A visible-light-promoted O-glycosylation with a thioglycoside donor

Article abstract of DOI:10.1002/anie.201601566

Visible-light irradiation of 4-p-methoxyphenyl-3-butenylthioglucoside donors in the presence of Umemoto's reagent and alcohol acceptors serves as a mild approach to O-glycosylation. Visible-light photocatalysts are not required for activation, and alkyl- and arylthioglycosides not bearing the p-methoxystyrene are inert to these conditions. Experimental and computational evidence for an intervening electron donor-acceptor complex, which is necessary for reactivity, is provided. Yields with primary, secondary, and tertiary alcohol acceptors range from moderate to high. Complete β-selectivity can be attained through neighboring-group participation. Visible-light irradiation of 4-p-methoxyphenyl-3-butenylthioglucoside donors in the presence of Umemoto's reagent serves as an exceptionally mild and orthogonal approach to O-glycosylation. Alkyl- and arylthioglycosides not containing the p-methoxystyrene moiety are inert under these conditions, and evidence suggests that an intervening electron donor-acceptor complex is necessary for reactivity.

Full text of DOI:10.1002/anie.201601566

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International Edition: DOI: 10.1002/anie.201601566
German Edition: DOI: 10.1002/ange.201601566
Photochemistry
AVisible-Light-Promoted O-Glycosylation with a Thioglycoside
Donor
Mark L. Spell, Kristina Deveaux, Caitlin G. Bresnahan, Bradley L. Bernard, William Sheffield,
Revati Kumar, and Justin R. Ragains*
Abstract: Visible-light irradiation of 4-p-methoxyphenyl-3-
butenylthioglucoside donors in the presence of Umemotoꢀs
reagent and alcohol acceptors serves as a mild approach to O-
glycosylation. Visible-light photocatalysts are not required for
activation, and alkyl- and arylthioglycosides not bearing the p-
methoxystyrene are inert to these conditions. Experimental and
computational evidence for an intervening electron donor–
acceptor complex, which is necessary for reactivity, is provided.
Yields with primary, secondary, and tertiary alcohol acceptors
range from moderate to high. Complete b-selectivity can be
attained through neighboring-group participation.
(a problem that plagues the entire field of photochemical
glycosylation)[5] suggests that further work is needed to make
visible-light O-glycosylation applicable to synthetically chal-
lenging targets.
While our own studies on visible-light photochemical O-
glycosylation proved successful with phenylselenoglycosi-
des,[5d] further investigations with electron-rich arylthioglyco-
sides and some of the most strongly oxidizing visible-light
photosensitizers[6] were unproductive. The formation of
sulfur-centered thioglycoside radical cations is a nontrivial
task under visible-light irradiation. As an alternative strategy,
we imagined a scenario in which visible-light photocatalysis
could be used to unburden the sulfur from an apparently
difficult single-electron oxidation. Taking inspiration from the
visible-light photocatalytic oxytrifluoromethylation of styr-
enes,[7] we envisioned an approach which would allow the use
of stable thioglycosides and the facile photocatalytic gener-
ation of trifluoromethyl radicals.
We imagined that visible-light-promoted excitation of
[Ru(bpy)3]2+ would precede single-electron transfer to Ume-
motoꢀs reagent to generate a trifluoromethyl radical, diben-
zothiophene, and [Ru(bpy)3]3+ (Scheme 1). Attack of the
trifluoromethyl radical on the styrene portion of glycosyl
donors, having the generic structure 1, would result in the
benzylic radical 2, which could be oxidized by [Ru(bpy)3]3+ to
generate the carbocation 3 and regenerate [Ru(bpy)3]2+.[7]
Cyclization of sulfur onto the cation of 3 would result in the
intermediate 4, which we deemed competent as an activated
donor for O-glycosylation. Such a process would provide
a mild approach to O-glycosylation with a thioglycoside
donor, which would have orthogonal reactivity to other
thioglycoside donors. Like thioglycosides, [Ru(bpy)3]2+ salts
and Umemotoꢀs reagent are easily handled, bench-stable
species. This approach could also prove useful for the iterative
synthesis of oligosaccharides even in a one-pot milieu. While
a mechanistically related approach has been reported with O-
pentenylgycoside donors,[8a] this approach would avoid the
use of molecular bromine and the intermediacy of moribund
glycosyl bromides.[8b]
T
hioglycosides are among the most commonly used glycosyl
donors for chemical O-glycosylation.[1] The ease of synthesis,
straightforward handling, configurational stability, and tuna-
ble reactivity are among the positive attributes associated
with this class of glycosyl donor. Thioglycosides have proven
to be useful in the late-stage synthesis of glycans and in
generating historically difficult glycosidic linkages.[1,2] The
development of easily performed O-glycosylations[3] using
thioglycosides and bench-stable reagents for high-yielding,
stereoselective O-glycosylations at or near ambient temper-
ature has been identified as a worthy (but lofty) goal. Progress
has been made with the development of, among others,
approaches using gold catalysis, iodine(III) reagents, and
bismuth(V) reagents.[4]
By contrast, we and others have identified irradiation with
light, especially visible light, as an intriguing approach to the
activation of thio- and selenoglycosides under mild, user-
friendly reaction conditions.[5] In this case, photons supply the
energy needed for the activation of recalcitrant thioglyco-
sides. The majority of photochemical glycosylations with
chalcogenoglycoside donors likely involve photoinduced
electron transfers which trigger the formation of S/Se-
centered radical cations that fragment to the putative
oxocarbenium intermediate. This approach has proven suc-
cessful in one case with visible-light irradiation of p-methoxy-
phenylthioglycoside donors in the presence of an iridium
photosensitizer.[5a] Though these initial results were encour-
aging, moderate yields with more difficult glycosidic linkages
Herein, we report our results which were inspired by the
hypothesis in Scheme 1. O-glycosylations proceed in moder-
ate to high (44–93%) yields and complete b-selectivity can be
afforded. The 4-p-methoxyphenyl-3-butenylthioglucosides
studied here react under reaction conditions to which
alkylthio- and arylthioglycosides are inert, thus supplying
a novel approach to orthogonality with potential applications
in oligosaccharide synthesis. We provide experimental and
computational evidence for the intervention of an electron
donor–acceptor (EDA) complex[9] which obviates photo-
[*] M. L. Spell, K. Deveaux, C. G. Bresnahan, B. L. Bernard, W. Sheffield,
R. Kumar, Prof. Dr. J. R. Ragains
Department of Chemistry, Louisiana State University
232 Choppin Hall, Baton Rouge, LA 70803 (USA)
E-mail: jragains@lsu.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201601566.
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over the 24 hour period of irradiation.
The sulfur atom in 5b is much more
resistant to oxidation[12] and has attenu-
ated nucleophilicity relative to the sulfur
in the analogous tetrabenzyl series.[1d,e]
Reaction of a sulfur atom with an acti-
vated intermediate may be inhibited with
5b. We also screened 5c–e (entries 8–10)
using the reaction conditions of entry 6,
and observed no consumption of these
donors. Species like 5c are highly reactive
toward activation by thiophilic electro-
philes[,1d,e] while the electron-rich nature
of the arylthio moiety of 5e makes it
particularly amenable to oxidation by
SET.[12]
We investigated the substrate scope of
the reaction (Table 2) by using the reac-
tion conditions specified in entry 6 of
Table 1. Glycosylations of 1-octanol,
cyclohexanol, and (À)-menthol with 5a
Scheme 1. Original hypothesis for visible-light-promoted O-glycosylation with thioglycosides.
bpy=2,2’-bipyridine, Tf =trifluoromethanesulfonyl.
sensitizers like [Ru(bpy)3]2+. This reaction represents the first
example of a visible-light-promoted glycosylation not requir-
ing a photocatalyst/photosensitizer.
proved to be high-yielding (Table 2, entries 1–3). As with
previous glycosylations, mixtures of anomers were obtained.
Further investigations with glucose- and galactose-derived
acceptors (entries 4 and 5) demonstrated that more-difficult
To test the hypothesis outlined in Scheme 1, we synthe-
sized a series of thioglucosides (Table 1), including the benzyl-
protected 5a, acetyl-protected 5b, and the aryl- and alkyl-
thioglycosides 5c–e.[10] We reasoned that an electron-rich
styrene moiety would react more quickly with the electro-
philic trifluoromethyl radical than an electron-neutral or
electron-poor styrene.[11] Thus, we targeted the para-methoxy-
phenyl-bearing substrates 5a/b. Our initial reaction condi-
tions involved irradiation with blue LEDs (lmax = 455 nm) in
the presence of Umemotoꢀs reagent, 2,6-di-tert-butyl-4-meth-
ylpyridine (DTBMP), and the acceptor 6 with 4 Š molecular
sieves in CH2Cl2. In the event (entry 1), irradiation of one of
these mixtures with the donor 5a resulted in a 55% yield of
the product 7a as a mixture of anomers. A solvent screen
demonstrated insignificant differences or inferior results from
those obtained using CH2Cl2 (see the Supporting Informa-
tion). Controls demonstrated that irradiation and Umemotoꢀs
reagent are essential (entries 2 and 3). However, irradiation
without [Ru(bpy)3]2+ provided similar yields of 7a (entry 4)!
This surprising outcome is likely due to the formation of an
EDA complex.[9] Further optimization showed that using 5a
in excess and increasing the concentration resulted in an
increase in yield (entry 5). Increasing the concentration but
using the acceptor 6 in excess, as in entries 1–4, did not
improve yields (data not shown). In addition, omission of
DTBMP (entry 6) provided comparable results to entry 5
while omission of DTBMP and molecular sieves resulted in
complex mixtures and difficult purification (data not shown).
Implementation of entry 6 conditions at À208C provided no
improvement (see the Supporting Information).
Table 1: Initial screening and optimization.
Entry
Donor
Yield [%][a]
a/b
1
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
55
0
0
50
76
75
0
0
0
0
1.4:1
n.a.
n.a.
1.3:1
1.1:1
1.6:1
n.a.
n.a.
n.a.
n.a.
2[b]
3[c]
4[d]
5[d,e]
6[d,e,f]
7[d,e,f]
8[d,e,f]
9[d,e,f]
10[d,e,f]
Unless otherwise stated, 0.15 mmol of the donor 5, 1 mol% Ru(bpy)3-
(BArF)2, 1.07 equiv Umemoto’s reagent, 1.2 equiv DTBMP, 3 equiv of the
acceptor 6, and 300 mg 4 Š M.S. in 2 mL CH2Cl2 were irradiated for 24 h
with blue LEDs. Reactions maintained a temperature of about 308C.
[a] Yields of isolated products. [b] No irradiation. [c] No Umemoto’s
reagent. [d] No Ru(bpy)3(BArF)2. [e] Used 0.5 equiv of 6, 150 mg 4 Š M.S.
in 1 mL CH2Cl2. [f] DTBMP omitted. M.S.=molecular sieves.
The potential orthogonality of this method toward other
thioglycosides intrigued us. Application of the reaction
conditions, in entry 6 of Table 1, for the acetyl-protected 5b
(entry 7) resulted in no detectable consumption of the donor,
and some decomposition of Umemotoꢀs reagent was detected
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Table 2: Scope of reaction.
With the establishment of substrate scope, we wished to
investigate the mechanism of this transformation. Proton
NMR spectra of crude O-glycosylation mixtures demon-
strated that substantial quantities of an unidentified product
were present. This compound was separated (as a single
diastereomer) from dibenzothiophene with some difficulty
using silica gel chromatography. Based on a combination of
1D and 2D NMR spectroscopy, comparison of coupling
constants to those of reported tetrahydrothiophenes,[15] as
well as mass spectrometry and polarimetry, we assigned the
structure (Æ)-22 to this species (Figure 1). This finding lends
credence to a glycosylation process which bears some
mechanistic resemblance to that in Scheme 1.
Figure 1. Tetrahydrothiophene by-product
We found that running the reaction under the reaction
conditions depicted in entry 6 of Table 1, in the presence of
15 mol% TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl)
resulted in a yield (72%) which was nearly as high as that
obtained in its absence (see the Supporting Information).
Finally, experiments conducted in an NMR tube, which was
intermittently irradiated and kept in the dark (see the
Supporting Information), demonstrated that this reaction
requires continuous irradiation to proceed. These pieces of
evidence weigh against a radical-chain process. However, the
aforementioned on/off light experiment does not rule out
short-chain processes[16] and the lack of any TEMPO effect
does not prove that radical intermediates are not present.[17]
Indeed, EPR spectroscopy detected the formation of a tri-
fluoromethyl radical (by spin-trapping; see the Supporting
Information) in an irradiated reaction mixture.
We also observed that CH2Cl2 and CH3CN solutions of
Umemotoꢀs reagent and the donors 5a/b turned yellow upon
mixing (see the Supporting Information for photograph)
whereas similar solutions of 5c–e remained colorless. Further,
dissolution of Umemotoꢀs reagent and p-methoxystyrene in
CH3CN resulted in formation of the familiar yellow color,
thus suggesting that the p-methoxystyrene moiety is necessary
and sufficient for color change to occur. Recent work[9] has
demonstrated that EDA complexes, marked by the appear-
ance of color upon dissolution of the electron donor and
electron acceptor, can be activated with visible light in
synthetic transformations. UV-vis spectrophotometry of mix-
tures of 26.6 mm Umemotoꢀs reagent and varying concen-
trations of 5a in CH3CN (Figure 2) demonstrated the
appearance of a new absorbance tailing into the visible
region and with an extinction at the 455 nm wavelength
associated with blue LEDs. We attribute this phenomenon to
the generation of an EDA complex by interaction of 5a/b and
Umemotoꢀs reagent. Importantly, Umemotoꢀs reagent is
Unless otherwise stated, 0.15 mmol of the donor 5, 1.07 equiv
Umemoto’s reagent, 0.5 equiv of the acceptor, and 150 mg 4 Š M.S. in
1 mL CH2Cl2 were irradiated for 24 h with blue LEDs. TBS=tert-
butyldimethylsilyl.
linkages can be forged readily, while the results of entry 6
demonstrate the compatibility of this method with a tertiary
acceptor, namely 1-adamantanol. The results of entry 4
demonstrate the orthogonality of this method toward alkyl-
thioglycosides.
Stereoselectivity was low with benzyl groups present at
the 2-position of 5a. By contrast, the donor 5 f, bearing an
acetate at the 2-position provided complete b-selectivity
(Table 2, entries 7–12) by neighboring group participation.
Finally, we demonstrate that challenging linkages involving
the glycosylation of a secondary carbohydrate acceptor are
possible with this method (entries 13 and 14). The silyl-
protected substrate (entry 11) deserves further comment. The
so-called superarmed thioglycoside alcohol precursor is
approximately 20 times as reactive as the analogous tetra-
benzyl-protected thioglucoside toward conventional activa-
tion methods.[13,14] The fact that our reaction conditions
provided substantial yields of the glycosidic product without
any detected oligomerization of the silylated acceptor is
remarkable and attests to the orthogonality of this method.
Such an effect may prove to be very useful in the one-pot or
multistep synthesis of oligosaccharides.
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Figure 3. Structure of the EDA complex having the highest charge
transfer between Umemoto’s reagent and 4-methoxystyrene as deter-
mined with DFT calculations.
Figure 2. Evidence for an EDA complex (varying concentrations of 5a
in the presence of 26.6 mm of Umemoto’s reagent in CH3CN)
reagent complex was around 50% higher than that of the
styrene complex. The interplanar distance in these complexes
is around 3 Š, which is consistent with literature values for
EDA complexes.[19] The TD-DFT[20] calculations of the UV-
VIS spectra showed that, unlike the styrene case, the
methoxystyrene complexes have a strong transition around
l = 500 nm. Although the results are not quantitative, these
calculations do show that there is a transition in the visible
region of the spectrum which is consistent with the exper-
imental results. The computational approach and the results
are discussed in greater detail in the Supporting Information
section.
known to form EDA complexes with species other than
styrenes.[18]
We observed that the glycosyl donor 23 (Scheme 2) did
not generate a yellow color upon dissolution with Umemotoꢀs
reagent. Further, spectrophotometry showed little or no
evidence for the EDA complex (see the Supporting Informa-
tion). To study the relevance of the EDA complex in the
We propose a preliminary mechanism based on our
computational and experimental investigations (Scheme 3).
The formation of an EDA complex of 5a (or 5 f) by p–p
stacking of the p-methoxystyrene moiety with the S-trifluoro-
methyldibenzothiophenium cation is a prerequisite to absorp-
tion of a photon. After absorption of a photon, a subsequent
series of events involving the addition of trifluoromethyl and
the intramolecular addition of the sulfur atom of 5a/5 f across
the styrene double bond will result in the direct formation of
either 24 (pathway 1) or 25 + 22 (pathway 2). During the
conversion of the EDA complex into 24/25, S-trifluorome-
thyldibenzothiophenium may undergo reduction by photo-
induced electron transfer from the thioglycoside sulfur atom
to generate the trifluoromethyl radical and dibenzothio-
phene. This SET process would be expected to be more facile
Scheme 2. Role of an EDA complex in O-glycosylation.
glycosylation reaction, we subjected 23 to glycosylation
conditions and determined that it was unreactive. Further,
we irradiated 5c in the presence of 1 equivalent of p-
methoxystyrene under glycosylation conditions. This combi-
nation also proved to be unreactive. These results demon-
strate that the EDA complex is necessary for reactivity and
that the activation of thioglycoside is intramolecular.
To gain further insight into the possibility of an EDA
complex, we conducted computational investigations on
a model system consisting of the complex of styrene and 4-
methoxystyrene with the S-trifluoromethyldibenzothiophe-
nium cation of Umemotoꢀs Reagent (Figure 3). Our elec-
tronic structure calculations (using DFT) on the ground-state
complex for each system revealed that the charge transfer for
certain low-lying isomers of the methoxystyrene/Umemotoꢀs
Scheme 3. Preliminary mechanistic proposal.
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b) A.-H. A. Chu, A. Minciunescu, V. Montanari, K. Kumar, C. S.
with the electron-rich tetrabenzyl-protected thioglycosides
than with the tetraacetyl-protected analogues, thus poten-
tially explaining the difference in reactivity seen with 5a and
5b. Rapid attack of the trifluoromethyl radical onto the
styrene double bond before escape from the solvent cage may
explain the lack of any negative effect of TEMPO, while
occasional escape from the solvent cage would result in spin-
trapping observed with EPR. Regardless, the formation of
either 24 or 25 are reasonable conduits toward O-glycosyla-
tion.
In conclusion, we have demonstrated that visible-light
irradiation of 4-p-methoxyphenyl-3-butenylthioglucoside
donors in the presence of Umemotoꢀs reagent serves as
a mild approach to O-glycosylation. Photocatalysts are not
required for activation. Alkyl- and arylthioglycosides are
inert to these reaction conditions, and evidence suggests that
an intervening EDA complex is necessary for reactivity.
Yields with primary, secondary, and tertiary alcohol acceptors
range from moderate to high, and complete b-selectivity can
be attained through neighboring-group participation. Future
efforts will be directed toward attaining a-selectivity, one-pot
and iterative synthesis of oligosaccharides, and experimental
and computational studies to further elucidate the mechanism
of this visible-light-promoted O-glycosylation.
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Acknowledgements
We acknowledge the Louisiana Board of Regents (LEQSF-
(2013-16)-RD-A-03 ) and Louisiana State University for
generous support of this research. We thank Ms. Connie
David for assistance with high resolution mass spectrometry
and Dr. Rafael Cueto for assistance with EPR.
Keywords: glycosylation · photochemistry ·
reaction mechanisms · sulfur
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Published online: April 15, 2016
Angew. Chem. Int. Ed. 2016, 55, 6515 –6519
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6519