Comparison of the armed/disarmed building blocks of the D -gluco and d -glucosamino series in the context of chemoselective oligosaccharide synthesis

Article abstract of DOI:10.1021/ol101089u

A very elegant Fraser-Reid armed-disarmed approach recently expanded to the building blocks of the superarmed and superdisarmed series shows very high utility in chemoselective oligosaccharide synthesis. Although a number of studies dedicated to the chemo

Full text of DOI:10.1021/ol101089u

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3078-3081
Comparison of the Armed/Disarmed
Building Blocks of the D-Gluco and
D-Glucosamino Series in the Context of
Chemoselective Oligosaccharide
Synthesis
Teerada Kamkhachorn, Archana R. Parameswar, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis, One
UniVersity BouleVard, St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received May 12, 2010
ABSTRACT
A very elegant Fraser-Reid armed-disarmed approach recently expanded to the building blocks of the superarmed and superdisarmed
series shows very high utility in chemoselective oligosaccharide synthesis. Although a number of studies dedicated to the chemoselective
activation of 2-amino-2-deoxysugars have emerged, little remains known about how the reactivity of the armed/disarmed building blocks
of the neutral sugars directly compares to that of their 2-aminosugar counterparts. A preliminary study of this comparative reactivity
is presented.
The involvement of complex carbohydrates in a wide variety
of disease-related cellular processes has given this class of
natural compounds tremendous diagnostic and therapeutic
potential. While scientists have been able to successfully isolate
certain classes of natural polysaccharides and glycoconjugates,
the availability of pure natural isolates is still inadequate to
address the challenges of modern glycoscience. As a conse-
quence, chemical synthesis has become a viable means to obtain
both natural complex carbohydrates and unnatural analogues
thereof. However, chemical synthesis of oligosaccharides of
even moderate complexity still remains a considerable chal-
lenge. As such, the development of efficient methods for
expeditious oligosaccharide synthesis remains a demanding area
of research.1
10.1021/ol101089u  2010 American Chemical Society
Published on Web 06/07/2010

Fraser-Reid’s rationalization of the fact that “protecting
groups do more than protect”2 opened an entirely new
direction in oligosaccharide synthesis. The chemoselective
armed-disarmed approach makes use of only one class of
leaving group for both the glycosyl donor and glycosyl
acceptor, which is either activated (armed) or deactivated
(disarmed), respectively, by the influence of the protecting
groups.3,4 Usually, protecting groups in both reaction com-
ponents have to be taken into consideration. This allows for
direct coupling between the armed glycosyl donor over the
disarmed glycosyl acceptor in the presence of a suitable
promoter. The disaccharide obtained can then be used for
subsequent direct glycosylation in the presence of a more
powerful promoter capable of activating the disarmed leaving
group. Recently, we expanded the scope of the classic Fraser-
Reid’s armed-disarmed concept for chemoselective oli-
gosaccharide synthesis by developing a series of building
blocks of the superarmed5 and superdisarmed series for
sequential activation.6 This discovery was based on the
phenomenon that we call the O-2/O-5 cooperative effect,7
and the superarming/disarming was achieved by simple
strategic placement of protecting groups. Another approach
to superarming using conformationally modified derivatives
was introduced by Bols et al.8-10
recently our group demonstrated that N-(2,2,2-trichloroet-
hyloxy)carbamoyl (Troc) protection activates (arms) 2-ami-
nosugars in comparison to that of the disarming effect of
the N-phthalimido group.20 However, very little remains
known about how the reactivity of the armed/disarmed
building blocks of the aminosugar series compares to that
of the corresponding armed/disarmed building blocks of the
neutral sugars.
Herein, we present our preliminary study focused on
the comparison of differently protected building blocks
of the D-gluco and D-glucosamino series. Thioglycosides
remain among the most common glycosyl donors and by
far the most investigated building blocks in various
expeditious strategies, including: two-step activation,21
armed-disarmed,22 active-latent,23 orthogonal,24,25 one-
pot,26,27 etc.28 Therefore, we chose to base this study on the
S-ethyl glycosides and for the comparative reactivity studies
obtained the superarmed donor 1,6 two N-substituted SEt
glycosides (refer to the Supporting Information for their
synthesis) armed 2 and disarmed 3, as well as the superd-
isarmed thioglycoside 4 (Figure 1).29
While the armed-disarmed concept has been developed
and applied to a broad range of neutral sugar derivatives,1
significantly less information has been acquired with building
blocks of the 2-amino-2-deoxy series.11 While a significant
disparity in reaction rates between various aminosugar
derivatives has been observed,12-15 no systematic studies
have yet become available.16-18 Baasov et al.19 and more
(1) Smoot, J. T.; Demchenko, A. V. AdV. Carbohydr. Chem. Biochem.
2009, 62, 161–250.
Figure 1. Glycosyl donors of the armed (1 and 2) and disarmed
series (3 and 4).
(2) Fraser-Reid, B.; Jayaprakash, K. N.; Lo´pez, J. C.; Go´mez, A. M.;
Uriel, C. In Frontiers in Modern Carbohydrate Chemistry; Demchenko,
A. V., Ed.; ACS Symposium Series; Oxford University Press: New York,
2007; Vol. 960, pp 91-117.
The key requirement for any chemoselective activation to
take place is the availability of a suitable promoter that can
differentiate between the armed and disarmed building
blocks. Therefore, having obtained glycosides 1-4, our next
aim was to find a promoter (or promoters) that would be
well suited for the activation of each of these glycosyl donors.
It is well established that thioglycosides can be activated
under a variety of reaction conditions, and the test glyco-
(3) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583–5584
(4) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem.
1990, 55, 6068–6070
.
.
(5) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2103–2106.
(6) Premathilake, H. D.; Mydock, L. K.; Demchenko, A. V. J. Org.
Chem. 2010, 75, 1095–1100.
(7) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215–3218.
(8) Jensen, H. H.; Pedersen, C. M.; Bols, M. Chem.sEur. J. 2007, 13,
7576–7582
(9) Pedersen, C. M.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc.
2007, 129, 9222–9235
.
.
(10) Pedersen, C. M.; Marinescu, L. G.; Bols, M. Chem. Commun. 2008,
(20) Bongat, A. F. G.; Kamat, M. N.; Demchenko, A. V. J. Org. Chem.
2007, 72, 1480–1483.
2465–2467
.
(11) Bongat, A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342,
(21) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. J. Am.
Chem. Soc. 1984, 106, 4189–4192.
374–406.
(12) Ellervik, U.; Magnusson, G. Carbohydr. Res. 1996, 280, 251–260
(13) Dullenkopf, W.; Castro-Palomino, J. C.; Manzoni, L.; Schmidt,
R. R. Carbohydr. Res. 1996, 296, 135–147
(14) Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.;
Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734–753
(15) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1998, 51–65
.
(22) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31,
275–278.
.
(23) Roy, R.; Andersson, F. O.; Letellier, M. Tetrahedron Lett. 1992,
33, 6053–6056.
.
(24) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073–
12074
.
.
(25) Pornsuriyasak, P.; Demchenko, A. V. Chem.sEur. J. 2006, 12,
6630–6646
(26) Ye, X. S.; Wong, C. H. J. Org. Chem. 2000, 65, 2410–2431
(27) Huang, X.; Huang, L.; Wang, H.; Ye, X. S. Angew Chem., Int. Ed.
(16) Hansson, J.; Garegg, P. J.; Oscarson, S. J. Org. Chem. 2001, 66,
6234–6243
(17) Ritter, T. K.; Mong, K.-K. T.; Liu, H.; Nakatani, T.; Wong, C.-H.
.
.
.
Angew. Chem., Int. Ed. 2003, 42, 4657–4660
(18) Yamada, T.; Kinjyo, S.; Yoshida, J.; Yamago, S. Chem. Lett. 2005,
34, 1556–1557
(19) Fridman, M.; Solomon, D.; Yogev, S.; Baasov, T. Org. Lett. 2002,
4, 281–283.
.
2004, 43, 5221–5224.
(28) Boons, G. J.; Geurtsen, R.; Holmes, D. Tetrahedron Lett. 1995,
.
36, 6325–6328.
(29) Mydock, L. K. Doctoral Dissertation, University of MissourisSt.
Louis, 2010.
Org. Lett., Vol. 12, No. 13, 2010
3079

Table 1. Search for the Appropriate Promoter for Glycosylation Reactions
a No significant difference between reactions at rt (shown) and at -20 °C, but the latter provided better stereoselectivity for the synthesis of 9 (R/ꢀ )
2/1, entry 4). b Incomplete reaction.
sylations of glycosyl acceptor 530 were initially performed
using common promoters. Not unexpectedly, NIS/TfOH was
very effective as the promoter. However, these activations
were too fast, even at low temperature. As a result, all
glycosyl donors reacted at a similar pace to provide very
good to excellent yields (86-98%) for the formation of
disaccharides 6-9 (Table 1, entries 1-4). Subsequently, we
chose a significantly milder promoter MeOTf, which was
very effective in our previous chemoselective studies with
2-aminosugars.20 Although the differentiation between build-
ing blocks of the armed series 1 and 2 in comparison to that
of the disarmed series 3 and 4 was notable (2-3 h vs 6 h,
respectively, entries 5-8), and the yields were excellent, we
continued our search for promoters. Recently, we reached
successfully differentiated superarmed vs armed building
blocks of the D-gluco series.6 The differentiation was
particularly efficient in the presence of iodine, which was
introduced as a mild promoter for thioglycoside activation
by Field et al.31 Also herein, reactions promoted with iodine
(3.3 equiv) showed a good differentiation trend ranging from
15 min activation of 1 at rt to 8 h activation of 2 at 50 °C
and activations of 3 and 4 that could not be driven to
completion even after 24 h at 50 °C (entries 9-12).
We deemed these results sufficient for proof of preliminary
differentiation and began studying direct competitive gly-
cosylations of glycosyl donors (1-4) with acceptor 5. These
competitive reactions were set up to allow two glycosyl
donors compete for the glycosyl acceptor 5 in a single flask. In
these experiments, 3.3 equiv of iodine was used to activate two
glycosyl donors (1.3 equiv each (see Table 2)) over the glycosyl
acceptor 5 (1.0 equiv). As anticipated, the superarmed glycosyl
donor 1 outperformed the donor 2: it reacted smoothly, and
the glycosyl acceptor 5 was entirely consumed within 1 h at rt.
As a result, the disaccharide 6 was isolated in 81% yield as the
sole product since no trace of disaccharide 7 could be detected
and the less reactive glycosyl donor 2 was recovered in 82%
(30) Kuester, J. M.; Dyong, I. Justus Liebigs Ann. Chem. 1975, 2179–
2189.
(31) Kartha, K. P. M.; Aloui, M.; Field, R. A. Tetrahedron Lett. 1996,
37, 5175–5178.
3080
Org. Lett., Vol. 12, No. 13, 2010

Table 2. Competitive Glycosylations Using Glycosyl Donors 1-4
Scheme 1. Chemoselective Synthesis of Trisaccharide 13
entry donors time (H) products yield (%) donor recovery (%)
1a
2
1 + 2
2 + 3
3 + 4
2 + 4
1
24
24
6
7
81
95
53 + 36
98
82 (2)
67 (3)
49 (4)
87 (4)
3
8 + 9
7
4b
9.5
a Reaction at rt, all others at 50 °C. b Incomplete reaction.
yield (entry 1). Subsequently, we investigated the relative
reactivities of glycosyl donors 2 and 3, and as expected, the
armed glycosyl donor 2 outperformed the disarmed donor 3: it
reacted smoothly and the glycosyl acceptor 5 was entirely
consumed within 24 h at 50 °C. As a result, the disaccharide 7
was isolated in 95% yield as the sole product and no trace of
disaccharide 8 was detected (entry 2). The less reactive glycosyl
donor 3 was recovered in 67% yield.
When relative reactivities of glycosyl donors 3 and 4 were
compared, both disaccharides 8 and 9 were formed in 53
and 36% yield, respectively, as a result of insufficient
reactivity difference of these two classes of disarmed glycosyl
donors (entry 3). It should be noted that the reaction was
very sluggish and did not go to completion even after 48 h.
With the focus of the chemoselective activation of the
aminosugars over their neutral counterparts, we also inves-
tigated relative reactivities of glycosyl donors 2 and 4, and
to our delight, the aminosugar donor 2 clearly outperformed
the disarmed glucosyl donor 4. This reaction proceeded very
smoothly, and the glycosyl acceptor 5 was entirely consumed
within 9.5 h at 50 °C. As a result, the disaccharide 7 was
isolated in 98% yield as the sole product. No formation of
disaccharide 9 was detected (entry 4), and the less reactive
glycosyl donor 4 was recovered in 87% yield.
The knowledge gained from the competitive glycosylations
created a solid foundation for attempting a multistep synthesis
of oligosaccharides with alternating neutral sugar-aminosugar
unit, a sequence commonly seen in many natural glycocon-
jugates and polysaccharides. As verification of the promising
results achieved in competition experiments, direct chemose-
lective activation of the superarmed glycosyl donor 1 over
the 2-amino-2-deoxy acceptor 10 (see the Supporting Infor-
mation for the synthesis) was investigated. Initially, when
glycosidation of 1 with acceptor 10 was carried out at rt,
the requisite disaccharide 11 was isolated in a poor yield
(see the Supporting Information), and the formation of a
number of byproducts was noted. However, when the
reaction was performed at -20 °C, the disaccharide 11 was
isolated in 77% yield (Scheme 1). As expected, a very similar
outcome was achieved in reactions with 2-deoxy-2-phthal-
imido acceptor (see the Supporting Information for details).
Encouraged by this promising result, we decided to apply
this approach to the synthesis of a trisaccharide. For this
purpose, we obtained glycosyl acceptor 12 derived from the
superdisarmed glycosyl donor 4 (see the Supporting Infor-
mation for synthesis). Chemoselective activation of the
disaccharide donor 11 over superdisarmed acceptor 12 was
successful in the presence of iodine at 50 °C and the target
trisaccharide 13 was isolated in 60% yield.
In conclusion, we performed a comparative study of the
armed and disarmed building blocks of the D-gluco and
glucosamino series. Competitive glycosylations clearly showed
the reactivity pattern of the building blocks investigated. The
synthesis of trisaccharide 13 performed by a two-step
chemoselective activation sequence clearly illustrated the
versatility of the developed approach in the context of the
synthesis of oligosaccharides with alternating neutral and
aminosugar units. It is apparent that the S-ethyl leaving group
of the trisaccharide 13 can be directly activated for the
subsequent synthesis of larger oligosaccharides. This activa-
tion, however, may need to employ a significantly more
powerful promoter, such as NIS/TfOH, and therefore is not
covered by the scope of this comparative chemoselective
activation study.
Acknowledgment. We thank NIGMS (GM077170) and
AHA (0855743G) for financial support of this work. Dr.
Winter and Mr. Kramer (UMsSt. Louis) are thanked for
HRMS determinations.
Supporting Information Available: Extended experi-
mental data, experimental procedures, and 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101089U
Org. Lett., Vol. 12, No. 13, 2010
3081