Radical Dehydroxymethylative Fluorination of Carbohydrates and Divergent Transformations of the Resulting Reverse Glycosyl Fluorides

Article abstract of DOI:10.1002/anie.201914557

A mild and convenient method for the synthesis of reverse glycosyl fluorides (RGFs) has been developed that is based on the silver-promoted radical dehydroxymethylative fluorination of carbohydrates. A salient feature of the reaction is that furanoid and pyranoid carbohydrates furnish structurally diverse RGFs bearing a wide variety of functional groups in good to excellent yields. Intramolecular hydrogen atom transfer experiments revealed that the reaction involves an underexploited radical fluorination that proceeds via β-fragmentation of sugar-derived primary alkoxyl radicals. Structurally divergent RGFs were obtained by catalytic C?F bond activation, and our method thus offers a concise and efficient strategy for the synthesis of reverse glycosides by late-stage diversification of RGFs. The potential of this method is showcased by the preparation and diversification of sotagliflozin, leading to the discovery of a promising SGLT2 inhibitor candidate.

Full text of DOI:10.1002/anie.201914557

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Radical Dehydroxymethylative Fluorination of Carbohydrates and
Divergent Transformations thereof
Authors: Xin Zhou, Han Ding, Pengwei Chen, Li Liu, Qikai Sun,
Xianyang Wang, Peng Wang, Zhihua Lv, and Ming Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914557
Angew. Chem. 10.1002/ange.201914557
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10.1002/anie.201914557
Angewandte Chemie International Edition
RESEARCH ARTICLE
Radical Dehydroxymethylative Fluorination of Carbohydrates and
Divergent Transformations thereof
Xin Zhou+, Han Ding+, Pengwei Chen+, Li Liu+, Qikai Sun, Xianyang Wang, Peng Wang, Zhihua Lv,
Ming Li*
Abstract: A mild and convenient protocol for synthesis of reversed
glycosyl fluorides (RGFs) has been developed relying on silver-
promoted radical dehydroxymethylative fluorination of carbohydrates.
The salient feature of the reaction is that furanoid and pyranoid
carbohydrates furnish structurally diverse RGFs bearing a wide
variety of functional groups in good-to-excellent yields.
Intramolecular hydrogen atom transfer experiments reveal that the
reaction mechanistically involves an underexploited radical
fluorination via -fragmentation of sugar-derived primary alkoxyl
radicals. Structural divergence of RGFs is achieved by catalytic
activation of C-F bonds, offering a concise and efficient strategy for
synthesis of reversed glycosides via late-stage diversification of
RGFs. The potential of this method is showcased by the preparation
and diversification of sotagliflozin, leading to the discovery of a
promising candidate of SGLT2 inhibitors.
Introduction
Structurally unique reversed glycosides, a class of saccharides
Figure 1. Representative Reversed Glycosides.
having skeletons of furanos-4-yl or pyranos-5-yl heteroatomic
groups like N-, O-, F-, S-, or P-substituents, are frequently found
in bioactive natural products, biological probes, and drug
candidates. The representative examples of such substances
are depicted in Figure 1 including the first fluorinated natural
nucleoside nucleocidin displaying antibacterial, trypanocidal and
antiviral activities,[1] pyranos-5-yl fluorides acting as useful
probes of carbohydrate-processing enzymes to investigate the
action mode of epimerases and dehydrases,[2] dragocin A with
cytotoxicity,[3] and sotagliflozin[4] emerging as a potential dual
inhibitor of sodium glucose co-transporter proteins 1 and 2
(SGLT1 and 2) for treatment of diabetes and so on.[5]
The uncommon structures and characteristic biological
activities of reversed glycosides have inspired the development
of numerous methods for their preparation. Current synthetic
approaches can be grouped into three major classes (Scheme 1
A-C). The first involves functionalizations of polar intermediates
such as iodofluorination of furanosyl-4-exo-olefins,[6] nucleophilic
ring opening of 5,6-epoxides of pyranosyl-5-exo-olefins,[2,7] and
enolate capture by electrophiles.[8] The second class capitalizes
on derivations of furanos-4-yl and pyranos-5-yl radicals[9] as
exemplified by oxidative radical decarboxylation of uronic acids
promoted by Pb(OAc)4,[10] (diacetoxyiodo)benzene (DIB)/I2,[11]
and
iridium-based
photoredox
catalysis,[12]
radical
dehydroxymethylation of furanoses mediated by DIB/I2,[13] and
1,5-hydrogen atom transfer (HAT) of imine radical of 6-O-
trichloroacetimides.[14] Ferrier’s photobromination and ensuing
displacement is the third widely used protocol for synthesis of
reversed glycosides.[15] Despite being reliable, these methods
suffer from tedious synthesis of sensitive alkenes from sugar
alcohols, harsh conditions, and/or narrow substrate scope.[6-8, 10-
13]
Taken together, these features contribute to the perception
that designing a mild, robust, and general protocol that enables
ready access to reversed glycosides is deemed necessary.
As part of our interest in making novel functionalized
molecules taking advantage of furanos-4-yl and pyranos-5-yl
radicals,[16] we herein wish to explore dehydroxymethylative
fluorination of carbohydrate-based alcohols via -fragmentation
of primary alkoxyl radicals, thus enabling concise synthesis of
various reversed glycosyl fluorides (RGFs) and structural
divergence thereof by catalytic activation of C-F bonds to
contribute to the growing arsenal of diverse synthesis of
functionalized sugars without opening the sugar rings (Scheme
1).[17] To reduce the idea to practice, several challenges have to
be overcome. Of various scenarios of generating alkoxyl radicals
which act as versatile intermediates applicable to a plethora of
organic transformations,[18] direct generation from alcohols is an
attractive approach since there is no necessity to convert
[*]
X. Zhou+, H. Ding+, P. Chen+, L. Liu+, Q. Sun, X. Wang, P. Wang, Z.
Lv, Prof. Dr. M. Li
School of Medicine and Pharmacy, Key Laboratory of Marine
Medicine, Chinese Ministry of Education, Ocean University of China,
5 Yushan Road, Qingdao, 266003 (P. R. China)
E-mail: lmsnouc@ouc.edu.cn
Prof. Dr. Z. Lv, Prof. Dr. M. Li
Laboratory for Marine Drugs and Bioproducts of Qingdao National
Laboratory for Marine Science and Technology Qingdao, 266237 (P.
R. China)
Dr. P. Chen
Hainan Key Laboratory for Research and Development of Natural
Products from Li Folk Medicine, Institute of Tropical Bioscience and
Biotechnology, Chinese Academy of Tropical Agricultural Sciences,
Haikou 571101 (P. R. China)
These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:.((Please delete this
text if not appropriate))
[+]
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10.1002/anie.201914557
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 1. Strategies for Synthesizing Reversed Glycosides.
hydroxyl group to O-functionalized compounds having a weak
oxygen-heteroatom bond such as N-alkoxyphthalimides.[18] On
the other side, it is challenging due to the high bond dissociation
energy of O-H bond (105 kcal mol-1).[19] Furthermore, compared
with tertiary and strained cyclic alkoxyl radicals readily
undergoing β-scission to construct various chemical bonds,[20]
primary alkoxyl radicals has relatively small tendency to undergo
β-fragmentation through homolytic cleavage of C-C bonds over
commonly encountered intramolecular HAT.[21] It has been
observed that pyranose-based primary alkoxyl radicals are
susceptible to 1,n-HAT (n = 5, 6, even 8) instead of homolytic β-
cleavage owing to the presence of multiple - or - hydrogen
atoms and restricted conformations of inherently complex and
highly functionalized carbohydrates.[22] These results indicate
that it is demanding to achieve excellently selective β-scission of
primary alkoxyl radicals for extending this strategy to
carbohydrates.
straightforward approach to RGFs of interest compared with
decarboxylative fluorination[12] since it avoids oxidation of
alcohols to acids.
With the optimized conditions established, substrate scope of
the reaction was examined (Table 1). Exposure of
monosaccharide alcohols 1b−k derived from glucose,
glucosamine, galactose and ribose in pyranoid or furanoid form
to dehydroxymethylative fluorination conditions smoothly
furnished the desired RGFs 2b−k in 58˗94% yields. These
transformations demonstrate that the reaction is distinguished by
broad substrate scope and good accommodation of protecting
groups and anomeric substituents including acetyl (Ac), benzoyl
(Bz), azido, fluoro, alkoxyl, phthalimido (phthN) groups, and
isopropylidene, attesting the mildness of the reaction conditions.
Remarkably, 2a could be prepared at gram-scale (1.15 g) in
90% yield and 2j at subgram-scale (730 mg) in 62% yield,
strongly demonstrating the feasibility of scale-up. The present
methodology also allows for conversion of branched sugars into
the corresponding RGFs having a tertiary C-F bond, a class of
important structural motifs in biological and medicinal science.[1,2]
Thus, branched lyxofuranoside, arabinofuranoside, and
idopyranoside alcohols 1l−1q worked well to produce fluorides
2l−2q. Of note, ready access to 2o demonstrates that uracil
heterocycle is tolerated toward the present reaction, opening up
an alternative approach to C-4' fluorinated nucleosides by a
post-glycosylational functionalization strategy.[17]
Next, we focused on fluorination of more complex and
challenging oligosaccharides. Successful access to RGFs 2r−2z
showed that trehalose, di- and trisaccharides 1r−1y, even β-
cyclodextrin (β-CD) 1z connected by α,α-1,1'-, β-1,6-, β-1,3-,
and/or α-1,4-linkages were competent substrates. Notably,
fluorinated trehalose derivative 2r was obtained in 79% yield
with 5R configuration as the exclusive product. 2r might be an
intriguing structure since modified trehaloses have proven to be
attractive synthetic targets due to their potential in investigating
trehalose metabolism in mycobacterium tuberculosis.[26] β-CD-
derived primary alkoxyl radicals have been observed to
exclusively undergo 1,8-HAT with DIB/I2 as the oxidant in
structural modifications of β-CDs.[22a,d,e] However, in our hands,
such reactive species were able to engender fluoride 2z in 62%
Results and Discussion
Substrate Scope. It has been well recognized that Ag(II)-
species are able to oxidize alcohols to the corresponding alkoxyl
radicals[23] and their β-fragmentation is strongly accelerated by
hydrogen-bond donating solvents.[24] As a consequence, we
focused on silver-mediated dehydroxymethylative fluorination of
carbohydrates in aqueous media. Mindful of the fact that radical
deoxymethylation
underexploited,[25]
of
we
pyranoid
commenced
primary
our
alcohols
studies
is
with
glucopyranoside alcohol 1a as the model substrate to optimize
the reaction conditions (See the Supporting Information (SI),
Table S1). After scrupulous evaluation of various reaction
parameters including the type and amounts of silver salt,
Selectfluor, and solvent, it was found that the reaction
proceeded smoothly in the presence of Ag2CO3 (0.5 equiv) and
Selectfluor (5-10 equiv) as the oxidant and fluorine source in
acetone/H2O (v/v 4:1) and provided fluorosugar 2a in the best
yield of 86% with a 5R/5S 1.7:1 ratio at room temperature in 3 h
(Table 1). As far as we know, this transformation is a hitherto
unknown fluorination reaction and presents
a
more
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10.1002/anie.201914557
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1. Substrate Scope of Dehydroxymethylative Fluorination.a,b,c
aUnless otherwise noted, the reaction was conducted with alcohol (0.1 mmol), Ag2CO3 (0.5 equiv), and Selectfluor (5.0 equiv). bThe products with the wedge C-F
bond viewed in the plane of the paper is denoted as 4/5R-isomers and those with the dash C-F bond as 4/5S-isomers. cdr based on the 1H NMR spectroscopic
ratio of 4/5R- to 4/5S-isomer. d10.0 equiv of Selectfluor. e1n having 5R configuration as the reactant. f40 oC of the reaction temperature. g15.0 equiv of Selectfluor.
yield by exclusive β-scission of primary alkoxyl radicals.
Fluorosugar 2z is the first example of one-carbon less
fluorinated β-CD derivative, offering opportunities for further
structural elaborations. It should be noted that methyl 2, 3, 4-tri-
O-benzyl-α-D-glucoside failed to give the desired product since
the methylene moiety of benzyl ethers is vulnerable to intra-
and/or intermolecular HAT mediated by alkoxyl radicals. The
conformation of the obtained RGFs in solution could be inferred
based on the coupling constants of vicinal protons on the sugar
ring and X-ray crystallographic analysis of 2i (see the SI).
Mechanistic Studies. To get insig into the reaction
mechanism, galactopyranoside alcoholht 3 was subjected to
dehydroxymethylative fluorination (Scheme 2). The reaction
performed well to stereoselectively deliver the mono- and
difluorosugars 4 and 4' at a ratio of 2.5:1 in overall 80% isolated
yield under the standard conditions (Method A). In addition, the
reaction was executed stepwise, i. e. stirring Ag2CO3 and
Selectfluor in acetone/H2O prior to addition of alcohol 3. Doing
so, we observed that the original suspension with the same
bright green color as Ag2CO3 turned to a homogenous and white
solution after stirring for 30 min at room temperature, implying
the formation of Ag(II) species.[27] Subsequent addition of 3 to
the mixture produced 4 and 4' in 68% and 13% yield,
respectively, in 30 min (Method B, for the details, see SI).
Combining these results and previous reports,[27] a plausible
mechanism is suggested as shown in Scheme 2. Initially, Ag(II)
species oxidizes primary hydroxyl group of 3 to give alkoxyl
radical A with loss of proton alongside regeneration of Ag(I)
species.[27] Alkoxyl radical A may react in two different ways,
namely, direct β-fragmentation (path a) and intramolecular 1,6-
hydrogen abstract (path b)[28] with the 4-OMe via a seven-
membered cyclic transition state. These two routes lead to
respective secondary and primary α-oxy C-radicals B and C.
Subsequent fluorine abstraction from Selectfluor by active
intermediate B forges fluorosugar 4, whereas the radical C is
converted into fluorinated alcohol D, which follows the same
reaction sequence as that of the transformation of 3 to 4, giving
difluorosugar 4' through the intermediates E and F. The
formation of 4 as the major product indicates that β-scission of
primary alkoxyl radical A is more energetically favorable than the
competing intramolecular 1,6-HAT under the present reaction
conditions. We assume that the driving force for this
transformation is associated with the accelerated release of
formaldehyde by solvation in aqueous acetone.[24] No other
multifluorinated product except 4' were observed, implying that
alkoxyl radical E, unlike A, does not participate in 1,6-HAT at
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10.1002/anie.201914557
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RESEARCH ARTICLE
glycosylating and alkylating agents to construct various C-C and
C-heteroatomic bonds through C-F bond activation,[32] we
assumed that RGFs would be powerful synthons for structurally
diverse furanos-4-yl and pyranos-5-yl substituted compounds by
activating C-F bond. We therefore screened several fluorophilic
reagents such as SnCl4, SnCl2/AgClO4, TMSOTf, and Tf2O (See
SI, Table S2), and found that 0.2 equiv of BF3∙Et2O was the
optimal catalyst of choice. Thus, armed RGF 6, prepared from
disarmed 2b, reacted with allyltrimethylsilane to provide L-ido
configured higher-carbon pyranoside 8a as an α:β 1/2.8
anomeric mixture. These results imply that epimerization of the
original glycosidic bond took place during the reaction. With silyl
enol ether 7b and 7c as the nucleophiles, 8b and 8c were
uneventfully obtained as mixtures of 5R-isomer with α-D-gluco
configuration and 5S-isomer assuming β-L-ido configuration at
the 1/2.2 and 1.8/1 ratios, respectively, without epimerization at
the anomeric position. Significant efforts have been devoted to
the synthesis of L-iduronic acids (L-idoAs) and derivatives
thereof since conformationally flexible L-idoA is
a
key
monosaccharide component of glycosaminoglycans (GAGs) of
biological relevance such as the well-known heparin, heparin
sulfate, and dermatan.[33] The facile preparation of 8a-c offers
prospects for synthesis of novel idoA analogues due to the rich
chemical reactivity of C-C double bond and carbonyl group, thus
facilitating the synthesis of diverse GAGs. Friedel-Crafts reaction
of 6 with furan 7 provided reversed aryl C-glycoside 8d in 70%
yield as a mixture of stereoisomer. Heteroatomic nucleophiles
were also viable coupling partners, yielding novel reversed
glycosides with the stereoselectivity depending on the nature of
nucleophiles. Thiolysis of 6 with octanethiol 7e provided 80% of
8e with the C-5 axially substituted isomer as the major product
while alcoholysis with sugar 1b showed reverse stereoselectivity,
furnishing 8f in 86% yield favoring the isomer with the C-5
Scheme 2. Proposed Mechanism for Dehydroxymethylative Fluorination.
OCH2F group due to the presence of electron-withdrawing
fluorine atom.[29] The stereoselective formation of 4 and 4' was
4
attributed to C1 conformation adopted by the intermediates B
and F,[30] where the axially-oriented C-4 methoxyl group
stabilizes vicinal C-radical through pseudo-homo-anomeric
effect,[31] thus leading to attack of Selectfluor to the α face of
such radicals. Combined these results with the literature,[9] the
plausible intermediate radicals were proposed to explain the
diastereoselectivity of RGF formation.
Structural Divergence of RGFs. Taking our cue from a
variety of glycosyl fluorides and alkyl fluorides serving as
Table 2. Structural Divergence of RGFs through C-F Bond Activation.a,b
aThe ratio based on the isolated yield. bdr based on the ratio of 5R- to 5S-isomer.
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10.1002/anie.201914557
Angewandte Chemie International Edition
RESEARCH ARTICLE
coupled with those of dapagliflozin and sotagliflozin demonstrate
that the equatorial substituent at C-5 position of pyranosyl unit is
crucial to SGLT2 inhibiting activities of sotagliflozin and other
similar molecules. Owing to the versatility of glycosyl azides,[36]
16 might be an attractive platform for discovering novel SGLT2
inhibitors.
Conclusion
In summary, an expedient protocol for RGFs synthesis has been
established
through
silver-promoted
radical
dehydroxymethylative fluorination of carbohydrate alcohols in
aqueous acetone. This reaction is distinguished by versatility
and excellent chemoselectivity profile, thus enabling access to
diverse RGFs from a wide range of mono- and oligosaccharides
under mild conditions. Mechanistic studies reveal that β-scission
of primary alkoxyl radicals and ensuing fluorination of α-oxy C-
radicals are involved. Divergent structural modifications of RGFs
to afford valuable furanos-4-yl and pyranos-5-yl substituted
carbohydrates have been achieved by reacting with C-, O-, S-,
and P-nucleophiles through catalytic activation of C-F bonds.
The application of present method in medicine discovery has
been highlightened by discovery of a potential candidate of
SGLT2 inhibitors based on synthesis of sotagliflozin and
analogues. We anticipate that our strategy composed of radical
dehydroxymethylative fluorination and ensuing C-F bond
activation should be useful in synthesizing higher-carbon or
exotic carbohydrates and other complex tetrahydrofuran and
tetrahydropyran fragments in natural products.
Scheme 3. Synthesis and Diversification of Sotagliflozin.
equatorially oriented substituent. Notably, coupling with triphenyl
phosphite 7g produced 8g with exclusive formation of
equatorially oriented C-P bonds. BF3∙Et2O also enabled C-F
bond activation of 2b bearing electron-withdrawing benzoates as
substituents, thus the reaction with cylcohexanol 7h furnished
8h as a mixture of C-5 stereoisomers in almost identical yields
(41% vs 40%) despite the potential presence of anchimerically
assistant C-4 benzoate. Taken together, these studies indicate
that RGFs are potential precursors for obtaining structurally
unique furanos-4-yl and pyranos-5-yl substituted sugars,
providing a straightforward protocol for divergent synthesis of
functionalized sugars.
Synthesis and Diversification of Sotagliflozin. To further
showcase the versatility of our methodology, we undertook
synthesis of sotagliflozin which is a promising candidate for
treatment of diabetes.[4] There is however a merely single de
novo synthesis available.[34] Structurally, sotagliflozin could be
Acknowledgements
We are grateful for financial support from the National Science
Funding of China (21672194 and 21272220), the NSFC-
Shandong Joint Fund (U1606403), the Shandong Provincial
National Natural Science Foundation (ZR2018MB015), and the
National Science and Technology Major Project for Significant
New Drugs Development (2018ZX09735004).
recognized as
a
congener of the approved medicine
dapagliflozin[35] with replaced hydroxymethyl by methylthio group.
These properties suggest that preparation of sotagliflozin and
analogues from dapagliflozin would be a stringent assessment
of our developed method. Exposure of 9, prepared from
dapagliflozin acetate[35] in two steps, to dehydroxymethylative
fluorination afforded a chromatographically separable mixture of
10 at the ratio of 5R/5S 1:6 in 78% yield. The combination of
NaBH4 and CF3COOH enabled deoxygenation of ketone, giving
11 in 70% yield leaving C-F bond untouched. Under the
promotion of BF3∙Et2O, fluoride 11 was treated with methylthiotri-
n-butylstannane (MeSSnBu3) and trimethylsilyl azide (TMSN3) to
give rise to sotagliflozin acetate 12 and azide analogue 13 in 87%
and 73% yield, respectively. The neighboring group assistance
of the acetate is responsible for the formation of 1,2-trans
glycosidic linkage in 12 and 13. Removing acetyl protecting
groups in 11−13 with NH3 in MeOH smoothly afforded
sotagliflozin 15 and analogues 14 as well as 16 in excellent
yields. Preliminary assessments showed that 16 equipped with
the equatorially oriented azide exhibited 61% inhibition rate
against SGLT2 at 10 nM while 16 having the axial fluorine
possessed much less potency (See SI, Table S3). These results
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkoxyl radicals • dehydroxymethylative fluorination •
β-scission • reversed glycosyl fluorides • C-F bond activation
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This article is protected by copyright. All rights reserved.

10.1002/anie.201914557
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
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X. Zhou , H. Ding , P. Chen , L. Liu ,
Q. Sun, X. Wang, P. Wang, Z. Lv, M. Li*
Page No. – Page No.
Radical Dehydroxymethylative
Fluorination of Carbohydrates and
Divergent Transformations thereof
Sweet Fluorination: Radical dehydroxymethylative fluorination of carbohydrate
alcohols has been achieved with versatility and excellent chemoselectivity profile,
affording a wide arrange of reversed glycosyl fluorides (RGFs) in good to excellent
yields. Structural divergence of RGFs with various nucleophiles by catalytic C-F
bond activation provides unique sugar architectures difficult to obtain otherwise,
demonstrating the potential of this method in the late-stage diversification of sugars.
This article is protected by copyright. All rights reserved.