Regioselective alkylation of carbohydrate derivatives catalyzed by a diarylborinic acid derivative

Article abstract of DOI:10.1021/ol200990e

Regioselective, catalyst-controlled monoalkylations of cis-vicinal diol motifs in carbohydrate derivatives, using a diphenylborinic ester precatalyst, are described. Selective installation of benzyl, naphthylmethyl, 4-bromobenzyl and benzyloxymethyl protective groups at a single secondary hydroxy group of ten representative carbohydrate derivatives illustrates the scope of this method. This new mode of catalytic reactivity represents an operationally simple method to access useful monoalkylated building blocks while avoiding the use of stoichiometric quantities of organotin reagents.

Full text of DOI:10.1021/ol200990e

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3090–3093
Regioselective Alkylation of Carbohydrate
Derivatives Catalyzed by a Diarylborinic
Acid Derivative
Lina Chan and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street,
Toronto ON M5S 3H6, Canada
mtaylor@chem.utoronto.ca
Received April 14, 2011
ABSTRACT
Regioselective, catalyst-controlled monoalkylations of cis-vicinal diol motifs in carbohydrate derivatives, using a diphenylborinic ester precatalyst, are
described. Selective installation of benzyl, naphthylmethyl, 4-bromobenzyl and benzyloxymethyl protective groups at a single secondary hydroxy
group of ten representative carbohydrate derivatives illustrates the scope of this method. This new mode of catalytic reactivity represents an
operationally simple method to access useful monoalkylated building blocks while avoiding the use of stoichiometric quantities of organotin reagents.
The laboratory synthesis of oligosaccharides has been
pursued for decades as a means to access new therapeutic
agents and probes of biological function.1 Crucial to such
efforts are reactions that provide access to selectively
protected monosaccharide building blocks for use in gly-
cosylation reactions. Benzyl ethers and their variants are
‘workhorse’ protective groups in this regard, due to their
favorable stability profiles, low propensities for migration,
and ease of removal under mild reaction conditions.2
Herein, we describe the regioselective alkylation of carbo-
hydrates bearing multiple secondary hydroxy groups using
a commercially available organoboron catalyst. This
method enables the selective introduction of benzyl,
4-bromobenzyl, naphthylmethyl, and benzyloxymethyl
protective groups to a wide range of monosaccharides,
with reliable selectivity for monoalkylation at the equator-
ial hydroxy groups of cis-vicinal diol motifs.
Several methods exist for selective installation of benzyl
and substituted benzyl ether groups;3 complementary
approaches based on regioselective cleavage of ether pro-
tective groups have also been developed.4 Selective alkyla-
tion of the most acidic hydroxy group (usually at C-2) may
be achieved in certain cases, with varying degrees of
efficiency.5 Reductive cleavage of benzylidene acetals
ꢀ
(3) Gomez, A. M. In Glycoscience; Fraser-Reid, B., Tatsuka, K., Thiem,
J., Eds.; Springer-Verlag: Berlin, 2008; pp 103ꢀ177.
(4) For recent examples, see: (a) Lewis, J. C.; Bastian, S.; Bennett, C. S.;
Fu, Y.; Mitsuda, Y.; Chen, M. M.; Greenberg, W. A.; Wong, C.-H.
Arnold, F. H. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 16550–16555.
(b) Yin, Z.-J.; Wang, B.; Li, Y.-B.; Meng, X.-B.; Li, Z.-J. Org. Lett. 2010,
12, 536–539.
(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: New York, 2009. (b)
Boltje, T. J.; Buskas, T.; Boons, G.-J. Nature Chem. 2009, 1, 611–622. (c)
Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051.
(2) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis; John Wiley & Sons, Inc.: NJ, 2007.
(5) For a review, see: Garegg, P. J. Pure Appl. Chem. 1984, 56,
845–858.
r
10.1021/ol200990e
Published on Web 05/17/2011
2011 American Chemical Society

represents a general, two-step protocol for the introduc-
tion of benzyl groups at O-4 or O-6 of the pyranosides.5
Reagents capable of promoting regioselective alkylation of
sugars bearing multiple hydroxy groups have been devel-
oped, including tin(IV), copper(II), mercury(II) and
nickel(II)-based complexes.6 The most widely applied of
these methods involve the use of stannylene acetals or
stannyl ethers.7 These protocols generally require the
generation and isolation of the stannylated species prior
to alkylation, and result in a stoichiometric amount of
potentially toxic di- or trialkyltin(IV) byproducts that
must be separated from the desired product.8 Achieving
catalyst-controlled variants of these reactions ꢀ ideally,
with promoters having a safety profilemore favorable than
those of organotin compounds ꢀ would represent a sig-
nificant advance.
other alkylated byproducts. The yield of 4a was not im-
proved by modification of the electronic properties of the
arylboronic acid (catalysts 1aꢀ1b: entries 5 and 7). In
contrast to the observations of Aoyama and co-workers
in the context of preformed boronate esters,9a the addition
of triethylamine suppressed the formation of 4a (entries 4,
6 and 8). Diphenylborinate ester 2a, the optimal precata-
lyst identified for the regioselective acylation of carbohy-
drates in our previous work, promoted high-yielding
monoalkylation of 3a at the 3-OH group (entry 9). The
formation of 2-(dibenzylamino)ethanol from 2a, benzyl
bromide and Ag2O under the reaction conditions, and the
Table 1. Evaluation of Catalysts for Regioselective Alkylation
of Mannose Derivative 3a
Our efforts to develop an organoboron-catalyzed regio-
selective alkylation of sugars draw on studies by Aoyama
and co-workers in which 3,4-boronate esters derived from
phenylboronic acid and fucose or arabinose were alkylated
at O-3 by 1-iodobutane in the presence of triethylamine
and Ag2O.9 An ‘ate’ complex generated from the boronate
ester and amine was proposed to undergo selective alkyla-
tion at the equatorial BꢀO bond. Boric acid (B(OH)3, in
catalytic quantities) is also known to influence the regios-
electivity of methylation of pyranose sugars with diazo-
methane, although these reactions are variable in yield and
usually result in multiple products.10 We have recently
discovered that derivatives of diphenylborinic acid
(Ph2BOH) catalyze the selective monoacylation of the
equatorial hydroxy groups of cis-vicinal diol motifs in a
wide range of carbohydrate derivatives.11 Tetracoordinate
borinic acidꢀcarbohydrate adducts, generated by reversi-
ble covalent BꢀO interactions, were proposed as catalyst-
substrate complexes based on data from competition
experiments and computational studies. We sought to
determine whether a similar mode of reactivity could be
employed to achieve catalyst-controlled, regioselective
monoalkylation of sugars bearing multiple secondary
hydroxy groups.
entry
catalyst
None
yield (%)a
1
<5
50
55
<5
55
<5
55
<5
90
95
50
2
B(OH)3
PhB(OH)2
PhB(OH)2
1a
3
b
4
5
6
1ab
7
1b
1bb
8
9
2a
10
11
2b
2c
a Yield of 3a determined by H NMR with mesitylene as a quanti-
tative internal standard. b Reaction carried out in the presence of
triethylamine (1.1 equiv).
1
Representative boron reagents were evaluated as cata-
lysts for the monobenzylation of mannose derivative 3a
(Table 1). In the absence of catalyst, only trace amounts of
3-OBn derivative 4a were observed: recovered starting
material was the predominant component of the crude
reaction mixture. Boric acid and phenylboronic acid pro-
moted the formation of 4a in moderate yields, along with
fact that diphenylborinic acid also serves as a catalyst for
this reaction (entry 10), suggests that 2a is a precatalyst
from which the ethanolamine ligand is alkylated prior to
displacement by carbohydrate substrate. Oxidation of
triphenylborane (2c) to 2b, either by adventitious oxygen
or by Ag2O, may be responsible for the moderate degree of
catalyst activity observed with the former (entry 11). The
efficiency of the alkylation is dependent on the halide-
abstracting Ag(I) salt employed: Ag2CO3, AgOAc and
AgOTf (with i-Pr2NEt to sequester the generated triflic
acid) provided inferior results. Attempts to activate the
alkyl halide by addition of iodide salts (in conjunction with
Brønsted bases) rather than Ag(I) reagents resulted in low
reactivity. Acetonitrile was identified as the optimal
(6) (a) Eby, R.; Webster, K. T.; Schuerch, C. Carbohydr. Res. 1984,
129, 111–120. (b) Osborn, H. M. I.; Brome, V. A.; Harwood, L. M.;
Suthers, W. G. Carbohydr. Res. 2001, 332, 157–166. (c) Gangadharmath,
U. B.; Demchenko, A. V. Synlett 2004, 12, 2191–2193.
(7) For a review, see: David, S.; Hanessian, S. Tetrahedron 1985, 41,
643–663.
(8) Boons, G.-J.; Castle, G. H.; Clase, J. A.; Grice, P.; Ley, S. V.;
Pinel, C. Synlett 1993, 913–914.
(9) (a) Oshima, K.; Kitazono, E.-i.; Aoyama, Y. Tetrahedron Lett.
1997, 38, 5001–5004. This work was later extended to include regiose-
lective glycosylation:(b) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc.
1999, 121, 2315–2316.
(10) Evtushenko, E. V. Carbohydr. Res. 1999, 316, 187–200.
(11) Lee, D.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 3724–3727.
Org. Lett., Vol. 13, No. 12, 2011
3091

(3eꢀ3g, 3j), fucose (3h) and arabinose (3i), each containing
a cis-diol motif (Table 2). Four alkylating agents were
employed, resulting in the installation of the benzyl (Bn,
4aꢀ4i), 4-bromobenzyl (4-BrBn, 5aꢀ5j),12 2-naphthyl-
methyl (Nap, 6aꢀ6i)13 and (benzyloxy)methyl (BOM,
7aꢀ7i) ether protective groups.
Table 2. Diphenylborinate-Catalyzed Regioselective Alkylation
of Monosaccharides 3aꢀ3j
The results of Table 2 indicate that borinic ester catalysis
enables reliable and high-yielding alkylation of the equa-
torial OH groups of cis-diol pairs. The method is tolerant
of variation of the stereochemistry of the anomeric posi-
tion(3evs3f) and, inthe galactoseries, a stericallyhindered
substituent at C-5 is not essential for obtaining high
regioselectivity (galactose derivative 3e vs fucose and
arabinose derivatives 3h, 3i). The 1,6-anhydro derivatives
of mannose (3b) and galactose (3g), in which the pyranose
ring adopts the 1C4 (rather than the usual 4C1) conforma-
tion, underwent alkylation at O-2 and O-4, respectively,
complementary regiochemical outcomes to those achieved
with 3a and 3e. Tribenzylated substrate 3c underwent
selective alkylation at O-1, delivering the challenging
β-mannosyl stereochemical outcome at the anomeric posi-
tion. Selective protections of the type shown in Table 2
havepreviouslyrequired the use ofstoichiometricamounts
of organotin reagents in the two-step protocols described
above.7
Limitations of the current protocol include sugars that
do not contain a cis-vicinal diol motif, such as glucose or
xylose derivatives, which do not yield products of mono-
alkylation under the optimized reaction conditions. Pro-
tection of the 6-hydroxy group in the manno and galacto
series is necessary to achieve efficient catalyst-controlled
alkylation: for example, using methyl R-galactopyranoside
as a substrate resulted in the formation of a complex
mixture, presumably due to competitive binding of the
boron catalyst to the 4,6- and 3,4-diol groups. However,
D-galactal (3j) underwent selective dialkylation at O-3 and
O-6 in the presence of the borinate ester catalyst (entry 34).
The use of activated (benzylic or alkoxymethyl) halides
seems to be essential for high reactivity with this catalyst
system: neither iodomethane nor bromobutane resulted in
alkylation under the conditions shown in Table 2.
Our working mechanistic model for the regioselectivity
observed in the acylation and alkylation reactions involves
the formation of tetracoordinate borinate complexes of
cis-diol motifs (Figure 1). Previous computational studies
from our group suggested an electronic basis for the
observed selectivity: the highest values of the condensed
Fukui indices fꢀ for nucleophilic reactivity14 wereobserved
at O-3 for borinate esters derived from representative sub-
strates in both the manno and galacto series (3d and 3h).11
Calculations of this type (DFT, B3LYP/6-311þG(d,p))
modeling the adducts of anhydro[1,6]galactose (3b) and
a Isolated yield on 0.2ꢀ1.0 mmol scale. X = Br for installation of the
Bn, 4-BrBn, and Nap groups; X = Cl for installation of the BOM group.
b 2.5 equiv of 4-BrBnBr and 2.1 equiv of Ag2O were employed.
(12) Plante, O. J.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem.
Soc. 2000, 122, 7148–7149.
(13) (a) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63,
4172–4173. (b) Xia, J.; Alderfer, J. L.; Piskorz, C. F.; Matta, K. L.
Chem.;Eur. J. 2001, 7, 356–367.
reaction solvent: details ofthe optimization are provided in
the Supporting Information.
A preliminary investigation of the scope of the catalytic
process was undertaken using ten carbohydrate substrates
derived from mannose (3aꢀ3c), rhamnose (3d), galactose
(14) Yang, W.; Mortier, W. J. J. Am. Chem. Soc. 1986, 108,
5708–5711.
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Org. Lett., Vol. 13, No. 12, 2011

of the dibutylstannylene acetal derived from 3c occurs at
the 1-OH group: a mechanistic rationale for this behavior
has not been advanced.16
In conclusion, borinic acid catalysis represents an effi-
cient and broadly applicable method for the regioselective
alkylation of carbohydrate derivatives bearing multiple
secondary hydroxy groups. The operational simplicity of
this method, and the ability to avoid the use of stoichio-
metric quantities of organotin-based reagents, are attrac-
tive features for applications in the preparation of
selectively protected carbohydrate derivatives. In a more
general context, the catalyst-controlled alkylation of
amines and alcohols is a challenging and underdeveloped
mode of reactivity: nucleophilic catalysis, the strategy
applied most broadly to influence the outcome of acyla-
tion, phosphorylation, sulfonylation, and silylation
reactions,17 has proven difficult to adapt to alkyl halides
and related electrophiles. The nucleophile activation strat-
egy developed here may present new opportunities in this
regard: exploiting this method to achieve other challenging
manipulations of unprotected carbohydrate derivatives
and developing chiral catalysts for asymmetric alkylation
of alcohols represent interesting directions for future
research.
Acknowledgment. This work was funded by NSERC
(Discovery Grants Program, Graduate Scholarship to L.
C.), the Canadian Foundation for Innovation, the Pro-
vince of Ontario and the University of Toronto.
Figure 1. Calculated structures and condensed Fukui indices
(B3LYP/6-311þG(d,p)) of diphenylborinates of 3bꢀ3d, 3g, and
3h. The site of observed reactivity under the catalytic reaction
conditions is indicated in bold type (red color). aFrom ref 11.
Supporting Information Available. Experimental pro-
cedures, details of computational studies, and character-
ization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
anhydro[1,6]mannose (3g) provide additional support for
this model: the Fukui indices indicate highest nucleophili-
city at O-4 and O-2, respectively, consistent with the
experimental data (Figure 1). On the other hand, the
selective alkylation of mannose derivative 3c at O-1 cannot
be rationalized by calculations of this type: Fukui index
calculations indicate that O-2 is the more nucleophilic
position of the borinate ester, as would be expected given
the electron-deficient nature of the C1 position. Selective
alkylation of the more acidic 1-OH group may indicate a
role for proton transfer equilibria in the regiochemical
outcome observed for this substrate.15 Selective alkylation
(15) Regioselective anomeric O-alkylations of partially unprotected
sugars have been developed (1 equiv of NaH, alkyl triflates): Schmidt,
R. R.; Klotz, W. Synlett 1991, 168–169.
(16) Srivastava, V. K.; Schuerch, C. Tetrahedron Lett. 1979, 20,
3269–3272.
(17) (a) France, S.; Guerin, D. J.; Miller, S. J.; Leckta, T. Chem. Rev.
2003, 103, 2985–3012. (b) Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610.
(c) Fu, G. C. Acc. Chem. Res. 2004, 37, 542–547. (d) Wurz, R. P. Chem.
Rev. 2007, 107, 5570–5595.
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