1,6:2,3 Cerny epoxides. An advantage of the approach over
previously reported methods6,7,12 is that the C-2, C-3, and
C-4 positions of the ring are differentiated in a minimal
number of steps. This extends earlier work and expands the
versatility of Cerny epoxides toward carbohydrate synthesis.
Notably, the approach can also be applied to D-galac-
tosamine derivatives. Oxidative 1,6-iodocyclization13 of
D-galactal followed by exposure to NaH and chloride in DMF
afforded 7 (Table 1). Reaction of 7 with potassium phthal-
imide using a modification of Paulsen’s method14 proceeded
with excellent regiocontrol to furnish 8. Thus, galactosamine
acceptors for chondroitin sulfate and other 1,3-linked amino
sugars are obtained in only three steps.
To demonstrate the utility of the approach toward glycos-
aminoglycan synthesis, we generated a key disaccharide
synthon of heparan sulfate (HS). Disaccharide 11 was chosen
because related synthons have previously been shown to
serve as useful building blocks for the assembly of HS
oligosaccharides (Scheme 2).4 Epoxide 2 was opened with
1,6-anhydro ring opening17 provided a primary alcohol,
which was smoothly oxidized18 to the corresponding tert-
butyl ester. Transesterification with concomitant deprotection
of the PMB ether was accomplished by treatment with acetyl
chloride and methanol to deliver HS acceptor 10.
With 9 and 10 in hand, we assembled the core HS
disaccharide. Formation of the R-glycosidic linkage is a
major challenge in the synthesis of HS and is typically
accomplished by masking the C-2 amino group of glu-
cosamine as a non-participating azide.4,5 However, anomeric
selectivities have been reported to vary greatly and often
depend on the electronic nature and conformational con-
straints of the specific donor and acceptor.4b,5 Thus, we were
delighted to find that coupling of donor 9 to acceptor 10
using the imidate methodology developed by Schmidt19
furnished the desired R-disaccharide 11 in 90% yield, with
no observed formation of the â-linked disaccharide. Tradi-
tionally, the preparation of highly differentiated HS disac-
charides has required more than 20 steps. In contrast, our
strategy requires approximately half the number of steps and,
to our knowledge, represents the shortest and most conver-
gent approach reported to date. Importantly, 11 can be readily
converted into other HS building blocks to alter the sulfation
pattern at the O-6, O-2, and N-2 positions or elaborated to
assemble oligosaccharides using established methodologies.3-5
Scheme 2. Heparan Sulfate Synthona
Finally, the versatility of the approach was further il-
lustrated by applying it to the synthesis of chondroitin sulfate
(CS). Opening of epoxide 7 with potassium phthalimide
afforded acceptor 8 (Scheme 3). Coupling of 8 to donor 12,
a Conditions: (a) NaN3, DMF/H2O (76%); (b) NaH, BnBr, DMF
(81%); (c) Ac2O, BF3‚Et2O, -65 °C (96%); (d) BnNH2, Et2O, then
Cl3CCN, K2CO3, CH2Cl2 (75%); (e) NaH, AllOH, DME (93%);
(f) NaH, BnBr, DMF (83%); (g) TMSSPh, ZnI2, CH2Cl2, then
TBAF, THF (84%); (h) PDC, Ac2O, t-BuOH (85%); (i) AcCl,
MeOH (76%); (j) TMSOTf, CH2Cl2, (90%, all R); (k) TIPSOTf,
2,6-lutidine, CH2Cl2 (91%).
Scheme 3. Chondroitin Sulfate Synthona
a Conditions: (a) phthalimide, KPhth, DMSO (63%); (b) 12, NIS,
TfOH, CH2CN (70%, â: R 6: 1); (c) TFA, Ac2O (83%).
NaN3, and the C-3 hydroxyl group was benzylated. Acetoly-
sis using BF3‚OEt2 was successful without any loss of the
PMB-protecting group at -65 °C. After selective anomeric
deacetylation15 and treatment with trichloroacetonitrile and
K2CO3,16 the â-trichloroacetimidate 9 was obtained. This
sequence provided the key glycosyl donor, in which each
hydroxyl group is differentiated, in only four steps and 44%
overall yield from 2.
Epoxide 2 also served as an entry point for the synthesis
of the D-glucuronic acid acceptor of HS. Opening of 2 with
NaH and allyl alcohol (the use of DME as a solvent was
crucial to ensure high yield) followed by benzylation and
which was obtained upon silylation of 10, was accomplished
using TfOH/NIS.20 The â-selectivity of the glycosylation
reaction was enhanced using CH3CN as a solvent.21 Upon
acetolysis, the â(1-3)-linked disaccharide 13, a key synthon
for the biologically active CS-C and CS-D motifs3c (Figure
1), was obtained in 83% yield.
(17) Wang, L. X.; Sakairi, N.; Kuzuhara, H. J. Chem. Soc., Perkin Trans.
1 1990, 1677-1682.
(18) Corey, E. J.; Samuelsson, B. J. Org. Chem. 1984, 49, 4735-4735.
(19) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21-123.
(20) (a) Zhang, A.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734-755. (b) Konradsson, P.;
Udodong, U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313-4316.
(c) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron
Lett. 1990, 31, 1331-1334.
(21) Marra, A.; Esnault, J.; Veyrieres, A.; Sinay, P. J. Am. Chem. Soc.
1992, 114, 6354-6360.
(12) (a) Sviridov, A. F.; Ermolenko, M. S.; Yashunshkii, D. V.;
Kochetkov, N. K. IzV. Akad. Nauk SSSR, Ser. Khim. 1985, 34, 1161-1165.
(b) Xue, J.; Guo, Z. W. Tetrahedron Lett. 2001, 42, 6487-6489.
(13) Leteux, C.; Veyrieres, A. J. Chem. Soc., Perkin Trans. 1 1994,
2647-2655.
(14) Paulsen, H.; Bunsch, A. Angew. Chem., Int. Ed. Engl. 1980, 19,
902-903.
(15) Helferich, B.; Portz, W. Chem. Ber., Recl. 1953, 86, 604-612.
(16) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826-1847.
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