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\DOI{10.5802/crchim.337}
\datereceived{2024-07-05}
\daterevised{2024-09-06}
\dateaccepted{2024-09-06}
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\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{Fluoroalkenes as biomolecules isosteres; preparation and
application: a personal account}

\alttitle{Les fluoroalc\`{e}nes comme isost\`{e}res de
biomol\'{e}cules ; pr\'{e}paration et applications : bilan personnel}

\author{\firstname{Thierry} \lastname{Lequeux}\CDRorcid{0000-0003-3783-4458}\IsCorresp}
\address{Laboratoire de Chimie Mol\'{e}culaire et Thioorganique LCMT
UMR 6507 ENSICAEN, UNICAEN, CNRS, Normandie Universit\'{e}, 6 Bd. du
Mar\'{e}chal Juin, 14050 Caen, France}
\email[T. Lequeux]{Thierry.Lequeux@ensicaen.fr}

\author{\firstname{Emmanuel} \lastname{Pfund}\CDRorcid{0000-0003-1896-0109}}
\addressSameAs{1}{Laboratoire de Chimie Mol\'{e}culaire et
Thioorganique LCMT UMR 6507 ENSICAEN, UNICAEN, CNRS, Normandie
Universit\'{e}, 6 Bd. du Mar\'{e}chal Juin, 14050 Caen, France}

\keywords{\kwd{Monofluoroalkenes}
\kwd{Olefination}
\kwd{Dipeptides}
\kwd{Acyclonucleosides}}

\altkeywords{\kwd{Monofluoroalc\`{e}ne}
\kwd{Ol\'{e}fination}
\kwd{Dipeptides}
\kwd{Acyclonucl\'{e}osides}}

\thanks{Excellence laboratory LabEx SYNORG (ANR-11-LABX-0029), 
Conseil R\'{e}gional de Normandie and European FEDER}

\begin{abstract}
Fluoroalkenes have been known for decades, but their preparation is
still a hot topic. Indeed, the olefination reactions of carbonyl
compounds with fluorinated derivatives are not trivial. For that
reason, new tools have been developed to efficiently access tri- and
tetrasubstituted alkenes. We report our contribution in this field and
their interest will be illustrated by the preparation of dipeptide
isosteres and acyclonucleoside analogues.
\end{abstract}

\begin{altabstract}
Les fluoroalc\`{e}nes sont connus depuis des d\'{e}cennies mais leur
pr\'{e}paration est toujours un sujet d'actualit\'{e}. En effet, les
r\'{e}actions de fluoro-ol\'{e}fination de type Wittig et Peterson ne
sont pas toujours triviales. Pour cette raison, de nouveaux outils ont
\'{e}t\'{e} d\'{e}velopp\'{e}s pour acc\'{e}der de mani\`{e}re efficace
\`{a} des fluorool\'{e}fines tri- et t\'{e}trasubstitu\'{e}s. Nous
d\'{e}crivons notre apport dans ce domaine, et leur int\'{e}r\^{e}t
sera illustr\'{e} par la pr\'{e}paration d'isost\`{e}res de
dipeptides et d'analogues d'acyclonucl\'{e}osides.
\end{altabstract}

\maketitle

\vspace*{10pt}

\twocolumngrid

\end{noXML}

\section{Introduction}\label{sec1}

The introduction of a fluorine atom into a biologically active molecule
significantly modifies its physicochemical properties. This
modification has been widely used for the preparation of
pharmaceuticals, agrochemicals and materials~\cite{1a,1b,1c,1d}.

In this field, the synthesis of fluorinated carbon--carbon double bonds
has been the source of a considerable and increasing interest in recent
years (Figure~\ref{fig1})~\cite{2a,2b}. It has been found that
fluoroalkenes have similar steric and electronic properties compared to
amides and can therefore act as peptidomimetics~\cite{3}.\ For example,
fluoro-olefin \textbf{2} was found to be an excellent DPP IV inhibitor
with a constrained \mbox{conformation}.

\begin{figure*}
\includegraphics{fig01}
\caption{\label{fig1}Fluoroalkenes as amide isosteres.}
{\vspace*{.9pc}}
\end{figure*}

The most common method for the synthesis of alkenes containing an
[(Alk)CF${=}$] moiety is the reaction of an aldehyde or ketone with
fluorinated Horner--Wadsworth--Emmons (HWE) reagents such as
Ph$_3$P${=}$CHF or (EtO)$_2$(O)PCHFCOOEt~\cite{4a,4b,4c,4d,4e}. While,
this approach is very efficient for the preparation of fluoroalkenes
bearing electron withdrawing groups, it is not well suited for the
synthesis of fluoroalkylidenes. Numerous efforts have been made in
order to develop alternative methods and to overcome these
drawbacks~\cite{2a,2b}. In this context, the modified Julia reaction
(or Julia--Kocienski reaction)~\cite{5}, has emerged as one of the most
effective methods since our pioneering work~\cite{6}. This reaction
developed by S. Julia was extended by our group and others to
fluorinated series in order to easily access fluoroalkenes from
aldehydes or ketones in one step
(Scheme~\ref{sch1})~\cite{7a,7b,7c,7d}. This story began with the
preparation of the potent insecticide precursor \textbf{3} from the
pyrethrin family~\cite{6}. This first example has stimulated the
preparation of new fluoroalkenes such as vinyl fluorides, which were
later reported from the corresponding
monofluoromethylsulfone~\cite{8a,8b}.

\begin{scheme*}
\includegraphics{sc01}
{\vspace*{.3pc}}
\caption{\label{sch1}Preparation of an insecticide precursor.}
{\vspace*{-1.2pc}}
\end{scheme*}

In this account, we will focus on the preparation of fluoroalkenes
{via} the modified Julia reaction that was reported by our
group. The aim is to report the main methods for the preparation of
di-, tri- and tetrasubstituted alkenes, with a particular emphasis on
highly functionalized fluoroalkylidenes acting as peptidomimetics and
nucleoside surrogates. 

\section{Synthesis of fluoroacrylate derivatives}\label{sec2}

The effect of the fluorine was important for the preparation of
acrylate derivatives \textbf{5} {(Scheme~\ref{sch2}). Indeed, the
destabilization of the intermediate carbanion by the fluorine atom
increased the reaction rate. The reaction with fluorosulfone}
\textbf{4} is 30 times faster than with the corresponding
non-fluorinated sulfone~\cite{9a,9b}. It was completed in only 30
minutes with the fluorosulfone at 20~\textdegree C, whereas the same
reaction took at least 16 h with the non-fluorinated \mbox{sulfone}. 
\looseness=-1

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{.3pc}}
\caption{\label{sch2}Yields and ratios for the olefination of
fluorinated and non-fluorinated aldehydes.}
{\vspace*{-.85pc}}
\end{scheme*}

In order to control the geometry of the newly formed carbon--carbon
double bond, we found that the reaction had to be carried out in the
presence or absence of metalated bases (Scheme~\ref{sch3}).\ Indeed, in
the presence of DBU, the \textit{(E)}-alkene was the main product,
whereas the \textit{(Z)}-alkene was mainly obtained in the presence of
NaHMDS~\cite{10}.\ The selectivity is strongly dependent on the nature
of the aromatic sulfone, and in particular on the $\uppi$-deficient
character of the heterocycle.\ In this way it is possible to control the
geometry of the carbon--carbon double bond by replacing the
benzothiazolyl (BT){\break} \cite{9a,10} \textbf{6} with a pyrimidine
(Pym) \textbf{8}~\cite{11b} or a \textit{bis}-trifluoromethylphenyl
(BTFP)~\cite{11a} ring \textbf{7}.

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{.5pc}}
\caption{\label{sch3}Control of the carbon--carbon double bond geometry.}
\vspace*{-.6pc}
\end{scheme*}

Other electron-deficient fluoroalkenes were prepared by the modified
Julia reaction using BT~\cite{12a,12b} or BTFP~\cite{11a} fluorosulfones.
Depending on the experimental conditions $Z$ isomers were
preferentially obtained. For example, fluorinated Weinreb amides
\textbf{10} were formed from
\textit{bis}-trifluoromethylphenyl-sulfones \textbf{9} and aldehydes
with an excellent $Z$-selectivity in contrast to
$\upalpha,\upbeta$-unsaturated fluoroacrylates reported in the same
work (Scheme~\ref{sch4})~\cite{11a}.

\begin{scheme*}
\includegraphics{sc04}
\caption{\label{sch4}Selective formation of unsaturated Weinreb amides.}
\end{scheme*}

\section{Fluoroalkylidenes substituted by an{\hfill\break} aromatic
ring}\label{sec3}

The most important advance in the field of the preparation of
fluoroalkenes has been the use of the modified Julia reaction to
prepare fluoroalkylidenes that cannot be obtained directly from
carbonyl compounds (Scheme~\ref{sch5}). Indeed, our initial work on the
modified Julia reaction opened up an easy access to tri- and
tetra-substituted fluoroalkenes bearing an aryl ring, alkyl chain or an
alkylamine. The main difficulties encountered were in the preparation
of the fluorosulfones involved in this reaction. As mentioned above,
the $Z/E$ selectivity is strongly dependent on the nature of the
carbonyl compound, the sulfone and the experimental conditions. In
general, bulky substituents on both reagents favoured the formation of
the \textit{(Z)}-alkenes. 

\begin{scheme*}
\includegraphics{sc05}
\caption{\label{sch5}One step synthesis of fluoroalkylidenes.}
{\vspace*{-1.25pc}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{.3pc}}
\caption{\label{sch6}Fluoroalkenes substituted by an aromatic ring.}
%\vspace*{-5pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc07}
{\vspace*{.3pc}}
\caption{\label{sch7}Preparation of fluoroethylidene derivatives.}
{\vspace*{-.5pc}}
\end{scheme*}

The preparation of monofluoroalkenes substituted by an aryl was
reported by the group of Zajc from monofluorosulfones \textbf{11}
(Scheme~\ref{sch6})~\cite{13a,13b}. \mbox{($E$)-alkenes} \textbf{12} were the
main product of the \mbox{reaction,} and the use of polar solvents (DMF:DMPU)
could drive the reaction in favour of the $Z$ isomers. This reaction
can also be carried out from ketones.

\section{Fluoroalkenes substituted by an alkyl chain or a saturated
ring} \label{sec4}

The synthesis of fluoroalkylidenes is the most challenging topic. As
mentioned above, the fluoroolefination reactions of carbonyl compounds
were limited and the modified Julia reaction opened a new way to access
a wide range of fluoroalkenes.

\begin{scheme*}
\includegraphics{sc08}
{\vspace*{.4pc}}
\caption{\label{sch8}Preparation of fluoroalkylidenes with tetrazolyl
sulfones.}
%{\vspace*{-.5pc}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc09}
{\vspace*{-.6pc}}
\caption{\label{sch9}Preparation of enantiopure allylic
$\upalpha$-branched fluoroalkenes.}
{\vspace*{-.38pc}}
%{\vspace*{-.5pc}}
\end{scheme*}

Our first example on the pyrethrin analogue was the cornerstone of the
fluoroolefination of carbonyl compounds based on the modified Julia
reaction~\cite{6}. For example, the expected alkenes \textbf{14} and
\textbf{15} were obtained in high yield but with a moderate $Z/E$
selectivity (Scheme~\ref{sch7}). This olefination reaction was applied
to the synthesis of exo-glycals which were obtained in moderate to good
yields and with moderate selectivity. Importantly, the reaction carried
out with lactones required a stepwise process. In this case, the
alcoholate intermediate had to be captured before the Smiles
rearrangement could be carried out at room temperature~\cite{14a,14b}. The
modest selectivity observed in these examples was related to the small
size of the methyl group even for the preparation of \textbf{16}. This
reaction has been applied to the preparation of glucosidase inhibitors.

To partially address the stereoselectivity issue, phenyltetrazolyl
sulfones \textbf{17} {were tested instead of benzothiazolyl sulfones
(Scheme~\ref{sch8})~\cite{15}. A rational analysis of the observed
results was not easy to perform as the $Z/E$ ratio was strongly
dependent on the carbonyl compounds and the nature of the alkyl chain. 

We have also reported the preparation of enantiomerically pure allylic
$\upalpha$-branched fluoroalkenes from chiral fluorosulfones in
the benzothiazolyl series (Scheme~\ref{sch9})~\cite{16}. The chiral
sulfones \textbf{18} were prepared by a Mitsunobu reaction followed by
a Krapcho decarbethoxylation reaction~\cite{17}. These sulfones were
involved in the modified Julia reaction which, despite a moderate
control of the carbon--carbon double bond geometry, provided an easy
route to chiral fluoroalkenes \textbf{19}.

\looseness=-1
Notably, the group of J. Hu reported a rapid synthesis of $Z$- and
$E$-fluoroalkenes by phase separation with
pyridine sulfone \textbf{20} (Scheme~\ref{sch10})~\cite{18}. In this
case, the \textit{anti}-periplanar elimination is slow and depends on
the relative configuration of the sulfinate intermediates. It has been
suggested that the \textit{anti}-lithium sulfinyl arylether, which
gives gives the \textit{(Z)}-alkene \textbf{21}, decomposes more
rapidly than the \textit{syn}-lithium sulfinyl arylether \textbf{22},
which gives the \textit{(E)}-alkene \textbf{23}. Because of the aqueous
solubility of the intermediate sulfinates, the kinetic control of the
reaction allowed the \textit{(Z)}-alkene to be extracted first with an
organic solvent. The aqueous layer containing the \textit{syn}-lithium
sulfinyl arylether was then treated with an acid (TsOH) to give after
extraction the corresponding \textit{(E)}-alkene.

\begin{scheme*}
\includegraphics{sc10}
{\vspace*{-.4pc}}
\caption{\label{sch10}Kinetic resolution for the synthesis of
fluoroalkenes.}
%\vspace*{-.4pc}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc11}
{\vspace*{-.4pc}}
\caption{\label{sch11}Preparation of dipeptide isosteres.}
%\vspace*{-.4pc}
\end{scheme*}

\looseness=-1
While the modified Julia reaction was efficient for the synthesis of
fluoroalkenes, the preparation of functionalized fluoroalkenes was
limited by the access to starting alkylfluorosulfones.\ In this area, we
were focused on the challenging synthesis of nitrogen-containing
fluoroalkenes.\ The preparation of aminosulfones was achieved from a
fluorovinyl sulfone, and involved the olefination reaction. The
aza-Michael addition of amines and amino acids to vinylsulfones
\textbf{24} afforded the corresponding sulfones \textbf{25} as new
fluoro-olefination reagents (Scheme~\ref{sch11})~\cite{19}, whose
reactivity in the modified Julia reaction was studied with carbonyl
compounds and allowed us to prepare dipeptide isosteres
\textbf{26}~\cite{20a,20b}, and functionalized \textit{exo}-glycal
derivatives. Regarding the access to \textbf{26}, the $N$-terminal
amino group was introduced by a conjugate addition of phtalimide onto
fluorinated vinylsulfones containing an $\upalpha$-amino-acid side
chain. The \textit{C}-terminal motif was attached to the fluorovinylic
peptide bond mimic \textit{via} the Julia--Kocienski reaction between
fluorosulfones and substituted aldehydes with $\upalpha$-amino-acid
side chains (Scheme~\ref{sch11}). In all cases, the
diastereoselectivity was in favour of the $Z$ isomers due to the steric
demand of the bulky\unskip\break 
substituents.

Finally, the incorporation of monofluoroalkene-based dipeptide
isosteres into peptide synthesis was tested (Scheme~\ref{sch12}).\ A
coupling reaction in solution between racemic
Boc-Gly-$\rmpsi$[CF${=}$CH]-Leu \textbf{27} and (L)-phenylalanine ethyl
ester was performed, yielding the corresponding tripeptide isostere
Boc-Gly-$\rmpsi$[CF${=}$CH]-Leu-Phe-OEt \textbf{28}.

\begin{scheme*}
\includegraphics{sc12}
\caption{\label{sch12}Fluorinated tripeptide analogue.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc13}
{\vspace*{.3pc}}
\caption{\label{sch13}Pyrrolidine as potential proline isosteres.}
\vspace*{-1pc}
\end{scheme*}

Following a similar approach, pyrrolidine fluorosulfone \textbf{29} was
also prepared and used in the olefination of carbonyl compounds to give
alkenes \textbf{30} in moderate to good yields with low} $E/Z$
selectivity (Scheme~\ref{sch13})~\cite{21}.

\begin{scheme*}
\includegraphics{sc14}
{\vspace*{-.5pc}}
\caption{\label{sch14}Preparation of an acyclonucleoside.}
\end{scheme*}

Finally, this aza-Michael addition onto vinyl sulfones provided access
to nucleic base-containing benzothiazolyl sulfones. For example, the
thymine-derived sulfone \textbf{31} was used in the modified Julia
reaction to prepare the acyclonucleoside precursor \textbf{33}
(Scheme~\ref{sch14})~\cite{22}.

\begin{scheme*}
\includegraphics{sc15}
{\vspace*{.4pc}}
\caption{\label{sch15}Ring-opening reaction of alkylidene oxetanes.}
\vspace*{-.5pc}
\end{scheme*}

\section{Access trisubstituted fluoroalkenes for the preparation of
acyclonucleosides}\label{sec6} 

For the synthesis of trisubstituted fluoroalkenes, we explored another
alternative route using alkylidene oxetanes \textbf{35} as key
intermediates (Figure~\ref{fig2})~\cite{23}. The selective
ring--opening reaction of fluoroalkylidene oxetanes was controlled by
the presence of the fluorine atom, providing a two-step access to
tetrasubstituted alkenes \textbf{34} with excellent geometry control
(Figure~\ref{fig2})~\cite{24}.

\begin{figure}
%{\vspace*{-.8pc}}
\includegraphics{fig02}
{\vspace*{-.35pc}}
\caption{\label{fig2}Ring--opening of oxetane derivatives.}
\vspace*{-8pt}
\end{figure}

The preparation of a series of fluoroalkylidene oxetanes was realized
from 3-oxetanone through an olefination reaction with benzothiazoyl
sulfones (Scheme~\ref{sch15})~\cite{23}. With these fluoroalkylidene
oxetanes \textbf{36a--f} in hand, the selectivity of the \mbox{ring--opening}
reaction with bromide ion to access to tetrasubstituted fluoroalkenes
was investigated. 

The ring-opening reaction of oxetane \textbf{36a}, substituted by a
phthalimido group, carried out with bromide ion sources (HBr 33~wt\% in
AcOH or Bu$_{4}$NBr in the presence of BF$_3$-Et$_2$O) afforded the
corresponding \textit{(E)}-alkene \textbf{37a} in an $E/Z$ ratio of
89:11 (Scheme~\ref{sch15}). This reaction was extended to other
fluoroalkylidene oxetanes \textbf{36b--d} substituted with bulky
substituents (an alkyl chain or a nucleic base) and different sources
of bromide ions~\cite{24,25}. The ring-opening of these oxetanes to
\textit{(E)}-alkenes was also highly selective, thus confirming our
initial observation. The reaction tested with oxetanes \textbf{36b--d}
selectively gave the corresponding $E$-fluoroalkenes {\textbf{37b--d},}
in up to 9:1 $E/Z$ ratios. On the other hand, when the reaction with
oxetanes \textbf{36e,f} was carried out in the absence of a fluorine
atom, only \textit{(E)}-alkenes \textbf{37e,f}, were formed. In this
case, the attack of the bromide ion occurred on the opposite side of
the bulky phthalimido or protected adenine substituents. \looseness=-1

\looseness=-1
The functionalization of alkene \textbf{37a} allowed an easy access to
a large series of tetrasubstituted fluoroalkenes. Indeed, the oxetane
ring-opening reaction was restricted to the bromide ion
(Scheme~\ref{sch16}).

\begin{scheme*}
\vspace*{.2pc}
\includegraphics{sc16}
\caption{\label{sch16}Functionalization by substitution reaction of the
bromide.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc17}
\vspace*{.8pc}
\caption{\label{sch17}Preparation of triazolyl derivatives in F-series.
(a) KOAc, DMF, 20~\textdegree C, 16 h, 86\%. (b) MsCl, Et$_3$N,
CH$_2$Cl$_2$, 0~\textdegree C, 2 h, (c) NaN$_{3}$, DMF, 20~\textdegree
C, 12 h, 74\% (2 steps). (d) $N$-Boc-amino-pentynone,
$\mathrm{CuSO}_{4}\cdot5\mathrm{H}_2\mathrm{O}$,
sodium ascorbate, $t$-BuOH, H$_2$O, 40~\textdegree
C, 24 h, 79\%. (d) HCl$_{\mathrm{aq}}$ (3N), MeOH, 20~\textdegree C, 
20~h,~76\%.}
\vspace*{-1pc}
\end{scheme*}

Functionalization of alkene \textbf{37a} by displacement of the bromine
atom, with nucleophiles such as CsF and NaN$_{3}$ afforded products
\textbf{40} and \textbf{38} in 92\% and 93\% yields, respectively.
Reactions with amines and thiols such as pyrrolidine and
\mbox{2-mercaptobenzothiazole,} afforded products \textbf{39} and \textbf{41}
in high yield. 

\begin{figure*}
\includegraphics{fig03}
{\vspace*{-.25pc}}
\caption{\label{fig3}Measured IC$_{50}$ values towards DltA of
\textit{E. faecalis}.}
{\vspace*{-.35pc}}
\end{figure*}

Finally, this rapid synthesis of tetrasubstituted alkenes by sequential
ring-opening and nucleophilic substitution reactions was intended to
test the robustness of a selective preparation of acyclonucleoside
precursors. In connection with our work on the preparation of
inhibitors of a protein involved in antibioresistance~\cite{26,27,28},
we focused on the synthesis of acyclic analogues of functionalized
\mbox{adenosine} derivatives as enzyme inhibitors. Our aim was to
determine the influence of the replacement of the ribosyl ring by a
fluoroalkenyl chain on the biological activity of the resulting
nucleoside analogue (Scheme~\ref{sch17}). To access the final target
compound \textbf{46}, the preparation of fluorinated azide \textbf{44}
was realized from the tetrasubstituted ($E$)-alkene \textbf{42}. The
substitution of the bromine atom was carried out with KOAc to give the
intermediate acetylated alcohol \textbf{43}, which was mesylated and
then treated with NaN$_{3}$ to produce azide \textbf{44} in 74\%
overall yield. {Finally}, the expected fluorinated triazolyl
derivative \textbf{45} was obtained in 79\% yield from \textbf{44} and
\textit{N}-Boc 4-amino-pentynone. Compound \textbf{45} was treated by
an acidic methanolic solution to afford \textbf{46} in 76\% yield
(Scheme~\ref{sch17}).\looseness=-1

The inhibitory activity of \textbf{46} against the DltA enzyme
(\textit{Enterroccus faecalis}) was investigated and compared with that
of nucleoside \textbf{47} ($\mathrm{IC}_{50}= 2.5~\upmu\mathrm{M}$) and
triazolyl derivative \textbf{48} ($\mathrm{IC}_{50}=
3.4~\upmu\mathrm{M}$) (Figure~\ref{fig3})~\cite{28}. It appeared that
the introduction of a triazolyl ring did interfere with the activity,
and the replacement of the ribosyl ring by a fluoro
\textit{trans}-butenyl moiety was also well tolerated. Compound
\textbf{46} exhibited an IC$_{50}$ value of 7.4~$\upmu$M, slightly
higher than that observed with adenosine derivative \textbf{48}. This
first example of the use of a fluoro \textit{trans}-butenyl moiety
shows that this moiety can be considered as a surrogate for the
nucleoside ribosyl moiety. In the present case, the presence of a
carbon--carbon double bond is important as reported for
\textit{trans}-butenyl substrates targeting thymidylate
kinase~\cite{29,30}, In contrast, the acyclic analogue \textbf{49}
containing an alkyl ether chain (2-oxa-butyl) instead of a
(fluoro)alkenyl chain was the less efficient inhibitor of the DltA
enzyme with an inhibition constant of 20.1~$\upmu$M. The loss of
activity was probably related to the high flexibility of the alkyl
chain, which allows conformational changes. The ($E$)-fluorobutenyl
moiety appeared to be the best nucleoside mimic in the butenyl series.
\vspace*{-.2pc}

\section{Conclusion}\label{sec7}

The modified Julia reaction has contributed to the development of new
approaches for the preparation of highly functionalized fluoroalkenes
including fluoroalkylidenes. The discovery of this reaction and its
application to the synthesis of fluorinated biomolecules has provided
access to fluoroalkene motifs as mimics of dipeptides and
\mbox{acyclonucleosides}.
\vspace*{-2pt}

\section*{Declaration of interests} 
The authors do not work for advise, own shares in, or receive funds
from any organization that could \mbox{benefit} from this article, and
have declared no affiliations other than their research organizations.
\vspace*{-2pt}

\section*{Funding} 
This work was supported by the excellence laboratory LabEx SYNORG
(ANR-11-LABX-0029), the Conseil R\'{e}gional de Normandie and the
European FEDER funding. 

\CDRGrant[ANR]{ANR-11-LABX-0029}

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