Synthesis of the C-linked disaccharide α-D-man-(1→4)-D-man employing a SmI2-mediated C-glycosylation step: En route to cyclic C-oligosaccharides

Article abstract of DOI:10.1021/jo020585a

Investigations are reported on the assembly of the C-linked disaccharide α-D-Man-(1→4)-D-Man, representing the first steps in our projected synthesis of a cyclic C-oligomer containing repeating units of this C-dimer. The key step in this synthesis uses a

Full text of DOI:10.1021/jo020585a

Syn th esis of th e C-Lin k ed Disa cch a r id e r-D-Ma n -(1f4)-D-Ma n
Em p loyin g a Sm I2-Med ia ted C-Glycosyla tion Step : En Rou te to
Cyclic C-Oligosa cch a r id es
Lise Munch Mikkelsen and Troels Skrydstrup*
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received September 4, 2002
Investigations are reported on the assembly of the C-linked disaccharide R-D-Man-(1f4)-D-Man,
representing the first steps in our projected synthesis of a cyclic C-oligomer containing repeating
units of this C-dimer. The key step in this synthesis uses a SmI2-mediated coupling of 2,3,4,6-
tetra-O-benzyl-R-D-mannopyranosyl 2′-pyridyl sulfone with a C4-formyl branched mannopyranoside
unit, affording the C-disaccharide derivative with complete stereocontrol at the two new stereogenic
centers. Subsequently, a modified tin hydride based deoxygenation produced the target carbohydrate
analogue. The synthesis of the C4-formyl monosaccharide makes use of a stereoselective radical-
based allylation followed by double bond migration and ozonolysis.
In tr od u ction
others8,9 have previously demonstrated that C-glycosy-
lations involving anomeric Sm(III) species are excellent
means for obtaining C-disaccharides and higher oligo-
mers thereof employing intact monosaccharide units in
a synthetic approach that lies close to those of the well-
R-, â-, and γ-cyclodextrins are macrocyclic oligomers
containing six, seven, and eight R-(1f4)-glucopyranose
units, respectively, which are prepared by the enzymatic
degradation of amylose. These compounds have occupied
a long-standing interest among chemists in industry and
academia because of their rigid and hydrophobic cavities,
which permits formation of inclusion complexes with
numerous low-weight molecular compounds.1 The ap-
plications of such cyclic oligosaccharides are vast and
range from their use to increase stability and/or solubility
of pharmaceuticals to starting materials for the design
of artificial enzymes and molecular machines. Structur-
ally modified cyclodextrins with increased stability or
selectivity are therefore constantly being sought. Such
modifications are commonly achieved by chemically
altering the cyclodextrins or by de novo synthesis with
monosaccharide units other than glucose.2,3 Another way
of increasing chemical stability, as well as altering the
hydrophobicity of the cavity, is to replace the intergly-
cosidic linkages with methylene groups.4-6 We7 and
(5) For recent examples of C-disaccharide synthesis, see: (a) Liu,
L.; Postema, M. H. D. J . Am. Chem. Soc. 2001, 123, 8602. (b)
Vauzeilles, B.; Sinay¨, P. Tetrahedron. Lett. 2001, 42, 7269. (c) J ime´nez-
Barbero, J .; Demange, R.; Schenk, K.; Vogel, P. J . Org. Chem. 2001,
66, 5132. (d) Postema, M. H. D.; Calimente, D.; Liu, L.; Gehrmann, T.
L. J . Org. Chem. 2000, 65, 6061. (e) Pasquarello, C.; Picasso, S.;
Demange, R.; Malissard, M.; Berger, E. G.; Vogel, P. J . Org. Chem.
2000, 65, 4251. (f) Griffin, F. K.; Paterson, D. E.; Taylor, R. J . K. Angew.
Chem., Int. Ed. 1999, 38, 2939. (g) Khan, N.; Cheng, X.; Mootoo, D. J .
Am. Chem. Soc. 1999, 121, 4918.
(6) For the synthesis of higher C-oligomers, see: (a) Haneda, T.;
Goekjian, P. G.; Kim, S. H.; Kishi, Y. J . Org. Chem. 1992, 57, 490. (b)
Wei, A.; Haudrechy, A.; Audin, C.; J un, H.-S.; Haudrechy-Bretel, N.;
Kishi, Y. J . Org. Chem. 1995, 60, 2160. (c) Sunderlin, D. P.; Armstrong,
R. W. J . Am. Chem. Soc. 1996, 118, 9802. (d) Sunderlin, D. P.;
Armstrong, R. W. J . Org. Chem. 1997, 62, 5267. (e) Dondoni, A.;
Kleban, M.; Zuurmond, H.; Marra, A. Tetrahedron Lett. 1998, 39, 7991.
(f) Xin, Y.-C.; Zhang, Y.-M.; Mallet, J .-M.; Glaudemans, C. P. J .; Sinay¨,
P. Eur. J . Org. Chem. 1999, 471. (g) Dondoni, A.; Mizuno, M.; Marra,
A. Tetrahedron Lett. 2000, 41, 6657. (h) Dondoni, A.; Marra, A.; Mizuno,
M.; Giovannini, P. P. J . Org. Chem. 2002, 67, 4186.
(7) (a) Maze´as, D.; Skrydstrup, T.; Beau, J .-M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 909. (b) J arreton, O.; Skrydstrup, T.; Beau, J .-M.
J . Chem. Soc., Chem. Commun. 1996, 1661. (c) Urban, D.; Skrydstrup,
T.; Riche, C.; Chiaroni, A.; Beau, J .-M. J . Chem. Soc., Chem. Commun.
1996, 1883. (d) J arreton, O.; Skrydstrup, T.; Beau, J .-M. Tetrahedron
Lett. 1997, 36, 303. (e) Skrydstrup, T.; J arreton, O.; Maze´as, D.; Urban,
D.; Beau, J .-M. Chem. Eur. J . 1998, 4, 655. (f) Urban, D.; Skrydstrup,
T.; Beau, J .-M. J . Org. Chem. 1998, 63, 2507. (g) Urban, D.; Skrydstrup,
T.; Beau, J .-M. J . Chem. Soc., Chem. Commun. 1998, 955. (h)
Andersen, L.; Mikkelsen, L. M.; Beau, J .-M.; Skrydstrup, T. Synlett
1998, 1393. (i) J arreton, O.; Skrydstrup, T.; Espinosa, J .-F.; J ime´nez-
Barbero, J .; Beau, J .-M. Chem. Eur. J . 1999, 5, 430. (j) Krintel, S. L.;
J ime´nez-Barbero, J .; Skrydstrup, T. Tetrahedron Lett. 1999, 40, 7565.
(k) Mikkelsen, L. M.; Krintel, S. L.; J ime´nez-Barbero, J .; Skrydstrup,
T. Chem. Commun. 2000, 2319. (i) Mikkelsen, L. M.; Krintel, S. L.;
J ime´nez-Barbero, J .; Skrydstrup, T. J . Org. Chem. 2002, 67, 6287.
(8) Miquel, N.; Doisneau, G.; Beau, J .-M. Angew. Chem., Int. Ed.
2000, 39, 4111.
(1) A whole issue of Chemical Reviews (Chem. Rev. 1998, 98, issue
5) has been devoted to the chemistry and applications of cyclodextrins.
(2) Khan, A. R.; Forgo, P.; Stine, K. J .; D’Souza, V. T. Chem. Rev.
1998, 98, 1977.
(3) Gattuso, G.; Nepogodiev, S. A.; Stoddart, J . F Chem. Rev. 1998,
98, 1919.
(4) (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
Raton, FL, 1995. (b) Levy, D. E.; Tang, C. The Chemistry of C-
Glycosides; Pergamon Press: Exeter, UK, 1995. (c) Vogel, P.; Ferritto,
R.; Kraehenbuehl, K.; Baudat, A. Carbohydrate Mimics, Concept and
Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, Germany, 1997;
Chapter 2, p 19. (d) Du, Y.; Linhardt, R. J .; Vlahov, I. R. Tetrahedron
1998, 54, 9913. (e) Beau, J .-M.; Vauzeilles, B.; Skrydstrup, T. Glyco-
science: Chemistry and Chemical Biology; Fraser-Reid, B., Tatsuta,
K., Thiem, J ., Eds.; Springer: Heidelberg, Germany, 2001; Vol. 3, p
2679. (f) Skrydstrup, T.; Vauzeilles, B.; Beau, J .-M. Oligosaccharides
in Chemistry and Biology-A Compresensive Handbook; Ernst, B.,
Sinay¨, P., Hart, G., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol.
1, p 495.
(9) (a) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J . J . Am. Chem.
Soc. 1997, 119, 1480. (b) Bazin, H. G.; Du, Y.; Polat, T.; Linhardt, R.
J . J . Org. Chem. 1999, 64, 7254.
10.1021/jo020585a CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003
J . Org. Chem. 2003, 68, 2123-2128
2123

Mikkelsen and Skrydstrup
SCHEME 1
SCHEME 2
ride 2 possessing a C1-Sm bond, as well as the acceptor
at C4′, could undergo a trimerization process to the
desired macrocycle after deoxygenation. Similar cycliza-
tion approaches have been successfully employed by
Stoddart and co-workers for the synthesis of nonnatural
cyclic oligosaccharides via O-glycosylation.10 Although
higher oligomers could also be anticipated, the number
of steps leading to 1 via a linear synthesis would be
dramatically reduced upon the successful outcome of this
cyclization step.
Pertinent for this approach, however, is whether the
C-R-(1f4) linkage can be formed employing a mannosyl
anomeric samarium species. We have earlier observed
the detrimental influence of sterical hindrance on some
of the SmI2-promoted C-glycosylations.7i As O-glycosyla-
tion of the C4-OH group in gluco- and mannopyrano-
sides is generally one of the most demanding to perform
due to the sterical environment surrounding this hy-
droxyl group, it was anticipated that the C-glycosylation
step could experience similar difficulties. It is therefore
crucial for the successful outcome of the cyclization that
this C-C bond-forming step can be performed in the
synthesis of the C-disaccharide building block 2. Access
to the C-glycosyl donor and acceptor, 3 and 4, respec-
tively, was envisaged to come from the same C-branched
methyl mannoside 5. Hence, the synthesis of 2 first boils
down to the introduction of an equatorially oriented
formyl group equivalent at the C4-position of methyl
4-deoxymannopyranoside.
known O-glycosylations. Exploiting the previous work on
cyclic oligosaccharide synthesis,3 we therefore set out to
prepare an R-C-cyclodextrin analogue in which all of the
six etheral linkages have undergone an O to CH2 ex-
change. In this paper, we reveal our first steps for
achieving this goal through the demonstration that the
crucial R-(1f4) linkage between the connecting pyrano-
sides can indeed be achieved by employing the low-valent
lanthanide reagent, samarium diiodide.
Two routes were esteemed possible for achieving this
transformation as shown in Scheme 2. The first route
exploits the known preference for trans-diaxial opening
of epoxides in 1,6-anhydrosugars such as 6 with nucleo-
philes. On the other hand, radical-based allylation at C4
with the partially protected mannopyranoside 7 was
predicted to be selective for the equatorial position.
Subsequent migration of the carbon-carbon double bond
to the internal position was expected to give the desired
precursor.
Resu lts a n d Discu ssion
Retr osyn th etic Con sid er a tion s. Our target cyclic
C-oligosaccharide 1 is illustrated in Scheme 1, assembled
with six R-(1f4)-mannopyranoside units. This choice is
based on (1) the previous syntheses of cyclic mannooli-
gosaccharides and the known capacity for appropriately
functionalized linear oligomers of mannose to undergo
cyclization upon treatment under standard glycosylation
conditions3 and (2) the 1,2-trans selectivity obtained in
the SmI2-induced C-glycosylations,7a,b,d,e,i-k,8 implying that
for R-selectivity at the anomeric carbon, an axially
oriented C2-substituent is required as is the case for
mannopyranosides. In the retrosynthetic analysis of such
a C-glycoside analogue, it is nevertheless tempting to
speculate whether a suitably functionalized C-disaccha-
Th e 1,6-An h yd r osu ga r Ap p r oa ch . Synthesis of the
required 1,6:3,4-dianhydro-â-talopyranose 9 has previ-
(10) (a) Ashton, P. R.; Brown, C. L.; Menzer, S.; Nepogodiev, S. A.;
Stoddart, J . F.; Williams, D. J . Chem. Eur. J . 1996, 2, 580. (b) Ashton,
P. R.; Cantrill, S. J .; Gattuso, G.; Menzer, S.; Nepogodiev, S. A.;
Shipway, A. N.; Stoddart, J . F.; Williams, D. J . Chem. Eur. J . 1997, 3,
1299. For other examples of other linkages, see ref 3.
2124 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of DisaccharideR-D-Man-(1f4)-D-Man
SCHEME 3
SCHEME 4
ously been reported in three steps11 starting from the
readily available levoglucosenone 8.12 In this work, the
selective reduction of the ketone followed by an io-
doacetylation step and concomitant ring closure under
basic conditions was reported to afford the epoxide 9 in
high yields (Scheme 3). However, in our hands, the latter
two steps proved less effective and typical yields of this
sequence were of the order of 30-40%. For the introduc-
tion of the formyl group precursor at C4, a regioselective
opening of 6 was attempted with vinylmagnesium bro-
mide.13 In contrast to our previous work on a similar
case,7i refluxing a solution of the Grignard reagent with
6 produced two alkene-containing products in a ratio of
3:2 which could be separated by column chromatography.
Whereas the major product was identified as the desired
alkene 10, the second proved to be the C4-epimer 11
rather than the C3-functionalized anhydrosugar. The low
and unexpected regioselectivity could be the result of a
strong coordination of the magnesium ion to both anhy-
dro oxygens in the concave cavity of 6 (Scheme 3),
resulting in partial epoxide opening and transfer of the
vinyl group to the more hindered face of the cation
intermediate.
Th e Ra d ica l Allyla tion Ap p r oa ch . The preparation
of the 2,3,6-tri-O-benzoate of methyl mannopyranoside
was achieved with benzoyl chloride and dibutyltin oxide
with use of a procedure recently reported for the synthe-
sis of the same tribenzoate in the gluco-series.16 This
selective benzoylation procedure of methyl R-D-manno-
pyranoside afforded the tribenzoate 7 in 67% yield
(Scheme 4). A standard Garegg iodination procedure
converted the remaining secondary alcohol to its corre-
sponding iodide 12 with inversion of configuration at
C4.17 Attempted allylation at this position with allyl-
tributyltin and AIBN or DLP in refluxing toluene as
earlier described in the gluco-series resulted in a slow
reaction that was not complete after 72 h. Although the
desired C-branched sugar was obtained, substantial
amounts of the 4-deoxy derivative were also produced.
Attributing this sluggishness to the 1,3-diaxial relation-
ship between the iodide and the C2-benzoate, we decided
to convert alcohol 7 to its corresponding thionocarbamate
and thereby perserve the equatorial position of the C4-
substituent.
Other conditions were also examined in an attempt to
improve the selectivity of the epoxide opening, although
in vain.14 Hence, this route was abandoned and recourse
was taken to introduce a formyl group precursor via a
radical-based allylation followed by migration of the C-C
double bond. This approach was inspired by the recent
work of Postema et al. in their synthesis of several â-C-
disaccharides.15
Treatment of alcohol 7 with N,N′-thiocarbonyldiimi-
dazole in THF or acetonitrile in the presence of DMAP
(cat.) produced, however, two separable products pos-
1
sessing identical mass and almost matching H and 13C
(11) (a) Matsumoto, K.; Ebata, T.; Koseki, K.; Okano, K.; Kawakami,
K.; Matsushita, H. Heterocycles 1992, 34, 1935. (b) Matsumoto, K.;
Ebata, T.; Koseki, K.; Okano, K.; Kawakami, K.; Matsushita, H.
Carbohydr. Res. 1993, 246, 345.
(12) Prepared by pyrolysis of acid-treated cellullose or newspaper
clippings. (a) Isobe, M.; Fukuda, Y.; Nishikawa, T.; Chabert, P.
Tetrahedron Lett. 1990, 31, 3327. (b) Shafizadeh, F.; Chin, P. P. S.
Carbohydr. Res. 1977, 58, 79.
(15) (a) Liu, L.; Postema, M. H. D. J . Am. Chem. Soc. 2001, 123,
8602. (b) Keck, G. E.; Enholm, E. J .; Yates, J . B.; Wiley, M. R.
Tetrahedron 1985, 41, 4079.
(16) Hakamata, W.; Nishio, T.; Oku, T. Carbohydr. Res. 2000, 324,
107. See also: Chowdhary, M. S.; J ain, R. K.; Rana, S. S.; Matta, K.
L. Carbohydr. Res. 1986, 152, 323.
(13) Inghardt, T.; Frejd, T. Synthesis 1990, 285.
(14) Similar attempts to open the epoxyalcohol 9 with vinylmagne-
sium bromide led to a complex mixture of products.
(17) Garegg, P.; J ohansson, R.; Ortega, C.; Samuelsson, B. J . Chem.
Soc., Perkin Trans. 1 1982, 681.
J . Org. Chem, Vol. 68, No. 6, 2003 2125

Mikkelsen and Skrydstrup
SCHEME 5
NMR spectra. Both 1H NMR spectra displayed the
characteristic peaks for the three imidazolyl protons
(8.25-6.80 ppm) where the greatest difference was
observed for the H4-proton appearing at 6.74 and 6.19
ppm. The two products were therefore assigned to the
thionocarbamate 13 and its corresponding thiocarbamate
14, resulting from a CdS to CdO rearrangement (Scheme
4). The best conditions for obtaining the thionocarbamate
were produced when using THF as the solvent, affording
a 71% yield of 13 whereas only 20% of the isomer 14 could
be isolated. Although this type of rearrangment is typi-
cally observed for systems involving the hydroxyl group
connected to an activated carbon, this is not the case for
7. We have previously noted the same rearrangement in
our attempt to prepare a thionocarbonate of a sterically
hindered secondary alcohol.7i As the C4-hydroxyl groups
of the sugar rings are in general more demanding to
functionalize compared to the adjacent groups, the driv-
ing force behind this rearrangement is most probably a
combination of the strain released on going from the
C4-O single bond to the corresponding but longer C4-S
bond and the formation of the stronger CdO bond.18
Subjecting 13 to allyl tributyltin and dilauoryl peroxide
(DLP) in refluxing benzene led to the isolation of the C4-
allyl branched sugar in a satisfactory 79% yield. Only
the equatorially allylated product 15 could be identified
from the reaction mixture, which contradicts similar
allylations in the gluco-series where epimeric C4 mix-
tures were obtained in favor of the equatorial product.
This increased selectivity observed for mannose is ex-
plained by the unfavorable approach of the incoming allyl
group from above the carbohydrate ring due to sterical
interactions with the axially oriented C2-substituent.19
The benzoyl groups were subsequently exchanged for
benzyl groups to give compound 16. Migration of the
double bond to give the internal alkene 5 was ac-
complished in excellent yield by treatment with rhodium
trichloride trihydrate (10%) and potassium carbonate in
boiling ethanol.20 The E-configuration of the double bond
was produced almost exclusively as seen by the charac-
teristic trans-coupling constant of 15.2 Hz. Finally,
ozonolysis of the olefin produced the C-formyl branched
monosaccharide 4 in high yield.
Com p letion of th e Syn th esis of th e C-Disa cch a -
r id e. The crucial coupling step was achieved by adding
dropwise a freshly prepared 0.1 M solution of SmI2 in
THF to a solution of the aldehyde 4 and 4 equiv of the
previously reported 2,3,4,6-tetra-O-benzyl-R-D-manno-
pyranosyl 2′-pyridyl sulfone (17) in the same solvent at
room temperature (Scheme 5).7e An immediate decolori-
zation of the low-valent lanthanide reagent was noted
until all the pyridyl sulfone had been consumed signaling
completion of the reaction. The C-disaccharide 18 could
thereby be isolated in 55% yield as a single stereoisomer
at the two newly formed stereogenic centers as deter-
mined by 1H NMR spectroscopy. This yield was quite
satisfactory and corresponded well with other coupling
yields performed at C2-, C3-, and C6-positions of previous
C-formyl branched mannopyranosides tested,7a,b,e,i-l im-
plying that sterical hindrance is not a problem at C4 as
was initially anticipated.
Finally, the newly formed hydroxyl group was removed
by a two-step sequence previously reported in the deoxy-
genation of other C-oligosaccharides.7e,i-l First, 18 was
converted to its thionocarbonate 19 upon subjecting the
secondary alcohol to a large excess of thiocarbonyldiimi-
dazole in refluxing acetonitrile followed by the slow
removal of the solvent upon heating. We have previously
noted the difficulties in functionalizing this position in
other C-disaccharides, hence explaining the use of these
unorthodox conditions. Subsequent application of our
method for deoxygenating these sterically hindered sec-
ondary alcohols employing triphenyltin hydride, AIBN
(cat.), and pentafluorophenol in refluxing toluene yielded
the desired heptabenzylated C-disaccharide 20 in 54%
yield.
Con clu sion s
We have rapidly assembled the C-linked disaccharide
R-D-Man-(1f4)-D-Man via the coupling of a mannosyl
(18) Barton, D. H. R.; Fontana, G.; Yang, Y. Tetrahedron 1996, 52,
2705 and references therein.
(19) The isomer 14 could not be transformed to 15 under identical
reaction conditions.
(20) (a) Warmerdam, E.; Tranoy, I.; Renoux, B.; Gesson, J .-P.
Tetrahedron Lett. 1998, 39, 8077. (b) Taber, D. F.; Meagley, R. P.;
Doren, D. J . J . Org. Chem. 1996, 61, 5723.
2126 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of DisaccharideR-D-Man-(1f4)-D-Man
dd, J ) 4.2, 10.2 Hz), 4.47-4.40 (1H, m), 3.54 (3H, s). 13C NMR
(50 MHz): δ 182.7, 166.2, 165.5, 165.4, 137.2, 134.0, 133.4,
133.5, 131.1, 130.1-128.7, 118.0, 98.9, 78.4, 69.3, 68.8, 66.5,
62.7, 56.0. IR (KBr, disk): 1728-1720, 1289, 1279 cm-1. HR-
MS (ES-TOF): calcd for C32H28N2NaO9S (M + Na) 639.1413,
found 639.1414.
anomeric samarium species with the C4-formyl branched
mannopyranoside as the key step. The successful outcome
of this coupling step lends support for the use of this
reaction in trimerization of an appropriately functional-
ized R-D-Man-(1f4)-D-Man disaccharide to its corre-
sponding cyclic C-oligosaccharide. Further work is now
required to prepare a C4-branched mannosyl donor,
which will allow introduction of a new formyl group in
the C-disaccharide.
Meth yl 2,3,6-Tr i-O-ben zoyl-4-d eoxy-4-C-a llyl-r-D-m a n -
n op yr a n osid e (15). Allyl tributylstannane (149 µL, 0.49
mmol) was added to the thionocarbamate 13 (100 mg, 0.16
mmol) dissolved in degassed benzene (3.0 mL). The mixture
was refluxed overnight, during which time a catalytic amount
of dilauroryl peroxide (DLP, 13 mg, 0.032 mmol) was added
in small portions. The solvent was removed in vacuo and the
residue was redissolved in MeCN (10 mL) and then washed
twice with pentane. Evaporation to dryness and column
chromatography (EtOAc:pentane, 1:15) yielded 15 as a color-
Exp er im en ta l Section
Gen er a l Meth od s. THF was dried and freshly distilled over
sodium/benzophenone. Dichloromethane was freshly distilled
over P2O5. HMPA was dried over CaH2 and distilled. DMF was
distilled and stored over molecular sieves (4 Å). Samarium
diiodide was prepared according to the literature.21 2,3,4,6-
Tetra-O-benzyl-R-D-mannopyranosyl 2′-pyridyl sulfone (17)
was prepared as previously reported.7e
1
less oil (68 mg, 79%). H NMR (200 MHz): δ 8.16-8.02 (4H,
m), 7.96-7.90 (2H, m), 7.66-7.30 (9H, m), 5.87 (1H, ddt, J )
7.6, 10.0, 17.4 Hz), 5.66 (1H, dd, J ) 3.0, 11.4 Hz), 5.52 (1H,
dd, J ) 1.8, 3.0 Hz), 5.08 (1H, br d, J ) 17.4 Hz), 5.06 (1H, br
d, J ) 10.0 Hz), 4.94 (1H, d, J ) 1.8 Hz), 4.66 (1H, d, J ) 2.4
Hz), 4.65 (1H, d, J ) 3.6 Hz), 4.13 (1H, ddd, J ) 2.4, 3.6, 11.2
Hz), 3.47 (3H, s), 2.73 (1H, ddt, J ) 4.2, 11.2, 11.4 Hz), 2.40-
2.32 (2H, m). 13C NMR (50 MHz): δ 166.5, 165.6, 165.6, 133.6,
133.4, 133.3, 133.2, 130.2-128.5, 118.6, 99.1, 69.7, 69.4, 69.1,
64.5, 55.5, 36.2, 31.1. HR-MS (ES-TOF): calcd for C31H30NaO8
(M + Na) 553.1838, found 553.1834.
Meth yl 2,3,6-Tr i-O-ben zoyl-r-D-m a n n op yr a n osid e (7).
Methyl R-D-mannopyranoside (200 mg, 1.03 mmol) and dibut-
yltin oxide (769 mg, 3.09 mmol) were dissolved in toluene and
benzene (1:1, 100 mL) and the mixture was refluxed in a
Dean-Stark apparatus until approximately 80 mL of the
solvent was distilled off. After the solution was cooled to 20
°C benzoyl chloride (400 µL, 3.40 mmol) was added, and the
mixture was stirred for 3 h at 20 °C and then at 100 °C
overnight. The solvent was then evaporated off in vacuo and
acetonitrile (20 mL) was added. The acetonitrile phase was
washed twice with pentane and then concentrated to dryness
in vacuo. The residue was purified by column chromatography
(EtOAc:pentane, 1:7) yielding 347 mg of the tribenzoate 7 as
a colorless powder (67%). 1H NMR (200 MHz): δ 8.16-7.89
(5H, m), 7.66-7.25 (10H, m), 5.70-5.59 (2H, m), 4.93 (1H, br
d), 4.91 (1H, dd, J ) 3.8, 12.4 Hz), 4.65 (1H, dd, J ) 2.0, 12.4
Hz), 4.28 (1H, ddd, J ) 5.0, 10.2, 10.2 Hz), 4.10 (1H, ddd, J )
2.0, 3.8, 10.2 Hz), 3.45 (3H, s), 3.02 (1H, d, J ) 5.0 Hz). 13C
NMR (50 MHz): δ 167.0, 166.8, 165.5, 133.6, 133.5, 133.4,
130.0-128.5, 98.9, 72.8, 71.3, 70.7, 66.4, 63.6, 55.5. IR (KBr,
disk): 3500, 1730-1720, 1452, 1273, 1102, 1069 cm-1. HR-
MS (ES-TOF): calcd for C28H26NaO9 (M + Na) 529.1474, found
529.1472.
Meth yl 4-C-Allyl-2,3,6-tr i-O-ben zyl-4-d eoxy-r-D-m a n -
n op yr a n osid e (16). A catalytic amount of freshly prepared
NaOMe in MeOH was added to the tribenzoate 15 (470 mg,
0.89 mmol) dissolved in MeOH (10 mL). The solution was
stirred for 5 h at 20 °C and then neutralized by the addition
of a small piece of dry ice. Evaporation and coevaporation twice
with toluene yielded the crude methyl 4-deoxy-4-C-allyl-R-D-
mannopyranoside, which was redissolved in DMF (15 mL) and
then cooled to 0 °C. NaH (213 mg, 5.31 mmol) was added
portionwise with stirring. After 10 min, benzyl bromide (631
µL, 5.31 mmol) was added and the mixture was stirred
overnight. After dilution with diethyl ether, the organic phase
was washed four times with water, dried (MgSO4), and
concentrated to dryness in vacuo. Column chromatography
(EtOAc:pentane, 1:10) yielded 367 mg of 16 as a colorless oil
1
(85% for two steps). H NMR (400 MHz): δ 7.38-7.23 (15H,
m), 5.66 (1H, ddt, J ) 7.0, 10.2, 17.2 Hz), 4.95-4.83 (2H, m),
4.83 (1H, d, J ) 1.8 Hz), 4.69 (2H, s), 4.55 (1H, d, J ) 12.2
Hz), 4.54 (1H, d, J ) 12.2 Hz), 4.51 (1H, d, J ) 11.6 Hz), 4.34
(1H, d, J ) 11.6 Hz), 3.76-3.61 (5H, m), 3.37 (3H, s), 2.51-
2.33 (2H, m), 2.18-2.03 (1H, m). 13C NMR (50 MHz): δ 138.7
(2C), 138.5, 135.2, 128.6-127.6, 117.2, 99.6, 75.9, 73.5, 72.6,
72.2, 71.6, 71.1, 70.9, 55.1, 37.1, 30.9. IR (CHCl3, film): 3018,
2917, 2400, 1363, 1216 cm-1. HR-MS (ES-TOF) m/z: calcd for
Meth yl 2,3,6-Tr i-O-ben zoyl-4-O-th iocar bon ylim idazolyl-
r-D-m a n n op yr a n osid e (13). Methyl 2,3,6-tri-O-benzoyl-R-D-
mannopyranoside (7) (500 mg, 0.99 mmol) and thiocarbonyl-
diimidazole (352 mg, 1.98 mmol) were dissolved in dry distilled
THF (5 mL) and the solution was refluxed overnight. After
being cooled to 20 °C, the mixture was evaporated in vacuo
and the residue was purified by column chromatography
(EtOAc:pentane, 1:5 to 1:2) yielding 432 mg of the thionocar-
C
31H36NaO5 (M + Na) 511.2460, found 511.2462.
1
bamate 13 as a colorless powder (71%). H NMR (200 MHz):
Meth yl 2,3,6-Tr i-O-ben zyl-4-deoxy-4-C-(1-E-pr op-1-en yl)-
δ 8.26 (1H, dd, J ) 0.8, 0.8 Hz), 8.12-8.06 (4H, m), 7.85-7.79
(2H, m), 7.67-7.25 (10H, m), 6.96 (1H, dd, J ) 0.8, 1.8 Hz),
6.74 (1H, dd, J ) 9.6, 9.8 Hz), 6.01 (1H, dd, J ) 3.4, 9.8 Hz),
5.71 (1H, dd, J ) 1.8, 3.4 Hz), 5.03 (1H, d, J ) 1.8 Hz), 4.73
(1H, dd, J ) 4.4, 13.6 Hz), 4.54-4.61 (1H, m), 4.50 (1H, dd, J
) 4.0, 13.6 Hz), 3.52 (3H, s). 13C NMR (50 MHz): δ 183.4,
166.2, 165.4, 165.4, 133.7, 133.8, 133.7, 133.5, 131.3, 130.0-
128.6, 118.1, 98.8, 75.4, 70.7, 69.9, 68.3, 62.7, 56.0. IR (KBr,
disk): 1730-1720, 1394, 1270, 1109 cm-1. HR-MS (ES-TOF):
calcd for C32H28N2NaO9S (M + Na) 639.1413, found 639.1414.
Further elution of the column gave the thiocarbamate 14
r-D-m a n n op yr a n osid e (5). A solution of the alkene 16 (349
mg, 0.71 mmol), solid K2CO3 (18 mg, 0.13 mmol, 18 mol %),
and RhCl3:3H2O (18.8 mg, 0.071 mmol, 10 mol %) in EtOH
(96%, 8.0 mL) was heated to reflux for 2.5 h, whereafter the
solvent was removed in vacuo. Saturated aqueous NaCl was
added and the mixture was extracted three times with EtOAc.
The combined organic phases were dried (MgSO4) and evapo-
rated under reduced pressure. Column chromatography (EtOAc:
pentane, 1:10) yielded 319 mg (91%) of the internal alkene 5
as a colorless oil. 1H NMR (200 MHz): δ 7.40-7.24 (15 H, m),
5.59 (1H, dq, J ) 6.6, 15.2 Hz), 5.03 (1H, ddq, J ) 1.6, 9.2,
15.2 Hz), 4.81 (1H, d, J ) 1.8 Hz), 4.73 (2H, s), 4.61 (1H, d, J
) 12.2 Hz), 4.53 (1H, d, J ) 12.2 Hz), 4.51 (1H, d, J ) 12.1
Hz), 4.38 (1H, d, J ) 12.1 Hz), 3.71-3.52 (5H, m, H2, H3, H5),
3.34 (3H, s), 2.77 (1H, ddd, J ) 9.2, 10.4, 10.4 Hz), 1.64 (1H,
dd, J ) 1.6, 6.6 Hz). 13C NMR (50 MHz): δ 138.8, 138.8, 138.7,
129.8, 128.8, 128.5-127.5, 77.5, 73.5, 72.7, 72.3, 72.1, 71.7,
71.4, 54.9, 43.1, 18.4. HR-MS (ES-TOF): calcd for C31H36NaO5
(M + Na) 511.2460, found 511.2459.
1
(121 mg, 20%) as a light yellow powder. H NMR (200 MHz):
δ 8.15-7.92 (7H, m), 7.61-7.48 (3H, m), 7.43-7.32 (7H, m),
6.84 (1H, dd, J ) 0.8, 1.6 Hz), 6.32 (1H, dd, J ) 3.2, 10.0 Hz),
6.19 (1H, dd, J ) 9.8, 10.0 Hz), 5.84 (1H, dd, J ) 1.8, 3.2 Hz),
5.01 (1H, d, J ) 1.8 Hz), 4.75 (1H, bd, J ) 10.2 Hz), 4.49 (1H,
(21) Namy, J . L.; Girard, P.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
J . Org. Chem, Vol. 68, No. 6, 2003 2127

Mikkelsen and Skrydstrup
Meth yl 2,3,6-Tr i-O-ben zyl-4-d eoxy-4-C-for m yl-r-D-m a n -
n op yr a n osid e (4). The alkene 5 (60 mg, 0.12 mmol) was
dissolved in CH2Cl2 (4.0 mL) and MeOH (1.0 mL) and cooled
to -78 °C. Ozone was bubbled through the solution for 2-3
min until the color changed to light blue. Excess ozone was
then removed by bubbling argon through the cold solution for
5 min. Triphenyl phosphine (74 mg, 0.28 mmol) was added
and after being stirred for 10 min at -78 °C the reaction was
warmed to 20 °C and stirred for an additional hour. Evapora-
tion to dryness and column chromatography (EtOAc:pentane,
1:7) yielded 50.0 mg (85%) of 4 as a colorless oil. The aldehyde
was used immediately in the following step. 1H NMR (200
MHz): δ 9.76 (1H, d, J ) 3.0 Hz), 7.36-7.23 (15H, m), 4.79
(1H, d, J ) 1.8 Hz), 4.71 (2H, s), 4.57 (1H, d, J ) 11.8 Hz),
4.54 (1H, d, J ) 11.4 Hz), 4.48 (1H, d, J ) 11.4 Hz), 4.35 (1H,
d, J ) 11.8 Hz), 4.17 (1H, dd, J ) 3.0, 11.2 Hz), 4.05 (1H, ddd,
J ) 5.0, 5.2, 10.2 Hz), 3.74 (1H, dd, J ) 2.0, 3.0 Hz), 3.65-
3.59 (2H, m), 3.42-3.35 (1H, m), 3.33 (3H, s). 13C NMR (50
MHz): δ 202.5, 138.4, 138.1, 137.9, 128.8-127.6, 99.6, 75.3,
73.7, 72.9, 71.7, 71.6, 71.2, 68.7, 55.3, 52.4. IR (KBr, disk):
3080-3010, 2914, 1727, 1505, 1454, 1114, 1075 cm-1. HR-MS
(ES-TOF): calcd for C29H32NaO6 (M + Na) 499.2097, found
499.2097.
mL) were refluxed overnight. Evaporation in vacuo and column
chromatography (EtOAc:pentane, 1:2) yielded 21.0 mg of 19
as a yellow oil (82%). 1H NMR (400 MHz): δ 8.28 (1H, s), 7.47
(1H, br s), 7.40-7.02 (35H, m), 6.94 (1H, br s), 6.65 (1H, br d,
J ) 8.4 Hz), 4.88 (1H, d, J ) 1.4 Hz), 4.72 (1H, d, J ) 11.6
Hz), 4.68 (1H, d, J ) 11.6 Hz), 4.65 (1H, d, J ) 11.6 Hz), 4.63
(1H, d, J ) 10.0 Hz), 4.56 (1H, d, J ) 11.6 Hz), 4.55 (1H, d, J
) 11.2 Hz), 4.53 (1H, d, J ) 10.8 Hz), 4.43 (1H, d, J ) 12.0
Hz), 4.41 (1H, d, J ) 10.0 Hz), 4.38 (1H, d, J ) 11.2 Hz), 4.32
(1H, d, J ) 12.0 Hz), 4.27 (1H, d, J ) 12.0 Hz), 4.21 (1H, d, J
) 12.0 Hz), 4.18 (1H, d, J ) 10.8 Hz), 4.15 (1H, m), 3.92-3-
73 (9H, m), 3.65 (1H, dd, J ) 5.2, 10.4 Hz), 3.53 (1H, dd, J )
2.8, 10.4 Hz), 3.34 (3H, s), 2.81 (1H, br dd, J ) 10.0, 10.4 Hz).
13C NMR (50 MHz): δ 185.1, 138.8, 138.8, 138.6, 138.6, 138.5,
138.4, 137.8, 137.7, 131.1, 129.0, 128.9, 128.7, 128.6, 128.5,
128.5, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.1,
127.9, 127.9, 127.9, 127.8, 127.7, 127.6, 127.6, 118.3, 99.6, 77.5,
76.3, 75.6, 74.9, 74.8, 74.4, 74.1, 73.4, 73.4, 73.3, 73.0, 72.3,
72.0, 71.8, 71.8, 71.8, 70.1, 69.4, 55.5, 38.5. HR-MS (ES-
TOF): calcd for C67H70N2NaO11S (M + Na) 1134.4598, found
1134.4592.
Met h yl 2,3,6-Tr i-O-b en zyl-4-d eoxy-4-C-(1′-(2′,3′,4′,6′-
tetr a-O-ben zyl-1′-deoxy-r-D-m an n opyr an osyl)m eth ylen e)-
r-D-m a n n op yr a n osid e (20). A mixture of the thionocarbam-
ate 19 (21 mg, 0.019 mmol), pentafluorophenol (7 mg, 0.038
mmol), triphenyltin hydride (15 µL, 0.057 mmol), and a
catalytic amount of AIBN (2 mg) in toluene (4.0 mL) was
refluxed for 3 h and then evaporated in vacuo. The residue
was redissolved in acetonitrile and washed two times with
pentane. Evaporation to dryness and column chromatography
(EtOAc:pentane, 1:5) yielded 10.0 mg of the C-disaccharide 20
as a colorless oil (54%). 1H NMR (400 MHz): δ 7.38-7.13 (35H,
m), 4.85 (1H, d, J ) 1.4 Hz), 4.73 (1H, d, J ) 11.2 Hz), 4.68
(1H, d, J ) 12.4 Hz), 4.64 (1H, d, J ) 12.4 Hz), 4.62 (1H, d, J
) 12.4 Hz), 4.55 (1H, d, J ) 13.2 Hz), 4.51 (1H, d, J ) 10.4
Hz), 4.49 (1H, d, J ) 13.2 Hz), 4.47 (1H, d, J ) 11.6 Hz), 4.46
(1H, d, J ) 11.2 Hz), 4.42 (1H, d, J ) 12.4 Hz), 4.37 (1H, d, J
) 10.4 Hz), 4.35 (1H, d, J ) 12.4 Hz), 4.28 (1H, d, J ) 12.4
Hz), 4.22 (1H, d, J ) 11.6 Hz), 4.25-4.18 (2H, m), 3.85 (1H,
dd, J ) 7.6, 8.0 Hz), 3.80-3.62 (8H, m), 3.36 (3H, s), 2.27 (1H,
m), 1.61-1.54 (2H, m). 13C NMR (50 MHz): δ 138.9-138.5,
128.5-127.6, 99.7, 78.7, 78.6, 76.2, 76.0, 75.3, 74.4, 73.1, 73.0,
72.6, 72.4, 72.2, 71.8, 71.8, 71.6, 71.6, 71.2, 69.9, 55.2, 35.5,
28.2. HR-MS (ES-TOF): calcd for C63H68NaO10 (M + Na)
1007.4710, found 1007.4710.
Met h yl 2,3,6-Tr i-O-b en zyl-4-d eoxy-4-C-(1′-(2′,3′,4′,6′-
t et r a -O-b en zyl-1′-d eoxy-r-D-m a n n op yr a n osyl)h yd r oxy-
m eth ylen e)-r-D-m a n n op yr a n osid e (18). Samarium diiodide
(0.10 M in THF, 4.2 mL, 0.42 mmol) was added dropwise to a
stirred solution of 2,3,4,6-tetra-O-benzyl-R-D-mannopyranosyl
2-pyridyl sulfone (17) (111.7 mg, 0.17 mmol) and aldehyde 4
(20.0 mg, 0.042 mmol) in THF (1.0 mL) under an argon
atmosphere until a persistent dark blue color was obtained.
The mixture was stirred at 20 °C for 10 min and then quenched
by the addition of saturated aqueous NH4Cl. The mixture was
diluted with CH2Cl2 and the aqueous phase was extracted once
with CH2Cl2. The combined organic phases were dried (MgSO4)
and concentrated in vacuo. Column chromatography (EtOAc:
pentane, 1:5 to 1:3) yielded 23.3 mg of the C-disaccharide 18
1
(55%) as a colorless oil. H NMR (CDCl3, 400 MHz): δ 7.37-
7.16 (35H, m), 4.84 (1H, d, J ) 2.4 Hz), 4.70 (2H, s), 4.56 (1H,
d, J ) 12.0 Hz), 4.56 (1H, d, J ) 12.0 Hz), 4.50 (1H, d, J )
10.4 Hz), 4.50 (1H, d, J ) 10.4 Hz), 4.47 (1H, d, J ) 12.4 Hz),
4.45 (1H, d, J ) 12.0 Hz), 4.44 (1H, d, J ) 11.6 Hz), 4.43 (1H,
d, J ) 12.0 Hz), 4.42 (1H, d, J ) 12.4 Hz), 4.39 (1H, d, J )
11.2 Hz), 4.39 (1H, d, J ) 11.6 Hz), 4.38 (1H, d, J ) 11.2 Hz),
4.25 (2H, m), 4.03 (1H, dd, J ) 2.8, 6.4 Hz), 4.03 (1H, m), 3.95
(1H, dd, J ) 4.0, 6.4 Hz), 3.91 (1H, m), 3.84 (1H, dd, J ) 7.2;
10.0 Hz), 3.80 (1H, dd, J ) 2.8; 3.0 Hz), 3.76 (1H, dd, J ) 2.4,
2.4 Hz), 3.72-3.68 (2H, m), 3.61 (1H, dd, J ) 3.0, 10.0 Hz),
3.33 (3H, s), 2.72 (1H, m). 13C NMR (50 MHz): δ 138.9, 138.8,
138.7, 138.7, 138.5, 138.5, 138.3, 128.7-127.5, 99.7, 78.2, 75.1,
74.5, 73.7, 73.5, 73.5, 73.2, 72.7, 72.7, 72.5, 72.3, 72.1, 71.3,
71.3, 71.2, 69.8, 69.2, 66.9, 55.0, 39.8. HR-MS (ES-TOF): calcd
for C63H68NaO11 (M + Na) 1023.4659, found 1023.4658.
Met h yl 2,3,6-Tr i-O-b en zyl-4-d eoxy-4-C-(1′-(2′,3′,4′,6′-
t et r a -O-b en zyl-1′-d eoxy-r-D-m a n n op yr a n osyl)oxyt h io-
car bon ylim idazolylm eth ylen e)-r-D-m an n opyr an oside (19).
The C-disaccharide 18 (23 mg, 0.023 mmol) and thiocarbonyl
diimidazole (82 mg, 0.46 mmol) dissolved in acetonitrile (3.0
Ack n ow led gm en t. We are indebted to the Danish
National Science Foundation (THOR Program), the
University of Aarhus, and the Carlsberg Foundation for
generous financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 4, 5, 13-16, and 18-20 and 13C NMR spectra for
4, 5, 13-16, 18, and 19. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O020585A
2128 J . Org. Chem., Vol. 68, No. 6, 2003