Regioselective activation of glycosyl acceptors by a diarylborinic acid-derived catalyst

Article abstract of DOI:10.1021/ja2062715

A derivative of diphenylborinic acid promotes catalytic, regioselective Koenigs-Knorr glycosylations of carbohydrate derivatives bearing multiple secondary hydroxyl groups. Robust levels of selectivity for the equatorial OH group of cis-1,2-diol motifs ar

Full text of DOI:10.1021/ja2062715

COMMUNICATION
pubs.acs.org/JACS
Regioselective Activation of Glycosyl Acceptors by a Diarylborinic
Acid-Derived Catalyst
Christina Gouliaras, Doris Lee, Lina Chan, and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6
S Supporting Information
b
protected carbohydrate building blocks using a commercially avail-
able diarylborinic acid derivative.
ABSTRACT: A derivative of diphenylborinic acid promotes
catalytic, regioselective KoenigsÀKnorr glycosylations of car-
bohydrate derivatives bearing multiple secondary hydroxyl
groups. Robust levels of selectivity for the equatorial OH group
of cis-1,2-diol motifs are demonstrated in reactions of seven
acceptors derived from galactose, mannose, fucose, and arabi-
nose using a variety of glycosyl halide donors. Catalyst control
presents a new means of generating defined glycosidic linkages
from unprotected or minimally protected carbohydrate
feedstocks.
We sought to test the hypothesis that an organoboron catalyst
could activate glycosyl acceptors through the formation of tetra-
coordinate adducts of cis-1,2-diol motifs. Precedent for this proposal
includes (1) an extensive literature of carbohydrate recognition by
organoboron derivatives through selective interactions with cis-1,2-
diol groups;11 (2) studies of the stoichiometric reactivity of sugar-
derived boronate esters, which demonstrated that tetracoordinate
adducts of this type undergo regioselective glycosylation;12a and (3)
our recent discovery that arylborinic acid derivatives catalyze the
acylation and alkylation of carbohydrate derivatives, with high
selectivity for functionalization of the equatorial hydroxyl group of
cis-1,2-diol moieties.13,14
ligosaccharides play central roles in a wide range of biological
Experiments assessing the ability of organoboron catalysts
1aÀe to promote regioselective KoenigsÀKnorr glycosylation
of mannose derivative 2a are summarized in Table 1. A glycosyl
acceptor in which the primary OH group was protected was chosen
to avoid complications arising from two-point binding of the
organoboron catalyst to O6 and O4, a known mode of coordination
in boron-based sugar receptors.11b In the absence of an organoboron
catalyst, use of silver(I) oxide as an activating reagent gave only a
trace amount (<5%) of disaccharide 3a; 1H NMR analysis with a
quantitative internal standard indicated 37 and 77% recovery of the
glycosyl donor and acceptor, respectively. Phenylboronic acid 1a
promoted the formation of β-[1,3]-linked disaccharide 3a in 52%
yield, and the corresponding orthoester 4a (15% yield) was formed
as one of several byproducts. Varying the electronic properties of the
boronic acid catalyst did not significantly improve the efficiency of
the reaction (entries 3 and 4). However, diphenylborinic acid
derivative 1d delivered 3a as the only observed disaccharide in
99% isolated yield. Borinic acids provide superior catalytic activity
and regioselectivity relative to boronic acids in the context of
acylations and alkylations of monosaccharides;13 the variation in
the ratio of disaccharide to orthoester observed here appears to
reflect differences in the nature of the nucleophilic species obtained
upon activation of diols by these two classes of catalysts.15 Mechan-
istic studies (see below) suggested that borinate ester 1d serves as a
precatalyst from which the ethanolamine ligand is displaced under
the reaction conditions. Triphenylborane (1e) promoted the for-
mation of 3a in moderate yield (entry 6); orthoester 4a and
recovered glycosyl donor were also evident in the crude reaction
mixture. The identity of the Ag(I) salt was crucial to the success
of this transformation: lower yields of 3a were obtained using
other insoluble (Ag2CO3) or soluble (AgOTf, AgOAc) promoters.
O
processes, including cellÀcell signaling, immune response,
cancer metastasis, and progression of human disease.1 Laboratory
synthesis often represents the only means of access to homoge-
neous, well-defined oligosaccharides for use in medical or biochem-
ical research or as new therapeutic agents. The preparation of oligo-
saccharides from readily available carbohydrate derivatives requires
efficient methods for the construction of O-glycosidic bonds,
and solutions to this problem have been pursued for more than a
century.2
Regioselectivity represents a key challenge for oligosaccharide
synthesis: an acceptor bearing multiple potentially reactive hydroxyl
(OH) groups must undergo glycosylation at a single site. The
problem of regioselectivity has generally been addressed through the
use of protecting groups to suppress glycosylation at undesired
positions; the additional operations required to install and remove
these protecting groups and the accompanying generation of
chemical waste represent disadvantages of this approach.3 In certain
instances, inherent differences in the steric and/or electronic pro-
perties of OH groups may be exploited to achieve selective glyco-
sylation.4,5 Such reactions are generally optimized on a case-by-case
basis, and the regiochemical outcome may depend on the structure
of the glycosyl donor.6 A third strategy employs activating agents to
enhance the reactivity of specific OH groups: in particular, organotin
derivatives promote regioselective reactions of carbohydrate deri-
vatives with a variety of electrophiles, including glycosyl donors.7
These methods generally require an additional synthetic step to
install the activating group, and the use of stoichiometric quantities
of toxic, lipophilic organotin species constitutes a limitation. None of
these strategies rivals biological machinery in its ability to achieve re-
gioselective, enzyme-catalyzed glycosylation of unprotected sugars.8
Here we report the first example of a synthetic “small-molecule”
(nonenzymatic) catalyst capable of regioselective activation of
glycosyl acceptors.9,10 This method enables the facile construction
of a variety of glycosidic linkages from unprotected or minimally
Received: July 6, 2011
Published: August 12, 2011
r
2011 American Chemical Society
13926
dx.doi.org/10.1021/ja2062715 J. Am. Chem. Soc. 2011, 133, 13926–13929
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Optimization of Organoboron-Catalyzed Regiose-
lective Glycosylation of Mannose Derivative 2a
Table 2. Borinic Ester-Catalyzed Regioselective Glycosyla-
tion: Variation of Glycosyl Donor and Acceptor Structures
a Isolated yields after purification by chromatography on silica gel.
Likewise, other classes of donors (trichloroacetimidates, phos-
phates, thioglycosides) did not give rise to regioselective organo-
boron-catalyzed glycosylation.16 The optimized reaction conditions
are noteworthy from the standpoint of their operational simplicity:
rigorous exclusion of moisture (or the addition of drying agents) is
not needed, and the deliberate addition of 4 equiv of water relative to
glycosyl acceptor resulted in only a moderate decrease in the yield of
3a (72 vs 99%).
Table 2 illustrates the range of glycosidic linkages that can be
accessed by this catalyst-controlled method. Selective glycosyla-
tion at O3 was observed for derivatives of mannose, galactose,
fucose, arabinose, and rhamnose, each bearing three potentially
reactive secondary hydroxy groups, with varied relative stereo-
chemistry at the anomeric position. Employing 1,6-anhydroga-
lactopyranose resulted in glycosylation at O4, a regiochemical
outcome distinct from that achieved using the nonbridged
galactopyranoside substrates. Our model for the observed re-
gioselectivity invokes the selective formation of tetracoordinate
borinate adducts of the cis-1,2-diol moiety as described above:
the boron-bound oxygen atom predicted to be most nucleophilic
by Fukui index calculations13,17 corresponds to the site of
observed reactivity for each substrate. Steric effects may also
play a role (e.g., the selective glycosylation of 3d at O4 rather
than O3 corresponds to reaction of the less hindered hydroxyl
group). Desilylation of 3a was followed by catalyst-controlled
glycosylation at O6 (presumably through binding to the 4- and
6-positions), generating branched trisaccharide 3m.
Variation of the structure of the glycosyl donor was also
investigated. Galactosyl, fucosyl, and arabinosyl moieties were
introduced in good yields (entries 6À9, 11, and 12), and glycosyl
donors bearing benzyl (rather than acetyl) protecting groups
were tolerated (entries 8À10). The use of glycosyl chlorides
rather than bromides was crucial for achieving regioselective
glycosylation with relatively reactive donors (e.g., fucosyl, arabi-
nosyl, and perbenzylated glycosyl halides). The nature of this
effect is illustrated in Scheme 1. Attempted glycosylation of 2a
using peracetylated fucosyl bromide as the donor resulted in a
complex mixture of products, but the yield of disaccharide was
improved by employing either the 4-nitrobenzoyl-protected
glycosyl bromide or the peracetylated glycosyl chloride, with
the latter providing the best result. Both the introduction of
a Isolated yields after purification by chromatography on silica gel;
reactions were carried out using the glycosyl bromide (X = Br) as the
donor, unless otherwise noted. b The reaction was carried out using the
glycosyl chloride (X = Cl).
Scheme 1. Tuning of the Glycosyl Halide Reactivity in Cat-
alyst-Controlled Regioselective Glycosylation
electron-withdrawing protecting groups and the stronger CÀX
bond of the glycosyl chloride relative to the bromide are expected
to destabilize oxocarbenium-like intermediates (consistent with
13927
dx.doi.org/10.1021/ja2062715 |J. Am. Chem. Soc. 2011, 133, 13926–13929

Journal of the American Chemical Society
COMMUNICATION
Scheme 2. Investigation of the Mechanism of Borinic Acid-
Catalyzed Regioselective Glycosylationa
targets. Efforts to expand the scope of this method and apply it
to target-oriented synthesis are underway in our laboratories.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and char-
b
acterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mtaylor@chem.utoronto.ca
’ ACKNOWLEDGMENT
This work was supported by NSERC (Discovery Grants
Program, graduate scholarships to D.L. and L.C.), Merck Research
Laboratories (CADP Grant), the CFI, and the Province of Ontario.
The authors thank Prof. Mark Nitz for advice and valuable com-
ments on this study.
1
a Kinetic orders were based on initial rates determined by H NMR
analysis (see the Supporting Information).
’ REFERENCES
(1) (a) Varki, A.; Cummings, R. D.; Esko, J. D.; Freeze, H. H.;
Stanley, P.; Bertozzi, C. R.; Hart, G. W.; Etzler, M. E. Essentials of
Glycobiology, 2nd ed.; Cold Spring Harbor Press: Woodbury, NY, 2009.
(b) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1, 611–622.
(c) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051.
(2) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.
(3) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193–205.
(4) For selected examples in oligosaccharide total synthesis, see: (a)
Deshpande, P. P.; Danishefsky, S. J. Nature 1997, 387, 164–166. (b) Lay,
L.; Manzoni, L.; Schmidt, R. R. Carbohydr. Res. 1998, 310, 157–171. (c)
Ellervik, U.; Magnusson, G. J. Org. Chem. 1998, 63, 9314–9322. (d)
F€urstner, A.; Jeanjean, F.; Razon, P.; Wirtz, C.; Mynott, R. Chem.—Eur.
J. 2003, 9, 307–319. (e) Ando, H.; Koike, Y.; Koizumi, S.; Ishida, H.;
Kiso, M. Angew. Chem., Int. Ed. 2005, 44, 6759–6763.
the extensive literature of armedÀdisarmed effects in glycosylation
chemistry18) in favor of a pathway with significant SN2 character.
The observation of more efficient borinic acid-mediated glycosyla-
tion with substrates that disfavor oxocarbenium ion formation is
consistent with stereochemical and kinetic studies suggesting an
SN2-type mechanism for the catalytic process (see below).
At present, this catalyst-controlled glycosylation protocol
provides efficient access to trans-1,2 linkages from donors having
a gluco or galacto configuration. Preliminary attempts to prepare cis-
1,2 linkages (e.g., by organoboron-catalyzed variants of the halide
ion catalysis method19) did not yield synthetically useful results.
However, when the range of donors and acceptors employed is
taken into account, the scope of the method is considerably broader
than those of previously developed stoichiometric activation proto-
cols based on organotin or organoboron reagents.7,12
(5) Glycosyl donors bearing unprotected hydroxyl groups have been
developed. Regioselective O-glycosylations employing these species
require superstoichiometric quantities of the glycosyl acceptor. See:
Hanessian, S.; Lou, B. Chem. Rev. 2000, 100, 4443–4463.
Experiments relevant to the mechanism of the borinic acid-
catalyzed glycosylation reaction are summarized in Scheme 2.
The outcome of the transformation is dependent on the configura-
tion of the glycosyl halide: subjecting the β-anomer of acetochlor-
oglucose to the optimized reaction conditions delivered orthoester
4a (rather than 3a) in moderate yield.20 This result suggests that 3a
is generated by an SN2-type inversion21 rather than through the
intermediacy of an oxocarbenium ion and is consistent with previous
observations regarding reactions of glycosyl halides in the presence
of insoluble silver-based promoters.22 Kinetic orders based on initial
rates determined by 1H NMR experiments were also consistent with
this proposal: the reaction showed first-order kinetics with respect to
the glycosyl donor, the acceptor, and the catalyst and zeroth-order
kinetics with respect to Ag2O. The zeroth-order kinetics may reflect
saturation-type behavior of reactive sites on the Ag2O surface. The
initial rates of reactions promoted by diphenylborinic acid
(Ph2BOH) were higher than those in which its ethanolamine ester
1d was employed, consistent with the hypothesis that the latter
serves as a precatalyst under the reaction conditions.
(6) Anilkumar, G.; Nair, L. G.; Fraser-Reid, B. Org. Lett. 2000, 2,
2587–2589.
(7) (a) Ogawa, T.; Katano, K.; Matsui, M. Carbohydr. Res. 1978,
64, C3–C9. (b) Cruzado, C.; Bernabe, M.; Martin-Lomas, M. Carbohydr.
Res. 1990, 203, 296–301. (c) Garegg, P. J.; Maloisel, J.-L.; Oscarson, S.
Synthesis 1995, 409–414. (d) Kaji, E.; Harita, N. Tetrahedron Lett. 2000,
41, 53–56.
(8) Bennett, C. S.; Wong, C.-H. Chem. Soc. Rev. 2007, 36, 1227–1238.
(9) Chemoenzymatic transformations represent the state-of-the-art
methods for achieving regioselective glycosylation of unprotected
acceptors. See ref 8 and: (a) Hancock, S. M.; Vaughan, M. D.; Withers,
S. G. Curr. Opin. Chem. Biol. 2006, 10, 509–519. (b) Gamblin, D. P.;
Scanlan, E. M.; Davis, B. G. Chem. Rev. 2009, 109, 131–163.
(10) For the development of catalysts capable of activating glycosyl
donors toward stereoselective glycosylation reactions, see: (a) Mensah, E. A.;
Nguyen, H. M. J. Am. Chem. Soc. 2009, 131, 8778–8780. (b) Mensah, E. A.;
Azzarelli, J. M.; Nguyen, H. M. J. Org. Chem. 2009, 74, 1650–1657. (c) Cox,
D. J.; Smith, M. D.; Fairbanks, A. J. Org. Lett. 2010, 12, 1452–1455.
(11) (a) Nishiyabu, R.; Kuboy, Y.; James, T. D.; Fossey, J. S. Chem.
Commun. 2011, 47, 1106–1123. (b) Jin, S.; Cheng, Y.; Reid, S.; Li, M.;
Wang, B. Med. Res. Rev. 2010, 30, 171–257.
The ability to influence the regiochemical outcome of glyco-
sylation reactions using a synthetic catalyst represents a new
mode of reactivity that presents interesting opportunities for
improving the efficiency of the synthesis of oligosaccharide
(12) (a) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999, 121,
2315–2316. (b) Oshima, K.; Yamauchi, T.; Shimomura, M.; Miyauchi, S.;
Aoyama, Y. Bull. Chem. Soc. Jpn. 2002, 75, 1319–1324. A regioselective
protocol employing stoichiometric quantities of 4-methoxyphenylboronic
13928
dx.doi.org/10.1021/ja2062715 |J. Am. Chem. Soc. 2011, 133, 13926–13929

Journal of the American Chemical Society
COMMUNICATION
acid has been developed. The regiochemical outcome has been interpreted
in terms of transient protection (rather than activation) by the boronic
acid. See:(c) Kaji, E.; Nishino, T.; Ishige, K.; Ohya, Y.; Shirai, Y. Tetrahedron
Lett. 2010, 51, 1570–1573.
(13) (a) Lee, D.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 3724–3727.
(b) Chan, L.; Taylor, M. S. Org. Lett. 2011, 13, 3090–3093.
(14) For other catalyst-controlled methods for the selective protec-
tion of carbohydrate derivatives, see: (a) Griswold, K. S.; Miller, S. J.
Tetrahedron 2003, 59, 8869–8875. (b) Hu, G.; Vasella, A. Helv. Chim.
Acta 2003, 86, 4369–4390. (c) Kawabata, T.; Muramatsu, W.; Nishio,
T.; Shibata, T.; Schedel, H. J. Am. Chem. Soc. 2007, 129, 12890–12895.
(d) Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama,
N.; Onomura, O. Org. Lett. 2008, 10, 5075–5077. (e) Dhiman, R. S.; Kluger,
R. Org. Biomol. Chem. 2010, 8, 2006–2008.
(15) Subjecting orthoester 4a to the optimal reaction conditions
(catalyst 1d, Ag2O, CH3CN, 23 °C) did not result in detectable rearrange-
ment to 3a.
(16) Peracetylated donors derived from D-glucose were employed in
these studies. The activating agents employed were TMSOTf (R-trichloro-
acetimidate and R-phosphate), BF3 OEt2 (R-trichloroacetimidate), AgOTf,
3
and Cu(OTf)2 (β-S-benzoxazolyl glycoside) in acetonitrile solvent.
(17) Yang, W.; Mortier, W. J. J. Am. Chem. Soc. 1986, 108, 5708–5711.
(18) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid,
B. J. Am. Chem. Soc. 1988, 110, 5583–5584. (b) Douglas, N. L.; Ley, S. V.;
L€ucking, Y.; Warriner, S. L. J. Chem. Soc., Perkin Trans. 1 1998, 51–65. (c)
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H.
J. Am. Chem. Soc. 1999, 121, 734–753. (d) Premathilake, H. D.; Demchenko,
A. V. Top. Curr. Chem. 2011, 301, 189–221.
(19) Lemieux, R. U.;Hendriks, K. B.;Stick, R. V.;James, K.J. Am. Chem.
Soc. 1975, 97, 4056–4062.
(20) The R-glycosyl chloride was cleanly converted to disaccharide
3a rather than orthoester 4a under these conditions (40 °C).
(21) For mechanistic studies of β-mannosylations that proceed with
inversion of stereochemistry, see: Crich, D. Acc. Chem. Res. 2010, 43,
1144–1153.
(22) For previous kinetic and stereochemical studies consistent with
such mechanisms for KoenigsÀKnorr glycosylations, see: (a) Wulff, G.;
R€ohle, G.; Kr€uger, W. Angew. Chem., Int. Ed. 1970, 9, 455–456. (b) Wulff,
G.; R€ohle, G.; Schmidt, U. Chem. Ber 1972, 105, 1111–1121. (c) Wulff, G.;
R€ohle, G. Chem. Ber 1972, 105, 1122–1232. (d) Van Boeckel, C. A. A.;
Beetz, T.; Van Aelst, S. F. Tetrahedron 1984, 40, 4097–4107 and references
cited therein.
13929
dx.doi.org/10.1021/ja2062715 |J. Am. Chem. Soc. 2011, 133, 13926–13929