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\DOI{10.5802/crchim.457}
\datereceived{2026-04-16}
\daterevised{2026-05-11}
\dateaccepted{2026-05-19}
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\COI{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.}

\begin{document}

%\dateposted{2026-08-06}

\begin{noXML}

\editornote{Article submitted by invitation}
\alteditornote{Article soumis sur invitation}

\CDRsetmeta{articletype}{research-article}

\title{Advanced strategies and methods for the total synthesis of
natural endoperoxides}

\alttitle{Strat\'{e}gies et m\'{e}thodes avanc\'{e}es pour la
synth\`{e}se totale d'endoperoxydes naturels}

\author{\firstname{Bastien} \lastname{Champciaux}\CDRorcid{0000-0002-5590-5144}}
\address{BioCIS, Facult\'{e} de Pharmacie, Universit\'{e} Paris-Saclay,
CNRS, 91400, Orsay, France}
\email[B. Champciaux]{champciaux.bastien@gmail.com}

\author{\firstname{Laurent} \lastname{Ferri\'{e}}\CDRorcid{0000-0002-1171-205X}\IsCorresp}
\addressSameAs{1}{BioCIS, Facult\'{e} de Pharmacie, Universit\'{e}
Paris-Saclay, CNRS, 91400, Orsay, France}
\email[L. Ferri\'{e}]{laurent.ferrie@universite-paris-saclay.fr}

\keywords{\kwd{Endoperoxide}\kwd{Total synthesis}\kwd{Asymmetric
catalysis}\kwd{Ring expansion}\kwd{Lewis
acid}\kwd{Allylation}\kwd{Aldol reaction}}

\altkeywords{\kwd{Endoperoxyde}\kwd{Synth\`{e}se totale}\kwd{Catalyse
asym\'{e}trique}\kwd{Expansion de cycle}\kwd{Acide de
Lewis}\kwd{Allylation}\kwd{Aldolisation}}

\thanks{Universit\'{e} Paris-Saclay,  Centre National de la Recherche
Scientique (CNRS), Minist\`{e}re de l'Enseignement Sup\'{e}rieur et de
l'Innovation (MESRI), Vietnamese Government (USTH Program 2012),
Fondation pour le d\'{e}veloppement de la chimie des substances
naturelles et ses applications (MYCOXY project).}

\begin{abstract}
Natural endoperoxides present a challenge in total synthesis. Over the
past decade, we have focused our research on developing new methods to
synthesize these heterocycles. These strategies involve the insertion
of molecular oxygen into strained cycloalcohols, followed by the
addition of silylated nucleophiles to peroxycarbenium species. This
approach has been successful in the total synthesis of marine
endoperoxides, such as mycaperoxides and ethyl plakortide Z, as well as
in the synthesis of analogs of mycangimycin, a natural antifungal and
antimalarial agent isolated from an insect--bacteria mutualism. Despite
the effectiveness of our strategy, controlling chirality remains a
formidable challenge in peroxide synthesis. Silylium-based asymmetric
counteranion-directed catalysis enabled the synthesis of chiral
endoperoxides and significantly improved previous results in terms of
diastereoselectivity.
\vspace*{-4pt}
\end{abstract}

\begin{altabstract}
Les endoperoxydes naturels constituent un d\'{e}fi en synth\`{e}se
totale. Au cours de la derni\`{e}re d\'{e}cennie, nous avons ax\'{e}
nos recherches sur le d\'{e}veloppement de nouvelles m\'{e}thodes de
synth\`{e}se de ces h\'{e}t\'{e}rocycles. Ces strat\'{e}gies impliquent
l'insertion d'oxyg\`{e}ne mol\'{e}culaire dans des cycloalcools
contraints, suivie de l'addition de nucl\'{e}ophiles silyl\'{e}s \`{a}
des esp\`{e}ces peroxycarb\'{e}nium. Cette approche a permis de
r\'{e}ussir la synth\`{e}se totale d'endoperoxydes marins, tels que les
mycaperoxydes et l'\'{e}thylplakortide Z, ainsi que la synth\`{e}se
d'analogues de la mycangimycine, un agent antifongique et antipaludique
naturel isol\'{e} \`{a} partir d'une relation de mutualisme entre un
insecte et une bact\'{e}rie. Malgr\'{e} l'efficacit\'{e} de notre
strat\'{e}gie, le contr\^{o}le de la chiralit\'{e} demeure un d\'{e}fi
de taille pour la synth\`{e}se de peroxydes. La catalyse
asym\'{e}trique dirig\'{e}e par un contre-anion \`{a} base de silylium
a permis la synth\`{e}se d'endoperoxydes chiraux et a
consid\'{e}rablement am\'{e}lior\'{e} les r\'{e}sultats ant\'{e}rieurs
en termes de diast\'{e}r\'{e}os\'{e}lectivit\'{e}.
\end{altabstract}

%\input{CR-pagedemetas}

\maketitle

\vspace*{-3pt}

\twocolumngrid

\end{noXML}

\section{Introduction} \label{sec1}

Endoperoxides are a special class of natural products found in many
types of organisms. Up to one thousand different compounds have been
reported so far~\cite{1,2,3}. Their role is diverse, often serving as a
means of defense for the host that produces them, but they are also
precursors of important biomolecules, such as prostaglandins. The value
of endoperoxides has been demonstrated in antiparasitic chemotherapy;
artemisinin and its semi-synthetic derivatives have become major drugs
in the fight against malaria. The reactivity of the peroxide function
explains bioactivities reported for this class of compounds, including
antiviral, antibacterial, and antifungal properties.\looseness=-1

\begin{figure*} 
\includegraphics{fig01}
\caption{\label{fig1}Selected examples of natural endoperoxides.}
\end{figure*}

The most commonly found scaffolds are 1,2-dioxolanes and 1,2-dioxanes,
which are widely represented in natural products (Figure~\ref{fig1}).
However, the natural occurrence of 1,2-dioxolanes is lower than that of
1,2-dioxanes, probably due to a higher instability of the five-membered
heterocycle (around 2.5~kcal/mol difference). Thus, 1,2-dioxolanes are
essentially represented in sponges by the plakinic acid subclass of
compounds, from which many natural analogs have been isolated and are
differentiated by their side chain and stereochemistry. Other
1,2-dioxolanes can be found in terpene derivatives from plants such as
arteincultone or tehranolide. Nevertheless, the most interesting
example concerns mycangimicyn, a heptaenic fatty acid featuring a
1,2-dioxolane ring at the 3,5-position~\cite{4,5}. This compound was
discovered and isolated from a pine beetle--\textit{Streptomyces}
mutualism, and showed high antimalarial and antifungal activity
(EC\tsub{50} ${=}$ 17~ng/mL on \textit{P.~falciparum}, MIC ${=}$ 0.2~mg/mL
on \textit{C.~albicans}).

1,2-Dioxanes, on the other hand, are prevalent in all types of living
organisms. Examples include rugosal in plants, talaroperoxides in
fungi, stolonoxides in tunicates, and mycaperoxides and plakortides in
sponges. The last two families of natural products were found in the
\textit{Mycale} and \textit{Plakortis} genera. Mycaperoxides exhibit
antiviral and ichthyotoxic properties, while plakortides exhibit
antifungal, antimalarial, and cytotoxic properties. These properties
explain their role as antifouling agents. These two endoperoxide
families differ in their structural features. On the one hand,
mycaperoxides have a sesquiterpene subunit that differentiates the
various analogs and exhibit a trisubstituted 1,2-dioxane with a
propionic acid residue. Plakortides, on the other hand, are mainly
characterized by ethyl groups at positions~4 and~6, and the naturally
occurring analogs are principally distinguished by their fatty chains,
which have different lengths with or without unsaturations. The
relative and absolute configurations also vary among the different
analogs of both mycaperoxides and plakortides.

The total synthesis of endoperoxides is a relatively underexplored
field, despite numerous reports of natural product isolation and
potential biological activities~\cite{6,7,8}. One of the main reasons
is obviously the fragility of the peroxyl bond, inherent to this family
of products, which imposes limitations on the feasible reactions. The
second probable reason is the limited number of methods available for
synthesizing these compounds. In particular, few methods are available
for accessing chiral peroxyl bonds, accentuating the difficulty of
total synthesis. In this article, we summarize our work over the past
decade on the synthesis of 1,2-dioxolanes and 1,2-dioxanes,
highlighting total synthesis of endoperoxides as a a central theme. Our
initial efforts focused on developing new tools and strategies for the
synthesis of 1,2-dioxolanes, with the aim of obtaining mycangimycin
and/or simpler analogs. Subsequently, our work expanded to the
synthesis of 1,2-dioxanes aiming to \mbox{address} new \mbox{synthetic}
challenges, illustrated in the total synthesis of several mycaperoxides
and ethyl plakortide~Z. The synthesis of endoperoxides reached a new
dimension with the development of new asymmetric methods based on
chiral counteranion-directed catalysis.

\begin{scheme*} 
{\vspace*{-.2pc}}
\includegraphics{sc01}
{\vspace*{.2pc}}
\caption{\label{sc1}General strategy toward the synthesis of
1,2-dioxolanes and 1,2-dioxanes.}
{\vspace*{-.8pc}}
\end{scheme*}

The strategy that we developed for the synthesis of endoperoxides
comprises two key steps (Scheme~\ref{sc1}). Primary, the insertion of
molecular oxygen into a strained cyclopropanol or cyclobutanol is
catalyzed by cobalt or manganese, which abstracts a hydrogen atom from
the hydroxy group, generating alkoxy radicals that readily open due to
ring strain. The resulting alkyl radicals can readily trap triplet
oxygen and further cyclize to form endoperoxyketals or acetals. The
second crucial step involves the activation of this function with a
Lewis acid to promote a reactive peroxycarbenium species, which can
then be trapped in situ by neutral silylated nucleophiles. The
orientation of the addition is controlled by the conformation of the
peroxycarbenium ion but can also be controlled at a higher level
through counteranion-directed catalysis.

\section{Synthesis of 1,2-dioxolanes} \label{sec2}
\subsection{First study toward mycangimycin} \label{sec2.1}

When we started our studies on the synthesis of endoperoxides, we were
attracted to mycangimycin, whose 1,2-dioxolane is highly similar to the
THF ring, a heterocycle that has been intensively studied in our
laboratory in past years~\cite{9}. The polyenic chain was presumably
unstable, and we believed at the time that the antimalarial activity of
mycangimycin could be attributed to the endoperoxide ring, while the
antifungal activity would come from the polyenic chain, in a manner
similar to amphotericin~B, for instance. However, the total synthesis
of mycangimycin still constitutes a challenge. On the one hand, the
synthetic access to the chiral endoperoxide core requires the
development of new methods. On the other hand, synthesizing the
polyenic chain appears to be unattainable due to presumed instability.
Some preliminary works have indeed shown that the synthesis of polyenes
with defined $E$ or $Z$ stereochemistry becomes increasingly
challenging after three or four conjugated double bonds. Thus, it was
preferred to focus on the synthesis of the endoperoxide, designing a
strategy to access saturated analogs of mycangimycin and evaluate their
biological properties. For this reason, access to chiral endoperoxides
was not a target at this stage; indeed, given the lack of appropriate
methods, this was beyond the scope of this study.

After numerous pioneering experiments, it was discovered that the
peroxidation of cyclopropanol is a convenient method for accessing the
1,2-dioxolane scaffold. Earlier reports indicated that cobalt~\cite{10}
and manganese~\cite{11} catalysis promote this transformation.
Cyclopropanol~\textbf{2} could be obtained in high yield through the
Kulinkovich reaction between alkene~\textbf{1} and methyl palmitate,
utilizing Cha's protocol, which enabled titanocene metathesis at the
terminal double bond~\cite{12} (Scheme~\ref{sc2}). Oxygen insertion in
cyclopropanol~\textbf{2} proceeded in high yield following a procedure
by Wu~\cite{10} that reported the use of Co(acac)\tsub{2} in EtOH. The
remaining OH group in 1,2-dioxolane \textbf{3} was reduced with
Et\tsub{3}SiH and TfOH activation, via a peroxycarbenium
intermediate~\cite{13}. By this route, the \textit{cis} configuration
was predominantly obtained (dr ${=}$ 83:17), with the hydride reacting on
the less hindered face. Fluoride cleavage of the TBDPS group
(\textit{tert}-butyldiphenylsilyl) and ruthenium-catalyzed oxidation
afforded~\textbf{6}, a racemic and saturated analog of mycangimicyn.

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{.4pc}}
\caption{\label{sc2}Synthesis of the saturated analog of mycangimycin.}
{\vspace*{-.8pc}}
\end{scheme*}

\subsection{Alkylation of 1,2-dioxolanyl acetates} \label{sec2.2}

Although the strategy used provided, in a few steps, a simplified
analog of mycangimycin, it lacked flexibility because the Kulinkovitch
reaction was not compatible with multiple unsaturations or \mbox{proximal}
steric hindrance~\cite{14}. Inspired by Dussault and Woerpel's
pioneering works~\cite{15,16,17}, it was found that endoperoxyacetals
could serve as an excellent platform for gaining molecular diversity in
the synthesis of 3,5-disubstituted-1,2-dioxolanes~\cite{18}. Indeed, it
would be possible to generate peroxycarbenium ions from these
precursors, which could be alkylated by various neutral silylated
nucleophiles. However, it is more challenging to obtain these reactive
species than regular oxycarbenium ions due to the electronegativity of
the second oxygen, which decreases the donor effect required for
stabilization (Figure~\ref{fig2}).\ The relative stability of different
oxy- and peroxycarbenium species was calculated using DFT
(B3LYP/6-311G++(d,p) level of theory), revealing a significant impact
of this phenomenon, with energy differences ranging from 13.4 to
21.5~kcal/mol compared to regular oxycarbenium species.\ The specific
cyclic constraint of 1,2-dioxolane peroxycarbenium ions also makes this
species more difficult to produce.\ The direct consequence was the
difficulty of synthesizing methoxyperoxyacetal \mbox{\textbf{9a--i}}
and subsequently making it react (Scheme~\ref{sc3}); we thus turned our
attention to the synthesis of acetoxy derivatives \textbf{8a--i}
(Scheme~\ref{sc3})~\cite{19,20}.\ Acetoxy is indeed a better leaving
group, facilitating the promotion of peroxycarbenium ions. The
synthesis of \textbf{8a--i} went through the ring expansion of
cyclopropanols \textbf{6a--i} with molecular oxygen under
Mn(acac)\tsub{3} or Co(acac)\tsub{2} catalysis in THF~\cite{10,11},
followed by an acetylation step. The conditions of acetylation were
crucial; regular pyridine or DMAP-mediated reactions led to a
fragmentation of the endoperoxide, whereas rare-earth metal catalysis,
such as with ytterbium, produced the target acetate in high
yields~\cite{21}. Cyclopropanols \textbf{6a--i} were prepared following
three different methods (A--C). Method~A involved a Kulinkovich
reaction~\cite{22}, but was only applicable to monosubstituted
cyclopropanols and in cases where a Grignard reagent could be prepared
or did not bear highly hindered substituents. Method~B offered an
alternative for the last two situations. Chromium (II)
chloride-mediated reductive cyclization of methacroleins~\cite{23,24}
limited the \mbox{$\upbeta$-elimination} pathway to produce \textbf{6f}
and allowed the introduction of a bulky \textit{tert}-butyl group
(\textbf{6g}). The synthesis of disubstituted 1,2-dioxolanes required
Method~C, which involved a dihalocyclopropanation and a Matteson
reaction, followed by a boron \mbox{oxidation}~\cite{25}.

\begin{figure}
\includegraphics{fig02}
{\vspace*{-.2pc}}
\caption{\label{fig2}Calculated relative stability of oxy- and
peroxycarbenium ions.}
{\vspace*{-.2pc}}
\end{figure}

\begin{scheme} 
\includegraphics{sc03}
{\vspace*{.7pc}}
\caption{\label{sc3}Synthesis of 3-acetoxy-dioxolanes following 3
different routes.}
{\vspace*{-1pc}}
\end{scheme}

The next objective was then to substitute the acetate function. The
first set-up conditions were inspired by Woerpel and Dussault's
works~\cite{16,17} and involved TiCl\tsub{4} or SnCl\tsub{4} as Lewis
acid (Scheme~\ref{sc4}, Conditions~A) to promote the peroxycarbenium
ion, enabling the addition of several nucleophile types (allylsilanes,
enoxysilanes, silanes, or silylcyanides and azides)~\cite{19}. Yields
were generally good, particularly with SnCl\tsub{4}. However,
silylketene acetals proved to be unreactive under these conditions
(\textbf{10m--o}). Diastereoselectivity was generally low (except with
TiCl\tsub{4}), such as with THF rings~\cite{26}. Stoichiometry was
optimum with 0.9 equiv of Lewis acid, which allowed full conversion and
minimized degradation pathways. TiCl\tsub{4} was particularly reactive
and consequently gave generally lower yields than SnCl\tsub{4} due to
greater degradations.\ However, the higher \mbox{diastereoselectivity}
toward the \textit{trans} product with TiCl\tsub{4} was surprising, and
it was proposed, supported by DFT calculations, that the \textit{cis}
diastereomer degrades faster than the \textit{trans} product,
explaining its prominence. Degradation pathways involve Lewis
acid-mediated fragmentation of the 1,2-dioxolane ring and
Kornblum--DeLaMare rearrangement~\cite{27}. 

\begin{scheme*} 
\includegraphics{sc04}
{\vspace*{.4pc}}
\caption{\label{sc4}Alkylation of 1,2-dioxolanes under stoichiometric
or catalytic conditions.}
{\vspace*{-.8pc}}
\end{scheme*}

Following this initial study, new conditions were needed to limit the
degradation pathways and improve the reproducibility of the various
alkylation reactions. Indeed, maintaining the temperature at
${-}$40~{\textdegree}C without proper equipment, as well as the high
reactivity of TiCl\tsub{4} and SnCl\tsub{4}, which can lead to
overdegradation, accounts for the variability in the results.
InCl\tsub{3}, in combination with TMSCl~\mbox{\cite{28,29,30}}, as well
as rare-earth triflate~\cite{31,32,33} have been reported for Sakurai
or Mukaiyama aldol reactions, with the main advantage being that they
can be used in catalytic amounts under mild conditions. The use of
InCl\tsub{3} (5~mol\%) with 2.5 equiv of TMSCl showed high capacity in
the substitution reaction from endoperoxyacetals \textbf{8a--g}
(Scheme~\ref{sc4}, Condition~B). The \mbox{reaction} typically
completes within 1--2~h at room temperature~\cite{20}. No significant
degradation was \mbox{observed}, unless the reaction was allowed to
continue for more than 24~h. The scope of the reaction is large, with
yields and selectivities comparable to those obtained with
SnCl\tsub{4}. However, halo-allylsilanes were unreactive with these
catalysts, giving no conversion to \textbf{10f} or \textbf{10i}. The
geminal halogen deactivates the silicon atom, which explains a lack of
reactivity in this case; however, the observed reactivity with
SnCl\tsub{4} or TiCl\tsub{4} is probably caused by a transmetallation
with silicon to produce more reactive species. In contrast, the
catalytic conditions enabled the reaction with silylketene acetals
(esters \textbf{10o} or thioesters \textbf{10m--n}), which is of great
importance considering the challenge that total synthesis of
endoperoxides represents. Rare-earth metal triflates were also studied
as mild Lewis acids. Among all salts tested, scandium was found to show
the highest reactivity, similar to that of InCl\tsub{3}/TMSCl. The main
advantage of Sc(OTf)\tsub{3} is that only one reagent needs to be added
to the reaction mixture; the diastereomeric ratio and yields were of
the same magnitude as those obtained with either SnCl\tsub{4} or
InCl\tsub{3}/TMSCl. It is noteworthy that \textit{cis}- and
\textit{trans}-1,2-dioxolanes are, in general, not separable by silica
gel chromatography; therefore, all the products were isolated and
characterized as \mbox{mixtures}. 

\subsection{Biological evaluation of 1,2-dioxolanes} \label{sec2.3}

Evaluation of twenty-three 1,2-dioxolanes, which constitute analogs of
1,2-mycangimycin, was performed against four different infectious
agents~\cite{34}. As mycangimycin possesses strong antifungal activity,
our 1,2-dioxolanes were evaluated against \textit{Candida albicans}
CAAL93 and \textit{Aspergillus fumigatus} ASFU76 strains. However, none
of them exhibited any significant antifungal activity. This finding
supports the hypothesis that this activity is related to the polyenic
chain of mycangimycin. Antimalarial and antileishmanial activities were
evaluated on \textit{Plasmodium falciparum} and \textit{Leishmania
Donovani}. The saturated analog of mycangimycin \textbf{5} did not
exhibit significant antimalarial activity, suggesting that the side
chain also plays a crucial role in the antimalarial activity.
Nevertheless, interesting results were found for dioxolanes \textbf{8g}
and \textbf{10a}, which possess activity in the same range as
chloroquine, as well as high selectivity indexes (SI)
(Figure~\ref{fig3}). Four other compounds were found to be quite active
against \textit{L.~Donovani} in its axenic amastigote form.
\textbf{10f} and \textbf{10i} bear a vinyl halide function, while
\textbf{10m} and \textbf{10n} possess a thioester function. However,
the selectivity index is disappointing overall and these compounds lost
most of their activity against intramacrophage amastigotes, suggesting
that they cannot properly cross the macrophage and parasitophorous
vacuole.

\begin{figure}
\vspace*{6pt}
\includegraphics{fig03}
\vspace*{6pt}
\caption{\label{fig3}Antiparasitic activity of selected 1,2-dioxolanes.
Activities are expressed as IC\tsub{50} ($\upmu$M); selectivity indexes
(SI) are calculated from the ratio with cytotoxicity on HUVEC cell
lines. Control: chloroquin and miltefosine.}
\end{figure}

\section{Synthesis of 1,2-dioxanes} \label{sec3}
\subsection{Oxidative ring expansion of cyclobutanols} \label{sec3.1}

After studying 1,2-dioxolanes, we were also interested in synthesizing
1,2-dioxanes. As outlined in the introduction, this heterocycle is
predominant among the natural endoperoxides. Our aim was to apply the
same strategy to obtain and functionalize the endoperoxide ring as
outlined in Scheme~\ref{sc1}, i.e., oxygen insertion on a strained ring
and addition to a peroxycarbenium ion. Although the \mbox{insertion} of
molecular oxygen was a known transformation, its application to
cyclobutanols had not been reported previously. The strain energy of
cyclobutane compared to cyclopropane is somewhat similar (26.90 versus
28.13~kcal/mol, respectively)~\cite{35}. However, the rate of ring
opening of methyl radicals is considerably different, making the
radical opening of methylcyclopropyl radical very fast~\cite{36},
whereas the reaction speed is moderate in the case of methylcyclobutyl
radical~\cite{37,38} (Figure~\ref{fig4}). Improvement can be achieved
through $\upalpha$-substitution, which stabilizes the newly formed
radical. Similar behavior can be anticipated regarding the relative
speed of ring opening with alkoxy radicals of strained rings,
suggesting that the radical insertion of molecular oxygen into
cyclobutanol would be more challenging.

\begin{figure}
{\vspace*{.3pc}}
\includegraphics{fig04}
{\vspace*{-.1pc}}
\caption{\label{fig4}Relative kinetics of ring opening of strained
methyl cycloalkyl radicals.}
{\vspace*{-.2pc}}
\end{figure}

The various studies on the insertion of molecular oxygen into
cyclobutanols implied the synthesis of such compounds. The general
synthetic route is based on a 3-step procedure from aldehydes or
ketones \textbf{11a--i} (Scheme~\ref{sc5}). The first step consisted of
the Wittig olefination with an \mbox{in-situ-formed}
\mbox{cyclopropylphosphonium} ylide. Cyclopropylidenes \textbf{12a--i}
underwent epoxidation and rearrangement into cyclobutanones
\textbf{13a--i}~\cite{39}.\ Following, secondary cyclobutanols
\textbf{14a--i} were obtained by reduction of \textbf{13a--i} with
NaBH\tsub{4}, while tertiary cyclobutanols \textbf{15a--d} were
synthesized by addition of a Grignard or lithium reagent. Optimal
conditions for oxygen insertion were identified as 5~mol\%
Co(acac)\tsub{2} in MeCN at 40~{\textdegree}C (8--48~h); Mn(II) or
Mn(III) acetylacetonate showed no reaction~\cite{40}. As anticipated,
the process was significantly more challenging compared to
cyclopropanols due to the slower ring opening of cyclobutyloxy
radicals, which required higher catalyst loading (5~mol\% versus
0.5~mol\%), higher temperatures (40~{\textdegree}C versus room
temperature), and longer reaction times (8--48~h versus 1--2~h).\ The
substitution also significantly affects the reaction rate. It works
particularly well when the 2-position is \mbox{disubstituted}
(\textbf{16a--c}, \textbf{16f}), indicating that the cyclobutane
scission is faster in that case; eight hours are generally sufficient
for full conversion. With one alkyl substituent, the reaction was more
difficult (\textbf{16d}) and required up to 48~h. The tertiary
cyclobutanols were also more difficult to react, requiring longer
reaction times and giving generally lower yields (\textbf{17a--c}). The
steric hindrance appeared to be the important factor, as the rate of
ring scission is little affected by the 1-substitution (see
Figure~\ref{fig4}); Cobalt needs to approach the alcohol function to
abstract the hydrogen. The more significant steric effect of the ethyl
group makes the reaction even more challenging to achieve
(\textbf{17a}). However, the combination of 1-substitution and
2-monosubstitution made the reaction unfavorable (\textbf{17d}, no
reaction).

\begin{scheme*}
\includegraphics{sc05}
{\vspace*{.5pc}}
\caption{\label{sc5}Insertion of molecular oxygen in cyclobutanols.}
{\vspace*{-.6pc}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{.5pc}}
\caption{\label{sc6}Acetylation and alkylation of 1,2-dioxanes.}
{\vspace*{-.8pc}}
\end{scheme*}

\subsection{Alkylation of 1,2-dioxanyl acetates} \label{sec3.2}

Endoperoxyacetals \textbf{16a--f} were then acetylated to intermediates
\textbf{18a--f} to be substituted under the conditions previously
developed for 1,2-dioxolanes~\cite{20} (Scheme~\ref{sc6}). Compound
\textbf{16f} had difficulties reacting in acetylation due to the Lewis
basicity of the carbamate function, which deactivated the acid catalyst
(\textbf{18f}: 22\% yield); all other substrates were acylated
efficiently. Nevertheless, it was discovered that 1,2-dioxanes are far
more stable than 1,2-dioxolanes toward organic bases; consequently,
pyridine-mediated acylation could also be performed efficiently to
overcome difficult cases (100\% yield for \textbf{18f})~\cite{41}.
Sc(OTf)\tsub{3} catalysis was then selected over indium-mediated
conditions because of its ease of handling. Several types of
nucleophiles could be added to acylated intermediates \textbf{18a--e};
however, \textbf{18f} was again unreactive due to the Boc group. The
scope of the nucleophiles includes allylsilanes (\textbf{19b},
\textbf{19e}, \textbf{19f--g}, \textbf{19j--k}), hydrides
(\textbf{19c}), cyanides (\textbf{19d}, \textbf{19h}), enolates
(\textbf{19a}, \textbf{19i}, \textbf{19l}), and siloxyfuranes
(vinylogous addition, \textbf{19m}).\ Unlike 1,2-dioxolane, the addition
can be more selective on this ring size, thanks to a preferred
half-chair conformation on the peroxycarbenium ion, in which the
substituent is in pseudoequatorial position~\cite{42}. The nucleophile
can also add preferentially in the axial position because it gives a
chair-like conformation to the substitution product directly. The low
yield for \textbf{19f} is attributed to the adjacent aromatic ring,
which enhanced Kornblum--DeLaMare or Hock rearrangements~\cite{40}.

Success in accessing differently substituted 1,2-dioxanes encouraged
the application of the method developed to the total synthesis of
natural endoperoxides. Mycaperoxides and ethyl plakortide Z were
selected for their interesting biological properties and structural
features, which present distinct challenges. No total synthesis of
these compounds had been reported prior to our studies.

\subsection{Total synthesis of mycaperoxides} \label{sec3.3}

As outlined in the introduction, mycaperoxides are marine endoperoxides
endowed with \mbox{various} \mbox{reported} biological activities.\ 
Several natural analogs exist, whose differences rely not only on the
sesquiterpene structure but also on the relative and absolute
configuration of the 1,2-dioxane scaffold. Synthetic studies toward
mycaperoxide B were reported by Harwood~\cite{43,44,45}. The total
synthesis of related analogs of mycaperoxides was nevertheless
accomplished by Seifert on diacarnoxide C in twenty steps~\cite{46} and
by Yikang Wu on muqubilin in twenty-nine steps~\cite{47}. To quickly
access the decalin subunit of mycaperoxides, the choice of sclareolide
as a starting material appeared to be the most appropriate. However,
only one configuration is available, which allows access to the natural
configuration of mycaperoxide~B (Figure~\ref{fig5}). Mycaperoxides~C,
D, and G have an inverse configuration for the decalin subunit;
therefore, the synthesis of their antipodes was here privileged.
Indeed, no other available resource enables direct access to their
natural configuration, unless one designs a complex, multistep
synthesis.

\begin{figure}
{\vspace*{-.2pc}}
\includegraphics{fig05}
{\vspace*{-.2pc}}
\caption{\label{fig5}Structures of mycaperoxides A--D and G and related
analogs, highlighting the configuration of the \mbox{decalin}.}
{\vspace*{-.2pc}}
\end{figure}

The first targeted analog was \textit{ent}-mycaperoxide D, which bears
the same decalin substructure as sclareol. The first step required the
KMnO\tsub{4}-mediated oxidative cleavage of the allylic alcohol,
yielding methyl ketone \textbf{20} (Scheme~\ref{sc7}). The construction
of the 1,2-dioxane relied on our cobalt-mediated oxygen insertion
reaction, which provided \textbf{23} in a good yield over a five-step
sequence. Acetylation needed some optimization, since Lewis
acid-catalyzed conditions induce the elimination of the silylated
alcohol. Instead, pyridine-mediated acylation led cleanly to
peroxyacetal \textbf{24}. Promotion of the peroxycarbenium ion with
Sc(OTf)\tsub{3} catalysis allowed the addition of silylated propionyl
thioester nucleophile \textbf{25} in high yield, but thioester
\textbf{26} was obtained as a mixture of eight different diastereomers.
This result was anticipated; the insertion of molecular oxygen could
not be stereoselective or stereoretentive due to the reaction's radical
mechanism, resulting in no control over the configuration at the C-6
position. The {addition} at C-2 was more selective, yielding an
interesting 4:1 ratio in favor of the 3,6-\textit{cis} product.
However, the configuration of the methyl group at C-2 was not
controlled, affording a 1:1 mixture of
2,3-\textit{anti}/\textit{syn}-products. Separation of most of the
diastereomers, after triethylsilane (TES) cleavage, enabled the
isolation with a 12.7\% yield of diastereomer \textbf{27}, which has
the same relative configuration as natural mycaperoxide~D. Two-step
transesterification gave rise to the antipode of mycaperoxide~D
(\textbf{28}). Spectroscopic data matched in all points the natural
product, for which the characterizations were reported as a methyl
ester, except for the optical rotation with an inverted value [${+}$68
(\textit{c} 0.25, CHCl\tsub{3}); lit~\cite{48}: ${-}$52 (\textit{c} 0.3,
CHCl\tsub{3})]. The synthesis of \textbf{28} was achieved in only
eleven chemical steps from sclareol~\cite{49}.\looseness=-1

The synthesis of other mycaperoxide analogs was then investigated but
required a modification of the decalin subunit. Methyl ketone
\textbf{20} was treated with catalytic iodine to promote the more
selective elimination of the tertiary alcohol toward \textbf{29} in an
85:15 mixture with regioisomer \textbf{30} (Scheme~\ref{sc7}). The
entire mixture was subjected to epoxidation with \textit{m}-CPBA,
followed by olefination to a cyclopropylidene. The two-step sequence
yielded a separable mixture of diastereomers \textbf{31a} and
\textbf{31b}, as well as regioisomer \textbf{32}, which came from
\textbf{30}. Next, \textbf{31a} and \textbf{31b} underwent distinct
LiAlH\tsub{4} reductions, enabling regioselective hydride addition, in
accordance with the F\"{u}rst--Plattner rule~\cite{50,51,52}. 

\begin{scheme*} 
\includegraphics{sc07}
{\vspace*{.4pc}}
\caption{\label{sc7}Stereodivergent synthesis of mycaperoxide B and the
antipodes of mycaperoxides C, D, and G's methyl esters.}
\end{scheme*}

Regioisomer \textbf{33b} exhibited the decalin scaffold of
\textit{ent}-mycaperoxyde C and underwent a sequence similar to that
used for \textit{ent}-mycaperoxide D from \textbf{21}
(Scheme~\ref{sc7}). Differences lie in the protecting group (TMS, less
bulky than a TES) and the choice of yttrium in replacement of scandium
for the aldol reaction, which prevented the elimination of the tertiary
silyl ether on the decalin, thanks to a more moderate reactivity.
Separation of the diastereomers and transesterification afforded the
antipode of \mbox{mycaperoxide~D (\textbf{37}).} Spectroscopic data agreed
with the natural product's methyl ester, except for the optical
rotation with an inverted value [${+}$50 (\textit{c} 0.198,
CHCl\tsub{3}); lit~\cite{48}: ${-}$71 (\textit{c} 1.1, CHCl\tsub{3})].
The synthesis of \textbf{37} was achieved in fourteen steps from
sclareol~\cite{49}.

The synthesis of mycaperoxide B and \textit{ent}-mycaperoxide G was
subsequently studied from \textbf{33a}, applying the same strategy
(Scheme~\ref{sc7}). Thus, thioester \textbf{40} was obtained as a
mixture of eight \mbox{diastereomers} in a four-step sequence. Because
the hydroxy group on decalin was highly prone to elimination, it was
left free, and yttrium catalysis was again applied with success. The
absence of a protecting group lowered the
3,6-\textit{cis}:\textit{trans} selectivity (dr ${=}$ 3:2) for the aldol
reaction, which was beneficial because mycaperoxides B and G have a
3,6-\textit{trans} configuration. Separation of diastereomers followed
by a saponification step afforded a mixture of mycaperoxide B
(\textbf{41}) and its 2,3,6-epimer (\textbf{42}) in about 1:1 ratio
(7.6\%), and in a total of eleven steps. However, no conditions for
further separation were found. In parallel, the diastereomeric mixture
\textbf{40} was treated with SOCl\tsub{2}, allowing elimination of the
tertiary alcohol. Subsequently, separation of isomers by chromatography
and two-step transesterification allowed the isolation of the antipode
of mycaperoxide G's methyl ester (\textbf{44}) and its 13,8-epimer
(\textbf{43}) in about 1:1 ratio (3.4\%) in a total of thirteen steps.

The total synthesis of various mycaperoxides was accomplished for the
first time, enabling access to these natural structures in a few steps
(from eleven to fourteen steps). This work highlights the effectiveness
of the strategy developed for the synthesis of 1,2 dioxanes. Although
the key transformations involved in endoperoxide formation suffer from
limited selectivity (radical and S\tsub{{N}}1 reaction),
this limitation is offset by the overall efficiency of the approach,
particularly in terms of step economy when compared with previous
reported studies in the field~\cite{43,44,45,46,47}.

\subsection{Total synthesis of ethyl plakortide Z} \label{sec3.4}

Plakortides have the unique characteristic of showing an ethyl
substituent at the C-4 position of the 1,2-dioxane ring, which presents
a new challenge in total synthesis. Gemma and Campiani reported the
total synthesis of 9,10-dihydroplakortin and its 6-\textit{epi} analog
in twenty-three steps, utilizing Mukaiyama \mbox{peroxysilylation} and
iterative Evans aldol reaction as key transformations~\cite{53}.
Despite a moderate \mbox{cytotoxic} activity, ethyl plakortide Z proved to be
a suitable target for validating our synthetic strategy within this
class of compounds; the side chain is simple and the 3,4-\textit{trans}
configuration seemed more adapted to the peroxycarbenium-mediated aldol
reaction.

Our designed pathway for synthesizing ethyl plakortide Z began with the
preparation of cyclobutanone \textbf{46} in two steps
(Scheme~\ref{sc8}).\ The first key step was controlling the ethyl group
at position C-4, which necessitated the utilization of an Enders
hydrazone to produce \textbf{48}. Hydrazone cleavage with ozone,
followed by reduction with NaBH\tsub{4} yielded \textbf{49}. The second
key step involved the cobalt-mediated insertion of oxygen, which
proceeded exclusively on the most substituted position to produce
\textbf{50} as a C-6 diastereomeric mixture. Activating the acetal
function to an acetate enabled the thioacetate insertion with
Sc(OTf)\tsub{3} catalysis in the final key step. The reaction proceeded
with a moderate diastereoselectivity (dr ${=}$ 4:1) toward the
3,4-\textit{trans} configuration. The desired diastereomer could be
isolated from the other three by preparative HPLC, and a two-step
transesterification provided ethyl plakortide Z as a pure enantiomer;
the spectral data of the synthetic ethyl plakortide Z matched those of
the reported natural one~\cite{54}.

\begin{scheme*} 
\includegraphics{sc08}
{\vspace*{.4pc}}
\caption{\label{sc8}Stereodivergent synthesis of ethyl plakortide Z.}
{\vspace*{-.9pc}}
\end{scheme*}

Ethyl plakortide Z was synthesized in only eleven steps, yielding 4.2\%
overall, constituting a significant advancement for this class of
compound. However, this stereodivergent strategy presents significant
limitations, notably the requirement for laborious chromatographic
separations of diastereoisomers, arising from insufficient control over
peroxy bond formation. A major advance would be designing asymmetric
versions of the key reactions, specifically the oxygen insertion and
Mukaiyama aldol reactions. In the first case, the radical pathway would
make it difficult to develop such a reaction with current knowledge in
the field. However, the ionic interaction in the final key step would
certainly enable asymmetric control with a chiral counteranion.

\section{Asymmetric counteranion-directed{\hfill\break} catalysis}
\label{sec4}
\subsection{Pioneering works} \label{sec4.1}

The lack of readily available asymmetric methods for forming peroxyl
bonds is a major obstacle to the \mbox{total} synthesis of endoperoxides. Past
known methods relied either on: {S}\tsub{{N}}2 displacement
of hydroperoxides to epoxides, halides, or sulfonates~\cite{46,47,55};
kinetic resolution of hydroperoxides by reduction~\cite{56,57,58};
asymmetric organocatalyzed 1,4-addition of a hydroperoxyl function to
enones or enals~\cite{13,59,60}.

The similarity between ether-based oxycarbenium ions and
peroxycarbenium species suggests that asymmetric methods used for
ethers could also be applied to peroxyl analogs. Indeed, in recent
years, List et~al.\ have demonstrated that new organocatalysts with
high acidity and confinement properties, called imidodiphosphorimidates
(IDPi), could be used in a large range of reactions involving reactive
cationic species~\cite{61,62}. One major breakthrough involved the
synthesis of chiral ethers from cyclic acetals \textbf{54a--c} with
high yields, high enantiomeric ratios, and low catalyst loadings of
IDPi-H \textbf{53} (Scheme~\ref{sc9}) \cite{63}. Consequently, we
thought that this asymmetric method could be applied to endoperoxides,
although some additional difficulties needed to be overcome, including
the fragility of the peroxyl bond and the reduced stabilization of the
peroxycarbenium species compared to classical oxycarbenium ions
(Figure~\ref{fig2}).

\begin{scheme*} 
\includegraphics{sc09}
{\vspace*{.5pc}}
\caption{\label{sc9}List's asymmetric functionalization of cyclic
acetals mediated by IDPi catalysis.}
{\vspace*{-.1pc}}
\end{scheme*}

\subsection{Synthesis of chiral endoperoxides} \label{sec4.2}

Searches for optimal reaction conditions led to the selection of IDPi
catalyst \textbf{53} as the most versatile and selective catalyst for
our substrates~\cite{64}, in accordance with List's previous work on
cyclic ethers that possess similar geometries~\cite{63}
(Scheme~\ref{sc10}). The reactions proceeded more selectively in
Et\tsub{2}O. Other nonpolar solvents, used to maximize intermolecular
interactions between the two ionic species, can also be employed, such
as methylcyclohexane or $n$-pentane, which provided results similar to
those obtained with Et\tsub{2}O. However, their limited solubilizing
power prevents their general use across a broad range of substrates.
Other solvents, such as dichloromethane (DCM) or toluene, led to no
reactivity or degradation. Temperature played a crucial role; carrying
out the reaction at low temperature (${-}$90~{\textdegree}C) diminished
acid-catalyzed peroxide degradation pathways, increasing the isolated
yields dramatically, albeit at the cost of a long reaction time
(\mbox{2--5} days). Nevertheless, increasing the reaction temperature
to ${-}$78~{\textdegree}C has been used as a compromise for less reactive
nucleophiles or substrates. Another important observation is that the
reaction does not tolerate variation of the leaving group, with the
acetate moiety remaining the only one capable of promoting this
transformation. A similar trend is observed for the silylated
nucleophiles. Various protecting groups, differing in both steric and
electronic properties, were evaluated, but only the TBS group
demonstrated satisfactory reactivity and reproducibility. \looseness=-1

\begin{scheme*}
\includegraphics{sc10}
{\vspace*{.5pc}}
\caption{\label{sc10}Scope of the endoperoxide acetal's IPDi-catalyzed
functionalization.}
{\vspace*{-.8pc}}
\end{scheme*}

This unprecedented use of IDPi catalysts for the functionalization of
1,2-dioxane acetates has enabled the preparation of a wide variety of
products by tuning the nucleophile (Scheme~\ref{sc10}). In this
context, several classes of nucleophiles were explored, \mbox{including} silyl
ketene acetals, as well as aromatic and cyclic silyl enol ethers. In
all cases, the corresponding addition products \textbf{55a--f},
\textbf{56a--c}, \textbf{57a--c}, \textbf{58a} were obtained in good
yields and with remarkable enantioselectivities (ee ${=}$
93--99\%)~\cite{64}. In the case of cyclic enol ethers, an outstanding
diastereoselectivity can be observed in favor of the \textit{anti}
product (dr ${=}$ 90:10--95:5).\ As anticipated, the 1,2-dioxolanes are
more \mbox{difficult} to produce due to their lesser stability. Ketone
adducts generally led to degradations, but the silyl ketene acetals
allowed in this instance the isolation of functionalized 1,2-dioxolanes
\textbf{59b} and \textbf{60b} in very good yields and high
enantioselectivity (ee ${=}$ 93 and 85\%, respectively). The reaction was
also successfully examined with vinylogous nucleophiles, such as
\mbox{siloxyfuranes}~\cite{64}.

The proposed reaction mechanism (Scheme~\ref{sc11}) is in line with some kinetic
investigations and previous studies~\cite{62,63,64}. The initial step
involves a protodesilylation between the nucleophile and
\textbf{IDPi-H}, generating silylium species \textbf{IDPi-TBS}, the
actual Lewis acid. It then promotes departure of the acetate group from
\textbf{18a}, leading to peroxycarbenium ion~\textbf{I}. The
\mbox{chiral} environment brought by the chiral counteranion allows a
controlled nucleophilic addition to the most accessible face of
intermediate~\textbf{I}. Adduct~\textbf{II} can subsequently release
\textbf{IDPi-TBS} after providing \textbf{55a}, thereby sustaining the
catalytic cycle.

\begin{scheme*} 
\includegraphics{sc11}
{\vspace*{.6pc}}
\caption{\label{sc11}Proposed mechanism for the asymmetric alkylation
of endoperoxides.}
{\vspace*{-.7pc}}
\end{scheme*}

\subsection{Second-generation total synthesis of ethyl{\hfill\break}
plakortide Z} \label{sec4.3}

The aforementioned asymmetric reaction was successfully applied to the
total synthesis of ethyl plakortide~Z, by employing acetate
intermediate \textbf{50}~\cite{64} (Scheme~\ref{sc12}).\ The use of IDPi
catalyst (\textit{S},\textit{S})-\textbf{53}, in combination with
silylated nucleophile \textbf{61}, enabled direct access to ethyl
plakortide Z with an \mbox{excellent} diastereomeric ratio of 18:1 in
favor of the 3,4-\textit{trans} configuration.\ As a reminder,
Sc(OTf)\tsub{3} provided the 3,4-\textit{trans} configuration with a
moderate 4:1 ratio in our previous studies and required an additional
transesterification step~\cite{54} (Scheme~\ref{sc8}).\ Interestingly,
the use of (\textit{R},\textit{R})-\textbf{53} catalyst decreased the
ratio to 1.3:1 without reversing the selectivity toward the
3,4-\textit{cis} product.\ This result suggests that the substrate's
chirality predominantly controls the substitution, rather than the
catalyst, in this example; the catalyst only amplifies or diminishes
the original \mbox{selectivity}.

\begin{scheme} 
\includegraphics{sc12}
{\vspace*{.9pc}}
\caption{\label{sc12}Effect of IDPi configuration in the synthesis of
ethyl plakortide~Z.}
{\vspace*{-.8pc}}
\end{scheme}

\section{Conclusions and perspectives} \label{sec5}

In conclusion, this account emphasizes the importance of creating new
methods to access natural products. These methods serve as a foundation
for innovative techniques and provide access to molecules with
promising in vitro properties, such as endoperoxides. Thus, we
demonstrated that these compounds are stable enough to withstand a wide
range of reaction conditions, thereby expanding their functional
diversity. Consequently, we showed how to access the 1,2-dioxolane
motif, and subsequently 1,2-dioxanes, by taking advantage of the cyclic
constraints of cyclopropanols and cyclobutanols, and of the reactivity
of peroxycarbenium ions, two key reactions at the root of our strategy.
As demonstrated, the developed methods have enabled several advances in
total synthesis, including access to simplified analogs of
mycangimycin, mycaperoxides, and ethyl plakortide~Z.

\begin{scheme*}
{\vspace*{-.3pc}}
\includegraphics{sc13}
{\vspace*{.2pc}}
\caption{\label{sc13}Synthesis of silylperoxides. Perspectives toward
the synthesis of endoperoxides.}
{\vspace*{-1pc}}
\end{scheme*}


One of the major challenges in the total synthesis of endoperoxides is
controlling chirality. We addressed this issue by developing a
pioneering asymmetric catalysis approach based on ion pairing with
reactive peroxycarbenium species. By optimizing \mbox{reaction} conditions and
systematically \mbox{screening} silylated enolates, we generated a wide range
of structurally diverse endoperoxides while maintaining excellent
control over chirality. This new method is expected to facilitate the
development of original synthetic routes toward natural endoperoxides,
as demonstrated by the second-generation total synthesis of ethyl
plakortide~Z.

Nevertheless, these recent studies are only a step toward achieving
complete control over the asymmetric centers that constitute
\mbox{endoperoxides}. \mbox{Several} significant challenges remain to
be addressed.\ The scope of nucleophiles in asymmetric synthesis is
currently limited to a small number of silylated enolates and must be
expanded further. Additionally, the mechanisms of asymmetric induction
in ``match'' and ``mismatch'' cases must be fully understood to predict
results. A major challenge lies in controlling the chirality of the
stereogenic center formed during the oxygen insertion reaction from
strained cycloalcohols. However, the radical nature of this reaction
makes this task especially challenging. Therefore, we have recently
explored an alternative strategy involving the synthesis of a
silylperoxide intermediate, which is formed by promoting acyclic
peroxycarbenium ion \textbf{62} from peroxyacetal \textbf{61}~\cite{65}
(Scheme~\ref{sc13}). It can be captured by various silylated
nucleophiles, and, for instance, peroxides \textbf{63} and \textbf{64}
were converted into acetoxy-dioxolane \textbf{9j} and dioxane
\textbf{18j} in a few steps. These compounds can then undergo further
functionalization using the aforementioned methods. The success of
IDPi-mediated asymmetric alkylation of \textbf{61} would likely
revolutionize endoperoxide synthesis by enabling control of chirality
and diastereoselectivity. Opportunities for developing original
methodologies in the field of organic peroxides remain, thereby
facilitating access to the total synthesis of unexplored\break endoperoxides.

\printCOI

\vspace*{-3pt}

\section*{Funding}

\vspace*{-3pt}

This work has been partially supported by Universit\'{e} Paris-Saclay,
Centre National de la Recherche Scientifique (CNRS). LF thanks the
``Minist\`{e}re de l'Enseignement Sup\'{e}rieur et de l'Innovation''
(MESRI) for the funding of two PhD scolarships (2017, 2020), the
Vietnamese government for the funding of one PhD scolarship (USTH
program 2012) and the CNRS and the ``Fondation pour le
d\'{e}veloppement de la chimie des substances naturelles et ses
applications'' for financing the project MYCOXY through a call for
projects on natural substances. BC thanks the ``Minist\`{e}re de
l'Enseignement Sup\'{e}rieur et de l'Innovation'' (MESRI) for the
funding of his PhD (2022--2025).\looseness=-1

\vspace*{-3pt}

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