Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C?O Bond Homolysis

Article abstract of DOI:10.1002/anie.202014991

C-aryl glycosyl compounds offer better in vivo stability relative to O- and N-glycoside analogues. C-aryl glycosides are extensively investigated as drug candidates and applied to chemical biology studies. Previously, C-aryl glycosides were derived from lactones, glycals, glycosyl stannanes, and halides, via methods displaying various limitations with respect to the scope, functional-group compatibility, and practicality. Challenges remain in the synthesis of C-aryl nucleosides and 2-deoxysugars from easily accessible carbohydrate precursors. Herein, we report a cross-coupling method to prepare C-aryl and heteroaryl glycosides, including nucleosides and 2-deoxysugars, from glycosyl esters and bromoarenes. Activation of the carbohydrate substrates leverages dihydropyridine (DHP) as an activating group followed by decarboxylation to generate a glycosyl radical via C?O bond homolysis. This strategy represents a new means to activate alcohols as a cross-coupling partner. The convenient preparation of glycosyl esters and their stability exemplifies the potential of this method in medicinal chemistry.

Full text of DOI:10.1002/anie.202014991

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9433–9438
International Edition: doi.org/10.1002/anie.202014991
German Edition: doi.org/10.1002/ange.202014991
Synthetic Methods
Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters
À
via C O Bond Homolysis
Yongliang Wei, Benjamin Ben-zvi, and Tianning Diao*
Abstract: C-aryl glycosyl compounds offer better in vivo
stability relative to O- and N-glycoside analogues. C-aryl
glycosides are extensively investigated as drug candidates and
applied to chemical biology studies. Previously, C-aryl glyco-
sides were derived from lactones, glycals, glycosyl stannanes,
and halides, via methods displaying various limitations with
respect to the scope, functional-group compatibility, and
practicality. Challenges remain in the synthesis of C-aryl
nucleosides and 2-deoxysugars from easily accessible carbo-
hydrate precursors. Herein, we report a cross-coupling method
to prepare C-aryl and heteroaryl glycosides, including nucleo-
sides and 2-deoxysugars, from glycosyl esters and bromoar-
enes. Activation of the carbohydrate substrates leverages
dihydropyridine (DHP) as an activating group followed by
offers a simple synthetic solution, but lacks the general
regiochemical control on the arene.[11] The nucleophilic
addition of aryllithium reagents to lactones precludes many
electrophilic and acidic functional groups.[12] Arylation of
glycals via the Heck reaction entails multiple steps from the
native sugars.[13] Stereospecific cross-coupling of glycosyl
stannanes provides excellent stereocontrol, but requires pre-
generation of the tin reagents with defined stereochemistry
and has not been applied to furanosides.[14] Cross-coupling of
glycosyl halides with organometalloarenes,[15] aromatic nucle-
ophiles,[16] or aromatic electrophiles[17] achieved success with
a range of carbohydrates, but 2-deoxy sugar substrates,
especially 2-deoxyriboses, are susceptible to decomposition,
due to the rapid elimination of glycosyl chlorides and
bromides to form glycals.[18] Thus, many glycosyl halides
often require in situ generation.[19] The Diels–Alder reaction
À
decarboxylation to generate a glycosyl radical via C O bond
homolysis. This strategy represents a new means to activate
alcohols as a cross-coupling partner. The convenient prepara-
tion of glycosyl esters and their stability exemplifies the
potential of this method in medicinal chemistry.
C
-aryl glycosyl compounds are prevalent drug candidates,
since the C-glycosidic linkage confers in vivo stability through
resistance to hydrolysis and enzymatic degradation.[1] C-aryl
nucleosides, such as tiazofurin 1,[2] are prototypical antiviral
compounds as they can be recognized by cellular or viral
polymerases,[3] while modifications to their structure lead to
disruption and/or termination of replication.[4] C-aryl nucleo-
sides, including 1[5] and benzamide C-ribose 2,[6] show
antiproliferative activity (Scheme 1A). Moreover, synthetic
C-aryl nucleoside analogues, including 3, are essential to
studying the origins of mutagenicity and understanding the
mechanism of replication and evolution.[7] Expanded genetic
codes, including dNaM (X) 4, provide a platform for creating
therapeutic proteins.[8] Since nucleosides have high solubility,
cell permeability, and in vivo stability, replacing nucleobases
with organic fluorophores creates fluorescent tags that can be
readily assembled on a DNA synthesizer and applied to
bioimaging.[9]
Efficient and sustainable synthesis of C-aryl glycosides
would facilitate drug discovery and chemical biology studies
(Scheme 1B).[10] Current methods exhibit various limitations.
The Friedel–Crafts type glycosylation of electron-rich arenes
[*] Dr. Y. Wei, B. Ben-zvi, Prof. Dr. T. Diao
Chemistry Department, New York University
100 Washington Square East, New York, NY 10003 (USA)
E-mail: diao@nyu.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202014991.
Scheme 1. A) Selected C-aryl nucleosides with medicinal and chemical
biology significance and B) synthetic strategies.
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À
is useful for preparing pyranoses, but cannot be applied to
furanosides.[20] A photoredox decarboxylation reaction lever-
ages an unnatural tetrahydrofuran derivative with a carboxylic
acid group at the C1 position, and therefore lacks a general
scope of sugar substrates.[21] Other photoredox coupling
reactions based on redox auxiliaries serve as an excellent
approach to non-classical C4 or C5-substituted sugars, but do
not offer substitution at the anomeric position.[22]
applied to synthesize unconventional glycosides via C C
bond cleavage at the C4 or C5 position (Scheme 2B).[20] We
hypothesize that DHP-mediated radical formation could be
combined with subsequent decarboxylation of an alkoxycar-
À
bonyl radical to activate the anomeric C O bond
(Scheme 2D). This mechanism represents a new strategy for
homolytic activation of hydroxyl groups and formation of
radicals.
Glycosyl esters represent the ideal precursor to C-glyco-
sides. Herein, we describe a method to synthesize C-aryl and
heteroaryl glycosides, including b-nucleosides and 2-deoxy-
sugars, via the cross-coupling of a redox-active glycosyl ester
with aryl and heteroaryl bromides. Upon photoredox activa-
We envision that ester 5 is readily available from the
condensation of carbohydrates to DHP carboxylic acid
(Scheme 3A). Oxidation of 5 by an excited photosensitizer
(PC*), followed by deprotonation, can afford radical 6.[25c]
Subsequent fragmentation is driven by the formation of
Hantzsch pyridine 8 and generates an alkoxycarbonyl radical
7. Upon ejection of CO2, 7 can be transformed to glycosyl
radical 9,[28] which enters the catalytic cycle mediated by
nickel and cross-couples with aryl bromides. Coordination of
9 to NiII 10 affords NiIII 11, followed by reductive elimination
to give C-aryl glycoside 14. The resulting NiI 12 is readily
reduced to Ni0 by [PC]ÀC.[29] The initial formation of Ni0 13
À
tion and electron transfer, the anomeric C O bond undergoes
homolysis and generates a glycosyl radical intermediate.
Convenient access to the glycosyl ester and its stability
exemplifies the potential of this method in medicinal chemis-
try.
Redox auxiliaries can transform hydroxyl groups into
À
viable leaving groups via C O bond homolysis to form radical
intermediates (Scheme 2A). Typical auxiliaries include xan-
thates,[23] phosphites,[24] and oxalates[25] activated through
electron transfer or light irradiation (Scheme 2A). These
methods, however, have not been applied to glycosylation,
possibly due to the instability of the corresponding glycosyl
esters.[26] Dihydropyridine (DHP) has emerged as a versatile
activating group to produce carbon radicals and carbamoyl
À
radicals, from aldehydes and amines, respectively, via C C
bond homolysis (Schemes 2B and C).[27] The former has been
Scheme 2. Comparison of radical-formation strategies based on photo-
Scheme 3. A) Proposed mechanism for C-aryl glycosylation based on
redox activation of DHP.
dihydropyridine (DHP) derived esters and B) optimized conditions.
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from a NiII precatalyst may be accomplished by reduction
on the stereochemical outcome. Arylation of the benzyl
with [PC]ÀC, as well.
protected 2-deoxy-d-ribose generated a mixture of a and b
anomers of 49–51 in a ratio of 2.1:1, presumably due to the
lack of steric strains to distinguish the b face from the a face.
b-2-deoxyriboses 50, 51 are unnatural nucleoside analogues
crucial to chemical biology studies. Although the yields for b-
50 and b-51 are low, the overall efficiency could still compete
with previous multiple-step syntheses based on the Heck
reaction and addition of lithium reagents to lactones.[7a] An
alternative approach to 50, 51 involves the preparation of
their b-C-aryl ribose analogues through this cross-coupling
reaction, followed by reduction of the 2-hydroxyl group.[34]
A variety of pyranoses, including d-mannopyranose,
2-deoxy-d-glucopyranose, l-rhamnopyranose, and 2-deoxy-
d-ribopyranose, proceeded to form C-aryl glycosides 52–58
under the standard conditions. Acetyl protected d-manno-
pyranose gave a low yield of 52, due to facile b-elimination to
afford glycals as the by-product. The observed a-selectivity
can be attributed to the kinetic anomeric effect.[35,36] The
mannopyranosyl radical intermediate adapts a chair-like
conformation 61,[37] stabilized by the hyperconjugation of
the nonbonding orbital of the ring oxygen, the radical orbital
Catalyst development focused on bis-acetonide protected
d-mannofuranose as a model substrate (Scheme 3B). A DHP
auxiliary 16 is readily available by the condensation of
aminocrotonate with glyoxylic acid.[30] Coupling DHP acid 16
with the bis-acetonide protected d-mannofuranose 15
afforded O-mannofuranosyl ester 17 in 90% yield. We
applied a modified variant of the photoredox-nickel dual
catalytic condition for carbamoyl radical generation to couple
17 with PhBr, using 4CzIPN as the photosensitizer,[25c,31]
NiBr2·DME (DME = 1,2-dimethoxyethane) as the catalyst,[32]
and bipyridine (bpy) as the ligand. The desired C-phenyl-1-
deoxy d-mannofuranose 18 was obtained in 81% isolated
yield under blue light (467 nm) irradiation at 848C, a temper-
ature required to facilitate DHP fragmentation and the
subsequent decarboxylation. A lower temperature led to the
formation of an ester byproduct, derived from the coupling of
7 to PhBr. Slight excess of 17 ensures a high yield of 18; Using
equal molarity of 17 and PhBr gave 18 in 74% yield. The
a and b anomers of 17 were separately subjected to the
conditions, and both transformed to 18 in comparable yields
and high a-selectivity. The stereochemistry was assigned
based on NOESY, COSY, and HSQC experiments and
compared with literature reports.
We applied the optimized conditions to couple
O-mannofuranosyl ester 17 with a range of aryl bromides
(Table 1). Due to fluctuations caused by light irradiation, we
recorded the actual temperature of the oil bath for each
reaction. In general, electron-deficient aryl bromides gave
excellent yields of the corresponding C-glycosyl arenes (19–
23, 27–29). Performing the synthesis of 17 on a 1.94-gram-
scale afforded 21 in 82% isolated yield. Electron-rich
electrophiles, including para-methyl and para-methoxy
phenyl bromides also gave good to excellent yields (24,25).
Para-dimethylaminophenyl bromide, however, is unsuccess-
ful in generating 26. Coupling of 17 with heterocycles,
including thiophene with electron-withdrawing substituents,
pyrimidine, and pyridines, proceeded to afford the corre-
sponding C-heteroaryl glycosides (32–37) in modest yields.
All reactions favor formation of the a-anomer, since the
concave b-face is sterically protected by C2, C3, and C4
substituents. The limitation with some electron-rich arenes
(26) and heterocycles, such as furan and pyrrole (28 and 29),
could be attributed to the incompatibility of these easily
oxidizable substrates with the excited photocatalyst.
À
(SOMO), and the s* orbital of the adjacent C2 O bond. The
attack of the nickel intermediate to the mannopyranosyl
radical favors the axial direction because the transition state
can be stabilized by the donation of the nonbonding electron
pairs on the ring oxygen to the antibonding orbital (s*°) of
the newly formed C1-Ni s-bond. In addition, the approach of
nickel from the a-face avoids the steric hindrance in the b-
face created by the C2-substituent. Benzyl and methyl-
protected glucopyranoses display poor reactivity to afford
glucopyranosides 58, 59 in low yields and as a mixture of
a and b-anomers. Product 57 is a precursor to dapagliflozin,
a treatment for type II diabetes.[38] The glucopyranosyl radical
intermediate prefers to accommodate a boat conformer 62.[30]
The poor selectivity can be attributed to the contradictory
preferences by the steric and the stereoelectronic effect. The
steric hindrance at C2 favors the b-attack, whereas the
transition state for the a-attack can be stabilized by the
kinetic anomeric effect. For a similar reason, d-galactopyr-
anose 60 also displayed unsatisfactory yield and selectivity.
The generality of this deoxygenative coupling method
implies applications in complex molecule synthesis via late-
state functionalization. We applied the method to derivatizing
natural product (+)-sclareolide (Scheme 4). DHP ester 63
underwent cross-coupling with para-bromobenzoate to afford
64 in 54% yield and 8:1 d.r.
We explored the scope of furanoses with various protect-
ing groups.[33] d-Ribofuranoses containing common protect-
ing groups, such as benzyl, silyl, and benzoyl, underwent
smooth C-arylation, forming 38–40 with excellent selectivity
for the b-anomer. Immediate application features the syn-
thesis of nucleoside analogues 41–44, precursors to pharma-
ceuticals 1, 2 and unnatural nucleosides 3, 4. The low yield of
42 may be attributed to the decomposition of thiazole at the
elevated temperature.
d-Xylofuranose and d-glucofuranose underwent b-aryla-
tion to afford 45, 46. The stereoselectivity was altered to favor
the a-anomer for d-galactofuranose 47 and d-arabinofura-
nose 48, reflecting a dominating effect of the C2 substituent
In summary, we prepared C-aryl and heteroaryl glycosides
through the cross-coupling of a redox-active glycosyl ester.
Upon light-induced electron-transfer of DHP, the glycosyl
ester can fragmentize and eject CO2 to generate a glycosyl
radical, which cross-couples with aryl and heteroaryl bro-
mides in the presence of nickel catalysts. The innovation
centers at the combination of DHP with decarboxylation as
À
a new means to induce C O bond homolysis and form
radicals. This method overcomes several limitations in exist-
ing glycosylation reactions for preparing furanoses and
pyranoses. The reaction is particularly useful in synthesizing
unnatural b-nucleosides, due to the accessibility, stability and
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Table 1: Scope of C-aryl glycosylation with DHP-derived glycosyl esters.[a]
[a] Isolated yields. Reaction conditions: ArBr, 0.20 mmol; glycosyl ester, 0.24 mmol (1.2 equiv). [b] Reaction performed with 1.94 grams of 17.
[c] 2,2’-Bipyridine-4,4’-dicarboxylic acid as the ligand. [d] NiBr2·DME (10 mol%), bpy (14 mol%). [e] 4,4’-Dimethoxy-2,2’-bipyridine as the ligand.
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Acknowledgements
Y. Wei thanks Qiao Lin for assistance in obtaining and
analyzing the EPR spectrum in Figure S4. T.D. thanks Prof.
Mark Taylor (University of Toronto) for helpful discussions
about the conformational assignment of the products. This
work was supported by the National Institute of Health (R01
GM-127778). T.D. thanks the Alfred P. Sloan Foundation
(FG-2018–10354) and the Camille and Henry Dreyfus
Foundation (TC-19-019) for providing fellowships to partially
support this work. The EPR spectrometer at New York
University was supported by an NSF MRI grant (1827902).
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Keywords: C-glycosylation · cross-coupling · glycosyl radicals ·
nucleoside analogues · photoredox
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Manuscript received: November 9, 2020
Revised manuscript received: December 10, 2020
Version of record online: March 10, 2021
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