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\DOI{10.5802/crchim.274}
\datereceived{2023-11-08}
\daterevised{2023-11-13}
\dateaccepted{2023-11-13}
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\dateposted{2024-03-26}
\begin{document}

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%\makeatletter
%\def\TITREspecial{\relax}
%\def\cdr@specialtitle@english{French Women in Chemistry in 2024}
%\def\cdr@specialtitle@french{Les chimistes fran\c{c}aises en 2024}
%\makeatother

\title{Control of atropoisomerism: an access to valuable~compounds}

\alttitle{Contr\^{o}le de l'atropoisom\'{e}rie : un acc\`{e}s \`{a} des
compos\'{e}s d'int\'{e}r\^{e}t}

\author{\firstname{Sabine} \lastname{Choppin}\CDRorcid{0000-0003-4809-0116}}
\address{Laboratoire d'Innovation Mol\'{e}culaire et Applications, ECPM, UMR 7042, Universit\'{e}~de Strasbourg/Universit\'{e} de Haute-Alsace, 25 rue Becquerel, Cedex 67087, Strasbourg, France}

\author{\firstname{Joanna} \lastname{Wencel-Delord}\CDRorcid{0000-0002-7094-5443}}
\address[1]{Laboratoire d'Innovation Mol\'{e}culaire et Applications, ECPM, UMR 7042, Universit\'{e}~de Strasbourg/Universit\'{e} de Haute-Alsace, 25 rue Becquerel, Cedex 67087, Strasbourg, France}

\author{\firstname{Fran\c{c}oise} \lastname{Colobert}\CDRorcid{0000-0003-4730-9868}\IsCorresp}
\address[1]{Laboratoire d'Innovation Mol\'{e}culaire et Applications, ECPM, UMR 7042, Universit\'{e}~de Strasbourg/Universit\'{e} de Haute-Alsace, 25 rue Becquerel, Cedex 67087, Strasbourg, France}
\email[F. Colobert]{francoise.colobert@unistra.fr}

\shortrunauthors

\keywords{\kwd{Atropoisomerism}
\kwd{C--H activation}
\kwd{Chiral sulfoxide}
\kwd{Natural products}
\kwd{Terphenyl ligands}
\kwd{C--N coupling}}

\altkeywords{\kwd{Atropoisom\'{e}rie}
\kwd{C--H activation}
\kwd{Sulfoxyde chiral}
\kwd{Produits naturels}
\kwd{Ligands terph\'{e}nyliques}
\kwd{Couplage C--N}}

\begin{abstract}
Many natural, biologically active compounds are stereogenic with a
unique tridimensional structure that is on the origin of the specific
interactions with the active binding site. 

This concept of chirality goes beyond chiral stereocenters, englobing
also atropoisomerism related to a hindered rotation around an axis with
the isolation of atropostable conformers at room temperature.
Atropoisomerism is well-known in biaryls, however this phenomenon is
encountered in many pharmaceutically relevant compounds such as
heterobiaryl, diarylamines, benzamides and anilides.

Currently four FDA-approved drugs are atropostable and many others are
in clinical trials. It is also important to note that almost 30\% of
recent FDA-approved small molecules are ``proatropisomeric'' and
interact with a target in a specific chiral conformation.

Given this vivid interest in C--C but also C--N atropisomerically stable
compounds, this account will detail the new atropoisomeric strategies we
developed and their applications in the synthesis of relevant molecules
and ligands.\vspace*{-3pt}
\end{abstract}

\begin{altabstract}
De nombreux compos\'{e}s naturels biologiquement actifs sont
st\'{e}r\'{e}og\'{e}niques avec une structure tridimensionnelle unique
qui explique les interactions sp\'{e}cifiques d'un \'{e}nantiom\`{e}re
avec le site de liaison actif.

Cette notion de chiralit\'{e} s'\'{e}tend non seulement aux centres
st\'{e}r\'{e}og\`{e}nes mais aussi \`{a} l'atropoisom\'{e}rie li\'{e}e
\`{a} un emp\^{e}chement de la rotation autour d'un axe.
L'atropisom\'{e}rie est bien connue dans les biaryles, cependant ce
ph\'{e}nom\`{e}ne est rencontr\'{e} dans de nombreux compos\'{e}s
pharmaceutiquement importants tels que l'h\'{e}t\'{e}robiaryle, les
diarylamines, les benzamides et les anilides.

Actuellement, quatre m\'{e}dicaments approuv\'{e}s par la FDA sont
atropostables et de nombreux autres sont en cours d'essais cliniques.
Il est \'{e}galement important de noter que pr\`{e}s de 30~\% des
petites mol\'{e}cules r\'{e}cemment approuv\'{e}es par la FDA sont
{\guillemotleft}~proatropisom\`{e}res~{\guillemotright} et
interagissent avec une cible dans une conformation chirale
sp\'{e}cifique.

Compte tenu de ce vif int\'{e}r\^{e}t pour les compos\'{e}s
pr\'{e}sentant un axe atropisom\'{e}rique stable de type 
C--C mais aussi C--N, cet article d\'{e}taillera les nouvelles
strat\'{e}gies atropos\'{e}lectives que nous avons d\'{e}velopp\'{e}es
et leur application dans la synth\`{e}se de mol\'{e}cules et de ligands
pertinents.
\end{altabstract}

\maketitle


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\section{Introduction}

The importance of axially chiral biaryl compounds is rapidly expanding.
The main reason is their presence in numerous biologically active
natural products and therapeutic agents. They are also the privileged
backbone of ligands and catalysts in asymmetric catalysis. Regarding
the importance of these scaffolds, numerous strategies have been
reported and among them atropo-enantioselective metallo- or
organo-catalyzed cross-coupling reactions have been successfully
employed to efficiently synthesize a large panel of these scaffolds
(for recent reviews on the synthesis of axially chiral biaryls
see \cite{1a,1b,1c,1d,1e}).
Recently asymmetric C--H activation has proved to be efficient to
control the chirality and more particularly to synthesize axially
chiral biaryls~\cite{2,2a}.


Over the past decade our laboratory has embarked on a research program
dedicated to the control of atropoisomerism and we targeted at first
differently substituted biaryl and triaryl skeletons bearing one or two
atropisomeric axis. Our idea was to use a Pd-catalyzed
atropo-diastereoselective C--H functionalization process using as chiral
auxiliary an enantiopure sulfoxide, fixed on a configurationally
unstable biaryl. Secondly, we turned our attention to the control of a
C--N atropisomeric axis in N--Ar units via a Cu-catalyzed atroposelective
aryl amination using hypervalent iodines as coupling partners  
(Figure~\ref{fig1}). 

\begin{figure*}
\includegraphics{fig01}
\caption{Csp$^{2}$-H activation: Axially chiral biaryl and triaryl
compounds/Control of C--N atropisomeric axis via Ullmann-type C--N
coupling reaction.\label{fig1}}
\end{figure*}

Capitalizing on our experience in total synthesis of biologically
active compounds, we applied our atroposelective methods towards the
synthesis of natural products as well as a new family of
terphenyl\break ligands.

\section{Results and discussion}

Our first successful contribution to control atropoisomerism through a
C--H activation-type protocol concerns a diastereoselective approach by
using a chiral Directing Group (DG*). The chiral DG is utilized in
stoechiometric amount and several criteria need to be fulfilled: the
chiral DG must be (1) easy to install and not expensive (2) traceless
or highly recyclable. The advantage compared to the enantioselective
approach is the obtention of separable atropo-diastereomers. In
addition the stereogenic center is in close proximity to both metal and
substrate insuring an efficient chiral induction. We chose a sulfinyl
moiety as chiral DG because we had already an extensive experience in
the use of sulfoxides as chiral auxiliary 
(for the use of sulfoxides in Suzuki coupling
reactions~\cite{3a,3b,3c}).
Moreover chiral sulfoxides are easily accessible on a large scale and the
most important is its traceless character~\cite{4}. Sulfoxyde motif can
be easily transformed via sulfoxide lithium exchange followed
by electrophilic trapping with a myriad of electrophiles. Our initial
hypothesis envisioned to start from a preformed biaryl, bearing the
sulfinyl group in \textit{ortho} position, and to introduce a
substituent at the \textit{ortho} position to the Ar--Ar$^\prime$ linkage
through a C--H functionalization process. One atropo-diastereomeric
\mbox{metallacycle} was expected to be favored and the subsequent
{functionalization} should thus occur in a stereoretentive manner,
keeping the already fixed chirality. The removal or modification of the
chiral sulfinyl group would allow the modular synthesis of axially
chiral biaryls (Figure~\ref{fig2}). 

\begin{figure*}
\includegraphics{fig02}
\caption{Axially chiral C--H functionalization of a biaryl moiety.\label{fig2}}
{\vspace*{5pt}}
\end{figure*}

Thus, the hypothesis was validated by designing a Fujiwara--Moritani
reaction with methyl acrylates or styrenes. We were delighted to obtain
the corresponding coupling products in high yields and high
atropo-diastereoselectivities~\cite{5a,5b,5c}.
\mbox{Remarkably,} the reaction is very tolerant towards many functional
groups. Progressively, similar C--H acetoxylation in the presence of
AcOH as well as the C--H iodination in the presence of 
$N$-iodosuccinimide ({NIS})
were developed, delivering the atropostable biaryls in excellent yields
and stereoselectivities (Scheme~\ref{sch1})~\cite{6}.


\begin{scheme*}
\includegraphics{sc01}
\vspace*{4pt}
\caption{Atropodiastereoselective oxidative Heck, acetoxylation and iodination.\label{sch1}}
\vspace*{-4pt}
\end{scheme*}

To rationalize these experimental results, a phenomenon of dynamic
kinetic asymmetric transformation has been proposed and corroborated by
DFT calculations. It was thus shown that the rotational barrier between
the two substrates \textbf{S1} and \textbf{S2} is much higher than
between the two palladacycles \textbf{C1} and \textbf{C2} (a difference
of 10~kcal/mol) (Figure~\ref{fig3}). Accordingly, the dynamic character
of the overall transformation arises from a possible rotation around
the chiral axis once the metallacyclic intermediates are formed whereas
the substrate remains atropostable under the reaction conditions. 

\begin{figure*}
\includegraphics{fig03}
\caption{Conventional DFT studies in gazeous phase without
solvatation.\label{fig3}}
\end{figure*}

To demonstrate the broad synthetic utility of this atroposelective
method, sulfinyl/Li exchange was performed at ${-}$78~\textdegree C to
avoid the epimerisation of the atropisomeric axis and quenching with
different electrophiles allows the introduction of different functional groups
with a total retention of the axial chirality (Scheme~\ref{sch2}).


\begin{scheme*}
\includegraphics{sc02}
\vspace*{4pt}
\caption{Traceless character of the sulfinyl group.\label{sch2}}
\vspace*{5pt}
\end{scheme*}

We applied this strategy to the formal synthesis of the biaryl subunit
of (-)steganone that has been often used to illustrate the efficiency
of a new atroposelective method. Starting from bromobenzodioxole we
performed the most expedient synthesis in 10 steps with a 42.3\%
overall yield and with a total atropostereoselectivity 
(Scheme~\ref{sch3})~\cite{7}.

\begin{scheme*}
\includegraphics{sc03}
\vspace*{4pt}
\caption{Formal synthesis of the biaryl subunit of (-)steganone.\label{sch3}}
\vspace*{-7pt}
\end{scheme*}

Moreover, in collaboration with  Speicher et~al., we applied our
method towards the first total synthesis of atropopure isoriccardin C.
An {atropostereoselective} macrocyclization through an oxidative Heck
type C--H activation process allowed complete control of the
atroposelectivity (de $>$ 98\%) and the traceless character of the
sulfinyl moiety in \textit{ortho} position of the biaryl enabled the
introduction of an OH group (Scheme~\ref{sch4})~\cite{8}.

\begin{scheme*}
\includegraphics{sc04}
{\vspace*{-8pt}}
\caption{Total synthesis of atropopure isoriccardin C.\label{sch4}}
\end{scheme*}

Following this work, we were interested in the synthesis of doubly
atropoisomeric, \textit{ortho}-orientated dissymmetrical terphenyls that
are truly appealing for the design of chiral ligands. Following this
idea we explored the C--H arylation of a biaryl bearing in~the
\textit{ortho} position the chiral sulfinyl DG with  
\textit{ortho}-substituted aryl iodides. After an extensive  
optimization of the reaction conditions, we succeeded in obtaining the
terphenyl in moderate to good yields but with excellent
atropo-diastereoselectivity. What is remarkable in this reaction is the
control of the two contiguous chiral axes in one step. An X-ray crystal
structure highlighted a unique architecture of these scaffolds, 
featuring a cavity comparable to the one of a seashell well
designed for the coordination with metal in organometallic catalysis
(Scheme~\ref{sch5})~\cite{9}.


\begin{scheme*}
\includegraphics{sc05}
\vspace*{-8pt}
\caption{Synthesis of terphenyls with two chiral axes.\label{sch5}}
\end{scheme*}


Of particular interest is the atropoenantiopure terphenyl scaffold \textbf{A},
bearing the sulfinyl group and the bromine which can be obtained in
good yield (49\%), with total atroposelectivity (${>}$98:2) and on a gram scale
in one day, this compound can be transformed by simple chemoselective
lithium exchange and then quenched by various electrophiles to give
access to a large variety of ligands. On the one hand, we performed the
double exchange with Li base giving access to diphosphines BiaxPhos
(Scheme~\ref{sch6}) and, on the other hand, we developed an elegant
two-step sequential chemoselective functionalization to install
different coordinating groups like two different phosphines BiaxPhos*
(Scheme~\ref{sch7})~\cite{10}.

\begin{scheme*}
\includegraphics{sc06}
\vspace*{1pt}
\caption{Synthesis of diphosphines BiaxPhos bearing the same phosphorus
moiety.\label{sch6}}
\vspace*{-.4pc}
\end{scheme*}

\begin{scheme*}
\vspace*{2pt}
\includegraphics{sc07}
\vspace*{6pt}
\caption{Synthesis of diphosphines BiaxPhos* bearing different
phosphorus moieties.\label{sch7}}
\vspace*{8pt}
\end{scheme*}

With the new ligands in hand, their potential in asymmetric catalysis,
focusing mainly on the  Ir-catalyzed hydrogenation of imines, was
explored~\cite{11}. After optimization of the reaction conditions and
catalyst screening, the desired chiral amines were isolated in high
yields and excellent enantioselectivities under a remarkably low
hydrogen pressure (Scheme~\ref{sch8})~\cite{10}.


\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc08}
\vspace*{5pt}
\caption{Ir-catalyzed asymmetric hydrogenation of imines with BiaxPhos*
ligands.\label{sch8}} 
\vspace*{-10pt}
\end{scheme*}

Intrigued by the growing interest of compounds with C--N atropoisomeric
axes in medicinal chemistry with unique kinase inhibitor
activities~\cite{12a,12b,12c,12d,12e,12f,12g,12h,12i,12j,12k}, 
we turned our attention to their atropo-stereoselective synthesis.
However, the stereoselective control of the C--N axially chiral
compounds remains a big challenge due to their low configurational
stability compared to the well-developed C--C atropisomers and also due
to the harsh reaction conditions generally required for the C--N
coupling reaction. The extremely challenging character of these
transformations is unambiguously illustrated by the lack of literature
precedents on asymmetric Ullmann and Buchwald--Hartwig couplings.

Following such an ambitious goal, our idea was to use highly
electrophilic coupling partners such as hypervalent iodines to perform
the Cu-catalyzed\unskip\break C--N Ullmann-type coupling at low temperature to ensure
the configurational stability of the C--N atropoisomer formed. Besides,
the sterecontrol could be reached either with enantiomerically pure,
stereogenic iodanes bearing a sulfinyl moiety allowing an
atropo-diastereoselective C--N coupling with different N-coupling
partners or using chiral ligands compatible with an
atropo-enantioselective C--N coupling (Figure~\ref{fig4}).

\begin{figure*}
\includegraphics{fig04}
\vspace*{2pt}
\caption{Cu-catalyzed atropo-stereoselective C--N coupling
reaction.\label{fig4}}
\end{figure*}

If we consider the atropo-diastereoselective\unskip\break C--N coupling occurring via
the chiral transfer from the iodanes (sulfoxide-substituted iodanes
were prepared by C--H functionalization of the arylsulfoxide with
Koser's reagent), we studied the C--N coupling with indolines first as
standard substrates, and we obtained the desired coupling products at
room temperature in excellent yield and high atropopurity. However, in
the first two examples, we noticed a slow racemization of the product
at room temperature. Therefore, to increase the atropostability of the
coupling products, substituted indolines at the C7 position or iodanes
\textit{ortho}-substituted by a methyl, instead of a methoxy, were used
as coupling partners to obtain atropostable products~\cite{13}.\looseness=1


Remarkably, the reaction tolerates many functional groups including
chlorine, bromine, methoxy, benzyloxy but also boronic ester compatible
for further functionalization (Scheme~\ref{sch9}).


\begin{scheme*}
\vspace*{3pt}
\includegraphics{sc09}
\vspace*{3pt}
\caption{Cu-catalyzed Ullmann-type C--N coupling using a chiral
sulfinyl directing group.\label{sch9}}
\vspace*{-.5pt}
\end{scheme*}

Subsequently, an atropo-enantioselective version of this C--N coupling
was explored. Drawing inspiration from  Gaunt et~al.\ and  Mc Millan
et~al.\ who investigated asymmetric copper-catalyzed coupling reaction
with hypervalent iodines, the BOX-type ligand was preselected as the
chirality source. We rapidly established that a free amide as DG
on the iodine substrate was important to reach high\unskip\break
enantioselectivity whereas the optimization of the {BOX} ligand revealed
that the presence of benzyl groups as well as gem-dimethyl group was
essential. Optimization of the reactions conditions indicated that the
addition of a Lewis acid such as
$\mathrm{BF}_{3}{\cdot}\mathrm{OEt}_{2}$ warrants significantly
increased yields~\cite{14}.

The results, in most of the examples, show excellent
enantioselectivities with moderate to good yields. As previously, a
substituent in the C7 position of the indoline is necessary to
guarantee atropostability of the newly formed axis. The presence of
Cl-,\unskip\break  Br-, F-substituents is well tolerated either on the
indoline or the iodane.

The X-ray crystal structure which shows the absolute
\textit{aR}-configuration and a hydrogen bonding between the N atom of
indoline and the free NH$_{2}$ is in agreement with the
importance of the free amide as DG (Scheme~\ref{sch10}).

\begin{scheme*}
\vspace*{3pt}
\includegraphics{sc10}
\vspace*{2pt}
\caption{Cu-catalyzed Ullmann-type C--N coupling using a BOX ligand.\label{sch10}}
\end{scheme*}

In order to highlight the synthetic potential of this method, the
post-modifications of the coupling products were studied. Thanks to the
traceless character of the sulfoxide, various functional groups could
be introduced such as, for example, an aldehyde. The halogenated
substrates allow mild Stille- and Suzuki-coupling under
micellar conditions, thus overcoming the racemization issues. Oxydation
of indoline to indole works very well with sulfinyl or amide DG.
Moreover, indoline-2,3-dione, a privileged synthetic intermediate of
oxindole scaffolds could also be obtained by oxydation with
\textit{t}-butylhydroperoxide in presence of copper. The amide
DG can be transformed in two steps into a carboxylic acid
with a complete atropostability (Figure~\ref{fig5}). 

\begin{figure*}
\includegraphics{fig05}
\vspace*{-7pt}
\caption{Postfunctionalization of the C--N atropoenriched coupling products.\label{fig5}}
\end{figure*}

In conclusion, this account summarizes our recent efforts to control
atropoisomerism in both biaryl and aryl-N-(het)aryl molecules. The
general methods described such as the C--H functionalization of the
biarylsulfoxide afforded complex molecules such as biologically active
natural products: steganone and isoriccardin C. In parallel, the
challenging C--H arylation gives access to unprecendented terphenyl
ligands with two atropisomeric axes that have been demonstrated to be
highly efficient in Ir-catalyzed asymmetric hydrogenation. Their
original scaffold as well as their modularity are appealing candidates
for asymmetric catalysis in the\break future.

In addition, the use of hypervalent iodines in Ullmann type C--N
coupling at room temperature solved the problem of the weak
atropostability of the C--N axis leading to C--N axially chiral compounds
in high stereoselectivities. This first example of atroposelective
N-arylation, using hypervalent iodines, is opening the way to
synthesize different C--N axially chiral products with different
N-coupling partners. 

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

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