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\DOI{10.5802/crchim.352}
\datereceived{2024-09-17}
\daterevised{2024-09-24}
\dateaccepted{2024-10-03}
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\CDRsetmeta{articletype}{review}

\title{Stereoselective strategies to access spirotetronate natural
products}

\alttitle{Approches st\'{e}r\'{e}os\'{e}lectives pour la synth\`{e}se
des produits naturels spirot\'{e}tronates}

\author{\firstname{Aur\'{e}lien} \lastname{Brion}\CDRorcid{0000-0002-4686-5865}}
\address{Institut de Chimie des Substances Naturelles (ICSN), CNRS UPR
2301, Universit\'{e} Paris-Saclay, 1 Avenue de la Terrasse,
Gif-sur-Yvette Cedex 91198, France}

\author{\firstname{Luc} \lastname{Neuville}\CDRorcid{0000-0002-4648-2469}}
\addressSameAs{1}{Institut de Chimie des Substances Naturelles (ICSN), CNRS UPR
2301, Universit\'{e} Paris-Saclay, 1 Avenue de la Terrasse,
Gif-sur-Yvette Cedex 91198, France}
\address{HitCat, Seqens-CNRS Joint Laboratory, Seqens'Lab, 8 Rue de
Rouen, Porcheville 78440, France}

\author{\firstname{G\'eraldine} \lastname{Masson}\CDRorcid{0000-0003-2333-7047}\IsCorresp}
\addressSameAs{1}{Institut de Chimie des Substances Naturelles (ICSN), CNRS UPR
2301, Universit\'{e} Paris-Saclay, 1 Avenue de la Terrasse,
Gif-sur-Yvette Cedex 91198, France}
\addressSameAs{2}{HitCat, Seqens-CNRS Joint Laboratory, Seqens'Lab, 8 Rue de
Rouen,  Porcheville 78440, France}
\email[G. Masson]{geraldine.masson@cnrs.fr}

\keywords{\kwd{Spirotetronates}
\kwd{Diels--Alder reaction}
\kwd{Stereoselective synthesis}
\kwd{Total synthesis}}

\altkeywords{\kwd{Spirot\'{e}tronates}
\kwd{R\'{e}action de Diels-Alder}
\kwd{Synth\`{e}se st\'{e}r\'{e}os\'{e}lective}
\kwd{Synth\`{e}se totale}}

\begin{abstract}
Spirotetronates constitute a large family of natural products that have
attracted significant attention due to their intriguing structures and
broad biological activities. These compounds share a common spirocyclic
4-hydroxy-1-oxaspiro[4.5]deca-3,7-dien-2-one unit, whose synthesis
has been actively pursued by chemists. In this review, we highlight
various approaches to accessing diversely substituted
spirotetronates, including methods that enable the total
synthesis of selected natural targets. The Diels--Alder/Dieckmann route
originally reported has been extensively developed and encompasses
various diastereoselective processes. Although enantioselective
transformations have been reported, they remain scarce. Additionally,
although less explored, alkylation of ketones has been employed for the
synthesis of alkoxyfuran-2(5\textit{H})-one scaffolds, and selected
ring-forming strategies have been investigated to construct
pre-functionalized cyclohexyl backbones.
\end{abstract}

\begin{altabstract}
Les spirot\'{e}tronates constituent une vaste famille de produits
naturels qui ont suscit\'{e} un int\'{e}r\^{e}t consid\'{e}rable en
raison de leurs structures fascinantes et de leurs activit\'{e}s
biologiques vari\'{e}es. Ces compos\'{e}s partagent une unit\'{e}
spirocyclique commune, \`{a} savoir le
(S)-4-hydroxy-1-oxaspiro[4.5]deca-3,7-di\`{e}ne-2-one, dont la
synth\`{e}se a fait l'objet d'intenses recherches par les chimistes.
Dans cette revue, nous pr\'{e}sentons diverses approches permettant
d'obtenir des spirot\'{e}tronates substitu\'{e}s de mani\`{e}re
diversifi\'{e}e, y compris des m\'{e}thodologies permettant la
synth\`{e}se totale de cibles naturelles sp\'{e}cifiques. La voie de
synth\`{e}se Diels-Alder/Dieckmann, initialement d\'{e}crite, a
\'{e}t\'{e} largement d\'{e}velopp\'{e}e et inclut divers processus
diast\'{e}r\'{e}os\'{e}lectifs. Bien que des transformations
\'{e}nantios\'{e}lectives aient \'{e}t\'{e} rapport\'{e}es, elles
demeurent rares. Par ailleurs, bien que moins \'{e}tudi\'{e}e,
l'alkylation des c\'{e}tones a \'{e}t\'{e} employ\'{e}e pour la
synth\`{e}se de squelettes alkoxyfuran-2(5\textit{H})-one, et certaines
strat\'{e}gies de formation de cycles ont \'{e}t\'{e} explor\'{e}es
pour construire des structures cyclohexyle
pr\'{e}-fonctionnalis\'{e}es.
\end{altabstract}

\shortrunauthors

\maketitle
\vspace*{10pt}

\twocolumngrid
\end{noXML}

\section{Introduction}\label{sec1}

Spirotetronates are a remarkable class of macrocyclic natural products
isolated predominantly from \textit{actinomycetes}, a phylum of
gram-positive bacteria. Since the discovery of chlorothricin in 1969,
the first isolated spirotetronate~\cite{1} (Figure~\ref{fig1}),
numerous related compounds have been structurally
characterized~\cite{2,3} such as spirohexenolide A and B~\cite{4},
abyssomicin C~\cite{5},  quartromicins~\cite{6},
versipelostatin~\cite{7}, streptaspironates A--C~\cite{8}, glenthmycins
\unskip\break 
A--M~\cite{9}, and others~\cite{10,11,12,12a,13,14,15,16,17,18,19}. These
compounds have attracted substantial interest due to their diverse and
potent biological activities, including antibacterial, antiviral, and
antitumoral properties. Their fascinating structures and significant
pharmacological \mbox{potential} have made spirotetronates central to ongoing
synthetic and pharmaceutical research.

\begin{figure}
{\vspace*{7pt}}
\includegraphics{fig01}
{\vspace*{3pt}}
\caption{\label{fig1}Structure of chlorothricin and its aglycon
chlorothricolide.}
\end{figure}

Structurally, spirotetronates feature a characteristic tetronic acid
(4-hydroxy-[5\textit{H}]furan-2-one) moiety that is spiro-linked to a
cyclohexene ring at the C-4 position, a distinctive motif within this
family (Figure~\ref{fig1}). The spirotetronate core consists of a
five-membered lactone ring with a high degree of oxidation and
unsaturation. This structural unit is typically substituted at the C-2
position by an acyl group or, in rare cases, by an acyloxy chain, such
as in chlorothricolide (Figure~\ref{fig1}). Adjacent to the
spiro-linkage at the C-5 position of the cyclohexene ring is another
stereocenter, which can lead to two diastereoisomeric arrangements: the
\textit{endo} configuration, where the higher alkyl chain is
\textit{cis} relative to C-3 of the spirotetronate (highlighted in
blue), and the \textit{exo} configuration, where these groups are
\textit{trans} (highlighted in red). Both diastereomers have been
observed in spirotetronates, posing a key synthetic challenge in
achieving diastereoselective access to the desired configuration
(Figure~\ref{fig2}A). 

\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}(A) Structure of the two different diastereomers.
(B) Spirotetronates harnessing a quaternary stereocenter at C$_{5}$.}
\end{figure*}

This stereocenter at the C-5 position of the cyclohexene ring can be
quaternary, which is a significant structural feature in some
spirotetronates (Figure~\ref{fig2}B). In these cases, a methyl group
replaces a hydrogen, as seen in compounds such as in spirohexenolides
\textbf{5a} and \textbf{5b}, maklamicin \textbf{6}, and quartromicins
\textbf{9--14}. This modification dramatically increases the complexity
of the synthesis by introducing steric hindrance in the form of
adjacent quaternary stereocenters. The presence of these bulky
neopentylic carbons restricts functionalization and adds strain to the
cyclohexene ring, making these molecules even more challenging targets
for synthetic chemists.

In addition to the tetronic acid core and the stereocenters at C-5,
spirotetronates exhibit diverse modifications at the C-7 and C-8
positions of the cyclohexene ring. These substituents vary from simple
methyl groups, as seen in okilactomycin \textbf{4} or spirohexenolides
\textbf{5a--b}, to more complex, oxidized alkyl chains in compounds like
maklamicin \textbf{6} and chlorothricolide~\textbf{2}
(Figure~\ref{fig3}). The oxidation state and size of these side chains
contribute to the structural diversity of spirotetronates and influence
their biological activities. In some cases, such as abyssomicin C
(compound \textbf{3}), the cyclohexene ring is further oxidized to form
vicinal diols. 

\begin{figure*}
\includegraphics{fig03}
\caption{\label{fig3}Diverse structures of Class I and Class II
spirotetronates.}
\end{figure*}

A key feature of spirotetronates is their macrocyclic structure, which
links the tetronic acid to the cyclohexene ring (C2--C5). The size
and substitution of the macrocycle vary, resulting in three subclasses:
small spirotetronates with 11-carbon macrocycles, medium-sized 
with 13 carbons, and larger structures with 15 carbons or more. These
macrocycles can range from simple structures to those bearing
conjugated alkenes, alcohols, or ketones. Additionally, some members of
the spirotetronate family contain a \textit{trans}-decalin ring system
within the macrocycle, further increasing structural complexity
(Figure~\ref{fig3}). Based on these features, spirotetronates are
divided into two main classes: Class I, containing a single
spirotetronate moiety in the macrocycle, and Class II, which
incorporates a decalin ring system in addition to the spirotetronate.

Perhaps one of the most intriguing subclasses within the
spirotetronates is the quartromicin family, which lies outside of the
conventional Class I and Class II designations. Unlike the typical
members of the spirotetronate family, quartromicins (first isolated in
1991 from a strain of \textit{Amycolatopsis orientalis})~\cite{6,20}
contain four spirotetronate units within their scaffold
(Figure~\ref{fig4}). These compounds exhibit strong metal-ion-binding
affinity and are a 32-carbon macrocycle, which contributes to their
highly symmetrical C2 axial structure. 


\begin{figure*}
\includegraphics{fig04}
\caption{\label{fig4}General structure of quartromicins and their
structural characteristics.}
\end{figure*}

Spirotetronates, with their fascinating structures, have captured
significant interest due to their diverse biological
activities~\cite{2,3,21}. For example, chlorothricin \textbf{1}
inhibits pyruvate carboxylase, an enzyme crucial for bacterial
metabolism, making it an effective antibacterial agent against
gram-positive bacteria~\cite{22}. The abyssomicin family, known for
inhibiting the growth of \textit{Mycobacterium tuberculosis} and
\textit{Staphylococcus aureus}, has also been extensively
studied~\cite{23}. Abyssomicin C specifically targets the chorismate
pathway, which is vital for the production of aromatic amino acids in
microorganisms~\cite{24}. This compound works by acting as a double
Michael acceptor, irreversibly modifying a cysteine residue in an
enzyme involved in this pathway, showcasing the importance of its enone
group and strained macrocyclic structure. In contrast, quartromicins
are recognized for their potent antiviral effects, including against
HIV and HSV-1~\cite{20,25}. Although their exact mechanisms are still
under investigation, their interactions with metal ions and their
complex macrocyclic \mbox{structures} suggest they might employ novel
modes of action.


The intricate structures and significant biological activities of
spirotetronates have fascinated synthetic chemists for decades.
Previous reviews have covered their biological activities,
biosynthesis, and total syntheses in detail, often focusing on the
macrocycle and decalin components~\cite{2,3,21,26,27}. However, they
often overlook the construction of the spirotetronate
core---a crucial element with significant stereoselective
challenges. The synthesis of this spiro-linked tetronic acid, in
particular, remains complex, requiring precise stereocontrol and
functionalization. This review aims to explore the methods developed
for constructing spirotetronates, highlighting both successful
strategies and ongoing challenges. By focusing on the stereochemical
and synthetic difficulties, we seek to provide a thorough understanding
of the progress made in synthesizing this intriguing class of natural
products.

\section{Synthetic strategies to access spirotetronates}\label{sec2}

We will discuss the key disconnections investigated up to date and their
drawbacks as well as their \mbox{benefits}. However, except when deemed
useful, we will not discuss the construction of the macrocycle and the
decalin moieties, as these have been reviewed and studied elsewhere and
are not the purpose of this 
review~\cite{2,3,21,26,27,28,29,30,31,32,33,34}.

\subsection{Seminal works established the Diels--Alder reaction as a
preferred strategy}\label{sec21}

One of the earliest synthetic studies on spirotetronates was conducted
by Ireland and co-workers in 1979, focusing on the synthesis of
chlorothricin (\textbf{2}), the aglycon of chlorothricolide~\cite{35}.
This molecule features an \textit{exo}-type spirotetronate moiety, a
functionalized decalin, and a macrocyclic structure with a single
unsaturation. Based on a retrosynthetic analysis, the authors assumed
that an Ireland--Claisen rearrangement could be key in forming the
macrocyclic backbone and therefore the first requirement would be to
build the advanced spirotetronate intermediate \textbf{15}
(Scheme~\ref{sch1}).

\begin{scheme*}
\includegraphics{sc01}
{\vspace*{6pt}}
\caption{\label{sch1}Retrosynthetic analysis to access chlorothricolide
\textbf{2} by Ireland and co-workers.}
{\vspace*{-5pt}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{6pt}}
\caption{\label{sch2}Construction of the unfunctionalized
spirotetronate moiety.}
\vspace*{-6pt}
\end{scheme*}

For constructing such a spirotetronate moiety, the authors proposed a
Diels--Alder reaction between maleic anhydride derivative \textbf{18}
and butadiene. The maleic anhydride was chosen not only for its
dienophilic properties but also because it enabled an intramolecular
Dieckmann condensation to form the tetronic acid moiety.

Although efficient, the Diels--Alder reaction between \textbf{18} and
butadiene produced an unfunctionalized diastereo- and regioisomeric
adduct of the desired spirotetronate backbone, requiring therefore
post-manipulation of the cyclohexene ring. Scheme~\ref{sch2} outlines
the high-pressure, high-temperature reaction of \textbf{18} with
butadiene, leading to cycloadduct \textbf{17} in 89\% yield
(Scheme~\ref{sch2}). Subsequent Dieckmann cyclization and methylation
produced \textbf{16} in 60\% yield. An epimerization event using sodium
methoxide resulted in the desired diastereomer \textbf{19}. Following a
series of redox manipulations and the addition of vinyl manganese
iodide, the \mbox{authors} obtained intermediate \textbf{20} (79\%
yield over three steps). 


\begin{scheme*}
\includegraphics{sc03}
\vspace*{6pt}
\caption{\label{sch3}(A) Post-functionalization of the cyclohexene
ring. (B) Reactivity of \textbf{18} toward substituted dienes.}
\vspace*{-4pt}
\end{scheme*}

The functionalization of the cyclohexene ring in \textbf{19} required
incorporation of a methyl and a {carboxylate} group, and regioselective
formation of an endocyclic double bond. The approach, started from
silyl-protected alcohol \textbf{21} and led to epoxide \textbf{22},
which was transformed to intermediate \textbf{23} (Scheme~\ref{sch3}A).
Further transformations produced intermediate \textbf{24}, which
allowed further functionalization of the spirotetronate. Despite
significant progress, Ireland's group was unable to complete the
synthesis of chlorothricin due to difficulties in the final stages,
particularly in further functionalizing the cyclohexene ring. This
first synthetic {access} to a {functionalized} spirotetronate was notable
but burdened by many protecting-group manipulations, redox steps, and
moderate selectivities. Attempts to improve the strategy by using an
already pre-functionalized {butadiene} analogue as a {reactive} dienophile in
the {Diels--Alder} reaction, namely {activated} silyl enol ether
\textbf{25}, was largely unsuccessful due to poor regioselectivity
(\textbf{26}/\textbf{27} ${=}$ 1:1; 67\% {overall} yield) observed during
cycloaddition (Scheme~\ref{sch3}B). Nevertheless, this research laid the
groundwork for future synthetic efforts by demonstrating the utility of
a cycloaddition and a Dieckmann condensation for constructing the
bicyclic tetronic acid ring, a key feature in spirotetronate synthesis.

\begin{scheme*}
\vspace*{-4pt}
\includegraphics{sc04}
\vspace*{5pt}
\caption{\label{sch4}Retrosynthetic analysis toward tetronolide by
Yoshii and co-workers.}
\vspace*{-8pt}
\end{scheme*}

Yoshii's group adopted a related Diels--Alder/Dieckmann cyclization
route during their effort toward the synthesis of tetronolide
\textbf{28}, a structurally related spirotetronate with anticancer and
antibacterial activity~\cite{36}. The synthesis relied on the
construction of a cyclohexene fused lactone that could subsequently
undergo a Dieckmann condensation to reveal an advance spirotetronate
(Scheme~\ref{sch4}A). In a model study, it was demonstrated that
tetrahydrophthalide (obtained from maleic anhydride/butadiene
cycloaddition and reduction) could be hydroxylated and converted to
spirotetronate \textbf{32a} (Scheme~\ref{sch4}B). In the second {approach},
diverging from Ireland and co-workers' \mbox{reported} work,
2-hydroxyacrylate derivative \textbf{34} rather than maleic anhydride
was used as the coupling partner in the Diels--Alder reaction and
opposed to symmetrical diene \textbf{35}, avoiding regioselectivity
{issues}. This allowed the progress toward a more functionalized
spirotetronate (Scheme~\ref{sch4}C).

Yoshii et~al.'s~second strategy began with diene \textbf{35} and acrylate
\textbf{34}, which upon Diels--Alder cycloaddition and heating in
methanol delivered bicyclic lactone \textbf{36} in 61\% yield
(Scheme~\ref{sch5}). After several steps, including
protection/deprotection, acylation, and redox manipulations, the Dieckmann
condensation led to the desired regioisomeric cyclohexene
spirotetronate \textbf{41}. Next, oxidation of the terminal alcohol to
the aldehyde allows the epimerization event to take place, leading to
\textbf{42} as a 5:1 mixture of \textit{exo}/\textit{endo}
diastereomers. Further post-transformations were then conducted to
install the required side chain on the cyclohexene~\cite{37}. This
sequence, although more efficient than Ireland and co-workers'
approach, still required 17 steps with an overall yield of less than
2\%, due in part to extensive protecting group manipulations~\cite{38}.

Despite these challenges, Yoshii et~al.'s~work represented the first use
of an acrylate derivative in a Diels--Alder reaction to access
spirotetronates. It was found to be particularly well suited to
spirotetronate synthesis, allowing the installation of both carboxyl
and acyloxy groups, critical to the tetronate ring formation.\looseness=-1

\begin{scheme*}
\vspace*{2pt}
\includegraphics{sc05}
\vspace*{6pt}
\caption{\label{sch5}Synthetic access to spirotetronate precursor
\textbf{70} by a Diels--Alder strategy with an acrylate and a
symmetrical diene.}
\end{scheme*}

Both Ireland et~al.~and Yoshii et~al.~studies underscore the centrality
of the Diels--Alder reaction and Dieckmann condensation in
spirotetronate synthesis despite the challenges in achieving regio-
and stereoselective control. Within such a strategy, the use of an
acrylate derivative in a Diels--Alder reaction was largely pursued in subsequent
work. Since costly post-functionalization remained a bottleneck,
efforts undertaken subsequently have increasingly focused on designing
more functionalized dienes and dienophiles to simplify the overall
synthetic routes. The biosynthetic insights gained over the past decade
have further reinforced the suitability of the Diels--Alder strategy,
providing a pathway for future \mbox{advancements} in the synthesis of this
complex class of natural products.


\subsection{Acrylates and acrolein derivatives as privileged
dienophiles in the synthesis of spirotetronates}\label{sec22}

As mentioned above, the utilization of deactivated alkenes such as
${\upalpha}$-acyloxy acrolein \textbf{44} and acrylate \textbf{45} and
substituted dienes in~[4+2]-cycloadditions has proven to be a
significant strategy in the synthesis of spirotetronates
(Scheme~\ref{sch6}). These dienophiles lead to intermediates containing
essential functional groups required for subsequent Dieckmann
condensation, while also establishing the requisite endocyclic double
bond and desired substituents.

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{6pt}}
\caption{\label{sch6}Diastereoselective outcome of a Diels--Alder
reaction using an acrolein or an acrylate as the dienophile.}
\vspace*{-5pt}
\end{scheme*}

Acrolein derivatives and ${\upalpha}$-substituted acrylates  are
characterized by their enhanced reactivity as dienophile partners,
attributed to the presence of electron-withdrawing groups. Their
reactivity under thermal conditions has been well documented with
simple cyclopentadiene or activated dienes \mbox{analogous} to Danishefsky's
diene~\cite{39,40,41}. However, the interaction of these dienophiles with
inactivated, highly substituted, in particular
${\upalpha}$,${\upalpha}'$ di-substituted acyclic dienes, was
scarcely explored until Roush et~al.~reported the use of Lewis acids to
promote such reactivity in 1997~\cite{42}. Their findings demonstrated
that aluminum(III) or tin(IV) based Lewis acids could
facilitate [4+2]-cycloadditions between hindered, inactivated
acyclic dienes and ${\upalpha}$-acyloxy acrolein, yielding good to
excellent selectivity. As shown in Scheme~\ref{sch7}, diene \textbf{46}
reacted with \textbf{44} upon exposure to stoichiometric amounts of
SnCl$_{4}$ at ${-}$78~\textdegree C, leading to cycloadduct
\textbf{47} bearing two vicinal quaternary carbons with excellent
regio- and diastereoselectivity in favor of the \textit{endo}
diastereomer. 

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc07}
{\vspace*{6pt}}
\caption{\label{sch7}Lewis acid--promoted Diels--Alder reaction with hindered
acyclic dienes.}
\vspace*{-4pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc08}
{\vspace*{6pt}}
\caption{\label{sch8}Diastereoselective outcome between diene 1.66 and
acryloyl chloride.}
\vspace*{-7pt}
\end{scheme*}

Further evaluations of various dienophiles, including
${\upalpha}$-bromoacrolein and methacrolein, \mbox{indicated} that
MeAlCl$_{2}$ could promote these reactions effectively even if longer
reaction times were observed for certain dienophiles. Importantly, the
application of MeAlCl$_{2}$ in these cycloadditions resulted in
cycloadducts exhibiting complete regioselectivity and good to excellent
diastereoselectivities (\textit{endo}/\textit{exo} ${<}$ 85:15) in favor of the
\textit{endo} cycloadduct. It should be mentioned that the
${\upalpha}$-substituent of the acrylate residue has a strong
influence on the outcome of the reaction; indeed, the use of acryloyl
and methacryloyl chlorides leads to the \textit{exo} adduct or poor
diastereoselectivity. An example is illustrated in Scheme~\ref{sch8},
where \textit{exo}-selective cycloaddition achieved from compound
\textbf{48} was followed by a methanol/pyridine treatment to facilitate
the formation of \textit{trans}-fused lactones \textbf{50}. The
successful application of Lewis acids not only demonstrated the
ability to achieve stereoselective outcomes that are often challenging
under thermal conditions but also highlighted their utility in
promoting the Diels--Alder reaction involving acrolein derivatives and
acyclic \mbox{dienes}.


In 2002, Roush's group employed this strategy to devise a
diastereoselective synthesis of both \textit{exo} and \textit{endo}
spirotetronate fragments of quartromicins~\cite{43}. Capitalizing on
the C$_{2}$ axial symmetry of quartromicins, they
reasoned that the tetramer could result from an incremental twofold
dimerization of \textit{endo} and \textit{exo} spirotetronates
(Scheme~\ref{sch9}). Specifically, this strategy could be accessible
from a coupling reaction between tetronates \textbf{51} and
\textbf{52}, which should be feasible by Diels--Alder cycloadditions
between \textbf{46} and an appropriate acrolein derivative. The
reaction with acrolein \textbf{44}, upon activation by a Lewis acid,
would lead to the \textit{endo} spirotetronate. For the \textit{exo}
spirotetronate, they relied on an \textit{endo}-selective Diels--Alder
reaction of ${\upalpha}$-bromoacrolein and \textbf{46}, followed by a
subsequent inversion of configuration of the quaternary stereocenter
described below~\cite{44}. 

\begin{scheme*}
\includegraphics{sc09}
{\vspace*{6pt}}
\caption{\label{sch9}Retrosynthetic analysis to access quartromicins by
Roush and co-workers.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc10}
{\vspace*{6pt}}
\caption{\label{sch10}Inversion of a quaternary stereocenter to access
\textit{exo} spirotetronate \textbf{78}.}
\vspace*{-8pt}
\end{scheme*}

Indeed, the reaction of \textbf{46} with ${\upalpha}$-bromoacrolein in the
presence of MeAlCl$_{2}$ produced cycloadduct \textbf{53} as
the single \textit{endo} diastereomer (Scheme~\ref{sch10}). Then, a
series of five synthetic steps enabled the conversion of cycloadduct
\textbf{53} to the spiroepoxide \textbf{54}, which was obtained in 72\%
yield. This involved the reduction of aldehyde \textbf{53} to the
corresponding alcohol, followed by an alkoxide-mediated inversion of
the quaternary stereocenter. Although spiroepoxide \textbf{54}
displayed reluctance to react with oxygen-based nucleophiles, it was
successfully opened by sodium thiophenolate, yielding sulfoxide
\textbf{55} upon oxidation with \textit{m}-CPBA. The subsequent
reaction with Ac$_{2}$O and NaOAc produced the desired intermediate
\textbf{56} via Pummerer rearrangement and acylation of the tertiary
alcohol. After further oxidation of the aldehyde using KMnO$_{4}$ and
conversion to the methyl ester with TMSCHN$_{2}$, the TBS-protected
hydroxyl group was deprotected using pyridinium
\textit{p}-toluenesulfonate. This allowed for further functionalization
to obtain the ${\upalpha}$,${\upbeta}$-unsaturated ester \textbf{58},
\mbox{ultimately} leading to the classical Dieckmann condensation that
produced spirotetronate \textbf{59} in good yield.\looseness=-1


For the construction of the \textit{endo} spirotetronate, diene
\textbf{46} was made to react with ${\upalpha}$-acyloxy acrolein to generate
cycloadduct \textbf{60}, followed by functional group interconversion
and redox manipulations to access the desired \textit{endo} product in
10 steps (24\% yield; Scheme~\ref{sch11}). These synthetic sequences
highlight the versatility of acrylates and acroleins as \mbox{privileged}
dienophiles, underscoring their significance in the efficient
construction of complex spirocyclic architectures relevant to
biologically active compounds. Further advance in the synthesis was
undertaken~\cite{45}, but the total synthesis of quartromicins remained
incomplete.

\begin{scheme*}
\vspace*{-3pt}
\includegraphics{sc11}
{\vspace*{6pt}}
\caption{\label{sch11}Synthesis of the \textit{endo} spirotetronate
moiety en route to quartromicins.}
\vspace*{-7pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc12}
{\vspace*{6pt}}
\caption{\label{sch12}Synthetic access to the spirotetronate moiety of
abyssomicin C.}
\vspace*{-11pt}
\end{scheme*}

Lewis acid--promoted cycloadditions of functionalized dienes with
acrolein derivatives or acrylates have proven effective for
synthesizing various \textit{endo} diastereocontrolled spirotetronates.
Several studies~\cite{46,47,48} have highlighted this approach,
\mbox{particularly} in the context of abyssomicin C. Two independent studies
published in 2005 reported the synthesis of the spirotetronate moiety
using diene \textbf{62}, which contains an unprotected allylic alcohol
(Scheme~\ref{sch12}). The reaction with ${\upalpha}$-acyloxyacrolein~\textbf{44} 
produced cycloadduct \textbf{63} as the sole \textit{endo}
diastereomer~\cite{47}. The fused lactol was subsequently oxidized to
lactone \textbf{64} and engaged in a Dieckmann condensation that first
required a TBSCl protection of the terminal alcohol to prevent
recyclization to the lactone. Attempts to achieve \mbox{enantioselectivity}
through aluminum/BINOL complexes during the cycloaddition were
unsuccessful. In the second study, methyl acrylate served as the
dienophile, leading to the fused lactone \textbf{66}, necessitating an
additional hydroxylation step to introduce the acetate group required
for the spirotetronate formation~\cite{48}. Both~studies ended with the
formation of compounds \textbf{65} or its deprotected variant
\textbf{68}, without completing the total synthesis of abyssomicin C. 

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc13}
{\vspace*{6pt}}
\caption{\label{sch13}Enantioselective access to the spirotetronate
moiety of abyssomicin C.}
\vspace*{-7pt}
\end{scheme*}


Burkart's group mimicked this method to access the core structure of
spirohexenolides \textbf{5a} and \textbf{5b}, previously isolated
compounds exhibiting antitumoral activity~\cite{4}. They achieved a
regio- and diastereoselective cycloaddition between a hindered triene
and ${\upalpha}$-acyloxyacrolein \textbf{44}~\cite{49}, but encountered
the undesired deacylation of the tertiary alcohol during aldehyde
oxidation, necessitating additional protection/deprotection steps and
reducing the overall synthetic efficiency. 

Nicolaou and co-workers implemented this strategy in a
diastereoselective process during their \mbox{synthesis} of enantioenriched
spirotetronate moiety of abyssomicin C~\cite{50,51}. Engaging
enantioenriched diene \textbf{69} bearing a chiral secondary alkoxy
side chain with methyl acrylate in a Diels--Alder reaction, they managed
to isolate lactone \textbf{70} as a single diastereoisomer in 80\% yield
(Scheme~\ref{sch13}). This magnesium-promoted reaction used
2-(pyrrolidin-1-yl)phenol as a ligand, which enhanced the reaction rate
by facilitating a favorable spatial arrangement between the magnesium
ions and the dienophile. The cycloadduct underwent further
transformations, including ${\upalpha}$-hydroxy ester formation,
lithium--sulfur exchange, epoxidation, and Dieckmann cyclization,
ultimately yielding \textit{endo} spirotetronate intermediate
\textbf{73}. Final macrocyclization was achieved through ring-closing
metathesis (RCM) using a Hoveyda--Grubbs catalyst, culminating in the
successful synthesis of abyssomicin C and its atropisomer alongside
numerous analogues, helping in understanding the structure--activity
relationship.

Exploration of chiral dienophiles to induce diastereoselectivity and
obtained enantioenriched cycloadducts have also been reported. Roush
et~al.~demonstrated that 2-alkyl-5-methylene-1,3-dioxolan-4-ones
participate in Diels--Alder \mbox{reactions} involving cyclobutene via an
\textit{exo} transition state~\cite{52,53,54,55}, leading essentially
to one diastereomer with an \textit{exo} configuration. In particular,
2-(\textit{tert}-butyl)-5-methylene-1,3-dioxolan-4-one \textbf{74}
with its bulky \textit{tert}-butyl substituent predominantly forms
product \textbf{75} from \textit{exo}-\textbf{TS-75}, with selectivity
attributed to the constrained s-\textit{cis} conformation of the
dienophile and steric interactions influencing the transition states
(Scheme~\ref{sch14}).

\begin{scheme*}
\includegraphics{sc14}
{\vspace*{6pt}}
\caption{\label{sch14}Diastereoselective Diels--Alder cycloaddition of
(\textit{R})-\textbf{74} with cyclopentadiene.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc15}
{\vspace*{6pt}}
\caption{\label{sch15}Diastereoselective outcome of the intramolecular
Diels--Alder reaction applied to \textbf{79}.}
\vspace*{-6pt}
\end{scheme*}

Utilizing this diastereoselective \textit{exo}-selective approach,
Roush and co-workers implemented an \mbox{intramolecular} Diels--Alder (IMDA)
strategy to access diverse diastereomers of spirotetronates relevant to
quartromicins~\cite{56}. The synthesis of the sulfone precursor
\textbf{79} was achieved in six steps from a known vinyl iodide
\textbf{78}, yielding an overall 50\% yield. The IMDA reaction
conducted at 210~\textdegree C generated cycloadducts \textbf{80, 81},
and \textbf{82}, albeit with low yields and poor stereoselectivity
(Scheme~\ref{sch15}). The absolute configurations of products
\textbf{80} and \textbf{82} were confirmed through crystallographic
analysis, while nOe correlations determined the relative configuration
of \textbf{81}~\cite{57,58}. Ring opening of the lactone was achieved
using ethanedithiol to reveal the key ${\upalpha}$-hydroxy ester motif
subsequently used to build the tetronate. This~IMDA strategy has proven
effective in the total synthesis of chlorothricolide~\cite{59,60},
tetronolide~\cite{61,62}, and kijanolide~\cite{63,64}, showcasing the
potential of spirotetronate derivatives.\looseness=1


Although 5-methylene-1,3-dioxolan-4-one deri\-vatives were demonstrated to
be competent partners in Diels--Alder reactions, their reactivity remained
low, and even under quite forcing conditions, furnished low yield and
limited selectivity. To improve the outcome, Roush's group explored the
reactivity of 1,3-oxazolidine-4-one analogues \textbf{83a--b} under
Lewis acid activation to facilitate an intermolecular Diels--Alder
reaction. However, the reaction between dienophile \textbf{74} and
diene \textbf{46} exhibited extensive decomposition at cryogenic
temperatures in the \mbox{presence} of a Lewis acid (Scheme~\ref{sch16}). An aza
analogue of 1,3-oxazolidine-4-one, in the form of oxazolidine
\textbf{83}, was more robust as a dienophile and underwent the
cycloaddition smoothly. Unfortunately, efforts to subsequently cleave
the lactam were unsuccessful~\cite{65}.

\begin{scheme*}
\includegraphics{sc16}
{\vspace*{6pt}}
\caption{\label{sch16}Reactivity issues posed by the chiral auxiliaries
developed by Roush et~al.}
\vspace*{-6pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc17}
\vspace*{6pt}
\caption{\label{sch17}Bicyclic chiral oxazolidinone enables access
to the \textit{exo} and the \textit{endo} fragments of quartromicins.}
\vspace*{-6pt}
\end{scheme*}

\begin{scheme*}
{\vspace*{2pt}}
\includegraphics{sc18}
\vspace*{6pt}
\caption{\label{sch18}(A) Use of camphorsultam-based auxiliary to
access both \textit{endo} and \textit{exo} spirotetronates of
quartromicins by Roush et~al. (B)~Scheidt et~al.~strategy
displaying a \textit{N}-acryloyl oxazolidinone.}
\vspace*{-8pt}
\end{scheme*}

To improve the strategy without struggling with low yields and
decomposition and for subsequent handling,  Roush's group turned its
attention toward bicyclic oxazolidinone based dienophiles
\textbf{85a--c}, each featuring substituents such as methyl,
isopropyl, or benzyl groups, designed to \mbox{enantioselectively}
access the spirotetronate moieties of quartromicins
(Scheme~\ref{sch17})~\cite{65}. These chiral building blocks proved to be
effective in the anticipated Lewis acid--activated Diels--Alder reaction
even if the reaction was specially slow (5~days). Among the dienophiles
tested, \textbf{85a} provided the most promising results leading to a
5:1 ratio with a total yield of 70\% for the \textit{exo} adduct.
Subsequent transformations involved the cleavage of the chiral
auxiliary using lithium aluminum hydride followed by oxidation of
the primary alcohol with DMSO, yielding the enantioenriched precursors
\textbf{88a} and \textbf{89a}. Despite the advancements achieved with
these bicyclic oxazolidinone dienophiles, their relatively low
diastereoselectivity in the Diels--Alder reaction (\textit{exo} vs
\textit{endo} ratio) highlights the \mbox{limitations} of this approach. Although
other chiral auxiliaries based on acrylates and acrolein derivatives
have been explored for spirotetronate synthesis, they \mbox{generally}
encounter similar challenges related to
post-functionalization~\cite{66,67}. 

Roush and co-workers also examined a Lewis acid--promoted Diels--Alder
reaction \mbox{using} \mbox{\textit{N}-acryloyl} camphorsultam \textbf{90} and diene
\textbf{46,} achieving a \mbox{diastereomeric} ratio of
\textit{exo}/\textit{endo} 7:1 (Scheme~\ref{sch18}A)~\cite{43}. Despite
this stereoselectivity, the approach did not provide direct access to
the required quaternary hydroxy carbon, thereby diminishing its
relevance. Post-manipulations nevertheless allowed building suitable
spirotetronate precursors. Subsequent attempts to utilize
${\upalpha}$-substituted \textit{N}-acryloyl camphorsultams were
unsuccessful, prompting further \mbox{investigations}.\looseness=-1 

\begin{scheme*}
\includegraphics{sc19}
{\vspace*{6pt}}
\caption{\label{sch19}Enantioselective Diels--Alder reaction with
achiral substrates with the use of CBS catalyst.}
\vspace*{-4pt}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc20}
{\vspace*{6pt}}
\caption{\label{sch20}First example of intermolecular Diels--Alder
reaction using a tetronate dienophile.}
\end{scheme*}

In a related approach, Scheidt and co-workers successfully utilized a
chiral $N$-acryloyl oxazolidinone~\cite{68} in the synthesis of the
\textit{endo} spirotetronate of (-)-okilactomycin, demonstrating that
this strategy could be extended to complex natural products
(Scheme~\ref{sch18}B)~\cite{69}. 

Given the challenges with chiral dienophiles, it would be advantageous
to achieve enantioenriched intermediates from achiral substrates by
\mbox{controlling} the enantioselectivity of the Diels--Alder reaction through
the use of chiral promoters or catalysts. In the synthesis of
spirotetronates, this approach remains underexplored, with the only
successful example reported by Marshall and Xie in 1992~\cite{44}. They
leveraged an enantioselective Diels--Alder \mbox{reaction} using reactive
dienes and acrolein derivatives, promoted by the Corey--Bakshi--Shibata
(CBS) catalyst, a boron-based oxazaborolidine. They conducted the
reaction between functionalized triene \textbf{95}, synthesized in
eight steps from glycolaldehyde, and ${\upalpha}$-bromoacrolein, using
one equivalent of the CBS catalyst \textbf{96}. This reaction led to
the formation of the \textit{endo} diastereomer \textbf{97} with
moderate enantiocontrol  ($\mathrm{ee}= 72$\%) but 
impressive regioselectivity
(Scheme~\ref{sch19}). The choice of bromo-substituted acrolein was
driven by its reactivity toward dienes when activated by the
oxazaborolidine catalyst and the requirement to invert the quaternary
stereocenter to access the \textit{exo} spirotetronate. Although the
authors did not provide a detailed mechanism, a plausible transition
state based on Corey and Loh's earlier work was proposed in
Scheme~\ref{sch19}~\cite{70}. The key inversion of the stereocenter
followed a sequence similar to that previously outlined by Roush
et~al., involving an epoxide intermediate, sulfide ring opening,
oxidation of the sulfoxide, and a Pummerer rearrangement. \mbox{Following}
this, a classical acylation of the tertiary alcohol and a subsequent
Dieckmann cyclization were used to form the spirocyclic intermediate
\textbf{98} in nine steps from \textbf{97} (overall yield 68\%).
Despite the moderate enantiomeric excess and the stoichiometric use of
the oxazaborolidine catalyst, this regio- and diastereoselective
cycloaddition represents a rare example of spirotetronate synthesis not
relying on \mbox{chiral} dienophiles.

\begin{scheme*}
\includegraphics{sc21}
\vspace*{6pt}
\caption{\label{sch21}Enantio- and diastereoselective access to
abyssomicin C via a biomimetic strategy by Sorensen and co-workers.}
\end{scheme*}

\subsection{Emergence and use of tetronate-derived dienophile in
Diels--Alder reactions}\label{sec23}

The use of Diels--Alder reactions to access spirotetronates has been
predominantly based on acrolein derivatives or acrylates, both chiral
and achiral. However, some studies have explored alternative
dienophiles, such as 5-methylenetetronate \textbf{100}
(Scheme~\ref{sch20}), which bypass the need for {post-functionalization}
steps required for Dieckmann condensation~\cite{71}. Yoshii's group
successfully synthesized \textbf{100} in just three steps starting from
4-methoxyfuran-2(5\textit{H})-one. They were the first to apply this
dienophile in an intermolecular Diels--Alder reaction with triene
\textbf{99} at high temperatures  (180~\textdegree C in
1,2-dichlorobenzene), obtaining a modest diastereoselectivity (dr ${=}$
1:3) and yield (43\%). The reaction favored the undesired
\textit{endo} diastereomer \textbf{102}, considering that targeted
kijanolide contains an \textit{exo}-type spirotetronate. Despite the
low yield and selectivity, the reaction showcased the ability of
tetronate dienophiles to form spirocycles in a single step. Following
this work, the same group explored ${\upalpha}$-acyloxy derivatives of
\textbf{100}, synthesized in two steps from \textbf{100}, to access the
spirotetronate moiety of chlorothricolide~\cite{72}. Although the
reaction conditions were less severe (140--150~\textdegree C in
chlorobenzene), the outcome was again a diastereomeric mixture favoring
the \textit{endo}-type spirotetronate along with regioisomeric
products. These results highlight the limitations of
5-methylenetetronate in terms of regio- and diastereoselectivity, yet
its use circumvents extensive post-reaction functionalization.

\begin{scheme*}
\includegraphics{sc22}
{\vspace*{6pt}}
\caption{\label{sch22}Alkylation of cyclohexanone with a
${\upbeta}$-lithiated acrylate.}
\vspace*{-7pt}
\end{scheme*}

The use of tetronate-derived dienophile as a synthetic precursor to
spirotetronate was illustrated by Sorensen and co-workers
(2005)~\cite{73}, who achieved the enantioselective and
diastereoselective synthesis of abyssomicin C. Sorensen et~al.'s~approach
relied on a biomimetic IMDA reaction that
constructs the spirotetronate and the macrocyclic ring in a single step
(Scheme~\ref{sch21}). The synthesis began with \mbox{\textit{meso}-anhydride}
\textbf{103}, which was accessible from diethyl methylmalonate in three
steps on a large scale. After several key transformations, including
stereoselective hydrolysis and aldolization with
\textit{trans},\textit{trans}-2,4-hexadienal, aldehyde \textbf{104} was
obtained in nine steps from \textbf{103} with a 22\% overall yield. A
critical step in the sequence was the addition of deprotonated
tetronate \textbf{105} to aldehyde \textbf{104}, followed by oxidation
of the resulting secondary alcohol using the Dess--Martin periodinane,
generating intermediate \textbf{106}. Initially, the authors attempted
to eliminate the protected alcohol and initiate the Diels--Alder
reaction by using scandium(III) triflate, but this approach produced an
unstable polyene intermediate. They subsequently found that treating
\textbf{106} with lanthanum(III) triflate triggered both polyene
formation and intramolecular cycloaddition in one step, furnishing the
key intermediate \textbf{107} in 50\% yield. Notably, this step was
completely diastereoselective, a significant improvement over previous
methods employing tetronate dienophiles. The Diels--Alder reaction
proceeded through a favorable transition state (\textbf{TS-107}) as
confirmed by computational studies. Further transformations, including
epoxidation of the cyclohexene ring and nucleophilic attack of the
deprotected tetronic acid, completed the synthesis of abyssomicin C.
This strategy not only provided the first enantioselective synthesis of
abyssomicin C but also closely mirrored the natural biosynthetic
pathway, which involves a similar IMDA reaction
with a tetronate dienophile. In addition to abyssomicin C, this method
has been extended to the synthesis of abyssomicin C analogues and
okilactomycin, further demonstrating the versatility of the
IMDA reaction with tetronate
dienophiles~\cite{74,75}. These efforts have significantly expanded the
scope of spirotetronate synthesis, offering a powerful tool for
accessing complex natural products with spirocyclic cores.


\section{Other strategies}\label{sec3}

As illustrated previously, the main strategies to access spirotetronates
rely on two key disconnections: a Diels--Alder reaction to build the
cyclohexene ring and a Dieckmann condensation to form the tetronate
unit. However, alternative retrosynthetic disconnections have been
explored to address the synthesis of this challenging spirotetronate
motive.

\subsection{Alkylation of cyclic ketones}\label{sec31}

The conversion of ketone with ${\upbeta}$-lithiated acrylates has been
reported as an alternative to the Dieckmann condensation in the context of
spirotetronate natural compound synthesis. For instance, selective
${\upbeta}$-lithiation of ${\upbeta}$-methoxyacrylate \textbf{108}
under kinetic control and subsequent addition to cyclohexanone produced
unfunctionalized spirotetronate \textbf{109}
(Scheme~\ref{sch22})~\cite{76,77}. Schmidt and Hirsenkorn used this
method in the synthesis of chlorothricolide~\cite{78,79}, and showed
that ${\upbeta}$-ethylthioacrylate improved yields compared to
methoxyacrylate, while both nucleophiles provided the same
diastereoselectivity. The resulting sulfide \textbf{111} could be
further converted into a methoxy derivative and
${\upalpha}$-hydroxylated to yield intermediate \textbf{112}, useful in
chlorothricolide synthesis.

Yoshii and co-workers also took advantage of this strategy in several
studies toward kijanolide and tetronolide~\cite{80,81}. They found
that using a cerium(III) derivative of \textbf{Li-108} allowed better
compatibility with enolizable ketones due to the nucleophilicity of
organocerium compounds, which are poor bases~\cite{82}. Their synthesis
of tetronolide started with enantioenriched cyclohexanol
\textbf{113}~\cite{83} and proceeded to cyclohexanone \textbf{114} in three
steps with 80\% yield. Addition of ${\upbeta}$-dichlorocerium salt of
\textbf{108} provided the spirotetronate intermediate \textbf{115} as
the \textit{exo} diastereomer (Scheme~\ref{sch23}).

\begin{scheme*}
\includegraphics{sc23}
\vspace*{6pt}
\caption{\label{sch23}Enantioselective access to an \textit{exo}
spirotetronate by alkylation of a cyclohexanone with a cerium salt.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc24}
{\vspace*{6pt}}
\caption{\label{sch24}Synthetic access to an intermediate in the
synthesis of (-)-atrop-abyssomicin by Saicic et~al.}
\vspace*{-6pt}
\end{scheme*}

Other notable efforts include the total synthesis of
(-)-atrop-abyssomicin C by Bihelovic and Saicic, relying on a
gold-catalyzed step to form the bridged spirotetronate
(Scheme~\ref{sch24})~\cite{84}. This approach involved the addition of
a lithium derivative of ethyl orthopropiolate to a cyclic ketone that
occurred with high diastereoselectivity, providing compound
\textbf{122} in 75\% yield~\cite{85}. A gold-catalyzed hydroxyl
addition to the alkyne was subsequently performed, leading to a
tricyclic (\textit{Z})-3-alkoxyacrylate. Photochemical
(\textit{Z})--(\textit{E}) isomerization did then offer the suitable
conformation for tetronate formation.

Interestingly in Bihelovic and Saicic's work, the synthesis of the
functionalized cyclohexanone precursor was not established by a
cycloaddition strategy (see vide infra)
but was achieved through a dual
organo/metal-catalyzed Tsuji--Trost cyclization of linear
allyl--aldehyde \textbf{118}~\cite{86}. This key \mbox{cyclization} involves a
transient enamine formation that undergoes a cyclative ${\uppi}$-allyl
palladium displacement. The resulting cyclic aldehyde was next
transformed through an oxidation into desired cyclohexanone~\textbf{120}.

\subsection{Alternatives to Diels--Alder reaction for cyclohexene ring
construction}\label{sec32}

The Dieckmann condensation of 1-acetoxycyclohex\-ene-1-carboxylate
derivatives was largely used when targeting spirotetronates, and the
Diels--Alder reaction has been found to be particularly well suited to
prepare these precursors. Selected ring-forming approaches, bypassing
cycloaddition strategies, were nevertheless also reported.

Roush's work related to quartromicins is a notable example of such an
alternative strategy, wherein enantioselective access to a
functionalized cyclohexene precursor is achieved through an
intramolecular aldol reaction~\cite{87}. The synthesis involves
trialdehyde \textbf{125} (obtained in 11 steps), which undergoes an
intramolecular aldol reaction, transiently forming a cyclohexanol that
is trapped by the third aldehyde leading to bicyclic lactol
\textbf{126} in 54\% yield. Elimination of the hydroxy after several
steps furnished an entry into the unsaturated cyclohexene that was finally
converted through a Dieckmann condensation to spirotetronate
(Scheme~\ref{sch25}).

\begin{scheme*}
\includegraphics{sc25}
{\vspace*{6pt}}
\caption{\label{sch25}Enantioselective synthesis of an \textit{endo}
spirotetronate via an intramolecular aldolization step.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc26}
{\vspace*{6pt}}
\caption{\label{sch26}Ireland--Claisen rearrangement followed by an RCM
step \textit{en route} to spirohexenolides.}
\vspace*{-6pt}
\end{scheme*}

Retrosynthetic disconnections employing RCM
have been explored in a few reports, \mbox{demonstrating} their utility in
synthesizing functionalized cyclohexenes. In the context of
spirotetronates, RCM requires the formation of a
${\upbeta}$-unsaturated ester, typically synthesized via a Claisen
rearrangement. An example of this strategy is found in the work of
Bedel and co-workers, who used an Ireland--Claisen/metathesis sequence
to generate precursors for quartromicins~\cite{88}. More recently, an
enantioselective total synthesis of spirohexenolides A and B
(\textbf{5a} and \textbf{5b}) utilized the same strategy, further
illustrating the power of this approach~\cite{89}. In this synthesis,
enantiopure ester \textbf{129} undergoes an Ireland--Claisen
rearrangement with high yield and diastereoselectivity, driven by a
chair-like transition state (Scheme~\ref{sch26}). Two adjacent
quaternary centers are formed in this step. The subsequent RCM
proceeded efficiently, achieving an 88\% yield using the Hoveyda--Grubbs
second-generation catalyst (HG-II). The succeeding steps included a Dieckmann
\mbox{cyclization} to form spirotetronate \textbf{132,} another RCM to
construct the macrocyclic backbone, and an {elimination} to introduce the
unsaturation into the macrocycle~\cite{91,92,93}\footnote{We encourage
the interested reader to refer to the study for this last step, as it
constitutes an elegant access to a bent ${\uppi}$-conjugated macrocyclic
system. For other examples of bent-${\uppi}$ macrocycle synthesis, see
refs~\cite{91,92,93}.}. An alternative RCM-based strategy targeting
versipelostatin involved the formation of a cyclohexenone, followed by
the stereoselective addition of a deprotonated alkyne to the
ketone~\cite{94}.


\section{Conclusion}

Among the strategies discussed, the Diels--Alder cycloaddition between a
diene and an acrolein derivative stands out as the most versatile and
widely studied approach for spirotetronate synthesis. The ease with
which functionalized dienes can be accessed through reactions like
Wittig olefination and vinyl lithium addition, combined with the
utility of substituted acroleins, makes this method highly efficient
for constructing spirotetronate frameworks. However, enantioselective
control remains a key challenge. Although asymmetric variants have been
developed, they often require pre- and \mbox{post-functionalization} steps to
manipulate chiral auxiliaries, adding complexity to the overall
synthesis. The reported enantioselective Diels--Alder reaction achieving
72\% enantiomeric excess using achiral substrates demonstrates
progress, but further refinement is needed to increase both efficiency
and stereocontrol.

The diastereoselective IMDA variants,
particularly those leveraging biomimetic approaches with tetronate-type
dienophiles, show promise for applications. Meanwhile, alternative
strategies like the addition of acrylates to cyclohexanone and the use
of RCM have shown potential but require further
optimization, particularly in improving the selectivity and overall
step economy of the synthesis. The recent successes in spirohexenolide
synthesis highlight the potential of these methods when effectively
applied, but they also underscore the significant challenges related to
step count, diastereoselectivities, and enantioselectivities.\looseness=-1

Looking ahead, future research should focus on improving the
enantioselective control in Diels--Alder reactions by exploring new
chiral catalysts or reagents that can enhance selectivity without
necessitating multiple auxiliary steps. Additionally, integrating
biomimetic strategies with catalytic approaches may offer new avenues
to streamline the synthesis of spirotetronates, particularly for
complex natural products like spirohexenolides. Further investigation
into RCM and the development of novel
organocatalytic systems could provide more efficient routes to
construct these intricate molecular architectures. Ultimately, the goal
will be to reduce the synthetic burden while achieving greater
precision in stereoselectivity, enabling broader access to
spirotetronate-based natural products and their analogues.

\section*{Declaration of interests}
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.

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