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\DOI{10.5802/crchim.433}
\datereceived{2025-10-28}
\dateaccepted{2025-11-20}
\daterevised{2025-11-19}

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\dateposted{2026-02-02}
\begin{document}

\begin{noXML}

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

\CDRsetmeta{articletype}{clarification}

\title{Metal-catalyzed enantioselective \tralicstex{\textit{α}}{$\upalpha$}-allylation of
nitriles}

\alttitle{\tralicstex{\textit{α}}{$\upalpha$}-Allylation m\'{e}tallo-catalys\'{e}e et
\'{e}nantios\'{e}lective de nitriles}

\author{\firstname{Quentin} \lastname{Chevrier}}  
\address{Universit\'{e} d'Orl\'{e}ans, CNRS, UMR 7311, ICOA, 45067
Orl\'{e}ans, France}

\author{\firstname{Cyril} \lastname{Nicolas}\CDRorcid{0000-0002-3748-2205}}
\addressSameAs{1}{Universit\'{e} d'Orl\'{e}ans, CNRS, UMR 7311, ICOA,
45067 Orl\'{e}ans, France}

\author{\firstname{Isabelle} \lastname{Gillaizeau}\CDRorcid{0000-0002-7726-3592}\IsCorresp}
\addressSameAs{1}{Universit\'{e} d'Orl\'{e}ans, CNRS, UMR 7311, ICOA,
45067 Orl\'{e}ans, France}
\email[I. Gillaizeau]{isabelle.gillaizeau@univ-orleans.fr}

\thanks{University of Orl\'{e}ans, R\'{e}gion Centre-Val de Loire, 
French National Research Agency (grant nos. ANR-20-CE07-0016-01 and
ANR-23-CE07-0014-04)}

\shortrunauthors

\keywords{\kwd{Chiral nitrile}\kwd{Metal-catalyzed
allylation}\kwd{Csp\tsup{3}--Csp\tsup{3} bond}\kwd{Quaternary or
tertiary stereogenic center}\kwd{Homoallylic nitrile}\kwd{Allylic
nitrile}}

\altkeywords{\kwd{Nitrile chiral}\kwd{Allylation
m\'{e}tallo-catalys\'{e}e}\kwd{Liaison
Csp\tsup{3}--Csp\tsup{3}}\kwd{Centre st\'{e}r\'{e}og\'{e}nique
quaternaire ou tertiaire}\kwd{Nitrile homoallylique}\kwd{Nitrile
allylique}}

\begin{abstract}
\tralicstex{\textit{α}}{$\upalpha$}-Chiral nitriles are key structural motifs found in numerous
natural products and pharmaceuticals. Nitriles play a central role in
synthetic chemistry and industry as versatile intermediates for diverse
functional groups. Considerable research has therefore been devoted to
developing efficient strategies for preparing
C\tralicstex{\textsuperscript{\textit{α}}}{$^{\upalpha}$}-tetrasubstituted and \tralicstex{\textit{α}}{$\upalpha$}-quaternary chiral
nitriles with varied architectures. This account highlights recent
advances in the enantioselective synthesis of homoallylic and allylic
nitriles achieved through transition-metal-catalyzed allylation. These
catalytic systems deliver high levels of selectivity and accommodate a
wide range of substrates, offering practical routes to complex nitrile
derivatives. Transition-metal-mediated allylation remains one of the
most powerful tools for forging C--C bonds under mild conditions. The
discussion also provides key mechanistic insights showing how catalyst
design and reaction dynamics control stereochemical outcomes. The
synthetic applications presented illustrate how these methods expand
access to intricate, stereochemically rich molecules relevant to
pharmaceutical and materials chemistry. These advances greatly enrich
the synthetic toolkit for the precise and efficient construction of
\tralicstex{\textit{α}}{$\upalpha$}-chiral nitriles.
\end{abstract}

\begin{altabstract}
Les nitriles \tralicstex{\textit{α}}{$\upalpha$}-chiraux constituent des motifs structuraux
essentiels pr\'{e}sents dans de nombreux produits naturels et
compos\'{e}s pharmaceutiques. En tant qu'interm\'{e}diaires
polyvalents, les nitriles occupent une place centrale en chimie de
synth\`{e}se et industrielle, permettant l'acc\`{e}s \`{a} une grande
diversit\'{e} de fonctions. Des efforts de recherche importants ont
\'{e}t\'{e} consacr\'{e}s au d\'{e}veloppement de strat\'{e}gies
efficaces pour la pr\'{e}paration de nitriles chiraux
\tralicstex{\textit{α}}{$\upalpha$}-quaternaires et de nitriles
C\tralicstex{\textsuperscript{\textit{α}}}{$^{\upalpha}$}-t\'{e}trasubstitu\'{e}s pr\'{e}sentant des architectures
vari\'{e}es. Cet article met en \'{e}vidence les progr\`{e}s
r\'{e}cents r\'{e}alis\'{e}s dans la synth\`{e}se
\'{e}nantios\'{e}lective de nitriles homoallyliques et allyliques
obtenus par allylation catalys\'{e}e par des m\'{e}taux de transition.
Ces syst\`{e}mes catalytiques offrent des niveaux \'{e}lev\'{e}s de
s\'{e}lectivit\'{e} et pr\'{e}sentent une large compatibilit\'{e}
fonctionnelle, proposant des voies efficaces vers des d\'{e}riv\'{e}s
nitriles complexes. L'allylation m\'{e}di\'{e}e par des m\'{e}taux de
transition reste l'un des outils les plus puissants pour former des
liaisons C--C dans des conditions douces et contr\^{o}l\'{e}es.
L'analyse m\'{e}canistique met en \'{e}vidence le r\^{o}le
d\'{e}terminant de la nature du m\'{e}tal, des ligands chiraux et des
\'{e}tapes cl\'{e}s du cycle catalytique dans le contr\^{o}le de la
st\'{e}r\'{e}ochimie du produit final. Les exemples d'applications en
synth\`{e}se illustrent clairement le potentiel de ces
m\'{e}thodologies pour l'acc\`{e}s \`{a} des architectures
mol\'{e}culaires \'{e}labor\'{e}es, riches en information
st\'{e}r\'{e}ochimique, pertinentes en chimie m\'{e}dicinale et pour
les mat\'{e}riaux avanc\'{e}s. Dans leur ensemble, ces avanc\'{e}es
renforcent et diversifient de mani\`{e}re significative l'arsenal
m\'{e}thodologique disponible pour la construction rationnelle,
pr\'{e}cise et efficace de nitriles \tralicstex{\textit{α}}{$\upalpha$}-chiraux.
\end{altabstract}

%\input{CR-pagedemetas}

\maketitle

%{\vspace*{12pt}}

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\end{noXML}

\section{Introduction}\label{sec1}

Recent studies have highlighted the crucial role of three-dimensional
architecture in bioactive molecules, and many drugs featuring a
quaternary chiral center are derived from natural products
(Figure~\ref{fig1})~\cite{1}. However, building structures with vicinal
tetrasubstituted stereocenters still remains elusive due to steric 
repulsions occurring at the Csp\tsup{3}--{Csp}\tsup{3} bond
formation~\cite{2,3,4}. $\upalpha$-Chiral nitriles are common
structural motifs in natural products, pharmaceuticals, and bioactive
compounds. Moreover, the cyano group serves as a highly versatile
chiral building block, readily convertible into aldehydes, ketones,
carboxylic acids, amides, amines, and N-heterocycles. In this context,
significant progress has been achieved in developing innovative
strategies for the synthesis of C$^{\upalpha}$-tetrasubstituted or
$\upalpha$-quaternary chiral nitriles with diverse architectures. This
account summarizes recent advances in this area, with particular
emphasis on the formation of homoallylic and allylic nitriles.

\begin{figure*}
\includegraphics{fig01}
\vspace*{-3pt}
\caption{\label{fig1}Examples of bioactive or natural compounds with
quaternary stereogenic centers.} 
\end{figure*}

\section{Asymmetric allylic alkylation}\label{sec2}

Since its introduction several decades ago, metal-catalyzed asymmetric
allylic alkylation (AAA) has proven remarkably powerful in enabling the
enantioselective synthesis of carbon--carbon bonds, \mbox{making} it a
cornerstone in modern organic synthesis \cite{5,6,7}. Extensive efforts
have since been devoted to expanding the scope of nucleophiles, with
notable advances achieved using carbon-based
nucleophiles~\cite{8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24}.
While $\upalpha$-carbanions derived from ketones and carboxylic acid
derivatives have been effectively employed in Pd-catalyzed
AAA~\cite{25,26,27,28,29,30,31}, reports on the use of nitrile-derived
$\upalpha$-carbanions remain scarce. This limitation likely stems from
the intrinsic ``hardness'' of such carbanions and their tendency to
interconvert between C- and N-metalated
forms~\cite{15,16,17,18,19,20,21,22,23,24}. As a result,  several
refined strategies have emerged that exploit electrophilic trapping of
the N-metalated intermediate with silicon, affording axially chiral
$N$-silyl ketene imines (SKIs)~\cite{32}. Despite these advances, the
direct enantioselective alkylation of an $\upalpha$-metalated nitrile
would represent a more straightforward and attractive approach. While
diastereoselective alkylation~\cite{33} and enantiospecific
acylation~\cite{34,35,36,37} of such anions have been documented,
achieving a truly enantioselective variant has proven elusive,
particularly in the case of asymmetric allylation, which is the focus
of this Section. \looseness=-1

Branch-selective allylic substitution catalyzed by iridium complexes
was first disclosed by Takeuchi and Kashio in 1997
(Scheme~\ref{sch1})~\cite{38}. Building on this pioneering study, the
Takeuchi group reported the enantioselective synthesis of chiral
homoallylic nitriles via iridium-catalyzed allylation of cyanoacetates,
followed by Krapcho demethoxycarbonylation. This strategy provided a
broad array of homoallylic nitriles in excellent enantiomeric excess
(${>}$95--99\% \textit{ee}). The resulting products serve as valuable
chiral building blocks, as further diversification can be achieved from
either the nitrile moiety or the terminal alkene.

\begin{scheme*}
{\vspace*{-4pt}}
\includegraphics{sc01}
{\vspace*{.6pc}}
\caption{\label{sch1}Highly selective Ir-catalyzed allylic alkylation
with a carbon nucleophile at the more substituted allylic terminus.
Redrawn from Ref.~\cite{38}.} 
\end{scheme*}

In 2005, Agbossou-Nidercorn demonstrated that Pd-catalyzed allylic
substitution with aryl \mbox{cyanoester} pronucleophiles affords allylated
products with significant enantioselectivity (\textit{ee} up to 54\%)
(Scheme~\ref{sch2})~\cite{39}. Although the precise structure of the
enolate involved in the addition step remains undefined, it seems to
exert a critical influence on the stereocontrol. The noncyclic nature
of the substrate likely accounts for the observed enantioselectivity,
in line with precedents involving pronucleophiles that generate acyclic
enolates. Among the chiral ligands examined, Trost-type ``chiral
pocket'' ligands provided the highest selectivities. Notably, chiral
alkylated cyanoesters bearing quaternary stereogenic centers constitute
versatile building blocks for asymmetric synthesis.

\begin{scheme*}
{\vspace*{-4pt}}
\includegraphics{sc02}
{\vspace*{.4pc}}
\caption{\label{sch2}Pd-catalyzed asymmetric allylic alkylation of
prochiral aryl cyanoesters. Redrawn from Ref.~\cite{39}.} 
{\vspace*{-6pt}}
\end{scheme*}

In this context, Sauthier also reported a nickel-catalyzed
$\upalpha$-allylation of phenyl- and $\upalpha$-alkyl phenyl
acetonitriles using allylic alcohols (Scheme~\ref{sch3})~\cite{40}. The
reaction proceeded under neutral conditions, using nickel complexes
generated in situ from Ni(cod)\tsub{2} and dppf
(1,1$'$-bis(diphenylphosphino){\ubreak}ferrocene). 

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{.9pc}}
\caption{\label{sch3}Ni-catalyzed $\upalpha$-allylation of phenyl and
$\upalpha$-alkyl phenyl acetonitrile with allylic alcohols. Adapted
with permission from Ref.~\cite{40}.}
{\vspace*{-5pt}}
\end{scheme*}

In 2015, Evans et al.\ described a direct and highly enantioselective
rhodium-catalyzed allylic alkylation of allyl benzoate with
$\upalpha$-substituted benzyl nitrile pronucleophiles
(Scheme~\ref{sch4})~\cite{22,41,42}. This protocol provided a new
approach toward the synthesis of acyclic quaternary carbon stereogenic
centers and is the first example of direct asymmetric alkylation of an
$\upalpha$-cyanocarbanion. The process is driven by the ability to
control the C- versus N-metalated equilibrium with a crown ether. The
synthetic utility of the nitrile products is amply demonstrated through
conversion to various functional groups and the asymmetric synthesis of
the calcium channel blocker ($S$)-verapamil in three steps and 55\%
overall\break yield.

\begin{scheme*}
\includegraphics{sc04}
{\vspace*{.4pc}}
\caption{\label{sch4}(a) Enantioselective Rh-catalyzed allylic
substitution. (b) Modular three-step synthesis of ($S$)-verapamil.
Redrawn from Ref.~\cite{22,41,42}.} 
{\vspace*{.5pc}}
\end{scheme*}

In 2017, Hou and Ding highlighted that the $\upalpha$-carbanion of
acetonitrile ($\mathrm{p}K_{\mathrm{a}}\approx 31$ in DMSO)~\cite{43}
was unreactive with allylic electrophiles~\cite{44}, \mbox{failing} to yield
the expected allylic-alkylation {products,} which instead underwent
self-condensation to form $\upbeta$-enaminonitriles
(Scheme~\ref{sch5}). A novel nucleophilic species, the 3-imino nitrile
carbanion, was subsequently generated in situ via the Thorpe reaction
and employed in Pd-catalyzed asymmetric allylic alkylation of
monosubstituted allyl reagents using the Pd/SIOCPHOX system. The
resulting $\upbeta$-enaminonitriles isolated in high yields with high
regio- and enantioselectivity constitute valuable building blocks for
the synthesis of heterocycles, polymers, and pharmaceutical compounds.
Regarding the reaction mechanism, the authors proposed that nitrile
\textbf{VI} arises from the coupling of allyl reagent with nucleophile
\textbf{III}, which is generated in situ through the attack of the
acetonitrile $\upalpha$-carbanion \textbf{I} on a second acetonitrile
molecule, followed by isomerization.

\begin{scheme*}
{\vspace*{.3pc}}
\includegraphics{sc05}
{\vspace*{.7pc}}
\caption{\label{sch5}(a) New type of nucleophile in Pd-catalyzed AAA.
(b) Proposed mechanism. Adapted with permission from Ref.~\cite{44}.} 
\end{scheme*}

Cao and coworkers developed a method to overcome the side reactions
associated with using nitrile $\upalpha$-carbanions as nucleophiles
(Scheme~\ref{sch6}). This strategy involved iridium-catalyzed
enantioselective coupling between vinyl azides and allylic
electrophiles~\cite{45}. Vinyl azides are cleverly employed as
surrogates for acetonitrile carbanions, enabling the synthesis of
$\upgamma$,$\updelta$-unsaturated $\upbeta$-substituted nitriles with
outstanding enantiomeric excess. These products can be efficiently
converted to chiral nitrogen-containing building blocks and
pharmaceutically relevant compounds. A mechanism has been proposed to
account for the observed chemoselectivity of the coupling process
(Scheme~\ref{sch6}b). In the presence of a Lewis acid (e.g.,
BF\tsub{3}${\cdot}$OEt\tsub{2} or a Zn(II) salt), the chiral Ir(I)
complex activates allylic carbonate \textbf{VII} through oxidative
addition, giving Ir(III) intermediate \textbf{VIII} and
[LA--OtBu]$^{-}$. An enantioselective C--C coupling between
\textbf{VIII} and the vinyl azide then produces chiral iminodiazonium
ion \textbf{IX}, which carries an $\upalpha$-2-hydroxypropan-2-yl group
and then undergoes fragmentation to form~\textbf{X}.\looseness=1

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{.6pc}}
\caption{\label{sch6}(a) Enantioselective Ir-catalyzed coupling
reaction of vinyl azides and racemic allylic carbonates. (b) Proposed
mechanism. Adapted with permission from Ref.~\cite{45}.} 
{\vspace*{-.2pc}}
\end{scheme*}

In 2022, a palladium(phosphinooxazoline)-catalyzed method for
asymmetric allylic alkylation of
$\upalpha$-aryl-$\upalpha$-fluoroacetonitriles was reported by Wolf and
Sripada (Scheme~\ref{sch7})~\cite{46}. This reaction involves C--C bond
formation and generates two contiguous chirality centers with moderate
to good yields, high enantioselectivities, and up to 15:1 \textit{dr}.
The procedure is scalable, and it is worth noting that the brominated
AAA products can be further derivatized using a Stille cross-coupling
reaction without significant HF elimination.

\begin{scheme*}
\includegraphics{sc07}
{\vspace*{.4pc}}
\caption{\label{sch7}Pd-catalyzed asymmetric allylic alkylation of
$\upalpha$-aryl-$\upalpha$-fluoroacetonitriles. Adapted with permission
from Ref.~\cite{46}.} 
\end{scheme*}

Ito, Sawamura, and Sudoh reported an innovative strategy involving dual
catalysis, in which each transition metal complex (Pd and Rh) activates
its own substrate (Scheme~\ref{sch8})~\cite{47}. The resulting
intermediates undergo an enantioselective coupling to afford optically
active products. The allylation of diethyl (1-cyanoethyl)phosphonate
proceeded with excellent enantioselectivity, yielding an optically
active phosphonic acid derivative ($ee=92\%$).  Notably, this remains
the only reported example of dual catalysis applied to nitriles.
However, in this case, the catalytic system is restricted to the
formation of a single quaternary stereogenic center. 

\begin{scheme*}
\includegraphics{sc08}
{\vspace*{.4pc}}
\caption{\label{sch8}Rh/Pd-Catalyzed allylic alkylation of activated
nitriles. Adapted with permission from Ref.~\cite{47}.} 
\end{scheme*}

Gillaizeau and Nicolas et al.\ established an enantioselective strategy
for constructing unprecedented homoallylic nitriles bearing vicinal
stereogenic centers through an allylic alkylation process
(Scheme~\ref{sch9})~\cite{48}. This transformation relied on a dual
catalytic system in which a palladium catalyst controls the
configuration of the allylic electrophile, while a copper catalyst
governs the stereochemistry of the nucleophilic carbon via an N-MKI
(metal ketenimine) active species \textbf{XI}. This strategy delivers
nitrile-substituted products bearing vicinal tertiary and quaternary
centers in up to 99\% yield and 91\% \textit{ee}. All four
stereoisomers are accessible, underscoring independent stereocontrol at
both reactive sites (Scheme~\ref{sch9}b). The reaction is readily
scalable without compromising efficiency. Computational studies
highlighted the pivotal role of the copper catalyst and attributed the
limited diastereoselectivity to an orthogonal alignment of the
ketenimine and allyl moieties within the key intermediate.

\begin{scheme*}
\includegraphics{sc09}
{\vspace*{.9pc}}
\caption{\label{sch9}Dual Pd/Cu-catalyzed enantioselective synthesis of
chiral homoallylic nitriles bearing vicinal stereogenic centers.
Redrawn from Ref.~\cite{48}.} 
{\vspace*{-6pt}}
\end{scheme*}

\section{Metal-catalyzed conversion of allylic alcohols to
nitrile}\label{sec3}

The transition-metal-catalyzed allylic substitution of diverse allylic
substrates has emerged as a highly versatile transformation,
particularly for constructing C--C bonds. This process typically relies
on activated allylic precursors, such as acetates or carbonates, which
promote the formation of $\upeta^{3}$--M complexes. The direct use of
allylic alcohols is particularly attractive, as it avoids the
generation of stoichiometric waste and eliminates the need for hydroxyl
protection~\cite{49,50}. In this regard, Tsuji and coworkers first
established allylic cyanation using TMSCN as the cyanide donor and
Pd(PPh\tsub{3})\tsub{4} as the catalyst~\cite{51}. Subsequent advances
were made by Kawatsura et al.,  who employed CuI as the
catalyst~\cite{52}, and by Rousseaux et al.,  who developed a
Ni(II)-based precatalyst in combination with Zn(CN)\tsub{2} as the
cyanide source~\cite{53}. Koert et al.\ also  reported that
rhodium-catalyzed allylic cyanation of 3-fluoroallylic
trifluoroacetates with TMSCN in the presence of a bulky phosphite
ligand provides 3-fluoroallylic nitriles with a broad range of
substrates and excellent $Z/E$ selectivity~\cite{54}. In
dialkyl-substituted substrates, the fluorine atom governs the
regioselectivity, favoring the formation of the distal product.
Investigation of selected scalemic substrates indicated stereocenter
inversion during cyanation, accompanied by minimal or no stereochemical
erosion. Despite extensive studies on asymmetric allylic substitution,
the enantioselective synthesis of allylic cyanides remains
underdeveloped. In 1998, Tsuji reported the catalytic enantioselective
cyanation of cyclic allylic carbonates with TMSCN using 5~mol\% of the
($S$)-MeO--MOP--Pd complex, yielding only two chiral allylic cyanides
with 19\% and 63\% \textit{ee}, respectively (Scheme~\ref{sch10},
Equation (1))~\cite{55}. Later, Hou and coworkers demonstrated an
asymmetric kinetic resolution of racemic 1,3-disubstituted
\mbox{unsymmetrical} allylic carbonates by Pd-catalyzed allylic cyanation,
affording allylic cyanides in 31--50\% yields with 25--65\%
\textit{ee}, alongside recovered chiral carbonates with an ($S$)
configuration in 21--54\% yields and with 24--99\% \textit{ee}
(Scheme~\ref{sch10}, Equation (2))~\cite{31}.

\begin{scheme*}
{\vspace*{.2pc}}
\includegraphics{sc10}
{\vspace*{.9pc}}
\caption{\label{sch10}Pd-Catalyzed asymmetric allylic cyanation of
allylic carbonates using TMSCN. Adapted with permission from
Ref.~\cite{55}.} 
\end{scheme*}

The Fang group described a one-pot conversion of allylic alcohols into
chiral 1,3-dinitriles by merging allylic cyanation with asymmetric
hydrocyanation through an auto-tandem catalysis strategy
(Scheme~\ref{sch11})~\cite{56,57}. Using 5~mol\% of a nickel \mbox{complex}
bearing a chiral bidentate phosphine ligand, a broad range of allylic
alcohols reacted efficiently with acetone cyanohydrin as the cyanide
donor to afford the corresponding enantioenriched 1,3-dinitriles in
37--89\% yield and 65--94\% \textit{ee}. The proposed mechanism
involves initial coordination of Ni(0)--L$^{*}$ species \textbf{XII}
with the allylic alcohol to form a $\uppi$-allyl--Ni(II)--OH
intermediate \textbf{XIV}, which subsequently reacts with acetone
cyanohydrin to generate intermediate \textbf{XV}. Reductive elimination
delivers allyl nitrile \textbf{XVI}, which undergoes asymmetric
hydrocyanation to furnish target dinitriles \textbf{XX} while
regenerating active catalyst \textbf{XII}. These chiral dinitriles can
be further transformed into piperidines \textbf{XXI}, a key step
enabling the formal synthesis of the antidepressant (${+}$)-paroxetine.

\begin{scheme*}
\includegraphics{sc11}
{\vspace*{.4pc}}
\caption{\label{sch11}One-pot conversion of allylic alcohols to chiral
1,3-dinitriles. Adapted with permission from Ref.~\cite{57}.} 
\end{scheme*}

The same group reported a Ni-catalyzed asymmetric hydrocyanation of
racemic allene- and methylene cyclopropanes (Scheme~\ref{sch12},
Equation~(1)). Using 10 mol\% ($R$,$R$)-Ph-BPE with Ni(cod)\tsub{2}, it
\mbox{delivered} enantioenriched allylic nitriles in up to 78\% yield and 98\%
\textit{ee} with excellent regioselectivity. Subsequently, a nickel
catalyst based on a TADDOL-derived diphosphate
($\mathbf{L}_{\mathbf{1}}$) enabled highly asymmetric hydrocyanation of
disubstituted methylene cyclopropanes, providing chiral allylic
nitriles in 82--99\% \textit{ee} 
(Scheme~\ref{sch12}, Equation (2))~\cite{58}.

\begin{scheme*}
{\vspace*{.4pc}}
\includegraphics{sc12}
{\vspace*{.7pc}}
\caption{\label{sch12}Ni-catalyzed asymmetric hydrocyanation of allene-
and methylene cyclopropanes. Adapted with permission from
Ref.~\cite{58}.} 
{\vspace*{-2pt}}
\end{scheme*}

A nickel-catalyzed direct transformation of allylic alcohols with
benzyl nitrile derivatives was also developed by Liu  et al.\ in 2023,
offering an \mbox{efficient} and racemic approach to access homoallylic
nitriles featuring $\upalpha$-tertiary or quaternary carbon centers
(Scheme~\ref{sch13})~\cite{59}. This protocol delivered good to
excellent yields with high regioselectivity, broad substrate
applicability, and high tolerance toward diverse functional groups.
Notably, $N$,$O$-bis(trimethylsilyl)-acetamide (BSA) was identified as
a key additive that significantly promotes the coupling, particularly
in reactions involving alkyl-substituted allylic alcohols.

\begin{scheme*}
\includegraphics{sc13}
{\vspace*{.1pc}}
\caption{\label{sch13}Ni-Catalyzed allylation of nitriles with allylic
alcohols. Adapted with permission from Ref.~\cite{59}.} 
{\vspace*{-2pt}}
\end{scheme*}

\section{Metal-catalyzed cyanofunctionalization of unsaturated bonds}
\label{sec4}

Copper has been shown to mediate cyanation of the $\uppi$-bond in
nitriles through C--CN activation~\cite{60}. Procter and co-workers
developed a regio- and enantioselective Cu-catalyzed borocyanation of
dienes using bis(pinacolato)diboron (B\tsub{2}pin\tsub{2}) and
electrophilic cyanamides (Scheme~\ref{sch14})~\cite{61}. With a
$P$,$N$-ligated copper complex (10~mol\%) and Cu(I)
thiophene-2-carboxylate (CuTC) (10~mol\%), allylic nitriles bearing a
Bpin substituent were obtained in up to 90\% yield and 94\%
\textit{ee}. The reaction is proposed to proceed through selective
borylcupration of the terminal alkene, isomerization to ($Z$)-allyl
copper intermediate \textbf{XXIV}, and subsequent cyanamide insertion.
Despite high efficiency with simple dienes, this led to a decrease in
reactivity and selectivity with multisubstituted substrates.

\begin{scheme*}
\includegraphics{sc14}
{\vspace*{.7pc}}
\caption{\label{sch14}Enantio- and regioselective Cu-catalyzed
borocyanation of 1-aryl-1,3-butadienes. Adapted with permission from
Ref.~\cite{61}.} 
{\vspace*{.1pc}}
\end{scheme*}

\section{Site-selective C(sp\tsup{3})--H cyanation of alkenes}
\label{sec5}

While traditional asymmetric cyanation typically employs unsaturated
substrates, recent advances have revealed that allylic C(sp\tsup{3})--H
bonds can also serve as radical precursors suitable for
enantioselective cyanation.
In 2019, Li et al.\ further addressed the challenge of trapping allylic
radical with chiral Cu(II) cyanide species, achieving site-selective
and enantioselective allylic  C(sp$^{3}$)--H cyanation of diverse \mbox{di-,}
tri-, and tetrasubstituted alkenes via \mbox{hydrogen} atom transfer (HAT)
pathways~\cite{62}. Using N-fluoroalkylsulfonamide (NFAS) as a
precursor of the N-centered radical (NCR), the authors successfully
realized allylic cyanation of trisubstituted alkenes bearing two
distinct sets of allylic hydrogens. Under catalysis by 5 mol\% of a
chiral bisoxazoline L*/CuOAc complex, a diverse array of chiral allylic
nitriles was obtained in yields of up to 91\% and enantiomeric excesses
as high as 99\% (Scheme~\ref{sch15}). Mechanistic studies suggested
that the in situ---generated  Cu(II)-bound NCR \textbf{XXVI} plays a
decisive role in controlling  site selectivity among multiple allylic
C(sp$^3$)--H  bonds with similar properties. This method features wide
substrate generality and excellent chemo-, regio-, and
enantioselectivity. Its synthetic utility was underscored by diverse
downstream derivatizations.

\begin{scheme*}
\includegraphics{sc15}
{\vspace*{.4pc}}
\caption{\label{sch15}Enantioselective allylic cyanation of alkenes. 
Redrawn from Ref.~\cite{62}.} 
\end{scheme*}

\begin{scheme*}
\includegraphics{sc16}
{\vspace*{.7pc}}
\caption{\label{sch16}Enantioselective construction of acyclic 
$\upalpha$-all-carbon quaternary nitriles via synergistic 
intramolecular Pd-catalyzed decarboxylative AAA and phase-transfer
catalysis (PTC) from allyl 2-cyanoacetate substrates. Adapted with
permission from Ref.~\cite{63}.} 
{\vspace*{-.4pc}}
\end{scheme*}

\begin{scheme*}
{\vspace*{-.2pc}}
\includegraphics{sc17}
{\vspace*{.2pc}}
\caption{\label{sch17}Enantioconvergent deacylative functionalization
toward $\upalpha$-quaternary nitriles. Redrawn from Ref.~\cite{64}.} 
{\vspace*{-.6pc}}
\end{scheme*}

\section{Intramolecular palladium-catalyzed decarboxylative allylic
alkylation}\label{sec6}

Tan, Luan, and Ren outlined a practical strategy for the asymmetric
synthesis of chiral acyclic nitriles bearing $\upalpha$-all-carbon
quaternary stereocenters, employing a synergistic combination of
palladium and phase-transfer catalysis on allyl 2-cyanoacetates under
mild conditions (Scheme~\ref{sch16})~\cite{63}. This method provides an
efficient and reliable route for the \mbox{in-situ} generation of tertiary
$\upalpha$-cyano carbanions via an intramolecular palladium-catalyzed
decarboxylative allylic alkylation. Moreover, it allows for exceptional
enantioselective control of simple nitriles through ion-pairing
interactions with chiral phase-transfer catalysts. The versatility of
this approach was \mbox{further} highlighted by its scalability to gram-scale
synthesis and its subsequent conversion into a range of chiral
functionalized molecules containing acyclic all-carbon quaternary
stereocenters. A plausible \mbox{reaction} mechanism was proposed
(Scheme~\ref{sch16}). The starting substrate is first activated by
Pd(0), releasing CO\tsub{2} and generating electrophilic
[$\upeta^{3}$-$\uppi$-ally-PdLn]$^{+}$ species \textbf{XXVIII} and
tertiary $\upalpha$-cyano carbanion \textbf{XXIX}, facilitated by
Cs\tsub{2}CO\tsub{3}. Subsequently, tertiary $\upalpha$-cyano carbanion
\textbf{XXIX} then associates with PN4 to form chiral ion pair
\textbf{XXX}. Enantioselective nucleophilic attack by the
$\upalpha$-cyano carbanion in \textbf{XXX} on the electrophilic species
\textbf{XXVIII} furnishes the desired \mbox{enantioenriched} final
homoallylic nitrile, while regenerating the palladium active catalyst
for subsequent cycles.

\section{Asymmetric deacylative allylation}\label{sec7}

The use of readily available prochiral or racemic quaternary carbons to
generate enantioenriched counterparts offers an efficient alternative
to conventional syntheses from tertiary or planar substrates. Unlike
desymmetrization, which modifies an existing substituent of limited
reactivity, functional-group \mbox{exchange} introduces a new, structurally
distinct motif. Achieving enantioconvergence in
quaternary-to-quaternary transformations remains challenging,
particularly for acyclic centers. Huang and coworkers reported a
palladium-catalyzed deacylative allylation in which the acyl group of
$\upbeta$-ketonitriles was stereoselectively replaced by an allyl
fragment using simple alcohols as alkyl donors
(Scheme~\ref{sch17})~\cite{64}. The transformation proceeded via a
retro-Claisen-type elimination with alkoxide, and the absence of
diastereoisomerism in the resulting ketenimine anion enabled highly
selective asymmetric addition. The combination of
$\upalpha$-substituents, retained nitrile, and introduced alkyl unit
confers broad derivatization potential to the resulting enantioenriched
quaternary stereocenters.

{\vspace*{-.1pc}}

\section{Conclusion}\label{sec8}

{\vspace*{-.1pc}}

Over the years, significant progress has been made in the
enantioselective synthesis of homoallylic and allylic nitriles through
transition-metal-catalyzed allylation, enabling access to
C$^{\upalpha}$-tetrasubstituted and $\upalpha$-quaternary chiral
nitriles with diverse architectures. These advances have broadened the
chemical space relevant to both academic and industrial research.
Nevertheless, this account highlights the continuing need for
enantioselective strategies capable of constructing chiral nitriles
bearing vicinal tertiary or quaternary carbon centers.

\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.

\section*{Funding}

This work was partially supported by University of Orl\'{e}ans,
R\'{e}gion Centre-Val de Loire, and the French National Research Agency
(ANR-20-CE07-0016-01 and ANR-23-CE07-0014-04).

\CDRGrant[ANR]{ANR-20-CE07-0016-01}
\CDRGrant[ANR]{ANR-23-CE07-0014-04}

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