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\begin{document}

\title{Synthesis of L-Hexopyranosyl Fluorides Enabled by Radical
Decarboxylative Fluorination: Assembly of a Pentasaccharide Repeating
Unit Corresponding to Extracellular Polysaccharide S-88}



\author[1]{Zhi Qiao}%
\author[1]{Dongwei Li}%
\author[1]{Jingru Gao}%
\author[1]{Zijiao Hou}%
\author[1]{Ningjie Yan}%
\author[1]{Ni Song}%
\author[1]{Peng Wang}%
\author[1]{Ming Li}%
\affil[1]{Ocean University of China}%


\vspace{-1em}



  
  \date{May 28, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
L-Hexoses are key components of many biologically relevant natural
products and pharmaceuticals. As rare sugars, L-hexoses are not readily
obtained from natural sources. Access to L-hexose building blocks from
commercially available and inexpensive D-sugars is highly desirable from
the viewpoints of organic synthesis and drug discovery. As demonstrated
by the convenient preparation of L-glucosyl, L-galactosyl, and
L-mannosyl fluorides from readily available \selectlanguage{greek}β-\selectlanguage{english}D-C-glucosyl,
\selectlanguage{greek}β-\selectlanguage{english}D-C-mannosyl, and \selectlanguage{greek}β-\selectlanguage{english}D-C-galactosyl derivatives, we describe a novel
and efficient approach to the demanding L-glycosyl fluorides. The
transformation features the installation of anomeric hydroxymethyl group
under mild conditions and head-to-tail inversion of sugar rings through
radical decarboxylative fluorination of uronic acids. The power of this
protocol is highlighted by the first assembly of a pentasaccharide
repeating unit of Pseudomonas ATCC 31554 extracellular polysaccharide
(S-88). This synthesis relies on the efficient extension of sugar chain
at the sterically hindered hydroxy group and the facile introduction of
L-mannosyl unit using L-mannosyl fluoride as glycosylating agent. The
methods developed in this work would provide new tools to the arsenal of
synthesis of L-sugar building blocks and of assembly of glycans
containing L-sugar moieties.%
\end{abstract}%



\sloppy


\textbf{Cite this paper:}\emph{Chin. J. Chem.} \textbf{2023} , \emph{41}
, XXX---XXX. \textbf{DOI: 10.1002/cjoc.202300XXX}

Synthesis of L-Hexopyranosyl Fluorides Enabled by Radical
Decarboxylative Fluorination: Assembly of a Pentasaccharide Repeating
Unit Corresponding to Extracellular Polysaccharide S-88

Zhi Qiao\textsuperscript{++,\emph{a}} , Dongwei
Li\textsuperscript{++,\emph{a}} , Jingru Gao\emph{\textsuperscript{a}} ,
Zijiao Hou\emph{\textsuperscript{a}} , Ningjie
Yan\emph{\textsuperscript{a}} , Ni Song\emph{\textsuperscript{a}} , Peng
Wang*\textsuperscript{,\emph{a}} , and Ming
Li*\textsuperscript{,\emph{a,b}}

\textsuperscript{a} Molecular Synthesis Center, Key Laboratory of Marine
Medicine, Chinese Ministry of Education, Shandong Provincial Key
Laboratory of Glycoscience and Glycotechnology, School of Medicine and
Pharmacy, Ocean University of China, Qingdao 266003,
China\textsuperscript{b} Laboratory for Marine Drugs and Bioproducts,
Pilot National Laboratory for Marine Science and Technology, Qingdao
266237, China\textsuperscript{}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Keywords}\tabularnewline
\midrule
\endhead
L-Glycosyl fluorides \textbar{} Extracellular Polysaccharide S-88
\textbar{} Radical decarboxylation \textbar{} Oligosaccharide synthesis
\textbar{} Uronic acids\tabularnewline
\textbf{Comprehensive Summary}\tabularnewline
L-Hexoses are key components of many biologically relevant natural
products and pharmaceuticals. As rare sugars, L-hexoses are not readily
obtained from natural sources. Access to L-hexose building blocks from
commercially available and inexpensive D-sugars is highly desirable from
the viewpoints of organic synthesis and drug discovery. As demonstrated
by the convenient preparation of L-glucosyl, L-galactosyl, and
L-mannosyl fluorides from readily available \selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}-glucosyl,
\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}-mannosyl, and \selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}-galactosyl derivatives, we
describe a novel and efficient approach to the demanding L-glycosyl
fluorides. The transformation features the installation of anomeric
hydroxymethyl group under mild conditions and head-to-tail inversion of
sugar rings through radical decarboxylative fluorination of uronic
acids. The power of this protocol is highlighted by the first assembly
of a pentasaccharide repeating unit of \emph{Pseudomonas} ATCC 31554
extracellular polysaccharide (S-88). This synthesis relies on the
efficient extension of sugar chain at the sterically hindered hydroxy
group and the facile introduction of L-mannosyl unit using L-mannosyl
fluoride as glycosylating agent. The methods developed in this work
would provide new tools to the arsenal of synthesis of L-sugar building
blocks and of assembly of glycans containing L-sugar
moieties.\tabularnewline
\bottomrule
\end{longtable}

Background and Originality Content

L-Hexoses are essential components of glycans and glycoconjugates of
biological relevance.\textsuperscript{{[}1{]}} They are also valuable
building blocks of certain therapeutic applications. For instance,
L-glucose tracers that emit fluorescence show potential in identifying
and characterizing cancerous cells among such cell
aggregates;\textsuperscript{{[}2{]}} Additionally, a recent study has
proposed 3,6-anhydro-L-galactose (AHG) as a novel anticariogenic agent
due to its higher inhibitory activity against \emph{Streptococcus
mutans} than commonly used xylitol.\textsuperscript{{[}3{]}}Furthermore,
agarobiose and agarooligosaccharides-containing AHG have also
demonstrated anticariogenic activity.\textsuperscript{{[}4{]}} It is
worth noting that L-hexoses are considered rare sugars, which are not
able to be obtained from natural sources on a scale. As a result, to
meet the demand for L-sugars, numerous strategies have been designed and
developed to substantially access to such
architectures.\textsuperscript{{[}5{]}} They include C-5 configuration
inversion of readily available
D-sugars,\textsuperscript{{[}6{]}}site-selective epimerization of
L-sugars,\textsuperscript{{[}7{]}}one-carbon homologation of
pentoses,\textsuperscript{{[}8{]}}head-to-tail
inversion,\textsuperscript{{[}9{]}} \emph{de
novo}synthesis,\textsuperscript{{[}10{]}} and C-H functionalization of
6-deoxy-L-hexoses.\textsuperscript{{[}12{]}} According to ''sugar
mapping'',\textsuperscript{{[}13{]}} L-glucose, L-galactose, and
L-mannose are good precursors to the other L-sugars. We thereby
envisaged that ready preparation of L-glucose, L-galactose, and
L-mannose would be an ideal route to access L-sugars by use of
biomass-derived and inexpensive D-sugars (D-glucose, D-mannose, and
D-galactose) and L-sugars (L-rhamnose and L-fucose). In this context, Li
and co-workers have described a methodology for the conversion of
D-glucosyl acetate into orthogonally protected L-glucosyl acetate
following a head-to-tail inversion.\textsuperscript{{[}9{]}} The
transformation features one-carbon extension of sugar chain at the
anomeric position through
Co\textsubscript{2}(CO)\textsubscript{8}-catalyzed silyloxymethylation
and head-to-tail inversion by use of Pb(OAc)\textsubscript{4}-mediated
decarboxylative acetoxylation. The prepared L-glucosyl acetate was
converted into L-galactosyl or L-mannosyl acetate by epimerizing the C4-
or the C2-OH. Additionally, the same strategy was applied by Li and
colleagues (Scheme 1a) to synthesize L-glucose and L-mannose derivatives
starting from 1-methyl-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C} -glucosyl)ethanone and
1-methyl-2-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C} -galactosyl)ethanone
constructs.\textsuperscript{{[}9{]}} Due to the limited reactivity
exhibited by glycosyl acetates, it is inevitable to covert L-glycosyl
acetates into more reactive glycosyl donors, such as glycosyl imidates,
thioglycosides, and glycosyl fluorides. A significant breakthrough was
achieved by the Pedersen group (Scheme 1b) utilizing the methodology
developed by Hartwig and co-workers to prepare 1,3-diol through
iridium-catalyzed C-H activation directed by a hydroxy
group.\textsuperscript{{[}11{]}} They successfully accomplished the
transformation of L-rhamnose and L-fucose into L-mannose and
L-galactose, respectively.\textsuperscript{{[}12{]}} Furthermore, the
same group extended this strategy to achieve synthesis of all eight
L-hexopyranosyl thioglycoside donors from their corresponding
6-deoxy-L-hexopyranosyl
thioglycosides.\textsuperscript{{[}7{]}}Recently, we have successfully
recorded a head-to-tail switch strategy that enables the convenient
synthesis of uncommon 6-deoxy-D-/L-heptopyranosyl fluorides. In this
method, allyl \selectlanguage{greek}α-\selectlanguage{english}D-\emph{C} -glycosides are employed as the starting
materials. This approach is noteworthy as it represents one of the
limited options available for generating L-sugar settings, which can be
directly utilized as glycosyl donors (Scheme
1c).\textsuperscript{{[}14-17{]}}The remarkable characteristics of the
transformation encompass two-carbon elongation of a sugar chain at the
anomeric position, along with shortening of a one-carbon segment through
either radical decarboxylative fluorination\textsuperscript{{[}14{]}} of
uronic acids or radical dehydroxymethylative
fluorination\textsuperscript{{[}15{]}}of sugar primary alcohols. We
employed these methodologies for the assembly of \emph{Camplybater
jejuni} strain CG8486\textsuperscript{{[}16{]}} and
BH0142\textsuperscript{{[}17{]}}capsular hexasaccharides composed of
-3)-\selectlanguage{greek}β-\selectlanguage{english}D-6d\emph{ido} Hep\emph{p} -(1-4)-\selectlanguage{greek}β-\selectlanguage{english}D-Glc\emph{p} NAc-(1- and
-3)-\selectlanguage{greek}α-\selectlanguage{english}D-6d\emph{ido} Hep\emph{p} -(1-4)-\selectlanguage{greek}α-\selectlanguage{english}D-Gal\emph{p} -(1-
disaccharide repeating units. These oligosaccharides have the potential
to serve as antigens against \emph{C. jejuni} infections.

Drawing inspiration from the aforementioned advancements and
acknowledging the biological relevance of glycans containing L-sugar
units, this study presents the synthesis of L-glucosyl, L-galactosyl,
and L-mannosyl fluorides utilizing a head-to-tail switch strategy
(Scheme 1d). Our hypothesis is that the desired L-glycosyl fluorides can
be obtained by means of radical decarboxylative fluorination of
hydroxymethyl \selectlanguage{greek}β-\selectlanguage{english}D-\emph{C} -uronic acid
derivatives.\textsuperscript{{[}14{]}} The introduction of anomeric
hydroxymethyl group can be achieved by reduction of the corresponding
aldehydes. These aldehydes can be prepared from 1-phenyl-2-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}
-glycosyl)ethanones, which can be easily derived from the condensation
of diphenyl 1,3-pentandione with cost-effective and readily available
D-glucose, D-galactose, and D-mannose.\textsuperscript{{[}18{]}}

\textbf{Scheme 1} Strategies for the synthesis of L-sugars

Results and Discussion

Synthesis of L-glucopyranosyl fluoride and L-galactosyl fluorides

In order to implement the concept, our study commenced with preparing
L-glucopyranosyl fluoride from the acetyl-protected
1-phenyl-2-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C} -glucosyl)ethanone\textbf{1a}
\textsuperscript{{[}18{]}} (Scheme 2). Initially, we attempted to
convert \textbf{1a} to olefin \textbf{2a} by means of the procedure
which was reported by the Prasad group.\textsuperscript{{[}19{]}}
However, \textbf{1a} was subjected to reduction with
NaBH\textsubscript{4} followed by
P\textsubscript{2}O\textsubscript{5}-mediated dehydration of the alcohol
in CH\textsubscript{2}Cl\textsubscript{2} at room temperature, resulting
in a 36\% yield of olefin \textbf{2a} . The unsatisfactory yield and the
difficulty in separating \textbf{2a} from a viscous and dark reaction
mixture prompted us to seek a more convenient approach to \textbf{2a} .
Fortunately, treatment of \textbf{1a} with NaBH\textsubscript{4}followed
by triflic anhydride in the presence of 2,6-lutidine at
-40\textsuperscript{o}C in
CH\textsubscript{2}Cl\textsubscript{2}\textsuperscript{{[}20{]}} yielded
the desired vinyl \emph{C} -glycoside \textbf{2a} in 75\% yield. The
dehydration reaction occurred through triflation of the hydroxy group
and simultaneous elimination of the reactive triflate. It should be
noted that the Liang group recently disclosed a novel approach
to\emph{C} -vinyl glycosides through a Heck-type coupling reaction of
glycosyl bromide with styrenes under visible light and palladium dual
catalysis, providing a new way to the constructs like\textbf{2a}
.\textsuperscript{{[}21{]}} With olefin \textbf{2a} in hand, we
successfully made benzyl (Bn)-protected \selectlanguage{greek}β-\selectlanguage{english}D-glucopyranosyl
methanol\textbf{3a} in 52\% overall yield through a four-step reaction
sequence composed of deacetylation, the benzylation of resultant
alcohol, the oxidative cleavage of C-C double bond, and the reduction of
liberated aldehyde. Conversion of \textbf{3a} into uronic acid
\textbf{5a} was achieved in 79\% yield through a four-step reaction
sequence consisting of the benzoyl protection of primary hydroxy group
in \textbf{3a}(leading to \textbf{4a} ), the chemoselective acetolysis
of the benzyl ether of primary hydroxy group, selective

\textbf{Scheme 2} Synthesis of L-glucopyranosyl fluoride and
L-galactopyranosyl fluoride

\textbf{Reagents and conditions:} (a) NaBH\textsubscript{4}, MeOH, ice
bath; (b) 2,6-lutidine, Tf\textsubscript{2}O,
CH\textsubscript{2}Cl\textsubscript{2}, 75\% for \textbf{2a} over two
steps, 82\% for \textbf{2b} over two steps; (c) 60\% NaH, MeOH; (d)
BnBr, 60\% NaH, DMF; (e) OsO\textsubscript{4}, 2,6-lutidine,
NaIO\textsubscript{4}, 1,4-dioxane/H\textsubscript{2}O; (f)
NaBH\textsubscript{4}, MeOH, 52\% for \textbf{3a} over four steps, 59\%
for \textbf{3b} over four steps; (g) BzCl, DMAP, pyridine; (h) TFA,
Ac\textsubscript{2}O; (i) AcCl, MeOH (j) TEMPO, BAIB,
CH\textsubscript{2}Cl\textsubscript{2}/H\textsubscript{2}O, 79\%
for\textbf{5a} over four steps, 64\% for \textbf{5b} over four steps;
(k) Selectfluor, KF\selectlanguage{ngerman}·2H\textsubscript{2}O,
Ag\textsubscript{2}CO\textsubscript{3}, acetone/H\textsubscript{2}O,
62\% for \textbf{6a} , 65\% for \textbf{6b} . BnBr = Benzyl bromide; DMF
=\emph{N} ,\emph{N} -dimethyl formamide; BzCl = Benzoyl chloride; DMAP =
4-\emph{N} ,\emph{N} -dimethylaminopyridine; TFA = Trifluoroacetic acid;
AcCl = Acetyl chloride; TEMPO = 2,2,6,6-Tetramethylpiperidinooxy; BAIB =
Iodobenzene diacetate.

deacetylation with methanolic hydrogen chloride, and the oxidation of
the obtained alcohol with TEMPO/BAIB. Uronic acid \textbf{5a} was
subjected to Ag\textsubscript{2}CO\textsubscript{3}-mediated radical
oxidatively decarboxylative fluorination\textsuperscript{{[}14{]}} to
afford 62\% of the expected L-glucosyl fluoride \textbf{6a} as an \selectlanguage{greek}α/β
\selectlanguage{english}1:1 mixture. Following the same procedure as above, the
olefin\textbf{2b} , derived from 1-phenyl-2-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}
-mannosyl)ethanone\textbf{1b} , was smoothly transformed into
L-galactosyl fluoride\textbf{6b} with \selectlanguage{greek}α/β \selectlanguage{english}2.4:1 stereoseletivity in 23\%
overall yield over nine steps.

\textbf{Assembly of a pentasaccharide repeating unit corresponding to
extracellular polysaccharide S-88}

Having achieved success in synthesizing L-glycosyl fluoride from the
corresponding D-sugars, our focus now shifts towards the application of
this method in the synthesis of intricate oligosaccharides obtained
from\emph{Pseudomonas} ATCC 31554 extracellular polysaccharide (S-88).
S-88 is a representative gellan which shows potential in food, chemical,
and pharmaceutical industries due to its functional
characteristics.\textsuperscript{{[}22{]}} Furthermore, recent
discoveries have revealed the probiotic potential of gellan
oligosaccharides derived from the hydrolysis of S-88, as they have the
capability to modulate gut flora in a manner that promotes human
health.\textsuperscript{{[}23{]}} S-88 is composed of a pentasaccharide
repeating unit made up of a backbone of -4)-\selectlanguage{greek}α-\selectlanguage{english}L-mannopyranosyl
(L-Man\emph{p} )-(1-3)-\selectlanguage{greek}β-\selectlanguage{english}D-glucopyranosyl (Glc\emph{p}
)-(1-4)-\selectlanguage{greek}β-\selectlanguage{english}D-glucuronic acid (Glc\emph{p} A)-(1-4)-\selectlanguage{greek}β-\selectlanguage{english}D-Glc\emph{p} -(1-
and a branch of \selectlanguage{greek}α-\selectlanguage{english}L-rhamnopyranosyl (Rha\emph{p} ) appended to C3-OH of
D-Glc\emph{p} at the reducing end.\textsuperscript{{[}24{]}} The
occurrence of L-Man\emph{p} moiety and of D-Glc\emph{p} A residue linked
to the sterically hindered C4-OH of D-Glc\emph{p} makes S-88 an
attractive, but synthetically challenging target. The pursuit of
comprehending the intricate structure and functionalities of S-88 has
driven our motivation to engage in chemical syntheses of S-88
oligosaccharides. Herein, we report the synthesis of a pentasaccharide
fragment (\textbf{7} ) corresponding to the repeating unit of
extracellular polysaccharide S-88. The synthesis features the successful
construction of challenging glycosidic linkage by which D-Glc\emph{p} A
is appended to D-Glc\emph{p} and the efficient installation of
L-mannosyl moiety with L-mannosyl fluoride as the glycosyl donor.
L-mannosyl fluoride was prepared from D-galactose \emph{via} a
head-to-tail inversion strategy.

Highly efficient incorporation of uronic acid residues is crucial for
assembly of oligosaccharides containing such units. Typically, two
strategies are employed to accomplish this
objective.\textsuperscript{{[}25{]}} The first approach involves the
postglycosylation oxidation strategy, wherein an oligosaccharide
backbone is constructed before converting a sugar into its uronic acid
form through oxidation. Despite additional protecting group
manipulations required, the advantages of this approach lie in the
higher reactivity of non-oxidized building blocks than the corresponding
carboxylate counterparts, deceased side reactions associated with
epimerization \selectlanguage{greek}α \selectlanguage{english}to carboxylate, and \selectlanguage{greek}β-\selectlanguage{english}elimination leading to the
formation of 4-deoxy-hex-4-enopyranuronic
acid.\textsuperscript{{[}26{]}} The second is preglycosylation oxidation
strategy, that is, directly using a uronic acid-based building block as
glycosylating donor and acceptor. Its strength is to prevent oxidation
event on a complex setting. However, the presence of carboxylate
substituent imposes challenges to glycosylation reaction due to the
withdrawing-electron effect of carboxylate resulting in decreased
reactivity of the building blocks as glycosyl donor and
acceptor.\textsuperscript{{[}27{]}} Mindful of these considerations, we
designed two retrosynthetic plans for the target
pentasaccharide\textbf{7} . As depicted in Scheme 3, we envisioned that
the target molecule \textbf{7} could be obtained from the fully
protected pentasaccharide \textbf{8} by a global deprotection. Glycan
\textbf{8}in turn was planned to assemble by glycosylation of
L-mannopyranosyl fluoride \textbf{9} with tetrasaccharide either
\textbf{10} or\textbf{11} . Compound \textbf{9} could be traced back to
readily available 1-phenyl-2-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C} -galactossyl)
ethanone\textbf{12} \textsuperscript{{[}18{]}}. Fluoride \textbf{9} is
designed to possess a benzoyl at C2-OH to ensure the formation of
1,2-\emph{trans}

\textbf{Scheme 3} Retrosynthetic analysis of pentasaccharide fragment
(\textbf{7} ) of extracellular polysaccharide S-88

\textbf{Scheme 4} Synthesis of L-mannosyl fluoride \textbf{9}

\textbf{Reagents and conditions:} (a) NaBH\textsubscript{4}, MeOH, ice
bath; (b) 2,6-lutidine, Tf\textsubscript{2}O,
CH\textsubscript{2}Cl\textsubscript{2}, 70\% over two steps; (c) MeONa,
MeOH; (d) PhCH(OMe)\textsubscript{2}, CSA, 40\selectlanguage{ngerman}°C, CH\textsubscript{3}CN;
(e) BnBr, KOH, 18-Crown-6, THF, 72\% over three steps; (f)
OsO\textsubscript{4}, 2,6-lutidine, NaIO\textsubscript{4},
1,4-dioxane/H\textsubscript{2}O; (g) NaBH\textsubscript{4}, MeOH, 73\%
over two steps; (h) BzCl, DMAP, pyridine; (i)\emph{p}
-TsOH·H\textsubscript{2}O, CH\textsubscript{2}Cl\textsubscript{2}/MeOH,
79\% over two steps; (j) TBSCl, DMAP, pyridine; (k) BzCl, DMAP,
pyridine; (l) 70\% HF·pyridine, CH\textsubscript{3}CN, 76\% for three
steps; (m) TEMPO, BAIB,
CH\textsubscript{2}Cl\textsubscript{2}/H\textsubscript{2}O, 93\%; (n)
Selectfluor, KF·2H\textsubscript{2}O,
Ag\textsubscript{2}CO\textsubscript{3}, acetone/H\textsubscript{2}O,
88\%. CSA = Camphorsulfonic acid; THF = Tetrahydrofuran; TBSCl
=\emph{tert} -Butyldimethylsilyl chloride.

glycosidic bonds through neighboring group participation. Given the
strength and weakness of post- or preglycosylation oxidation strategy,
tetrasaccharides either \textbf{10} or \textbf{11} embedded by
GlcA\emph{p} residue could be constructed by coupling reaction of
disaccharide acceptor \textbf{13} with either uronic acid-based
disaccharide donor \textbf{14} or the corresponding non-oxidized
donors\textbf{15} . These disaccharides \textbf{13} , \textbf{14} ,
and\textbf{15} could be disconnected to D-glucosyl
thioglycoside\textbf{16} and L-rhamnosyl trichloroacetimidate (TCAI)
\textbf{17} . Glucosyl thioglycoside \textbf{16} was designed to allow
for direct incorporation of rhamnosyl residue at C3-OH while
4,6-\emph{O} -benzylidene would facilitate the incorporation of
carboxylate group and the glycosylation of C4-OH by the hydrolysis of
acetal functionality and subsequent differentiation between the primary
alcohol and the secondary one. The presence of 2-\emph{O} -benzoyl (Bz)
substituent in \textbf{16} could enable anchimerically assisted
glycosylation leading to \selectlanguage{greek}β-\selectlanguage{english}glucosidic linkage formation. The
incorporation of a spacer 6-amino-hexanoxyl at the reducing end would
provide feasibility for conjugation of \textbf{7} with biomolecules such
as carrier protein. Orthogonal levulinoyl (Lev) group on the
disaccharide fragment either \textbf{14} or \textbf{15} allows for its
chemoselective removal and ensuing glycosylation at that site.

Our synthesis began with the preparation of rare L-mannosyl
fluoride\textbf{9} following a head-to-tail switch strategy (Scheme 4).
Similar to the synthesis of \textbf{6a} and \textbf{6b} , \emph{C}
-galactoside\textbf{12} was converted to vinyl \emph{C} -glycoside
\textbf{18} in 70\% yield over two steps. To differentiate the 4-OH and
the 6-OH from the 2,3-diol for late-stage equipment of benzoyl group at
the C4-OH and the formation of carboxylic acid, \textbf{18} was
converted into\textbf{19} in 72\% yield over three steps involving
deacetylation, the benzylidene protection of 4,6-diol, and the
benzylation of 2,3-diol. The oxidative cleavage of C-C double bond in
\textbf{19} followed by the reduction of aldehyde group led to the
introduction of hydroxymethyl at the anomeric position, providing 73\%
of \textbf{20} over two steps. Benzoyl protection of \textbf{20} coupled
with hydrolysis of benzylidene produced diol \textbf{21} in 79\% overall
yield. Selective benzoyl protection of C4-OH was smoothly realized
leading to \textbf{22} in 76\% overall yield through TBS protection of
the primary hydroxy group, the benzoylation of the remaining secondary
hydroxy group, and the cleavage of TBS ether with hydrogen
fluoride-pyridine complex. Uronic acid\textbf{23} , prepared by
oxidation of \textbf{22} in 93\% yield, was exposed to
Ag\textsubscript{2}CO\textsubscript{3}-mediated decarboxylative
fluorination to give rise to the required \selectlanguage{greek}α-\selectlanguage{english}L-mannosyl fluoride
\textbf{9} in 88\% yield as the sole product.

Having successfully prepared the L-mannosyl fluoride \textbf{9} , we
turned to constructing the tetrasaccharide \textbf{10} . To this end,
disaccharide acceptor \textbf{13} was first made. As shown in Scheme 5a,

\textbf{Scheme 5} Synthesis of disaccharide acceptor \textbf{13} as well
as donors \textbf{14} and \textbf{28}

\textbf{Reagents and conditions:} (a) TMSOTf, -40 \selectlanguage{ngerman}°C,
CH\textsubscript{2}Cl\textsubscript{2}, 4 Å MS, 87\%; (b)
Et\textsubscript{3}SiH, TFA, 5 Å MS,
CH\textsubscript{2}Cl\textsubscript{2}, 91\%, (c)
HO(CH\textsubscript{2})\textsubscript{6}N\textsubscript{3}, NIS, AgOTf,
4 Å MS, -20 °C, CH\textsubscript{2}Cl\textsubscript{2}, 70\%; (d)
BF\textsubscript{3}·Et\textsubscript{2}O, -40 °C,
CH\textsubscript{2}Cl\textsubscript{2}, 4 Å MS, 77\%; (e) TCCA,
H\textsubscript{2}O, ice bath, acetone; (f) \emph{o} -hexynylbenzoic
acid, DCC, DMAP, THF, 70\% over two steps. TMSOTf = Trimethylsilyl
trifluoromethanesulfonate; MS = Molecular sieve; NIS =\emph{N}
-Iodosuccimide; AgOTf = Silver triflate; TCCA = Trichloroisocyanuric
acid; DCC = Dicyclohexylcarbodiimide; \emph{n} -Bu =\emph{n} -butyl.

Glucose-derived alcohol \textbf{16} \textsuperscript{{[}27{]}} was
glycosylated with Bz-masked L-rhamnosyl TCAI\textbf{17}
\textsuperscript{{[}28{]}}. The coupling reaction proceeded smoothly and
delivered the desired disaccharide \textbf{24} in 81\% yield in
CH\textsubscript{2}Cl\textsubscript{2} at -40\textsuperscript{o}C under
the catalysis of 0.1 equiv of TMSOTf. Reductive ring- opening of the
benzylidene in \textbf{24} with TFA and Et\textsubscript{3}SiH in the
presence of 5 Å molecular sieves resulted in the formation of
\textbf{25} with C4'-OH free in 91\% yield. Reactivity-based
chemoselective glycosylation of
6-azido-1-hexanol\textsuperscript{{[}29{]}} with \textbf{25} produced
disaccharide glycoside \textbf{13} in 70\% yield under the combined
promotion of NIS and AgOTf. The reaction left C4'-OH intact, which is
ready for sugar chain elongation at this site.

With \textbf{13} in hand, the application of preglycosylation oxidation
strategy was first explored in construction of
tetrasaccharide\textbf{10} . We therefore embarked on the preparation of
uronic acid-based disaccharide \textbf{14} . As outlined in Scheme 5b,
BF\textsubscript{3}·Et\textsubscript{2}O-catalyzed glycosylation
of\textbf{26} \textsuperscript{{[}30{]}} with\textbf{27}
\textsuperscript{{[}31{]}} supplied 77\% of disaccharide\textbf{14} in
CH\textsubscript{2}Cl\textsubscript{2} in the presence of 4 Å MS. At
this stage, the coupling reaction of \textbf{14} and\textbf{13} was
explored. As tabulated in Table 1, we were disappointed to find that the
reaction under the promotion of NIS with either TfOH or Lewis acids such
as AgOTf and TBSOTf supplied the desired tetrasaccharide \textbf{10} in
the best yield up to 23\% (Table 1, entries 1--5). Gold-catalyzed
glycosylation of challenging nucleophiles with glycosyl \emph{ortho}
-alkynylbenzoate donors has

\textbf{Table 1} Optimization of glycosylation reactions of
acceptor\textbf{13} with donor \textbf{14} or\textbf{28}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Entry} & \textbf{Donor} & \textbf{Promoters (equiv)} &
\textbf{Solvent} & \textbf{T (\textsuperscript{o}C)} & \textbf{Yield
(\%)}\tabularnewline
\midrule
\endhead
1 & \textbf{14} & TfOH (0.2)/NIS (2.5) & PhMe & -78 to -40 &
16\tabularnewline
2 & \textbf{14} & TfOH (0.2)/NIS (2.5) & CHCl\textsubscript{3} & -40 &
trace\tabularnewline
3 & \textbf{14} & TfOH (0.2)/NIS (2.5) & DCE & -40 &
trace\tabularnewline
4 & \textbf{14} & AgOTf (0.4)/NIS (2.5) & PhMe & 0 & 10\tabularnewline
5 & \textbf{14} & TBSOTf (0.4)/NIS (2.5) & PhMe & 0 & 23\tabularnewline
6 & \textbf{28} & (PhO)\textsubscript{3}PAuCl (0.75)/AgOTf (0.75) & PhCl
& 0 & 37\tabularnewline
7 & \textbf{28} & (PhO)\textsubscript{3}PAuCl (0.3)/AgOTf (0.3) & PhCl &
-20 & 30\tabularnewline
8 & \textbf{28} & (PhO)\textsubscript{3}PAuCl
(0.3)/AgNTf\textsubscript{2} (0.3) & PhCl & 0 & 21\tabularnewline
9 & \textbf{28} & Ph\textsubscript{3}PAuCl (0.3)/AgOTf (0.3) & PhCl & 0
& 13\tabularnewline
\bottomrule
\end{longtable}

TfOH = Trifluoromethanoic acid; DCE = 1,2-Dichloroethane; TBSOTf
=\emph{tert} - Butyldimethylsilyl trifluormethansulfonate;
AgNTf\textsubscript{2} = Sliver bis(trifluoromethane sulfonimide); T =
temperature.

proven to be a powerful tool for constructing structurally complex
molecules.\textsuperscript{{[}32{]}} Encouraged by these advances and in
order to improve the preparation efficacy of tetrasaccharide\textbf{10}
, we converted thioglycoside \textbf{14} into glycosyl\emph{ortho}
-hexnylbenzoate (OABz) donor \textbf{28} in 70\% yield through a
two-step reaction sequence involving TCCA-mediate hydrolysis of
thioglycoside and subsequent DCC-promoted esterification of the
resultant hemiacetal with \emph{ortho} -hexynylbenzoic acid (Scheme 5b).
The impact of various factors, including gold salts, silver salts, and
reaction temperature, was scrutinized on the outcome of glycosylation
of\textbf{28} with \textbf{13} . It was found that the reaction gave

\textbf{Scheme 6} Synthesis of pentasaccharide \textbf{7}

\textbf{Reagents and conditions:} (a) \emph{p}
-TsOH\selectlanguage{ngerman}·H\textsubscript{2}O, 40 °C,
CH\textsubscript{2}Cl\textsubscript{2}/MeOH; (b) TBSCl, DMAP, pyridine,
89\% over two steps; (c) \textbf{26} ,
BF\textsubscript{3}·Et\textsubscript{2}O, -40 °C,
CH\textsubscript{2}Cl\textsubscript{2}, 4 Å MS, 77\%; (d) \textbf{13} ,
NIS, TBSOTf, 0 °C, PhMe, AW-300 MS, 65\%; (e) 70\% HF·pyridine,
pyridine, 93\%; (f) TEMPO, BAIB,
CH\textsubscript{3}CN/H\textsubscript{2}O; (g) MeI,
NaHCO\textsubscript{3}, DMF, 89\% over two steps; (h)
NH\textsubscript{2}·NH\textsubscript{2}·H\textsubscript{2}O (5.0 equiv),
AcOH (10.0 equiv), CH\textsubscript{2}Cl\textsubscript{2}, 97\%;
(i)\textbf{9} , Cp\textsubscript{2}ZrCl\textsubscript{2}, AgOTf, -20 °C,
PhCF\textsubscript{3}, 4 Å MS, 90\%; (j) LiOH·H\textsubscript{2}O, 30\%
H\textsubscript{2}O\textsubscript{2}, THF/H\textsubscript{2}O, 92\%; (k)
10\% Pd/C, H\textsubscript{2}, 1 M HCl, THF/\emph{i}
-PrOH/H\textsubscript{2}O, 74\%.
Cp\textsubscript{2}ZrCl\textsubscript{2} =
Bis(pentamethylcyclopentadienyl) zirconium dichloride.

tetrasaccharide \textbf{10} in the best yield of 37\% under the
promotion of 0.75 equiv of (PhO)\textsubscript{3}PAuOTf, \emph{in
situ}generated from equal molar units of (PhO)\textsubscript{3}PAuCl and
AgOTf. We attributed the unsatisfactory outcome mentioned above to the
low reactivity of uronic acid-based donors and weak nucleophilicity of
the C4'-OH due to steric hinderance resulting from the presence of the
adjacent 3'-\emph{O} -L-rhaminosyl residue.

Basing on the observations of the Huang group that increasing the
reactivity of glycosyl donors favors the glycosylation of glycosyl
acceptors with weak nucleophilicity,\textsuperscript{{[}33{]}} we moved
our focus to the construction of tetrasaccharide \textbf{11} following a
postglycosylation oxidation strategy. For this purpose, glucopyranosyl
thioglycoside acceptor \textbf{30} was made from\textbf{29}
\textsuperscript{{[}34{]}} through hydrolysis of benzylidene and
regioselective TBS protection of the resulting primary hydroxy group.
Then thioglycoside \textbf{30} was subjected to glycosylation with
glucosyl TCAI donor \textbf{26} . Under the catalysis of
BF\textsubscript{3}·Et\textsubscript{2}O the reaction worked well and
afforded the expected disaccharide \textbf{15} in 77\% yield.

With disaccharides \textbf{15} and \textbf{13} in hand, glycosylation
between them was executed (Scheme 6). To our delight, the reaction
efficiently proceeded and provided the desired
tetrasaccharide\textbf{11} in 65\% yield when slowly adding a solution
of \textbf{15}to a flask charged with \textbf{13} , 2.5 equiv of NIS,
and 0.2 equiv of TBSOTf in toluene at 0 \textsuperscript{o}C. The
transformation of\textbf{11} into the uronic acid-embedded counterpart
\textbf{31} was uneventfully achieved by the removal of TBS masking
group, the oxidation of primary hydroxy group, and methylation of the
resulting carboxylic acid. The orthogonal cleavage of Lev group with
hydrazine acetate furnished alcohol \textbf{32} that is ready for
mannosylation \emph{via}the formation of \selectlanguage{greek}α-\selectlanguage{english}glycosidic linkage.

After obtaining tetrasaccharide \textbf{32} and L-mannosyl
fluoride\textbf{9} , we proceeded to synthesize the desired
pentasaccharide\textbf{7} . (Scheme 6). Tetrasaccharide \textbf{32} was
mannosylated with glycosyl fluoride \textbf{9} under the action of 1.2
equiv of Cp\textsubscript{2}ZrCl\textsubscript{2} and 2.4 equiv of AgOTf
to afford the fully protected pentasaccharide \textbf{8} in a high yield
of 90\%. It should be noted that the coupling could also promoted with
(C\textsubscript{6}F\textsubscript{5})\textsubscript{3}B\selectlanguage{ngerman}·(H\textsubscript{2}O)\textsubscript{n}as
the initiator.\textsuperscript{{[}35{]}} However, the reaction required
0.6 equiv of
(C\textsubscript{6}F\textsubscript{5})\textsubscript{3}B·(H\textsubscript{2}O)\textsubscript{n}and
pentasaccharide \textbf{8} was obtained in 59\% yield in
PhCF\textsubscript{3} in the presence of 4 Å MS.

With \textbf{8} successfully prepared, its deprotection was performed.
Pentasaccharide \textbf{8} was treated with LiOH·H\textsubscript{2}O in
the presence of H\textsubscript{2}O\textsubscript{2} in a mixed solvent
of H\textsubscript{2}O and THF, resulting in concomitant hydrolysis of
one methyl ester and five benzoates to afford hexol \textbf{S7} in 92\%
yield (see the Supporting Information). Then, exposure of the
hexol\textbf{S7} to 1 atmosphere of dihydrogen in the presence of
palladium over charcoal and 1 M HCl resulted in hydrogenolysis of one
benzylidene and benzyl ethers as well as hydrogenation of azido
substituent, uneventfully affording the desired the target
pentasaccharide \textbf{7}in 74\% yield.

Conclusions

We have developed an efficient protocol for synthesis of rare L-glycosyl
fluorides using a head-to-tail inversion strategy.
L-glucosyl/galactosyl/mannosyl fluorides were successfully prepared with
readily available 1-phenyl-2-(\selectlanguage{greek}β-\selectlanguage{english}D-\emph{C} -glucosyl, mannosyl, and
galactosyl)ethanone as the starting materials. The transformation
involves installing the anomeric hydroxymethyl group and switching the
sugar ring in a head-to-tail manner through radical oxidative
decarboxylative fluorination of uronic acids. To demonstrate the
practical application of our protocol, we successfully assembled the
pentasaccharide repeating unit of extracellular polysaccharide S-88 for
the first time. The synthesis is characterized by sugar chain extension
at a sterically hindered hydroxy group and the incorporation of a
L-mannosyl residue with L-mannosyl fluoride as the glycosylating agent.
Considering the challenges associated with accessing biologically
important oligosaccharides and glycoconjugates that contain L-sugar
residue(s), our work offers an additional tool for the synthesis of
these constructs.

Experimental

Experimental procedures and characterization data are available in
Supporting Information.

Supporting Information

The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.

Acknowledgement

We are grateful for financial support from the Marine S\&T Fund of
ShandongProvince for Pilot National Laboratory for Marine Science and
Technology (Qingdao) (No. 2022QNLM030003-2), the National Natural
Science Foundation of China (Nos. 21977088 and 21672194), and the
National Natural Science Foundation of China-Shandong Joint Fund (No.
U1906213).

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\end{enumerate}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
Manuscript received: XXXX, 2023 Manuscript revised: XXXX, 2023
Manuscript accepted: XXXX, 2023 Accepted manuscript online: XXXX, 2023
Version of record online: XXXX, 2023\tabularnewline
\bottomrule
\end{longtable}

The Authors\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& After acceptance, please insert a group photo of the authors taken
recently. &\tabularnewline
& \textbf{Left to Right:} Authors Names &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Entry for the Table of Contents}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Synthesis of L-Hexopyranosyl Fluorides Enabled by Radical
Decarboxylative Fluorination: Assembly of a Pentasaccharide Repeating
Unit Corresponding to Extracellular Polysaccharide S-88} Zhi
Qiao\textsuperscript{++}, Dongwei Li\textsuperscript{++}, Jingru Gao,
Zijiao Hou, Ningjie Yan, Ni Song, Peng Wang*, and Ming Li* \emph{Chin.
J. Chem.} \textbf{2023}, \emph{41}, XXX---XXX. \textbf{DOI:
10.1002/cjoc.202300XXX}\tabularnewline
A novel and efficient approach has been established for the synthesis of
demanding L-glycosyl fluorides. This approach is exemplified by the
convenient preparation of L-glucosyl and L-galactosyl fluorides from
readily available \selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}-glucosyl and \selectlanguage{greek}β-\selectlanguage{english}D-\emph{C}-mannosyl
derivatives. The transformation features the equipment of hydroxymethyl
group at the anomeric position under mild conditions and the
head-to-tail inversion of sugar rings through radical decarboxylative
fluorination of uronic acids. The effectiveness of this protocol is
demonstrated by the first assembly of a pentasaccharide repeating unit
of extracellular polysaccharide S-88. This was made possible by the
facile equipment of L-mannosyl unit with L-mannosyl fluoride as
glycosylating agent and the efficient extension of sugar chain at the
sterically hindered hydroxy group. Our work not only enriches the
methodologies for preparing L-sugar building blocks, but also holds
promise for the synthesis of glycans containing L-sugar
residues.\tabularnewline
\bottomrule
\end{longtable}

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