Blue Light Photocatalytic Glycosylation without Electrophilic Additives

Article abstract of DOI:10.1021/acs.orglett.7b00932

Photocatalytic formation of glycosidic bonds employing stable and readily accessible O-glycosyl derivatives of 2,2,6,6-tetramethylpiperidin-1-ol is presented that employs an iridium-based photocatalyst and blue LEDs. The reaction proceeds at room temperature and in the absence of additives other than 4 ? molecular sieves. Stereoselectivities are modest but nevertheless dependent on the anomeric configuration of the donor, suggesting a substantial degree of concerted character.

Full text of DOI:10.1021/acs.orglett.7b00932

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Letter
pubs.acs.org/OrgLett
Blue Light Photocatalytic Glycosylation without Electrophilic
Additives
Peng Wen and David Crich*
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: Photocatalytic formation of glycosidic bonds
employing stable and readily accessible O-glycosyl derivatives of
2,2,6,6-tetramethylpiperidin-1-ol is presented that employs an
iridium-based photocatalyst and blue LEDs. The reaction
proceeds at room temperature and in the absence of additives
other than 4 Å molecular sieves. Stereoselectivities are modest but nevertheless dependent on the anomeric configuration of the
donor, suggesting a substantial degree of concerted character.
hotostimulated glycosylation revolves around the notion of
single electron transfer from a suitable electron-rich glycosyl
Noyori employed electron-rich aryl glycosides (Scheme 1, RX
= ArO) and dicyanobenzene as the photostimulated oxidant by
irradiation with a 200 W Hg lamp,1 whereas subsequent work
focused on the more readily oxidized thio- and selenoglycosides,
with the use of charged photosensitizers to minimize back
electron transfer,7 irradiation in the visible range of wave-
lengths,4,8 or both.9 More recently, a number of photocatalytic
methods employing visible-light-stimulated transition metal
complex-based photo-oxidants and thio- or selenoglycosides
have been described.3,10−14 These latter processes employ
readily available LEDs emitting visible light and offer broad
functional group compatibility. Nevertheless, it is apparent that
the simple photocatalytic mechanism envisaged by Noyori1 is
not operative in most of these cases and that potent electrophilic
species, either generated in situ or added in stoichiometric
fashion, contribute to the activation of the glycosyl donor.3,10−14
Consequently, we were attracted by recent work on the
photocatalytic generation of simple tertiary alkyl, allyl, and
benzyl cations from sterically hindered O-alkyl hydroxylamines
that proceeds in the absence of stoichiometric additives in which
the photocatalytic cycle is closed by reduction of the expelled
nitroxyl radical (Scheme 2, R = t-Alkyl).15
P
donor to a photostimulated one-electron oxidant to give a radical
cation−radical anion pair. In competition with back electron
transfer, the radical cation expels a radical to give a glycosyl cation
or oxocarbenium ion. The oxocarbenium ion is trapped directly
either by the acceptor alcohol or by an anion present in the
reaction mixture to form a reactive glycosylating species that
undergoes reaction with the alcohol (Scheme 1), with the
Scheme 1. Photoglycosylation Concept
Encouraged by application of the process to O-tetrahydrofur-
anyl 2,2,6,6-tetramethylpiperidinoxide,15 we considered that this
process might be adapted to photocatalytic glycosylation through
the use of O-glycosyl 2,2,6,6-tetramethylpiperidinoxides16,17 as
donors if the highly destabilizing effect of adjacent C−O bonds
on cations18 and oxocarbenium ions19−23 could be overcome.
Here, we report the successful reduction of this concept of LED-
energized photocatalytic glycosylation in the absence of added
electrophiles to practice employing O-glycosyl 2,2,6,6-tetrame-
thylpiperidinoxides (Scheme 2, R = glycosyl).
understanding that suitably protected systems may also engage in
neighboring group participation. The expelled radical is typically
considered to undergo degradation by radical−radical pathways
such as dimerization. Alternatively, the expelled radical may
suffer reduction by the radical anion resulting from the initial
single electron transfer step, thereby rendering the process
catalytic in the photostimulated oxidant, as envisaged by early
workers in the field,1 and now commonly called photocatalysis. A
related concept is the homolytic scission of the anomeric C−S
bond in thioglycosides on irradiation with UV light through
quartz, followed by oxidation of the formed anomeric radical to
the oxocarbenium ion with a stoichiometric oxidant.2,3 Another
approach is the use of photochemically stimulated strong acids
with which to activate glycosyl donors through protonation and
promote more conventional glycosylations.4−6
Three α-glycopyranosyl fluorides 1−3 were prepared
according to literature methods,24−26 whereas 4 was accessed
by hydrolysis of phenyl 2-azido-2-deoxy-3,4,6-tri-O-benzyl β-D-
Received: March 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00932
Org. Lett. XXXX, XXX, XXX−XXX

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it is recognized that other hydroxylamine derivatives may
eventually prove advantageous. Blank reactions conducted in
the dark or by photolysis in the absence of 10 did not proceed
and indicated the need for 10 and its photolytic activation.
Experiments conducted in the absence of molecular sieves were
marred by formation of significant amounts of the hydrolyzed
donor (hemiacetals) but also proceeded significantly more
slowly, suggesting involvement of the sieves in the reaction
mechanism.
Scheme 2. Photocatalytic Cation Generation from Tempol
Ethers and Tempol Glycosides
thioglucopyranoside 5 to the corresponding hemiacetal followed
by treatment with HF·pyridine according to the method of
Noyori et al. (Scheme 3).27
Table 2 reveals that good to excellent yields were obtained in
all couplings conducted in this survey, with only modest
differences in yield observed between the α- and β-anomers of
a particular donor (compare Table 2, entries 4, 6, and 8 with 5, 7,
and 9; and entries 10, 12, and 14 with 11, 13, and 15). Although
the anomeric selectivity of the coupling reactions is modest, it is
reproducibly a function of the anomeric configuration of the
donor (compare Table 2, entries 4, 6, and 8 with 5, 7, and 9; and
entries 10, 12, and 14 with 11, 13, and 15). Greater differences in
selectivity between the two anomers of a given donor are
observed with the more reactive cyclohexanol, which was
additionally used in greater excess, and with the primary acceptor
12, than with the less reactive secondary acceptor 13. The
implication is that glycosylation proceeds at least in part in a
concerted manner in which displacement of the Tempo radical
from the oxidatively activated donor is coupled with attack by the
incoming acceptor. Such a concerted process can be interpreted
as either a direct attack on the activated donor or an attack on the
initially formed radical ion triplet before diffusive equilibration
(Scheme 4). There is a steadily increasing body of kinetic
evidence28−37 that a variety of stereoselective glycosylation
reactions proceed by associative reaction pathways rather than by
dissociatively free glycosyl oxocarbenium ions that have only
been observed in super acidic media.22,23,38,39 In such classical
glycosylation reactions, the associative pathways are more
prevalent with more reactive acceptor alcohols,40−43 consistent
with the observed pattern in Table 2. The hexafluorophosphate
counterion is not considered to intervene directly in the reaction
mechanism except for providing charge stabilization consistent
with studies on the influence of a variety of counterions on the
stereoselectivity of glycosylation reactions.38,44 The part of the
reaction manifold that affords substitution with overall retention
of configuration is best interpreted as taking place via solvent-
separated ion triplets rather than via equilibration of the donor
configuration followed by concerted displacement, as no
evidence was found for donor anomerization in these reactions.
The root cause of the observed acceleration of reaction rate by
the 4 Å MS is presumably associated with their basic character45
and the relative acidity46 of the hydroxylamine Tempol.
Scheme 3. Synthesis of Glycosyl Fluoride 4
Glycosyl fluorides 1−4 were then coupled to the persistent
radical Tempo with activation by BF3·OEt2 in acetonitrile at
room temperature in the presence of tetramethylguanidine
following the method of Sato.17 Manno-configured donor 1 gave
a single α-glycoside 6, whereas gluco- and galacto-configured
glycosyl fluorides 2−4 afforded separable α,β mixtures of the
corresponding glycosides 7−9 (Table 1) by a reaction whose
mechanism remains to be clarified.
Table 1. Synthesis of Tempol Glycosides
entry
glycosyl fluorides
tempol glycosides (yield, %)
1
2
3
4
1
2
3
4
6α (64) and 6β (0)
7α (38) and 7β (37)
8α (41) and 8β (30)
9α (22) and 9β (63)
Adapting the method of Knowles,15 we photolyzed 0.1 M
nitromethane solutions of the various Tempol glycosides with
blue LEDs through Pyrex at room temperature in the presence of
powdered 4 Å MS, 5 mol % of iridium photocatalyst 10,15 and the
model acceptor alcohols 11−13, monitoring with TLC or ESI
MS.
Catalyst 10 was selected for this study as the optimum system
in the Knowles work15 on tertiary cation generation. Similarly,
nitromethane was chosen as solvent by extrapolation from that
study;15 indeed, a brief investigation of acetonitrile as solvent
revealed it to be far inferior. This preliminary investigation was
limited to the use of Tempol derivatives following Knowles,15 but
In summary, a new photocatalytic glycosylation method is
presented that functions under irradiation through Pyrex by blue
LEDs and in the absence of additives other than 10 and 4 Å MS.
The method uses stable and readily accessible Tempol glycosides
as donors and neither requires nor generates in situ any strongly
B
DOI: 10.1021/acs.orglett.7b00932
Org. Lett. XXXX, XXX, XXX−XXX

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Table 2. Photoglycosylation of Alcohols with Donors 6−9 and Catalytic 10
a
b
Combined yield of the isolated anomers. Anomeric ratios were determined by integration of the 1H NMR spectra of the crude photolysates before
purification.
C
DOI: 10.1021/acs.orglett.7b00932
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00932.
■
S
́
́
ez, J. C.; Uriel, C.; Guillamon-Martín, A.; Valverde, S.;
́
́
́
ez, A.
Full experimental details and 1H and 13C NMR spectra for
all new compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dcrich@chem.wayne.edu.
ORCID
(30) Huang, M.; Retailleau, P.; Bohe,
2012, 134, 14746.
́
L.; Crich, D. J. Am. Chem. Soc.
(31) Adero, P. O.; Furukawa, T.; Huang, M.; Mukherjee, D.; Retailleau,
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(32) D’Angelo, K. A.; Taylor, M. S. J. Am. Chem. Soc. 2016, 138, 11058.
́
David Crich: 0000-0003-2400-0083
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM62160) for support of this work and
acknowledge support from the NSF (MRI-084043) for the
purchase of the 600 MHz NMR spectrometer in the Lumigen
Instrument Center at Wayne State University.
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DOI: 10.1021/acs.orglett.7b00932
Org. Lett. XXXX, XXX, XXX−XXX