New Synthetic Methodology for Regio- and Stereoselective Synthesis of Oligosaccharides via Sugar Ortho Ester Intermediates

Full text of DOI:10.1021/jo981135e

5744
J . Org. Chem. 1998, 63, 5744-5745
Ta ble 1
New Syn th etic Meth od ology for Regio- a n d
Ster eoselective Syn th esis of Oligosa cch a r id es
via Su ga r Or th o Ester In ter m ed ia tes
Wei Wang and Fanzuo Kong*
Research Center for Eco-Environmental Sciences,
Academia Sinica, P.O. Box 2871, Beijing 100085, China
Received J une 15, 1998
Great effort has been devoted to the development of new
strategies for glycosidic coupling owing to the growing
importance of synthetic oligosaccharides in glycobiology.1 In
the past decades, methods for construction of glycosidic
linkages have progressed considerably.2 However, compared
to the synthesis of oligopeptides and oligonucleotides, the
synthesis of oligosaccharides is still laborious work. The use
of unprotected or partially protected sugars in glycosidic
coupling is of particular interest since synthetic routes can
be substantially simplified. In addition, chemistry on
unprotected sugars represents a great challenge, as there
are only tiny differences in coupling sugar hydroxyl groups,
particularly secondary hydroxyl groups.
Formation of sugar-sugar ortho esters in glycosylation
is well-known, and these ortho esters are obtained in
variable yields,3a-i sometimes as byproducts,3j but there have
been no reports dealing with the preparation of ortho esters
using unprotected or partially protected glycosides as the
glycosyl acceptors. In addition, TMSOTf-promoted rear-
rangement4 has only been used to treat fully protected ortho
esters formed from reaction with either the primary4a,b
hydroxyl group of a sugar acceptor or a simple aglycon
alcohol.4c We now report a new methodology for highly
regio- and stereoselective synthesis of oligosaccharides. That
is, (1) the preparation of sugar-sugar ortho esters by
coupling acetobromosugars with unprotected alkyl glycosides
or partially protected sugar acceptors in high yields and
excellent selectivity and (2) the rearrangement of either
partially protected or fully protected ortho esters of diverse
structure by the catalytic use of TMSOTf.
A typical example is presented in entry 1 of Table 1.
Coupling5 of acetobromoglucose 1 with 4,6-unprotected
glucoside 6 promoted by AgOTf in the presence of 2,4-
lutidine selectively afforded the ortho ester 7 in nearly
quantitative yield. Rearrangement6 of 7 with a catalytic
amount TMSOTf selectively furnished 9 in a satisfactory
yield (78%), and subsequent acetylation gave 10. To confirm
the selectivity of the rearrangement, acetylation of 7 (giving
8) followed by rearrangement (80%) gave the same disac-
charide 10. The structures 9 and 10 were determined by
(1) (a) Dwek, R. A. Chem. Rev. 1996, 96, 683. (b) Synthetic Oligosaccha-
rides. Indispensable Probes for the Life Sciences; Kovac, P., Ed.; ACS
Symposium Series 560; American Chemical Society, Washington, DC, 1994.
(2) General reviews: (a) Preparative Carbohydrate Chemistry; Hanessian,
S., Ed.; Marcel Dekker Inc.: New York, 1997; Chapters 12-22. (b) Barresi,
F.; Hindsgaul, O. J . Carbohydr. Chem. 1995, 14, 1043. (c) Schmidt, R. R.;
Kinzy, W. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21. (d) Toshima, K.;
Tatsuta, K. Chem. Rev. 1993, 93, 1503. Glycal donors: Dannishefsky, S.
J .; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. Glycosyl
sulfoxide donors: Yan, L.; Kahne, D. J . Am. Chem. Soc. 1996, 118, 9239.
1-Hydroxy glycosyl donors: Garcia, B. A.; Poole, J . A.; Gin, D. Y. J . Am.
Chem. Soc. 1997, 119, 7597. 1,2-Anhyrdo glycosyl donors: Du, Y.; Kong, F.
Tetrahedron Lett. 1995, 427.
(3) (a) Modern Methods in Carbohydrate Synthesis; Khan, S. H., O’Neil,
R. A., Eds.; Harwood Academic Publishers: United States, 1996; p 125. (b)
Ernst, B.; De Mesmaeker, A.; Wagner, B.; Winkler, T. Tetrahedron Lett.
1990, 6167. (c) Banoub, J .; Boullanger, P.; Potier, M.; Descotes, G.
Tetrahedron Lett. 1986, 4145. (d) Dahlin, B. M.; Garegg, P. J .; J ohansson,
R.; Samuelsson, B.; Orn, U. Acta Chem. Scand. B 1981, 35, 669. (e) Banoub,
J .; Bundle, D. R. Can J . Chem. 1979, 57, 2091. (f) Ogawa, T.; Matsui, M.
Carbohydr. Res. 1976, 51, C13. (g) Zurabyan, S. E.; Tikhomirov, M. M.;
Nesmeyanov, V. A.; Khorlin, A. Y. Carbohydr. Res. 1973, 26, 117. (h) Wulff,
G.; Kruger, W. Carbohydr. Res. 1971, 19, 139. (i) Kochetkov, N. K.; Bochkov,
A. F.; Sokolovskaya, T. A.; Snyatkova, V. J . Carbohydr. Res. 1971, 16, 17.
(j) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky, S. J . J .
Am. Chem. Soc. 1997, 119, 10064. Kunz, H. Liebigs Ann. Chem. 1986, 717.
Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41. Garegg, P. J .;
Konvadsson, P.; Kvanstrom, I.; Norberg, T.; Svensson, S. C. T.; Wigilius,
B. Acta Chem. Scand. B 1985, 39, 569.
(5) Typical conditions for ortho ester preparation: To a stirred mixture
of 1 (238 mg, 0.58 mmol), 6 (188 mg, 0.577 mmol), 2,4-lutidine (68 µL, 0.58
mmol), and molecular sieves (0.2 g) in dichloromethane (6 mL) was added
silver triflate (148 mg, 0.58 mmol) under nitrogen atmosphere in a dark
room, and the reaction was carried out at room temperature and monitored
by TLC (2:1 petroleum ether/ethyl acetate). After completion of the reaction,
the mixture was partitioned between dichloromethane and water, and the
organic phase was concentrated under reduced pressure. The residual oil
was purified by silica gel column chromatography with 2:1 petroleum ether/
ethyl acetate as the eluent, giving the product 7 as an amorphous solid in
a yield of 95% (360 mg), capable of being used for further rearrangement.
(6) Typical rearrangement conditions: To a stirred solution of sugar-
sugar ortho ester 7 (360 mg, 0.55 mmol) in dichloromethane (6 mL) was
added TMSOTf (10 µL, 0.1 equiv) at 0 °C under nitrogen atmosphere, and
the reaction was monitored by TLC (2:1 petroleum ether/ethyl acetate). After
completion of the reaction, to the mixture was added triethylamine (15 µL)
and then the mixture was treated at the same way as described in (5), giving
9 in a yield of 78%.
(4) (a) Gass, J .; Strobl, M.; Kosma, P. Carbohydr. Res. 1993, 244, 69. (b)
Sznaidman, M. L.; J ohnson, S. C.; Crasto, C.; Hecht, S. M. J . Org. Chem.
1995, 60, 3942. (c) Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res.
1981, 93, C6.
S0022-3263(98)01135-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/01/1998

Communications
J . Org. Chem., Vol. 63, No. 17, 1998 5745
Sch em e 1a
D-glucopyranose as the glucosyl donor and 11 as the acceptor
(the ratio of 2-O-glucosylation to 3-O-glucosylation was 3:1
with a total yield of 28%). The selectivity of entry 2 (Table
1) was confirmed by the fact that the disaccharide 14
obtained from the rearrangement of 13 gave the same 1H
NMR data as the reported values.10 The selectivity of entry
3 (Table 1) was verified by comparison of the disaccharide
formed from the rearrangement with an authentic sample,11
1
1
giving exactly the same H NMR data. The H NMR data
of 30 showed H-4 at δ 5.01, downfield compared to H-3 (δ
4.00-3.88), confirming the 3-O-linkage in entry 6 (Table 1).
We rationalize that the high regioselectivity, which cannot
be achieved by direct coupling under normal glycosylation
conditions, is mainly the result of steric factors, i.e., the
attack to the acyloxnium carbon of A (Scheme 1) by less
hindered hydroxyl group, while the high regio- and stereo-
selectivity of the rearrangement results from the C-1
backside attack of A by the trimethylsilylated acceptor
(Scheme 1).
In summary, we have presented a new and very effective
method for regio- and stereoselective synthesis of 1,2-trans-
linked oligosaccharides using acetobromoglycose as the
glycosyl donor. The high regioselectivity of ortho ester
formation can result in a high yield synthesis of 1f6 and
1f3 linked oligosaccharides, while the high selectivity of
rearrangement allows further modification at the unpro-
tected hydroxyl groups of the rearrangement products. This
new methodology will be very useful for the synthesis of di-
and trisaccharides, and in combination with the known
methods, synthesis of complex oligosaccharides may be
substantially simplified. Further investigation of the ap-
plication of this new method to the synthesis of complex
oligosaccharides is in process.
a
Key: (a) AgOTf (1 equiv), 2,4-lutidine (1 equiv), DMF, molecular
sieves (4A), rt, N2, 5 h; (b) Pyr, Ac2O, rt, 2 h; (c) TMSOTf (0.1 equiv),
CH2Cl2, molecular sieves (4A), 0 °C, N2, 2 h.
1H NMR as described in ref 7. Similar results were obtained
for coupling of acetobromogalactose 23 with the acceptor 6
(see entry 5 in Table 1, isolated yields are indicated in
parentheses following each product). Again, the rearrange-
ment selectivity was confirmed by the fact that the two
paths, i.e., acetylation of 24 followed by rearrangement of
25 and rearrangement of 24 followed by acetylation of 26,
gave the same disaccharide 27. Exciting results were
obtained when this new method was used for the coupling8
of acetobromoglycose with unprotected methyl glycosides
(see Scheme 1 and Table 1, entries 4 and 7). Coupling of 1
with 2 gave ortho ester 3 as the sole product, and its in situ
acetylation (giving 4) followed by rearrangement afforded
1,6-â-linked disaccharide 5 in a high yield. Coupling of 1
with an unprotected 1,6-linked disaccharide 19 followed by
rearrangement dramatically furnished 1,6-linked trisaccha-
ride 22.8 Excellent regioselectivity for coupling with accep-
tors having 2,3 or 3,4 free secondary hydroxyl groups was
also achieved (see Table 1, entries 2, 3, and 6). It is
interesting to note that selective 3-O-glucosylation for either
11 or 15 was achieved. This result is different from the
reported selective, mercuric bromide promoted 2-O-gluco-
sylation9 using 3,4,6-tri-O-acetyl-1,2-O-ethylorthoacetyl-R-
Ack n ow led gm en t. Project 39740022 was supported by
the National Natural Science Foundation of China.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR data for
compounds 4, 7-10, 12, 13, 16-18, 21, and 24-30 (5 pages).
(7) 1H NMR data for 10: δ 4.52 (d, H-1′â), 4.63 (d, H-1R), 5.41, 5.20,
5.05, 5.01, 4.86 (5t, H-2′,3′,4′, and H-3,4), 4.67, 4.56 (ABq, BnCH2), 4.26
(dd, H-6′a), 4.12 (dd, H-6′b), 3.94-3.44 (m, 4H, H-5,5′,6), 3.50 (dd, H-2). 1
H
J O981135E
NMR data for 9: δ 4.58 (d, H-1′â), 4.64 (d, H-1 R), 5.20 (t, H-3), 5.18 (t,
H-3′), 5.08 (t, H-4′), 5.03 (t, H-2′), 4.66, 4.60 (ABq, BnCH2), 4.24 (dd, H-6′a),
4.16 (dd, H-6′b), 4.05 (dd, H-6a), 3.96-3.91 (m, H-5′), 3.78 (dd, H-6b), 3.70-
3.66 (m, H-5), 3.52 (t, H-4), 3.48 (dd, H-2).
(9) Kochetkov, N. K.; Khorlin, A. J .; Bochkov, A. F. Tetrahedron 1967,
23, 693.
(10) Takeo, K. Carbohydr. Res. 1979, 75, 245. The reported 1H NMR data
of 14: δ 8.22-7.25 (m, 10H, Bz-H), 5.60 (s, 1H, PhCH), 3.38 (s, 3H, CH3),
(8) Typical procedure: To a mixture of 2 (108 mg, 0.56 mmol), 2,4-lutidine
(65 µL, 0.56 mmol), and molecular sieves (0.1 g) in DMF (12 mL) under
nitrogen atmosphere was added 1 (250 mg, 0.61 mmol) followed by silver
triflate (145 mg, 0.56 mmol). The reaction was carried out in a dark room
at room temperature. After being stirred for 5-6 h, the reaction mixture
was evaporated under reduced pressure, and pyridine (dry, 1.0 mL) and
acetic anhydride (0.8 mL) were added. After 2 h, the reaction mixture was
filtered, and the filtrate was washed with aqueous NaCO3 and water and
treated the same way as described in (5). The yields of ortho ester with
unprotected glycoside acceptors were not very high mainly due to the poor
1.97, 1.95, 1.88, and 1.57 (s, 12H, 4CH3CO); mp 185-186 °C; [R]20 +35.3°
D
(c 1.7, CHCl3); Observed: δ 8.17-7.27 (m, 10H, Bz-H), 5.60 (s, 1H, PhCH),
5.16-4.94 (m, 5H, H-1,2,2′,3′,4′), 4.77 (d, 1H, H-1′), 4.43-3.56 (m, 8H,
H-3,4,5,5′,6,6′), 3.38 (s, 3H, CH3), 1.97, 1.95, 1.88, and 1.57 (4s, 12H, 4CH3-
CO); mp 184-186 °C; [R]16 +34.1° (c 1.2, CHCl3). Anal. Calcd for
D
C
35H40O16: C, 58.66; H, 5.63. Found: C, 58.76; H, 5.62.
(11) An authentic sample was synthesized for confirming the selectivity
of entry 3 of Table 1 as follows. Selective 2-O-benzoylation followed by
chloroacetylation of allyl 4,6-O-benzylidene-R-D-glucopyranoside gave allyl
4,6-O-benzylidene-2-O-benzoyl-3-O-chloroacetyl-R-D-glucopyranoside. Re-
moval of benzylidene by acidic hydrolysis followed by selective 6-O-
benzoylation afforded allyl 2,6-di-O-benzoyl-3-O-chloroacetyl-R-D-glucopy-
ranoside. Acetylation followed by dechloroacetylation with thiourea gave
the key compound allyl 4-O-acetyl-2,6-di-O-benzoyl-R-D-glucopyranoside
solubility of the acceptors in the reaction medium.1H NMR data for 5:
δ
5.46, 5.21, 5.08, 5.02, 4.91 (5t, 5H, J ) 9.6 Hz, H-2′,3,3′,4,4′), 4.92 (d, 1H,
J 1,2 ) 3.8 Hz, H-1), 4.84 (dd, 1H, H-2), 4.55 (d, 1H, J 1′,2′ ) 8.0 Hz, H-1′),
4.28 (dd, 1H, H-6′a), 4.13 (dd, 1H, H-6′b), 3.96-3.91 (m, 2H, H-5′,6a), 3.71-
3.69 (m, 1H, H-5), 3.54 (dd, 1H, H-6b), 3.38 (s, 3H, CH3), 2.09, 2.07, 2.05,
2.03, 2.02, 2.01, 2.00 (7s, 7CH3CO). 1H NMR data for 22: δ 5.47-4.90 (m,
8H, H-1, 2′,2′′,3,3′,3′′,4,4′,4′′), 4.85 (dd, 1H, H-2), 4.58, 4.51 (2d, 2H, H-1′,1′′),
4.30-3.50 (m, 9H, H-5,5′,5′′,6,6′,6′′), 3.39 (s, 3H, CH3), 2.10, 2.07, 2.06, 2.05,
2.05, 2.04, 2.03, 2.02, 2.00, 1.99 (10s, 30H, 10CH3CO). 1H NMR data for
35: δ 5.33-5.25 (m, 6H, H-2,2′,3,3′,4,4′), 4.88, 4.70 (2s, 2H, H-1,1′), 4.28
(dd, 1H, H-6′a), 4.14 (dd, 1H, H-6′b), 4.12-3.78 (m, 2H, H-5,5′), 3.80 (dd,
1H, H-6a), 3.58 (dd, 1H, H-6b), 3.43 (s, 3H, CH3), 2.18, 2.17, 2.13, 2.08,
2.06, 2.01, 2.00 (7s, 7CH3CO).
[[R]20 +102° (c 4.0, CHCl3); 1H NMR δ 8.15-7.40 (m, 10H, Bz-H), 5.96-
D
5.74 (m, 1H, CH2dCHCH2-), 5.34-5.09 (m, 4H, H-2, 4, CH2dCHCH2-),
5.21 (d, 1H, J 1,2 ) 4.0 Hz, H-1), 4.58-3.98 (m, 6H, H-3, 5, 6, CH2dCHCH2-),
2.16 (s, 3H, CH3CO). Anal. Calcd for C25H26O9: C, 63.76; H, 5.60. Found:
C, 63.82; H, 5.58], the direct coupling of which with acetobromoglucose in
the presence of AgOTf furnished allyl 4-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-
â-D-glucopyranosyl)-2,6-di-O-benzoyl-R-D-glucopyranoside (18), identical
with the product obtained from rearrangement of 17.