Stereoselective synthesis of L-oliose trisaccharide via iterative alkynol cycloisomerization and acid-catalyzed glycosylation.

Article abstract of DOI:10.1021/ol026886o

[formula: see text] The synthesis of an all-alpha L-oliose diastereomer of digitoxin provides valuable insights into the generality and protective-group dependence of acid-catalyzed glycosylations of glycals to 2-deoxycarbohydrates.

Full text of DOI:10.1021/ol026886o

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3979-3981
Stereoselective Synthesis of L-Oliose
Trisaccharide via Iterative Alkynol
Cycloisomerization and Acid-Catalyzed
Glycosylation†
Frank E. McDonald* and Minglang Wu
Department of Chemistry, Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
fmcdona@emory.edu
Received September 11, 2002
ABSTRACT
The synthesis of an all-r L-oliose diastereomer of digitoxin provides valuable insights into the generality and protective-group dependence of
acid-catalyzed glycosylations of glycals to 2-deoxycarbohydrates.
The synthesis of oligosaccharides has become an important
area of synthetic organic chemistry due in part to the
biological activity associated with many oligosaccharides and
carbohydrate-containing conjugates.1 However, the synthetic
carbohydrate chemist continues to face challenging issues
of stereoselectivity and regioselectivity in forming many
desired oligosaccharide structural patterns, but experience
has shown that each stereoisomer requires specific solutions
to glycoside synthesis. Furthermore, many suitable methods
for monosaccharide synthesis prove to be more difficult to
apply to oligosaccharide components.
We recently developed a novel strategy for synthesis of
oligosaccharides composed of 2-deoxysugars, featuring itera-
tive application of tungsten-catalyzed alkynol cycloisomer-
ization and stereoselective acid-catalyzed glycosylation,
which was applied to the stereoselective synthesis of the
D-digitoxose trisaccharide of digitoxin.2 In this communica-
tion, we describe a synthesis of the L-oliose3 trisaccharide
diastereomer of digitoxin. In the course of this work, we
have discovered some similarities as well as differences in
reactivity of the oliose vs digitoxose stereoisomers in the
course of iterative acid-catalyzed glycosylation chemistry.
The synthesis began with the fully protected alkynyl triol
1,2a which upon deprotection to alkynyl alcohol 2 and
tungsten-catalyzed cycloisomerization afforded L-oliose (lyxo)
glycal 5.2a Acid-catalyzed glycosylation of the monosilyl
alkynyl alcohol 4 with glycal 5 provided R-glycoside 6 with
virtually complete stereoselectivity.4 Deprotection of the
para-nitrobenzoate ester and tungsten-catalyzed cycloisomer-
(2) (a) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304. (b) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001,
40, 3653.
(3) (a) Also known as 2-deoxy-L-fucose or 2,6-dideoxy-L-galactose. (b)
A similar L-lyxo trisaccharide is present in the pregnane natural product
brevine: Oberai, K.; Khare, M. P.; Khare, A. Phytochemistry 1985, 24,
3011.
(4) Diastereomeric R-glycoside (1-2%) is isolated from this glycosy-
lation transformation. We tentatively assigned this diastereomer as arising
from minor amounts of enantiomers from 4 and/or 5, which were prepared
with approximately 98% ee.
† Dedicated to our colleague, Prof. Albert Padwa, on the occasion of his
65th birthday.
(1) Reviews: (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(b) Boons, G. J. Contemp. Org. Synth. 1996, 3, 173. (c) Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. (d) Davis,
B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137. (e) Kirschning, A.;
Jesberger, M.; Schoning, K. U. Synthesis 2001, 507.
10.1021/ol026886o CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

Scheme 1. Stereoselective Synthesis of L-Oliose Trisaccharide Analog of Digitoxina
a Reagents and Conditions: (a) DIBAL, CH2Cl2, -78 °C (2, 95% yield; 7, 83% yield; 12, 82% yield). (b) HF-pyridine, THF, 0 °C. (c)
TBSCl (1.1 equiv), imidazole, CH2Cl2 (72% yield, two steps). (d) W(CO)6 (25 mol %), Et3N, THF, hν (350 nm), 65 °C (5, 92% yield; 8,
87% yield; 13, 59% yield). (e) 4, camphorsulfonic acid (2 mol %), toluene (95% yield). (f) Bu4NF (5 equiv), THF, from 0 to 20 °C; then
Ac2O, DMAP, Et3N, THF (46% yield). (g) 4 (9 equiv), Ph3P-HBr (10 mol %), CH2Cl2 (11, 61% yield + 94% recovery of excess 4). (h)
Ac2O, DMAP, Et3N, THF (73% yield). (i) Digitoxigenin, camphorsulfonic acid (2 mol %), toluene/CH2Cl2 (75% yield). (j) HF-pyridine,
THF, 0 °C (63% yield). (k) K2CO3, MeOH/H2O (82% yield).
ization of alkynyl alcohol 7 gave the disaccharide glycal 8.
Initial glycosylation studies on trisilyl ether glycal 8 with
the alkynyl alcohol 4 provided a 64% yield of a mixture of
compounds that was determined to be an inseparable 4:3
mixture of glycoside 10 accompanied by 6, which arose from
competitive glycoside hydrolysis. On the basis of earlier
observations that electron-withdrawing acetate substituents
on the nonreducing sugar of disaccharide glycals provided
a “protective” effect on glycoside linkages in acid-catalyzed
glycosylations of glycals,5 we elected to change the protective
group pattern to triacetate glycal 9. Glycosylation of triacetate
9 proceeded slowly and required an excess of alkynyl alcohol
reactant 4 in order to obtain complete conversion of limiting
reactant 9, but glycoside 11 was produced in good yield and
complete stereoselectivity as well as with efficient recovery
of unreacted alkynyl alcohol 4. Removal of all ester
protective groups and tungsten-catalyzed cycloisomerization
of alkynyl tetraol substrate 12 afforded trisaccharide glycal
13, with acylation of the unreacted alcohols to 14. The choice
of silyl group on the glycal of 14 favored glycosylation with
commercially available digitoxigenin under mild conditions,
whereas the acetate esters on the remaining sugars stabilized
preexisting glycosidic linkages, to give the protected digitoxin
stereoisomer 15. Removal of the single silyl group from the
relatively unhindered equatorial position could be ac-
complished in good yield with HF-pyridine, and removal of
acetate protective groups from 16 afforded the all-R-linked
L-oliose digitoxin stereoisomer 17.
Two other strategies were explored in order to facilitate
the formation of the glycosidic bond between the second and
third sugars. In the first alternative approach (Scheme 2),
glycosylation of diacetyl-L-fucal (18)6,7 with the alkynyl
alcohol 4 proceeded slowly but provided a good yield of
axial glycoside 19, again as a single stereoisomer. Conversion
to alkynyl triol 20, tungsten-catalyzed cycloisomerization and
acylation of the unreacted hydroxyl groups of 21 afforded
disaccharide glycal 22 bearing a silyl ether protective group
at the allylic oxygen of the glycal sugar. With this protective
group combination, disaccharide glycal 22 was considerably
more reactive to acid-catalyzed glycosylation, so only 1 equiv
of alcohol 4 was required in order to provide a satisfactory
yield of glycoside 23. This product was converted into
trisaccharide glycal 26 by a route similar to that shown in
Scheme 1. Unfortunately, attempts to glycosylate bissilyl
ether-protected trisaccharide 26 with digitoxigenin resulted
only in degradation of the previously formed glycosidic bond
(6) Iselin, B.; Reichstein, T. HelV. Chim. Acta 1944, 27, 1200.
(7) For other acid-catalyzed glycosylations of fucose glycal derivatives,
see: (a) Wakamatsu, T.; Nakamura, H.; Naka, E.; Ban, Y. Tetrahedron
Lett. 1986, 27, 3895. (b) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem.
Soc. Jpn. 1988, 61, 2369. (c) Kolar, C.; Kneissl, G.; Wolf, H.; Ka¨mpchen,
T. Carbohydr. Res. 1990, 208, 111. (d) Sabesan, S.; Neira, S. J. Org. Chem.
1991, 56, 5468. (e) Kaila, N.; Yu, H.-A.; Xiang, Y. Tetrahedron Lett. 1995,
36, 5503.
(5) (a) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. 1988, 27, 1697.
(b) Unverzagt, C.; Kunz, H. Bioorg. Med. Chem. 1994, 2, 1189. (c)
McDonald, F. E.; Danishefsky, S. J. J. Org. Chem. 1992, 57, 7001.
3980
Org. Lett., Vol. 4, No. 22, 2002

Scheme 2. Alternate Protective Group Scheme for the
Scheme 3. Alternate Glycosylation Strategy for Digitoxigenin
Synthesis of L-Oliose Trisaccharide Glycala
Oligosaccharidea
a Reagents and Conditions: (a) 4, camphorsulfonic acid (2 mol
%), toluene (19, 86% yield; 23, 65% yield). (b) DIBAL, CH2Cl2,
-78 °C (20, 88% yield; 24, 100% yield). (c) W(CO)6 (33 mol %),
Et3N, THF, hν (350 nm), 65 °C. (d) Ac2O, Et3N, DMAP (50 mol
%), THF (22, 65% yield, two steps; 26, 41% yield, two steps).
a Reagents and Conditions: (a) digitoxigenin, camphorsulfonic
acid (2 mol %), CH2Cl2/toluene (84% yield). (b) (NH4)HF2,
N-methylpyrrolidinone, DMF (73% yield). (c) Ac2O, Et3N, cat.
DMAP, THF (94% yield). (d) HF-pyridine, THF, 0 °C (93%
yield). (e) 22, Ph3P-HBr (10 mol %), CH2Cl2 (38% yield, 2:1 R:â).
between the two silyl-protected sugars. This behavior is
attributed to the higher reactivity of axial anomers of
2-deoxyglycosides to acid-catalyzed glycoside cleavage.8
The other alternative explored was formation of the
oligosaccharide by reaction of a monosaccharide digitoxi-
genin conjugate 31 with disaccharide glycal 22 (Scheme 3).
Glycosylation of silylated monosaccharide glycal 27 with
digitoxigenin gave glycoside 28 in good yield as the
R-anomer. At this stage, the triethylsilyl ether at the
equatorial and less hindered O-3 was selectively removed
to provide the hydroxyl group of 29, which was acylated to
give 30. Removal of the remaining silyl ether was ac-
complished with HF-pyridine to provide 31. However,
glycosylation of 31 with disaccharide glycal 22 proceeded
in moderately low yield, and a mixture of anomers was
observed.
formation of the axial (R) anomeric 2-deoxyglycosides, as
previously demonstrated for L-fucose glycal monosaccha-
rides.7,9 For the fucose (lyxo) stereoisomers, acid-catalyzed
glycosylation occurs without elimination with both trialkyl-
silyl ether and acetate ester protective groups at the allylic
center when camphorsulfonic acid7a,b or triphenylphosphine-
hydrogen bromide9 are used as glycosylation catalysts.10
Acknowledgment. We thank the National Institutes of
Health (CA 59703) for support of this research. We also
acknowledge the use of shared mass spectroscopy instru-
mentation provided by grants from the National Science
Foundation.
In summary, we have shown that acid-catalyzed glyco-
sylations of oligosaccharides bearing L-fucose glycal at the
reducing termini are generally stereoselective favoring
Supporting Information Available: Experimental details
and procedures for compounds 2, 4-9, 11-17, 19-26, 28,
and 30-32. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Overend, W. G.; Rees, C. W.; Sequeira, J. S. J. Chem. Soc. 1962,
3429.
OL026886O
(9) In addition to refs 7c-e, see acid-catalyzed glycosylations of
rhamnose (arabino) glycals bearing equatorial allylic acetates: (a) Bolitt,
V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem. 1990, 55, 5812.
(b) Kaila, N.; Blumenstein, M.; Bielawska, H.; Franck, R. W. J. Org. Chem.
1992, 57, 4576. (c) France, C. J.; McFarlane, I. M.; Newton, C. G.; Pitchen,
P.; Webster, M. Tetrahedron Lett. 1993, 34, 1635.
(10) In contrast, Lewis acids such as BF3-OEt2 or SnCl4 generally
promote glycosylation with elimination of the allylic substituent. (a) Ferrier,
R. J.; Prasad, N. J. Chem. Soc. C 1969, 570. (b) Ferrier, R. J. Top. Curr.
Chem. 2001, 215, 153.
Org. Lett., Vol. 4, No. 22, 2002
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