Sonochemistry: A powerful way of enhancing the efficiency of carbohydrate synthesis

Article abstract of DOI:10.1021/jo060374w

Using sonication as a means of facilitating organic reactions in carbohydrate chemistry was explored under the conditions used for traditional organic synthesis. An array of representative reactions, including hydroxy group manipulation (acylation, protection/deprotection, acyl group migration), thioglycoside synthesis, azidoglycoside synthesis, 1,3-dipolar cycloaddition and reductive cleavage of benzylidene, commonly used in the synthesis of carbohydrate derivatives was examined. A series of glycosylation reactions that employ thioglycosides, glycosyl trichloroacetimidate, glycosyl bromide and glycosyl acetate as the glycosyl donors was also examined. Our results demonstrate that sonication can significantly shorten the reaction time, enhance the reactivity of reactant and lead to superior yield and excellent stereoselectivity. More importantly, a general protocol of glycosylation may finally be developed. Sonication is compatible to the conditions used for traditional organic synthesis. We believe that sonication can also be applied to other areas of synthetic processes.

Full text of DOI:10.1021/jo060374w

Sonochemistry: A Powerful Way of Enhancing the Efficiency of
Carbohydrate Synthesis
Shenglou Deng, Umesh Gangadharmath, and Cheng-Wei Tom Chang*
Department of Chemistry and Biochemistry, Utah State UniVersity,
0300 Old Main Hill, Logan, Utah 84322-0300
chang@cc.usu.edu
ReceiVed February 22, 2006
Using sonication as a means of facilitating organic reactions in carbohydrate chemistry was explored
under the conditions used for traditional organic synthesis. An array of representative reactions, including
hydroxy group manipulation (acylation, protection/deprotection, acyl group migration), thioglycoside
synthesis, azidoglycoside synthesis, 1,3-dipolar cycloaddition and reductive cleavage of benzylidene,
commonly used in the synthesis of carbohydrate derivatives was examined. A series of glycosylation
reactions that employ thioglycosides, glycosyl trichloroacetimidate, glycosyl bromide and glycosyl acetate
as the glycosyl donors was also examined. Our results demonstrate that sonication can significantly shorten
the reaction time, enhance the reactivity of reactant and lead to superior yield and excellent stereoselectivity.
More importantly, a general protocol of glycosylation may finally be developed. Sonication is compatible
to the conditions used for traditional organic synthesis. We believe that sonication can also be applied to
other areas of synthetic processes.
Introduction
glycosyl donors have been reported.6-10 Sophisticated methods,
like chemoenzymatic synthesis,11 one-pot glycosylation,12,13
solid-phase oligosaccharide synthesis,14,15 and iterative glyco-
sylation,16 have been developed for the goal of alleviating the
challenges in oligosaccharide synthesis.
On the other hand, the idea of promoting reactivity by using
traditional synthetic methods, such as raising the reaction
temperature, for less reactive or so-called “disarmed” glycosyl
donors is considered to be less applicable, presumably because
the reactive intermediates, such as oxycarbenium, are thought
to be labile at higher temperature. To conveniently utilize the
knowledge of carbohydrate chemistry in the literature, our group
Owing to the remarkable biological relevance of carbo-
hydrate,1-3 the synthesis of oligosaccharides or carbohydrate
derivatives has long been the goal pursued by researchers from
various areas.4,5 The complexity and diversity of carbohydrates
found in nature, however, makes the synthesis of carbohydrates
a challenging task despite numerous efforts documented in the
literature. One of the reasons is that different carbohydrate
scaffolds often manifest moderate to drastic different reactivity
in various reactions thus resulting in the requirement of
optimizing conditions for each individual carbohydrate scaffold.
The vast number of developed and employed protecting groups
further fuel the complexity in carrying out carbohydrate
synthesis, one such example being glycosylation. Due to the
difference in the reactivity of glycosyl donors as a result of the
employed protecting groups and the intrinsic structure-associated
reactivity, numerous methods designed for activating various
(6) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(7) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem. Int. Ed. 2001, 40,
1576-1624.
(8) Paulsen, H. Angew. Chem. Int. Ed. 1982, 21, 155-173.
(9) Schmidt, R. R. Angew. Chem. Int. Ed. 1986, 25, 212-235.
(10) Demchenko, A. V. Synlett 2003, 9, 1225-1240.
(11) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV. 1996,
96, 443-474.
* To whom correspondence should be addressed. Fax: 435-797-3390.
(1) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 99-110.
(2) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(3) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357-2364.
(4) PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997.
(12) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734-753.
(13) Koeller, K. M.; Wong, C.-H. Chem. ReV. 2000, 100, 4465-4494.
(14) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000, 100, 4349-4394.
(15) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291,
1523-1527.
(5) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem.
ReV. 1996, 96, 1195-1220.
(16) Huang, X.; Huang, L.; Wang, H.; Ye, X.-S. Angew. Chem. Int. Ed.
2004, 43, 5221-5224.
10.1021/jo060374w CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/10/2006
J. Org. Chem. 2006, 71, 5179-5185
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Deng et al.
SCHEME 1. Hydroxy Group Manipulation
a Reagents and conditions: (a) Ac2O, Et3N; (b) Ac2O, cat. H2SO4; (c) PhCH(OMe)2, TsOH-H2O, DMF; (d) Me2C(OMe)2, TsOH, DMF; (e) TsCl, py.,
b
c
DMAP. Reagents and conditions: (a) TsOH-H2O, MeOH; (b) NaOMe, MeOH. Reagents and conditions: (a) Ag2O, TBAI, DMF.
has devoted effort in developing general protocols for the
systematic synthesis of unusual sugars.17,18 Hence, the develop-
ment of a general protocol for effective glycosylation is always
a goal that we wish to pursue. With the development of such a
general protocol, it is our hope that the complexity involved in
carbohydrate synthesis can be minimized.
Sonication19-23 and microwaves24,25 have long been employed
as the energy source for enhancing the rate of chemical reactions.
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Enhancing the Efficiency of Carbohydrate Synthesis
SCHEME 2. Synthesis of Thioglycosidesa
a Reagents and conditions: (a) PhSH, BF3-OEt2, CH2Cl2.
SCHEME 3. Azidoglycoside Synthesisa
a Reagents and conditions: (a) NaN3, DMF.
While the interest of using microwaves for assisting chemical
reactions has reemerged recently, the use of sonication as the
tool for organic synthesis is rather under-explored. For better
efficiency, microwave-assisted synthesis is often performed
without solvent, thus making this method not ideally compatible
for syntheses involving molecules with high molecular weight
or low solubility, such as in the case of carbohydrate synthesis.
Sonication, on the other hand, may provide the needed energy
to overcome the different reactivity among carbohydrates, and
enable the development of general protocols for facilitating the
synthesis of complex carbohydrates. Therefore, we have started
to experiment with the use of sonication as an alternative energy
source for carbohydrate synthesis.
Results and Discussion
We selected five types of commonly employed reactions in
carbohydrate synthesis for our initial studies. These include
hydroxy group manipulation (acylation, diol protection, tosy-
lation, deprotection, acyl group migration) (Scheme 1),26
thioglycoside synthesis (Scheme 2), azidoglycoside synthesis
(Scheme 3),27 1,3-dipolar cycloaddition (Scheme 4),28 and
reductive cleavage of benzylidene (Scheme 5).29 To our delight,
all the sonication-mediated reactions are compatible with the
traditionally employed conditions. Furthermore, the reaction time
is dramatically shorter than previously required and with
excellent yields in most of the cases. For example, acetylation
of carbohydrate usually takes hours. For the trehalose deriva-
tives, 7, the reaction is hard to reach completion, probably due
(17) Elchert, B.; Li, J.; Wang, J.; Hui, Y.; Rai, R.; Ptak, R.; Ward, P.;
Takemoto, J. Y.; Bensaci, M.; Chang, C.-W. T. J. Org. Chem. 2004, 69,
1513-1523.
(18) Wang, J.; Chang, C.-W. T. In Carbohydrate Drug Design; Klyosov,
A. A., Witczak, Z. J., Platt, D., Eds.; ACS Symp. Ser. No. 932; American
Chemical Society: Washington, DC, 2005.
(19) For example: Lepore, S. D.; He, Y. J. Org. Chem. 2003, 68, 8261-
8263.
(20) For example: Gholap, A. R.; Venkatesan, K.; Daniel, T.; Lahoti,
R. J.; Srinivasan, K. V. Green Chem. 2003, 6, 693-696.
(21) For example: Chen, M.-Y.; Lu, K.-C.; Lee, A. S.-Y.; Lin, C.-C.
Tetrahedron Lett. 2002, 43, 2777-2780.
(22) For example: Adewuyi, Y. G. Ind. Eng. Chem. Res. 2001, 40,
4681-4715.
(23) For example: Kardos, N.; Luche, J.-L. Carbohydr. Res. 2001, 332,
115-131.
(26) Deng, S.; Chang, C.-W. T. Synlett 2006, 756-760.
(27) Small molecular weight azido compounds are known to be explosive.
Extreme safety measurements should be taken when carry out this reaction.
(28) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; pp 1-176.
(29) Garegg, P. J. In PreparatiVe Carbohydrate Chemistry; Hanessian,
S., Ed.; Marcel Dekker: New York, 1997; pp 53-67.
(24) Kappe C. O.; Stadler, A. In Methods and Principles in Medicinal
Chemistry; Mannhold, R., Kubinyi, H., Folkers, G., Eds.; VCH: Weinheim,
Germany, 2005; Vol. 409, p 139.
(25) MicrowaVe Assisted Organic Synthesis; Tierney, J. P., Lidstrom,
P., Eds.,; Blackwell Publishing: Oxford, UK, 2005; Vol. 280, p 89.
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Deng et al.
SCHEME 4. 1,3-Dipolar Cycloadditiona
a Reagents and conditions: (a) Cu(OAc)2, sodium ascorbate, MeOH, THF, H2O.
to the steric hindrance. However, with the aid of sonication,
the acetylation of all four hydroxyl groups of 7 can be
accomplished in several minutes. Likewise, the deprotection of
various protecting groups of the hydroxy group, such as acetyl,
benzylidene, and trityl groups, can also be completed in a few
minutes (Scheme 1b). We have recently developed a general
protocol for regiospecific migration of acyl groups.26 The
reaction usually takes days to complete. Nevertheless, under
the sonication condition, the reaction time can be shortened to
only several minutes (Scheme 1c).
The synthesis of thioglycosides is another prominent example
of utilizing sonication (Scheme 2). The synthesis of thioglyco-
sides, the versatile glycosyl donor for glycosylation, is typically
accomplished under Lewis acid-mediated condition for several
hours or even days.18 The reaction time for converting 44 to
the corresponding thioglycoside, 45, is even longer (as long as
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Enhancing the Efficiency of Carbohydrate Synthesis
SCHEME 5. Reductive Cleavage of Benzylidenea
a Reagents and conditions: (a) Cu(OTf)2, BH3-THF.
SCHEME 6. Glycosylation with Phenylthioglycosides
a week under traditional condition). However, under sonication,
the reaction can be completed in several minutes up to 2 h.
The rapidness in completing such a reaction may lead to the
creation of environmentally friendly processes, emphasizing the
role of employing ultrasound in Green chemistry.
Azidoglycosides have been commonly utilized for the syn-
thesis of various N-glycosides. The synthesis of azidoglycosides
often requires the use of TMSN3 under the catalysis of Lewis
acid for several hours.30 By using sonication, azidoglycosides
can be prepared from the corresponding glycosyl bromides in
a few minutes via a substitution reaction even without the
presence of Ag(I) (Scheme 3).27
The 1,3-dipolar cycloaddition (Scheme 4), the “click” reac-
tion, has been the recent focus for incorporating carbohydrate
components or for the preparation of glycomimetics. By using
sonication, the reaction time can be shortened from days to less
than an hour with excellent regioselectivity favoring the
formation of 1,4-disubstituted 1,2,3-triazoles.
synthesis. Recently, Hung31 reported that combination of Cu-
(OTf)2/BH3‚THF can regioselectively reduce benzylidene in
glucopyranoside. In our studies, all the tested reactions can be
accomplished in minutes with high yields and excellent regi-
oselectivity under similar conditions (Scheme 5). In particular,
the so-called disarmed donor 80 still reacts smoothly in higher
rate, yield and regioselectivity while the counterpart in the
literature only gave moderate yield with longer reaction time
(>20 h).
Encouraged by the success of these reactions, we began to
examine the use of sonication for one of the most challenging
reactions in oligosaccharide synthesis: glycosylation. Despite
countless endeavors, the statement made by Paulsen in a review
article8 more than 20 years ago, “There are no universal reaction
conditions for oligosaccharide syntheses”, remains largely
unchanged, particularly regarding the problem of glycosylation
as we have pointed out previously. We selected “disarmed”
phenylthioglycosides as the glycosyl donors for examining the
effectiveness of using sonication based on the following reasons.
First, phenylthioglycoside can be readily prepared in large
Regioselective reductive cleavage of the benzylidene protec-
tion group is commonly used for complex carbohydrate
(30) For example: Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org.
Chem. 2000, 65, 5249-5252.
(31) Shie, C.; Tzeng, Z.; Kulkarni, S. S.; Uang, B.; Hsu, C.; Hung, S.
Angew. Chem. Int. Ed. 2005, 44, 1665-1668.
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Deng et al.
SCHEME 7. Glycosylation with Glycosyl Acetates
SCHEME 8. Glycosylation with Glycosyl
Trichloroacetimidate and Glycosyl Halide
needed for a larger scale reaction. Finally, as expected,
sonication is also applicable for a more reactive donor, glycosyl
trichloroacetimidate, 92, and glycosyl bromide, 94 (Scheme 8).
Conclusion
We have demonstrated that sonication can be an excellent
energy source for accelerating a wide variety of organic reactions
used for complex carbohydrate synthesis. Our results may lead
to the revolutionized developments in this area. It is our belief
that sonication can be applied to many other reactions in related
areas. For example, sonication can be conveniently applied to
the synthesis of complex glycoconjugates, which are decorated
by specific terminal carbohydrates, such as mannose, fucose,
or sialic acid. By using sonication, a general glycosylation
protocol compatible with traditional solution organic synthesis
is finally a goal within reach. We have begun to explore the
application of using sonication in several advancing topics in
organic chemistry. Large-scale applications are also being
undertaken.
quantity, which is advantageous for complex carbohydrate syn-
thesis. Second, phenylthioglycoside is stable in many chemical
conditions needed for derivatization of the carbohydrate scaffold,
which simplifies the synthesis of carbohydrate analogues, such
as unusual sugars. Finally, phenylthioglycoside is known for
its relatively lower reactivity as compared to the other glycosyl
donors, such as glycosyl trichloroacetimidate and glycosyl
halide, especially with the acyl protecting groups attached, which
is termed “disarmed” donor. The lower reactivity of “disarmed”
donor often results in the difficulty or unsatisfactory yields in
glycosylation. Therefore, it will be a great improvement if we
can use sonication to carry out glycosylation for such less
reactive glycosyl donors, the “disarmed” donors.
The results from sonication-mediated glycosylation are very
encouraging. All the examined reactions can be accomplished
in minutes with high yield even for the donors of much lower
reactivity (Schemes 6-8). Many sulfur-philic reagents have been
developed for activating thioglycosides that have various degrees
of relative reactivity.10,18 Nevertheless, the reaction time typically
ranges from hours to days, and the yield is often unsatisfactory,
especially for “disarmed” donors such as 41 and 45. In contrast,
under standard NIS/TMSOTf condition for the activation of
phenylthioglycosides, all the glycosylation can be accomplished
in a short time with high yield. Steric hindrance often hampers
the success of glycosylation. However, by using sonication, a
diglycosylation at sterically hindered trans-1,2-diol was achieved
in a short time and with excellent yield (Scheme 6, compound
86). More significantly, the sonication protocol can even work
on a much less reactive glycosyl donor, glycosyl acetate
(Scheme 7). Most of the examined reactions can be completed
in minutes although we do discover that longer reaction time is
Experimental Section
General Procedure for Sonication. This general procedure was
employed for hydroxy group manipulation (acylation, diol protec-
tion, tosylation, deprotection), thioglycoside synthesis, azidogly-
coside synthesis, 1,3-dipolar cycloaddition, reductive cleavage of
benzylidene, and glycosylation with phenylthioglycosides, glycosyl
trichloroacetimidate, and glycosyl bromide. All the studied reactions
were performed in the range of 0.1-0.2 g of starting material,
according to the reported procedures and molar ratio of the materials
in the cited references. The reactions were carried out in a 20 mL
vial equipped with a sealed cap. The mixture was sonicated at
ambient temperature until complete consumption of starting material
(monitored by TLC). (Caution: Sonication of reaction for longer
times (10 min or longer) may raise the temperature of the reaction
vessel and thus increase the pressure inside. If longer reaction time
is needed, it is recommended that the reaction vessel should be
allowed to cool after sonication every 10 min before the next run.)
After the reaction was quenched, the crude products were purified
by gradient column chromatography.
General Procedure for Acyl Migration with Sonication. A
solution of starting material (0.12 mmol), tetrabutylammonium
iodide (TBAI) (4.2 mg, 0.012 mmol), and silver oxide (0.12 mmol)
in anhydrous DMF (5 mL) was sonicated at ambient temperature.
The reaction was monitored by TLC. When the appearance of
byproduct was noted by TLC analysis, the reaction mixture was
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Enhancing the Efficiency of Carbohydrate Synthesis
subsequently filtered then concentrated. The filtrate was subject to
flash column chromatography to yield the desired product.
General Procedure for BF3-Mediated Glycosylation of Gly-
cosyl Acetate with Sonication. A solution of glycosyl acetate (1
equiv), glycosyl acceptor (1 equiv), and BF3-OEt2 (1 equiv) in
anhydrous CH2Cl2 (3 mL) was sonicated at ambient temperature
until the complete consumption of the starting material (monitored
by TLC). The reaction mixture was quenched by addition of
NaHCO3(s) then filtered through Celite. The filtrate was subject to
flash column chromatography to yield the desired product.
Acknowledgment. The authors acknowledge support from
Department of Chemistry and Biochemistry, Utah State Uni-
versity.
Supporting Information Available: 1H and 13C spectra of the
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060374W
J. Org. Chem, Vol. 71, No. 14, 2006 5185