Regenerative glycosylation under nucleophilic catalysis

Article abstract of DOI:10.1021/ja411746a

This article describes 3,3-difluoroxindole (HOFox)-mediated glycosylation. The uniqueness of this approach is that both the in situ synthesis of 3,3-difluoro-3H-indol-2-yl (OFox) glycosyl donors and activation thereof can be conducted in a regenerative fashion as is a typical reaction performed under nucleophilic catalysis. Only a catalytic amount of the OFox imidate donor and a Lewis acid activator are present in the reaction medium. The OFox imidate donor is constantly regenerated upon its consumption until glycosyl acceptor has reacted.

Full text of DOI:10.1021/ja411746a

Communication
pubs.acs.org/JACS
Regenerative Glycosylation under Nucleophilic Catalysis
Swati S. Nigudkar, Keith J. Stine, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri−St. Louis, One University Boulevard, St. Louis, Missouri 63121,
United States
S
* Supporting Information
(Scheme 1) that represents a potentially cheaper, cyclic
ABSTRACT: This article describes 3,3-difluoroxindole
(HOFox)-mediated glycosylation. The uniqueness of this
approach is that both the in situ synthesis of 3,3-difluoro-
3H-indol-2-yl (OFox) glycosyl donors and activation
thereof can be conducted in a regenerative fashion as is
a typical reaction performed under nucleophilic catalysis.
Only a catalytic amount of the OFox imidate donor and a
Lewis acid activator are present in the reaction medium.
The OFox imidate donor is constantly regenerated upon
its consumption until glycosyl acceptor has reacted.
analogue of PTFAI would provide an efficient alternative.
While developing the new class of O-imidates, we noticed a
feature of the OFox leaving group that differentiates it from all
others developed for and used in chemical glycosylation. The
aglycone structure needed to introduce OFox and that of the
departed leaving group are essentially the same, cyclic amide
3,3-difluoroxindole (HOFox).22,23 The significance of this
observation is that, in principle, one should be able to conduct
both the introduction and activation of this leaving group in the
catalytic “donor-regenerative” fashion, which is routinely done
in enzymatic glycosylations,24,25 but represents a new direction
in the field of chemical glycosylation. This new method falls
into the general classification of nucleophilic (covalent)
catalysis that is broadly used in synthetic26 and enzymatic
transformations.27 Examples wherein nucleophilic catalysis is
used to obtain glycomimetics have been reported.28,29 The
effect of stoichiometric nucleophilic additives on the outcome
of O-glycosylation has been investigated.30−34
Prior to establishment of the regenerative approach, we first
validated that OFox imidate 3 performs similarly to that of
common O-imidate donors 1 and 2.20,35 As depicted in Table 1,
coupling of donors 1−3 with acceptor 4 produced disaccharide
536 in 5 min either at −78 °C or at ambient temperature in
comparable yields. We further conducted an exploratory study
of OFox imidates and investigated a number of factors that
affect stereoselectivity and reactivity of these glycosyl donors.
This study is presented as a part of the Supporting Information
ractically all complex carbohydrates have an oligomeric
Psequence wherein monosaccharide residues are linked via
glycosidic linkages.1 Both simple methods and sophisticated
strategies for glycoside synthesis and oligosaccharide assembly
exist.2,3 However, the complexity of glycosylation reactions4−7
is responsible for many drawbacks that all current methods
experience. In spite of significant progress, chemical glyco-
sylation remains challenging due to the requirement to achieve
complete stereocontrol and to suppress side reactions.8 Among
a plethora of leaving groups developed, a vast majority of
glycosylations make use of thioglycosides9−12 and O-trichlor-
oacetimidates (TCAI).13−15 Our laboratory has also been
developing new leaving groups for chemical glycosylation.16,17
For instance, we developed S-benzoxazolyl (SBox) donors18
and more recently introduced O-benzoxazolyl (OBox)
imidates,19 which represent a hybrid structure between SBox
and TCAI (Scheme 1), but it is more reactive than either.
N-Phenyl trifluoroacetimidates (PTFAI) introduced by
Yu20,21 have recently gained a considerable niche among
methods used for chemical glycosylation. Excellent results have
been achieved with these donors, and we decided to investigate
whether the 3,3-difluoro-3H-indol-2-yl (OFox) leaving group
Table 1. Comparative Investigation of O-Imidates 1−3
Scheme 1. O-Imidates, Established and New
entry
donor
temperature
yield of 5
ratio α/β
1
2
3
4
5
6
1
1
2
2
3
3
−78 °C
rt
92%
94%
70%
91%
94%
93%
1/15
4.0/1
1/4.4
1/2.2
1/24
1/1.2
−78 °C
rt
−78 °C
rt
Received: November 18, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja411746a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(SI) and details the effect of promoter, solvent, protecting
groups, leaving group orientation, primary and secondary
acceptors, glycosyl donors of other sugar series, etc. Excellent
yields have been achieved in a majority of cases, and some
reactions provided high stereoselectivity (see the SI)
Having established basic principles of the synthesis and
activation of OFox imidates, we turned our attention to the
investigation of regenerative glycosylation, a concept that sets
use of OFox donors apart from other known methods for
chemical glycosylation. Both TCAI and PTFAI are obtained
from hemiacetal precursors, using either inexpensive trichlor-
oacetonitrile or rather costly 2,2,2-trifluoro-N-phenylacetimi-
doyl chloride, respectively, but their syntheses often originate
from thioglycosides (Scheme 2). The use of thioglycosides as
converted into OFox imidate 3 in the presence of HOFox. The
amount of the reactive glycosyl donor present in the reaction
medium can be controlled by the amount of HOFox added
(range studied 0.1−1.0 equiv). OFox imidates have reasonable
shelf life but are readily activated with various Lewis acids (5−
10 mol %, see the SI). Thus, an attempt to activate bromide 7
in the presence of BF3-Et2O showed very sluggish conversion
into disaccharide 5 (9% in 5 h, entry 1, Table 2). Since this
Table 2. Regenerative Glycosylation
Scheme 2. Common Approaches and the New Concept
entry
HOFox (equiv)
reaction time
yield of 5
ratio α/β
1
2
3
4
5
6
0
5 h
9%
1/1.1
1/1.9
1/1.9
1/1.2
1/1.2
1/1.2
0.1
0.25
0.5
0.75
1.0
3 h
84%
79%
86%
88%
90%
2 h
40 min
30 min
10 min
reaction was performed in the presence of Ag2O with the
primary purpose of scavenging HBr released in this reaction,
bromide 7 would eventually react with the acceptor 4 and is
likely to require more than 24−48 h to react completely. We
managed to achieve reasonable glycosylation rate (3 h) with as
little as 10 mol % of HOFox aglycone. As a result, disaccharide
5 was isolated in a commendable yield of 84% (entry 2, Table
2). With the increase of the amount of HOFox, the reaction
rate steadily increased (entries 3−6). This culminated in a swift
10 min reaction in the presence of 1.0 equiv of HOFox that
produced disaccharide 5 in 90% (entry 6).
In the further expansion of the regenerative glycosylation we
investigated secondary glycosyl acceptors and OFox imidates of
other common sugar series (see the SI). A model NMR study
of the reaction conducted in the absence of glycosyl acceptor
showed the presence of OFox glycosides in ratios comparable
to the amount of HOFox additive in respect to the starting
bromide (see the SI).
In conclusion, we discovered a new regenerative concept for
chemical glycosylation that allows for generating reactive OFox
glycosyl donors and activation thereof in the catalytic fashion in
situ. The concept has some similarities with the two-step
activation by Nicolaou38−40 and Danishefsky41−44 and
preactivation strategy by Huang and Ye45−48 but differs in
the catalytic conversion and continuous regeneration of the
glycosyl donor. In the previous methods, the entire precursor
(thioglycoside or glycal) is first converted into reactive
intermediates (Br, F, OTf/NTf2 or epoxide) and then acceptor
is added. This regenerative approach is expected to help reduce
side reactions commonly found in conventional glycosylations
wherein excess of the highly reactive or stoichiometrically
preactivated glycosyl donor is present from the beginning.
general building blocks is very broad. Thioglycosides are also
excellent glycosyl donors, but their relatively low reactivity
profile and the requirement for stoichiometric promoters
sometimes hinders their application in direct glycosidations.
Conversely, O-imidates are very reactive and require only a
catalytic amount of the activator. Many O-imidates can be
purified, but none can be stored and hence have to be used in
glycosidations right away. Leaving groups in the previously
studied imidates TCAI or PTFAI depart as unreactive amides,
trichloroacetamide or 2,2,2-trifluoro-N-phenylacetamide, re-
spectively, and cannot be reused directly (Scheme 2).
Uniquely, since both the reagent for the introduction of the
OFox leaving group and the departed leaving group are
essentially the same (HOFox), both the synthesis and
glycosidation of OFox imidates can be conducted using
catalytic amounts of the HOFox aglycone. HOFox aglycone
will first react with a stable precursor to form highly reactive
OFox imidate donor. The latter will then react with the
acceptor while regenerating HOFox aglycone, which will be
available for the next catalytic cycle to regenerate the OFox
donor. Resultantly, only a relatively small amount of the
reactive donor is present in the reaction mixture, but it can vary
based on the amount of added HOFox. It should be
emphasized that the OFox donor can be regenerated only
upon consumption of the first batch (Scheme 2).
In our preliminary study of the regenerative concept
disclosed herein, we first reacted S-ethyl glycoside 637 with
stoichiometric bromine to form glycosyl bromide 7. The latter
is rather stable under the reaction condition but gets readily
B
dx.doi.org/10.1021/ja411746a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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(23) Torres, J. C.; Garden, S. J.; Pinto, A. C. Tetrahedron 1999, 55,
1881−1892.
ASSOCIATED CONTENT
* Supporting Information
Additional experimental details and characterization data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(24) Ichikawa, Y.; Liu, J. L. C.; Shen, G. J.; Wong, C. H. J. Am. Chem.
Soc. 1991, 113, 6300−6302.
(25) Chen, X.; Fang, J.; Zhang, J.; Liu, Z.; Shao, J.; Kowal, P.;
Andreana, P.; Wang, P. G. J. Am. Chem. Soc. 2001, 123, 2081−2082
and references therein.
(26) Fu, G. C. Acc. Chem. Res. 2000, 33, 412−420.
(27) Vocadlo, D. J.; Davies, G. J.; Laine, R.; Withers, S. G. Nature
2001, 412, 835−838.
AUTHOR INFORMATION
Corresponding Author
demchenkoa@umsl.edu
■
(28) Loskot, S. A.; Zhang, J.; Langenhan, J. M. J. Org. Chem. 2013,
78, 12189−12193.
Notes
(29) Thygesen, M. B.; Munch, H.; Sauer, J.; Clo, E.; Jorgensen, M.
R.; Hindsgaul, O.; Jensen, K. J. J. Org. Chem. 2010, 75, 1752−1755.
(30) Park, J.; Kawatkar, S.; Kim, J. H.; Boons, G. J. Org. Lett. 2007, 9,
1959−1962.
(31) Chu, A.-H. A.; Nguyen, S. H.; Sisel, J. A.; Minciunescu, A.;
Bennett, C. S. Org. Lett. 2013, 15, 2566−2569.
(32) Liu, C.-Y. I.; Mulani, S.; Mong, K.-K. T. Adv. Synth. Catal. 2012,
354, 3299−3310.
(33) Lu, S. R.; Lai, Y. H.; Chen, J. H.; Liu, C. Y.; Mong, K. K. Angew.
Chem., Int. Ed. 2011, 50, 7315−7320.
(34) Nogueira, J. M.; Issa, J. P.; Chu, A.-H. A.; Sisel, J. A.; Schum, R.
S.; Bennett, C. S. Eur. J. Org. Chem. 2012, 2012, 4927−4930.
(35) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249−
1256.
(36) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269−
4279.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by awards from the NIGMS
(GM090254 and GM077170). We thank Dr. Rensheng Luo
(UM−St. Louis) for aquiring spectral data using 600 MHz
NMR spectrometer that was purchased thanks to the NSF
(Award CHE-0959360). Dr. Winter and Mr. Kramer (UM−St.
Louis) are thanked for HRMS determinations.
REFERENCES
■
(1) Varki, A.; Cummings, R. D.; Esko, J. D.; Freeze, H. H.; Bertozzi,
C. R.; Stanley, P.; Hart, G. W.; Etzler, M. E. Essentials of Glycobiology;
2nd ed.; CSH Laboratory Press: New York, 2009.
(2) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900−
1934.
(3) Smoot, J. T.; Demchenko, A. V. Adv. Carbohydr. Chem. Biochem.
2009, 62, 161−250.
(4) Crich, D. Acc. Chem. Res. 2010, 43, 1144−1153.
(5) Crich, D. J. Org. Chem. 2011, 76, 9193−9209.
(6) Ranade, S. C.; Demchenko, A. V. J. Carbohydr. Chem. 2013, 32,
1−43.
(7) Mydock, L. K.; Demchenko, A. V. Org. Biomol. Chem. 2010, 8,
497−510.
(8) Handbook of Chemical Glycosylation: Advances in Stereoselectivity
and Therapeutic Relevance; Demchenko, A. V., Ed.; Wiley-VCH:
Weinheim, 2008.
(37) Andersson, F.; Fugedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron
Lett. 1986, 27, 3919−3922.
(38) Randall, J. L.; Nicolaou, K. C. ACS Symp. Ser. 1988, 374, 13−28.
(39) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. J.
Am. Chem. Soc. 1984, 106, 4189−4192.
(40) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40,
1576−1624.
(41) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661−6666.
(42) Williams, L. J.; Garbaccio, R. M.; Danishefsky, S. J. In
Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay,
P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, pp 61−92.
(43) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380−1419.
(9) Zhong, W.; Boons, G.-J. In Handbook of Chemical Glycosylation;
Demchenko, A. V., Ed.; Wiley-VCH: Weinheim, 2008; pp 261−303.
(10) Codee, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.;
Overkleeft, H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005, 34, 769−
782.
(44) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6656−6660.
(45) Huang, X.; Huang, L.; Wang, H.; Ye, X. S. Angew. Chem., Int. Ed.
2004, 43, 5221−5224.
(11) Oscarson, S. In Carbohydrates in Chemistry and Biology; Ernst,
B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1,
pp 93−116.
(46) Huang, L.; Huang, X. Chem.Eur. J. 2007, 13, 529−540.
(47) Zeng, Y.; Wang, Z.; Whitfield, D.; Huang, X. J. Org. Chem. 2008,
73, 7952−7962.
(12) Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52, 179−
(48) Huang, L.; Wang, Z.; Huang, X. Chem. Commun. 2004, 1960−
1961.
205.
(13) Zhu, X.; Schmidt, R. R. In Handbook of Chemical Glycosylation;
Demchenko, A. V., Ed.; Wiley-VCH: Weinheim, 2008, pp 143−185.
(14) Schmidt, R. R.; Jung, K. H. In Carbohydrates in Chemistry and
Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim,
2000; Vol. 1, pp 5−59.
(15) Schmidt, R. R.; Jung, K. H. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New York, 1997;
pp 283−312.
(16) Hasty, S. J.; Demchenko, A. V. Chem. Heterocycl. Compd. 2012,
48, 220−240.
(17) Yasomanee, J. P.; Demchenko, A. V. Trends Glycosci.
Glycotechnol. 2013, 25, 13−42.
(18) Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett.
2003, 5, 455−458.
(19) Nigudkar, S. S.; Parameswar, A. R.; Pornsuriyasak, P.; Stine, K.
J.; Demchenko, A. V. Org. Biomol. Chem. 2013, 11, 4068−4076.
(20) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405−2407.
(21) Yu, B.; Sun, J. Chem. Commun. 2010, 46, 4668−4678.
(22) Zhu, J.; Zhang, W.; Hu, J. J. Org. Chem. 2010, 75, 5505−5512.
C
dx.doi.org/10.1021/ja411746a | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX