Recognition and site-selective transformation of monosaccharides by using copper(II) catalysis

Article abstract of DOI:10.1002/chem.201400133

We demonstrate copper(II)-catalyzed acylation and tosylation of monosaccharides. Various carbohydrate derivatives, including glucopyranosides and ribofuranosides, are obtained in high yields and regioselectivities. Using this versatile strategy, the site

Full text of DOI:10.1002/chem.201400133

DOI: 10.1002/chem.201400133
Full Paper
&
Carbohydrates
Recognition and Site-Selective Transformation of
Monosaccharides by Using Copper(II) Catalysis
I-Hon Chen,[a] Kevin G. M. Kou,[a, b] Diane N. Le,[a] Colin M. Rathbun,[a] and Vy M. Dong *[a]
Abstract: We demonstrate copper(II)-catalyzed acylation and
tosylation of monosaccharides. Various carbohydrate deriva-
tives, including glucopyranosides and ribofuranosides, are
obtained in high yields and regioselectivities. Using this ver-
satile strategy, the site of acylation can be switched by
choice of ligand. Preliminary mechanistic studies support nu-
cleophilic addition of a copper–sugar complex to the acyl
chloride to be turnover limiting.
Introduction
As an abundant natural resource, monosaccharides appear to
be an ideal feedstock for constructing medicines,[1] fuels,[2] and
polymers.[3] These sugars are generally difficult to derivatize,
however, owing to their many reactive hydroxyl sites. Organo-
tin-based methods can be used to achieve selective transfor-
mation of various sugars[4] en route to valuable oligosacchar-
ides, including anti-cancer vaccines.[5,6] To replace these toxic
stoichiometric reagents, catalytic strategies have emerged, fea-
turing Lewis acid catalysis (e.g., the use of organotin chloride
by Matsumura et al. and borinic acids by Taylor et al.)[7,8] and
organocatalysis (e.g., the use of chiral 4-dimethylaminopyridine
(DMAP) by Kawabata et al., peptides by Miller et al., scaffolding
imidazoles by Tan et al., and phosphoric acids by Nagorny
et al.).[9–12] Designing catalytic methods for site-selective trans-
formations with carbohydrates represents a valuable goal that
promises to streamline access to oligosaccharides. Herein, we
report that chiral copper complexes are versatile catalysts for
the regioselective functionalization of monosaccharides. Our
findings complement and corroborate an independent report
by Allen and Miller.[13] In comparison to current methods, our
strategy allows easy tailoring of the catalyst to transform
a wide range of sugars, and control site selectivity by ligand
choice.
Figure 1. Binding-site structure of LangA lectin and proposed metal-complex
binding.
metal complexes bearing a chiral ligand, would similarly bind
and possibly activate sugars for selective functionalization
(Figure 1).[17] We chose to investigate copper on the basis of re-
ports in which stoichiometric salts, for example, Cu(acac)2
(acac=acetylacetonate) and Cu(TFA)2 (TFA=trifluoroacetate),
were used to promote acylation of sugars.[18,19] As summarized
in Figure 2, we imagined that the appropriate ligands (Ln) on
copper would allow selective activation of hydroxyl groups in
a wide range of sugars, including both pyranosides and fura-
nosides.[20] Besides enhancing regiocontrol, the ligand should
promote catalysis. Indeed, Onomura et al. has reported chiral
copper(II) catalysts for desymmetrization of meso-1,2-vicinal
diols.[21] Although widely applied in enantioselective catalysis,
Our study draws inspiration from lectins, which are proteins
that recognize sugars with high specificity through diol coordi-
nation to a metal center (e.g., Ca, Mn, and Cu).[14–16] By analogy
to these natural metalloproteins, we reasoned that synthetic
[a] Dr. I.-H. Chen, K. G. M. Kou, D. N. Le, C. M. Rathbun, Prof. Dr. V. M. Dong
Department of Chemistry, University of California, Irvine
Natural Sciences 1, University of California,
Irvine, California 92697 (USA)
E-mail: dongv@uci.edu
[b] K. G. M. Kou
Department of Chemistry, University of Toronto,
80 St. George Street (Canada)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400133.
Figure 2. Proposed ligand-controlled site-selective binding with copper(II)
complexes.
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the use of chiral copper complexes for site-selective transfor-
mations warrants study.[22]
Table 1. Selective acylation of a-glucopyranosides.[a,b]
Results and Discussion
To test our hypothesis, we studied the benzoylation of a-glu-
copyranoside 1a (Scheme 1). The silyl group protects the pri-
mary alcohol, leaving three secondary hydroxyl groups for pos-
Entry
Substrate
Acyl chloride
Product
Yield[%]
2-O/4-O
1
2
1a
1a
BzCl
2aa
2ab
84
80
>20:1
>20:1
2-NO2-
C6H4COCl
iPrCOCl
Piv-Cl
Cbz-Cl
Fmoc-Cl
BzCl
3
4
5
6
7
1a
1a
1a
1a
1b
2ac
2ad
2ae
2af
2b
82
74
83
71
83
9:1
>20:1
15:1
7:1
>20:1
1
[a] Isolated yields. [b] Selectivity ratios determined by H NMR spectroscopy.
Piv=pivaloyl.
effective electrophiles (71–84% yields, entries 1–4). Commonly
used protecting groups, such as carbobenzyloxy (Cbz) and 9-
fluorenylmethoxycarbonyl (Fmoc) groups[27] can be incorporat-
ed (83% and 71% yields, entries 5–6, respectively). Glucose de-
rivative 1b, containing a 4,6-O-benzylidene acetal, undergoes
acylation to provide 2-O-benzoylated 2b in 83% yield and
>20:1 regioselectivity. Asymmetric copper catalysis provides
an organotin-free alternative for the regioselective transforma-
tion of a-glucopyranosides.[28,29]
To help explain the high regioselectivity observed, we per-
formed a competition experiment between a-glucopyranoside
1a and the corresponding b-anomer (Figure 3). The a-anomer
Scheme 1. Selective acylation of a-glucopyranosides. Yields for 2aa and 3a
1
were determined by H NMR spectroscopy (see the Supporting Information).
1
The selectivity between 2aa and 2aa’ was determined by H NMR spectros-
1
copy. The 3-O-acylated product was not observed by H NMR spectroscopy.
(Bz=benzoyl, TBS=tert-butyldimethylsilyl) [a] CH2Cl2 was used instead of
THF; in THF, 87% yield and 16:1 selectivity was obtained.
sible functionalization. A control experiment in the absence of
copper salts displayed no reactivity. In the absence of ligand,
no catalyst turnover is observed; using 10 mol% copper(II) tri-
flate yields less than 10% benzoylation after 16 h. Nitrogen-
based ligands that are known to coordinate well to copper(II)
species (e.g., bipyridine, terpyridine, and 1,10-phenanthroline)
do not promote catalysis. The privileged chiral bisoxazoline
(Box, L1–L3)[23] and pyridinebisoxazoline (PyBox, L4 and L5)
structures, however, enable catalyst turnover (33 to 90%
yields).[24,25] In all cases, the 2-O-acylated isomer, 2aa, is formed
as the major product with regiocontrol (3:1 to >20:1,
Scheme 1). The minor products include 4-O-acylated 2aa’ and
dibenzoylated 3a.[26] The absolute configuration of the ligand
impacts selectivity. For example, (R,R)-Ph-PyBox L4 results in
benzoylation with 7:1 selectivity in favor of 2-O-benzoylated
2aa, whereas its enantiomer (L5) gives >20:1 selectivity.
Figure 3. Competition study of a- and b-glucopyranoside with copper catal-
ysis.
of glucose 1a undergoes benzoylation exclusively to give 2aa
in 87% yield. In agreement with the organotin study carried
out by Muramatsu and Takemoto,[30] we reason that metal
binding to the cis-dioxy motif (1-O and 2-O) of a-glucopyrano-
side occurs to activate the 2-O-hydroxyl group toward acyla-
tion.
Next, we studied the acylation of a-galactopyranoside 4a,
which unlike a-glucopyranosides, contains two sets of cis-
dioxy motifs (Scheme 2). Evtushenko proposed a 1,2-cis-dioxy
copper intermediate, I, to explain the selective acylation of the
2-O-position of a-galactopyranosides when using stoichiomet-
With the copper–L5 catalyst in hand, we found that a-gluco-
pyranosides undergo acylation with a wide range of electro-
philes (Table 1). Both aromatic and aliphatic acid chlorides are
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Scheme 2. Ligand-controlled switch in regioselectivity by using copper catal-
ysis. [a] 68% yield (>20:1 regioselectivity) when THF was used as the sol-
vent.
Scheme 3. Copper(II)-catalyzed acylation of carbohydrate derivatives con-
taining cis-diol motif. Isolated yields are shown. Ratios determined by
1H NMR spectroscopy. [a] 3-O/2-O=1:1.5 when (R,R)-Ph-Box was used as
ligand [b] (R,R)-Ph-PyBox used as ligand.
ric Cu(TFA)2.[19] In contrast, we found a marked ligand effect.
Treatment with (R,R)-Ph-Box L1 affords a mixture of 3- and 2-
O-benzoylated products (1:1.5), whereas the enantiomeric
ligand (S,S)-Ph-Box L2 enables preferential access to the 3-O-
benzoylated 5a with>20:1 regioselectivity (Scheme 2,
[Eq. (4)]).[31] Moreover, by applying achiral N,N,N’,N’-tetramethyl-
ethylenediamine (TMEDA) as the ligand, we can switch the re-
gioselectivity to favor 2-O-acylated 5a’ with 10:1 regioselectivi-
ty (Scheme 2, [Eq. (5)]).[32] The ligand choice (amino-based
TMEDA versus imino-based Ph-Box) influences the catalyst
preference for “1,2-dioxygen” (XL-type binding) versus “3,4-
diol” (XX-type binding).
Through the choice of ligand, the copper catalyst can be
tuned for a specific sugar substrate (Scheme 3). For example,
the copper-(S,S)-L2 catalyst enables wide scope, including ben-
zoylation and pivaloylation of both a- and b-galactopyrano-
sides to afford acylated 5a–5c (entries 1–3, 80–99%,>20:1).
Acylation of l-rhamnose gives 3-O-benzoylated 5d (entry 4,
94%,>20:1), but l-fucose, containing a 3,4-cis-diol, requires
(R,R)-Ph-Box L1 to afford high regioselectivity (entry 5) for 3-O-
Bz 5e.[33] For substrates containing 2,3-cis diols (e.g., d-man-
nose and d-lyxose, entries 6–8), (R,R)-Ph-Box L1 is the
“matched” ligand and provides 3-O-acylated products 5 f–5h
in regioselectivities from 9:1 to >20:1. In general, our results
are consistent with site-selective functionalization occurring at
the more reactive equatorial OH group adjacent to axial OH/
OR groups.[34]
Scheme 4. Copper(II)-catalyzed carbohydrate differentiation and recognition.
selectively with 4a to give benzoate 5a in 71% yield (5a/5 f=
8:1). Another competition experiment was performed with two
pseudo-enantiomeric sugars (d-b-galactopyranoside 4b and l-
a-fucopyranoside 4e). The benzoylation occurred exclusively in
4b to give 3-O-benzoylated 5b in 85% yield (>20:1 regiose-
lectivity).
A mixture of two carbohydrates can be selectively acylated
by enzyme catalysis.[35] Inspired by these enzymatic studies, we
performed competition experiments to demonstrate the ability
of simple copper complexes to recognize sugars (Scheme 4).[36]
In the presence of (S,S)-Ph-Box L2, a mixture of a-galactopyra-
noside 4a and a-mannopyranoside 4 f, both containing a cis-
diol motif (3,4-cis-diol and 2,3-cis-diol), undergoes benzoylation
Our strategy extends to making ribofuranosides, which are
of interest because of their potential as nucleoside therapeu-
tics.[37] Acylation of a-ribofuranoside[38] 6a with (S,S)-Ph-Box L2
in CH2Cl2 solvent favors benzoylation at the 3-O-position,
whereas (R,R)-Ph-PyBox L4 in THF solvent favors benzoylation
at the 2-O-position (Scheme 5, [Eq. (8) and (9)]).[39] As a comple-
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Figure 4. Proposed mechanism for copper(II)-catalyzed acylation of 1a.
Scheme 5. Ligand-controlled switch in regioselectivity by using copper catal-
1
ysis. Isolated yields are shown. Selectivity ratios determined by H NMR spec-
troscopy. [a] Isolated as a mixture of isomers. Tr=trityl.
versibly to glucopyranoside 1a through the 1,2-cis-dioxy motif
to form complex IV. The copper–sugar adduct, IV, is deproton-
ated by diisopropylethylamine to form copper(II) alkoxide V.
This species (V) is analogous to organotin complexes proposed
previously, in which metal coordination occurs through an LX-
type interaction to enhance the nucleophilicity at the 2-O-posi-
tion. In the turnover-limiting step, benzoylation occurs to fur-
nish product 2aa and regenerate catalyst III. Our study shows
no rate dependence on varying the glucose concentration, im-
plying saturation kinetics in glucose substrate. A first-order de-
pendence on the electrophile suggests that nucleophilic addi-
tion of alkoxide V to benzoyl chloride is turnover-limiting. Fur-
ther mechanistic studies are ongoing.
Conclusion
We have described a copper(II)-catalyzed strategy for activat-
ing a wide variety of carbohydrate derivatives, including thio-
glycosides and ribofuranosides. Furthermore, switching the re-
gioselectivity is facilitated by the tunable copper complex. The
versatility of this approach promises to streamline access to
materials derived from sugar feedstocks.
Scheme 6. Selective tosylation of thioglycosides. Tol=para-tolyl.
ment to the silylation of ribofuranosides reported by Tan et al.,
we show control over the site of functionalization.[11b] Further-
more, the copper(II)-PyBox L5 system promotes tosylation of
b-ribofuranoside 8 to give isomer 9 in 75% yield and>20:1 re-
gioselectivity (Scheme 5, [Eq. (10)]).
Carbohydrate recognition is achieved by use of these
unique ligand–metal–carbohydrate interactions in facilitating
the differentiation of structurally similar carbohydrate deriva-
tives. This protocol can be extended to develop chiral metal
complexes capable of recognizing specific oligosaccharides. Ex-
panding the scope of this protocol to other electrophiles and
complex carbohydrates is underway.
These copper(II) catalysts regioselectively tosylate thioglyco-
sides that contain no cis-diol motifs (Scheme 6).[40] In the pres-
ence of an anomeric b-thioether, the 3-O-position of b-thioglu-
coside 10 transforms into 11 in 65% yield with high selectivity
(Scheme 6, [Eq. (11)]). Remarkably, maltose derivative 12, with
five free hydroxyl groups, can be selectively tosylated by using
the copper-L5 catalyst. In this case, tosylation occurs at the 2-
O-position adjacent to the a-glycosidic bond (Scheme 6,
[Eq. (11)]).[41] These examples showcase the generality of our
strategy for preparing complex carbohydrate derivatives that
are not feasible with previous catalysts.
Experimental Section
A
vial was charged with copper(II) trifluoromethanesulfonate
(3.6 mg, 0.01 mmol), (S,S)-Ph-PyBox L5 (3.7 mg, 0.01 mmol), TBS-
glucopyranoside 1a (30.8 mg, 0.1 mmol), and dichloromethane
(0.5 mL) in a N2-filled glovebox. Diisopropylethylamine (26 mL,
0.15 mmol) was added and this mixture was stirred at ambient
temperature for 5 min. Benzoyl chloride (12 mL, 0.1 mmol) was
then added by using a microsyringe and the reaction mixture was
maintained at room temperature for 16 h. The reaction mixture
On the basis of literature reports,[7b,8a] and our preliminary ki-
netic studies with a-glucopyranoside 1a,[42] we propose the
mechanism shown in Figure 4. Copper(II) complex III binds re-
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[6] For an enzymatic synthesis of Globo H, see: T.-I. Tsai, H.-Y. Lee, S.-H.
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was diluted with dichloromethane (2 mL) and quenched with H2O.
After allowing the mixture to undergo phase separation, the or-
ganic layer was removed and dried over anhydrous Na2SO4. The in-
organic salts were removed by filtration through a small cotton
plug, and the filtrate was concentrated in vacuo. The regioselectivi-
ty for the transformation was measured by performing 1H NMR
analysis of the unpurified reaction mixture. The crude material was
purified by preparative thin-layer chromatography (eluting with
hexanes/EtOAc=2:1) to give the acylated product 2aa 34.6 mg,
84% yield. [a]D20 = +80 cm3 gÀ1 dmÀ1 (c=1.0 in CHCl3); 1H NMR
(500 MHz, CDCl3, 258C): d=8.05–8.12 (m, 2H), 7.66–7.56 (m, 1H),
7.57–7.42 (m, 2H), 5.15 (d, J=3.7 Hz, 1H), 4.92 (d, J=3.7 Hz, 1H),
4.19–4.10 (m, 1H), 3.94 (dd, J=10, 4.4 Hz, 1H), 3.82–3.89 (m, 1H),
3.60–3.72 (m, 2H), 3.38 (s, 3H), 2.48 (broad s, 1H), 1.56 (broad s,
1H), 0.92 (s, 9H), 0.12 (s, 3H); 0.11 ppm (s, 3H); 13C NMR (126 MHz,
CDCl3) d=166.5, 133.3, 129.9, 129.6, 128.4, 97.1, 73.8, 73.3, 71.7,
69.8, 64.4, 55.3, 25.9, 18.3, À5.5 ppm; IR (ATR, neat): n˜ =3429, 3414,
2955, 1714, 1276, 1049, 837, 711 cmÀ1; HRMS (ESI+) m/z calcd for
C20H32O7Si+H+: 413.1990 [M+H+]; found 413.1979.
[13] During the preparation of our manuscript, the Miller group reported
copper(II)-catalyzed reactions of partially protected carbohydrates, see:
C. L. Allen, S. J. Miller, Org. Lett. 2013, 15, 6178.
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Acknowledgements
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[17] Lectins are not catalytically active, see: N. Sharon, H. Lis, Lectins, Spring-
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[18] H. M. I. Osborn, V. A. Brome, L. M. Harwood, W. G. Suthers, Carbohydr.
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Funding support provided by the University of California at
Irvine and Eli Lilly. KGMK is grateful for an NSERC CGS-D. DNL
and CMR acknowledge the NSF for graduate fellowships. We
thank Professor Jik Chin (U Toronto) for help.
[19] E. V. Evtushenko, Carbohydr. Res. 2012, 359, 111.
Keywords: carbohydrates · catalysis · molecular recognition ·
site-selective functionalization · transition metals
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[26] Under these conditions, acylation at the 3-O-position of 1a does not
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[32] The ability to switch selectivities based on catalyst suggests that acyl
group migration is not occurring.
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Full Paper
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[34] For a discussion on the reactivity of the equatorial OH group adjacent
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[41] Compound 13 was obtained in 6% yield when pyridine was used as
the base and without copper catalyst.
[42] See the Supporting Information for details.
Received: January 12, 2014
[36] For relevant sugar differentiation, see: Ref. [13] and [30].
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Published online on March 13, 2014
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