Application of the anomeric samarium route for the convergent synthesis of the C-linked trisaccharide α-D-Man-(1→3)-[α-D-Man-(1→6)]-D-Man and the disaccharides α-D-Man-(1→3)-D-Man and α-D-Man-(1→6)-D-Man

Article abstract of DOI:10.1021/jo020339z

Studies are reported on the assembly of the branched C-trisaccharide, α-D-Man-(1→3)-[α-D-Man-(1→6)]-D-Man, representing the core region of the asparagine-linked oligosaccharides. The key step in this synthesis uses a SmI₂-mediated coupling of two mannosylpyridyl sulfones to a C3,C6-diformyl branched monosaccharide unit, thereby assembling all three sugar units in one reaction and with complete stereocontrol at the two anomeric carbon centers. Subsequent tin hydride-based deoxygenation followed by a deprotection step produces the target C-trimer. In contrast to many of the other C-glycosylation methods, this approach employes intact carbohydrate units as C-glycosyl donors and acceptors, which in many instances parallels the well-studied O-glycosylation reactions. The synthesis of the C-disaccharides α-D-Man-(1→3)-D-Man and α-D-Man-(1→6)-D-Man is also described, they being necessary for the following conformational studies of all three carbohydrate analogues both in solution and bound to several mannose-binding proteins.

Full text of DOI:10.1021/jo020339z

Ap p lica tion of th e An om er ic Sa m a r iu m Rou te for th e Con ver gen t
Syn th esis of th e C-Lin k ed Tr isa cch a r id e
r-D-Ma n -(1f3)-[r-D-Ma n -(1f6)]-D-Ma n a n d th e Disa cch a r id es
r-D-Ma n -(1f3)-D-Ma n a n d r-D-Ma n -(1f6)-D-Ma n
Lise Munch Mikkelsen,† Sussie Lerche Krintel,†,‡ J esu´s J ime´nez-Barbero,§ and
Troels Skrydstrup*,†
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark, and
Instituto de Quı´mica Orga´nica, CSIC, J uan de la Cierva 3, E-28006 Madrid, Spain
ts@chem.au.dk
Received May 17, 2002
Studies are reported on the assembly of the branched C-trisaccharide, R-D-Man-(1f3)-[R-D-Man-
(1f6)]-D-Man, representing the core region of the asparagine-linked oligosaccharides. The key step
in this synthesis uses a SmI2-mediated coupling of two mannosylpyridyl sulfones to a C3,C6-diformyl
branched monosaccharide unit, thereby assembling all three sugar units in one reaction and with
complete stereocontrol at the two anomeric carbon centers. Subsequent tin hydride-based deoxy-
genation followed by a deprotection step produces the target C-trimer. In contrast to many of the
other C-glycosylation methods, this approach employes intact carbohydrate units as C-glycosyl
donors and acceptors, which in many instances parallels the well-studied O-glycosylation reactions.
The synthesis of the C-disaccharides R-D-Man-(1f3)-D-Man and R-D-Man-(1f6)-D-Man is also
described, they being necessary for the following conformational studies of all three carbohydrate
analogues both in solution and bound to several mannose-binding proteins.
In tr od u ction
information could lead to the design of less flexible
analogues whereby their binding efficiency is substan-
tially increased due to reduced entropic costs in the
recognition process. Replacement of the exocyclic oxygen
atoms in an oligosaccharide with methylene groups
affords the analogous C-linked glycoside,6 thereby intro-
ducing a new handle for studying the conformational
preferences around the interglycosyl linkage, where
mobility of such sugars is highest.7,8 Of course, O to CH2
substitution will undoubtedly lead to an alteration in
both the size and the electronic properties around the
glycosidic linkage, eliminating the exoanomeric effect. In
this context, such methylene-bridged analogues have
been reported to occupy additional conformations around
the interglycosidic linkage that are not observed for the
parent O-glycosides.8,9
Carbohydrate-protein interactions represent key cel-
lular recognition events that are associated with many
human-inflicting diseases, ranging from inflammation
and viral and bacterial infections to cancer.1 With a
growing understanding of the precise function cell surface
carbohydrates play in such disorders, numerous carbo-
hydrate-related pharmaceuticals have now been devel-
oped and have entered into clinical studies.2 An impor-
tant requisite for the rational design and understanding
of how such sugar-based drugs operate involves an
extensive knowledge of the conformational behavior and
flexibility of the natural carbohydrates in solution and
especially when protein bound.3-5 In particular, such
† University of Aarhus.
To provide further insight into the usefulness of
C-linked saccharides as tools for studying carbohydrate-
protein interactions, it is imperative that an ensemble
‡ Current address: Department of Chemistry, Loughborough Uni-
versity, England.
§ Instituto de Qu´ımica Orga´nica, CSIC.
(1) (a) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357. (b)
Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A. Science
2001, 291, 2370. (c) Glycosciences: Status and Perspectives; Gabius,
H.-J ., Gabius, S., Eds.; Chapman & Hall: London, U.K., 1997. (d)
Sears, P.; Wong, C.-H. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 12086.
(e) Kiessling, L. L.; Pohl, N. L. Chem. Biol. 1996, 3, 71. (f) Beuth, J .;
Ko, H. L.; Pulverer, G.; Uhlenbruck, G.; Pichlmaier, H. Glycoconjugate
J . 1995, 12, 1. (g) Lasky, L. Annu. Rev. Biochem. 1995, 64, 113. (h)
Toyokuni, T.; Singhal, A. K. Chem. Soc. Rev. 1995, 24, 231. (i) Varki,
A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7390. (j) Feizi, T. Curr. Opin.
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(6) (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
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Glycosides; Pergamon Press: Exeter, 1995. (c) Vogel, P.; Ferritto, R.;
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9913. (e) Beau, J .-M.; Vauzeilles, B.; Skrydstrup, T. Glycoscience:
Chemistry and Chemical Biology; Fraser-Reid, B., Tatsuta, K., Thiem,
J ., Eds.; Springer: Heidelberg, 2001; Vol. 3, p 2679. (f) Skrydstrup,
T.; Vauzeilles, B.; Beau, J .-M. Oligosaccharides in Chemistry and
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10.1021/jo020339z CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/14/2002
J . Org. Chem. 2002, 67, 6297-6308
6297

Mikkelsen et al.
of such compounds be available. Owing to the synthetic
challenge of assembling C-oligosaccharides, which in
essence requires the construction of a minimum of two
carbon-carbon bonds in a stereoselective fashion, most
of the conformational and biological studies have been
restricted to the use of C-disaccharides.6,10 Less promi-
nent, therefore, are reported cases on the synthesis of
more complex methylene-linked glycosides, namely C-
oligosaccharides. Whereas, two reports have demon-
strated the straightforward but linear assembly of
C-(1f6)-tetra- and pentaglycosides composed of repeat-
ing units of galactose,11,12 access to branched C-oligosac-
charides represents a more formidable synthetic chal-
lenge. An example has been illustrated by the Kishi group
in their partial de novo approach to the C-linked mimics
of the central trisaccharide unit of the type II(H) cellular
antigen.7h,l Armstrong and co-workers have also applied
the de novo route combined with combinatorial chemistry
techniques to access a library of C-trimer analogues of
the Lewis type I blood group determinant.13
F IGURE 1. The core region of the asparagine-linked oligosac-
charides.
N-acetylgalactosamine and -glucosamine.14-17 When the
same coupling reaction is performed with a C-formyl-
branched monosaccharide as the carbonyl substrate, this
route provides a rapid entry to C-disaccharides following
a radical deoxygenation step.14a,e,h-j,16,17 The similarities
of this approach with the more conventional O-glycoside
syntheses through the use of intact and appropriately
functionalized carbohydrate units are apparent and
therefore suggested the possibility of extending this
methodology to the preparation of more elaborate C-
linked sugars such as the branched oligosaccharides. To
illustrate this potential, we present our first work in this
area directed to the synthesis of the C-linked analogue
of the trisaccharide R-D-Man-(1f3)-[R-D-Man-(1f6)]-D-
Man, representing the core branching region of the
aspargine-linked oligosaccharides (Figure 1).18 The con-
vergent nature of the synthetic route chosen, in addition
to the total R-stereoselectivity at C1 in the carbon-carbon
bond forming event, makes this approach a simple and
an attractive alternative for accessing these interesting
glycoside mimics. As a spin-off of this work, we also
disclose the synthesis of the previously unknown C-
It has previously been shown that reductive samaria-
tion of glycosylpyridyl sulfones in the presence of carbonyl
substrates represents an effective means of generating
1,2-trans-C-glycosides of manno-, gluco-, galacto- and
fucopyransosides, as well as the 1,2-cis-stereoisomer of
(7) (a) Wu, T.-C.; Goekjian, P. G.; Kishi, Y. J . Org. Chem. 1987, 52,
4819. (b) Goekjian, P. G.; Wu, T.-C.; Kang, H.-Y.; Kishi, Y. J . Org.
Chem. 1987, 52, 4823. (c) Babirad, S. A.; Wang, Y.; Goekjian, P. G.;
Kishi, Y. J . Org. Chem. 1987, 52, 4825. (d) Miller, W. H.; Ryckman,
D. M.; Goekjian, P. G.; Wang, Y.; Kishi, Y. J . Org. Chem. 1988, 53,
5580. (e) Wang, Y.; Goekjian, P. G.; Ryckman, D. M.; Kishi, Y. J . Org.
Chem. 1988, 53, 4151. (f) Goekjian, P. G.; Wu, T.-C.; Kang, H.-Y.; Kishi,
Y. J . Org. Chem. 1991, 56, 6422. (g) Goekjian, P. G.; Wu, T.-C.; Kishi,
Y. J . Org. Chem. 1991, 56, 6412. (h) Haneda, T.; Goekjian, P. G.; Kim,
S. H.; Kishi, Y. J . Org. Chem. 1992, 57, 490. (i) O_Leary, D. J .; Kishi,
Y. J . Org. Chem. 1993, 58, 304. (j) O_Leary, D. J .; Kishi, Y. J . Org.
Chem. 1994, 59, 6629. (j) Wei, A.; Kishi, Y. J . Org. Chem. 1994, 59,
88. (k) Wei, A.; Boy, K. M.; Kishi, Y. J . Am. Chem. Soc. 1995, 117,
9432. (l) Wei, A.; Haudrechy, A.; Audin, C.; J un, H.-S.; Haudrechy-
Bretel, N.; Kishi, Y. J . Org. Chem. 1995, 60, 2160. (m) Ravishankar,
R.; Surolia, A.; Vijayan, M.; Lim, S.; Kishi, Y. J . Am. Chem. Soc. 1998,
120, 11297.
(14) (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) Miquel, N.;
Doisneau, G.; Beau, J .-M. Angew. Chem., Int. Ed. 2000, 39, 4111.
(15) Skrydstrup, T.; Beau, J .-M. In Advances in Free Radical
Chemistry, Zard, S. Z., Ed.; J AI Press: Stamford, 1999; Vol 2, p 89.
(16) Glycosylpyridyl sulfones have also been adapted for the con-
struction of R-C-glycosides of N-acetylneuraminic acid, although in
these cases the corresponding anomeric phenyl sulfones were found
to be equally effective: (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.
(17) Other functional groups at C1 of monosaccharides have also
been used in the SmI2-promoted C-glycosylation with carbonyl sub-
strates. Halides: (a) Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 4903. (b) Polat, T.; Du, Y.; Linhardt, R. J . Synlett 1998, 1195. (c)
Koketsu, M.; Kuberan, B.; Linhardt, R. J . Org. Lett. 2000, 2, 3361. (d)
Miquel, N.; Doisneau, G.; Beau, J .-M. Chem. Commun. 2000, 2347.
Phenyl sulfones: (e) Du, Y.; Linhardt, R. J . Carbohydr. Res. 1998, 308,
161. (f) de Pouilly, P.; Che´nede´, A.; Mallet, J .-M.; Sinay¨, P. Bull. Soc.
Chim. Fr. 1993, 130, 256. Phosphates: (g) Hung, S.-C.; Wong, C.-H.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2671.
(8) (a) Espinosa, J .-F.; Can˜ada, F. J .; Asensio, J . L.; Dietrich, H.;
Mart´ın-Lomas, M.; Schmidt, R. R.; J ime´nez-Barbero, J . Angew. Chem.,
Int. Ed. Engl. 1996, 35, 303. (b) Espinosa, J .-F.; Can˜ada, F. J .; Asensio,
J . L.; Martin-Pastor, M.; Dietrich, H.; Mart´ın-Lomas, M.; Schmidt, R.
R.; J ime´nez-Barbero, J . J . Am. Chem. Soc. 1996, 118, 10862. (c)
Espinosa, J .-F.; Dietrich, H.; Mart´ın-Lomas, M.; Schmidt, R. R.;
J ime´nez-Barbero, J . Tetrahedron. Lett. 1996, 37, 1467. (d) Espinosa,
J .-F.; Montero, E.; Vian, A.; Garcia, J . L.; Dietrich, H.; Mart´ın-Lomas,
M.; Schmidt, R. R.; Imberty, A.; Can˜ada, F. J .; J ime´nez-Barbero, J . J .
Am. Chem. Soc. 1998, 120, 1309. (e) Espinosa, J . F.; Bruix, M.;
J arreton, O.; Skrydstrup, T.; Beau, J .-M.; J ime´nez-Barbero, J . Chem.,
Eur. J . 1999, 5, 442. (f) Asensio, J . L.; Espinosa, J .-F.; Dietrich, H.;
Can˜ada, F. J .; Schmidt, R. R.; Mart´ın-Lomas, M.; Andre´, S.; Gabius,
H.-J .; J ime´nez-Barbero, J . J . Am. Chem. Soc. 1999, 121, 8995.
(9) Rubinstenn, G.; Sinay¨, P.; Berthault, P. J . Chem. Phys. A 1997,
101, 2536.
(10) 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. Engl. 1999, 38, 2939. (g) Khan, N.; Cheng, X.; Mootoo,
D. J . Am. Chem. Soc. 1999, 121, 4918.
(11) (a) Dondoni, A.; Kleban, M.; Zuurmond, H.; Marra, A. Tetra-
hedron Lett. 1998, 39, 7991. (b) Dondoni, A.; Mizuno, M.; Marra, A.
Tetrahedron Lett. 2000, 41, 6657.
(12) Xin, Y.-C.; Zhang, Y.-M.; Mallet, J .-M.; Glaudemans, C. P. J .;
Sinay¨, P. Eur. J . Org. Chem. 1999, 471, 1.
(13) (a) Sunderlin, D. P.; Armstrong, R. W. J . Am. Chem. Soc. 1996,
118, 9802. (b) Sunderlin, D. P.; Armstrong, R. W. J . Org. Chem. 1997,
62, 5267.
(18) For preliminary accounts of this work, see: (a) Krintel, S. L.;
J ime´nez-Barbero, J .; Skrydstrup, T. Tetrahedron Lett. 1999, 40, 7565.
(b) Mikkelsen, L. M.; Krintel, S. L.; J ime´nez-Barbero, J .; Skrydstrup,
T. Chem. Commun. 2000, 2319.
6298 J . Org. Chem., Vol. 67, No. 18, 2002

Convergent Synthesis of C-Linked Di- and Trisaccharides
SCHEME 1
disaccharides R-D-Man-(1f3)-D-Man and R-D-Man-(1f6)-
D-Man.19-21
Resu lts a n d Discu ssion
Th e Syn th etic P la n n in g. In our earlier work, we
established the configurational stability of anomeric
samarium species obtained from the direct reduction of
mannosylpyridyl sulfones in the presence of the single-
electron reducing agent samarium diiodide.14,15 In the
company of aliphatic aldehydes or ketones, R-C-glycosides
are the sole coupling products generated in both good
yields and with minimal â-elimination. With this in mind,
inspection of the target C-linked mannostrioside clearly
revealed that the most convergent route for its prepara-
tion, employs as the key step a simultaneous double
samarium diiodide-promoted C-glycosylation of a di-C3,-
C6-formyl branched mannopyranoside 2, as illustrated
in Scheme 1. Subsequent deoxygenation of the diol
product and deprotection would then lead to the desired
C-branched oligosaccharide. In this planned double-
coupling reaction, we anticipated the first C-C bond-
forming event to take place at the sterically less hindered
C6-aldehyde group of 2. As we have previously observed
the efficiency of such coupling reactions to be sensitive
to the sterical environment neighboring the aldehyde
functionality, it gave some concern about how effective
the second C-glycosylation would be at the C3 position
in the C-(1f6)-disaccharide intermediate. Nevertheless,
simple molecular modeling of the desired C-trisaccharide
quickly exposed the inability of these two branching
sugars to come in close contact with one another and
hence sterical blocking of the second coupling step should
not come into play.
To access the C-branched mannose derivative 2, we
initially contemplated introducing simultaneously masked
equivalents of both formyl groups through the nucleo-
philic substitution of the diiodide 3 with either cyanide
or an alkene/alkyne anion. Nevertheless, nucleophilic
substitution at one of the ring carbons in a monosaccha-
ride is not always evident due to sterical and electronic
repulsion from the flanking protected hydroxyl groups.22
Another approach could implement a double chain exten-
sion procedure from the dicarbonyl compound 4 involving
a sequence of Wittig or Wittig-type reactions, stereose-
lective hydroboration, and finally oxidation.16b,23 In the
event of failure in these two cases, resort could be made
to a stepwise route, exploiting the well-established diaxial
opening of epoxides in 1,6-anhydrosugars with sp1 or sp2
carbon nucleophiles for the introduction of a masked C3-
formyl group. Commencement of the synthesis could then
take place with the crystalline Cerny’s epoxide 5,24 easily
obtainable from starch in five steps and only two chro-
matographic purifications. Subsequent opening of the
anydrosugar and chain extension at C6 should then
proceed without incident.
Th e Sim u lta n eou s F u n ction a liza tion Rou te. Ini-
tial attempts to prepare the dialdehyde 2 were focused
on the simultaneous functionalization at C3 and C6 of
methyl mannopyranoside, as depicted in Scheme 2, due
to the brevity of the synthetic route planned. The diiodide
3 was effectively prepared by starting with the selective
tin oxide-promoted allylation of the mannopyranoside,
affording diallyl ethers at the C3- and C6-positions.25
(19) For other examples of C-disaccharides containing an R-man-
noside unit in the nonreducing end, see refs 7g, 10e, 14i,j, and
Vauzeilles, B.; Cravo, D.; Mallet, J .-M.; Sinay¨, P. Synlett 1993, 522.
(20) We have recently examined the conformational preferences of
the C-linked trimer in comparison to its natural analogue through a
combination of NMR spectroscopy and molecular mechanics and
dynamics calculations. Mikkelsen, L. M.; Herna´iz, M. J .; Skrydstrup,
T.; J ime´nez-Barbero, J . J . Am. Chem. Soc., accepted for publication.
(21) A recent report has disclosed both the synthesis of a single
C-glycoside analogue of the branched mannotrioside at the Man-R-
(1f6)-Man linkage and its affinity to concanavalin A: Tsuruta, O.;
Yuasa, H.; Kurono, S.; Hashimoto, H. Bioorg. Med. Chem. Lett. 1999,
9, 807.
(22) Richardson, A. C. Carbohydr. Res. 1969, 10, 395.
(23) For a few applications of this sequence en route to C-formyl-
branched monosaccharides, see: (a) Preuss, R.; Schmidt, R. R.
Tetrahedron Lett. 1989, 30, 3409. (b) Daley, S. M.; Armstrong, R. W.
Tetrahedron Lett. 1989, 30, 5713. (c) Preuss, R.; Schmidt, R. R. J .
Carbohydr. Chem. 1991, 10, 887. (d) Preuss, R.; J ung, K.-H.; Schmidt,
R. R. Liebiegs Ann. Chem. 1992, 377. (e) Schmidt, R. R.; Beyerbach,
A. Liebiegs Ann. Chem. 1992, 983. (f) Eisele, T.; Ishida, H.; Hummel,
G.; Schmidt, R. R. Liebiegs Ann. Chem. 1995, 2113. (g) Alzeer, J .; Cai,
C.; Vasella, A. Helv. Chim. Acta 1995, 78, 242.
(24) Dolezalova´, J .; Trnka, T.; Cerny, M. Collect. Czech. Chem.
Commun. 1982, 47, 2415.
(25) Ogawa, T.; Katano, K.; Sasajima, K.; Matsui, M. Tetrahedron
1981, 37, 2786.
J . Org. Chem, Vol. 67, No. 18, 2002 6299

Mikkelsen et al.
SCHEME 2
SCHEME 3
TBDPSi-ether at C6, but again its treatment with either
NaCN or nBu4NCN afforded predominantly the alkene
12 (Scheme 3).
An alternative route to the dialdehyde 2 calls for an
initial chain extension at C3 and C6 with a Wittig or
Tebbe reagent followed by a selective hydroboration/
oxidation sequence.16b,23 In this synthesis, the stereose-
lectivity of the hydroboration step at the C3 exocyclic
C-C double bond is of little concern. It was assumed that
eventually an axially oriented C-formyl group would
freely equilibrate to the more stable equatorial position
under mild basic conditions, as has previously been
demonstrated in the preparation of other C-formyl
branched sugars, including at the C3-position of a
galactoside.16b,23c-f,h To test the feasibility of this ap-
proach, the model compound 13 was first subjected to
oxidation with DMSO/Ac2O, followed by Tebbe’s reagent,
affording the exocyclic alkene 14 in 70% yield for the two
steps (Figure 4).
Subsequent standard benzylation and then deallylation
with Pd/C and acetic acid produced the diol 6. Transfor-
mation to the corresponding diiodide proceeded without
incident under the conditions described by Garegg.26 That
indeed the axially oriented iodide at C3 was attained was
confirmed by the small vicinal coupling constant between
H3 and H4 (J H3,H4 ) 3.3 Hz). Subjection of the diiodide 3
to excess sodium cyanide in DMF for 5 h at 20 °C led to
a quantitative conversion of the C6-substituted product
7. However, upon heating to 80 °C for an extra 2 h with
additional NaCN, only the elimination product 8 could
be isolated with no trace of the dinitrile 9.
Attempted hydroboration with 9-BBN proved unre-
warding and only led to unreacted starting material. On
the other hand, with BH3‚THF a single primary alcohol
15 could be isolated after oxidation, though in a yield of
1
33%. The H NMR spectrum of this branched monosac-
charide revealed an axially oriented hydroxymethyl
group due to the lack of a large J H3,H4 vicinal coupling
constant observed for the C3 proton at 2.28 ppm. To
invert this undesired stereochemistry, the alcohol was
first oxidized with PDC. The isomerization of an axially
oriented formyl group on a sugar ring to the thermody-
namically more stable equatorial position in neat tri-
ethylamine has been successfully carried out by Schmidt
and co-workers.23d,f However, quite unexpectedly, upon
treatment of the aldehyde 16 under the same conditions,
the C3-aldehyde group remained reluctant to epimerize,
as observed by the preservation of the small J H3,H4
coupling constant of 4.4 Hz compared to approximately
9 Hz for the correct product (see below). Subsequently,
these routes were abandoned and recourse was taken to
the stepwise difunctionalization of the Cerny epoxide 5.
The diiodide 3 is obviously set up to undergo trans-â-
elimination with the C4-proton, but Vasella and co-
workers have previously reported the successful substi-
tution of a C4-triflate in galactose with cyanide, even-
though a trans-diaxial relationship exists between the
C3- or C5-protons with the C4-triflate group.23g Attempts
to prepare the corresponding ditriflate from 6 followed
by its immediate subjection to sodium cyanide without
isolation led only to the 3,6-anhydro sugar 10 as the main
product and no traces of a product possessing a C3-nitrile
group (Scheme 2).27 To prevent the adverse elimination
reaction, a stepwise approach to the dinitrile was con-
ceived whereby installation of a bulky protecting group
on the C6-OH would potentially prevent the C4 depro-
tonation. Hence, the iodide 11 was prepared with a
Th e Step w ise Ap p r oa ch a n d Syn th esis of Meth yl
r-1,3- a n d r-1,6-C-Ma n n obiosid e. Initial efforts were
made to introduce a nitrile group at C3 of 5 owing to the
previous successful epoxide openings in anhydrosugars
with diethyl aluminum cyanide reported by Fraser-Reid
(26) Garegg, P.; J ohansson, R.; Ortega, C.; Samuelsson, B. J . Chem.
Soc., Perkin Trans. 1 1982, 681.
(27) As in the previous cases (ref 23c-f,h), it was anticipated that
the corresponding C-branched aldehyde obtained after DIBALH reduc-
tion of the axially oriented C3-cyanide would epimerize upon base
treatment to the more favored equatorial position.
6300 J . Org. Chem., Vol. 67, No. 18, 2002

Convergent Synthesis of C-Linked Di- and Trisaccharides
SCHEME 4
SCHEME 6
SCHEME 5
the corresponding aldehyde 24. Coupling to the manno-
sylpyridyl sulfone 25 was then achieved by quickly
adding a 0.1 M etheral solution of SmI2 (3.5 equiv) to a
mixture of 25 (1.5 equiv) with the aldehyde at 20 °C.
Without chromatographic separation, the crude reaction
mixture was immediately subjected to a large surplus of
thiocarbonyldiimidazole in refluxing acetonitrile. This
afforded a 38% yield of two diastereomeric thiocarbon-
ylimidazole C-dimer derivatives (26) in a ratio of 2.7:1.
The low yield in this coupling step was attributed to the
steric congestion surrounding the aldehyde functionality.
Deoxygenation was next achieved by employing our
earlier described conditions for the removal of sterically
hindered secondary alcohols.14i Treatment of 26 with
pentafluorophenol, triphenyltin hydride, and AIBN in hot
toluene led to a 56% yield of the C-disaccharide 27.
Unfortunately, all attempts to convert this compound
directly to the fully protected R-1,3-C-mannobioside 28
via acid-catalyzed methanolysis failed, affording complex
mixtures.
and co-workers.28 Hence, protection of the C2-alcohol of
5 and then treatment of the epoxide 17 with Et2AlCN in
refluxing benzene afforded the expected C3-cyano com-
pound 18 in 54% yield, as deduced by the J H2,H3 (6.2 Hz)
and J H3,H4 (0.6 Hz) vicinal coupling constants (Scheme
5). Problems, however, arose in the second OH-protecting
step, as attempted benzylation under standard conditions
(NaH/BnBr/DMF) led to exclusive epimerization at C3.
A large trans-diaxial vicinal coupling constant of 10.2 Hz
was now observed between the H2 and H3 protons in
compound 20. This obstacle could only be partially
remedied with the milder benzylating conditions employ-
ing Ba(OH)2 as base, furnishing a 2:1 mixture of 20 and
19. The unwanted epimerization at C3 could easily be
solved by installation of a vinyl group instead as the
formyl group equivalent (Scheme 6).29 Therefore, the
epoxide 17 was first treated with vinylmagnesium bro-
mide, generating an inseparable 4:1 mixture of the alkene
21 and bromide 22. Subsequent benzylation proceeded
uneventfully in this case, leading to the crystalline 23
(mp 52-53 °C) after chromatographic separation.30
To access the C-glycoside analogue of R-D-Man-(1f3)-
D-Man, necessary for the following conformation studies,
attempts were undertaken to carry 23 through to this
C-dimer. First, ozonolysis led to a quantitative yield of
To circumvent this problem, we decided to promote the
acid-catalyzed ring opening of the 1,6-anhydro bond in
23 prior to the C-glycosylation step, as shown in Scheme
7. In this manner, acetolysis of 23 in a 10:1 mixture of
acetic anhydride and trifluoroacetic acid produced the
corresponding C1,C6-diacetate, which underwent a clean
TMSOTf-catalyzed glycosylation with methanol, afford-
ing exclusively the methyl R-mannoside 29 in a 62%
overall yield. Following the preceding synthesis, ozonoly-
sis to the aldehyde 30 and subsequent SmI2-promoted
coupling with 25 secured the C-glycoside 31 in this case
as a sole diastereomer at C7 after functionalization with
(28) Mubarak, A.; Fraser-Reid, B. J . Org. Chem. 1982, 47, 4265.
(29) Inghardt, T.; Frejd, T. Synthesis 1990, 285.
(30) Upon benzylation of the mixture of compounds 21 and 22, the
bromide 22 cylized back to the epoxide 17.
J . Org. Chem, Vol. 67, No. 18, 2002 6301

Mikkelsen et al.
SCHEME 7
SCHEME 8
thiocarbonyldiimidazole. As previously observed with
aldehyde 24, this two-step sequence resulted only in a
modest coupling yield of the C-dimer 31, which was of
some concern considering the extrapolation of this work
to the C-trisaccharide 1. At any rate, radical deoxygen-
ation proceeded as expected, providing the fully protected
C-disaccharide 32 in a 65% yield,31 which was deprotected
to the required C-dimer 33 via a classical two-step
protocol. To facilitate its characterization, the methyl
R-1,3-C-mannobioside was peracetylated with acetic an-
hydride to the heptaacetate 34.
ozonolysis step would produce the dialdehyde 2. In this
context, we were attracted by a recent account disclosed
by Clark et al. in their adaptation of the chiron approach
toward the synthesis of the brevitoxin and ciguatoxin
class of polycyclic ethers.32 A three-step sequence was
developed in this work for the introduction of a similar
C6-functionalization on a sugar moiety.
It is interesting to note the deviation of the nonreduc-
4
ing sugar in 34 from the normal C1 chair conformation,
as deduced by the medium size vicinal coupling constants
observed between the H3′ and H4′ protons, as well as
1
that of the H4′ and H5′ protons in the H NMR spectrum
To test this route, efforts were first made with the
readily available methyl 2,3,4-tri-O-benzyl-R-D-mannopy-
ranoside, thereby providing access to methyl R-1,6-C-
mannobioside (Scheme 8). Treatment with triflic anhy-
dride and lutidine afforded the unstable C6-triflate,
which was immediately alkynylated with the lithium
anion of trimethylsilylacetylene. Upon desilylation, the
alkyne 35 was thus obtained. Partial hydrogenolysis then
gave the alkene 36 and finally the aldehyde 37 upon
ozonolysis.33 Samarium diiodide-promoted coupling with
the pyridyl sulfone 25 and thionocarbamate formation
proceeded as expected, affording the C-dimer 38 as a 5:1
mixture of C7-diastereomers in a 62% yield. At last,
radical deoxygenation to 39 and deprotection provided
the C-glycoside analogue 40 of methyl R-1,6-mannobio-
side, characterized as its heptaacetate 41. Not unexpect-
edly, both the sugar rings occupy in this case the normal
chair conformation.
(J H3′,H4′ ) 5.4 Hz and J H4′,H5′ ) 4.8 Hz). This result
contradicts those observed for the analogous C-disaccha-
ride of R-D-Man-(1f2)-D-Man, where both peracetylated
monosaccharide units possess the normal ring confor-
mation14i and hence clearly reflects the greater sterical
congestion between the two sugars in the (1f3)-dimer.
Consequently, it is not surprising that a lower yield for
31 was observed in the SmI2-mediated coupling step
compared to the same C-C bond-forming reaction in the
synthesis of the methyl R-1,2-C-mannobioside. More
importantly for the subsequent studies, upon deacetyla-
tion of 34 to the R-1,3-C-mannobioside, the 4C1 chair
conformation was restored for the nonreducing sugar, as
illustrated by the large trans-diaxial coupling constants
between the same ring protons (J H3′,H4′ ) 9.4 Hz and
J H4′,H5′ ) 9.0 Hz).
To push forward to the C-trisaccharide, it was neces-
sary at this stage to develop a second chain extension
sequence at C6 of the central carbohydrate unit. Although
exchange of the liberated C6-hydroxyl group in 29 to
iodide followed by substitution with cyanide represented
a plausible route, it was more convenient to introduce a
second vinyl group in this position such that a single
Syn th esis of th e Dia ld eh yd e 2 a n d Com p letion of
th e C-Tr isa cch a r id e. With the successful preparation
of the two C-disaccharides 33 and 44, we felt confident
this synthetic approach could now be carried through to
the requisite C-trisaccharide. This necessitated the ad-
(31) The protected C-dimer 32 could undoubtedly have been carried
through to the target C-trisaccharide via an initial deactylation and
chain-extending sequence followed by a second C-glycosylation step.
(32) Clark, J . S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372.
(33) Interestingly, when phenylacetylene was introduced, selective
hydrogenation of the triple bond failed.
6302 J . Org. Chem., Vol. 67, No. 18, 2002

Convergent Synthesis of C-Linked Di- and Trisaccharides
SCHEME 9
The crucial dicoupling step was next performed by the
quick addition of 10 equiv of the lanthanide reducing
agent directly to a mixture of the dialdehyde 2 with a
large excess of the pyridyl sulfone 25 (4.7 equiv). The
crude product mixture from this instantaneous coupling
reaction was thereafter refluxed in acetonitrile with
excess thiocarbonyldiimidazole for 12 h, followed by the
slow concentration of the reaction mixture under heating.
This latter procedure is important for the successful
functionalization of the exocyclic hydroxyl groups. To our
delight, with this two-step protocol a respectable 63%
yield was obtained for the functionalized C-trisaccharide
45 as a mixture of inseparable diastereomers. Conversely,
when these dithionocarbamates were treated under the
above-described deoxgenation conditions, a single C-
trisaccharide product 46 was furnished in a 53% yield.
Further, Pd-catalyzed hydrogenation afforded the target
C-oligosaccharide 1, which was characterized as its
undecaacetate 47, as previously described. The assign-
ment of the R-configuration for both of the nonreducing
sugars was made on the related pattern observed for the
proton coupling constants between the C-trisaccharide
and the two C-disaccharides.
Con clu sion s
The C-trisaccharide analogue of the core region R-D-
Man-(1f3)-[R-D-Man-(1f6)]-D-Man of the asparagine-
linked oligosaccharides has been synthesized using a
SmI2-promoted reductive C-glycosylation as the key
reaction for assembling the three monosaccharide units
in a single step. The two C-disaccharides R-D-Man-(1f3)-
D-Man and R-D-Man-(1f6)-D-Man were also prepared as
model studies to the C-trisaccharide, in addition to
allowing for a comparative study of the conformational
behavior of all three C-oligosaccharides.
In comparison to many of the previous C-oligosaccha-
rides syntheses, this highly convergent approach to the
branched trisaccharide is distinguished by its use of
glycosyl donors and acceptors, where the key coupling
step occurs at the anomeric center, in a manner similar
to the well-studied O-glycosylation reactions. Our ap-
proach should also be applicable to the synthesis of mixed
branched oligosaccharides via a stepwise introduction of
the two sugar units on to the central glycoside. This has
already been partially demonstrated in the synthetic
approach to the C-disaccharide R-D-Man-(1f3)-D-Man
with the protected C-dimer 32. A second glycosyl donor
other than mannose could have been installed at the C6-
position after liberation of C6-hyroxyl group and chain
extension.
ditional functionalization at C6 of the C3-branched
mannoside 29. As illustrated in Scheme 9, several
modifications of the original synthesis of this compound
were however made in order to shorten the number of
the synthetic steps. First, introduction of the C3-vinyl
group was accomplished directly on the epoxide 5 with
excess of the vinyl Grignard reagent, whereafter benzy-
lation of the diol afforded 23. Second, simple methanoly-
sis with concentrated HCl in refluxing methanol for 4
days opened the anhydro-ring, leading directly to the
desired alcohol 42 as a single methyl glycoside in a 56%
yield. This reaction proved to be somewhat delicate and
required careful monitoring by TLC analysis. In most
cases, the methanolysis never reached completion and
the starting anhydrosugar was recovered. Nevertheless,
with these adjustments the number of steps required for
the synthesis of 42 was reduced by three. Elongation of
the alcohol 42 with acetylene via a similar sequence as
described above for the synthesis of the C-(1f6)-dimer
then led to the dialkene 44 after selective hydrogenation
with Lindlar’s catalyst. Finally, ozonolysis afforded the
dialdehyde 2 in near quantitative yield, as revealed by
the two signals at 9.80 and 9.63 ppm in the 1H NMR
spectrum.
Exp er im en ta l P r oced u r e
Gen er a l Meth od s. The SmI2-promoted coupling reactions
were performed under Ar, while all other reactions were
carried out under N2. 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). The following
compounds were prepared according to literature procedures:
samarium diiodide,34 the mannosylpyridyl sulfone 25,14e and
the Cerny epoxide 5.24
(34) Namy, J . L.; Girard, P.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
J . Org. Chem, Vol. 67, No. 18, 2002 6303

Mikkelsen et al.
1,6:3,4-Dia n h yd r o-2-O-ben zyl-â-D-a ltr op yr a n ose (17).
NaH (112 mg, 60% in mineral oil, 2.8 mmol) was added to a
cooled (0 °C) solution of the Cerny epoxide 5 (225 mg, 1.56
mmol) in THF (11 mL). After vigorous stirring for 20 min,
benzyl bromide (285 µL, 2.4 mmol) and Bu4NI (157 mg, 0.48
mmol) were added and the mixture was stirred for another 2
h. The reaction was quenched with MeOH and diluted with
diethyl ether. The organic phase was washed four times with
water and once with brine, dried (MgSO4), and evaporated to
dryness in vacuo. Column chromatography (EtOAc:pentane,
1:2) yielded 280 mg (78%) of 17 as a colorless syrup: IR (film)
vacuo, and the resulting oil was redissolved in CH2Cl2, dried
(MgSO4), and again evaporated to dryness. The resulting
yellow oil was used in the next step without further purifica-
tion. A pure sample was nevertheless obtained by column
chromatography (MeOH:CH2Cl2, 1:20) to give 1,6-anhydro-3-
deoxy-3-C-vinyl-â-D-mannopyranose as a colorless syrup: 1H
NMR (200 MHz) δ ) 5.97 (1H, ddd, J ) 10.0, 11.2, 16.2 Hz),
5.43 (1H, d, J ) 2.0 Hz), 5.33 (1H, m), 5.31 (1H, m), 4.48 (1H,
d, J ) 5.0 Hz), 3.94 (1H, d, J ) 8.2 Hz), 3.87 (1H, dd, J ) 2.0,
8.6 Hz), 3.80 (1H, dd, J ) 5.0, 8.2 Hz), 3.74 (1H, m), 2.90 (1H,
dd, J ) 8.6, 10.0 Hz), 2.61 (1H, bs), 2.07 (1H, bs); 13C NMR
(50 MHz) δ ) 134.9, 122.1, 102.4, 77.2, 73.2, 67.5, 65.8, 50.7.
1
2957, 2894, 1639, 1497, 1454 cm-1; H NMR (200 MHz) δ )
7.40-7.28 (5H, m), 5.31 (1H, dd, J ) 2.4, 2.6 Hz), 4.74 (1 H, d,
J ) 12.1 Hz), 4.68 (1H, m), 4.65 (1H, d, J ) 12.1 Hz), 4.11
(1H, d, J ) 7.4 Hz), 3.85 (1H, dd, J ) 4.4, 7.4 Hz), 3.63 (1H,
dd, J ) 0.8, 2.8 Hz), 3.11 (1H, bd, J ) 3.9 Hz), 3.05 (1H, dd, J
) 3.9, 2.4 Hz); 13C NMR (50 MHz) δ ) 137.2, 128.6, 128.1,
98.2, 72.1, 72.0, 70.0, 67.4, 50.2, 49.7; MS (EI) m/z 234 (M),
143 (M - CH2Ph).
Benzylation of the crude 1,6-anhydro-3-deoxy-3-C-vinyl-â-
D-mannopyranose (approximately 2.77 mmol) was performed
according to the procedure outlined for the previous synthesis
of 23, with the following quantities: DMF (15 mL), NaH (60%
in mineral oil, 416 mg, 10.4 mmol), benzyl bromide (0.99 mL,
8.33 mmol). Column chromatography (EtOAc:pentane, 1:10)
yielded 412 mg of 23 (42% for two steps).
1,6-An h ydr o-2,4-di-O-ben zyl-3-deoxy-3-C-vin yl-â-D-m an -
n op yr a n ose (23) fr om Ep oxid e 17. Vinylmagnesium bro-
mide (6 mL, 1.0 M in THF, 6.0 mmol) was added dropwise to
a solution of the epoxide 17 (281 mg, 1.2 mmol) in THF (3.5
mL). The mixture was refluxed for 8 h, whereafter it was
cooled to 20 °C and then added to an aqueous saturated
solution of NH4Cl (30 mL). The mixture was extracted with
EtOAc, and the organic phase was washed with water, dried
(MgSO4), and concentrated to dryness in vacuo. Column
chromatography (EtOAc:pentane, 1:1) yielded 168 mg of a
mixture of an approximately 4:1 mixture of the alkene 21 and
the bromide 22. For 21: 1H NMR (200 MHz) δ ) 7.32 (5H,
m), 6.32 (1H, ddd, J ) 8.4, 10.4, 17.3 Hz), 5.47 (1H, bs), 5.28
(1H, ddd, J ) 1.4, 1.4, 17.3 Hz), 5.25 (1H, ddd, J ) 1.4, 1.4,
10.4 Hz), 4.62 (1H, d, J ) 12.0 Hz), 4.46 (1H, m), 4.41 (1H, d,
J ) 12.0 Hz), 3.98 (1H, d, J ) 7.8 Hz), 3.79 (1H, dd, J ) 5.4,
7.8 Hz), 3.78 (1H, bs), 3.70 (1H, dd, J ) 1.5, 6.9 Hz), 3.09 (1H,
ddddd, J ) 1.4, 1.4, 1.4, 6.9, 8.4 Hz), 2.43 (1H, bs); 13C NMR
(50 MHz) δ ) 137.1, 136.4, 136.2, 127.9, 127.8, 127.4, 127.2,
117.9, 100.7, 76.5, 74.0, 73.0, 69.6, 64.6, 47.0; MS (EI) m/z 262
(M), 171 (M - CH2Ph).
To a cooled (0 °C) solution of the above mixture (154 mg) in
DMF (4.6 mL) was carefully added NaH (36 mg, 60% in
mineral oil, 0.90 mmol). After stirring for 20 min, benzyl
bromide (105 µL, 0.88 mmol) was added and the mixture was
stirred for another 2 h. The reaction mixture was then
quenched by the addition of MeOH and diluted with diethyl
ether. The organic phase was washed four times with water
and once with brine, dried (MgSO4), and evaporated to dryness
in vacuo. Column chromatography (EtOAc:pentane, 1:8) yielded
the benzyl ether 23 (104 mg, 64%) as colorless crystals: mp
52-53 °C; IR (film) 2922, 1636, 1454 cm-1; 1H NMR (200 MHz)
δ ) 7.40-7.25 (10H, m), 6.33 (1H, ddd, J ) 8.4, 10.4, 18.8 Hz),
5.48 (1H, bs), 5.17 (1H, ddd, J ) 1.4, 1.4, 10.4 Hz), 5.10 (1H,
ddd, J ) 1.4; 1.4; 18.8 Hz), 4.70 (1H, d, J ) 12.4 Hz), 4.60
(1H, d, J ) 12.4 Hz), 4.60 (1H, d, J ) 11.8 Hz), 4.51 (1H, m),
4.41 (1H, d, J ) 11.8 Hz), 3.84 (1H, dd, J ) 0.8, 7.8 Hz), 3.76
(1H, dd, J ) 1.6, 7.0 Hz), 3.72 (1H, dd, J ) 5.4, 7.8 Hz), 3.44
(1H, bs), 3.13 (1H, ddddd, J ) 1.4, 1.4, 1.4, 7.0, 8.4 Hz); 13C
NMR (50 MHz) δ ) 137.7, 137.7, 137.3, 128.4-127.6, 117.8,
101.0, 80.8, 75.0, 74.1, 71.0, 70.3, 65.2, 44.2; HR-MS (ES) calcd
for C22H24O4Na (M + Na) 375.1572, found 375.1570.
Meth yl 6-O-Acetyl-2,4-d i-O-ben zyl-3-d eoxy-3-C-for m yl-
r-D-m a n n op yr a n osid e (30). Trifluoroacetic acid (245 µL) was
added to a solution of 23 (98 mg, 0.23 mmol) in Ac2O (2.5 mL),
and the mixture was stirred overnight. The crude material
obtained by coevaporation with toluene was dissolved in dry
CH2Cl2 (3.0 mL). MeOH (113 µL, 2.78 mmol) and crushed 4 Å
molecular sieves (approximately 200 mg) were added, and the
mixture was stirred for 1 h. After cooling to 0 °C, TMSOTf
(72 µL, 0.37 mmol) was added dropwise. After 45 min at 0 °C,
the reaction mixture was diluted with CH2Cl2 and then filtered
through Celite. The organic phase was washed with aqueous
NaHCO3, dried (MgSO4), and evaporated to dryness in vacuo.
Column chromatography (EtOAc:pentane, 1:6) yielded 73 mg
of methyl glycoside 29 (62% for two steps) isolated as a
colorless syrup: 1H NMR (200 MHz) δ ) 7.40-7.28 (10H, m),
6.11 (1H, ddd, J ) 9.4, 10.3, 17.4 Hz), 5.31 (1H, dd, J ) 2.2,
17.4 Hz), 5.20 (1H, dd, J ) 2.2, 10.3 Hz), 4.71 (1H, d, J ) 1.5
Hz), 4.66 (1H, d, J ) 11.8 Hz), 4.62 (1H, d, J ) 10.4 Hz), 4.51
(1H, d, J ) 11.8 Hz), 4.39 (1H, dd, J ) 2.2, 11.7 Hz), 4.38 (1H,
d, J ) 10.4 Hz), 4.29 (1H, dd, J ) 5.1, 11.7 Hz), 3.83 (1H, ddd,
J ) 2.2, 5.1, 9.9 Hz), 3.71 (1H, dd, J ) 9.9, 9.9 Hz), 3.57 (1H,
dd, J ) 1.5, 2.9 Hz), 3.40 (3H, s), 2.78 (1H, ddd, J ) 2.9, 9.4,
9.4 Hz), 2.11 (3H, s); 13C NMR (CDCl3, 50 MHz) δ ) 171.1,
138.2, 137.9, 136.5, 128.5, 128.4, 128.2, 127.9, 127.8, 118.6,
97.2, 79.5, 74.0, 73.5, 72.8, 70.0, 64.0, 54.8, 47.5, 21.1.
Ozone was bubbled through a solution of the alkene 29 (51
mg, 0.12 mmol) dissolved in dry CH2Cl2 (16 mL) and MeOH
(4.0 mL) at -78 °C until a blue color was obtained. After
removal of the excess ozone by bubbling nitrogen through the
solution for 5-10 min at -78 °C, triphenylphosphine (56 mg,
0.28 mmol) was added, and the reaction mixture was warmed
to 20 °C over a period of 15 min. Stirring was continued for
an additional 30 min, and the solvents were removed by
evaporation to dryness in vacuo. Column chromatography
(EtOAc:pentane, 1:4) gave 30 (48 mg, 94%) as a colorless syrup,
which was immediately used in the subsequent step. A small
sample was characterized by NMR spectroscopy: 1H NMR (200
MHz) δ ) 9.61 (1H, d, J ) 1.2 Hz), 7.36-7.27 (10H, m), 4.76
(1H, bs), 4.76 (1H, d, J ) 10.6 Hz), 4.63 (1H, d, J ) 12.2 Hz),
4.52 (1H, d, J ) 10.6 Hz), 4.43 (1H, dd, J ) 2.4, 12.2 Hz), 4.42
(1H, d, J ) 12.2 Hz), 4.30 (1H, dd, J ) 5.0, 12.2 Hz), 4.18 (1H,
dd, J ) 10.0, 10.0 Hz), 3.98 (1H, dd, J ) 1.8, 3.2 Hz), 3.79
(1H, ddd, J ) 2.4, 5.0, 10.0 Hz), 3.37 (3H, s), 2.94 (1H, ddd, J
) 1.2, 3.4, 10.0 Hz), 2.10 (3H, s); 13C NMR (50 MHz) δ ) 200.8,
171.0, 137.6, 137.3, 128.6, 128.1, 127.9, 96.5, 74.7, 74.5, 72.3,
70.1, 69.5, 63.4, 54.9, 54.5, 21.0.
1,6-An h ydr o-2,4-di-O-ben zyl-3-deoxy-3-C-vin yl-â-D-m an -
n op yr a n ose (23) fr om Ep oxid e 5. Vinylmagnesium bromide
(8.33 mL, 1.0 M in THF, 8.33 mmol) was added dropwise to
the Cerny epoxide 5 (400 mg, 2.78 mmol) dissolved in dry THF
(4.5 mL) at 20 °C. The reaction mixture was heated to 60 °C
for 4 h, after which TLC analysis indicated complete consump-
tion of the starting material (MeOH:CH2Cl2, 1:20). The reac-
tion mixture was quenched with a few drops of saturated
aqueous NH4Cl. The mixture was filtered through a 1-2 cm
pad of silica gel with methanol as the eluent in order to remove
the formed salts. The filtrate was evaporated to dryness in
Meth yl 6-O-Acetyl-2,4-di-O-ben zyl-3-deoxy-3-C-(1′-(2′,3′,-
4′,6′-tetr a -O-ben zyl-1′-d eoxy-r-D-m a n n op yr a n osyl)(oxy-
t h ioca r b on ylim id a zolylm et h ylen e)-r-D-m a n n op yr a n o-
sid e (31). The aldehyde 30 (45 mg, 0.105 mmol) and pyridyl
sulfone 25 (120 mg, 0.181 mmol) were loaded into an oven-
dried flask and flushed with argon for 5 min. A 0.1 M solution
of freshly prepared samarium diiodide in THF was added until
6304 J . Org. Chem., Vol. 67, No. 18, 2002

Convergent Synthesis of C-Linked Di- and Trisaccharides
a permanent dark blue color persisted (approx 5 mL, 0.51
mmol). The reaction mixture was quenched by the addition of
aqueous saturated NH4Cl and then diluted with CH2Cl2. The
organic phase was filtered through a small Celite pad, dried
(MgSO4), and concentrated to dryness in vacuo. A short column
(EtOAc:pentane, 1:3) gave the crude 1,3-C-disaccharide, which
was redissolved in dry distilled MeCN (2 mL). Thiocarbonyl-
diimidazole (187 mg, 1.05 mmol) was added, and the mixture
was refluxed overnight. The solvent was thereafter slowly
evaporated off by continued heating. The residue obtained was
subjected to column chromatography (EtOAc:pentane, 1:2),
yielding 35 mg of 31 (35% for two steps) as a thick colorless
syrup: 1H NMR (200 MHz) δ ) 8.25 (1H, s), 7.50 (1H, s), 7.40-
7.08 (30H, m), 6.80 (1H, s), 6.43 (1H, dd, J ) 1.4, 2.6 Hz), 4.90
(1H, d, J ) 10.6 Hz), 4.69 (1H, d, J ) 1.4 Hz), 4.53-4.31 (11H,
m), 4.23 (1H, dd, J ) 4.8, 12.2 Hz), 4.18 (2H, m), 4.11 (1H, bd,
J ) 1.4 Hz), 4.07 (1H, dd, J ) 9.2, 11.4 Hz), 3.94-3.63 (6H,
m), 3.57 (1H, dd, J ) 4.4, 10.2 Hz), 3.30 (3H, s), 2.97 (1H, ddd,
J ) 2.6, 5.2, 10.6 Hz), 2.10 (3H, s).
Meth yl 2,4,6-Tr i-O-acetyl-3-deoxy-3-C-(1′-(2′,3′,4′,6′-tetr a-
O-a cetyl-1′-d eoxy-r-D-m a n n op yr a n osyl)m eth ylen e)-r-D-
m a n n op yr a n osid e (34). To a solution of 31 (35 mg, 0.033
mmol) in dry distilled toluene (2.0 mL) were added pentafluo-
rophenol (12 mg, 0.066 mmol), triphenyltin hydride (22 mg,
0.436 mmol), and a catalytic amount of AIBN (approximately
2 mg). The reaction mixture was refluxed for 30 min. The
solvent was removed by evaporation in vacuo, and the residue
was redissolved in acetonitrile and washed twice with pentane
to remove the residual tin compounds. The acetonitrile phase
was evaporated to dryness in vacuo, and subsequent column
chromatography (EtOAc:pentane, 1:3) gave 20 mg of 32 (65%)
as a colorless thick syrup: 1H NMR (CDCl3, 200 MHz) δ )
7.44-7.10 (30H, m), 4.69 (1H, d, J ) 11.1 Hz), 4.64 (1H, d, J
) 1.8 Hz), 4.58-4.44 (11H, m), 4.38 (1H, dd, J ) 2.1, 11.7 Hz),
4.23 (1H, d, J ) 5.4, 11.7 Hz), 4.12 (1H, m), 3.84-3.61 (7H,
m), 3.52 (1H, dd, J ) 9.9; 9.9 Hz), 3.51 (1H, dd, J ) 3.2, 5.1
Hz), 3.32 (3H, s), 2.17 (1H, m), 2.10 (3H, s), 1.82 (2H, m).
Meth yl 2,3,4-Tr i-O-ben zyl-6-deoxy-6-C-eth yn yl-r-D-m an -
n op yr a n osid e (35). Trifluoromethanesulfonic anhydride (109
µL, 0.646 mmol) was slowly added to a solution of methyl 2,3,4-
tri-O-benzyl-R-D-mannopyranoside (200 mg, 0.431 mmol) and
2,6-lutidine (63 µL, 0.538 mmol) in CH2Cl2 (2 mL) and cooled
to -40 °C. After stirring for 1 h, the reaction mixture was
quenched by the addition of saturated aqueous NaHCO3, and
the resulting mixture was extracted three times with diethyl
ether. The combined organic phases were dried (MgSO4) and
evaporated to dryness in vacuo, keeping the temperature below
30 °C. The crude product was purified by rapid column
chromatography (EtOAc:pentane, 1:15), giving 205 mg (80%)
of methyl 2,3,4-tri-O-benzyl-6-trifluoromethansulfonyl-R-D-
mannopyranoside as a colorless syrup, which was immediately
used for the next step.
nBuLi (827 µL, 1.6 M in THF, 1.32 mmol) was added
dropwise to a solution of trimethylsilylacetylene (170 µL, 1.20
mmol) dissolved in THF (0.5 mL) and HMPA (60 µL) at -78
°C. After stirring for 15 min, the triflate (205 mg, 0.344 mmol)
in THF (1.0 mL) was added dropwise. The reaction mixture
was slowly warmed to 20 °C and stirred overnight. After
quenching by the addition of saturated aqueous NH4Cl, the
mixture was extracted three times with diethyl ether. The
combined organic phases were dried (MgSO4) and concentrated
to dryness in vacuo. Column chromatography (EtOAc:pentane,
1:15) gave 112 mg (60%) of the disubstituted alkyne as a
colorless syrup: 1H NMR (200 MHz) δ ) 7.40-7.22 (15H, m),
4.93 (1H, d, J ) 10.8 Hz), 4.73 (1H, d, J ) 1.8 Hz, H1), 4.70
(1H, d, J ) 12.6 Hz), 4.67 (1H, d, J ) 12.6 Hz), 4.61 (1H, d, J
) 10.8 Hz), 4.58 (2H, s), 3.85-3.76 (2H, m), 3.76 (1H, dd, J )
1.8, 2.8 Hz), 3.64 (1H, ddd, J ) 2.8, 7.4, 10.0 Hz), 3.31 (3H, s),
2.71 (1H, dd, J ) 2.8, 17.2 Hz), 2.52 (1H, dd, J ) 7.4, 17.2
Hz), 0.10 (9H, s); 13C NMR (50 MHz) δ ) 138.7, 138.7, 138.6,
128.6-127.8, 104.1, 99.1, 86.3, 80.5, 77.8, 75.6, 75.1, 73.0, 72.3,
70.6, 54.7, 23.3, 0.4; HR-MS (ES) calcd for C33H40O5SiNa (M
+ Na) 567.2543, found 567.2542.
Tetra-n-butylammonium fluoride (1.0 M in THF, 578 µL,
0.578 mmol) was added to a cooled solution (0 °C) of the above
alkyne (105 mg, 0.193 mmol) in THF (1.0 mL) followed by
stirring overnight. The reaction mixture was diluted with
ether, and the organic phase was washed with water and brine
and then dried (MgSO4) and evaporated to dryness in vacuo.
This afforded 81.6 mg (62%, 3 steps) of 35 as a slightly yellow
syrup, which was sufficiently pure both by TLC analysis and
1H NMR to be used without any further purification: 1H NMR
(200 MHz) δ ) 7.40-7.22 (15H, m), 5.00 (1H, d, J ) 11.0 Hz),
4.79 (1H, d, J ) 1.6 Hz), 4.75 (2H, s), 4.68 (1H, d, J ) 11.0
Hz), 4.63 (2H, s), 3.90 (2H, m), 3.82 (1H, dd, J ) 1.8, 2.2 Hz),
3.72 (1H, m), 3.36 (3H, s), 2.73 (1H, ddd, J ) 3.0, 3.0, 17.0
Hz), 2.57 (1H, ddd, J ) 2.6, 7.0, 17.0 Hz), 2.06 (1H, dd, J )
2.6, 3.0 Hz); 13C NMR (50 MHz) δ ) 138.6, 138.6, 138.5, 128.6-
127.8, 99.1, 81.1, 80.3, 77.6, 75.6, 74.8, 72.8, 72.2, 70.2, 70.1,
54.9, 22.0.
Meth yl 2,3,4-Tr i-O-ben zyl-6-d eoxy-6-C-vin yl-r-D-m a n -
n op yr a n osid e (36). A flask was charged with Lindlar’s
catalyst (5% palladium on CaCO3 poisoned with lead, 36 mg,
0.017 mmol). The flask was thereafter evacuated under
vacuum and filled with hydrogen three times. To this flask
was added a solution of alkyne 35 (81 mg, 0.171 mmol) and
quinoline (11 µL, 0.089 mmol) dissolved in EtOAc (1.0 mL).
After 5 min at 20 °C, the reaction was stopped by filtering off
the catalyst through a pad of Celite. Evaporation to dryness
in vacuo and column chromatography (EtOAc:pentane, 1:20)
gave 62 mg (76%, 78% corrected) of 36 as a colorless syrup
and 1.5 mg (2%) of recovered starting material: 1H NMR (200
MHz) δ ) 7.45-7.25 (15H, m), 5.97 (1H, dddd, J ) 6.4, 7.2,
10.0, 17.2 Hz), 5.17 (1H, dddd, J ) 1.8, 1.8, 1.8, 17.2 Hz), 5.11
(1H, dddd, J ) 1.8, 1.8, 1.8, 10.0 Hz), 4.98 (1H, d, J ) 10.8
Hz), 4.76 (2H, s), 4.72 (1H, d, J ) 1.8 Hz), 4.66 (1H, d, J )
10.8 Hz), 4.63 (2H, s), 3.89 (1H, dd, J ) 3.2, 9.0 Hz), 3.81 (1H,
dd, J ) 1.8, 3.2 Hz), 3.75 (1H, dd, J ) 8.8, 9.0 Hz), 3.63 (1H,
ddd, J ) 2.6, 8.0, 8.8 Hz), 3.30 (3H, s), 2.66 (1H, m), 2.38 (1H,
A catalytic amount of freshly prepared NaOMe in MeOH
was added to the protected C-disaccharide 32 dissolved in
MeOH (1.0 mL). After stirring overnight at 20 °C and
concentration to dryness in vacuo, the residue was redissolved
in MeOH (6 mL), and glacial acetic acid (1 mL), and 10% Pd/C
(30 mg) were added. The reaction was stirred overnight under
an atmosphere of hydrogen, filtered through a pad of Celite,
and then coevaporated three times with toluene. A single
product was detected by TLC analysis (Rf ) 0.28, MeOH:CH2-
Cl2, 1:1): 1H NMR (D2O, 500 MHz) δ 4.60 (1H, d, J ) 1.3 Hz),
4.02 (1H, ddd, J ) 1.9, 4.9, 8.8 Hz), 3.86 (1H, dd, J ) 1.9, 3.4
Hz), 3.85 (1H, dd, J ) 1.3, 2.1 Hz), 3.82 (1H, dd, J ) 2.0, 11.5
Hz), 3.79 (1H, dd, J ) 2.1, 11.5 Hz), 3.76 (1H, dd, J ) 3.4, 9.0
Hz), 3.68 (1H, dd, J ) 6.2, 11.5 Hz), 3.68 (1H, dd, J ) 5.6,
11.5 Hz), 3.59 (1H, dd, J ) 9.0, 9.4 Hz), 3.56 (1H, ddd, J )
2.1, 6.2, 9.4 Hz), 3.55 (1H, ddd, J ) 2.0, 5.6, 10.3 Hz), 3.43
(1H, dd, J ) 9.8, 10.3 Hz), 3.37 (3H, s), 2.00-1.77 (3H, m); 13
C
NMR (125 MHz) δ 100.3, 78.2, 73.8, 72.1, 71.3, 70.5, 69.3, 68.4,
67.7, 60.6 (2C), 39.2, 22.9.
The free 1,3-C-disaccharide 33 was dissolved in pyridine (4
mL) and Ac2O (2 mL) and left standing overnight. Coevapo-
ration three times with toluene and column chromatography
(EtOAc:pentane, 1:3) yielded 7 mg (54% for three steps) of 34
as a colorless thick syrup: 1H NMR (C6D6, 300 MHz) δ ) 5.58
(1H, dd, J ) 3.3, 5.4 Hz), 5.44 (1H, dd, J ) 10.4, 10.4 Hz),
5.31 (1H, dd, J ) 3.3, 7.2 Hz), 5.29 (1H, bs), 5.18 (1H, dd, J )
4.8, 5.4 Hz), 4.78 (1H, dd, J ) 7.8, 11.4 Hz), 4.72 (1H, s), 4.44
(1H, dd, J ) 5.1, 12.0 Hz), 4.22-4.12 (2H, m), 4.06 (1H, ddd,
J ) 2.5, 5.7, 7.8 Hz), 3.99 (1H, dd, J ) 3.5, 11.4 Hz), 3.89 (1H,
m), 2.97 (3H, s), 2.58 (1H, m), 1.86 (3H, s), 1.81 (3H, s), 1.72
(3H, s), 1.68 (3H, s), 1.63 (3H, s), 1.54 (3H, s), 1.50 (3H, s),
1.40-1.24 (2H, m); 13C NMR (50 MHz) δ 170.8, 170.6, 170.5,
170.1, 169.7, 97.3, 72.3, 72.0, 71.7, 70.3, 69.0, 68.4, 68.1, 67.4,
63.0, 61.5, 55.1, 36.5, 27.7, 21.2, 20.9, 20.7; MS (EI) m/z 648
(M).
J . Org. Chem, Vol. 67, No. 18, 2002 6305

Mikkelsen et al.
ddd, J ) 7.2, 8.0, 14.6 Hz); 13C NMR (50 MHz) δ ) 138.8, 138.8,
138.5, 135.3, 128.6-127.8, 117.1, 99.1, 80.6, 78.5, 75.4, 74.8,
72.9, 72.3, 71.5, 54.8, 36.1; HR-MS (ES) calcd for C30H34O5Na
(M + Na) 497.2304, found 497.2303.
) 6.8, 7.5 Hz), 3.81 (1H, dd, J ) 3.2, 9.2 Hz), 3.77 (1H, dd, J
) 3.2, 6.8 Hz, H3_), 3.76 (1H, dd, J ) 1.2, 3.2 Hz), 3.75-3.70
(3H, m), 3.63 (1H, dd, J ) 9.2, 9.2 Hz), 3.59 (1H, dd, J ) 3.2,
3.2 Hz), 3.47 (1H, ddd, J ) 1.6, 8.8, 9.2 Hz), 3.20 (3H, s), 1.95-
1.80 (2H, m), 1.71 (1H, m), 1.41 (1H, m); 13C NMR (50 MHz)
δ ) 138.8, 138.7, 138.6, 138.6, 138.6, 138.5, 138.5, 128.5-127.6,
99.0, 80.4, 79.0, 78.5, 76.0, 75.5, 75.2, 74.8, 74.5, 73.6, 73.5,
73.1, 72.9, 72.2, 72.2, 71.5, 71.3, 69.5, 54.8, 28.1, 25.7; HR-MS
Meth yl 2,3,4-Tr i-O-ben zyl-6-d eoxy-6-C-for m yl-r-D-m a n -
n op yr a n osid e (37). Ozonolysis was performed according to
the procedure outlined for the synthesis of compound 30, with
the following quantities: alkene 36 (58 mg, 0.12 mmol)
dissolved in dry CH2Cl2 (4 mL) and MeOH (1 mL), triph-
enylphosphine (74 mg, 0.28 mmol). Column chromatography
(EtOAc:pentane, 1:10) gave 30 (53 mg, 91%) as a colorless
syrup: 1H NMR (200 MHz) δ ) 9.74 (1H, dd, J ) 2.2, 2.2 Hz),
7.40-7.20 (15H, m), 4.96 (1H, d, J ) 11.0 Hz), 4.72 (1H, d, J
) 12.4 Hz), 4.70 (1H, d, J ) 12.4 Hz), 4.64 (1H, d, J ) 1.6 Hz),
4.61 (2H, s), 4.58 (1H, d, J ) 11.0 Hz), 4.12 (1H, ddd, J ) 4.0,
9.0, 9.2 Hz), 3.90 (1H, dd, J ) 3.0, 9.4 Hz), 3.80 (1H, dd, J )
1.6, 3.0 Hz), 3.72 (1H, dd, J ) 9.2, 9.4 Hz), 3.33 (3H, s), 2.79
(1H, ddd, J ) 2.2, 4.0, 16.4 Hz), 2.63 (1H, ddd, J ) 2.2, 9.0,
16.4 Hz); 13C NMR (50 MHz) δ ) 200.5, 138.5, 138.5, 138.3,
128.6-127.8, 99.3, 80.4, 76.6, 75.3, 74.7, 73.1, 72.2, 67.1, 55.2,
46.2; HR-MS (ES) calcd for C29H32O6Na (M + Na) 499.2097,
found 499.2099.
Met h yl 2,3,4-Tr i-O-b en zyl-6-d eoxy-6-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 (38).
Samarium diiodide (9.6 mL, 0.10 M in THF, 0.96 mmol) was
added to a solution of the pyridyl sulfone 25 (291 mg, 0.437
mmol) and aldehyde 37 (52 mg, 0.109 mmol) dissolved in THF
(1.0 mL) under argon. After stirring for 10 min, the reaction
mixture was quenched with aqueous saturated NH4Cl. CH2-
Cl2 was added, and the organic phase was filtered through a
Celite pad, dried (MgSO4), and concentrated to dryness in
vacuo. The residue was redissolved in MeCN (2.0 mL), and
thiocarbonyldiimidazole (291 mg, 1.64 mmol) was added. After
refluxing overnight, the reaction mixture was concentrated to
dryness in vacuo. Column chromatography (EtOAC:pentane,
1:8 to 1:4) gave 75 mg (62%, 2 steps) of 38 as a thick colorless
syrup. A 5:1 ratio of diastereomers at the newly created C-7-
stereocenter was obtained. For the major diastereomer: 1H
NMR (200 MHz) δ ) 8.34 (1H, s), 7.56 (1H, m), 7.40-7.10
(35H, m), 6.92 (1H, m), 6.13 (1H, ddd, J ) 3.0, 5.2, 8.6 Hz),
4.88 (1H, d, J ) 11.2 Hz), 4.71 (1H, d, J ) 12.4 Hz), 4.69 (1H,
d, J ) 12.4 Hz), 4.67 (1H, d, J ) 12.4 Hz), 4.61 (1H, d, J )
12.4 Hz), 4.59 (1H, d, J ) 11.2 Hz), 4.59 (1H, d, J ) 1.4 Hz),
4.51 (2H, s), 4.49 (2H, s), 4.48 (1H, d, J ) 12.0 Hz), 4.40 (1H,
d, J ) 9.4 Hz), 4.39 (1H, d, J ) 12.0 Hz), 4.36 (1H, d, J ) 9.4
Hz), 4.29 (1H, dd, J ) 2.0, 7.6 Hz), 4.13 (1H, dd, J ) 5.8, 9.2
Hz), 3.91-3.58 (9H, m), 3.09 (3H, s), 2.49 (1H, ddd, J ) 2.2,
8.6, 11.8 Hz), 2.10 (1H, ddd, J ) 5.2, 8.8, 11.8 Hz); 13C NMR
(50 MHz) δ ) 138.5, 138.9, 138.6, 138.5, 138.5, 138.2 138.2,
137.8, 137.5, 130.7, 128.6-127.6, 118.1, 99.5, 80.0, 80.0, 78.8,
75.1, 75.0, 74.8, 74.8, 74.8, 74.3, 73.4, 73.0, 72.9, 72.3, 72.3,
71.1, 69.9, 68.9, 68.8, 55.7, 31.2; HR-MS (ES) calcd for
(ES) calcd for
1007.4724.
C63H68O10Na (M + Na) 1007.4710, found
Meth yl 6-Deoxy-6-C-(1′-(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 (40). A mixture of the
perbenzylated 1,6-C-disaccharide 39 (47 mg, 0.048 mmol) and
10% Pd/C (67 mg) in MeOH (6.0 mL) and glacial acetic acid
(1.0 mL) was stirred under an atmosphere of hydrogen
overnight. The reaction mixture was filtered through Celite
and coevaporated three times with toluene. TLC analysis
1
revealed a single product (Rf ) 0.48, MeOH:CH2Cl2, 1:1): H
NMR (D2O, 500 MHz) δ ) 4.61 (1H, bs), 4.03 (1H, bdd, J )
4.3, 9.0 Hz), 3.89-3.85 (2H, m), 3.85 (1H, dd, J ) 1.7, 9.8 Hz),
3.82 (1H, bd, J ) 12.6 Hz), 3.76 (1H, dd, J ) 2.8, 8.7 Hz), 3.66
(1H, bd, J ) 12.6 Hz), 3.56 (1H, dd, J ) 8.7, 9.7 Hz), 3.56-
3.54 (2H, m), 3.40 (1H, dd, J ) 9.8, 9.9 Hz), 3.37 (3H, s), 2.05-
1.77 (4H, m); 13C NMR (125 MHz) δ 100.2, 78.1, 73.9, 72.2,
71.9, 70.8, 70.2, 70.1, 69.9, 67.9, 60.9, 27.2, 23.7; HR-MS (ES)
calcd for C14H26O10Na (M + Na) 377.1424, found 377.1435.
Methyl2,3,4-Tri-O-acetyl-6-deoxy-6-C-(1′-(1′-deoxy-2′,3′,4′,-
6′-t et r a -O-a cet yl-r-D-m a n n op yr a n osyl)m et h ylen e)-r-D-
m a n n op yr a n osid e (41). The free 1,6-C-disaccharide 40 was
dissolved in pyridine (4.0 mL) and Ac2O (2.0 mL), and left
standing overnight. Coevaporation three times with toluene
and column chromatography (EtOAc:pentane, 1:3) yielded 19
mg (63%, two steps) of 41 as a colorless thick syrup: 1H NMR
(400 MHz) δ ) 5.29 (1H, dd, J ) 3.6, 9.6 Hz), 5.27-5.23 (2H,
m), 5.20 (1H, dd, J ) 8.4, 8.4 Hz), 5.16 (1H, dd, J ) 2.8, 3.2
Hz), 5.10 (1H, dd, J ) 9.6, 10.0 Hz), 4.65 (1H, d, J ) 1.6 Hz),
4.37 (1H, dd, J ) 6.4, 12.0 Hz), 4.08 (1H, dd, J ) 2.8, 12.0
Hz), 3.96 (1H, ddd, J ) 3.2, 3.2, 10.8 Hz), 3.88 (1H, ddd, J )
2.8, 6.4, 8.4 Hz), 3.76 (1H, ddd, J ) 2.6, 7.6, 9.6 Hz), 3.39 (3H,
s), 2.16 (3H, s), 2.13 (3H, s), 2.12 (3H, s), 2.07 (3H, s), 2.05
(3H, s), 2.05 (1H, m), 2.03 (3H, s), 1.99 (3H, s), 1.68-1.57 (3H,
m); 13C NMR (50 MHz) δ 170.9, 170.5, 170.3, 170.2, 170.2,
170.1, 169.9, 98.6, 74.7, 71.0, 70.4, 69.8, 69.4, 69.3, 69.2, 69.0,
67.1, 62.5, 55.3, 27.0, 23.9, 21.2 (2C), 21.0 (3C), 20.9 (2C); HR-
MS (ES) calcd for C28H40O17Na (M + Na) 671.2163, found
671.2158.
Meth yl 2,4-Di-O-ben zyl-3-deoxy-3-C-vin yl-r-D-m an n opy-
r a n osid e (42). Concentrated aqueous hydrochloric acid (0.2
mL) was added to a solution of 23 (50.0 mg, 0.142 mmol) in
MeOH (3.5 mL) and heated to reflux for 2 days. Another
portion of concentrated HCl (0.2 mL) was added and the
mixture was refluxed for a further 2 days. The reaction
mixture was neutralized by the addition of saturated aqueous
NaHCO3 (3 mL). After extracting with CH2Cl2, the combined
organic phases were dried (MgSO4) and concentrated to
dryness in vacuo. Column chromatography (EtOAc:pentane,
1:10 to 1:4) gave first 12 mg (23%) of recovered starting
material 23 and then 24 mg (43%, corrected yield: 56%) of 42
as a colorless syrup: 1H NMR (200 MHz) δ ) 7.45-7.25 (10H,
m), 6.09 (1H, ddd, J ) 9.2, 10.2, 17.2 Hz), 5.31 (1H, ddd, J )
0.6, 1.2, 17.2 Hz), 5.20 (1H, dd, J ) 1.2, 10.2 Hz), 4.68 (1H, d,
J ) 1.6 Hz), 4.63 (2H, s), 4.60 (1H, d, J ) 10.6 Hz), 4.49 (1H,
d, J ) 10.6 Hz), 3.90-3.75 (2H, m), 3.85 (1H, dd, J ) 6.8, 9.6
Hz), 3.67 (1H, ddd, J ) 3.4, 6.0, 6.8 Hz), 3.53 (1H, dd, J ) 1.6,
2.8 Hz), 3.38 (3H, s), 2.78 (1H, ddd, J ) 2.8, 9.2, 9.6 Hz), 2.03
(1H, bs); 13C NMR (50 MHz) δ ) 138.3, 138.3, 136.8, 128.5-
127.8, 118.5, 97.5, 79.8, 74.3, 73.6, 73.2, 72.1, 62.8, 54.9, 47.4;
HR-MS (ES) calcd for C23H28O5Na (M + Na) 407.1834, found
407.1839.
C
67H70N2O11SNa (M + Na) 1133.4598, found 1133.4612.
Met h yl 2,3,4-Tr i-O-b en zyl-6-d eoxy-6-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 (39). To a solution of 38 (73 mg, 0.066
mmol) in toluene (4.0 mL) were added pentafluorophenol (24
mg, 0.131 mmol), triphenyltin hydride (44 µL, 0.171 mmol),
and a catalytic amount of AIBN (5 mg, 0.030 mmol). This
mixture was refluxed for 3 h, and then the solvent was
removed by evaporation in vacuo. The residue was redissolved
in acetonitrile and washed two times with pentane. After
concentration to dryness in vacuo, column chromatography
(EtOAc:pentane, 1:7) afforded 47 mg (73%) of 39 as a colorless
syrup: 1H NMR (400 MHz, CDCl3) δ ) 7.37-7.20 (35H, m),
4.91 (1H, d, J ) 10.8 Hz), 4.76 (1H, d, J ) 10.8 Hz), 4.73 (1H,
d, J ) 12.4 Hz), 4.70 (1H, d, J ) 12.4 Hz), 4.65 (1H, d, J )
12.4 Hz), 4.63 (1H, d, J ) 1.2 Hz), 4.61 (1H, d, J ) 12.0 Hz),
4.59 (1H, d, J ) 12.4 Hz), 4.59 (2H, s), 4.58 (1H, d, J ) 11.2
Hz), 4.53 (2H, s), 4.51 (1H, d, J ) 11.2 Hz), 4.50 (1H, d, J )
12.0 Hz), 4.05 (1H, ddd, J ) 3.2, 3.6, 7.6 Hz), 3.96 (1H, dd, J
Met h yl 2,4-Di-O-b en zyl-3,6-d id eoxy-6-C-et h yn yl-3-C-
vin yl-r-D-m a n n op yr a n osid e (43). The triflation and ethy-
nylation sequence was performed according to the procedure
6306 J . Org. Chem., Vol. 67, No. 18, 2002

Convergent Synthesis of C-Linked Di- and Trisaccharides
outlined for the synthesis of compound 35, with the following
quantities (a) for the triflation step: alcohol 42 (69.5 mg, 0.181
mmol) in CH2CH2 (2.0 mL), 2,6-lutidine (182 µL, 1.56 mmol),
and trifluoromethanesulfonic anhydride (315 µL, 1.87 mmol).
Column chromatography on a short column (EtOAc:pentane,
1:25) gave 62 mg (66%) of methyl 2,4-di-O-benzyl-3-deoxy-6-
O-triflouromethanesulfonyl-3-C-vinyl-R-D-mannopyranoside as
a colorless oil. The following quantities were used (b) for the
ethynylation step: trimethylsilylacetylene (220 µL, 1.56 mmol)
in THF (1.0 mL), nBuLi (1.02 mL, 1.6 M in hexanes, 1.64
mmol), and HMPA (54 µL, 0.31 mmol). Column chromatogra-
phy (EtOAc:pentane, 1:40 to 1:15) afforded 40.3 mg of methyl
2,4-di-O-benzyl-3,6-dideoxy-6-C-trimethylsilylethynyl-3-C-vinyl-
R-D-mannopyranoside as a colorless syrup along with also 4.1
mg of the desilylated product 43. This gave a total yield of
53% for the two steps. Characterization of the 6-C-trimethyl-
silylethynyl compound: 1H NMR (200 MHz) δ ) 7.39-7.29
(10H, m), 6.10 (1H, ddd, J ) 9.2, 10.0, 17.2 Hz), 5.29 (1H, ddd,
J ) 0.6, 2.0, 17.2 Hz), 5.18 (1H, dd, J ) 2.0, 10.0 Hz), 4.73
(1H, d, J ) 1.2 Hz), 4.66 (1H, d, J ) 11.6 Hz), 4.64 (1H, d, J
) 10.4 Hz), 4.49 (1H, d, J ) 11.6 Hz), 4.46 (1H, d, J ) 10.4
Hz), 3.79-3.60 (2H, m), 3.51 (1H, dd, J ) 1.2, 3.2 Hz), 3.41
(3H, s), 2.76 (1H, ddd, J ) 0.6, 3.2, 9.2 Hz), 2.74 (1H, dd, J )
tography (EtOAc:pentane, 1:5) gave the dialdehyde 2 (96 mg,
96%) as a colorless syrup: 1H NMR (200 MHz) δ ) 9.80 (1H,
dd, J ) 1.6, 2.6 Hz), 9.63 (1H, d, J ) 1.2 Hz), 7.37-7.25 (10H,
m), 4.83 (1H, d, J ) 10.8 Hz), 4.68 (1H, d, J ) 1.4 Hz), 4.63
(1H, d, J ) 11.8 Hz), 4.55 (1H, d, J ) 10.8 Hz), 4.44 (1H, d, J
) 11.8 Hz), 4.18 (1H, ddd, J ) 3.8, 8.6, 9.4 Hz), 4.00 (1H, dd,
J ) 1.4, 3.0 Hz), 3.99 (1H, dd, J ) 9.4, 9.4 Hz), 3.41 (3H, s),
2.98 (1H, ddd, J ) 1.2, 3.0, 9.4 Hz), 2.83 (1H, ddd, J ) 1.6,
3.8, 16.4 Hz), 2.69 (1H, ddd, J ) 2.6, 8.6, 16.4 Hz); 13C NMR
(50 MHz) δ ) 200.7, 200.3, 137.7, 137.3, 128.7-128.1, 96.5,
74.8, 74.8, 73.5, 72.6, 66.7, 55.3, 54.8, 46.0; MS (ES) m/z 453.0
(M + MeOH + Na), 485.0 (M + 2MeOH + Na).
Meth yl 2,4-Di-O-ben zyl-3,6-d id eoxy-3,6-C-d i-(1′/1′′-(2′/
2′′,3′/3′′,4′/4′′,6′/6′′-tetr a-O-ben zyl-1′/1′′-deoxy-r-D-m an n opy-
r a n osyl)m eth ylen e)-r-D-m a n n op yr a n osid e (46). The di-
aldehyde 2 (21 mg, 0.053 mmol) and the pyridyl sulfone 25
(164 mg, 0.246 mmol) were coevaporated with benzene in an
oven-dried flask and dried on the vacuum line for approxi-
mately 15 min. Samarium diiodide (5.4 mL, 0.10 M in THF,
0.542 mmol) was added directly to this mixture under argon.
After stirring for 15 min, the reaction mixture was quenched
with aqueous saturated NH4Cl. CH2Cl2 was added, and the
organic phase was filtered through a Celite pad, dried (MgSO4),
and concentrated to dryness in vacuo. Column chromatography
on a short column afforded 71 mg of a thick colorless syrup,
which contained the coupling product as determed by MS
(ES): m/z 1469.0 (M + Na).
2.8, 17.0 Hz), 2.54 (1H, dd, J ) 7.2, 17.0 Hz), 0.13 (9H, s); 13
C
NMR (50 MHz) δ ) 138.1, 138.0, 136.5, 128.2-127.5, 118.1,
103.9, 96.9, 86.0, 79.6, 76.2, 74.0, 72.7, 70.3, 54.3, 47.6, 23.2,
0.0; HR-MS (ES) calcd for C28H36O4SiNa (M + Na) 487.2281,
found 487.2274. The following quantities were used (c) for the
desilylation step: THF (0.5 mL) and tetra-n-butylammonium
fluoride (259 µL, 1.0 M in THF, 0.259 mmol). This yielded 33.4
mg (100%) of the alkyne 43 as a pale yellow syrup, which
according to TLC and 1H NMR was sufficiently pure for the
next step: 1H NMR (200 MHz) δ ) 7.40-7.25 (10H, m), 6.10
(1H, ddd, J ) 9.2, 10.0, 17.2 Hz), 5.28 (1H, ddd, J ) 0.6, 2.0,
17.2 Hz), 5.17 (1H, dd, J ) 2.0, 10.0 Hz), 4.72 (1H, d, J ) 1.4
Hz), 4.66 (1H, d, J ) 11.8 Hz), 4.65 (1H, d, J ) 10.4 Hz), 4.50
(1H, d, J ) 11.8 Hz), 4.46 (1H, d, J ) 10.4 Hz), 3.79-3.62
(2H, m), 3.51 (1H, dd, J ) 1.4, 3.0 Hz), 3.40 (3H, s), 2.80-2.69
(1H, m), 2.70 (1H, ddd, J ) 2.6, 2.6, 17.0 Hz), 2.54 (1H, ddd,
J ) 2.6, 6.6, 17.0 Hz), 2.05 (1H, dd, J ) 2.6, 2.6 Hz); 13C NMR
(50 MHz) δ ) 138.4, 138.3, 136.7, 128.5-127.8, 118.5, 97.4,
81.3, 79.8, 76.4, 74.3, 72.9, 70.2, 70.1, 54.8, 47.7, 22.1; HR-MS
(ES) calcd for C25H28O4Na (M + Na) 415.1885, found 415.1883.
Meth yl 2,4-Di-O-ben zyl-3,6-d id eoxy-3,6-d i-C-vin yl-r-D-
m a n n op yr a n osid e (44). The hydrogenation step was per-
formed according to the procedure outlined for the synthesis
of compound 36, with the following quantities: alkyne 43 (38
mg, 0.171 mmol) in EtOAc (0.5 mL), quinoline (6 µL, 0.050
mmol), and Lindlar’s catalyst (5% palladium on CaCO3 poi-
soned with lead, 20 mg, 9.6 µmol). Column chromatography
(EtOAc:pentane, 1:25) gave 28 mg (74%, 77% corrected) of 44
as a colorless syrup and 1.4 mg of recovered starting mate-
rial: 1H NMR (200 MHz) δ ) 7.37-7.25 (10H, m), 6.09 (1H,
ddd, J ) 9.4, 10.0, 17.2 Hz), 5.95 (1H, dddd, J ) 6.4, 7.2, 10.2,
17.2 Hz), 5.26 (1H, ddd, J ) 0.6, 2.0, 17.2 Hz), 5.16 (1H, dd, J
) 2.0, 10.0 Hz), 5.14 (1H, dddd, J ) 0.8, 0.8, 0.8, 17.2 Hz),
5.08 (1H, dddd, J ) 0.8, 0.8, 0.8, 10.2 Hz), 4.65 (1H, d, J )
11.8 Hz), 4.64 (1H, d, J ) 1.6 Hz), 4.61 (1H, d, J ) 10.6 Hz),
4.50 (1H, d, J ) 11.8 Hz), 4.44 (1H, d, J ) 10.6 Hz), 3.65 (1H,
ddd, J ) 3.0, 8.4, 9.4 Hz), 3.51 (1H, dd, J ) 9.4, 9.4 Hz), 3.49
(1H, dd, J ) 1.6, 3.0 Hz), 3.33 (3H, s), 2.73 (1H, ddd, J ) 3.0,
9.4, 9.4 Hz), 2.63 (1H, ddddd, J ) 0.8, 0.8, 3.0, 6.4, 15.4 Hz),
2.32 (1H, ddddd, J ) 0.8, 7.2, 8.4, 15.4 Hz); 13C NMR (50 MHz)
δ ) 138.1, 138.1, 136.7, 135.7, 128.2-127.6, 118.0, 116.7, 97.0,
79.6, 77.0, 72.7, 71.2, 54.4, 47.5, 36.1; HR-MS (ES) calcd for
The crude product was dissolved in MeCN (1.0 mL), and
thiocarbonyldiimidazole (219 mg, 1.23 mmol) was added. After
refluxing overnight, the solvent was slowly evaporated off by
continued heating. The residue obtained was subjected to
column chromatography (EtOAc:pentane, 1:3 to 1:1), yielding
52 mg (63% for two steps) of the dithionocarbamate 45 as a
thick colorless syrup. MS (ES) m/z 1667.7 (M + H), 1689.8 (M
+ Na), 1705.8 (M + K).
To a solution of 45 (140 mg, 0.084 mmol) in toluene (4.0
mL) were added pentafluorophenol (62 mg, 0.34 mmol),
triphenyltin hydride (111 mg, 0.44 mmol), and a catalytic
amount of AIBN (3 mg). This mixture was refluxed for 2.5 h,
and then the solvent was removed by evaporation in vacuo.
The residue was redissolved in acetonitrile and washed two
times with pentane. After concentration to dryness in vacuo,
column chromatography (acetone:CH2Cl2, 1:100 to 1:40) af-
forded 64 mg (53%) of the trisaccharide 46 as a colorless
syrup: 1H NMR (400 MHz, CDCl3) δ ) 7.36-7.15 (50H, m),
4.76 (1H, d, J ) 11.2 Hz), 4.71 (1H, d, J ) 11.6 Hz), 4.64 (1H,
d, J ) 12.4 Hz), 4.59 (1H, bs), 4.55 (1H, d, J ) 12.4 Hz), 4.55
(2H, s), 4.54 (1H, d, J ) 11.6 Hz), 4.52 (1H, d, J ) 11.2 Hz),
4.51 (2H, s), 4.50 (1H, d, J ) 10.8 Hz), 4.49 (2H, s), 4.48 (1H,
d, J ) 10.8 Hz), 4.48 (2H, s), 4.45 (1H, d, J ) 10.8 Hz), 4.44
(1H, d, J ) 11.6 Hz), 4.43 (1H, d, J ) 10.8 Hz), 4.41 (1H, d, J
) 11.6 Hz), 4.10 (1H, ddd, J ) 4.0, 4.4, 8.4), 4.05 (1H, ddd, J
) 4.0, 4.0, 9.2), 3.96 (1H, dd, J ) 7.2, 7.6), 3.84-3.66 (10H,
m), 3.64 (1H, bs), 3.59 (1H, dd, J ) 3.2, 3.2), 3.53-3.47 (2H,
m), 3.24 (3H, s), 2.11-2.04 (1H, m), 2.00-1.89 (1H, m), 1.85-
1.62 (4H, m), 1.44-1.34 (1H, m); 13C NMR (50 MHz, CDCl3) δ
) 138.6, 138.6, 138.5, 138.5, 138.4, 138.4, 138.4, 138.4, 138.4,
138.3, 128.6-127.7, 97.0, 79.6, 79.6, 78.4, 77.6, 77.5, 76.4, 76.2,
75.2, 75.2, 74.6, 74.1, 73.6, 73.6, 73.5, 73.5, 73.2, 73.0, 72.3,
72.3, 72.3, 72.0, 71.7, 71.7, 69.7, 69.4, 54.9, 28.6, 26.9, 25.6,
25.6; HR-MS (ES) calcd for C91H98O14Na (M + Na) 1437.6854,
found 1437.6859.
Meth yl 3,6-Did eoxy-3,6-C-d i-(1′/1′′-d eoxy-r-D-m a n n op y-
r a n osyl)m eth ylen e)-r-D-m a n n op yr a n osid e (1). A mixture
of the perbenzylated C-trisaccharide 46 (63 mg, 0.045 mmol)
and 10% Pd/C (47 mg) in MeOH (6.0 mL) and glacial acetic
acid (1.0 mL) was stirred under an atmosphere of hydrogen
overnight. The reaction mixture was filtered through Celite
and coevaporated three times with toluene. TLC analysis
C
25H30O4Na (M + Na) 417.2042, found 417.2041.
Meth yl 2,4-Di-O-ben zyl-3,6-d id eoxy-3,6-d i-C-for m yl-r-
D-m a n n op yr a n osid e (2). Ozonolysis was performed accord-
ing to the procedure outlined for the synthesis of compound
30, with the following quantities: dialkene 44 (98.1 mg, 0.249
mmol) dissolved in dry CH2Cl2 (4 mL) and MeOH (1 mL), and
triphenylphosphine (150 mg, 0.572 mmol). Column chroma-
1
revealed a single product (Rf ) 0.30, MeOH:CH2Cl2, 1:1): H
NMR (D2O, 800 MHz) δ ) 4.60 (1H, d, J ) 1.2 Hz), 4.06 (1H,
ddd, J ) 1.7, 4.6, 9.2 Hz), 3.94 (1H, ddd, J ) 1.9, 3.6, 10.8
J . Org. Chem, Vol. 67, No. 18, 2002 6307

Mikkelsen et al.
Hz), 3.91-3.90 (2H, m), 3.90 (1H, dd, J ) 1.9, 3.4 Hz), 3.86
(1H, dd, J ) 2.3, 12.1 Hz), 3.84 (1H, dd, J ) 2.4, 12.2 Hz),
3.84 (1H, dd, J ) 3.4, 9.5 Hz), 3.80 (1H, dd, J ) 3.3, 8.7 Hz),
3.71 (1H, dd, J ) 6.3, 12.2 Hz), 3.70 (1H, dd, J ) 6.0, 12.1
Hz), 3.63 (1H, dd, J ) 9.5, 9.5 Hz), 3.62 (1H, dd, J ) 8.7, 9.6
Hz), 3.60 (1H, ddd, J ) 2.3, 6.0, 9.6 Hz), 3.55 (1H, ddd, J )
2.6, 9.4, 10.1 Hz), 3.54 (1H, ddd, J ) 2.4, 6.3, 9.5 Hz), 3.40
(3H, s), 3.32 (1H, dd, J ) 9.7, 10.1 Hz), 2.02 (1H, ddd, J )
10.3, 10.5, 10.8 Hz), 1.93 (1H, ddd, J ) 9.2, 9.2, 15.7 Hz), 1.89-
1.82 (3H, m), 1.62-1.55 (2H, m); 13C NMR (125 MHz) δ 99.8,
77.8, 77.7, 73.1, 73.0, 72.2, 71.1, 71.0, 70.1, 70.0, 69.1, 68.2,
67.2, 67.1, 60.5, 60.4, 39.0, 26.9, 24.1, 22.5; HR-MS (ES) calcd
for C21H38O14Na (M + Na) 537.2159, found 537.2172.
Met h yl 2,4-Di-O-a cet yl-3,6-d id eoxy-3,6-C-d i-(1′/1′′-(2′/
2′′,3′/3′′,4′/4′′,6′/6′′-tetr a -O-a cetyl-1′/1′′-d eoxy-r-D-m a n n op y-
r a n osyl)m eth ylen e)-r-D-m a n n op yr a n osid e (47). The free
C-trisaccharide 1 was dissolved in pyridine (4 mL) and Ac2O
(2 mL) and left standing overnight. Coevaporation three times
with toluene and column chromatography (EtOAc:pentane, 1:2
to 1:1) yielded 47 as a colorless thick syrup: 1H NMR (400
MHz) δ ) 5.25 (1H, dd, J ) 3.2, 8.4 Hz), 5.21 (1H, dd, J ) 8.4,
8.4 Hz), 5.18 (1H, dd, J ) 3.6, 7.6 Hz), 5.15 (1H, dd, J ) 3.2,
3.2 Hz), 5.07 (1H, dd, J ) 6.0, 7.6 Hz), 4.99-4.94 (2H, m), 4.87
(1H, dd, J ) 10.0, 10.8 Hz), 4.59 (1H, bs), 4.45 (1H, dd, J )
7.6, 12.0 Hz), 4.36 (1H, dd, J ) 6.4, 12.0 Hz), 4.07 (1H, d, J )
12.0 Hz), 4.07 (1H, d, J ) 12.0 Hz), 3.97-3.91 (2H, m), 3.89-
3.82 (2H, m), 3.68-3.62 (1H, m), 3.36 (3H, s), 2.32 (1H, m),
2.15 (3H, s), 2.12 (3H, s), 2.11 (3H, s), 2.11 (3H, s), 2.11-2.08
(1H, m), 2.10 (3H, s), 2.08 (3H, s), 2.08 (3H, s), 2.06 (3H, s),
2.05 (3H, s), 2.02 (3H, s), 1.70-1.46 (5H, m); 1H NMR (400
MHz, benzene-d6) δ ) 5.53 (1H, dd, J ) 3.0, 6.0 Hz), 5.48 (1H,
dd, J ) 3.6, 8.8 Hz), 5.45 (1H, dd, J ) 7.6, 8.8 Hz), 5.38 (1H,
dd, J ) 3.2, 3.6 Hz), 5.28 (1H, dd, J ) 3.0, 6.4 Hz), 5.25 (1H,
dd, J ) 1.6, 2.4 Hz), 5.23 (1H, dd, J ) 9.2, 10.4 Hz), 5.17 (1H,
dd, J ) 4.8, 6.0 Hz), 4.72 (1H, dd, J ) 7.2, 11.6 Hz), 4.64 (1H,
d, J ) 1.6 Hz), 4.48 (1H, dd, J ) 7.2, 12.0 Hz), 4.16 (1H, ddd,
J ) 4.8, 6.4, 7.6 Hz), 4.04 (1H, dd, J ) 2.8, 12.0 Hz), 4.00 (2H,
m), 3.95 (1H, ddd, J ) 3.2, 3.6, 10.4 Hz), 3.89 (1H, ddd, J )
2.8, 7.2, 7.6 Hz), 3.69 (1H, ddd, J ) 2.8, 9.2, 9.2 Hz), 2.96 (3H,
s), 2.54 (1H, m), 2.06 (1H, m), 1.88 (3H, s), 1.84 (3H, s), 1.81
(3H, s), 1.81 (2H, m), 1.67 (3H, s), 1.65 (3H, s), 1.65 (3H, s),
1.61 (3H, s), 1.58 (3H, s), 1.57 (3H, s), 1.57 (1H, m), 1.49 (3H,
s), 1.30 (2H, m); HR-MS (ES) calcd for C41H58O24Na (M + Na)
957.3215, found 957.3216.
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: Experimental de-
tails for the synthesis of methyl 2,3,4-tri-O-benzyl-R-D-man-
nopyranoside; 1H NMR spectra for compounds 1, 2, 17, 21,
23, 29-34, TMS-35, 36-47; and 13C NMR spectra for
compounds 2, 17, 21, 23, 29, 30, 32, 34, TMS-35, 36-39, 41-
46. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O020339Z
6308 J . Org. Chem., Vol. 67, No. 18, 2002