Glycoside bond formation via acid-base catalysis

Article abstract of DOI:10.1021/ol201231v

Acid-base catalyzed glycosyl donor and then glycosyl acceptor activation with phenylboron difluoride or diphenylboron fluoride permits hydrogen bond mediated intramolecular S_N2-type glycosidation in generally high anomeric selectivity.

Full text of DOI:10.1021/ol201231v

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3612–3615
Glycoside Bond Formation via AcidꢀBase
Catalysis
Amit Kumar, Vipin Kumar, Ravindra T. Dere, and Richard R. Schmidt*
€
Fachbereich Chemie, Universitat Konstanz, Fach 725, D-78457 Konstanz, Germany
richard.schmidt@uni-konstanz.de
Received May 9, 2011
ABSTRACT
Acidꢀbase catalyzed glycosyl donor and then glycosyl acceptor activation with phenylboron difluoride or diphenylboron fluoride permits
hydrogen bond mediated intramolecular SN2-type glycosidation in generally high anomeric selectivity.
Major problems associated with glycoside bond forma-
tion have been addressed by the many recent advances in
glycoside synthesis. Efficient strategies and powerful meth-
ods for accessing complex oligosaccharides and glycocon-
jugates of biological significance have been developed.1ꢀ5
However, the synthesis of glycosidic linkages is still by no
means routine and not comparable to peptide and nucleo-
tide synthesis. Often careful optimization of all parameters
including the leaving group, promoter/catalyst, protecting
group, and glycosidation conditions is crucial for high
yield and high stereoselectivity. Hence, new conceptual ap-
proaches to glycosidation are still welcome to meet the in-
trinsic diversity of carbohydrates.
intramolecular glycosidation has attracted great interest.6
In this context it is emphasized that O-glycosyl trichloro-
acetimidates transfer the glycosyl moiety to phosphate
esters and related AdBꢀCꢀH systems without a catalyst
highly diastereoselectively.1a,7 Thus, from the R-glucopyr-
anosyl trichloroacetimidate (Scheme 1, 1R) via an eight-
membered cyclic (extended cyclohexane-like) transition
state the β-products and vice versa were obtained. Even
R-pyridone with a pKa of ∼12,8 possessing the required
AdBꢀCꢀH geometry (Scheme 1), served as a substrate in
this reaction. Hence, it is envisioned that corresponding
AꢀBꢀCꢀH type intermediates, reversibly generated from
as acceptor AꢀH, should react in the same way.7 Thus, the
anomeric stereocontrol is connected via a concerted in-
tramolecular acceptor transfer to the configuration of the
glycosyl donor (Scheme 2).
The ideal catalyst BdC should fulfill the following criteria:
(a) very fast and reversible generation of the AꢀBꢀCꢀH
adduct with AꢀH; (b) increase of the proton acidity of AꢀH
a catalystBdC (orBtC, B C) and, for instance, alcohol
3 3 3
To overcome some difficulties of intermolecular glycosi-
dations, particularly the demanding anomeric stereocontrol,
(1) (a) Schmidt, R. R. Angew. Chem. 1986, 98, 213–236. Angew.
Chem., Int. Ed. Engl. 1986, 25, 212–235. (b) Zhu, X.; Schmidt, R. R.
Angew. Chem. 2009, 121, 1932–1967. Angew. Chem., Int. Ed. 2009, 48,
1900–1934.
(2) Toshima, K. Carbohydr. Res. 2006, 341, 1225–1240.
(3) Demchenko, A. V. Handbook of Chemical Glycosylation; WILEY-
VCH: Weinheim, 2008.
(4) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137–2160.
(5) Pelissier, H. Tetrahedron 2005, 61, 2947–2993.
(7) Schmidt, R. R.; Gaden, H.; Jatzke, H. Tetrahedron Lett. 1990, 31,
327–330.
€
(6) Jung, K.-H.; Muller, M.; Schmidt, R. R. Chem. Rev. 2000, 100,
4423–4442.
(8) Perrin, D. D.; Dempsey, B.; Serjeant, E. P. In pKa Prediction for
Organic Acids and Bases; Chapman and Hall: London, 1981; p 55.
r
10.1021/ol201231v
Published on Web 06/15/2011
2011 American Chemical Society

this intramolecular acidꢀbase catalysis concept for gly-
cosidations is related to the mechanism of glycosyl trans-
fer in enzymatic reactions,6 proof of principle studies are
of great interest.13
Scheme 1. Site-Selective Glycosidation of AdB;C;H
Acceptors with O-Glucopyranosyl Trichloroacetimidate
As Donor Supporting an SN2-Type Mechanism
Boron trifluoride as a catalyst for O-glycosyl trichloro-
acetimidate activation favors, in low polarity solvents at
low temperatures, SN2-type reactions. Yet, the preferential
inversion product formation is presumably due to tight
ion pair generation prior to reaction with the glycosyl
acceptor.1a,14 Similar results were obtained with glycosyl
iodides or with, under acid conditions, in situ generated
O-glycosyl triflate intermediates, respectively, that also
furnish preferentially inversion products formally based
on SN2-type reactions.15ꢀ17 However, these catalysts for
leaving group activation do not fulfill criteria (c) as shown
for boron trifluoride and TMSOTf (Table 1, entries 1 and
2); therefore the desired reaction course is not favored.
Hence, for instance, less acidic boron fluoride derivatives
are required as catalysts. As the first compound phenyl-
boron difluoride (PhBF2) was selected that could be pre-
pared in pure form.18 Gratifyingly, this reagent fulfilled the
criteria for a good catalyst system as shown in Table 1: At
0 °C (and even at rt) PhBF2 did not activate and hence not
in the AꢀBꢀCꢀH adduct; (c) no activation (this way even-
tually leading to decomposition) of the glycosyl donor in the
absence of the acceptor AꢀH, thus supporting the intra-
molecular, bimolecular concerted reaction course of the Aꢀ
BꢀCꢀH adduct; (d) increase of the nucleophilicity of the
acceptor hydroxy group to facilitate glycosidation.
Scheme 2. Formation of Intermediate AcceptorꢀCatalyst Ad-
ducts AꢀBꢀCꢀH Reacting with O-Glucopyranosyl Trichloro-
acetimidate as Donor
Table 1. Reaction of Glycosyl Donors 1rꢀ5r with Alcohols (A)
under Various Conditions and Some Comparisons
reaction cond.a
activator
(equiv)
product β/Rb
time (yield) ratio
entry donor acc.
temp
Studies along these lines with addition prone carbonyl
compounds7 and recently with electron-deficient imines9
as catalysts BdC exhibited some success. However, the
investigated compounds did not fully meet criteria (a), (c),
and (d), thus leading also to undesired product formation.
Hence, BꢀF bond containing compounds could be sui-
table for this purpose as the empty orbital at boron readily
accepts oxygen containing compounds and the fluorine is
known to form strong H-bonds.10 Thus with alcohols (R1ꢀ
OH) adducts are obtained that do not only provide an acidic
proton that is H-bonded to fluorine in nonpolar solvents10
but also an acceptor that carries an induced partial negative
charge.
1
2
3
1r None BF3•OEt2 (0.1) 0 °C
1r None TMSOTf (0.1) 0 °C
1r None PhBF2 (0.1)
30 min Decomp. of 1r
30 min Decomp. of 1r
0 °C f rt 2 d
No reaction,
no decomp.c
4
5
6
1r
1r
1r
A
A
A
BF3•OEt2 (0.1) 0 °C
TMSOTf (0.1) 0 °C
10 min 1A (84%) 2:1
10 min 1A (88%) 1:1
10 min 1A (73%) 8:1
PhBF2 (0.1)
0 °C
7
8
9
1r
1r
1r
A
A
A
BF3•OEt2 (0.1) ꢀ78 °C 10 min 1A (89%) 6:1
TMSOTf (0.05) ꢀ78 °C 10 min 1A (88%) 12:1
PhBF2 (0.1)
ꢀ78 °C 10 min 1A (93%) 24:1
d
10
1r A0
HF•Pyr (1.0) 0 °C
10 min 1A (71%) 24:1
11
12
13
14
3r
4r
5r
2r
A
A
A
A
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
ꢀ78 °C 10 min 3A (86%) 24:1
ꢀ78 °C 10 min 4A (69%) 4:1
ꢀ78 °C 10 min 5A (86%) 6:1
ꢀ78 °C 10 min 2A (89%) 24:1
Thus, a nucleophilicity increase of the acceptor is gained
that supports the reaction with the glycosyl donor.11,12 As
15
1r None Ph2BF (0.1)
0 °C
30 min No reaction,
no decomp.
16
17
1r
1r
A
A
Ph2BF (0.1)
Ph2BF (0.1)
0 °C
10 min 1A (89%) 7:1
(9) Kumar, A.; Schmidt, R. R., unpublished results.
ꢀ78 °C 10 min 1A (91%) 24:1
(10) (a) Huduall, T. W.; Melaimi, M.; Gabbai, F. P. Org. Lett. 2006,
8, 2747–2749. (b) He, Q.; Yang, J.; Meng, X.-m. Chin. J. Chem. Phys.
2009, 22, 517–522 and references therein.
(11) The activation of the acceptor in glycosidations has recently
been addressed: (a) Ferrier, R. J.; Furneaux, R. H. Aust. J. Chem. 2009,
62, 585–589. (b) Kaji, E.; Nishino, T.; Ishige, K.; Ohyo, Y.; Shirai, Y.
Tetrahedron Lett. 2010, 51, 1570–1573.
(12) By alkoxide groups negatively charged arylboronates were
shown to be good acceptors in standard glycosidations: Oshima, K.;
Aoyama, Y. J. Am. Chem. Soc. 1999, 121, 2315–2316.
18
19
1β
1β
A
B
PhBF2 (0.1)
PhBF2 (0.1)
ꢀ78 °C 10 min 1A (85%) 1:4
ꢀ78 °C 10 min 1B (90%) 1:15
a Inverse procedure and dry CH2Cl2 as solvent were employed. b The
β/R ratio was determined by the 1H NMR signals of the isopropyl methyl
groups; the detection limit for the R-anomer is about 4%. c Very slow
formation of glucosyl fluoride was observed. d A’ = B(OiPr)3.
Org. Lett., Vol. 13, No. 14, 2011
3613

Table 2. Reaction of Glycosyl Donors 1rꢀ5r with Carbohy-
drate Acceptors BꢀG with PhBF2 or Ph2BF, Respectively, As
Catalysts
Scheme 3. Glycosyl Donors 1rꢀ5r and Their Reactions with
Alcohols (for details, see Table 1)
decompose the donor 1r (entry 3); however, fast adduct
formation with isopropanol could be observed by 1H
NMR studies. This adduct reacted readily with 1r19 at
0 °C or even at ꢀ78 °C to afford essentially (entry 6) or
practically exclusively (entry 9) the desired β-glucopyrano-
side 1A.20 Comparisons with BF2 OEt2 and TMSOTf as a
3
catalyst under these conditions (entries 4, 5 and 7, 8) clearly
showed that the PhBF2 alcohol adduct is superior in terms
3
of stereocontrol. Comparison studies with alkyl phenyl-
boronates and borate esters as acceptors and HF as a
promoter (entry 10) led to similar results. These studies
showed that fluorine bound to boron is required for the
success of the reaction. As presumed, the transition state in
the reaction of 1r with the AꢀBꢀCꢀH adduct is quite
sensitive to temperature variations (entries 6 and 9); how-
ever, solvents (as for instance acetonitrile, toluene, cyclo-
hexane) had only a minor effect on the results. Due to the
fast adduct formation, the use of the inverse procedure (IP,
i.e. adding the catalyst to the dissolved acceptor) or the
normal procedure (NP, i.e. adding the catalyst to a solu-
tion of the acceptor and donor) had only a small effect on
the result (not shown). Hence, PhBF2 as the catalyst in
dichloromethane as the solvent at ꢀ78 °C under IP condi-
tions seems to be a good choice for the synthesis of 1,2-
trans glycosides with 1r as the donor. Similar results were
reaction cond.a
catalyst
(equiv)
product β/Rb
(yield) ratio
entry donor acc.
temp
time
1
2
3
4
5
6
7
8
9
1r
1r
1r
1r
1r
1r
1r
1r
1r
C
C
C
D
E
F
PhBF2 (0.1)
PhBF2 (0.1)
0 °C 10 min 1C (83%) 13:1
ꢀ78 °C 10 min 1C (87%) 24:1
TMSOTf (0.1) ꢀ78 °C 10 min 1C (80%)
6:1
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
ꢀ78 °C 10 min 1D (73%)c 4:1
ꢀ78 °C 10 min 1E (74%)c 8:1
ꢀ78 °C 10 min 1F (65%)
3:1
G
H
H
ꢀ78 °C 10 min 1G (62%)c 15:1
ꢀ78 °C 4 h
1H (64%) 24:1
BF3•OEt2 (0.1) ꢀ78 °C 3 h
1H (66%)
5:1
10
11
12
13
14
15
3r
3r
4r
4r
5r
5r
C
D
C
D
C
F
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
PhBF2 (0.1)
ꢀ78 °C 10 min 3C (82%) 24:1
ꢀ78 °C 10 min 3D (68%) 3:1
ꢀ78 °C 10 min 4C (68%) 24:1
ꢀ78 °C 30 min 4D (68%) 4:1
ꢀ78 °C 10 min 5C (72%) 24:1
ꢀ78 °C 10 min 5F (60%) 7:1
(13) The activation of O-glycosyl trichloroacetimidates with HBF4
follows the standard reaction course: (a) Chiba, H.; Funasake, S.;
Mukaiyama, T. Bull. Soc. Chem. Jpn. 2003, 76, 1629–1644. (b) Hashihayata,
T.; Mandai, H.; Mukaiyama, T. Chem. Lett. 2003, 32, 442–443.
(14) Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41, 8753–
8758.
(15) (a) El-Badry, M. H.; Gervay-Hague, J. Tetrahedron Lett. 2005,
46, 6727–6728. (b) El-Badry, M. H.; Willenbring, D.; Tantillo, D. J.;
Gervay-Hague, J. J. Org. Chem. 2007, 72, 4663–4672.
(16) Crich, D. Acc. Chem. Res. 2010, 43, 1144–1153 and references
therein.
16
17
18
19
20
1r
1r
3r
4r
5r
C
D
D
C
C
Ph2BF (0.1)
Ph2BF (0.1)
Ph2BF (0.1)
Ph2BF (0.1)
Ph2BF (0.1)
ꢀ78 °C 10 min 1C (96%) 24:1
ꢀ78 °C 10 min 1D (74%) 10:1
ꢀ78 °C 10 min 3D (76%)
6:1
ꢀ78 °C 10 min 4C (71%) 24:1
(17) Callam, C. S.; Gadikota, R. R.; Klein, D. M.; Lowary, T. L.
J. Am. Chem. Soc. 2003, 125, 13112–13119.
ꢀ78 °C 10 min 5C (80%) 24:1
(18) Farvoq, O. J. Fluorine Chem. 1995, 70, 225–227.
(19) Schmidt, R. R.; Michel, J. Angew. Chem. 1980, 92, 763–764.
Angew. Chem., Int. Ed. Engl. 1980, 19, 731–732.
(20) Briner, K.; Vasella, A. Helv. Chim. Acta 1989, 72, 1371–1382.
(21) Wegmann, B.; Schmidt, R. R. J. Carbohydr. Chem. 1987, 6, 357–
375.
a All reactions were carried out in dry CH2Cl2 as solvent using the
inverse procedure. b The β/R ratio was determined with the help of 1H
NMR data; the detection limit for the R-anomers is about 4%. c About
5% glucosyl fluoride was obtained.
3614
Org. Lett., Vol. 13, No. 14, 2011

obtained for glycosyl donors 3r,21 4r,22 and 5r23 having
no anchimerically assisting neighboring groups in the
2-position; again, mainly the β-glycosides of 3A,24 4A,
and 5A were formed (entries 11, 12, and 13). Even the less
reactive fully O-acetylated glucosyl donor 2r19 could be
activated with PhBF2 in the presence of isopropanol as an
acceptor (entry 14) furnishing as expected the β-glucopyr-
anoside 2Aβ (Scheme 3).25
As PhBF2 gave mainly excellent glycosidation results at
temperatures as low as ꢀ78 °C, hence also the less Lewis
acidic Ph2BF was prepared18 and studied as a catalyst
under the same conditions. Entries 15ꢀ17 (Table 1) show
that this compound also fulfills the criteria for a good
catalyst.
furnish better results than PhBF2, for instance in the
formation of 1C or 1H (entries 3 and 9). Preferential 1,2-
trans product formation was also observed for glycosyl
donors 3rꢀ5r (entries 10ꢀ15), thus furnishing mainly
3Cβ,37 3Dβ,21 4Cβ, 4Dβ, 5Cβ, and 5Fβ.
Investigationswith Ph2BF asthe catalyst(entries 16ꢀ20,
formation of 1C, 1D, 3D, 4C, 5C) exhibited very good
glycosidation results. It was particularly pleasing that
Ph2BF provided in the reactions of 1r with D to 1D
(entry 17) and of 3r with D to 3D (entry 18) better results
than PhBF2 (see entries 4 and 11); thus, as expected, the
steric effect of the two phenyl groups supports the con-
certed donor activationꢀacceptor transfer. Hence, the
choice of catalyst is of great importance in these intramo-
lecular acidꢀbase catalyzed glycosidations.
Preliminary experiments were also performed with the
correspondingO-β-D-glucopyranosyltrichloroacetimidate
1β1a as a glycosyl donor. With isopropanol (A) as the
acceptor there is a clear preference for R-product (1Ar)26
formation (entry 18). Almost exclusive β-selectivity was
observed for allyl alcohol (B) as the acceptor affording
mainly 1Br27 (entry 19). Possibly, some steric hindrance in
the transition state leads to lower anomeric selectivity than
observed for 1r. Hence, other catalyst types may be
required for the selective generation of 1,2-cis-glycosides.
The glycosidation results with glycosyl donors 1r, 3r,
4r, and 5r with more demanding carbohydrate acceptors
C,26 D,29 E,30 F,30 G,31 and H32 in the presence of different
catalysts are compiledinTable 2. Reaction of1r with these
acceptors having unprotected hydroxy groups at 6-, 4-, 2-,
and 3-positions with PhBF2 as the catalyst (entries 1, 2,
4ꢀ8) exhibited preferential formation of the β-glucopyr-
anosides of 1C,28 1D,21 1E,33 1F,34 1G,35 and 1H. The re-
actions did not proceed at the same rate (entry 8); the ap-
pearance of some glycosyl fluoride (entries 4, 5, 7) showed
that the catalyst is partly consumed, thus leading to a
decreased reaction rate that also influenced the product
yield. However, no phenyl C-glycoside formation was
In conclusion, PhBF2 and Ph2BF, formally representing
BdC, basically fulfill the requirements for good cata-
lysts for O-glycosyl trichloroacetimidate (and related
systems) activation: Not the catalyst itself, but only the
adduct AꢀBꢀCꢀH with acceptor AꢀH is sufficiently
acidic to activate the glycosyl donor. Hence, the catalyst
carries the acceptor to the donor generating a tempora-
rily H-bonded noncovalent donor leaving groupꢀ
catalystꢀacceptor complex that permits via an intramo-
lecular reaction course proton transfer to the leaving
group and the nucleophilicity increase of the acceptor
facilitating the concomitant glycoside bond formation.
The results support the prevalence of this concerted
SN2-type mechanism between the glycosyl donor and
the AꢀBꢀCꢀH adduct, as preferentially the inversion
product is obtained. Competing reaction courses lead-
ing to R-product and glycosyl fluoride formation were
only effective in some cases. H-bonding as a means for
intramolecular acidꢀbase catalyzed glycosidation re-
sulting in concomitant glycosyl donor and glycosyl
acceptor activation obviously has the potential to be-
come a general and very efficient glycosidation method.
observed.36 TMSOTf or BF3 OEt2 as catalysts did not
3
Acknowledgment. This work was supported by the
University of Konstanz and the Fonds der Chemischen
Industrie. V.K. is particularly grateful for a fellowship
from the Alexander von Humboldt Foundation.
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Supporting Information Available. Experimental details
and NMR spectra of new compounds (1H, 4A, 4C, 4D,
5A, 5C, 5F) and NMR spectra of 1Aꢀ1G, 2A, 3A, 3C, 3D.
This material is available free of charge via the Internet
at http://pubs.acs.org.
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Org. Lett., Vol. 13, No. 14, 2011
3615