An olefin metathesis route for the preparation of (1 → 6)-linked C-disaccharide glycals. A convergent and flexible approach to C-saccharide synthesis

Article abstract of DOI:10.1021/jo0005159

A convergent route to a variety of C-1-disaccharide glycals based on the olefin metathesis reaction of enol ethers and alkenes is described. The DCC-mediated coupling reaction of a variety of pentose enitols (1a-c) with a number of C-5- and C-6-monosaccharide carboxylic acids (2a-e) gave the corresponding esters 3a-1 in good yield. Methylenation of these compounds was followed by ring-closing metathesis, mediated by the Schrock molybdenum catalyst 8 in warm toluene, to provide the target C-disaccharide glycals 5a-1. The formed enol ether double bond in 5a was then transformed, via standard manipulations, into a variety of C-disaccharide derivatives 21-25.

Full text of DOI:10.1021/jo0005159

J . Org. Chem. 2000, 65, 6061-6068
6061
An Olefin Meta th esis Rou te for th e P r ep a r a tion of (1f6)-Lin k ed
C-Disa cch a r id e Glyca ls. A Con ver gen t a n d F lexible Ap p r oa ch to
C-Sa cch a r id e Syn th esis
Maarten H. D. Postema,* Daniel Calimente, Lei Liu, and Tonja L. Behrmann
Department of Chemistry, Wayne State University, Detroit, Michigan 48202
mpostema@chem.wayne.edu
Received April 5, 2000
A convergent route to a variety of C-1-disaccharide glycals based on the olefin metathesis reaction
of enol ethers and alkenes is described. The DCC-mediated coupling reaction of a variety of pentose
enitols (1a -c) with a number of C-5- and C-6-monosaccharide carboxylic acids (2a -e) gave the
corresponding esters 3a -l in good yield. Methylenation of these compounds was followed by ring-
closing metathesis, mediated by the Schrock molybdenum catalyst 8 in warm toluene, to provide
the target C-disaccharide glycals 5a -l. The formed enol ether double bond in 5a was then
transformed, via standard manipulations, into a variety of C-disaccharide derivatives 21-25.
It has been well established that cell surface carbohy-
drates are involved in key molecular recognition events
with protein receptors. These interactions are important
for normal cell functions, such as recognition and binding,
but they can also be harmful since they are a launch point
for bacterial and viral infections as well as cell adhesion
in inflammation and tumor metastasis1 One strategy to
prevent these events from occurring is to prepare small
carbohydrate-based therapeutics which will inhibit the
recognition event by preferentially binding to the protein
receptor. The disadvantage of using carbohydrates for
these purposes is that they are easily hydrolyzed by a
large number of extra- and intracellular glycosidases. It
is here that C-saccharides show their strength; with their
stability at low pH and resistance to enzymatic cleavage,
they make ideal sugar mimics.
was the replacement of the interglycosidic oxygen atom
with a methylene group. From these works,8-10 it was
shown that, although substitution of the interglycosidic
oxygen atom with a methylene group may change the
conformation during binding, the change does not inter-
fere with the binding of the C-glycoside substrate to the
active site. Although there has been much synthetic work
in the area of C-glycosides, relatively little has appeared
in regard to biological evaluation of C-saccharides and
C-saccharide glycals. C-Glycosides are extremely stable
entities which will not be fragmented by biological or
chemical hydrolysis.12,13 If carbohydrates are to be used
as potential drug candidates, then stable compounds,
such as C-saccharides, are an excellent starting point.
There have been interesting and novel approaches to
C-saccharide synthesis over the past decade, and many
of these have been reviewed.14 Recently, Armstrong
employed an approach to the preparation of C-trisaccha-
rides that relied on nonstereoselective methods in con-
junction with de novo ring synthesis to gain access to a
number of stereochemically diverse C-trisaccharides.15,16
Inhibitors of glycosidase have been shown to exhibit
both antiviral2 and antitumor3,4 activity in a variety of
models. Inhibitors of R-glucosidase also have potential
for therapeutic use in the treatment of diabetes.5
The importance of sugar-based enzyme inhibitors
cannot be understated. The main problem with carbo-
hydrate-based therapeutics, however, is their instability
to enzymatic cleavage and chemical hydrolysis. One way
to increase the stability of the anomeric linkage is to
replace the interglycosidic oxygen atom with a methylene
group to furnish a C-saccharide. There has been some
debate over the validity of this substitution since the
conformation and, hence, the binding affinity of the
C-saccharide mimic may not be the same as that of the
parent O-saccharide.6-11 In these above cases, the only
change from the natural substrate to the C-saccharides
(8) Espinosa, J . F.; Asensio, J . L.; Can˜ada, F. J .; Martin-Pastor, M.;
Dietrich, H.; Mart´ın-Lomas, M.; Schmidt, R. R.; J ime´nez-Barbero, J .
J . Am. Chem. Soc. 1996, 118, 10862.
(9) 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.
(10) Espinosa, J . F.; Montero, E.; Vian, A.; Garcia, J . L.; Dietrich,
H.; Schmidt, R. R.; Mart´ın-Lomas, M.; Imberty, A.; Can˜ada, F. J .;
J ime´nez-Barbero, J . J . Am. Chem. Soc. 1998, 120, 1309.
(11) Wang, J .; Kova´c, P.; Sinay¨, P.; Glaudemans, C. P. J . Carbohydr.
Res. 1998, 308, 191.
(12) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides, 1st ed.;
Elsevier Science: Oxford, 1995; Vol. 13, p 4.
(13) Postema, M. H. D. C-Glycoside Synthesis, 1st ed.; CRC Press:
Boca Raton, FL, 1995; p 346.
(1) Varki, A. Glycobiology 1993, 3, 97.
(14) For reviews on C-glycoside synthesis, see: (a) Du, Y.; Lindhart,
R. J . Tetrahedron 1998, 54, 9913-9959. (b) Beau, J .-M.; Gallagher, T.
Top. Curr. Chem. 1997, 187, 1-54. (c) Nicotra, F. Top. Curr. Chem.
1997, 187, 55-83. (d) Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett
1998, 700-717. (e) Postema, M. H. D. C-Glycoside Synthesis, 1st ed.;
CRC Press: Boca Raton, FL, 1995. (f) Levy, D. E.; Tang, C. The
Chemistry of C-Glycosides, 1st ed.; Elsevier Science: Oxford, 1995; Vol.
13.
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M.; Rosen, C.; Rohrschneider, L.; Haseltine, W. A.; Sodroski, J . Proc.
Natl. Acad. Sci. U.S.A. 1987, 84, 8120.
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Passasiti, A. Cancer Res. 1995, 55, 2920.
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10.1021/jo0005159 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/24/2000

6062 J . Org. Chem., Vol. 65, No. 19, 2000
Postema et al.
Sch em e 1
Schmidt employed C-1-lithiated glycals that were then
coupled to the appropriate sugar aldehydes.17 Recent
work by Sinay¨ relied on the use of tethered 8- and 9-endo
tin hydride mediated radical closures to prepare C-
disaccharides.18 Skrydstrup and Beau have used orga-
nosamarium chemistry to construct R-manno-C-disac-
charides,19 while a very recent approach for C-disaccharide
preparation relied on the novel use of the Ramberg-
Ba¨cklund reaction.20
We have previously shown that olefin metathesis can
be used to prepare alkyl and aryl C-glycosides21 as well
as (1f6)-linked C-disaccharides.22 In this full paper, we
describe the details of our metathesis-based approach for
the formation of (1f6)-C-disaccharide glycals. Conceptu-
ally, it was thought that olefin metathesis and carbohy-
drate chemistry could mesh together23 quite well to
provide a convergent and flexible route to a wide variety
of C-disaccharides (Scheme 1). The sequence begins with
a dehydrative coupling of an appropriate olefin alcohol
1 with generic acid 2 to give carbohydrate-based ester 3.
Methylenation of 3 to acyclic enol ether 4, via standard
methods, is then followed by ring-closing metathesis to
give the C-disaccharide glycal 5. Compound 5 can serve
as an intermediate to both the â-C-saccharides with the
general structures 6 and 7 by hydroboration24,25 (followed
by oxidative workup) or stereoselective reduction,26 re-
spectively. Access to other types of linked saccharide
structures should be possible by simply changing the
F igu r e 1.
stereochemical disposition and/or location of the acid
function on the carbohydrate ring.
Initial work by Grubbs established the viability of
employing ring-closing metathesis for the preparation of
cyclic enol ethers from simple substrates.27 Subsequent
work by Nicolaou focused on the one-pot preparation of
cyclic enol ethers directly from esters using stoichiometric
titanium reagents for the convergent assembly of poly-
ethers.28,29 This one-pot methodology has recently been
employed by Hirama and co-workers for the convergent
preparation of the IJ KLM ring fragment of Ciguatoxin
CTX3C.30 The preparation of polyether-based cyclic enol
ethers from olefinic acyclic enol ethers using a two-step
protocol has also been reported.31 The same group has
also studied metathesis-based ring closures involving
olefinic alkynyl ethers to give cyclic alkenyl enol ethers.32
This two-step protocol was also later used as an iterative
method of fusing glycals onto a carbohydrate to gain
access to polyether-type structures.33 In addition, scien-
tists at Merck-Frosst have found that some unsubstituted
(on the enol ether olefin) enol ethers can undergo ring-
closing metathesis, albeit in low yield, with the use of
the Grubbs catalyst 9b (Figure 1) to give unsubstituted
glycals.34
The use of olefin metathesis35 to prepare functionalized
organic structures has been made possible by the avail-
ability of the appropriate precatalysts, Figure 1. The
Schrock catalyst 836 has been available for several years
now, and the ruthenium-based carbenes 9a and 9b,
developed by Grubbs,37 have become very popular due
(17) Streicher, H.; Geyer, A.; Schmidt, R. R. Chem. Eur. J . 1996, 2,
502.
(18) Rubinstenn, G.; Esnault, J .; Mallet, J .-M.; Sinay, P. Tetrahe-
dron: Asymmetry 1997, 8, 1327.
(19) J arreton, O.; Skrydstrup, T.; Espinosa, J .-F.; J ime´nez-Barbero,
J .; Beau, J .-M. Chem. Eur. J . 1999, 5, 430.
(20) Griffin, F. K.; Paterson, D. E.; Taylor, R. J . K. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 2939.
(21) Postema, M. H. D.; Calimente, D. J . Org. Chem. 1999, 64, 1770.
(22) Postema, M. H. D.; Calimente, D. Tetrahedron Lett. 1999, 40,
4755.
(27) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J . Org. Chem. 1994, 59,
4029.
(28) Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J .
Am. Chem. Soc. 1996, 118, 10335.
(29) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J . Am.
Chem. Soc. 1996, 118, 1565.
(30) Oishi, T.; Nagumo, Y.; Shoji, M.; Le Brazidec, J .-Y.; Uehara,
H.; Hirama, M. J . Chem. Soc., Chem. Commun. 1999, 2035.
(31) Clark, J . S.; Kettle, J . G. Tetrahedron 1999, 55, 8231.
(32) Clark, J . S.; Trevitt, G. P.; Boyall, D.; Stammen, B. J . Chem.
Soc., Chem. Commun. 1998, 2629.
(33) Rainier, J . D.; Allwein, S. P. J . Org. Chem. 1998, 63, 5310.
(34) Sturino, C. F.; Wong, J . C. Y. Tetrahedron Lett. 1998, 39, 9623.
(35) For recent reviews on olefin metathesis chemistry, see: (a)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Ivin,
K. J . J . Mol. Catal., A 1998, 133, 1-16. (c) Randall, M. L.; Snapper,
M. L. J . Mol. Catal., A 1998, 133, 29-40. (d) Armstrong, S. K. J . Chem.
Soc., Perkin Trans. 1 1998, 371-388. (e) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056. (f) Fu¨rstner, A.
Top. Catal. 1997, 4, 285-299. (g) Grubbs, R. H.; Miller, S. J .; Fu, G.
C. Acc. Chem. Res. 1995, 28, 446-452. (h) Schmalz, H.-G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1833-1836.
(23) For some recent examples of the application of the olefin
metathesis reaction to carbohydrates see: (a) Fu¨rstner, A.; Mu¨ller, T.
J . Am. Chem. Soc. 1999, 121, 7814. (b) Haque, A.; Panda, J .; Ghosh,
S. Indian J . Chem., B 1999, 38, 8. (c) Sellier O.; Van de Weghe, P.; Le
Nouen, D.; Strehler, C.; Eustache, J . Tetrahedron Lett. 1999, 40, 853.
(d) Roy, R.; Dominique, R.; Das, S. K. J . Org. Chem. 1999, 64, 5408.
(e) El Sukkari, H.; Gesson, J . P.; Renoux, B. Tetrahedron Lett. 1998,
39, 4043-4046. (f) O’Leary, D. J .; Blackwell, H. E.; Washenfelder, R.
A.; Grubbs, R. H. Tetrahedron Lett. 1998, 39, 7427-7430. (g) van Hooft,
P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G.
A.; van Boeckel, C. A. A.; van Boom, J . H. Tetrahedron Lett. 1998, 39,
6061-6064.
(24) Schmidt, R. R.; Preuss, R.; Betz, R. Tetrahedron Lett. 1987, 28,
6591.
(25) Hanessian, S.; Martin, M.; Desai, R. C. J . Chem. Soc., Chem.
Commun. 1986, 926.
(26) (a) Dubois, E.; Beau, J .-M. Carbohydr. Res., 1992, 228, 103. (b)
Ousset, J . B.; C. Mioskowski, C.; Yang, Y.-L.; Falck, J . R. Tetrahedron
Lett. 1984, 25, 5903-5906.

Preparation of (1f6)-Linked C-Disaccharide Glycals
J . Org. Chem., Vol. 65, No. 19, 2000 6063
Sch em e 2
to their increased stability to air and various solvents
over 8. Several other variants based on both ruthenium
(11,38 1239) and tungsten (1040) have also appeared.
Recently, catalyst 13 in which one of the tricyclohexyl-
phosphine ligands of 9b has been replaced with an
imazolidine group has been prepared.41 Both catalysts
11 and 13 are more reactive than the parent catalyst 9b
and both possess greater stability to air and moisture
than the Schrock catalyst 8. Catalysts 11 and 13 are
capable of forming tri- and tetrasubstituted cycloalkenes
by ring-closing metathesis.41,42
This work outlines the preparation of 1,6-linked C-
disaccharides, compounds in which two monosaccharide
units are joined at the 1- and 6′-positions by a -CH2-
CH2- linker.43 We wished to determine whether our
metathesis-based methodology was suitable for C-disac-
charide synthesis, since the substrates are more densely
oxygenated than simple C-glycosides, and it was not clear
whether the methylenation or metathesis chemistry
would proceed efficiently. In previous cases of cyclic enol
ether formation via olefin metathesis,28,29,33,44,45 the two
reactive ends (olefin and acyclic enol ether) were fused
onto an existing ring, bringing them proximal to each
other for cyclization. In this case, no fused ring system
is present since benzyl groups were chosen for protection
of the hydroxyl functionality. Our concerns were unwar-
ranted, and the results described below demonstrate that
glycal formation via olefin metathesis is a viable synthetic
approach to this class of carbohydrate mimics.
Sch em e 3
The preparation of the needed olefin alcohols was
straightforward and modeled upon literature guidelines
as shown in Scheme 2.46 We targeted three olefin alcohols
that would lead to the galacto, gulo, and gluco 1,6-linked
C-disaccharide glycals. Methanol solutions of D-xylose
(14a ) and D-lyxose (14c) were treated with acid to furnish
the kinetically favored furanosides which were then
benzylated to give 15a and 15c. Anomeric deprotection
then gave lactols 15a and 15c as mixtures of anomers.
The first three steps were routinely carried out without
purification of the intermediates. Only the lactols were
purified and characterized when necessary. Wittig reac-
tion of lactols 16a -c with the ylide derived from meth-
yltriphenylphosphonium bromide and n-butyllithium
gave the three olefin alcohols 1a ,47 1b48 and 1c corre-
sponding to the gulo, gluco, and galacto sugars, respec-
tively. The arabino lactol 16b is commercially available.49
The starting acids were prepared by simple chain
extension of a suitably protected free O-6-monosaccharide
derivative.50,51 The sequence is described with the gluco
derivative 17 (Scheme 3). Swern oxidation of alcohol 17
was followed by Wittig reaction of the crude aldehyde 18
to give 20 after reduction of the double bond (81% over
three steps). Saponification of 20 then delivered the
requisite acid 2a .52 All the acids used for the preparations
of esters 3a -l (Table 1) were prepared in a fashion
analogous to that employed for 2a . Thus far, only benzyl,
methyl, and acetonide protecting groups have been
examined.
(36) (a) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .;
DiMare, M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875-3886.
(b) Feldman, J .; Murdzek, J . S.; Davis, W. M.; Schrock, R. R.
Organometallics 1989, 8, 2260-2265.
(37) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc.
1993, 115, 9856-9857. (b) Nguyen, S. T.; J ohnson, L. K.; Grubbs, R.
H.; Ziller, J . W. J . Am. Chem. Soc. 1992, 114, 3974-3975. (c) Nguyen,
S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1993, 115, 9858-
9859. (d) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
(38) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann,
W. A. Angew. Chem., Intl. Ed. Engl. 1998, 37, 2490.
(39) Fu¨srtner, A.; Ackermann, L. J . Chem. Soc., Chem. Commun.
1999, 95.
(40) Nugent, W. A.; Feldman, J .; Calabrese, J . C. J . Am. Chem. Soc.
1995, 117, 8992.
(41) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(42) Ackermann, L.; Fu¨rstner, A.; Weskamp, T.; Kohl, F. J .; Her-
rmann, W. A. Tetrahedron Lett. 1999, 40, 4787.
(43) For some recent approaches to the synthesis of 1,6-linked
C-disaccharides see: (a) Griffin, F. K.; Paterson, D. E.; Taylor, R. J .
K. Ramberg-Backlund Approaches to the Synthesis of C-Linked
Disaccharides. Angew Chem., Int. Ed. Engl. 1999, 38, 2939-2942. (b)
Leeuwenburgh, M. A.; Timmers, C. M.; van der Marel, G.; van Boom,
J . H.; Mallet, J . M.; Sinay¨, P. Stereoselective Synthesis of R-C-
(Alkynyl)-Glycosides via Ring-Opening of R-1,2-anhydrosugars. Tet-
rahedron Lett. 1997, 38, 6251-6254. (c) Dondoni, A.; Zuurmond, H.;
Boscarato, A. Synthesis of R- and â-D-(1f6)-C-Disaccharides by Wittig
Olefination of Formyl C-Glycosides with Glycopyranose 6-Phospho-
ranes. J . Org. Chem. 1997, 62, 8114-8124. (d) Kobertz, W. K.; Bertozzi,
C. R.; Bednarski, M. D. C-Glycosyl Aldehydes: Synthons for C-Linked
Disaccharides. J . Org. Chem. 1996, 61, 1894-1897. (e) Armstrong, R.
W.; Sutherlin, D. P. Strategies for the Synthesis of C-Disaccharides
Containing D-Sugar and L-Sugar. Tetrahedron Lett. 1994, 35, 7743-
7746. (f) Martin, O. R.; Lai, W. Synthesis and Conformational Studies
of â-(1-6)-Linked and â,â-(1-1)-Linked-C-Disacchardies. J . Org. Chem.
1993, 58, 176-185.
The general strategy is delineated in Scheme 4 and
follows our approach to C-glycoside synthesis.21 Coupling
(47) Pearson, W. H.; Hines, J . V. Tetrahedron Lett. 1991, 32, 5513.
(48) Freeman, F.; Robrage, K. D. Carbohydr. Res. 1987, 171, 1.
(49) Available from Sigma.
(50) Duclos, O.; Dure´ault, A.; Depezay, J . C. Tetrahedron Lett. 1992,
33, 1059.
(51) Zheng, W. J .; DeMattei, J . A.; Wu, J . P.; Duan, J . J . W.; Cook,
L. R.; Oinuma, H.; Kishi, Y. J . Am. Chem. Soc. 1996, 118, 7946.
(52) Detailed procedures for the preparations of these compounds
can be found in the Supporting Information.
(44) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 123.
(45) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 127.
(46) Our approach to this type of structure is based on work used
to prepare the lactol 16b: (a) Barker, R.; Fletcher, H. G. J . Org. Chem.
1961, 26, 4605-4609. (b) Pearson, W. H.; Hines, J . V. Tetrahedron
Lett. 1991, 32, 5513.

6064 J . Org. Chem., Vol. 65, No. 19, 2000
Ta ble 1. P r ep a r a tion of 1,6-Lin k ed C-Disa cch a r id e Glyca ls
Postema et al.
a
b
Yields refer to chromatographically homogeneous (1H NMR, 500 MHz) material. 20-60 mg scale at 0.01-0.02 M in substrate using
15-30 mol % metathesis catalyst 8.
Sch em e 4
The key esterification reaction was carried out with
DCC in the presence of 4-DMAP, and the acids were used
in slight excess. Yields for these couplings were good as
seen from Table 1. Methylenations were carried out using
the modified Takai conditions53 with an excess of reagent
and gave fair yields of the acyclic enol ethers.54 Purifica-
tion of the acyclic enol ethers was important since
impurities impeded the subsequent ring-closing metath-
esis step.27 Exposure of the pure acyclic enol ethers to
catalyst 8 then gave the (1f6)-C-glycals 5 (Table 1).54
The reactions were generally complete within 30-60 min
at 60 °C in dry degassed toluene. We briefly examined
the use of catalyst 9b to effect the key RCM reaction.
Exposure of 4a to 50 mol % 9b in hot toluene gave only
1
50% conversion to 5a after 8 h as observed by H NMR.
of olefin alcohol 1b with the sugar-based acid 2a gave
ester 3a in 94% yield. Methylenation of 3a to 4a was
performed in the usual way53 and exposure of the
resulting enol ether to the Schrock catalyst 8 (10-15 mol
%) in a glovebox delivered the target C-disaccharide
glycal 5a in 68% yield.
These results are consistent with what has been observed
previously with much simpler, but related systems.34 We
are currently screening the remaining catalysts shown
in Figure 1 for their ability to mediate the key conversion
(4 f 5).
(53) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J . Org. Chem.
1994, 59, 2668.
(54) The compounds are stable to silica gel chromatography provided
that 1% triethylamine is used in the eluting solvent.

Preparation of (1f6)-Linked C-Disaccharide Glycals
J . Org. Chem., Vol. 65, No. 19, 2000 6065
benzophenone ketyl. Dichloromethane and TMEDA were
distilled from calcium hydride, while benzene and toluene were
distilled from sodium. All reactions were conducted in oven-
or flame-dried glassware under an atmosphere of argon.
Organic solutions were dried over magnesium sulfate. TLC
analyses were carried out using (Merck 60F-254) thin-layer
chromatography plates and visualized under UV light or by
charring with phosphomolybdic solution. Silica gel for flash
chromatography was Merck type 60 (230-400 mesh).
Gen er a l P r oced u r e for th e Wittig Rea ction Exem p li-
fied by th e P r ep a r a tion of Eth yl (Meth yl 6,7-d id eoxy-r-
D-glu co-octo-6(Z)-en op yr a n osid )u r on a te (19a ). Dry DMSO
(1.23 mL, 17.3 mmol) was added dropwise to a -78 °C solution
of oxalyl chloride (1.23 mL, 12.9 mmol) in dry CH2Cl2 (20 mL).
After the reaction mixture was stirred for 15 min at -78 °C,
a CH2Cl2 (10 mL plus 5 mL rinse) solution of alcohol 17a (5.20
g, 11.2 mmol) was cannulated into it dropwise over a period
of 3 min. After the resulting mixture was stirred at -78 °C
for 30 min, Et3N (7.7 mL, 54.3 mmol) was added, and the
mixture was allowed to warm to 0 °C, at which point H2O (20
mL) was added. The mixture was allowed to warm to room
temperature, and the aqueous layer was separated and
extracted with CH2Cl2. The combined organic extracts were
dried (MgSO4) and concentrated in vacuo to afford a yellow
oil.
A benzene (30 mL) solution of Ph3PdCHCO2Et (5.4 g, 15.5
mmol) was added to a cool (0 °C) solution of the crude product
obtained above in dry benzene (30 mL). The reaction mixture
was allowed to warm to ambient temperature, stirred for an
additonal 4 h, and then concentrated in vacuo. Flash chroma-
tography of the residue over silica gel using 20% Et2O-
hexanes gave unsaturated ester 19a (5.10 g, 85%) as a pure
(TLC, silica 30% ether-hexanes; 1H NMR, 500 MHz) white
solid: mp ) 69 °C; [R]D ) +16.8 (c ) 0.28, CHCl3); FT-IR (neat)
3063, 3031, 2982, 2940, 2906, 1721, 1303; 1H NMR (500 MHz,
CDCl3) δ 7.33-7.27 (m, 15 H, Ph), 7.02 (dd, 1 H, J ) 15.7, 4.9
Hz, H-6), 6.11 (dd, 1 H, J ) 15.7, 1.8 Hz, H-7), 4.96 (d, 1 H, J
) 10.7 Hz, OCH2Ph), 4.83 (d, 1 H, J ) 10.6 Hz, OCH2Ph), 4.81
(d, 1 H, J ) 10.7 Hz, OCH2Ph), 4.79 (d, 1 H, J ) 11.9 Hz,
OCH2Ph), 4.66 (d, 1 H, J ) 11.9 Hz, OCH2Ph), 4.59 (d, 1 H, J
) 3.5 Hz, H-1), 4.56 (d, 1 H, J ) 10.9 Hz, OCH2Ph), 4.25 (ddd,
1 H, J ) 9.9, 4.6, 1.5 Hz, H-5), 4.19 (q, 2 H, J ) 7.1 Hz, OCH2-
CH3), 4.00 (dd, 1 H, J ) 9.3, 9.3 Hz, H-3), 3.51 (dd, 1 H, J )
9.6, 3.6 Hz, H-2), 3.34 (s, 3 H, OCH3), 3.23 (dd, 1 H, J ) 9.9,
8.9 Hz, H-4), 1.28 (t, 1 H, J ) 7.1 Hz, CH2CH3); 13C NMR (125
MHz, CDCl3) δ 166.2, 143.8, 138.5, 137.9, 137.6, 128.5, 128.4,
128.4, 128.1, 128.1, 127.9, 127.9, 127.6, 122.1, 98.1, 81.8, 81.7,
79.7, 77.2, 77.0, 76.7, 75.8, 75.4, 73.4, 69.2, 60.4, 55.3, 14.2;
HRMS (EI) calcd for C25H29O7 (M - C7H7)+ 441.1913, found
441.1912.
Sch em e 5
Glycal 5a was employed to explore the functionaliza-
tion chemistry of the double bond (Scheme 5). Hydroge-
nation of the double bond and removal of the benzyl
groups in one pot were also tried and gave 21 (66%), after
acetylation. An NOE enhancement of 5% at H-1 was
observed when H-5 was irradiated. Osmylation was also
performed on 5a and gave the keto-C-disaccharide 22 in
68% yield. Hydroboration of 5a gave 23 as the major
1
product (5:1, H NMR, 500 MHz) fully characterized as
its peracetate.55 The stereochemistry of the major isomer
was assigned on the basis of the large coupling constants
of the C-2 proton (J ) 9.5, 9.5 Hz) in acetylated 23 (where
X ) OAc, Y ) H, and R ) Bn), indicating an all-axial
relationship among H-1, H-2, and H-3. Selective reduc-
tion of the double bond in 5a using slightly poisoned (1%
Et3N) Pd/C catalyst gave the â-C-disaccharide 25 in 65%
yield.26
The flexibility of our route is illustrated by the different
types of glycals that have been prepared from readily
available monosaccharides (Table 1). The nature of the
acid can be varied although we have not yet examined
C-2 amino sugars or deoxygenation of the remaining
positions either prior to or after cyclization. Acetonide
blocking groups (entries 8-12) as well as benzyl moieties
are tolerant of the reaction conditions. Entries 4-6 and
10 (Table 1) show that the stereochemistry of the
adjacent allylic benzyloxy group does not interfere with
the ring-closing metathesis reaction.
Gen er a l P r oced u r e for Hyd r ogen a tion Exem p lified
w ith th e P r ep a r a tion of Eth yl (Meth yl 2,3,4-tr i-O-ben zyl-
6,7-d id eoxy-r-D-glu co-octop yr a n osid )u r on a te (20a ). Lind-
lar catalyst (2.00 g) was added in portions to a solution of the
unsaturated ester 19a (2.16 g, 4.058 mmol) in EtOAc (35 mL),
and the resulting suspension was agitated in a Parr shaker
apparatus under an atmosphere of H2 (35 psi) for 12 h at
ambient temperature. The reaction mixture was filtered
through a pad of Celite using EtOAc (50 mL) as the eluent,
and the resulting soultion was concentrated in vacuo. Flash
chromatography of the residue over silica gel using 20% Et2O-
hexanes gave saturated ester 20a (2.06 g, 95%) as a pure (TLC,
silica 40% ether-hexanes; 1H NMR, 500 MHz) white solid: mp
) 69 °C; [R]D ) +22.6 (c ) 1.7, CHCl3); FT-IR (neat) 3030,
Our metathesis-based approach to C-saccharide forma-
tion allows for structural diversity in both the olefin and
acid portions as evidenced from the data shown in Table
1. The starting acids and olefin alcohols are readily
prepared in good yield from known and inexpensive
monosaccharide derivatives. The route is convergent
since two pieces of roughly equal molecular weight are
joined together during the initial esterification step to
eventually deliver target C-saccharide structures in good
overall yield. The preparation of the 1,6-linked C-sac-
charide mimics described above opens the door for the
preparation of more complex and biologically relevant
C-saccharides.
2981, 2926, 1731, 1255 cm-1 1H NMR (500 MHz, CDCl3) δ
;
7.33-7.27 (m, 15 H, Ph), 4.95 (d, 1 H, J ) 10.8 Hz, OCH2Ph),
4.88 (d, 1 H, J ) 10.9 Hz, OCH2Ph), 4.80-4.76 (m, 2 H, OCH2-
Ph), 4.64 (d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.61 (d, 1 H, J )
10.9 Hz, OCH2Ph), 4.49 (d, 1 H, J ) 3.5 Hz, H-1), 4.09 (q, 1 H,
J ) 7.1 Hz, OCH2CH3), 3.93 (dd, 1 H, J ) 9.3, 9.3 Hz, H-3),
3.57 (ddd, 1 H, J ) 9.6, 9.6, 2.2 Hz, H-5), 3.48 (dd, 1 H, J )
9.6, 3.5 Hz, H-2), 3.32 (s, 3 H, OCH3), 3.17 (dd, 1 H, J ) 9.2,
9.2 Hz, H-4), 2.41-2.27 (m, 2 H, H-7), 2.19-2.15 (m, 1 H, H-6),
1.69-1.63 (m, 1 H, H-5), 1.21 (t, 3 H, J ) 7.2 Hz, OCH2CH3);
13C NMR (125 MHz, CDCl3) δ 173.5, 138.9, 138.3, 128.6, 128.6,
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise noted, reagents
were commercially available and were used without purifica-
tion. Tetrahydrofuran (THF) was freshly distilled from so-
dium-
(55) (a) Hanessian, S.; Martin, M.; Desai, R. C. J . Chem. Soc., Chem.
Commun. 1986, 926-927. (b) Schmidt, R. R.; Preuss, R.; Betz, R.
Tetrahedron Lett. 1987, 28, 6591-6594.

6066 J . Org. Chem., Vol. 65, No. 19, 2000
Postema et al.
128.5, 128.3, 128.2, 128.1, 128.1, 127.9, 127.8, 98.0, 82.2, 82.0,
80.3, 76.0, 75.4, 73.5, 69.6, 60.5, 55.2, 30.8, 27.2, 14.4; HRMS
(EI) calcd for C25H31O7 (M - C7H7)+ 443.2069, found 443.2067.
Gen er a l P r oced u r e for Sa p on ifica tion Exem p lified
w ith th e P r ep a r a tion of Meth yl 2,3,4-Tr i-O-ben zyl-6,7-
d id eoxy-R-D-glu co-octop yr a n osid u r on ic Acid (2a ). LiOH
(1.03 g, 24.5 mmol) was added to a 0 °C solution of saturated
ethyl ester 20a (655 mg, 1.23 mmol) in THF (15 mL). Water
(15 mL) was then added to the resulting suspension, and the
mixture was vigorously stirred at 0 °C for 1 h, allowed to warm
to ambient temperature, and stirred overnight. The mixture
was cooled to 0 °C and acidified by the addition of HCl (20
mL, 2 M) until litmus red was obtained. The resulting solution
was extracted with EtOAc, dried (MgSO4), and concentrated
in vacuo. Flash chromatography of the residue over silica gel
using 20% f 60% EtOAc-hexanes gave carboxylic acid 2a
tetrachloride (1.5 mL, 2 M in CH2Cl2, 3.07 mmol) was added
to cool (0 °C) THF (6 mL). The resulting mixture was stirred
for 5 min, at which point TMEDA (0.89 mL, 5.93 mmol) was
added in one portion. The resulting yellow-brown suspension
was allowed to warm to ambient temperature and stirred for
15 min. At this point, zinc dust (437 mg, 6.69 mmol) and lead-
(II) chloride (5 mg, 0.18 mmol) were added in portions and
stirring at ambient temperature was continued for 15 min. A
solution of ester 3a (164 mg, 0.18 mmol) and dibromomethane
(0.12 mL, 1.68 mmol) in THF (2 mL) was then added via
cannula to the reaction flask in one portion. The mixture was
stirred at 60 °C for 45 min, cooled to 0 °C, and then quenched
by the addition of saturated potassium carbonate (1.5 mL).
The resulting mixture was stirred for 30 min, while being
warmed to ambient temperature, diluted with ether (20 mL),
and stirred vigorously for 15 min. The resulting mixture was
filtered through neutral alumina using 3% triethylamine-
ether as the eluent. The green-blue precipitate that resulted
was crushed (mortar and pestle) and thoroughly extracted by
vigorous stirring over diethyl ether (15-20 mL) for 30 min.
The combined ethereal extracts were concentrated in vacuo,
and gravity chromatography of the residue over silica using
18% Et2O-hexanes-1% triethylamine gave 4a (116 mg, 71%)
as a pure (Rf ) 0.22, TLC silica, 30% Et2O-hexanes; 1H NMR,
500 MHz) oil: [R]D ) +21.1 (c ) 0.81, CH2Cl2); FT-IR (neat)
3087, 3063, 3030, 2919, 2866, 1652 cm-1; 1H NMR (500 MHz,
C6D6) δ 7.35-7.02 (m, 30 H, Ph), 5.88 (ddd, 1 H, J ) 17.4,
10.3, 7.0 Hz, H-2), 5.20 (d, 1 H, J ) 17.2 Hz, H-1), 5.05 (d, 1
H, J ) 10.4, 1.3 Hz, H-1), 4.98 (d, 1 H, J ) 11.2 Hz, OCH2Ph),
4.88 (d, 1 H, J ) 11.4 Hz, OCH2Ph), 4.76-4.74 (m, 3 H, OCH2-
Ph), 4.71-4.68 (m, 1 H, H-5), 4.59 (d, 1 H, J ) 3.6 Hz, H-1′),
4.56-4.50 (m, 3 H, OCH2Ph), 4.45 (d, 1 H, J ) 11.9 Hz, OCH2-
Ph), 4.31 (d, 1 H, J ) 11.7 Hz, OCH2Ph), 4.29 (s, 2 H, OCH2-
Ph), 4.17 (dd, 1 H, J ) 9.1, 9.1 Hz, H-3′), 4.13 (dd, 1 H, J )
5.3, 5.3 Hz, H-3), 4.10-4.07 (m, 3 H, H-4, 2 × H-9′), 3.96 (dd,
1 H, J ) 10.4, 3.3 Hz, H-6), 3.83 (dd, 1 H, J ) 9.3, 1.7 Hz,
H-5′), 3.79 (dd, 1 H, J ) 10.4, 4.3 Hz, H-6), 3.51 (dd, 1 H, J )
9.6, 3.6 Hz, H-2′), 3.21 (dd, 1 H, J ) 9.1, 9.1 Hz, H-4′), 3.10 (s,
3 H, OCH3), 2.58-2.52 (m, 1 H, H-7′), 2.36-2.26 (m, 2 H, H-6′,
H-7′), 1.82-1.74 (m, 1 H, H-6′); 13C NMR (125 MHz, C6D6) δ
161.8, 140.1, 139.9, 139.6, 139.5, 139.5, 139.4, 136.5, 128.8,
128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 128.1, 128.0,
127.9, 127.9, 127.9, 127.8, 118.9, 98.4, 83.1, 82.9, 82.6, 81.7,
81.7, 81.6, 75.9, 75.8, 75.6, 75.6, 73.7, 73.1, 71.4, 70.2, 68.8,
55.3, 32.2, 30.5; MS (FAB) m/ z 927 (M + Na)+, 905 (M + H)+,
873, 799, 647, 591, 541, 474, 398, 329, 271, 181, 154, 107.
Gen er a l P r oced u r e for th e Meta th esis Exem p lified by
th e P r ep a r a tion of Meth yl 6-C-(2,6-An h yd r o-4,5,7-tr i-O-
ben zyl-1,3,-d id eoxy-D-a r a bin o-h ep t-2-en it-1-yl)-2,3,4-tr i-
O-ben zyl-6-d eoxy-r-D-glu co-p yr a n osid e (5a ). In th e Box.
To a toluene (3.6 mL) solution of 4a (33 mg, 0.036 mmol) was
added catalyst 8 (7 mg, 0.009 mmol, 25 mol %) in one portion,
and the resulting mixture was heated to 60 °C for 1 h. The
resulting solution was taken out of the box and concentrated
in vacuo. Flash chromatography of the residue over silica using
18% Et2O-hexanes-1% Et3N gave 5a (22 mg, 68%) as a pure
(Rf ) 0.15, TLC silica, 30% Et2O-hexanes; 1H NMR, 500 MHz)
white solid: mp ) 100-101 °C; [R]D ) +23.3 (c ) 0.82, CH2-
1
(600 mg, 97%) as a pure (TLC, silica 40% ether-hexanes, H
NMR, 500 MHz) oil: [R]D ) +140.2 (c ) 1.32, CHCl3); FT-IR
(neat) 3220, 3062, 3031, 2927, 1738 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.37-7.29 (m, 15 H, Ph), 5.00 (d, 1 H, J ) 11 Hz,
OCH2Ph), 4.92 (d, 1 H, J ) 10.5 Hz, OCH2Ph), 4.83 (d, 1 H, J
) 11 Hz, OCH2Ph), 4.81 (d, 1 H, J ) 11.5 Hz, OCH2Ph), 4.68
(d, 1 H, J ) 12.2 Hz, OCH2Ph), 4.64 (d, 1 H, J ) 10.9 Hz,
OCH2Ph), 4.54 (d, 1 H, J ) 3.5 Hz, H-1), 3.98 (dd, 1 H, J )
9.2, 9.2 Hz, H-3), 3.63 (ddd, 1 H, J ) 9.6, 9.6, 2.6 Hz, H-5),
3.52 (dd, 1 H, J ) 9.6, 3.6 Hz, H-2), 3.36 (s, 3 H, OCH3), 3.21
(dd, 1 H, J ) 9.1, 9.1 Hz, H-4), 2.52-2.38 (m, 2 H, H-7), 2.24-
2.18 (m, 1 H, H-6), 1.73-1.67 (m, 1 H, H-6); 13C NMR (125
MHz, CDCl3) δ 179.2, 138.6, 138.0, 137.9, 128.4, 128.4, 128.3,
128.0, 127.9, 127.9, 127.8, 127.7, 127.6, 97.7, 81.8, 81.6, 79.9,
75.7, 75.2, 73.3, 69.2, 55.1, 30.1, 26.6; HRMS (EI) calcd for
C
23H27O7 (M - C7H7)+ 415.1756, found 443.1761.
Gen er a l P r oced u r e for DCC-Med ia ted Ester ifica tion
E xem p lified by t h e P r ep a r a t ion of 3,4,6-Tr i-O-b en zyl-
1,2-d id eoxy-D-a r a bin o-h ex-1-en yl (Met h yl 2,3,4-t r i-O-
ben zyl-6,7-dideoxy-R-D-glu co-octopyr an osid)u r on ate (3a).
4-DMAP (30 mg, 0.25 mmol) and DCC (236 mg, 1.15 mmol)
were added in one portion to a solution of acid 2a (387 mg,
0.764 mmol) and alcohol 1b (250 mg, 0.60 mmol) in dry CH2-
Cl2 (3 mL). The resulting solution was then stirred for 18 h at
ambient temperature, at which point TLC (2 × silica, 50%
ether-hexanes) showed the reaction was complete. The reac-
tion mixture was diluted with ether (30 mL) and filtered by
gravity through cotton to remove most of the formed dicyclo-
hexylurea. The resulting organic solution was washed with
NH4Cl (1 × 30 mL), dried, and concentrated in vacuo. Gravity
chromatography over silica gel using 10% f 20% ether-
hexanes gave ester 3a (508 mg, 94%) as a pure (TLC, silica
1
40% ether-hexanes; H NMR, 500 MHz) viscous oil: [R]D
)
+22.0 (c ) 2.5, CH2Cl2); FT-IR (neat) 3082, 3054, 3025, 2913,
1731 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 30 H,
Ph), 5.85 (ddd, 1 H, J ) 17.5, 10.4, 8.1 Hz, H-2), 5.29-5.19
(m, 3 H, H-1, H-5), 4.94 (d, 1 H, J ) 11.9 Hz, OCH2Ph), 4.85
(d, 1 H, J ) 10.9 Hz, OCH2Ph), 4.77 (d, 1 H, J ) 10.9 Hz,
OCH2Ph), 4.76 (d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.66 (d, 1 H, J
) 11.2 Hz, OCH2Ph), 4.63 (d, 1 H, J ) 12.3 Hz, OCH2Ph), 4.60
(d, 1 H, J ) 11.4 Hz, OCH2Ph), 4.56 (d, 1 H, J ) 11.6 Hz,
OCH2Ph), 4.55 (d, 1 H, J ) 11.7 Hz, OCH2Ph), 4.48 (d, 1 H, J
) 3.6 Hz, H-1′), 4.44 (d, 1 H, J ) 11.9 Hz, OCH2Ph), 4.41 (d,
1 H, J ) 11.9 Hz, OCH2Ph), 4.28 (d, 1 H, J ) 11.6 Hz, OCH2-
Ph), 3.92 (dd, 1 H, J ) 9.3, 9.3 Hz, H-3′), 3.87 (dd, 1 H, J )
7.9, 5.1 Hz, H-3), 3.76-3.73 (m, 3 H, H-4, 2 × H-6), 3.55 (ddd,
1 H, J ) 9.6, 9.6, 2.2 Hz, H-5′), 3.46 (dd, 1 H, J ) 9.6, 3.5 Hz,
H-2′), 3.28 (s, 3 H, OCH3), 3.13 (dd, 1 H, J ) 9.2, 9.2 Hz, H-4′),
2.36-2.20 (m, 2 H, H-6′), 2.18-2.12 (m, 1 H, H-7′), 1.64-1.54
(m, 1 H, H-7′); 13C NMR (125 MHz, CDCl3) δ 172.3, 138.6,
138.2, 138.1, 138.0, 135.1, 128.4, 128.3, 128.3, 128.2, 128.2,
128.0, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6, 127.5, 127.4,
119.3, 97.7, 81.9, 81.9, 80.8, 80.7, 80.0, 75.7, 75.1, 75.0, 73.3,
73.0, 72.5, 70.4, 69.2, 68.1, 55.0, 30.4, 26.7; HRMS (FAB) calcd
for C57H62O10Na (M + Na)+ 929.4240, found 929.4226.
Cl2); FT-IR (neat) 3087, 3062, 3030, 2920, 2864, 1673 cm-1
;
1H NMR (500 MHz, C6D6) δ 7.31-7.22 (m, 10 H, Ph), 7.16-
7.02 (m, 20 H, Ph), 4.99 (d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.89
(d, 1 H, J ) 11.3 Hz, OCH2Ph), 4.77-4.74 (m, 3 H, H-2, 2 ×
OCH2Ph), 4.59 (d, 1 H, J ) 3.8 Hz, H-1′), 4.58 (d, 1 H, J )
11.2 Hz, OCH2Ph), 4.55 (d, 1 H, J ) 11.7 Hz, OCH2Ph), 4.51
(d, 1 H, J ) 11.9 Hz, OCH2Ph), 4.46 (d, 1 H, J ) 11.9 Hz,
OCH2Ph), 4.45 (d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.39 (d, 1 H, J
) 11.4 Hz, OCH2Ph), 4.36 (d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.32
(d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.21-4.19 (m, 2 H, H-3, H-3′),
4.17-4.14 (m, 1 H, H-5), 4.01 (dd, 1 H, J ) 8.1, 5.8 Hz, H-4),
3.82-3.78 (m, 2 H, H-6), 3.75 (dd, 1 H, J ) 10.4, 3.1 Hz, H-5′),
3.50 (dd, 1 H, J ) 9.6, 3.6 Hz, H-2′), 3.21 (dd, 1 H, J ) 9.4, 9.4
Hz, H-4′), 3.13 (s, 3 H, OCH3), 2.48-2.43 (m, 1 H, H-7′), 2.28-
2.23 (m, 2 H, H-7′, H-6′), 1.75-1.69 (m, 1 H, H-6′); 13C NMR
(125 MHz, C6D6) δ 156.4, 140.1, 139.8, 139.6, 139.6, 139.3,
128.8, 128.8, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2,
Gen er a l P r oced u r e for th e Meth ylen a tion Exem p li-
fied by th e P r ep a r a tion of Meth yl 8-O-(3,4,6-Tr i-O-ben -
zyl-1,2-d id eoxy-D-a r a bin o-h ex-1-en yl)-6,7,9-tr id eoxy-r-D-
glu co-n on a -8-en op yr a n osid e (4a ). A solution of titanium

Preparation of (1f6)-Linked C-Disaccharide Glycals
J . Org. Chem., Vol. 65, No. 19, 2000 6067
128.1, 128.1, 128.0, 127.9, 127.8, 127.6, 127.4, 98.4, 96.0, 82.7,
82.7, 81.6, 77.7, 77.0, 75.8, 75.5, 75.3, 73.8, 73.8, 73.1, 70.6,
70.1, 69.5, 55.3, 30.4, 29.8; HRMS (FAB) calcd for C56H60O9-
Na (M + Na)+ 899.4135, found 899.4119.
µL, 66 µmol) was added dropwise to a solution of 5a (29 mg,
33 µmol) in 2 mL of THF cooled in an ice bath. After being
stirred for 4 h at 0 °C, the mixture was treated with NaOH
(0.8 mL of a 1 M solution), followed by H2O2 (0.1 mL, 30%,
w/w). The biphasic mixture was allowed to warm to room
temperature and stirred vigorously for 1 h. The resulting
solution was extracted with Et2O, washed with NH4Cl and
brine, and dried. Flash chromatography of the residue over
silica gel using 40-80% Et2O-hexanes gave compound 23 (22
mg, 73%) as a pure (TLC silica, 40% Et2O-hexanes; 1H NMR,
500 MHz) white solid: mp ) 155-156 °C; [R]D ) +23.7 (c )
0.9, CHCl3); FT-IR (KBr pellet) 3437, 3088, 3063, 3029, 2986,
Meth yl 6-C-(2,6-An h yd r o-4,5,7-tr i-O-a cetyl-1,3-d id eoxy-
D-glycer o-D-gu lo-h ep tit-1-yl)-2,3,4-tr i-O-a cetyl-6-d eoxy-r-
D-glu co-p yr a n osid e (21). To a solution of 5a (28 mg, 31 umol)
in EtOAc/MeOH (5 mL) was added Pd/C (10 mg), and the
resulting suspension was stirred under an atmosphere of H2
(40 psi) for 6 h. The reaction mixture was filtered through
Celite using MeOH (20 mL) as the eluent, and the resulting
solution was concentrated. The residue was dissolved in
pyridine (2 mL), 4-DMAP (5 mg) and Ac2O (1 mL) were
sequentially added, and the resulting solution was stirred at
ambient temperature for 12 h. The solution was diluted with
ether (20 mL) and washed with saturated NH4Cl and brine.
The ethereal solution was dried and concentrated. Flash
chromatography of the residue over silica using 40% EtOAc-
hexanes gave 21 (12 mg, 66%) as a fairly pure (Rf ) 0.20, TLC
silica, 40% EtOAc-hexanes; 1H NMR, 500 MHz) off-white
foam: [R]D ) +27.0 (c ) 0.75, CHCl3); FT-IR (neat) 2958, 2938,
1
2923, 2907 cm-1; H NMR (500 MHz, C6D6) δ 7.31-7.02 (m,
30 H, Ph), 5.0 (d, 1 H, J ) 11.6 Hz, OCH2Ph), 4.93 (d, 1 H, J
) 11.7 Hz, OCH2Ph), 4.85 (d, 1 H, J ) 11.7 Hz, OCH2Ph), 4.78
(d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.77 (d, 1 H, J ) 11.2 Hz,
OCH2Ph), 4.65 (d, 1 H, J ) 11.7 Hz, OCH2Ph), 4.62 (d, 1 H, J
) 5.1 Hz, H-1′), 4.61 (d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.51 (d,
1 H, J ) 12.2 Hz, OCH2Ph), 4.46-4.49 (m, 2 H, OCH2Ph), 4.35
(d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.21 (dd, 1 H, J ) 9.3, 9.3 Hz,
H-3′), 3.84-3.80 (m, 1 H, H-5′), 3.73 (dd, 1 H, J ) 9.3, 9.3 Hz,
H-4), 3.69 (dd, 1 H, J ) 11.2, 4.1 Hz, H-6), 3.65 (dd, 1 H, J )
10.6, 2.0 Hz, H-6), 3.53 (dd, 1 H, J ) 9.7, 3.6 Hz, H-2′), 3.41
(dd, 1 H, J ) 8.8, 8.8 Hz, H-3), 3.34-3.30 (m, 2 H, H-5, H-2),
3.27 (dd, 1 H, J ) 9.8, 9.8 Hz, H-4′), 3.19-3.16 (m, 1 H, H-1),
3.12 (s, 3 H, OCH3), 2.36-2.26 (m, 2 H, H-7′), 1.78 (bs, 1 H,
OH), 1.70-1.60 (m, 2 H, H-6′); 13C NMR (125 MHz, C6D6) δ
139.7, 139.4, 139.3, 139.1, 138.9, 128.5, 128.4, 128.4, 128.3,
128.2, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6,
127.5, 127.5, 127.4, 127.3, 97.8, 87.1, 82.6, 82.2, 81.2, 80.0, 79.5,
78.8, 75.4, 75.0, 74.9, 74.6, 74.5, 73.5, 72.6, 70.8, 69.5, 54.6,
28.3, 27.9; HRMS (FAB) calcd for C56H62O10Na (M + Na)+
917.4241, found 917.4206.
1
1368, 1327, 1226 cm-1; H NMR (500 MHz, C6D6) δ 5.83 (dd,
1 H, J ) 9.6, 9.1 Hz, H-3′), 5.12 (dd, 1 H, J ) 9.6, 9.6 Hz,
H-4), 5.07-4.98 (m, 3 H, H-2′, H-3, H-4′), 4.85 (d, 1 H, J ) 3.5
Hz, H-1′), 4.30 (dd, 1 H, J ) 12.1, 5.0 Hz, H-6), 4.03 (dd, 1 H,
J ) 12.2, 2.0 Hz, H-6), 3.67-3.63 (m, 1 H, H-5′), 3.21 (ddd, 1
H, J ) 7.6, 5.6, 2.5 Hz, H-5), 2.91 (s, 3 H, OCH3), 2.86-2.81
(m, 1 H, H-1), 1.75 (s, 3 H, CH3), 1.72 (s, 3 H, CH3), 1.73-1.66
(m, 1 H, H-2), 1.69 (s, 3 H, CH3), 1.67 (s, 3 H, CH3), 1.65 (s, 3
H, CH3), 1.59 (s, 3 H, CH3), 1.49-1.39 (m, 1 H, H-7′), 1.36-
1.30 (m, 2 H, H-7′,6′), 1.26-1.19 (m, 2 H, H-6′,2); 13C NMR
(125 MHz, C6D6) δ 170.0, 169.7, 169.6, 169.5, 169.3, 96.8, 76.2,
75.4, 72.7, 72.2, 71.5, 70.6, 69.7, 68.5, 62.6, 54.6, 36.7, 30.9,
27.7, 20.4, 20.2, 20.2, 20.2, 20.2, 20.1; HRMS (FAB) calcd for
Meth yl 6-C-(2,6-An h yd r o-4,5,7-tr i-O-a cetyl-1-d eoxy-D-
glycer o-D-gu lo-h ep tit-1-yl)-2,3,4-tr i-O-a cetyl-6-d eoxy-r-D-
glu co-p yr a n osid e (24). Pd on carbon (10%, 100 mg) was
added to a solution of 23 (16 mg, 17 µmol) in 4 mL of 3:1
EtOAc-MeOH. The heterogeneous mixture was shaken in a
Parr hydrogenation apparatus for 9 h, filtered through Celite,
and washed with MeOH (3 × 4 mL). The solution was
concentrated, and the residue was dried on the pump. The
crude product was treated with excess acetic anhydride and
pyridine (1 mL of each), and the mixture was stirred overnight
at room temperature. After the reaction was quenched with
MeOH (3 mL), the solvents were evaporated and the crude
product was purified by flash chromatography over silica gel
using 5:3 hexanes-EtOAc to give compound 24 (8 mg, 73%)
as a pure (TLC silica, 40% Et2O-hexanes; 1H NMR, 500 MHz)
white solid: mp ) 166-168 °C; [R]D ) +15.3 (c ) 0.56, CHCl3);
FT-IR (neat) 2920, 1750, 1224, 1171 cm-1; 1H NMR (500 MHz,
C6D6) δ 5.82 (dd, 1 H, J ) 9.7, 9.6 Hz, H-3′), 5.32 (dd, 1 H, J
) 9.6, 9.1 Hz, H-3), 5.18 (dd, 1 H, J ) 10.2, 9.6 Hz, H-4), 5.05
(dd, 1 H, J ) 9.6, 9.6 Hz, H-4′), 5.04-4.99 (m, 2 H, H-2, H-2′),
4.83 (d, 1 H, J ) 4.0 Hz, H-1′), 4.17 (dd, 1 H, J ) 12.6, 5.0 Hz,
H-6), 3.99 (dd, 1 H, J ) 12.1, 1.5 Hz, H-6), 3.66-3.63 (m, 1 H,
H-5′), 3.19 (ddd, 1 H, J ) 7.1, 5.1, 2.1 Hz, H-5), 3.08-3.05 (m,
1 H, H-1), 2.90 (s, 3 H, OCH3), 1.82-1.80 (m, 2 H, CH2), 1.76
(s, 3 H, CH3), 1.72 (s, 3 H, CH3), 1.68 (s, 3 H, CH3), 1.67 (s, 3
H, CH3), 1.65 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 1.57 (s, 3 H,
CH3), 1.48-1.31 (m, 2 H, CH2); 13C NMR (125 MHz, C6D6) δ
169.9, 169.8, 169.6, 169.5, 169.4, 169.1, 169.0, 96.7, 77.9, 76.0,
74.6, 72.6, 72.1, 71.6, 70.5, 68.9, 68.5, 62.0, 54.7, 27.2, 26.9,
20.2, 20.2, 20.2, 20.1, 20.0, 20.0, 20.0; HRMS (FAB) calcd for
C
26H38O15Na (M + Na)+ 613.2108, found 613.2109.
Meth yl 6-C-(2,6-An h yd r o-4,5,7-tr i-O-ben zyl-1-d eoxy-D-
glycer o-D-gu lo-h ep t-2-u lo-1-yl)-2,3,4-tr i-O-ben zyl-6-d eoxy-
r-D-glu co-p yr a n osid e (22). To a solution of C-disaccharide
glucal 5a (20.2 mg, 23.1 µmol) in THF (0.4 mL) and t-BuOH
(0.4 mL) were sequentially added pyridine (100 µL), H2O (200
µL), NMNO (65 mg, 0.55 mmol), and OsO4 (1 crystal). The
mixture was heated to reflux for 1 h, cooled to room temper-
ature, and quenched by the addition of aqueous NaHSO3 (1
mL, 20%, w/v). The resulting brown mixture was stirred for 3
h over ether (5 mL) and then extracted with Et2O. The
combined ethereal extracts were washed with brine, dried
(MgSO4), and concentrated in vacuo. Flash chromatography
of the residue over silica gel using 40% f 80% Et2O-hexanes
gave diol 22 (14 mg, 68%) as a pure (Rf ) 0.35, TLC, silica,
1
80% Et2O-hexanes; H NMR 500 MHz] oil: [R]D ) +18.1 (c
) 0.77, CHCl3); FT-IR (neat) 3403, 3063, 3030, 2924, 2854,
1
1496, 1453 cm-1; H NMR (500 MHz, C6D6) δ 7.35-7.01 (m,
30 H, Ph), 4.95 (d, 1 H, J ) 11.2 Hz, OCH2Ph), 4.91 (m, 2 H,
OCH2Ph, O-H), 4.87 (d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.83 (d, 1
H, J ) 11.2 Hz, OCH2Ph), 4.74-4.71 (m, 2 H, OCH2Ph), 4.63
(d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.48 (d, 1 H, J ) 11.1 Hz,
OCH2Ph), 4.46 (d, 1 H, J ) 3.5 Hz, H-1′), 4.45 (d, 1 H, J )
12.2 Hz, OCH2Ph), 4.41 (d, 1 H, J ) 12.2 Hz, OCH2Ph), 4.37
(d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.35 (d, 1 H, J ) 12.2 Hz,
OCH2Ph), 4.26 (ddd, 1 H, J ) 10.1, 4.1, 2.0 Hz, H-5), 4.10 (dd,
1 H, J ) 9.1, 9.1 Hz, H-3′), 3.92 (dd, 1 H, J ) 9.1, 9.1 Hz,
H-3), 3.77-3.69 (m, 3 H, H-4, 2 × H-6), 3.64 (ddd, 1 H, J )
9.6, 9.6, 1.5 Hz, H-5′), 3.49 (dd, 1 H, J ) 8.6, 8.6 Hz, H-2),
3.36 (dd, 1 H, J ) 9.6, 3.5 Hz, H-2′), 3.12 (dd, 1 H, J ) 9.6, 9.6
Hz, H-4′), 3.08 (s, 3 H, OCH3), 2.10-2.00 (m, 2 H, H-7′), 1.97-
1.90 (m, 1 H, H-6′), 1.81 (ddd, 1 H, J ) 13.1, 8.1, 5.0 Hz, H-6′);
13C NMR (125 MHz, C6D6) δ 139.6, 139.5, 139.3, 139.0, 138.9,
128.4, 128.4, 128.3, 128.3, 128.2, 128.1, 128.0, 128.0, 127.8,
127.8, 127.7, 127.5, 127.4, 98.1, 97.5, 84.7, 82.3, 81.8, 80.7, 78.5,
76.8, 75.4, 75.2, 75.2, 74.7, 73.3, 72.7, 71.9, 71.7, 69.6, 55.1,
35.3, 30.3, 24.3; HRMS (FAB) calcd for C56H62O11Na (M + Na)+
933.4189, found 933.4165.
C
28H40O17Na (M + Na)+ 671.2163, found 671.2139.
Meth yl 6-C-(2,6-An h ydr o-4,5,7-tr i-O-ben zyl-1,3-dideoxy-
D-glycer o-L-m a n n o-h ep tit-1-yl)-2,3,4-tr i-O-a cetyl-6-d eoxy-
R-D-glu co-p yr a n osid e (25). Glycal 5a (11 mg, 12 µmol) was
dissolved in a mixture of 2 mL of EtOAc, 2 mL of EtOH, and
40 µL of Et3N, and the solution stirred under hydrogen (1 atm)
for 7 h. The reaction mixture was filtered through Celite and
washed with EtOAc and the solvent evaporated in vacuo. Flash
chromatography of the residue over silica gel using 30% Et2O-
hexanes gave compound 25 (7 mg, 65%) as a pure (TLC silica,
Meth yl 6-C-(2,6-An h yd r o-4,5,7-tr i-O-ben zyl-1-d eoxy-D-
glycer o-D-gu lo-h ep tit-1-yl)-2,3,4-tr i-O-ben zyl-6-d eoxy-r-D-
glu co-p yr a n osid e (23). Borane-tetrahydrofuran complex (66
1
40% Et2O-hexanes; H NMR, 500 MHz) oil: [R]D ) +15.2 (c
) 0.32, CHCl3); FT-IR (neat) 3080, 3063, 3030, 3005, 1311,

6068 J . Org. Chem., Vol. 65, No. 19, 2000
Postema et al.
1207, 1155, 1086 cm-1; 1H NMR (500 MHz, C6D6) δ 7.32-7.01
(m, 30 H, Ph), 5.02 (d, 1 H, J ) 11.6 Hz, OCH2Ph), 5.01 (d, 1
H, J ) 11.7 Hz, OCH2Ph), 4.94 (d, 1 H, J ) 11.1 Hz, OCH2-
Ph), 4.78 (d, 1 H, J ) 11.1 Hz, OCH2Ph), 4.64 (d, 1 H, J )
11.1 Hz, OCH2Ph), 4.61 (d, 1 H, J ) 3.5 Hz, H-1′), 4.59 (d, 1
H, J ) 11.1 Hz, OCH2Ph), 4.53-4.48 (m, 2 H, OCH2Ph), 4.47
(d, 1 H, J ) 12.2 Hz, OCH2Ph), 4.45 (d, 1 H, J ) 12.2 Hz,
OCH2Ph), 4.40 (d, 1 H, J ) 12.1 Hz, OCH2Ph), 4.39 (d, 1 H, J
) 12.7 Hz, OCH2Ph), 4.22 (dd, 1 H, J ) 9.6, 9.1 Hz, H-3′),
3.79-3.75 (m, 3 H, H-5′, 2 × H-6), 3.64 (dd, 1 H, J ) 9.6, 9.1
Hz, H-4), 3.53 (dd, 1 H, J ) 9.7, 3.56 Hz, H-2′), 3.50-3.45 (m,
1 H, H-1), 3.37 (ddd, 1 H, J ) 6.1, 3.6, 2.5 Hz, H-5), 3.26 (dd,
1 H, J ) 9.7, 9.1 Hz, H-4′), 3.11 (s, 3 H, OCH3), 3.08-3.03 (m,
1 H, H-3), 2.17-2.11 (m, 1 H, H-7′), 1.84 (ddd, 1 H, J ) 6.6,
5.1, 1.5 Hz, H-2), 1.75-1.61 (m, 2 H, H-7′, H-6′), 1.52-1.45
(m, 1 H, H-6′), 1.38-1.31 (m, 1 H, H-2); 13C NMR (125 MHz,
C6D6) δ 139.6, 139.6, 139.5, 139.2, 139.1, 139.1, 128.4, 128.4,
128.3, 128.3, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.5,
127.5, 127.4, 97.9, 82.2, 81.3, 81.2, 79.6, 79.0, 75.6, 75.4, 74.9,
74.9, 73.4, 72.6, 71.0, 70.3, 70.2, 54.6, 37.1, 31.9, 28.3; HRMS
(FAB) calcd for C56H62O9Na (M + Na)+ 901.4292, found
901.4314.
Ack n ow led gm en t. We are grateful to Wayne State
University for financial support and thank Professor
Chuck Winter of this department for unlimited use of
his glovebox. Acknowledgment is also made to the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for support of this
research (Grant 33075-G1).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 1c, 2b-e, 3b-l, 4b-l, 5b-l,
19b-e, 20b-e, and acids 2b-e and spectral data listing for
as well as copies of 1H NMR spectra of 1c, 2a -e, 3a -l, 4a -l,
5a -l, 21-25, 19b-e, and 20b-e. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0005159