Synthesis of Reverse Glycosyl Fluorides and Rare Glycosyl Fluorides Enabled by Radical Decarboxylative Fluorination of Uronic Acids

Article abstract of DOI:10.1021/acs.orglett.0c03514

An efficient protocol for synthesizing reverse glycosyl fluorides is described, relying on silver-promoted decarboxylative fluorination of structurally diverse pentofuran- and hexopyranuronic acids under the mild reaction conditions. The potential applications of the reaction are further demonstrated by converting readily available d-uronic acid derivatives into uncommon d-/l-glycosyl fluorides through a C1-to-C5 switch strategy. The reaction mechanism is corroborated by 5-exo-trig radical cyclization of allyl α-d-C-glucopyranuronic acid triggered by decarboxylative fluorination.

Full text of DOI:10.1021/acs.orglett.0c03514

pubs.acs.org/OrgLett
Letter
Synthesis of Reverse Glycosyl Fluorides and Rare Glycosyl Fluorides
Enabled by Radical Decarboxylative Fluorination of Uronic Acids
Pengwei Chen, Peng Wang, Qing Long, Han Ding, Guoqiang Cheng, Tiantian Li, and Ming Li*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03514
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ABSTRACT: An efficient protocol for synthesizing reverse glycosyl fluorides is described, relying on silver-promoted
decarboxylative fluorination of structurally diverse pentofuran- and hexopyranuronic acids under the mild reaction conditions.
The potential applications of the reaction are further demonstrated by converting readily available D-uronic acid derivatives into
uncommon D-/L-glycosyl fluorides through a C1-to-C5 switch strategy. The reaction mechanism is corroborated by 5-exo-trig radical
cyclization of allyl α-D-C-glucopyranuronic acid triggered by decarboxylative fluorination.
Scheme 1. Methods for Synthesis of RGFs through a Radical
Process
everse glycosyl fluorides (RGFs)namely, furanos-4-yl-
Rand pyranos-5-yl fluoridesare the essential constituents
of either naturally occurring nucleosides and drug candidates.1
RGFs have been found to be probes of carbohydrate
processing enzymes of particular biological importance.2 The
very recent work reported by Zhou and Plavec has revealed
that 4′-fluorinated RNA can serve as a promising probe and
exhibits wide applications in structural elucidation and
functional clarification for RNA by 19F NMR spectrometry.3
As such, numerous methods relying on a nucleophilic or
electrophilic fluorination process have been developed to get
access to structurally unique RGFs.2,4 In this context, we
recently reported Ag2CO3/Selectfluor-promoted radical dehy-
droxymethylative fluorination of carbohydrates to afford RGFs
with one carbon less sugar chain than the starting materials in
aqueous solvent under mild reaction conditions (see Scheme
1a).5 The mechanistic studies revealed that the reaction
involves β-fragmentation of primary alkoxy radicals. Further-
more, our work also demonstrates that RGFs are valuable
platforms for divergent elaborations of carbohydrates through
C−F bond functionalization. Despite enjoying good substrate
scope, the reaction of dehydroxymethylative fluorination shows
some limitations: both benzyl group-protected sugars and
certain oligosaccharides containing hexp-(1 → 4)-hexp moiety
Received: October 24, 2020
are problematic, likely the result of alkoxy radicals with
relatively high tendency to engage in 1,n-hydrogen atom
transfer (n = 5, 6, 8, etc.).6
To circumvent these limitations, we turned our attention to
decarboxylation of acyloxy radicals, based on the following
salient features of the species:
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© XXXX American Chemical Society
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A

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a b
,
Scheme 2. Substrate Scope of Decarboxylative Fluorination
a
Unless otherwise noted, the reaction was conducted with 0.1 mmol of the uronic acid, 0.5 equiv of Ag2CO3, and 5.0 equiv of Selectfluor, 25 °C, 3
b
1
c
h. The diastereomeric ratio (dr) value refers to the ratio of 5R-/5S-isomer determined by H NMR spectroscopy. 2.0 equiv of Selectfluor, 0.2
equiv of Ag2CO3, and 2.0 equiv of KF·2H2O was used. d1.0 equiv of Ag2CO3 was used. e5.0 equiv of KF·2H2O was added. f2.0 equiv of Ag2CO3 was
g
h
used. Reaction temperature = 60 °C. Acetone/H2O (v/v = 30:1) as the solvent.
visible-light photoredox-catalyzed radical decarboxylative fluo-
(i) compared to primary alkoxy radicals, the corresponding
acyloxy radicals are less electrophilic due to the presence
of electron-withdrawing carbonyl group, thus decreasing,
even eliminating, the tendency of hydrogen atom
abstraction of the intermediates; and
(ii) decarboxylation of acyloxy radicals has been found to be
several orders of magnitude faster than β-cleavage of
primary alkoxy radicals.
rination (see Scheme 1b).10c However, the reaction was not
found to bring about the transformation of glucopyranuronic
acid, which is a typically representative hexopyranuronic acid.
Herein, we would like to unveil our finding of silver-promoted
radical decarboxylative fluorination of various uronic acids,
providing a complementary and more general methodology for
the synthesis of RGFs (see Scheme 1c). The reaction works
well under the mild reaction conditions and accommodates
structurally diverse and densely functionalized carbohydrates,
such as those having benzyl protecting groups. The present
transformation also provides a novel protocol for the synthesis
of rare D-/L-configured glycosyl fluorides from easily available
D-uronic acid derivatives through a C1-to-C5 switch strategy.11
Uronic acids can be readily prepared using 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO)/[bis(acetoxy)iodo]
benzene (BAIB)-mediated oxidization of carbohydrate-based
primary alcohols, which features a wide substrate scope and
good chemoselectivity.12 Inspired by silver-catalyzed decar-
boxylative fluorination of aliphatic carboxyl acids13 and driven
by our previous works on the synthesis of C-glycosylated
phenanthandines and isoquinolines relying on silver-mediated
decarboxylative functionalization of uronic acids,14 we
commenced our studies with glucopyranuronic acid 1a as a
model substrate to establish the optimal reaction conditions.
This statement is supported by rate constant for decarbox-
ylation of alkyl acyloxy radicals, ∼1.0 × 1010 s−1 vs 1.8 × 105
s−1 for β-fragmentation of tert-butyloxyl radical, which is
recognized to be more inclined to β-scission than primary
alkoxy radicals.7 With these results in mind, we thereby
undertook radical decarboxylative fluorination of uronic acids
with the hope to find a more general method for synthesizing
RGFs.
Alongside the well-established functionalization of aliphatic
carboxylic acids through decarboxylation of acyloxy radicals,8
radical decarboxylation of uronic acids and derivatives under
oxidative or reductive conditions has proven to be a powerful
tool to enable elaborations of carbohydrates by constructing
either carbon−carbon or carbon−heteroatom linkages.9,10
Among these impressive works, MacMillan and co-workers
reported a single example that dealt with conversion of
ribofuranuronic acid into D-erythros-4-yl fluoride through
B
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Scrupulous evaluation of the reaction parameters revealed that
treatment of 1a with 5.0 equiv of Selectfluor in the presence of
0.5 equiv of Ag2CO3 afforded 2a in 85% yield at 25 °C for 3 h
in acetone/H2O (v/v = 6/1) (see Table S1 in the Supporting
Information (SI)). Given that carbohydrates are densely
functionalized molecules, we selected the recipe as the optimal
reaction conditions attributable to its mildness.
To assess the scalability of this method, we performed the
scale-up reactions of 1b, 1g, and 1l. All of the reactions
performed at equal efficiency on the gram scale.
The potential of the present transformation in complex
natural products was also explored. Fluorinated spirosaponin
2u derived from tigogen-3-yl glucuronic acid 1u was obtained
with the spiroketal and tertiary C−H functionalities intact.
As a typical example of open-chain sugars, gluconic acid 1v
possesses more flexible conformation than the cyclic uronic
acids. To our delight, 1v underwent smooth decarcarboxylative
fluorination to produce α-fluoroalkyl ester 2v in 72% yield with
a diastereomeric ratio of 1/1. α-Haloalkyl esters originated
from carbohydrates are a class of interesting chiral synthons in
organic synthesis. While α-bromo- and iodoalkyl esters are
known,17 the present transformation represents the first
example of sugar-based α-fluoroalkyl ester synthesis.
L-Sugar moieties are frequently found as integral compo-
nents of oligosaccharides, glycopeptides, saponins, and nucleo-
sides of biological relevance.11,18 Given the poorly commercial
and natural availability of most of L-sugars and the related
building blocks, a plethora of approaches to prepare these
types of molecules have been devised.11 Glycosyl fluorides
have been established to be a class of glycosylating agents for
chemical and enzymatic synthesis of oligosaccharides and
glycoconjugates.19 With the protocol established for the
fragmentation of uronic acids to RGFs with one carbon less
degradation, we envisaged that the transformation could
permit conversion of readily available β-D-C-glycosides or
1,5-anhydroalditols into rare L-glycosyl fluorides, thus devel-
oping a novel route to L-configured sugar constructs through a
C1-to-C5 switch strategy. To reduce this concept to practice,
we set out to synthesize L-glycosyl fluorides. As shown in
Scheme 3, uronic acid 3, readily prepared by means of a four-
step sequence of reaction in overall 54% yield using D-glucose
and 2,4-pentane-dione as the starting materials,20 was
subjected to Ag2CO3-promoted decarboxylative fluorination
in the presence of Selectfluor. Gratifyingly, the reaction
proceeded smoothly at 60 °C to afford L-gluco-octopyranosyl
With the optimized conditions in hand, we set out to explore
the scope of decarboxylative fluorination of uronic acids. The
results are compiled in Scheme 2. Consistent with our
expectations, decarboxylative fluorination is applicable to not
only pyranosides and furansides equipped with acetate,
benzoate, isopropylidene, or azido groups (1b−1h), but also
those bearing a benzyloxy group at the C4 or the anomeric
position (1i−1k). The latter are not amenable to dehydrome-
thylative fluorination via β-scission of primary alkoxyl radicals.5
Of particular note, the reaction exhibits good selectivity toward
carboxylic acid over secondary hydroxyl groups, as exemplified
by the preparation of 2e, where the transformation selectively
occurred to carboxylic acid with the C4 hydroxy group intact.
Notably, 2k might be an interesting fluoride, since (2-
benzyloxycarbo-nyl)-benzyl glycosides could act as the
precursor to (2-hydroxycarboxylic)-benzyl glycosides, which
represent a class of proven and efficient glycosyl donors.15
Encouraged by these results, we turned our attention toward
decarboxylative fluorination of more challenging uronic acids
having multiple benzyl protecting groups (1l−1o). When
2,3,4-tri-O-benzyl-glucuronic acid 1l was exposed to decarbox-
ylative fluorination, the desired product 2l was obtained in
48% yield under the standard conditions. The rapid
decomposition of 2l resulted in the moderate yield attributable
to the presence of electron-donating benzyl ethers favoring C−
F cleavage in the acidic reaction medium.5,13a To eliminate this
unexpected reaction, we tried to use KF·2H2O as the base to
modulate the acidity of the reaction medium. To our delight,
inclusion of 5.0 equiv of KF·2H2O increased the yield of 2l to
67%. Furthermore, it was found that the reaction could be
conducted without erosion of yield and diastereochemistry by
reducing molar equivalents of Ag2CO3, Selectfluor, and KF·
2H2O to 0.2, 2.0, and 2.0, respectively. Under these conditions,
2m with the C4 hydroxy group free was smoothly obtained in
69% yield. The configuration of anomeric substituent might
exert a profound influence to diastereoselectivity of the
reaction. For instance, β-D-mannuronic acid 1n afforded 2n
as the sole product, while its α-isomer 1o resulted in 2o as a
diastereomeric mixture. Taken together, these results demon-
strate that decarboxylative fluorination enjoys a broader
substrate scope than dehydromethylative fluorination, provid-
ing thereby a complementary approach to various RGFs of
importance. We assume that the diastereoselectivity of the
reactions is governed by the preferential conformation of
furanos-4-yl- and pyranos-5-yl radical intermediates coupled
with the steric hindrance of substituents.9b,c,14,16
Scheme 3. Synthesis of L-Glycosyl Fluorides by
Decarboxylative Fluorination
Oligosaccharides were also competent substrates for
decarboxylative fluorination, as exemplified by uneventful
synthesis of disaccharide fluorides 2p−2r, trisaccharide
fluoride 2s, and cyclodextrin fluoride 2t in yields of 63%−
96%. Remarkably, access to benzoylated 2q and benzylated 2r,
both of which have an α-L-rhamnosyl-(1 → 4)-β-D-glucoside
backbone, illustrates another salient feature of decarboxylative
fluorination, because such linkage impedes the dehydrome-
thylative fluorination of primary alkoxy radical stemming from
the competitive intramolecular hydrogen atom transfer.6
C
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fluoride 4 in 74% overall yield as an anomeric mixture of α/β
(3.6/1) (see Scheme 3a). Under the identical conditions
benzoyl-protected uronic acids 5 and 7 derived from D-
mannose and galactose, however, afforded L-galacto- and
manno-octopyranosyl fluorides 6 and 8 in decreased yields of
44% and 26%. To our delight, the addition of KF·2H2O greatly
improve the outcome of both transformations, and glycosyl
fluorides 6 and 8 were obtained in 89% and 80% yields with α-
anomer as the sole product (see Schemes 3b and 3c). To
further showcase the utility of the obtained glycosyl fluorides
as glycosyl donors, the coupling of 4 with one of the alcohol
acceptors was explored (see Table S2 in the SI). The
octopyranside building blocks obtained might serve as valuable
precursors to L-hexopyranoside constructs since shortening the
side chain by two C atoms has been reported.21
L-Lyxose, as a rare sugar, has been identified as a component
of oligosaccharide antibiotics, including flambamycin, curamy-
cin, avilamycin, and everninomicin.22 There are sporatic
reports describing synthesis of L-lyxose by chemical methods
and biotransformations.23 We were pleased to find that the
exposure of D-1,5-anhydrogalactinol 9 to decarboxylative
fluorination to generate α-L-lyxopyranosyl fluoride 10 in 84%
yields (see Scheme 3d). This transformation not only provides
valuable building blocks for synthesizing structurally unique
antibiotics but also represents the first example of converting
1,5-anhydroaldotiols to usual pentopyranosyl fluorides. Dis-
tinct from the conventional methods to prepare glycosyl
fluorides usually involving a polar pathway,24 the present
transformations represent a few of the examples wherein
glycosyl fluorides were reached by using a radical reaction.25
To shed light on the reaction mechanism, a radical clock
experiment was set up. As shown in Scheme 4, exposure of allyl
of silver(I) with Selecfluor, enables the decarboxylation of acid
11, leading to the formation of the intermediate radical B
through decarboxylation of the acyloxy radical A. Direct
fluorination of carbon-centered radical B afforded the fluoride
12a (path a). On the other side, the kinetically favored
transannular 5-exo-trig addition of B to the CC double bond
located at the anomeric allyl group gives the primary radical C,
and then it undergoes fluorination and hydrogen abstraction to
eventually provide 12b and 12c (path b), respectively. The
prevalence of combined 12b (17%) and 12c (20%), compared
to 12a (15%), implies that 5-exo-trig cyclization reaction of the
intermediate B outcompetes the direct fluorination. Since D-
ido-configured building blocks are attractive but challenging
synthetic targets,27 access to 12a, albeit in the low yield,
suggests the potential of decarboxylative fluorination in
synthesis of this unique sugar. In addition, oxa-[3,2,1]-bridged
cycloheptane skeleton is present in various natural products;28
therefore, decarboxylative fluorination of uronic acids offers a
carbohydrate-based approach to such architectures with novel
structure and potential bioactivities.
In summary, a mild and operationally simple approach to
RGFs has been developed, capitalizing on silver-promoted
radical decarboxylative fluorination of structurally diverse
uronic acids. The reaction is superior to dehydroxymethylative
fluorination reported by us, with respect to substrate scope and
functional group compatibility as exemplified by the successful
transformation of sugars bearing benzyl groups and/or hexp-(1
→ 4)-hexp moiety. The reaction also opens up a radical way to
D-/L-glycosyl fluorides with uncommon configuration from
easily accessible D-C-glycosides following a C1-to-C5 inter-
change strategy. The applications of the present method in the
synthesis of structurally unique glycosyl fluorides and their
incorporations in the related oligosaccharides are underway in
our laboratory.
Scheme 4. Proposed Mechanism for Decarboxylative
Fluorination of Uronic Acids
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03514.
Experimental procedures, characterization data for all
new compounds, results of optimization and glycosyla-
tion, and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ming Li − Key Laboratory of Marine Medicine, Chinese
Ministry of Education, School of Medicine and Pharmacy and
Shandong Provincial Key Laboratory of Glycoscience and
Glycotechnology, School of Medicine and Pharmacy, Ocean
University of China, Qingdao 266003, China; Laboratory for
Marine Drugs and Bioproducts, Pilot National Laboratory
for Marine Science and Technology, Qingdao 266237,
China; orcid.org/0000-0003-2719-5429;
Email: lmsnouc@ouc.edu.cn
α-D-C-glucopyranuronic acid 11 to decarboxylative fluorina-
tion stereoselectively produced 15% of D-ido-configured
glycosyl fluoride 12a, along with the fluorinated oxa-[3,2,1]-
bridged cycloheptane 12b and its reduced analogue 12c, in
respective yields of 17% and 20%. Combining these
observations and literature precedents,13,26 a radical mecha-
nism was proposed. Silver(II) species, generated by oxidation
Authors
Pengwei Chen − Key Laboratory of Marine Medicine, Chinese
Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Qingdao 266003, China; Hainan
Key Laboratory for Research and Development of Natural
Products from Li Folk Medicine, Institute of Tropical
D
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Letter
2001, 66, 2624−2635. (c) Lee, S.; Uttamapinant, C.; Verdine, G. L. A
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Reverse Glycosyl Fluorides. Angew. Chem., Int. Ed. 2020, 59, 4138−
4144.
Bioscience and Biotechnology, Chinese Academy of Tropical
Agricultural Sciences, Haikou 571101, China
Peng Wang − Key Laboratory of Marine Medicine, Chinese
Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Qingdao 266003, China
Qing Long − Key Laboratory of Marine Medicine, Chinese
Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Qingdao 266003, China
Han Ding − Key Laboratory of Marine Medicine, Chinese
Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Qingdao 266003, China
Guoqiang Cheng − Key Laboratory of Marine Medicine,
Chinese Ministry of Education, School of Medicine and
Pharmacy, Ocean University of China, Qingdao 266003,
China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03514
Notes
The authors declare no competing financial interest.
̈
(8) Schwarz, J.; Konig, B. Decarboxylative Reactions with and
ACKNOWLEDGMENTS
without Light−a Comparison. Green Chem. 2018, 20, 323−361.
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Inoue, M. Direct Assembly of Multiply Oxygenated Carbon Chains by
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Z.; Wang, W.; Zhang, Y. Highly Stereoselective Synthesis of Aryl/
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■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21672194 and 21977088),
the National Natural Science Foundation of China-Shandong
Joint Fund (Nos. U1906213 and U1606403), the Shandong
Provincial National Natural Science Foundation (No.
ZR2018MB015), and the Central Public-interest Scientific
Institution Basal Research Fund for Chinese Academy of
Tropical Agricultural Sciences (No. 1630052019026).
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