Simple glycosylation reaction of allyl glycosides

Article abstract of DOI:10.1021/jo070512x

(Chemical Equation Presented) A simple glycosylation strategy employing only allyl glycosides is described. In a one-pot fashion, an allyl glycoside is first isomerized to the reactive 1-prop-en-yl glycoside intermediate, which subsequently undergoes glyc

Full text of DOI:10.1021/jo070512x

can be avoided, dramatically improving the overall efficiency
of an oligosaccharide synthesis. However, this straightforward
strategy is difficult to execute due to the fact that commonly
utilized LGs are not stable enough to be anomeric PGs. Although
thio3 and n-pentyl4 groups merit themselves as anomeric PGs
as well as anomeric LGs, consecutive utilization of thioglyco-
sides or n-pentyl glycosides in an oligosaccharide synthesis from
the reducing end often requires the anomeric group in the
glycosyl acceptors to be properly disarmed to avoid undesired
activation. This reactivity tuning process involves extensive
protecting group manipulations and/or anomeric group modi-
fications.5,6
Simple Glycosylation Reaction of Allyl Glycosides
Pengfei Wang,* Pranab Haldar, Yun Wang, and Huayou Hu
Department of Chemistry, UniVersity of Alabama at
Birmingham, Birmingham, Alabama 35294
wangp@uab.edu
ReceiVed March 12, 2007
Here, we report a simple glycosylation strategy wherein the
anomeric PG placed in the very first step of a glycosylation
building block preparation also acts as a latent LG. We envision
that the widely used allyl group is ideal in serving this dual
role (i.e., as a PG and LG) (Scheme 1). Thus, the readily
available allyl glycoside 1 can be isomerized to the prop-1-
enyl glycoside 2 that should be a reactive intermediate under
certain activation conditions.7 With the glycosyl acceptor 3, a
new saccharide 4 will form that can serve as a glycosyl donor
for the next round of glycosylation also with an allyl glycoside
acceptor. This iterative process may continue until the targeted
oligosaccharide is synthesized. With this novel glycosylation
strategy, preparation of an oligosaccharide can start from either
the reducing end or the non-reducing end without any reactivity
tuning of the anomeric group.
O-Allyl 2,3,4-tri-O-benzyl-D-xylopyranoside 5 (â/R ) 3:1)
was first chosen as the donor to test the new approach (Scheme
2). Clean isomerization of 5 to the prop-1-enyl glycoside 6 was
achieved in the presence of 1 mol % of [Ir(COD)(PMePh2)2]-
PF6, pre-activated with hydrogen, in THF at room temperature.8
Upon completion of the isomerization in 90 min, THF was
removed, and the glycosyl acceptor (NuH) in acetonitrile was
A simple glycosylation strategy employing only allyl gly-
cosides is described. In a one-pot fashion, an allyl glycoside
is first isomerized to the reactive 1-prop-en-yl glycoside
intermediate, which subsequently undergoes glycosylation
with a glycosyl acceptor, promoted by NIS at room tem-
perature.
Chemical synthesis of structurally well-defined olio- or
polysaccharides and glycoconjugates is of the utmost importance
to life sciences.1 Numerous efforts have been devoted to the
development of novel glycosylation methodologies during the
last several decades;2 however, despite progress in the field,
the synthesis of complex carbohydrates in an efficient fashion
remains a challenging task.
Ideally, in the preparation of glycosylation building blocks,
the group first installed at the anomeric position of an
unprotected free sugar unit should remain at that position as a
protecting group (PG) against further functional group adjust-
ment on this glycosyl building block. At the glycosylation step,
this same anomeric PG should serve as a latent leaving group
(LG). In this manner, time-consuming anomeric group replace-
ment (i.e., from PG to LG) and intermediate purification
frequently encountered in a conventional carbohydrate synthesis
(3) Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N. Carbohydr. Res. 1973,
27, 55.
(4) (a) Fraser-Reid, B.; Konradsson, P.; Mootoo, D. R.; Udodong, U.
Chem. Commun. 1988, 823. (b) Mootoo, D. R.; Date, V.; Fraser-Reid, B.
J. Am. Chem. Soc. 1988, 110, 2662.
(5) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J.
Am. Chem. Soc. 1988, 110, 5583. (b) Konradsson, P.; Mootoo, D. R.;
McDevitt, R. E.; Fraser-Reid, B. Chem. Commun. 1990, 270. (c) Fraser-
Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem. 1990, 55,
6068. (d) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269. (e) Ley,
S. V.; Priepke, H. W. M.; Angew. Chem., Int. Ed. Engl. 1994, 33, 2292. (f)
Baeschlin, D. K.; Chaperon, A. R.; Charbonneau, V.; Green, L. G.; Ley, S.
V.; Lu¨cking, U.; Walther, E. Angew. Chem., Int. Ed. 1998, 37, 3423. (g)
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 734. (h) Ye, X.-S.; Wong, C.-H. J.
Org. Chem. 2000, 65, 2410. (i) Huang, L.; Wang, Z.; Huang, X. Chem.
Commun. 2004, 1960.
(6) Several iterative glycosylation methods employing thioglycosides,
which do not require anomeric group reactivity tuning, have been recently
published: (a) Yamago, S.; Yamada, T.; Maruyama, T.; Yoshida, J.-I.
Angew. Chem., Int. Ed. 2004, 43, 2145. (b) Huang, X.; Huang, L.; Wang,
H.; Ye, X.-S. Angew. Chem., Int. Ed. 2004, 43, 5221. (c) Yamada, T.;
Takemura, K.; Yoshida, J.-I.; Yamago, S. Angew. Chem., Int. Ed. 2006,
45, 7575.
(7) (a) The only known case of utilizing a prop-1-enyl glycoside as the
glycosyl donor was reported by Sinay¨ and coworkers.7c In their procedure,
a stoichiometric amount of TMSOTf was used as the promoter. (b) Sinay¨
et al.,7c Boons and Isles,7d and Chenault et al.7e also explored using other
vinyl glycosides as glycosyl donors. (c) Marra, A.; Esnault, J.; Veyrieres,
A.; Sinay¨, P. J. Am. Chem. Soc. 1992, 114, 6354. (d) Boons, G.-J.; Isles, S.
J. Org. Chem. 1996, 61, 4262. (e) Chenault, H. K.; Castro, A.; Chafin, L.
F.; Yang, J. J. Org. Chem. 1996, 61, 5024.
* Corresponding author. Tel.: (205) 996-5625; fax: (205) 934-2543.
(1) (a) Kova´e`, P. ACS. Symp. Ser. 1994, 560. (b) Dwek, R. A. Chem.
ReV. 1996, 96, 683. (c) Burton, D. R.; Dwek, R. A. Science 2006, 313,
627.
(2) For reviews, see: (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982,
1, 155. (b) Sinay¨, P. Pure Appl. Chem. 1991, 63, 519. (c) Toshima, K.;
Tatsuta, K. Chem. ReV. 1993, 93, 1503. (d) Schmidt, R. R.; Kinzy, W.
AdV. Carbohydr. Chem. Biochem. 1994, 50, 21. (e) Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. (f) Boons,
G.-J. Tetrahedron 1996, 52, 1095. (g) PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; Ch. 12-22. (h)
Hanessian, S.; Lou, B. Chem. ReV. 2000, 100, 4443. (i) Jung, K.-H.; Mueller,
M.; Schmidt, R. R. Chem. ReV. 2000, 100, 4423. (j) Nicolaou, K. C.;
Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576. (k) Sears, P.; Wong,
C. H. Science 2001, 291, 2344. (l) Fraser-Reid, B. O.; Tatsuta, K.; Thiem,
J. Glycoscience 1-3; Springer-Verlag: Berlin, 2001. (m) Kiefel, M. J.;
von Itzstein, M. Chem. ReV. 2002, 102, 471. (n) Davis, B. G. Chem. ReV.
2002, 102, 579. (o) Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35. (p)
Li, M.; Shao, J.; Xiao, M.; Wang, P. G. ACS. Symp. Ser. 2004, 873, 165.
(q) Yu, B.; Yang, Z.; Cao, H. Curr. Org. Chem. 2005, 9, 179. (r) Pellissier,
H. Tetrahedron 2005, 61, 2947. (s) El Ashry, E. S. H.; Awad, L. F.; Atta,
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341, 1282.
10.1021/jo070512x CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/20/2007
5870
J. Org. Chem. 2007, 72, 5870-5873

SCHEME 1
SCHEME 2
introduced. Treatment of the glycosyl donor and acceptor with
NIS at room temperature afforded the desired glycosylation
product within a few minutes.9 Presumably, reaction of 6 with
NIS led to the formation of the iodo oxocarbenium intermediate
7 and subsequently to the oxocarbenium 8. In the presence of
a glycosyl acceptor (NuH), a new glycoside 9 formed. With 1
equiv of allyl rhamnoside 10 as the glycosyl acceptor, disac-
charide 11 was obtained in 74% yield with a â/R ratio of 1.6:1
after treatment of 1 equiv of NIS. The yield was further
improved to 83% by increasing the donor/NIS/acceptor ratio
from 1:1:1 to 1.5:1.5:1 (Table 1, entry 1). With acceptors 12
and 13, the desired disacchrides 14 and 15 both were obtained
in 85% yields by using 1.5 equiv of donors (Table 1, entries 2
and 3). The â/R ratios varied with different acceptors under the
same reaction conditions, but the â anomers were always
favored.
The same protocol was also extended to the glycosyl donor
16. Thus, isomerization of 16 (â/R ) 1:3) with 3% of the
catalyst was completed in 90 min at room temperature.
Subsequent glycosylation with acceptors 10, 12, or 17 afforded
the disaccharides 18-20 in good yields (Table 1, entries 4-6).
It is worth noting that acid sensitive isopropylidene groups in
the products survived the reaction conditions (Table 1, entries
1, 3, and 4). Most importantly, the anomeric allyl protecting
groups in the products remained intact (Table 1, entries 1, 2,
and 4-6),10 which will allow an iterative glycosylation approach
to oligosaccharides with only allyl glycosides.
The new approach was further tested in the synthesis of a
protected trisaccharide fragment of QS-21Axyl, a powerful and
frequently used immune adjuvant (Scheme 3).11 The new glycos-
ylation procedure with the glycosyl donor 14â and the glycosyl
donor 10 afforded the trisaccharide in 67% yield with a â/R
ratio of 1.3:1 at the new bond formation site, favoring the desired
21ââ. With the three allyl building blocks 5, 10, and 12, the
protected trisaccharide fragment of QS-21Axyl was prepared in
seven steps from unprotected D-xylose and L-rhamnose.
Alternatively, synthesis of the same trisaccharide was per-
formed starting from the non-reducing end of the rhamnoside
10 (Scheme 3). Thus, the allyl xyloside 12 was first protected
with a PMB group and then isomerized to the corresponding
anomeric enol ether in the presence of 1 mol % of [Ir(COD)-
(PMePh2)2]PF6 for 15 h at room temperature. Subsequent
glycosylation with the acceptor 10 in acetonitrile activated by
NIS provided the disaccharide 22 in 72% yield as a 1:1.6 R,â
mixture, favoring the desired 22â. Removal of the PMB group
with DDQ afforded the glycosyl acceptor 23â in 83% yield.
The final step of glycosylation of 23â with the donor 5 generated
the trisaccharide in 75% yield as a 1:2 R,â mixture, favoring
the desired anomer 21ââ.
(8) (a) Baudry, D.; Ephritikhine, M.; Felkin, H. J. Chem. Commun. 1978,
694. (b) [Ir(COD)(PMePh2)2]PF6 is commercially available (CAS number:
38465-86-0). Other catalysts were not screened for the isomerization step.
(9) (a) Treatment of prop-1-enyl glycosides with NIS or NBS in the
presence of water has been used in removing allyl protecting groups in a
two-step sequence.9b Interestingly, the replacement of water with other
nucleophiles in this protocol for oligosaccharide synthesis had never been
explored. (b) Halkes, K. M.; Slaghek, T. M.; Vermeer, H. J.; Kamerling, J.
P.; Vliegenthart, J. F. G. Tetrahedron Lett. 1995, 36, 6137.
(10) Prolonged reaction time did not lead to observable isomerization
of the allyl group in the products in the presence of the iridium catalyst
residue.
(11) Wang, P.; Kim, Y.-J.; Navarro-Vallalobos, M.; Rohde, B. D.; Gin,
D. Y. J. Am. Chem. Soc. 2005, 127, 3256 and references cited therein.
J. Org. Chem, Vol. 72, No. 15, 2007 5871

TABLE 1. One-Pot Glycosylation of Allyl Glycosides
a Two anomers were separated by flash column chromatography. b Donor/NIS/acceptor ) 1:1:1. c Donor/NIS/acceptor ) 1.5:1.5:1. d Donor/NIS/acceptor
) 2:2:1.
In summary, a simple glycosylation strategy employing only
allyl glycosides was described. In a one-pot fashion, an allyl
glycoside was first isomerized to the reactive 1-prop-en-yl
glycoside intermediate that subsequently underwent glycosyla-
tion promoted by NIS at room temperature. This single
procedure can be repeatedly used to prepare oligosaccharides.
5872 J. Org. Chem., Vol. 72, No. 15, 2007

SCHEME 3
4.36 (AB, J ) 11.7 Hz, 1 H), 4.26 (t, J ) 9.1 Hz, 1 H), 4.09
(ABMX2, J ) 12.8, 5.1, 1.4 Hz, 1 H), 3.94 (dd, J ) 11.5, 4.9 Hz,
1 H), 3.90 (ABMX2, J ) 12.8, 5.8, 1.1 Hz, 1 H), 3.67-3.50 (m, 4
H), 3.48-3.34 (m, 3 H), 3.16 (dd, J ) 11.6, 10.0 Hz, 1 H); 13C
NMR (101 MHz, CDCl3) δ 139.0, 138.9, 138.8, 138.4, 138.3, 133.8,
128.7, 128.5, 128.5, 128.5, 128.2, 128.2, 128.0, 128.0, 128.0, 127.8,
127.8, 127.7, 118.5, 103.2, 95.4, 84.2, 83.0, 81.1, 78.5, 75.9, 75.8,
75.2, 73.6, 73.6, 73.5, 68.2, 63.9, 60.2; FTIR (neat) cm-1 3062,
3030, 2886, 1496, 1363, 1076; HRMS (ESI) m/z: Calcd for
C48H52O9Na (M + Na) 795.3509, found 795.3531.
Disaccharide 14r. Rf 0.30 (petroleum ether/ethyl acetate 7:1);
1H NMR (400 MHz, CDCl3) δ 7.45-7.15 (m, 25 H), 5.60 (d, J )
3.5 Hz, 1 H), 5.30 (dq, J ) 17.2, 1.6 Hz, 1 H), 5.22 (ddt, J ) 10.3,
1.7, 1.1 Hz, 1 H), 4.92 (s, 2 H), 4.76-4.71 (m, 2 H), 4.68-4.52
(m, 7 H), 4.19 (t, J ) 9.2 Hz, 1 H), 4.12 (ABMX2, J ) 11.5, 5.1,
1.4 Hz, 1 H), 4.10-4.04 (m, 1 H), 4.00-3.92 (m, 2 H), 3.59-3.46
(m, 5 H), 3.44 (dd, J ) 9.7, 3.6 Hz, 1 H); 13C NMR (101 MHz,
CDCl3) δ 139.2, 138.8, 138.4, 138.3, 138.0, 134.0, 128.8, 128.6,
128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 127.8, 127.7, 127.7, 127.2,
118.6, 97.0, 95.2, 81.4, 80.0, 79.4, 78.8, 78.1, 75.8, 74.8, 73.6, 73.2,
73.0, 72.5, 68.2, 60.4, 59.6; FTIR (neat) cm-1 3030, 2873, 1032;
HRMS (ESI) m/z: Calcd for C48H52O9Na (M + Na) 795.3509,
found 795.3537.
However, with NIS as the activator, disarmed glycosides did
not undergo the desired glycosylation. Further exploration to
expand the application scope of this method is in progress.
Experimental Section
General Procedure for the Glycosylation Reaction (Synthesis
of Disaccharide 1412). [Ir(COD)(PMePh2)2]PF6 (13 mg, 0.015
mmol) in 1.0 mL of THF was degassed and stirred under hydrogen
atmosphere for 15 min at room temperature. The clear solution
obtained was injected to O-allyl 2,3,4-tir-O-benzylxylopyranoside
5 (â/R ) 4:1) (622 mg, 1.35 mmol) in 10 mL of THF under nitrogen
at room temperature. The reaction mixture was stirred for 90 min,
and THF was removed. The residue was azeotroped with toluene
and then was treated with O-allyl 2,4-di-O-benzyl-R-D-xylopyra-
noside 12 (370 mg, 1.0 mmol) in 5.0 mL of acetonitrile, followed
by NIS (304 mg, 1.5 mmol). The reaction was stirred under argon
at room temperature for 15 min. The reaction solution was then
concentrated and purified with flash column chromatography (eluted
with benzene/ethyl acetate 19:1) to afford a mixture of 14â and
14R, 641 mg (85%), Rf 0.24. The mixture of anomers was separated
by a second flash column and eluted with petroleum ether/ethyl
acetate 7:1.
Disaccharide 14â. Rf 0.4 (petroleum ether/ethyl acetate 7:1);
1H NMR (400 MHz, CDCl3) δ 7.45-7.15 (m, 25H), 5.87 (m, 1
H), 5.27 (dq, J ) 17.2, 1.5 Hz, 1 H), 5.20 (ddt, J ) 10.3, 1.6, 1.1
Hz, 1 H), 4.96 (AB, J ) 11.6 Hz, 1 H), 4.95 (d, J ) 7.5 Hz, 1 H),
4.91 (AB, J ) 11.0 Hz, 2 H), 4.86-4.80 (m, 2 H), 4.72 (AB, J )
11.7 Hz, 1 H), 4.65 (AB, J ) 12.0 Hz, 1 H), 4.62 (AB, J ) 11.5
Hz, 1 H), 4.60 (AB, J ) 10. 7 Hz, 1 H), 4.57 (d, J ) 3.5 Hz, 1 H),
Acknowledgment. This work was supported by the Uni-
versity of Alabama at Birmingham. We thank Dr. M. Renfrow
of the UAB Biomedical FT-ICR MS Laboratory for assistance
in mass spectroscopy.
Supporting Information Available: General information,
spectroscopic data, and NMR spectra for glycoside products 11,
14, 15, 18-21, and 23. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Known compounds but no detailed spectroscopic data were reported.
See: Fukase, K.; Hase, S.; Ikenaka, T.; Kusumoto, S. Bull. Chem. Soc.
Jpn. 1992, 65, 436.
JO070512X
J. Org. Chem, Vol. 72, No. 15, 2007 5873