–169.0 (acetate COs), 138.53, 138.23,
138.03, 137.94 (ArCs), 128.5–127.0 (ArCHs), 100.84,
100.69 (C-14s), 98.03 (C-1s), 86.40, 82.82, 81.63, 81.54,
81.38 (2C), 79.89, 79.78, 77.05, 76.78, 76.14 (2C), 75.80,
75.67, 74.83, 73.89, 73.53, 73.30, 72.85, 72.07, 71.58,
70.18, 68.94, 67.80, 66.29, 61.87, 61.60, 55.69, 55.42
(OCH3s), 31.18, 30.57 (C-6s), 20.6–20.3 (acetate CH3s);
FABMS (3-NBAϩNaϩ): m/z 1148 [MϩNa]ϩ; HR-
FABMS: calcd for C55H67NNaO24 m/z 1148.3951; found
1148.3973.
Methyl 8,12-anhydro-6,7-dideoxy-11-O-(b-d-glucopyra-
nosyl)-a-d-glycero-d-gulo-d-gluco-trideco-1,5-pyrano-
side (12). To a solution of compound 10 (51.2 mg;
0.0486 mmol) in EtOH (40 mL) was added Pd(OH)2 (20%
on C, 70 mg) and AcOH (0.05 mL). The mixture was
degassed and then hydrogenated (H2, 1 atm) for 2 days at
r.t. under vigorous stirring. The mixture was then diluted
with EtOH (50 mL) and the catalyst removed by filtration
through a nylon membrane (0.45 mm). The filtrate was
concentrated and the resultant clear syrupy product (11)
was used in the next step without further purification. 13C
NMR of 11 (CD3OD): d 172.58, 172.21, 172.12, 171.64,
171.22, 171.01, 101.85, 101.13, 79.03, 78.44, 77.90, 75.75
(2C), 75.14, 74.50, 73.99, 73.73, 73.16, 72.90, 72.39, 69.37,
64.12, 62.88, 55.50, 28.92, 28.59, 21.00, 20.78, 20.66,
20.62, 20.53. To a solution of crude 11 obtained above in
MeOH (40 mL) was added a 0.3M solution of MeONa in
MeOH (4 mL). The mixture was stirred for 30 h, then
neutralized with Amberlite IR-120 (Hϩ) resin and treated
with activated charcoal (spatula tip). The suspension was
filtered and the solvent evaporated. The residual syrup
was then redissolved in H2O (10 mL) by brief sonication,
the solution washed with CH2Cl2 (3 × 10 mL) and concen-
trated under high vacuum to afford compound 12 (24.2 mg;
97%) as a light yellow syrup. [a]2D0ϩ37.6 (c 1.17, CH3OH);
Rf 0.64 (CHCl3/EtOAc/MeOH/H2O 3.5:3.5:8:2); IR (film,
cmϪ1) 3364 (v br O–H); 13C NMR (CD3OD): d 104.64,
101.10, 81.42, 81.05, 80.16, 78.12 (2C), 77.88, 75.77,
75.35, 75.10, 74.96, 73.76, 72.73, 71.40, 62.46, 62.36,
Methyl 9,10,13-tri-O-acetyl-11-O-(tetra-O-acetyl-b-d-
glucopyranosyl)-8,12-anhydro-2,3,4-tri-O-benzyl-6,7-
dideoxy-a-d-glycero-d-gulo-d-gluco-trideco-1,5-pyrano-
side (10).
A solution of tridecoside (9) (199 mg;
0.182 mmol) in dry toluene was purged with dry, deoxy-
genated N2 and then heated under reflux. To this hot solution
was added a solution of Bu3SnH (0.255 mL; 0.948 mmol)
and AIBN (16 mg; 0.097 mmol) in degassed toluene
(10 mL). The resulting solution was stirred under reflux
for 30 min. The toluene was then removed under vacuum.
The resulting residue was dissolved in a minimum amount
of CHCl3 and applied to a column of silica gel; the column
was flushed with several volumes of hexane (to remove tin
by-products) and then eluted with EtOAc/hexanes (1:2) to
afford 106 mg (0.1 mmol) of white solid product (56%
yield). [a]2D0 Ϫ7.6 (c 5.5, CHCl3); mp 168–169ЊC; Rf 0.32
(EtOAc/hexanes 1:1); IR (film, cmϪ1) 1755.2 (CyO); 13C
NMR: d 170.39, 170.25, 170.11, 169.87, 169.78, 169.22,
168.99 (acetate COs), 138.70, 138.17, 138.14 (ArCs),
128.7–127.5 (ArCHs), 100.77 (C-10), 97.74 (C-1), 82.07
(C-4), 81.92 (C-3), 80.09 (C-2), 77.70 (C-8), 76.85
(C-11), 76.46 (C-12), 75.69 (benzyl CH2), 75.19 (benzyl
CH2), 74.09 (C-30), 73.24 (benzyl CH2), 72.95 (C-10),
72.30 (C-9), 71.91 (C-50), 71.62 (C-20), 70.27 (C-5), 67.86
1
55.50, 29.14, 28.77; H NMR (CD3OD): d 4.56 (d, 1H,
0
0
0
J1,2ˆ3.7 Hz, H-1), 4.34 (d, 1H, J1 ,2 ˆ7.8 Hz, H-1 );
FABMS [(Ϫ)-ions, glycerolϩthioglycerol]: m/z 515
[MϪH]Ϫ; HR-FABMS (Ϫ): calcd for C20H35O15 m/z
515.1976; found 515.1969.
(Hepta-O-acetyl-b-d-cellobiosyl)methanol
methyl ether (13). Dimethoxymethane (20 mL;
230.0 mmol) was added to compound (1.45 g;
2.23 mmol) followed by CHCl3 (27 mL) and phosphorus
methoxy-
3

S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
223
pentoxide (3 g). The reaction mixture was vigorously
stirred for 1 h. The mixture was then cooled in an ice
bath, neutralized with aqueous Na2CO3, transferred to a
separating funnel and extracted with ether (3×100 mL).
The organic phases were combined, washed with brine
(3×10 mL), and the solvent was evaporated. The residual
solid was then redissolved in CH2Cl2, the solution dried over
Na2SO4 and concentrated to yield a yellowish-white solid
(1.44 g; 93%). The protected disaccharide was used without
further purification in the next step. A sample was purified
by flash chromatography (EtOAc/hexanes 2:1): [a]2D0 Ϫ18.5
(c 1.49, CHCl3); mp 168.5–169.5ЊC; Rf 0.45 (EtOAc/
hexanes 2:1); 13C NMR: d 170.39, 170.22, 170.09,
169.89, 169.63, 169.20, 168.97, 100.79, 96.66 (MOM-
CH2), 77.01, 76.66, 76.57, 74.07, 72.95, 71.96, 71.62,
69.10, 67.85, 66.04, 62.26, 61.59, 55.27, 20.79, 20.60,
20.55, 20.48. Anal. calcd for C29H42O19: C, 50.14; H,
6.09; found: C, 50.16; H, 6.08.
concentrated. Purification of the residual product by flash
chromatography (EtOAc/hexanes, 1:3!1:1) afforded
compound 16 as
a slightly opaque syrup (1.23 g;
1.26 mmol; 51%). [a]D21ϩ18.3 (c 0.93, CHCl3); Rf 0.25
(EtOAc/hexanes 1:2); IR (film, cmϪ1) 3448 (OH); 13C
NMR: d 139.4, 138.63, 138.59, 138.44, 138.30, 138.19,
138.00 (ArCs), 128.4–127.2 (ArCHs), 102.47 (C-10),
85.19 (C-2), 84.95 (C-40), 82.80 (C-30), 79.28 (C-20),
78.99 (C-5), 78.16 (C-50), 77.66 (C-6), 76.73 (C-3), 75.62
(benzyl CH2), 75.20 (C-4), 75.14, 75.05, 75.00, 74.81, 73.33
(benzyl CH2s), 69.08 (C-60), 68.30 (C-7), 62.53 (C-1);
FABMS (3-NBAϩNaϩ): m/z 1009 [MϩNa]ϩ; HR-
FABMS: calcd for C62H66NaO11 m/z 1009.4503; found
1009.4484.
(Hepta-O-benzyl-b-d-cellobiosyl)iodomethane
(17).
Compound 16 (1.21 g; 1.24 mmol) was dissolved in THF
(35 mL). Iodine (0.51 g; 2.0 mmol), imidazole (0.27 g;
4.0 mmol) and triphenylphosphine (0.50 g; 1.9 mmol)
were added to the solution. The mixture was vigorously
stirred under reflux for 24 h. Additional amounts of each
reagent were added after 8 h (total number of equivs. of
reagents added: 3.0, 6.0, and 3.0, respectively). The solvent
was then evaporated and the solid dissolved in CH2Cl2
(100 mL). The reaction mixture was processed by slowly
adding an equal volume of saturated aqueous sodium
bicarbonate, followed by iodine in portions until the organic
phase remained iodine-colored; the mixture was stirred for
10 min. Excess iodine was destroyed by the addition of
saturated aqueous sodium thiosulfate. The organic layer
was separated, dried over MgSO4 and concentrated. The
residue was submitted to flash chromatography (EtOAc/
hexanes, 1:10!1:5) which afforded white solid 17
(0.78 g; 0.92 mmol; 74%). [a]2D1ϩ51.5 (c 1.24, CHCl3);
mp 113.0–114.0ЊC; Rf 0.66 (EtOAc/hexanes 1:2); 13C
NMR: d 138.66, 138.43 (2C), 138.29 (2C), 138.17 (2C)
(ArCs), 128.4–127.3 (ArCHs), 102.45 (C-10), 84.99
(C-40), 84.87 (C-30), 82.88 (C-20), 80.97 (C-50), 79.49
(C-6), 78.19 (C-4), 77.57 (C-2), 76.66 (C-5), 75.64, 75.34,
75.21 (benzyl CH2s), 75.16 (C-3), 75.04, 74.83, 73.35 (2C)
(benzyl CH2s), 69.06 (C-60), 67.93 (C-7), 7.61 (C-1). Anal.
calcd. for C62H65IO10: C, 67.88; H, 5.97; Found: C, 68.01;
H, 6.10; FABMS (3-NBAϩNaϩ): m/z 1119 [MϩNa]ϩ; HR-
FABMS: calcd for C62H65INaO10 m/z 1119.3520; found
1119.3521.
(Hepta-O-benzyl-b-d-cellobiosyl)methanol (16). To a
suspension of compound 13 (1.35 g; 1.94 mmol) in dry
MeOH (95 mL) was added a 5.2M solution of MeONa in
MeOH (5 mL). The reaction was vigorously stirred for 24 h.
The solution was then neutralized with Amberlite IR-
120(Hϩ) resin (prewashed by refluxing with MeOH in a
Soxhlet extractor), the resin was removed by filtration and
the solvent was evaporated. The residual solid was then
dissolved in CH2Cl2, the solution dried over Na2SO4, and
concentrated to yield crude (b-d-cellobiosyl)methanol
methoxymethyl ether (14) as a clear syrup in essentially
quantitative yield: Rf 0.65 (CHCl3/EtOAc/CH3OH/H2O
3.5/3.5/8/2); 13C NMR (D2O): d 102.59, 96.30 (MOM-CH2),
78.82, 78.47, 77.94, 76.05, 75.91, 75.58, 73.24, 69.69,
69.52, 66.97, 60.65, 60.36, 55.20. DMF (40 mL) was
added to crude 14 (0.86 g; 2.2 mmol). To the resulting,
vigorously stirred suspension was added hexane-washed
NaH (60% dispersion in mineral oil, 0.91 g) followed,
after cooling to 0ЊC, by BnBr (2.2 mL; 18.5 mmol). The
ice bath was removed and the mixture was stirred for 29 h
at r.t. The reaction was quenched by the addition of MeOH
(10 mL) and the mixture was stirred for an additional
20 min. The solution was then concentrated to about one-
third of its original volume and the product precipitated by
pouring the solution onto ice-water (200 mL). The precipi-
tate was then collected on a ice-cooled Bu¨chner funnel,
washed with water and then with cold MeOH. The beige-
white solid was allowed to dry in the open air. The product
was dissolved in CH2Cl2, the solution dried over Na2SO4
and concentrated to give crude (hepta-O-benzyl-b-d-
cellobiosyl)methanol methoxymethyl ether (15) (2.34 g,
Ϸ100%; syrup). This product was used without further puri-
fication in the next step. (15): Rf 0.49 (EtOAc/hexanes 1:2);
13C NMR: d 139.4–138.2 (ArCs), 130.9–127.1 (ArCHs),
102.46, 96.74 (MOM-CH2), 85.40, 84.97, 82.80, 79.22,
78.89, 78.16, 77.80, 77.20, 76.65, 75.62, 75.10, 74.99
(2C), 74.81, 73.27 (2C), 69.05, 68.17 (2C), 66.99, 55.24.
Crude 15 (2.50 g; 2.46 mmol) was dissolved in a mixture
of THF (20 mL), H2O (5 mL) and 6M aq HCl (26 mL). The
reaction was stirred under reflux for 12 h. The mixture was
then neutralized by adding an equal volume of saturated
aqueous sodium bicarbonate. The solution was extracted
with CH2Cl2 (3×50 mL), the organic phases were combined,
washed with H2O (3×10 mL), dried over MgSO4 and
(Hepta-O-benzyl-b-d-cellobiosyl)nitromethane
(18).
Compound 17 (0.76 g; 0.67 mmol) was dissolved in a
mixture of DMSO (5 mL) and DMF (25 mL). To the solu-
tion were added NaNO2 (0.14 g; 2.0 mmol) and phloro-
glucinol dihydrate (0.15 g; 1.0 mmol). The mixture was
stirred at r.t. for 4 days. In the course of the reaction, addi-
tional amounts of reagents were added (total amount of
NaNO2, 4 mmol; phloroglucinol, 1.4 mmol). Approxi-
mately 15 mL of DMF was then evaporated under high
vacuum. The mixture was poured onto ice-water
(300 mL). The resulting precipitate was collected on a
cooled Bu¨chner funnel and dried in the open air for 24 h.
The product was then purified by flash chromatography
(EtOAc/hexanes 1:4), to afford white solid 18 (0.51 g;
75% yield). [a]2D1 Ϫ1.7 (c 1.18, CHCl3); mp 142.5–
143.5ЊC; Rf 0.60 (EtOAc/hexanes 1:2); IR (film, cmϪ1
1557.0, 1360.8 (NO2); 13C NMR: d 138.95, 138.57,
)

224
S. J. Spak, O. R. Martin / Tetrahedron 56 (2000) 217–224
´
4. Wang, J.; Kovac, P.; Sinay¨, P.; Glaudemans, C. P. J. Carbohydr.
138.54, 138.29, 138.25, 137.92, 137.51 (ArCs), 128.6–
127.3 (ArCHs), 102.37 (C-10), 85.12 (C-4), 84.90 (C-30),
82.78 (C-20), 79.29 (C-6), 78.09 (C-40), 77.18 (C-3), 76.35
(C-1), 76.06 (C-5), 75.70 (C-2), 75.19 (C-50), 69.06 (C-60),
67.49 (C-7), 75.61, 75.31, 75.04, 74.80 (2C), 73.29 (2C)
Res. 1998, 308, 191–193.
5. (a) Vogel, P.; Ferrito, R.; Kraehenbuehl, K.; Baudat A. in Ref.
1, pp. 19–48. (b) Postema, M. H. D. C-Glycoside Synthesis; CRC
Press: Boca Raton, 1995.
6. Haneda, T.; Goekjian, P. G.; Kim, S. H.; Kishi, Y. J. Org.
Chem. 1992, 57, 490–498.
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5267–5283.
8. Dondoni, A.; Kleban, M.; Zuurmond, H.; Marra, A. Tetra-
hedron Lett. 1998, 39, 7991–7994.
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Sinay¨, P. Eur. J. Org. Chem. 1999, 471–476.
10. Rouzaud, D.; Sinay¨, P. J. Chem. Soc., Chem. Commun. 1983,
1353–1354.
11. Berthault, P.; Birlirakis, N.; Rubinstenn, G.; Sinay¨, P.;
Desvaux, H. J. Biomol. NMR 1996, 8, 23–35.
12. Martin, O. R.; Lai, W. J. Org. Chem. 1993, 58, 176–185.
13. Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. J. Org.
Chem. 1996, 61, 1894–1897.
1
(benzyl CH2s); H NMR: d 7.42–7.14 (m, 35H, ArHs),
5.22 (d, 1H, Jˆ11.2 Hz), 4.96–4.69 (several d, 6H) and
4.57–4.37 (several d, 7H) (7 OCH2Ph), 4.50 (d, 1H, H-10),
4.43 (dd, 1H, H-1b), 4.22 (dd, 1H, J1b,1aˆ13.1, J1a,2ˆ8.9 Hz,
H-1a), 4.07 (t, 1H, J5,4ˆJ5,6ˆ9.5 Hz, H-5), 3.97 (td, 1H,
J1b,2ˆ1.6, J2,3ˆ10 Hz, H-2), 3.82 (dd, 1H, J7b,7aˆ11.4,
0
0
0
0
J7b,6ˆ3.1 Hz, H-7b), 3.73 (dd, 1H, J6 b,6 aˆ11.0, J6 b,5
ˆ
1.9 Hz, H-60b), 3.67 (t, 1H, Jˆ8.8 Hz, H-4), 3.60 (t, 1H,
0
0
0
0
0
J4 ,3 ˆJ4 ,5 ˆ9.0 Hz, H-4 ), 3.57 (m, 1H, H-7a), 3.54 (m,
1H, H-60a), 3.53 (t, 1H, Jˆ9.0 Hz, H-30), 3.39 (dd, 1H,
0
0
0
0
0
0
J1 ,2 ˆ7.9, J2 ,3 ˆ8.7 Hz, H-2 ), 3.34 (ddd, 1H, H-5 ), 3.29
(m, 1H, H-6), 3.27 (dd, 1H, H-3). Anal. calcd for
C62H65NO12: C, 73.28; H, 6.45; N, 1.38; found: C, 73.10;
H, 6.57; N, 1.28.
ˇ
´
14. Petrus, L.; Bystricky, T.; Sticzay, T.; Bılik, V. Chem. Zvesti.
Acknowledgements
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Support of this research program by a grant from the U.S.
National Institutes of Health (grant DK 35766) is gratefully
acknowledged.
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