Organocatalyzed direct glycosylation of unprotected and unactivated carbohydrates

Article abstract of DOI:10.1021/ol402914v

Organocatalyzed direct glycosylation of unprotected and unactivated carbohydrates is reported. This process is catalyzed by triphenylphosphine and tetrabromomethane at room temperature under neutral conditions. With this operationally simple protocol thermodynamically favored, glycosides were obtained in a very straightforward reaction.

Full text of DOI:10.1021/ol402914v

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5854–5857
Organocatalyzed Direct Glycosylation of
Unprotected and Unactivated
Carbohydrates
Sebastian Schmalisch and Rainer Mahrwald*
Institute of Chemistry, Humboldt-University, Brook-Taylor Str. 2, 12489 Berlin, Germany
rainer.mahrwald@rz.hu-berlin.de
Received October 10, 2013
ABSTRACT
Organocatalyzed direct glycosylation of unprotected and unactivated carbohydrates is reported. This process is catalyzed by triphenylphosphine
and tetrabromomethane at room temperature under neutral conditions. With this operationally simple protocol thermodynamically favored,
glycosides were obtained in a very straightforward reaction.
Polysaccharides, glycoconjugates, or glycosides are mostly
linked by O-glycosidic bonds. Hence, the synthesis of
O-glycosidic bonds is of great interest. There exist a great
many methods to synthesize glycosides of defined config-
uration in high yield.1 These are mostly based on the
following protocol. To differentiate the reactivities of the
different hydroxyl groups, the carbohydrate is usually
completely protected. Afterward a leaving group is in-
stalled at the anomeric center of the carbohydrate. After
successful glycosylation a final deprotection step releases
the newly made glycoside. To avoid this multistep meth-
odology, several efforts have been made to increase the
reactivity of the hydroxy group at the anomeric center
and thus to exploit this difference for a direct glycosyla-
tion.2 Also, direct glycosylations of unprotected and
unactivated carbohydrates that are based on the Fischer
glycosylation3 conditions have been developed. These
reactions are carried out in strongly acidic media and
mostly at high temperature.4 For more current examples
of this methodology see ref 5. Also, Lewis acids have been
deployed in glycosylation reactions of unprotected car-
bohydrates.6 But for quantitative performance an excess
of Lewis acid is necessary in such reactions. Recently,
Auge and Sizun reported the catalytic deployment of
Lewis acids in a glycosylation reaction (10 mol %). These
reactions were performed at 80À100 °C for 24 h in ionic
€
(4) (a) Helferich, B.; Schafer, W. Org. Synth. 1926, 6, 64. (b) Cadotte,
J. E.; Smith, F.; Spriestersbach, D. J. Am. Chem. Soc. 1952, 74, 1501.
(5) (a) Optimization of Fischer conditions in ionic liquids: Park,
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S.; Linhardt, R. Carbohydr. Res. 2007, 342, 614. (b) Zhao, G.; Lou, Y.;
Zhang, L.; Shao, H.; Xu, W.; Tang, L.; Zou, M. Synth. Commun. 2012,
42, 2885. (c) Abreu, M. F.; Salvador, V. T.; Vitorazi, L.; Gatts, C. E. N.;
dos Santos, D. R.; Giacomini, R.; Cardoso, S. L.; Miranda, P. C. M. L.
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D.; Mackenzie, G.; Watson, M. J.; Haley, J. A.; Goodby, J. W.; Pindak,
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(1) For current and comprehensive overviews in this field, see: (a)
Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576.
(b) Toshima, K.; Sasaki, K. In Comprehensive Glycoscience; Kamerling,
J. P., Ed.; Elsevier: 2007; Vol. 1, p 261. (c) Brito-Arias, M. In Synthesis and
Characterization of Glycosides; Springer: 2007. (d) Demchenko, A. V.
Handbook of Chemical Glycosylation; WILEY-VCH: Weinheim, 2008. (e)
Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900. (f) Ranade,
S. C.; Demchenko, A. V. J. Carb. Chem. 2013, 32, 1. (g) For a recent
review of organocatalyzed glycosylations, see: Balmond, E. I.; Galan,
M. C.; McGarrigle, E. M. Synlett 2013, 2335.
(2) (a) Hannesian, S.; Lou, B. Chem. Rev. 2000, 100, 4443. (b)
Bernardes, G. J. L.; Gamblin, D. P.; Davis, B. G. Angew. Chem., Int.
Ed. 2006, 45, 4007.
(3) (a) Fischer, E. Chem. Ber. 1893, 26, 2400. (b) Fischer, E. Chem.
Ber. 1895, 28, 1145.
ꢀ
(7) (a) Auge, J.; Sizun, G. Green Chem. 2009, 11, 1179. (b) Monasson,
ꢀ
ꢀ
O.; Sizun-Thome, G.; Lubin-Germain, N.; Uziel, J.; Auge, J. Carbohydr.
Res. 2012, 352, 202.
r
10.1021/ol402914v
Published on Web 11/01/2013
2013 American Chemical Society

liquids.7 Catalytic glycosylation of unprotected and un-
activated carbohydrates remains a challenge.8 Recently,
we have reported a direct glycosylation methodology that
is performed in the presence of catalytic amounts of
titanium(IV) alkoxides and mandelic acid. The reaction
proceeds under near-neutral conditions.9
During our ongoing studies in the field of organocata-
lysis we observed a rapid and quantitative formation of
acetals of enolizable aldehydes or cyclic hemiacetals in the
presence of catalytic amounts of triphenylphosphine and
substituted trihalomethanes. After optimizing the process,
we obtained the best results for yield and reaction time by
deployment of catalytic amounts of tetrabromomethane
and triphenylphosphine.
By extending these initial results to the glycosylation of
other pentoses, unexpected and differing results were
obtained. Clean reactions were detected when ribose 3
and deoxyribose 4 were used under the described condi-
tions (3a: 77% and 4a: 75% inisoPrOH, 10mol % PPh3/10
mol % CBr4, rt, procedure A). In contrast, only low
reaction rates and yields were observed when arabinose
(5), xylose (6), and lyxose (7) were employed.12 During
optimization, several different solvents and additives were
tested in these reactions. Nitromethane, acetonitrile, or
propylene carbonate proved to be optimal solvents for the
direct glycosidation of these pentoses. To increase the yields
of this direct glycosylation, several lithium salts were ana-
lyzed as additives. Lithium perchlorate is known to promote
glycosylation processes,13 and as a consequence, its effects
were examined under these conditions, and a direct catalytic
glycosylation of unprotected carbohydrates was achieved.
Again, averycleanreactionwas observed where byproducts
were not detected. The best results were obtained in acet-
onitrile in the presence of 2 equiv of lithium perchlorate as
an additive (procedure C). The isopropyl glycosides 4a, 5a,
6a, and 7a were obtained mostly in the pyranoid form,
indicating thermodynamic control of these transforma-
tions. Support for this is provided by the glycosidation of
D-mannose 8. In direct glycosylation reactions of man-
nose 8, the R-configured isopropyl glycoside 8a was isolated
as the main product, which is known to be the thermodyna-
mically favored anomer in the mannose series14 (Scheme 3).
Scheme 1. Acetalization of Cyclic Hemiacetals
These reactions were carried out at room temperature in
the presence of 5 mol % of triphenylphosphine and tetra-
bromomethane in propanol. After 2 h the propyl acetals 1
and 2 of hydroxytetrahydropyrans and hydroxytetrahy-
drofurans were isolated in quantitative yield (Scheme 1).
Similar results have been reported for acetalisation of
aromatic aldehydes.10 Cleavage of acetals was not detected
under these conditions, as is known under Appel conditions.11
Encouraged by these findings we tested these conditions
for the glycosylation of ribose 3 with isopropanol. We
obtained the corresponding isopropylriboside 3a in high
yield and with high β-selectivity (Scheme 2). The reactions
were carried out directly in isopropanol in the presence of
catalytic amounts of triphenylphosphine/tetrabromomethane
(10 mol %) at room temperature. A clean and rapid
reaction was observed. Side products were not detected.
The reaction proceeds under genuinely catalytic and
neutral reaction conditions.
Scheme 3. Yields and Anomeric Ratio of Isopropyl Glycosides
Scheme 2. Catalytic Glycosidation of D-Ribose with Isopropanol
Reaction conditions: 2 equiv of isoPrOH, 2 mL of MeCN, 2 equiv of
LiClO4, rt, 12 h (procedure C). b R/β ratio. c Corresponding isopropyl
furanosides were detected as minor products (yields <10%); see Table 1
in Supporting Information.
(9) Pfaffe, M.; Mahrwald, R. Org. Lett. 2012, 14, 792.
(10) Huo, C.; Chan, T. H. Adv. Synth. Catal. 2009, 351, 1933.
(11) (a) Johnstone, C.; Kerr, W. J.; Scott, J. S. Chem. Commun. 1996,
341. (b) Lee, A. S.-Y.; Cheng, C.-L. Tetrahedron 1997, 53, 14255. (c)
Wagner, A.; Heitz, M. P.; Mioskowski, C. J. Chem. Soc. Chem. Comm
1989, 1619. (c) David, S.; De Sennyey, G. Tetrahedron Lett. 1981, 22,
4503.
(8) With the exception of an enzymatic glycosylation. For recent
reviews in this field, see: (a) Bojarova, P.; Rosencrantz, R. R.; Elling, L.;
Kren, V. Chem. Soc. Rev. 2013, 42, 4774. (b) Flitsch, S. L. In Compre-
hensive Chirality; Carreira, E. M., Yamamoto, H., Eds.; Elsevier: 2012; Vol.
7, p 454.
Org. Lett., Vol. 15, No. 22, 2013
5855

We have explored the scope and limitations of this new
glycosylation methodology, reacting several different agly-
cones with D-ribose 3 under the standard conditions
(Scheme 4).
Scheme 4. Catalytic Glycosidation of D-Ribose with Different
Aglycones
The glycosylation reactions were performed in the pre-
sence of catalytic system PPh3/CBr4 (10 mol % of each) at
room temperature without additional solvent (procedure A).
The corresponding ribosides 3bÀ3k were isolated in
moderate-to-high yield except for the reactions of ribose
with tert-butanol (3c) and trifluoroethanol (3f). These
results indicate extreme influences of the deployed agly-
cons on the glycosylation: both an electronic effect (3f)
and a steric effect (3c). These yield-minimizing effects can
be overcome by the additional application of lithium
salts, especially lithium perchlorate.15 Furthermore, a
moderate-to-high β-selectivity was noticed in these gly-
cosylation reactions. Excellent diastereoselectivities were
obtained with aglycones containing oxygen (3e: de >99%).
When used with solid aglycones (e.g., menthol) propylene
carbonate was deployed as solvent (procedure B).
The application of triphenylphosphine and tetrabromo-
methane in glycosylation processes has been described in
the literature.16 These conditions were deployed for glyco-
sylation of fully protected 1-hydroxy carbohydrates. In
these reactions triphenylphosphine and tetrabromo-
methane were used in excess (up to 9 equiv) under inert
and dry reaction conditions to generate the protected
1-bromo glycosyl derivative. The following glycosylation
was achieved by the addition of amines or DMF.
The present conditions cannot be compared with those
described in literature. Water generated during the reac-
tion is tolerated. Also, alterations to the yields and selec-
tivities were not noticed by adding 1 or 2 equiv of water.
The formation of 1-bromoglycosyl intermediates was not
observed. Additional bases or DMF are not necessary for
this glycosylation. These results are in contrast with reac-
tions carried out in the presence of an excess of triphenyl-
phosphine and tetrabromomethane. Also, the formation
a R/β ratio. b Corresponding isopropyl furanosides were detected as
minor products (yields <10%), see Supporting Information. c 2 equiv of
LiClO4 were added. d Reactions were carried out in propylen carbonate.
of triphenylphosphine oxide cannot be the driving force of
this catalytic procedure.16 This consideration is not con-
sistent with the high yields of compounds 6a (99%) or 8a
(84%) by deployment of a 10 mol % catalyst system.
Furthermore, this catalytic reaction proceeds in an
essentially neutral medium. To demonstrate the neutral
reaction medium, we have reacted 5-tritylated ribose 9
under the described standard reaction conditions
(procedure A). A very rapid, clear, and selective glycosyla-
tion was observed. Cleavage of the trityl group was not
detected as is normal in the presence of the Appel
reagent.17 After 2 h at room temperature 5-protected
isopropylriboside 9a was isolated with high yields as a
single stereoisomer (Scheme 5).
(12) A similar tendency has been observed in glycosylations using a
mandelic acid/titanium(IV) alkoxide catalyst. See ref 9.
(13) (a) Worm-Leonhard, K.; Larsen, K.; Jensen, K. J. J. Carb.
Chem. 2007, 26, 349. (b) Babu, B. S.; Balasubramanian, K. K. Carb.
Lett. 1999, 3, 339. (c) Schene, H.; Waldmann, H. Synthesis 1999, 1411.
(d) Schene, H.; Waldmann, H. Chem. Commun. (Cambridge, U.K.)
1998, 2759. (e) Schmid, U.; Waldmann, H. Chem.;Eur. J. 1998, 4, 494.
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Int. Ed. Engl. 1994, 33, 1994. (i) Mukaiyama, T.; Matsubara, K. Chem.
Lett. 1992, 1041. (j) Mukaiyama, T.; Shimpuku, T.; Takashima, T.;
Kobayashi, S. Chem. Lett. 1989, 145. (k) See also ref 9.
Scheme 5. Organocatalyzed Glycosylation of 5-Tritylated
Ribose
(14) (a) Cumpstey, I. Org. Biomol. Chem. 2012, 10, 2503 and refer-
ences cited therein. (b) Taubken, N.; Thiem, J. Synthesis 1992, 517.
(15) Also, quantitative yields are obtained by increasing the catalyst
system up to 50 mol %.
a R/β ratio.
To demonstrate the utility of this operationally simple
protocol we have reacted Cbz-protected serine methyl
ester with ribose under the reported standard conditions
(procedure B, Scheme 6). After 12 h at room tempera-
ture the riboside 3m was isolated in 25% yield. For a
(16) (a) Arumugam, N.; Abdul Rahim, A. S.; Abd Hamid, S.;
Osman, H. Molecules 2012, 17, 9887. (b) Shingu, Y.; Nishida, Y.;
Shingu, Y.; Dohi, H.; Kobayashi, K. Org. Lett. 2003, 5, 2377. (c) Shingu,
Y.; Nishida, Y.; Dohi, H.; Kobayashi, K. Org. Biomol. Chem. 2003, 1,
2518. (d) Shingu, Y.; Miyachi, A.; Miura, Y.; Kobayashi, K.; Nishida,
Y. Carbohydr. Res. 2005, 340, 2236. (e) Nishida, Y.; Shingu, Y.; Menfai,
Y.; Fukuda, K.; Dohi, H.; Matsuda, S.; Matsuda, K. Beilstein J. Org.
Chem. 2012, 8, 629. (f) Chitchirachan, P.; Pluempanupat, W. J. Chem.
Chem. Eng. 2012, 6, 778. (g) Shingu, Y.; Nishida, Y.; Dohi, H.; Matsuda,
K.; Kobayashi, K. J. Carb. Chem. 2002, 21, 605.
(17) For cleavage of triyl ethers under Appel-conditions see Yadav,
J. S.; Reddy, B. V. S. Carb. Res. 2000, 329, 885.
5856
Org. Lett., Vol. 15, No. 22, 2013

This new transformation utilizes catalytic amounts of
triphenylphosphine and tetrabromomethane. Also, the
use of lithium perchlorate as an additive strongly increases
the yields of products observed. Under these reaction
conditions, thermodynamic control of the glycosidation
is observed. As a consequence, the formation of pyrano-
sides is preferred. Further extension of these findings and
investigations into the reaction mechanism are underway.
Scheme 6. Synthesis of Protected Serine Riboside
a Reactions were carried out in propylene carbonate. For ratio of R-
and β-anomers of pyranoid and furanoid structures see Table 4 in the
Supporting Information.
Acknowledgment. Beatrice Braun (Department of Che-
mistry, Humboldt-University) is gratefully acknowledged
for the X-ray structure analysis. The authors acknowledge
COSTÀORCA action (CM0905) for creating networking
and exchange opportunities.
comparison with the classical synthesis of Cbz-protected
serine methyl ester glycoside in the xylose series (protec-
tionÀglycosylationÀdeprotection) see ref 18.
In summary, we have developed an organocatalyzed
method for the direct glycosylation of unprotected and
unactivated carbohydratesunder mild reaction conditions.
Supporting Information Available. NMR data for all of
the synthesized compounds, full characterization of novel
compounds, and X-ray crystallographic data (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) (a) Garcia-Garcia, J. F.; Corrales, G.; Casas, J.; Fernandez-
Mayoralas, A.; Garcia-Junceda, E. Mol. System 2011, 7, 1312. (b)
Wong, C. H.; Schuster, M.; Wang, P.; Sears, P. J. Am. Chem. Soc.
1993, 115, 5893.
The authors declare no competing financial interest.
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