The first polymer-assisted solution-phase synthesis of deoxyglycosides

Article abstract of DOI:10.1021/ol016545v

Figure presented A glycosylation protocol for the synthesis of 2-deoxyglycosides has been developed which is based on the use of polymer-bound reagents. Glycals are transformed into 2-iodoglycosyl acetates using polymer-bound bis(acetoxy)iodate(I) complex

Full text of DOI:10.1021/ol016545v

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3623-3626
The First Polymer-Assisted
Solution-Phase Synthesis of
Deoxyglycosides
,†
Andreas Kirschning,* Martin Jesberger,‡ and Andreas Scho1nberger‡
Institut fu¨r Organische Chemie der UniVersita¨t HannoVer, Schneiderberg 1B,
D-30167 HannoVer, Germany, and Technische UniVersita¨t Clausthal, Leibnizstrasse 6,
D-38678 Clausthal-Zellerfeld, Germany
andreas.kirschning@oci.uni-hannoVer.de
Received August 8, 2001
ABSTRACT
A glycosylation protocol for the synthesis of 2-deoxyglycosides has been developed which is based on the use of polymer-bound reagents.
Glycals are transformed into 2-iodoglycosyl acetates using polymer-bound bis(acetoxy)iodate(I) complex (1). Activation of the anomeric center
is achieved by employing polymer-bound silyl triflate (2). In the presence of different glycosyl acceptors, 2-deoxy-2-iodoglycosides are generated
in very good yields. Furthermore, it is shown that this method can be embedded in multistep sequences toward glycosylated testosterone and
rhodinosyl-olivosyl-olivoside.
Glycoconjugates composed of an (oligo)deoxysugar portion
and an aglycon are widely distributed in nature and are of
wide clinical importance.1 Importantly, alterations of the
saccharide structures can result in improved biological
activity, in particular against drug-resistant microorganisms.2
However, preparation of these glycoconjugates is still a
challenging topic. In view of the importance and success of
solid-phase chemistry, various polymer-supported syntheses
of oligosaccharides including deoxysugar analogues3 have
been developed.4
One major disadvantage of solid-phase synthesis is its
requirement of robust linkers which are stable under various
reaction conditions. In addition, the target glycoconjugate
needs to be cleaved from the linker without affecting the
diverse functionalities present in both the saccharide and the
aglycon domain.
(3) Jesberger, M.; Jaunzems, J.; Jung, A.; Jas, G.; Scho¨nberger, A.;
Kirschning, A. Synlett 2000, 1289-1293. (b) Hunt, J. A.; Roush, W. R. J.
Am. Chem. Soc. 1996, 118, 9998-9999.
† Institut fu¨r Organische Chemie der Universita¨t Hannover.
‡ Technische Universita¨t Clausthal.
(1) (a) Kirschning, A.; Bechthold, A.; Rohr, J. Top. Curr. Chem. 1997,
188, 1-88. (b) Kennedy, J. F., White, C. A. BioactiVe Carbohydrates in
Chemistry, Biochemistry, and Biology; Ellis Horwood: Chichester, 1983.
(c) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem. 1996, 108, 1482-
1522; Angew. Chem., Int. Ed. Engl. 1996, 35, 1380-1419.
(2) For example, modifying the aminodeoxy sugar vancosamine as a
constituent of the antibiotic vancomycin can dramatically increase the
activity against vancomycin-resistant strains: Malabarba, A.; Nicas, T. I.;
Thompson, R. C. Med. Res. ReV. 1997, 17, 69-173.
(4) Reviews: (a) Polymers as Aids in Organic Chemistry; Mathur, N.
K., Narang, C. K., Williams, R. E., Eds.; Academic Press: New York, 1980;
pp 105-116. (b) Kahne, D. Curr. Opin. Chem. Biol. 1997, 1, 130-135.
(c) Danishefsky, S. J.; Roberge, J. Y. Glycopept. Relat. Compd. 1997, 245-
294. (d) Sofia, M. J. Mol. DiV. 1998, 3, 75-94. (e) Schweizer, F.; Hindsgaul,
O. Curr. Opin. Chem. Biol. 1999, 3, 291-298. (f) Osborn, H. M. I.; Khan,
T. H. Tetrahedron 1999, 55, 1807-1850. (g) St. Hilaire, P. M.; Meldal,
M. Angew. Chem. 2000, 112, 1210-1228; Angew. Chem., Int. Ed. 2000,
39, 1162-1179.
10.1021/ol016545v CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001

Recently, the development and application of polymer-
supported reagents have seen a dramatic increase5 which has
moved functionalized polymers from an academic curiosity
to a widely recognized synthetic technique. This hybrid solid/
solution-phase technique possesses all the intrinsic advan-
tages of classical solid-phase techniques (i.e., use of excess
reagents to drive reactions to completion followed by a
simple filtration step to isolate products). Additionally, all
advantages associated with solution-phase chemistry are
exploited here.
D-olival 5 was converted into glycosyl acetates 6a,b (R-
manno/â-gluco 2.7:1) in excellent yield after separation
(Scheme 1). The key step of this project, however, is the
Scheme 1 Polymer-Assisted Activation of Glycals and
Subsequent Glycosidation (Refer Also to Table 1)
In conjunction with our research activities in this field,6
we initiated a program dedicated to the polymer-assisted
solution-phase synthesis of deoxysugar-based glycoconju-
gates using polymer-bound reagents.7 In this Letter, we
describe the first concise polymer-assisted preparation of
oligodeoxysaccharides and glycconjugates derived therefrom.
The strategy includes four steps: (1) glycal activation, (2)
glycosidation, (3) deiodination, and (4) O-desilylation. The
final step is necessary for creating a new glycosyl acceptor
and thus opens up the opportunity for repeating the glycosi-
dation.
glycosidation step using acetate 6 as glycosyl donor and
various alcohols as glycosyl acceptors. In solution phase,
silyl triflates have proven to be powerful activating reagents
for 2-iodo-2-deoxyglycosyl acetates9 so we looked for the
polymer-based variant. We found that Nafion R SAC-13 and
TMS-Nafion,10 which have occasionally been promoted as
strong polymer-bound acid and Lewis acid, respectively,11
turned out to be moderate promotors in this case.
We envisaged a set of polymer-bound reagents and
activators, 1-4 (Figure 1), that we reckoned to be ideally
Likewise, Montmorillonite K-10 was ineffective in this
glycosidation step.12 Polymer-bound silyl triflate 2,13 how-
ever, turned out to be a very powerful activator for 2-deoxy-
2-iodoglycosyl acetates (Table 1). Starting from the R-manno-
isomer 6a, glycosylations of structurally diverse alcohols
were achieved either in dichloromethane or diethyl ether with
total stereocontrol in excellent yield. In most cases filtration
and removal of the solvent gave pure R-glycosides 8-17.14
In some cases, concentration of the reaction mixture led to
total decomposition of the products, which can be ascribed
to the presence of TfOH. This problem was overcome by
adding Amberlyst A-21 7 prior to removal of the solvent.
Figure 1. Functionalized polymers for polymer-assisted solution-
phase synthesis of deoxygenated oligosaccharides.
(8) Kirschning, A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett.
1999, 40, 8999-9002.
suited for performing the steps mentioned above. These
reagents can be easily prepared and have the potential to be
recovered and recycled. More importantly, they are highly
reactive and can overcome kinetic restrictions and diffusional
limitations associated with polymer-assisted synthesis.
Earlier studies have proven that iodate(I) complex 1
promotes 1,2-iodo-acetoxylation of glycals under mild condi-
tions in excellent yields.8 For example, fully protected
(9) (a) Roush, W. R.; Briner, K.; Sebesta, D. P. Synlett 1993, 264-266.
(b) Kosma, P.; Sekljic, H.; Balint, G. J. Carbohydr. Chem. 1996, 15, 701-
714. (c) Lafont, D.; Boullanger, P.; Carvalho, F.; Vottero, P. Carbohydr.
Res. 1997, 297, 117-126. (d) Lafont, D.; Boullanger, P.; Rosenzweig, M.
J. Carbohydr. Chem. 1998, 17, 1377-1393. (e) Kirschning, A.; Plumeier,
C., Rose, L. J. Chem. Soc., Chem. Commun. 1998, 33-34. (f) Roush, W.
R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541-3542. (g) Roush,
W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891-893. (h) Roush,
W. R.; Narayan, S.; Bennett, C. E.; Briner, K. Org. Lett. 1999, 1, 895-
897. (i) Roush, W. R.; Narayan, S. Org. Lett. 1999, 1, 899-902.
(10) (a) Olah, G. A.; Mehrotra, A. K., Synthesis 1982, 962-962. (b)
Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis 1986, 513-531.
(11) Toshima, K.; Nagai, H.; Matsumura, S. Synlett 1999, 1420-1422.
(12) Jyoima, T.; Miyamoto, N.; Ogawa, Y.; Matsumura, S.; Toshima,
K. Tetrahedron Lett. 1999, 40, 5023-5026. (b) Florent, J.-C.; Monneret,
C. J. Chem. Soc., Chem. Commun. 1987, 1171-1172. (c) Laszlo, P. Science
1987, 235, 1473-1477. (d) Sieskind, O.; Albrecht, P. Tetrahedron Lett.
1993, 34, 1197-1200.
(5) Recent reviews on polymer-supported reagents: (a) Kirschning, A.;
Monenschein, H.; Wittenberg, R. Angew. Chem.. Int. Ed. 2001, 40, 650-
679. (b) Kirschning, A.; Monenschein, H.; Wittenberg, R. Chem Eur. J.
2000, 6, 4445-4450. (c) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson,
P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R.
I.; Taylor, S. J., J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195. (d)
Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res. ReV. 1999, 19, 97-148.
(6) (a) Sourkouni-Argirusi, G.; Kirschning, A. Org. Lett. 2001, 2, 3781-
3784. (b) Kirschning, A.; Monenschein, H.; Schmeck, C. Angew. Chem.
1999, 111, 2720-2722; Angew. Chem., Int. Ed. 1999, 38, 2594-2596.
(7) Monenschein, H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare,
T.; Kirschning, A. Org. Lett. 1999, 1, 2101-2104.
(13) Smith, E. M. Tetrahedron Lett. 1999, 40, 3285-3288.
(14) In some cases, oligo- and polymeric impurities originated from the
resins were present in the crude product as judged by 1H NMR analysis.
Under these circumstances, a simple gel-filtration step became necessary
for obtaining analytically pure samples.
3624
Org. Lett., Vol. 3, No. 23, 2001

Scheme 2
Table 1. Polymer-Assisted Glycosidation of
2-Deoxy-2-iodo-R-D-glycosyl Acetate 6a (Refer Also to Scheme
1)
Next, we extended the concept of polymer-assisted solu-
tion-phase glycosidation to the preparation of a steroid-
derived glycoconjugate as well as a deoxytrisaccharide.
For the glycosylation of testosterone 22, a three-step
synthesis based on polymer-bound reagents was devised. 1,2-
Iodoacetoxylation of per-O-acetylated 6-deoxy-D-glucal 20
afforded an R-manno/â-gluco diasteromeric mixture from
which the major 1,2-addition product 21a was employed for
the next step after chromatographic isolation (Scheme 3).
Scheme 3. Polymer-Assisted Glycosylation of Testosterone
a For details refer to the Supporting Information. b Yields refer to isolated
c
pure products. L-6a was employed. d In this case, Nafion-TMS (4 equiv,
Et2O, -70 °C to rt, 4.5 d) gave 39% of the desired glycoside 11. e Reduced
yield due to partial decomposition of glycosl acceptor.
Besides simple alcohols (Table 1, entries 1-3), carbohydrate-
derived glycosyl acceptors (entries 4-7), steroids (entries 8
and 9), and even hindered alcohols such as (-)-linalool (entry
10) were employed successfully. Neighboring group par-
ticipation of the adjacent iodine atom completely governs
the selectivity as is also seen in solution-phase variants. The
good efficiency of the process can be rationalized by
assuming that the reactive oxonium-type intermediates are
located on the polymeric support at isolated spots so that
interactions between activated species are suppressed to a
large extent. It is noteworthy that polymer-bound silyl triflate
2 can be regenerated after use by treatment with TMSCl for
removing traces of water followed by treatment with an
excess of TMSOTf.
Activation of the anomeric center using reagent 2 followed
by coupling with steroid 22 and debenzoylation with Am-
berlyst A-26 (OH- form) 23 afforded the unprotected
R-glucoside 24 in very good yield with high purity (>95%).
The final product was purified by gel filtration and the
analytical data confirmed the structure of 24.
In a more advanced study, we envisaged the preparation
of a trisaccharide composed of two D-olivose units and 2,3,6-
trideoxyhexose L-rhodinose (Scheme 4). These deoxyhexoses
are widely found as carbohydrate components in various
glycoconjugates from microbial sources such as the lando-
While the TBS-protection is tolerated under the glycosi-
dation conditions decribed Table 1, entry 4) the polymer-
bound Lewis acid 2 may also cleave the TES group as is
demonstrated for glycosyl acetate 18 in Scheme 2.
Org. Lett., Vol. 3, No. 23, 2001
3625

Therefore, we turned to a conventional deiodination protocol
(Bu3SnH, AIBN) at this point. Subsequently, desilylation was
achieved using the HF-pyridine complex.18 Excess desily-
lating reagent was removed with Amberlite A-200 (Na+
form) 4. This scavenging reagent turned out to be very
efficient for trapping protonated pyridine as well as the
fluoride anion as its sodium salt. Both solids were simply
filtered off. Now, the stage was set for a second glycosidation
step using olivosyl acetate 6a and polymer-bound silyl triflate
2. After neutralization, filtration, and removal of the solvent
in the usual manner, methyl glycoside 25 was deiodinated
and desilylated as described previously to yield the next
glycosyl acceptor 26. The sequence toward trisaccharide 28
was terminated by a third glycosidation step, this time using
rhodinosyl acetate 27 as the glycosyl donor. In the presence
of the usual set of polymer-bound reagents 1 and 7, the
coupling afforded the R-glycosidation product 28 as a single
isomer.
Scheme 4. Synthesis of a Rhodinosyl-olivosyl-olivoside
In conclusion, we have developed the first synthetic
approach to 2-deoxyoligosaccharides and glyconjugates
which relies on polymer-supported reagents. The strategy
includes polymer-assisted glycal activation, glycosidation,
and O-desilylation and affords glycosides in good to excellent
yield without tedious workup and product isolation. Hence,
this synthetic strategy should have the potential to be
applicable for automated parallel synthesis.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 416) and the Fonds
der Chemischen Industrie. This project is part of the joint
initiative Biologisch aktive Naturstoffe-Chemische Diver-
sita¨t at the University of Hannover. Expert synthetic as-
sistance by Janis Jaunzems is gratefully acknowledged. We
thank Dr. G. Jas (Chelona GmbH, Potsdam) for helpful
discussions.
mycine group of antibiotics.15 Activation of D-glucal deriva-
tive 5 was the starting point of the synthesis of trisaccharide
28 as described previously.
Supporting Information Available: Spectra and descrip-
tions of experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
Separation of the diastereomeric mixture and glycosidation
of 6a with methanol as acceptor led to methyl glycoside 8
(Table 1, entry 1) which was further modified after deiodi-
nation and O-desilylation. It has been reported that polymer-
bound borohydrides doped with metal salts such as Ni(OAc)2,
or CuSO4 3 are powerful reductants for alkyl iodides.16
However, in our hands these reagents gave only minor
amounts of deiodinated products when reacted with 2-iodo-
glycoside 8. Likewise, polymer-bound tin hydrides17 were
found to be inefficient reducing agents in this context.
OL016545V
(17) (a) Delmond, B.; Dumartin, G. In Solid State Organometallic
Chemistry: Methods and Applications; Gielen, M., Willem, R., Wrackm-
eyer, B., Eds.; Wiley: Chichester, 1999; pp 445-471. (b) Gerigk, U.;
Gerlach, M.; Neumann, W. P.; Vieler, R.; Weintritt, V. Synthesis 1990,
448-452. (c) Neumann, W. P.; Peterseim, M. React. Polym. 1993, 20, 189-
205.
(18) In analogy to tetra-n-butylammonium fluoride, Amberlyst A-26 (F-
form) was employed for the treatment of various silyl ethers. While both
primary and secondary triethylsilyl groups can rapidly be removed, this
polymer-bound reagent is not reliable when cleaving secondary primary
TBS ethers.
(15) (a) Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127-205. (b)
Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103-137.
(16) Kirschning, A. J. Prak. Chem. 2000, 342, 508-511.
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