Development of an arming participating group for stereoselective glycosylation and chemoselective oligosaccharide synthesis

Article abstract of DOI:10.1002/anie.200502694

(Chemical Equation Presented) Armed and dangerous: A new armed-disarmed glycosylation strategy (see picture) allows chemoselective introduction of a 1,2-trans glycosidic linkage prior to other linkages through the use of a 2-O-picolyl moiety. This neighbo

Full text of DOI:10.1002/anie.200502694

Angewandte
Chemie
Selective Glycosylations
DOI: 10.1002/anie.200502694
Development of an Arming Participating Group
for Stereoselective Glycosylation and
Chemoselective Oligosaccharide Synthesis**
James T. Smoot, Papapida Pornsuriyasak, and
Alexei V. Demchenko*
Dedicated to Professor Andras Liptak
on the occasion of his 70th birthday
Carbohydrates are involved in many harmful processes such
as bacterial and viral infections, development and growth of
tumors, metastasis, tissue rejection, etc. Many of these
processes are directly associated with deadly diseases of the
21st century including AIDS, cancer, meningitis, hepatitis,
septicemia, etc.[1] Elucidation of the exact mechanisms of the
carbohydrate involvement in disease pathogenesis would be
significantly facilitated if we could rely on the comprehensive
knowledge of the structure, conformation, and properties of
the carbohydrate molecules. It is critical to make complex
carbohydrates more accessible to general chemical, biochem-
ical, and industrial audiences to keep pace with the exploding
area of glycobiology.[2] One way to increase the access to
carbohydrates is to develop reliable methods for stereo-
selective glycoside synthesis and convergent oligosaccharide
assembly that would be applicable to both laboratory and
industrial preparation.
Many, if not all, known convergent strategies for oligo-
saccharide synthesis are based on the selective activation of
one leaving group (LG) over another, which allows a decrease
in the number of synthetic steps.[3,4] One of the most efficient
procedures, the Fraser–Reid “armed–disarmed” approach, is
based on the chemoselectivity principle.[5,6] Accordingly, in
the presence of a mild promoter, a benzylated (armed)
glycosyl donor is chemoselectively activated in preference to
an acylated (disarmed) derivative bearing the same type of
leaving group (Scheme 1). At this stage, a 1,2-cis-linked
disaccharide is obtained preferentially as a result of the
necessity to use the ether-type substituent (arming nonpartic-
ipating group). The obtained disaccharide can then be used
[*] J. T. Smoot, P. Pornsuriyasak, Prof. Dr. A. V. Demchenko
Department of Chemistryand Biochemistry
Universityof Missouri–St. Louis
One UniversityBoulevard, St. Louis, MO 63121 (USA)
Fax: (+1)314-516-5342
E-mail: demchenkoa@umsl.edu
[**] The authors thank the Universityof Missouri–St. Louis and the ACS
PRF 42397-G1 for financial support of this research; the NSF for
grants to purchase an NMR spectrometer (CHE-9974801) and the
mass spectrometer (CHE-9708640) used in this work, Dr. R. S. Luo
for assistance with 500 MHz 2D NMR experiments, and Dr. R. E. K.
Winter and Mr. J. Kramer for HRMS determinations.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 7123 –7126
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7123

Communications
to the synthesis of trans,cis- or trans,trans-linked oligosac-
charide fragments. The use of other techniques, such as
orthogonal[25] or semiorthogonal synthesis[26] offer further
advantages; however, these strategies require a set of at least
two orthogonal leaving groups, which may not always be
accessible. To address this challenge, we initiated studies of
the “inverse armed–disarmed strategy”, which would enable
the stereoselective introduction of a 1,2-trans linkage prior to
another 1,2-trans or 1,2-cis linkage.
Scheme 1. The “armed–disarmed” strategy. Bn=benzyl
Such an inverse approach would require the use of a
neighboring substituent that is capable of both activation and
participation (arming participating group (APG)). For this
purpose we investigated a number of substituents A–C as
APGs (Scheme 3). Our studies were based on STaz glycosides
directly for 1,2-trans glycosylation (in the presence of a more
potent promoter that can activate the disarmed leaving
group) to afford a cis,trans-linked trisaccharide.
This concept was initially designed for O-pentenyl glyco-
sides and was further explored for the chemoselective
glycosidations of other glycosyl donors, including thioglyco-
sides,[7] selenoglycosides,[8] fluorides,[9] phosphoroamidates,[10]
substituted thioformimidates,[11] and S-benzoxazolyl glyco-
sides.[12] Glycal reactivity was also found to be influenced by
disarming acyl substituents.[13] Fraser-Reid et al.[14] and Ley
and co-workers[15] found that torsional effects of cyclic acetal
and dispiroketal protecting groups also promote anomeric
deactivation. Moreover, Zhu and Boons demonstrated that
thioglycosides that are protected as cyclic 2,3-carbonates are
even less reactive than traditional disarmed acylated deriv-
atives.[16] The chemoselective activation principles were
summarized and expanded on by Ley and co-workers,[17]
Wong and co-workers,[18–20] and other groups.[21,22] As a
result, programmable multistep reactivity-based techniques,
including highly efficient one-pot approaches, have become
available.
S-thiazolinyl (STaz) glycosides, recently developed in our
laboratory, were found to be compatible with the armed–
disarmed procedure. Thus, chemoselective activation of 1[23]
over 2[24] in the presence of either AgOTf or Cu(OTf)2
afforded the disaccharide 3 as an anomeric mixture in 79–
88% yield (Scheme 2). The latter was then converted into the
cis,trans-linked trisaccharide 5 by treatment with the acceptor
4.
Scheme 3. Outline of an inverse armed–disarmed strategy.
owing to their superb glycosyl-donor properties.[23] The
preliminary results obtained with a 2-O-(o,o-dimethoxyben-
zyl) glycosyl donor (type A) showed a fairly high diaster-
eoselectivity (up to a/b 1:5), which was a significant improve-
ment over the 2:1 a/b ratio found with perbenzylated STaz
glycosyl donor 1 under the same reaction conditions. Never-
theless, it remained uncertain if the high b stereoselectivity is
attributable to the anticipated participation of a seven-
membered transition state (Scheme 3 or rather to the
increased steric hindrance of the bottom face of the ring.
The same uncertainty was anticipated for glycosyl donors of
type B. To exclude the possibility of the increased steric
hindrance, our further studies focused on the investigation of
the 2-pyridylmethylpicolyl group, which is capable of a six-
membered ring participation through the nitrogen atom (C,
Scheme 3).
The glycosyl donor 8 bearing a picolyl substituent at C2
was synthesized from thioorthoester 6a[27] (Scheme 4). Con-
veniently, the picolyl moiety was introduced with commercial
picolyl bromide in the presence of NaH in DMF. In this
Scheme 2. Chemoselective activation of the STaz glycosides.
a) 1. AgOTf, 1,2-DCE, 1 h, room temperature, 79%, a/b=2:1; or
2. Cu(OTf)2, 1,2-DCE, 3.5 h, room temperature, 88%, a/b=1.5:1;
b) AgOTf, 1,2-DCE, 2.5 h, room temperature, 83%. Bz=benzoyl,
Tf =trifluoromethanesulfonyl, DCE=dichloroethane.
The armed–disarmed strategy thus offers an efficient tool
for the synthesis of oligosaccharides with a cis,trans glyco-
sylation pattern. Although the synthesis of cis,cis-linked
derivatives is also possible,[5,6] this method is not applicable
Scheme 4. Synthesis of the glycosyl donor 8. a) 1) MeONa, MeOH,
2) BnBr, NaH, DMF, 85%; b) HSTaz/TMSOTf, CH2Cl2, 85%;
c) MeONa, MeOH, 92%; d) PicBr, NaH, DMF, 90%. DMF=N,N-
dimethylformamide, Pic=picolyl, TMS=trimethylsilyl.
7124
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7123 –7126

Angewandte
Chemie
context, although an approach for the control of the
anomeric stereoselectivity with a neighboring substitu-
ent that is capable of six-membered participation is
relatively unexplored, a number of moieties for stereo-
selective glycosylation have recently been reported.[28,29]
Having synthesized the glycosyl donor 8, we turned
our attention to glycosidation studies. For this purpose, a
range of differently protected glycosyl acceptors 2, 4,
and 9–12 was selected. Based on our preliminary results
Scheme 5. Proposed reaction mechanism for the glycosidation of 8.
presence of peaks that correspond to two compounds,
presumably 19 (major) and 20 (minor) with a ratio that
varied with the reaction conditions (5:1 (508C) to 20:1 (room
temperature)). During this transition, the signal for the
anomeric H atom of 8 (1-H, Figure 1a) shifted downfield
from d ꢀ 5.30 to ꢀ 6.15 ppm for the anticipated intermediate
19 (1-b-H) and d ꢀ 5.75 ppm for the anticipated intermediate
20 (1-a-H, Figure 1b), which could be an indication of the N-
glycosidic linkage.
(Scheme 2), we employed Cu(OTf)2 either alone, or in
combination with catalytic TfOH as a promoter. All of the
glycosylations summarized in Table 1 proceeded with com-
plete 1,2-trans stereoselectivity.
Table 1: Synthesis of 1,2-trans-linked disaccharides 13–18.
EntryAcceptor
Promoter
Product
Yield [%]
1
2
3
4
5
6
4
9
10
11
12
2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2/TfOH
Cu(OTf)2/TfOH
Cu(OTf)2
13
80
84
82
80
77
74
14
15
16
17
18
Cu(OTf)2/TfOH
Notably, the glycosidation of 8 at room temperature
required significantly more time than that of 1 (48 vs. 1–3 h,
respectively). Therefore, to shorten the reaction time (12–
16 h), all of the glycosylations shown in Table 1 were
performed in 1,2-DCE at 508C. As the chemoselective
activation of 8 in reference to the benzoylated acceptor 2
was also possible under these reaction conditions, the
observed phenomenon could not be simply explained by the
very low reactivity of 8. In this context, perbenzoylated STaz
glycosides typically require 1–20 h for glycosidation at room
temperature.[23] The working hypothesis for subsequent
studies was that upon departure of the promoter-assisted
leaving group, the formed oxocarbenium ion is converted into
a stable intermediate, such as 19, which results from the
anticipated 2-O-picolyl participation through a six-membered
ring (Scheme 5).
To establish whether the process actually follows the
anticipated pathway, the AgOTf-promoted glycosidation of 8
with methanol was monitored by 1H NMR spectroscopy
(synthesis of 21, Scheme 5). It was determined that 8 is
entirely consumed in approximately 1 h, regardless of
whether the reaction is performed at room temperature or
at 508C. At this stage, the 1H NMR spectrum shows the
Figure 1. NMR analysis of the reaction of 8, indicating the formation
of the major intermediate 19. a) 1H NMR spectum of 8; b) 1H NMR
spectrum of the major intermediate 19 and the minor intermediate 20;
c) NOESY spectrum of 19; d) TOCSY spectrum of 19.
Glycosylation experiments performed through glycosyl
donor preactivation with subsequent addition of the glycosyl
acceptor, provided a very similar outcome. The bicyclic
intermediate 19 was isolated from the reaction of 8 with
Cu(OTf)2 (2 h at room temperature) and purified by column
chromatography (silica gel).[30,31] The intermediate 19 was
found to be reactive with potent nucleophiles such as NaOMe,
even in the absence of a promoter, to afford 21 (Scheme 5).
However, in all cases the b intermediate 20 remained
completely inert and could typically be isolated from the
reaction mixture.[32]
The 2D NMR determinations were also found to be very
informative for the structural elucidation of 19. Thus,
correlations in the NOESY experiment between 1-H (d =
6.15 ppm) and the aromatic H atom located adjacent to the
picolyl nitrogen atom (Hc, d = 9.00 ppm) indicated that these
Angew. Chem. Int. Ed. 2005, 44, 7123 –7126
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7125

Communications
H atoms were situated in close proximity (Figure 1c). The
Keywords: carbohydrates · glycosides · glycosylation ·
oligosaccharides · thioimidates
.
TOCSY data revealed that 1-H and the benzylic H atoms of
the picolyl group (Ha and Hb, d = 5.15 ppm) were part of the
same spin system (Figure 1d). Furthermore, long-range
coupling between C1 (d = 84.89 ppm) and Hc was confirmed
by the HMBC data, which indicated that C1 and Hc were
three bonds apart.
Subsequently, to broaden the scope of the developed
approach, we demonstrated that the 2-O-picolyl moiety could
be removed under conventional catalytic hydrogenation
conditions (Pd/C). Thus, hydrogenolysis of the O-picolyl
moiety in 13 with concomitant removal of the benzyl
protecting groups afforded 22 in 92% yield (Scheme 6). The
[1] Z. J. Witczak in Carbohydrates in Drug Design (Eds.: Z. J.
Witczak, K. A. Nieforth), Marcel Dekker, New York, 1997, p. 1.
[2] S. I. Nishimura in Glycoscience: Chemistry and Chemical
Biology, Vol. 3 (Eds.: B. Fraser-Reid, K. Tatsuta, J. Thiem),
Springer, Berlin, 2001, p. 1993.
[3] G.-J. Boons, Tetrahedron 1996, 52, 1095.
[4] A. V. Demchenko, Lett. Org. Chem. 2005, 2, 580.
[5] D. R. Mootoo, P. Konradsson, U. Udodong, B. Fraser-Reid, J.
Am. Chem. Soc. 1988, 110, 5583.
[6] B. Fraser-Reid, U. E. Udodong, Z. F. Wu, H. Ottosson, J. R.
Merritt, C. S. Rao, C. Roberts, R. Madsen, Synlett 1992, 927.
[7] G. H. Veeneman, J. H. van Boom, Tetrahedron Lett. 1990, 31,
275.
[8] D. K. Baeschlin, A. R. Chaperon, V. Charbonneau, L. G. Green,
S. V. Ley, U. Lucking, E. Walther, Angew. Chem. 1998, 110, 3609;
Angew. Chem. Int. Ed. 1998, 37, 3423.
[9] M. I. Barrena, R. Echarri, S. Castillon, Synlett 1996, 675.
[10] S. I. Hashimoto, H. Sakamoto, T. Honda, H. Abe, S. I. Naka-
mura, S. Ikegami, Tetrahedron Lett. 1997, 38, 8969.
[11] H. Chiba, S. Funasaka, K. Kiyota, T. Mukaiyama, Chem. Lett.
2002, 746.
[12] M. N. Kamat, A. V. Demchenko, Org. Lett. 2005, 7, 3215.
[13] R. W. Friesen, S. J. Danishefsky, J. Am. Chem. Soc. 1989, 111,
6656.
[14] B. Fraser-Reid, Z. Wu, C. W. Andrews, E. Skowronski, J. Am.
Chem. Soc. 1991, 113, 1434.
Scheme 6. Picolyl moiety removal and the synthesis of a trans,trans-linked
trisaccharide 23.
[15] G.-J. Boons, P. Grice, R. Leslie, S. V. Ley, L. L. Yeung,
Tetrahedron Lett. 1993, 34, 8523.
[16] T. Zhu, G.-J. Boons, Org. Lett. 2001, 3, 4201.
[17] N. L. Douglas, S. V. Ley, U. Lucking, S. L. Warriner, J. Chem.
Soc. Perkin Trans. 1 1998, 51.
disaccharide 18, obtained by the chemoselective activation of
8 in preference to 2 (Table 1), was glycosidated with 4 in the
presence of AgOTf to afford trans,trans-linked trisaccharide
23 in 91% yield (Scheme 6). Further investigation of this
approach and its application to convergent target synthesis is
underway in our laboratory. We anticipated that the use of a
disarming nonparticipating group for the second activation
step would be required to achieve the ꢀinverseꢁ trans, cis-
linked oligosaccharide pattern. This type of a neighboring
moiety includes, but perhaps is not limited to, halodenoacyls
(trichloroacetyl, Scheme 3) or other functionalities recently
reported by Crich et al.[33]
In conclusion, a new method for stereocontrolled glyco-
sylation was developed. We demonstrated that complete 1,2-
trans selectivity can be achieved with the use of a 2-O-picolyl
moiety, a novel neighboring group that is capable of efficient
participation through a six-membered intermediate. The 2-O-
picolyl moiety has been shown to retain the glycosyl donor in
the armed state as opposed to conventional acyl participating
moieties. The application of a novel arming participating
moiety to complementary chemoselective oligosaccharide
synthesis also has been developed. This new armed–disarmed
glycosylation strategy allows chemoselective introduction of a
1,2-trans glycosidic linkage prior to other linkages, in contrast
to the Fraser-Reid approach. We expect that the developed
technique, along with the classic armed–disarmed approach
will allow convergent chemoselective synthesis of virtually
any oligosaccharide sequence.
[18] Z. Zhang, I. R. Ollmann, X. S. Ye, R. Wischnat, T. Baasov, C. H.
Wong, J. Am. Chem. Soc. 1999, 121, 734.
[19] X. S. Ye, C. H. Wong, J. Org. Chem. 2000, 65, 2410.
[20] F. Burkhart, A. Zhang, S. Wacowich-Sgarbi, C. H. Wong,Angew.
Chem. 2001, 113, 1314; Angew. Chem. Int. Ed. 2001, 40, 1274.
[21] M. Fridman, D. Solomon, S. Yogev, T. Baasov, Org. Lett. 2002, 4,
281.
[22] Y. Wang, X. Huang, L. H. Zhang, X. S. Ye, Org. Lett. 2004, 6,
4415.
[23] A. V. Demchenko, P. Pornsuriyasak, C. De Meo, N. N. Maly-
sheva, Angew. Chem. 2004, 116, 3131; Angew. Chem. Int. Ed.
2004, 43, 3069.
[24] P. Pornsuriyasak, U. B. Gangadharmath, N. P. Rath, A. V.
Demchenko, Org. Lett. 2004, 6, 4515.
[25] O. Kanie, Y. Ito, T. Ogawa, J. Am. Chem. Soc. 1994, 116, 12073.
[26] A. V. Demchenko, C. De Meo, Tetrahedron Lett. 2002, 43, 8819.
[27] N. K. Kochetkov, L. V. Backinowsky, Y. E. Tsvetkov, Tetrahe-
dron Lett. 1977, 3681.
[28] J. H. Kim, H. Yang, J. Park, G. J. Boons, J. Am. Chem. Soc. 2005,
127, 12090.
[29] J. H. Kim, H. Yang, G. J. Boons, Angew. Chem. 2005, 117, 969;
Angew. Chem. Int. Ed. 2005, 44, 947.
[30] Notably, the 1H and 13C NMR data of 19 and 20 are in good
aggreement with those reported for a- and b-N-pyridinium salts:
R. U. Lemieux, A. R. Morgan, Can. J. Chem. 1965, 43, 2205.
[31] K. Bock, C. Pedersen, J. Chem. Soc. Perkin Trans. 2 1974, 293.
[32] One of the possible explanations for the higher stability of 20
could be the influence of the reverse anomeric effect: I.
Tvaroska, T. Bleha, Adv. Carbohydr. Chem. Biochem. 1989, 47,
45.
[33] D. Crich, T. K. Hutton, A. Bangerjee, P. Jayalath, J. Picione,
Tetrahedron: Asymmetry 2005, 16, 105.
Received: August 1, 2005
Published online: October 13, 2005
7126
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 7123 –7126