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\DOI{10.5802/crchim.373}
\datereceived{2024-09-23}
\daterevised{2024-11-22}
\datererevised{2024-12-05}
\dateaccepted{2024-12-09}
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\dateposted{2025-02-27}
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\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{Diversity in glycochemistry through metal-catalyzed reactions}

\alttitle{Les r\'{e}actions m\'{e}tallo-catalys\'{e}es au service de la
diversit\'{e} en glycochimie}

\author{\firstname{Ang\'{e}lique} \lastname{Ferry}\CDRorcid{0000-0001-9141-5479}}
\address{Universit\'e Paris-Saclay, CNRS, BioCIS, 91400, Orsay, France}
\address{CY Cergy-Paris Universit\'e, BioCIS, CNRS, 5 mail Gay-Lussac, 95000 Cergy-Pontoise cedex, France}
\address{Institut universitaire de France (IUF), France}
\email{angelique.ferry@cyu.fr}

\keywords{\kwd{Metal catalysis}
\kwd{Glycals}
\kwd{Cross-coupling}
\kwd{C--H functionalization}}

\altkeywords{\kwd{Catalyse m\'{e}tallique}
\kwd{Glycals}
\kwd{Couplage crois\'{e}}
\kwd{Fonctionnalisation C--H}}

\begin{abstract}
The importance and  ubiquity of glycosides in both compounds of
interest and biological processes make these biomolecules an interesting
topic of study. The development of unnatural analogues is equally compelling
and has already led to the production of several marketed drugs. The discovery of
novel carbohydrates is thus a field of interest. In order to open up this
chemical space, it is necessary to set up new and efficient synthetic
methods, which lead to  diverse unnatural glycosides, 
some of which could become beneficial new compounds. This account deals with the 
benefits presented by
metal-catalyzed reactions, especially cross-couplings and C--H
functionalization, to enable glycoside diversity.
\end{abstract}

\begin{altabstract}
L`importance et l'omnipr\'{e}sence des glycosides dans des
compos\'{e}s d'int\'{e}r\^{e}t et dans les processus biologiques font
de ces biomol\'{e}cules des motifs int\'{e}ressants. Le
d\'{e}veloppement d'analogues non naturels est d'importance et a
d\'{e}j\`{a} permis d'acc\'{e}der a de nombreux m\'{e}dicaments. La
d\'{e}couverte de nouveaux glycosides est donc un domaine
d'int\'{e}r\^{e}t. Afin d'ouvrir l'espace chimique, il est
n\'{e}cessaire de mettre au point de nouvelles m\'{e}thodes de
synth\`{e}se efficaces permettant d'acc\'{e}der \`{a} une
diversit\'{e} de glycosides non naturels dont certains pourraient se
r\'{e}v\'{e}ler \^{e}tre de nouveaux chefs de file. Cet article
rapporte le b\'{e}n\'{e}fice des r\'{e}actions
m\'{e}tallo-catalys\'{e}es, en particulier les couplages crois\'{e}s et
la fonctionnalisation C--H, pour acc\'{e}der \`{a} une diversit\'{e} de
glycosides.
\end{altabstract}

\maketitle

{\vspace*{5pt}}

\twocolumngrid

\end{noXML}

\section{Introduction}

Carbohydrates are defined as ``compounds such as aldoses and ketoses
having the stoichiometric formula
$\mathrm{C}_{n}(\mathrm{H}_{2}\mathrm{O})_{n}$'' (IUPAC
definition)~\cite{1} including derivatives. When they are attached
by a glycosyl group to a non-acyl moiety forming a mixed acetal, they
are called ``glycosides'' (IUPAC definition)~\cite{2}. They generally
contain a six-membered (pyranoside) or a five-membered (furanoside) cyclic
structure. They are key biomolecules found in living cells and
ubiquitously involved in numerous biological processes~\cite{3a,3b}. 
They adorn cell surfaces in the
form of oligomers linked in a covalent manner via $O$- or
$N$-glycosidic bonds to proteins or lipids anchored in cell membranes. 
Their interactions with enzymes are
responsible for cell adhesion, cell recognition, and immunological
processes~\cite{4}. In the furanose series, they constitute the
skeleton of crucial biopolymers, namely RNA and DNA, composed of \mbox{ribose}
or 2-deoxyribose units. Therefore, from a therapeutic point of view,
these compounds are interesting targets as drug candidates. However, to
attain a suitable administration--distribution--metabolism--elimination
(ADME) profile, the development of analogues possessing unnatural
structures is often a profitable approach~\cite{5}. Indeed, many
unnatural saccharide-type drugs have been already commercialized such as
dapagliflozin for type II diabetes, miglustat for type I Gaucher
disease, zanamivir for influenza A or B infections, and zidovudine
for HIV infection, and so on (Scheme~\ref{sch1}).


\begin{scheme*}
{\vspace*{-2pt}}
\includegraphics{sc01}
\vspace*{6pt}
\caption{\label{sch1}A few examples of carbohydrate mimics with therapeutic interest.}
{\vspace*{-6pt}}
\end{scheme*}




Unnatural chemical bonds may possess a superior chemical and enzymatic
stability compared to their natural counterparts while retaining a
similar conformation. The development of unnatural biomolecule
analogues aims not only at increased biostability but also at
increased specificity or biological activity compared to the natural
substrate~\cite{6a,6b}.  In addition to medicinal applications,
glycoside analogues have attracted  interest from cosmetic and 
biotechnology fields as biosourced materials~\cite{7a,7b}.  Despite their
huge potential, the application of such analogues is limited due to
their poor availability, which frequently requires significant
synthetic effort~\cite{8a,8b,8c}. Indeed, the discovery of new
glycosides of interest is conditioned by the chemical space accessible
by using the current synthetic toolbox. 


As such, the development of innovative synthetic methods is of great
importance. In recent decades, among the synthetic tools developed in
organic synthesis, metal-catalyzed reactions, such as cross-coupling or
C--H functionalization, have gained huge popularity but have been mainly
explored on aryl and heteroaryl compounds~\cite{9a,9b,9c}.   Indeed,
the application of these powerful reagents on glycosides is an emerging
field~\cite{10a,10b}.   This observation can be explained by the fact
that the application of new synthetic methods on complex biomolecules
is generally challenging and needs  double expertise 
(e.g., glycochemistry and organometallic chemistry).  \looseness=-1


This account presents the contribution of our group to the
development of metal-catalyzed methods on glycals (unsaturated
carbohydrates) to generate unnatural analogues. Two types of reactivity
are presented, namely, C--H functionalization and cross-coupling
reactions, to produce substituted glycals. Glycals represent all
carbohydrates possessing a double bond between the C1 position
(pseudo-anomeric position, close to the endocyclic oxygen) and the C2
position. The reactivity of glycals is diverse, allowing the
modification of several positions of the ring (C1, C2, and C3
positions)~\cite{11}. For instance, the so-called Ferrier rearrangement
allows the introduction of a substituent at the C1 position by using
different nucleophiles. In this reaction, a glycal bearing a leaving
group at the C3 position can be activated by an acidic reagent and
then be attacked at the C1 position by a nucleophile, inducing the
shift of the double bond between the C2 and \mbox{C3} carbons with the
elimination of the leaving group at C3~\cite{12a,12b}. In addition
to standard reactivity, the unsaturation was shown to be particularly
suitable in metal-catalyzed reactivity. The two developed methods allow
the functionalization of the two positions of the endocyclic double
bond. As the accessibility and the reactivity of C1 and C2
positions of the glycal double bond are different, the synthetic
strategy to target one specific position as well as the design of the
starting substrates has to be soundly chosen (Scheme~\ref{sch2}).



\begin{scheme*}
\vspace*{3pt}
\includegraphics{sc02}
\vspace*{8pt}
\caption{\label{sch2}The two developed strategies to target the different positions
of the glycal double bond.}
\vspace*{6pt}
\end{scheme*}


{\vspace*{-2pt}}
\section{Metal-catalyzed cross-couplings on\hfill\break 2-iodoglycals}

{\vspace*{-2pt}}
\subsection{State of the art}

{\vspace*{-2pt}}
Iodoglycals are glycosidic compounds containing a vinylic carbon--iodine
bond with huge potential for functionalization using metal-catalyzed
reactions. 1-Iodoglycals have been investigated as partners in
metal-catalyzed cross-coupling but have faced two major problems,
namely, the instability of the structure and the necessity to work on
TIPS-protected compounds as the usual way to synthesize such molecules
requires difficult conditions such as the use of
$t$-BuLi~\cite{13a,13b,13c,13d,13e}.  On the contrary, the development
of easily accessible and bench-stable 2-iodoglycals by Vankar
et~al.~\cite{14}  in 2014 presented to the glycochemist a very
interesting platform to plan diverse metal-catalyzed reactivities at the
C2 position and thus to extend the chemical space with potential
glyco-analogues~\cite{15a,15b,15c,15d,15e,15f,15g,15h,15i,15j,15k,15l,15m,15n,15o,15p,15q,15r,15s,15t,15u,15v,15w,15x,15y,15z,15aa,15ab,15ac,15ad,15ae,15af}. 
Before this pioneering publication, only standard cross-couplings have
been investigated on 2-iodoglycals, namely Suzuki--Miyaura, Sonogashira,
and Heck reactions. Since 2015, numerous carbonylative methods have
been described. A few examples of carbon--heteroatom bond formation
(C--S, C--N, and C--P) have also been reported (Scheme~\ref{sch3}).
\looseness=-1


\begin{scheme*}
\includegraphics{sc03}
\vspace*{8pt}
\caption{\label{sch3}State of the art of 2-iodoglycal functionalization
using metal-catalyzed cross-couplings.}
\end{scheme*}


\subsection{Contribution to the field}

Our first contribution to the field of metal-catalyzed cross-coupling
on 2-iodoglycals started in 2016 in a context where cross-coupling
reactions on these substrates were an underexplored field. 


\begin{scheme*}
\vspace*{-4pt}
\includegraphics{sc04}
\vspace*{5pt}
\caption{\label{sch4}Aminocarbonylation.}
\vspace*{-4pt}
\end{scheme*}



\subsubsection{Carbon--carbon bond formation} \label{sec2.2.1}

Our first objective was to propose a way to link a glycoside with an
amine {via} a stable C--C bridge, and we turned our attention to
an aminocarbonylation process. To transform 2-iodoglycals into
\mbox{2-amidoglycals,} palladium catalysis in the presence of
``CO'' and amines as partners was used
(Scheme~\ref{sch4}). The optimized setup involved a Pd(II)
catalyst [$\mathrm{Pd}(\mathrm{OAc})_{2}$] and a phosphine ligand
($\mathrm{PPh}_{3}$) under basic conditions
($\mathrm{K}_{2}\mathrm{CO}_{3}$) and the use of an easy-to-handle
solid ``CO'' source (e.g., $\mathrm{Mo}(\mathrm{CO})_{6}$) in the
\mbox{presence} of 2 equiv of amine in dioxane at 80~\textdegree C. The
palladium catalyst appeared to be crucial since its absence failed to
form the desired C2-amidoglycal. To determine the role of the metallic
``CO'' source ($\mathrm{Mo}(\mathrm{CO})_{6}$) in the catalytic cycle,
a CO gas atmosphere was used instead of $\mathrm{Mo}(\mathrm{CO})_{6}$,
and the desired compound was formed with a similar yield. These results
suggest that palladium is the species involved in the catalytic
cycle and that $\mathrm{Mo}(\mathrm{CO})_{6}$ acts only as a ``CO''
generator. Under these conditions, diverse amine derivatives (aliphatic
and cyclic amines, anilines, sulfonamides) have been successfully
introduced, and the amido derivatives have been isolated in 36--94\%
yield. Glycosylated amino acids were also obtained (yields ${=}$
33--60\%). Different protecting groups on the glycal, such as acetyl,
benzyl, and isopropylidene as well as two glycal examples bearing a
\textsc{d}-galactal configuration completed the scope of the study. 
Four obtained
perbenzylated or peracetylated examples have been finally deprotected
by hydrogenolysis or Zemplen-type conditions (MeONa in MeOH) to produce
unprotected C2-amidoglycals where the glycal double bond remained
intact (Scheme~\ref{sch4}) \cite{15v}.


In 2019, our team took advantage of carbonylative reactions to propose
the formation of 2-ketoglycals {via} a carbonylative Suzuki--Miyaura
reaction between 2-iodoglycals and boronic acids as nucleophiles. The
optimized conditions were quite similar to those employed in the
aminocarbonylation method except for the palladium source and the
solvent ($\mathrm{Pd}_{2}\mathrm{dba}_{3}$ instead of
$\mathrm{Pd}(\mathrm{OAc})_{2}$ and DMF instead of dioxane). Despite similar
reactivity, the mechanism seems to be different since the unique
presence of $\mathrm{Mo}(\mathrm{CO})_{6}$ as the metallic species in the
medium (in the absence of the palladium catalyst) still generated
small amounts of the desired compound whereas the replacement of the
solid ``CO'' source by ``CO'' gas failed to form the 2-ketoglycal. The
formation of a new active species formed between 
$\mathrm{Mo}(\mathrm{CO})_{6}$ and  boronic acid may be possible but remains
to be proven. Different arylboronic acids bearing electron-donating or
electron-withdrawing groups have been used. Whereas electron-donating
groups led to good yields, electron-withdrawing groups furnished lower
yields. Heteroaryl boronic acids (\mbox{furan,} thiophene, isoquinoline, and
benzofuran types) showed good reactivity in addition to two alkenylboronic
acids giving rise to unsymmetrical dialkenylated ketones. Three other
2-iodoglycals, a \textsc{d}-galactal, a \textsc{d}-xylal, and a
\textsc{d}-lactal derivative, bearing benzyl or acetyl protecting
groups proved to be also compatible with the reaction conditions. Due
to the introduction of a ketone, conditions other than hydrogenolysis
had to be considered to deprotect the compounds. Thus, two obtained
perbenzylated compounds have been deprotected by applying $\mathrm{BCl}_{3}$
conditions. The products were obtained in moderate to good yields.
However, the presence of this ketone allowed post-functionalizations.
Indeed, the introduced carbonyl function has been successfully reduced
to the corresponding mixture of two diastereomeric alcohols in good
yield, which have then been engaged in an indium-mediated allylic
substitution in the presence of oxygenated nucleophiles. The
corresponding exocyclic double bond has been finally reduced under
hydrogenolysis conditions ($\mathrm{H}_{2}$ (1~atm), Pd/C (20~wt\%),
$\mathrm{NH}_{4}\mathrm{OH}$ (2.5--5 equiv), MeOH, rt) to furnish
C2-$\upalpha$-glucopyranosides (50--92\%)\break
(Scheme~\ref{sch5})~\cite{15y}.



\begin{scheme*}
\includegraphics{sc05}
\vspace*{6pt}
\caption{\label{sch5}Carbonylative Suzuki--Miyaura reaction.}
\end{scheme*}




Most of the results reported in metal-catalyzed cross-couplings applied
to 2-iodoglycals do not deal with the deprotection of the obtained
structures. The deprotection step can be problematic depending
on the sensitivity of the function introduced at the C2 position,
which has been already pointed out for the carbonylative Suzuki--Miyaura
reaction. In the case where the introduction of a sensitive functional
group is planned, the synthetic strategy has to be rethought. In this
context, we considered working on unprotected 2-iodoglycals in order to
develop a cyanation reaction. Thus, the deprotection step was achieved
before the cross-coupling reaction in order to directly generate
unprotected cyano derivatives at the end of the metal-catalyzed
reaction. Unprotected 2-iodoglycals can be easily obtained by
deacetylation of the corresponding peracetylated 2-iodoglycals. From
these unprotected 2-iodoglycals, a palladium-catalyzed cyanation in
aqueous medium using $\mathrm{K}_{4}[\mathrm{Fe}(\mathrm{CN})_{6}]$ as
a safe and non-toxic ``$\mathrm{CN}^{-}$'' source has been developed
leading to the desired 2-cyanoglycals. The developed conditions took
advantage of the reactive palladium precatalyst, which allowed the use
of mild temperatures. The crucial parameter was the quantity of 
base ($\mathrm{CH}_{3}$COOK), which has to be in slight excess compared
to the palladium species. The reaction was performed in a mixture of
$t$-$\mathrm{BuOH}/\mathrm{H}_{2}\mathrm{O}$. Diverse pyranosidic glycals
(2-iodo-\textsc{d}-galactal, 2-iodo-\textsc{d}-xylal,
2-iodo-\textsc{l}-rhamnal), a disaccharide-type glycal
(2-iodo-\textsc{d}-lactal), a furanosidic glycal
(2-iodo-\textsc{d}-ribal) as well as diversely protected
2-iodo-\textsc{d}-glucals (perbenzylated or persilylated) have been
successfully converted to the corresponding cyano derivatives in
excellent yields (44--100\%). The nitrile group can be a versatile
platform to generate other functional groups. 
With this objective in mind,
the obtained 2-cyanoglycals were transformed into five glyco-analogues
bearing an amine (with and without the glycal double bond), an amide, a
triazole, or a ketone at the C2 position of the glycal
(Scheme~\ref{sch6}) \cite{15u}.



\begin{scheme*}
\vspace*{-3pt}
\includegraphics{sc06}
\vspace*{5pt}
\caption{\label{sch6}Cyanation of unprotected 2-iodoglycals.}
\vspace*{-6pt}
\end{scheme*}


\subsubsection{Carbon--heteroatom bond formation}


Before 2020, the formation of C2--heteroatom bonds on 2-iodoglycals
were underreported in the literature (only one example of a C--S bond
formation). The creation of the C--N bond was first explored by
our team due to the importance of $N$-acetylglycosamine structures in
biology. With this aim, an amidation reaction has been developed using 
dual catalysis combining a nickel and a copper salt catalyst in the
presence of a ligand and a base, in $N$,$N$-dimethylacetamide at
120~\textdegree C, with an excess of amides (2 equiv) as the coupling
partners. Cyclic amides such as pyrrolidinone, morpholinone, and
oxazolidinone as well as diversely substituted benzamides have been
tolerated. The resulting coupling products were isolated in moderate
to excellent yields (20--82\%). Diverse perbenzylated as well as
unprotected 2-iodo-\textsc{d}-glucals and 2-iodo-\textsc{d}-galactals
have been considered. Aliphatic linear and primary amides unfortunately
failed to form the desired compounds as did peracetylated
2-iodoglycals. The hydrogenolysis of the obtained structures led to the
removal of the benzyl protecting groups as well as to the reduction of
the glycal double bond, forming a unique isomer: \textsc{d}-mannosamide
structures from \textsc{d}-glucals and \textsc{d}-talosamides from
\textsc{d}-galactals (Scheme~\ref{sch7})~\cite{15t}.


\begin{scheme*}
{\vspace*{1pt}}
\includegraphics{sc07}
\vspace*{6pt}
\caption{\label{sch7}Amidation of 2-iodoglycals.}
\end{scheme*}


The possibility of inserting a phosphonate group at the C2 position
appeared to be interesting from a biological point of view considering
the ubiquity of phosphorylation in cells. The creation of a C--P bond
has been explored {via} a palladium-catalyzed Hirao-type
reaction. The use of trialkyl P(III) phosphite partners instead of a
dialkyl P(V) phosphite led to excellent yields in only 1 h. From a
mechanistic point of view, after the standard oxidative \mbox{addition} of 
\mbox{palladium} to the C--I bond of the glycal, a ligand exchange allowed
the chelation of the nucleophilic P(III) form of the phosphite at the
palladium center. Thanks to a nucleophilic species present in the
medium, an Arbuzov rearrangement occurs to form the P(V) intermediate.
The desired product is finally generated after  reductive elimination.
The developed conditions showed  wide compatibility not only with numerous
2-iodoglycals (with a \textsc{d}-glucal, a \textsc{d}-galactal, a
\textsc{l}-rhamnal, or a \textsc{d}-lactal configuration) bearing
benzyl, acetyl, or \textit{para}-methoxybenzyl protecting groups but
also with unprotected 2-iodoglycals (Scheme~\ref{sch8}). Different
phosphites (trimethyl, triethyl, triisopropyl phosphites)
have been successfully coupled. The protic cosolvent has to be adapted
to the phosphite reagents (MeOH when trimethyl phosphite is used, EtOH
when triethyl phosphite is used, etc.). The deprotection of a
perbenzylated and a peracetylated compound has been also successfully
demonstrated~\cite{15s}.


\begin{scheme*}
\includegraphics{sc08}
\vspace*{5pt}
\caption{\label{sch8}Phosphonylation of 2-iodoglycals.}
\vspace*{-4pt}
\end{scheme*}


In 2022, in a collaboration with Malinowski et~al.\ (Warsaw University
of Technology, Poland), the Sonogashira reaction on peracetylated
2-iodoglycals was revisited with alkynyl partners ready to be
used in porphyrin heterocycle synthesis. This \mbox{reaction} was 
developed to create unnaturally glycosylated porphyrins. The
Sonogashira cross-coupling was realized with a dual
palladium/copper catalyst (Scheme~\ref{sch9})~\cite{15l}.


\begin{scheme*}
\includegraphics{sc09}
\vspace*{6pt}
\caption{\label{sch9}Synthesis of unnatural glycoporphyrins via a Sonogashira reaction.}
\vspace*{-4pt}
\end{scheme*}

{\vspace*{3pt}}

\section{Directed metal-catalyzed C--H functionalization of unsaturated carbohydrates} 

{\vspace*{3pt}}

\subsection{State of the art}

{\vspace*{3pt}}

The goal here is to directly functionalize a C--H bond while avoiding
the necessity to synthesize reactive intermediates~\cite{9a,9b,9c}. The
application of such reactivity to carbohydrates is therefore highly
challenging, and the number of such examples in the literature is scarce
but slowly increasing~\cite{10a}. The main challenge is to selectively
mono-functionalize complex structures having several similar C--H bonds.
A few metal-catalyzed C--H functionalizations of $\mathrm{Csp}^{3}$--H
bonds of saturated carbohydrates have been developed in the last few decades
by Compain et~al., Lecourt et~al., and more recently by Messaoudi et~al.\ 
using rhodium- or palladium-catalyzed
processes~\cite{10a,13a,16a,16b,16c,16d,16e,16f,16g,16h,16i,16j}.  The
strategy consists of introducing a reactive group (intramolecular
reactivity) or a metal-chelating directing group (DG) (intermolecular
reactivity) on the carbohydrate, close enough to target a C--H bond
specifically and  more generally the anomeric position (C1~position) or
the C2 or C5 position (Scheme~\ref{sch10}). However, these methods depend on
a fine design of the starting carbohydrate, which frequently needs to be
synthesized {via} a multi-step sequence, and suffer generally
from a lack of versatility. On the contrary, the C--H activation of
unsaturated glycosides \mbox{bearing} differentiated $\mathrm{Csp}^{2}$--H
bonds appeared to be a good option to easily functionalize a specific
position~\cite{10a,17a,17b,17c,17d,17e,17f,17g,17h,17i,17j,17k,17l}. 
In the \mbox{absence} of a DG, the reactivity of glycals operates generally at
the nucleophilic C2 position (Scheme~\ref{sch10}). However, the
numerous options to easily fill the C2 position of the glycal by a
cross-coupling reaction allows the addition of a DG at this strategic
position, which further allows the possibility of functionalizing other
positions. By using this strategy, several \mbox{C--H} functionalizations of
glycals have been developed using a pre-installed amide-type DG
(Scheme~\ref{sch10}).



\begin{scheme*}
\vspace*{-1pt}
\includegraphics{sc10}
\vspace*{6pt}
\caption{\label{sch10}State of the art of metal-catalyzed C--H
functionalization of glycosides.}
\vspace*{-2pt}
\end{scheme*}

The C--H activation of carbohydrates was sporadic until 2019. Since
then, several studies have been reported, but the complexity of the
sugars makes the C--H activation somewhat elusive. 


\subsection{Contribution to the field}

\subsubsection{Simple pyranosidic glycals}

First, we considered the functionalization of the C--H bond at the
C1 position of the glycals. However, in the absence of a DG,
the C--H functionalization operates almost exclusively at the C2
position, which is the nucleophilic position of the enol ether. In
order to guide the reactivity to the C1 position, the introduction of
a metal-chelating DG at the C2 position was envisaged. 
The C2-amidoglycals obtained by the aminocarbonylation
method (see Section~\ref{sec2.2.1};
Scheme~\ref{sch4}) appeared to be ideal starting
substrates for the C--H functionalization at the C1 position of glycals
thanks to the metal-chelating amide function at C2
(Scheme~\ref{sch11}). 


\begin{scheme*}
{\vspace*{-2pt}}
\includegraphics{sc11}
\vspace*{4pt}
\caption{\label{sch11}Directed C--H functionalization strategy on glycals.}
\end{scheme*}


A starting C2-amidoglycal possessing a strong metal-chelating bidentate
group, namely \mbox{8-aminoquinolide,} has been designed and synthesized
{via} aminocarbonylation. For a proof of concept, we turned our
attention to the development of  palladium-catalyzed intermolecular C--H
arylation (Scheme~\ref{sch12}). This method uses aryl or alkenyl
iodides as electrophilic partners. The reaction was catalyzed by
palladium in the presence of silver salts and was achieved in the
presence of a weak base and citric acid in toluene at 130~\textdegree
C. Aryl iodides bearing electron-withdrawing and electron-donating
groups were successfully coupled in good yields (38--78\%). A
heteroaryl and an alkenyl iodide have also been introduced under these
conditions. Different types of C2-amidoglycals (\textsc{d}-galactal and
\textsc{d}-lactal) protected by benzyl and isopropylidene groups have
been synthesized. Finally, this method was  applied for the
synthesis of glycosylated amino acids (mono- and disaccharide) as well
as for the synthesis of an analogue of the dapagliflozin drug. However,
the removal of the DG failed due to the poor reactivity of
the conjugated amide function. Similarly, the deprotection of 
benzyl groups has not been achieved so far~\cite{17h}.

\begin{scheme*}
{\vspace*{-4pt}}
\includegraphics{sc12}
\vspace*{4pt}
\caption{\label{sch12}C--H arylation.}
{\vspace*{-8pt}}
\end{scheme*}
                                                      
With the C2-amidoquinolide glycals in hand, we took advantage of these
substrates to introduce alkynyl groups by C--H alkynylation
(Scheme~\ref{sch13}). {Indeed,} the presence of an alkynyl group allows
access to further compounds {via} click chemistry. However, the
introduction of an alkynyl substituent failed under palladium
catalysis. Inspired by the work of Li et~al.~\cite{18},  we turned our
attention to nickel catalysis utilizing alkynyl bromide partners. The
conditions involve a nickel salt in the presence of a base in toluene
at 140~\textdegree C. 
The key parameter was the introduction of 
nickel powder after 4~h of preheating with the rest of the reagents.
The reason  behind this observation is still unclear. Silylated
alkynes were also well tolerated and led to moderate to good yields of
the coupling products: 22--64\%. More interestingly,
cyclopropylacetylenyl bromide allowed the formation of the
corresponding product in moderate yield (29\%). Diverse C2-amidoglycals
(\textsc{d}-galactal and \textsc{l}-rhamnal) were involved successfully
(21--62\%) in the C--H functionalization with alkynes. The
post-functionalization of the obtained alkynyl glycosides was finally
explored. A preliminary Boc protection of the amide was necessary to
successfully remove the silylated group, and the corresponding compound
was involved in a one-pot sequence to a copper-catalyzed click reaction
with azide partners. This led to several complex glycoconjugates. A
glycosylated amino acid, a disaccharide, and a glycosylated biotin were
obtained by applying these conditions (Scheme~\ref{sch12}). The removal of
the DG using pyrrolidine was equally described, and the
product was obtained in moderate yield. However, the deprotection of
the \mbox{benzyl} groups of these structures was not successful~\cite{17i}.
\looseness=1


\begin{scheme*}
\vspace*{2pt}
\includegraphics{sc13}
\vspace*{10pt}
\caption{\label{sch13}C--H alkynylation.}
\end{scheme*}


In 2022, the starting C2-amidoquinolide glycal was used in C--H
thiolation to furnish trehalose \mbox{analogues} using the reactivity of
thiosugars in metal-catalyzed reactions developed by  Messaoudi\ 
et~al.~\cite{19a,19b,19c,19d,19e}. The utilization of copper catalysis in
the presence of silver salts and 2 equiv of thiosugars allowed the
formation of several trehalose analogues in moderate to good yields
(21--67\%). The active species appeared to be thiol since the use
of the corresponding disulfide failed to form the desired compound.
Diverse C2-amidoglycals (\textsc{d}-glucal, \textsc{d}-galactal, and
\textsc{l}-rhamnal) and diverse thiosugars (with glucose, galactose,
and disaccharide types) protected by benzyl, acetyl, benzoyl, and
\textit{para}-methoxybenzyl protecting groups were coupled. It is
interesting to point out here the importance and influence of the
protecting groups on the reactivity of each partner. Indeed, benzyl
groups were crucial to the reactivity of the glycal partner whereas
peracetylated thiosugars were the best option for thiol. These
conditions have been also extended to thiophenols, aliphatic thiols, and
to protected cysteine partners with success. The oxidation of the
sulfur function into sulfoxide was demonstrated, leading to a mixture of
two separable diastereoisomers (Scheme~\ref{sch14}). However, for the
same reasons as those mentioned previously, the removal of the DG as well as the
deprotection of the molecules was unsuccessful~\cite{17j}.


\begin{scheme*}
\includegraphics{sc14}
\vspace*{6pt}
\caption{\label{sch14}C--H thiolation.}
{\vspace*{-1pt}}
\end{scheme*}

In 2023, the synthetic method involving C2-amidoquinolide glycals was
used by Mandal et~al.\ in  palladium-catalyzed pseudo-anomeric C--H
functionalization with \textit{para}-quinone methide partners to
generate unsymmetrical gem-diarylmethyl
$C$-glycosides~\cite{17k}.



\subsubsection{Unsaturated sialic acids}

The directed C--H functionalization of unsaturated sugars has been then
adapted to more complex structures, namely, unsaturated sialic acids. 
In collaboration with
Messaoudi et~al., the C--H amination at the C3
position of unsaturated sialic acids, bearing an amidoquinoline group
at the \mbox{C1} position, was developed. The bidentate amidoquinoline
DG has been introduced by derivatization of the carboxylic
acid function already present at C2. Thanks to copper catalysis,
diverse nitrogen-containing heterocycles were introduced by C--H
amination. Among the successful heterocycles, different substituted
7-azaindoles were used as well as diverse 5,7-diazaindoles,
6-azaindoles, 5-azaindoles, 4-azaindoles, indazoles, imidazoles,
carbazoles, azacarbazoles, and indoles. Perbenzylated,
\mbox{per-\textit{para}-methoxybenzylated,} and peracetylated unsaturated
sialic acid substrates were {tolerated.} The removal of the DG
was successfully carried out by preactivation of the amide by a
Boc protecting group followed by cleavage to the corresponding
carboxylic acid under oxidative conditions. The deprotection of the
benzyl groups has been successfully realized by applying $\mathrm{BCl}_{3}$
conditions, and the desired product was isolated in moderate yield.
Finally, three different post-functionalizations of the obtained
structure bearing a 4-iodo-7-azaindole moiety were developed using
palladium-catalyzed cross-coupling reactions (thiolation and
Suzuki--Miyaura reactions) (Scheme~\ref{sch15})~\cite{17l}.


\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc15}
\vspace*{4pt}
\caption{\label{sch15}C--H amination.}
\vspace*{-2pt}
\end{scheme*}


\section{Conclusion}

In the past decades, metal-catalyzed reactions made a real
breakthrough, offering new possibilities to extend the glycoside
chemical space. This review showed that cross-coupling reactions as
well as \mbox{C--H} activation could be successfully applied to 
\mbox{carbohydrates}
while being complementary. These two methods opened up the possibility of
introducing substituents on glycals especially at the C1 and  \mbox{C2}
positions, which are two key sites. These recent advances have pushed 
glycochemistry towards a new direction. This new field is just at its
infancy but promises to expand in the near future. However, numerous
aspects are still underexplored such as the use of unprotected starting
sugars, which would avoid protection/deprotection steps. Indeed, the
deprotection of the obtained structures is problematic, which limits
potential therapeutic applications. In addition, the use of more
environmentally friendly metals, such as iron, manganese, and so on, has to be
considered as palladium catalysis dominates the literature even if
some nickel or copper catalysis were used. The C--H activation methods
also suffer, in some examples, from the inability of removing the DG.
A better design of the DG or the use of transient DG (as it was 
proposed by Messaoudi et~al.\ in only one paper~\cite{16j}) should
increase the attractiveness of the method. Another point of improvement 
could be the development of  late-stage metal functionalization of
complex oligosaccharides, which possess  high therapeutic value
but are currently absent from the literature. To conclude, in
addition to metal-catalyzed reactions, in the last few years, glycochemists
have shown that other emerging tools such as photochemistry and
electrocatalysis can be useful in producing different types of 
sugars~\cite{10a}. This heralds a fruitful future for
glycochemistry and promises the discovery of original and innovative
glyco-analogues of interest.

\vspace*{-2pt}

\section*{Declaration of interests}

\vspace*{-2pt}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

\vspace*{-2pt}

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