C O M M U N I C A T I O N S
Scheme 6. Synthesis of 1,4-Trisaccharides
Scheme 10. Synthesis of 2,3-Deoxy-1,4-R-oligosaccharides
(Scheme 6). The C-4 alcohols in 16a/b were used as glycosyl donors
with their corresponding glycosyl acceptor pyranones 2a/b9 to
fashion the 1,4-linked trisaccharides 17a/b with excellent stereo-
control and overall yield (57% and 86% for the two steps).10,11
As with the 1,6-linked pyranones (Scheme 4), the OsO4/ NMO
oxidation of allylic alcohols 16a/b afforded the 1,4-bis-R-manno-
pyanoses 18a/b both as single diastereomers in 88% and 77% yields,
respectively (Scheme 7).8,12 Thus, 10 stereocenters were selectively
installed in 18a/b in only 10 and 8 steps from achiral furfural and
2-acylfuran, respectively.13
saccharides from furan alcohols by the iterative use of a Pd-cata-
lyzed glycosylation reaction.5 This new route was also used for
the preparation of 2,3-dideoxy-oligosaccharides. The 1,4- and 1,6-
R-manno-disaccharides were achieved in 8 or 10 total steps starting
from achiral 2-acylfuran or furfural, respectively. Similarly, 1,4-
and 1,6-R-manno-trisaccharides were also synthesized in 10 or 12
total steps using a sequential Pd-catalyzed glycosylation reaction.
Key to the overall efficiency of this process was the use of highly
diastereoselective 1,2-reductions and dihydroxylations. This three-
step protocol allows for the rapid incorporation of either D- or
L-pyranoses in oligosaccharides in good yields and with complete
stereocontrol.13 We believe this route is amenable to multigram-
scale preparation of various natural and unnatural oligosaccharides.
Scheme 7. Conversion to 1,4-R-manno-Disaccharides
Acknowledgment. This paper is dedicated to Prof. Leo A.
Paquette in honor of his 70th birthday. We thank both the Arnold
and Mabel Beckman Foundation and the NIH (1R01 GM63150-
01A1) for their generous support of our research program. Funding
for a 600 MHz NMR by the NSF-EPSCoR (0314742) is also
gratefully acknowledged.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
This high degree of stereocontrol remained at the 1,4-trisaccha-
ride level (Scheme 8). Thus, diastereoselective 1,2-reduction of the
ketone in 17a/b with NaBH4 followed by double-bond oxidation
with OsO4/NMO afforded the 1,4-tri-R-manno-pyranoses 20a/b in
good overall yields.8 Amazingly, the 15 stereocenters of 20a and
20b were induced in only 12 and 10 steps from achiral furfural
and 2-acylfuran, respectively.
References
Scheme 8. Conversion to 1,4-R-manno-Trisaccharides
(1) (a) Ichikawa, Y.; Halcomb, R. L.; Wong, C.-H. Chem. Br. 1994, 30, 117-
118. (b) Wong, P. G.; Bertozzi, C. R., Eds. Glycochemistry. Principles,
Synthesis and Applications; Marcel Dekker: New York, 2001. (c) Bertozzi,
C. R. Chem. Biol. 1995, 2, 703-708.
(2) (a) Kobata, A. Acc. Chem. Res. 1993, 26, 319. (b) Crocker, P. R.; Feizi,
T. Curr. Opin. Struct. Biol. 1996, 6, 679-91.
(3) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem. 1999,
64, 2982-2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young,
V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17-36.
(4) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-176.
(5) While the diastereoselective transfer of a pyranone ring to an alcohol is
an uncommon glycosylation reaction because the pyranone ring is at the
same oxidation state as a traditional sugar (one OH per carbon atom), we
feel this transfer of a bis-anhydro-sugar is as much a glycosylation reaction
as other common glycosylation reactions (e.g. the transfer of a deoxysugar).
(6) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406-
12407. (b) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa, B. L.
J. Am. Chem. Soc. 2003, 125, 8714-8715. (c) Kim, H.; Men, H.; Lee, C.
J. Am. Chem. Soc. 2004, 126, 1336-1337.
Dideoxy-oligosaccharides can be prepared by employing a di-
imide reduction on the 1,6-linked di- and tripyrans 10 and 12.14
Thus, the 1,6-bis-R-2,3-deoxy-L-manno-pyranose 21 and 1,6-tri-
R-2,3-deoxy-L-manno-pyranose 22 were prepared from exhaustive
reduction of allylic alcohols 10 and 12, using excess triethylamine
and o-nitrophenylsulfonylhydrazide as a diimide precursor (Scheme
9).15
(7) Important to the successful execution of this process, both reactions must
occur with virtually complete diastereocontrol.
Scheme 9. Synthesis of 2,3-Deoxy-1,6-R-oligosaccharides
(8) While the dihydroxylation products were easily purified by silica gel
chromatography, no efforts were taken to detect for trace levels of osmium.
(9) For glycosylation at the C-4 position we found that the best yields were
obtained when a 2:1 ratio of glycosyl donor to acceptor was used.
(10) Not surprisingly, the glycosylation reaction consistently occurs in higher
yields with the substrates having the smaller C-6 methyl substituents.
(11) The Pd-catalyzed glycosylation was significantly slower and occurred in
lower yields (14a to 15a and 16a to 17a), when using a pyranone with a
C-1 pivaloate-leaving group.
(12) Using a different retrosynthetic bond disconnection, Sinou used a
palladium-allylation reaction to prepare 1,4-disaccharides, see: Sinou, D.;
Frappa, I.; Lhoste, P.; Porwanski, S.; Kryczka, B. Tetrahedron Lett. 1995,
36, 1251-1254.
This diimide methodology also worked perfectly for the prepara-
tion of 1,4-linked 2,3-dideoxyoligosaccharides. Two 2,3-dideoxy-
disaccharides (1,4-di-R-2,3-deoxymannose 23a/b) and two 2,3-
dideoxy-trisaccharides (1,4-tri-R-2,3-deoxymannose 24a/b) were
prepared in nearly quantitative yields by exposing the allylic
alcohols 16a/b and 19a/b to excess diimide precursor and base
(Scheme 10).13
(13) To demonstrate the generality of this process we prepared 18b, 20b, 23b
and 24b in the all D-enantiomeric form.
(14) For a related alterative approach to 2-deoxysugars, see: (a) McDonald,
F. E.; Reddy, K. S.; Diaz, Y., J. Am. Chem. Soc. 2000, 122, 4304-4309.
(b) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979-3981.
(15) We have found o-nitrophenylsulfonylhydrazide/triethylamine to be an
excellent diimide precursor, ideal for reducing pyrans of this type, see:
Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771-1774.
In summary, we have synthesized natural and unnatural 1,4- and
1,6-R-manno-disaccharides as well as 1,4- and 1,6-R-manno-tri-
JA039400N
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