Review Article

https://doi.org/10.1038/s44160-021-00002-3

Stereoselective synthesis through remote

functionalization
Itai Massad   , Rahul Suresh   , Lucas Segura    and Ilan Marek    ✉

Transition-metal-catalysed alkene isomerization is instrumental to remote functionalization processes, in which a chemical

transformation is induced at a position remote from the initial reactive site. The dynamic nature of alkene isomerization, which
is crucial for such transformations, often leads to substantial difficulties in controlling the stereochemistry of C(sp3) centres
along the carbon skeleton. This review features synthetic methods that tackle this issue and strategically leverage alkene isom-
erization to control C(sp3) stereocentres in complex organic molecules. Stereocentres can be created at either the initiation or
termination site of an isomerization process, retained during chain-walking across the molecular backbone or revealed through
restructuring of the carbon skeleton by selective ring-opening of a strained ring. As each of these options imposes different
mechanistic requirements, the different examples are divided according to the stage in the chain-walking process at which ste-
reochemistry is established and the type of intermediates that lead to stereodefined products.

T
ransition metal complexes have been known to promote the
positional isomerization of alkenes for over half of a century,
a process also termed ‘chain-walking’. Although this simple
process was historically deemed a bothersome side reaction, con-
temporary synthetic methods that capitalize on controlled alkene
isomerization have provoked researchers to explore its synthetic
potential1–7. A unique feature of methods that employ alkene isom-
erization is the possibility to induce a chemical transformation at
a position isolated from the initial reactive site, a concept termed
remote functionalization (Fig. 1a). Every remote functionalization
process requires an ‘initiation’ moiety that steers and chemically
interacts with the reagent or catalyst. As the ‘termination’ step occurs
at a structurally distant location from the initiation site, a commu-
nicative process must take place between these sites. Alternatively,
relocation of a π bond to a neighbouring position can also be
achieved in a controlled manner via monoisomerization, with com-
plete control over the alkene stereochemistry in certain cases.
The synthetic power of remote functionalization through alkene
isomerization is convincingly demonstrated by the Ni-catalysed
carboxylation of alkyl bromides reported by Martin and co-work-
ers, in which alkane-derived mixtures of regioisomeric alkyl bro-
mides 2 are funnelled into valuable linear carboxylic acids, such
as 3 (Fig. 1a)8.
Although the dynamic nature of alkene isomerization is at the
heart of the above transformation and its many congeners, it often
leads to substantial difficulties in other contexts. Specifically, the
configuration of neighbouring stereocentres is at constant peril
in the presence of an alkene isomerization catalyst capable of their
epimerization. There is considerable incentive to overcome this chal-
lenge and develop stereoselective remote functionalization processes,
which would form stereocentres at otherwise desolate positions in
the molecule or even establish several stereocentres in a single step.
This Review showcases synthetic methods that control the ste-
reochemistry of C(sp3) stereocentres through alkene isomerization.
These methods can be divided into three categories (Fig. 1b):
1. Formation of stereocentres at the initiation site of a chain-walk-
ing event (through migratory insertion onto alkenes).
2. Retention of stereochemistry during the chain-walking process.
3. Formation of stereocentres at the termination site of alkene
isomerization (through the capture of alkyl- or allylmetal inter-
mediates or by subsequent reactions of the isomerized alkene).
Stereocentre formation at the initiation site
C–H bond formation. Arguably, the simplest way to establish ste-
reochemistry at the initiation site of a remote functionalization pro-
cess is by face-selective insertion of a hydride onto a trisubstituted
alkene or an allylmetal intermediate.
The first notable feat in this field was the enantioselective isom-
erization of allylamines to give enamines. After pioneering work
on cobalt-catalysed isomerization9, a significant step forward was
achieved using rhodium catalysts. In 1984, Noyori reported the first
use of the then newly developed BINAP ligand (BINAP, (S)- or (R)-
2,2′-bis(diphenylphosphino)-1,1′-binaphthalene), which enabled
the Rh-catalysed isomerization of allylamines to give their isomeric
enamines with extremely high enantioselectivity and close to quan-
titative yields (Fig. 2a,b)10,11. The power of this catalytic system is
underlined by its use in the Takasago ton-scale route towards men-
thol (10, Fig. 2a), in which enantioselective isomerization serves as
the key step12.
The isomerization was identified to proceed through a
1,3-hydride shift at a relatively early stage11, with the enantioselec-
tivity being dependent on the ligand and the alkene stereochemistry
of the starting material 5 (Fig. 2b). Therefore, a close correlation
between the initial E/Z ratio of the starting material and the enantio-
meric excess of the resulting product 7 is to be expected. Extensive
computational and experimental work helped to shed light on the
complete mechanism and specifically showed that the enantioselec-
tivity is determined prior to the cleavage of the allylic C–H bond,
during which the allylic hydrogen atom migrates to the Rh(I) as a
hydride with the assistance of the nitrogen lone pair13.
The enantioselective isomerization of allylic alcohols to give
aldehydes represents a simple and atom-economic route towards
β-stereogenic aldehydes, but has unfortunately proved more chal-
lenging than the isomerization of the corresponding allylamines.
The first noteworthy example was reported by Tani in 1985 and

Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Haifa, Israel. ✉e-mail: chilanm@technion.ac.il

Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth 37

Review Article NATure SynThesis
a Alkene isomerization
(or chain-walking)
Reactive initiation
site M
M

Unreactive remote Functionalized

position product

Representative example

O
1 equiv. Br2 Br [Ni] catalyst
.
OH
MnO2 0
CO2 (1 atm), Mn
DMF, r.t.
1 2 3
Linear alkane Mixture of regioisomeric Valuable carboxylic acid
alkyl bromides 65% (from heptane)
No isolation required

b
At the At the
initiation site? termination site?

M
Formation of stereocentres

During the
chain-walking process?

Fig. 1 | Remote functionalization and general considerations. a, Remote functionalization processes that rely on alkene isomerization to access a
remote position through repeated isomerization (chain-walking). A representative example is shown, in which a readily available regioisomeric mixture
of alkyl bromides is funnelled into a single carboxylic acid. b, This review highlights remote functionalization processes that selectively establish C(sp3)
stereocentres in the product. Stereochemical information may be established at any position from the initiation to the termination site, each imposing
different requirements on the catalytic system. M, transition-metal-based reagent or catalyst; r.t., room temperature.

achieved a 53% enantiomeric excess at best11. Later, extensive opti-
mization of a planar chiral phosphaferrocene ligand by Fu and co-
workers for Rh-based catalysts led to an 86% enantiomeric excess14.
The limitations of this system remain substantial, because efficient
enantioinduction is limited to substrates that bear bulky substitu-
ents, and long reaction times at high temperatures are required15,16.
In 2009, Mazet and collaborators reported an Ir-based cata-
lyst for the highly enantioselective isomerization of trisubstituted
allylic alcohols, such as 11 (Fig. 2c)17,18. Several generations of
ligand optimization culminated in a system that operates at room
temperature with excellent levels of enantioselectivity and a rela-
tively general substrate scope, which represents significant progress
in the field19. Further efforts were dedicated to the development
of Ru- (refs. 20–22), Pd- (ref. 23) and Rh- (refs. 24,25) based catalysts,
which achieved high levels of enantioinduction for otherwise chal-
lenging substrate classes, such as tetrasubstituted secondary allylic
alcohols (albeit with imperfect diastereoselectivity), and higher
homologues, such as homoallylic alcohols. Overall, however, a gen-
eral catalytic system for the enantioselective isomerization of allylic
alcohols remains elusive.
An alternative approach towards the enantioselective isom-
erization of allylic alcohols was reported by Martín-Matute and
co-workers26, in which the base TBD (1,5,7-triazabicyclo-[4.4.0]
dec-5-ene) was used to enantiospecifically isomerize secondary
allylic alcohols and ethers. The enantiospecificity achieved is close
to perfect (Fig. 2d) and is proposed to originate from the short-lived
nature of the intimate ion pair 16 resulting from deprotonation,
which ensures protonation on the same enantiotopic face. The sub-
stantial decrease in enantiospecificity in more polar solvents lends
credence to this hypothesis.
An elegant strategy to control stereochemistry by isomerization
relates to desymmetrization reactions (Fig. 2e), in which stereocen-
tres can be established at a remote position from the initiation site.
This approach is unfortunately restricted to specific substrates to a
achieve high enantioselectivity27.
C–C and C–B bond formation. The enantioselective formation of
a C–C or C–B bond as an initiation event for a chain-walking pro-
cess leads to further increase in molecular complexity compared
with that of the formation of a C–H bond. The Sigman group has
developed an enantioselective redox-relay Heck reaction, in which
a quaternary carbon stereocentre is formed at the initiation site by
face-selective migratory insertion (Fig. 3a)28. The resulting alkyl-
palladium intermediate 22 then undergoes a series of β-hydride
elimination and reinsertion steps to reach the thermodynamic
sink of carbonyl formation. This transformation, which allows the
highly enantioselective formation of remote quaternary carbon
stereocentres, is joined by analogous C–C, C–N and C–O bond-
forming reactions which together wield considerable synthetic
power29–43 and has even been applied in the total synthesis of com-
plex natural products44.
Another notable example that establishes a stereocentre at the
initiation site while allowing further increase of molecular com-
plexity was reported by Hall and co-workers, who converted vinyl
nonaflates into enantioenriched allylboronate esters, such as 25, in
the presence of a palladium catalyst and pinacolborane (Fig. 3b)45–47.
Recent studies support a mechanism in which the initial genera-
tion of a vinylboronate directs the [Pd]-H species to one enantio-
topic face of the alkene, followed by alkene isomerization to set the
stereochemistry of the borylated centre48. The allylboronate reacts
with aldehydes in the same pot, affording diastereo- and enantioen-
riched allylation product 26.
Stereoretentive remote functionalization processes
At first glance, any chain-walking process that crosses a tertiary ste-
reocentre should proceed with complete racemization, as an achiral

38 Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth

NATure SynThesis Review Article
a
NEt2 [Rh] H

LiNEt2 [Rh((S)-BINAP)] NEt 2

NEt2

4 E- 5 6 (R,E)-7
Myrcene

H3O

H2, Raney Ni ZnBr2

OH OH O

10 9 8
(–)-Menthol Isopulegol (R)-Citronellal

b c
Cy 12 (7.5 mol%) Cy

[Rh((R)-BINAP)] NEt2
Ph OH H 2 activation, Ph O
11 then degassed 14
NEt2 THF, 35 °C, 22 h
85%, 99/1 e.r.

Z-5 [Rh((S )-BINAP)] (R,E)-7 OMe

H
P N
NEt 2 NEt2 [Ir] Cy Ph
O H
N
[Rh((R)-BINAP)] Ir O
P H
t t
Bu Bu –
BArF
E -5 (S,E )-7
12 13

d e
NiBr2
N (–)-diop
Ph OH Ph O LiBHEt3
TBD [Ni]
N N O O O O O
Ph Et 2O O
F3 C Ph F3C H t
Bu
Toluene H H H
F3C Ph –70 °C
15 80 °C 17
18 h 144 h
Ph OH 82%, 95% e.s. 19
18 20
86%, 96/4 e.r.
16

Fig. 2 | Asymmetric C-H bond formation at the initiation site. a, Noyori’s application of asymmetric allylamine isomerization to the total synthesis of
menthol, still used today for ton-scale production. b, Rh/BINAP-catalysed isomerization of allylamines to give enantioenriched E-enamines. c, Asymmetric
Ir-catalysed mono-isomerization of primary allylic alcohols through a 1,2-hydride shift mechanism. d, Base-catalysed enantiospecific isomerization of
electron-poor allylic alcohols. e, Desymmetrization via isomerization opens the possibility to reveal an C(sp3) stereocentre at a distal position from the
isomerized double bond. coe, cyclooctene; DCE, 1,2-dichloroethane; BArF, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; diop, 2,3-O-isopropylidene-2,3-
dihydroxy-1,4-bis(diphenylphosphino)butane; d.r., diastereomeric ratio; e.r., enantiomeric ratio; e.s, enantiospecificity; TBD, 1,5,7-triazabicyclodec-5-ene.

trisubstituted alkene is intermediately formed (Fig. 4a). It was, how-
ever, observed that the redox-relay Heck arylation of (R)-citronellol
(27), shown in Fig. 4a, displays complete stereoretention of the
remote tertiary stereocentre28. Importantly, the configuration of the
tertiary centre in the product was independent of the enantiomer
of the chiral ligand employed. A contrasting result was reported by
Mazet and colleagues23,49, in which the Pd-catalysed isomerization
of the same substrate led to complete racemization of the tertiary
centre (Fig. 4b).
The difference between these two contrasting outcomes lies in
the strength of the association between the catalyst and the alkene
formed during chain-walking. If the catalyst remains strongly bound
to the newly formed alkene, as in Prater and Sigman’s case42, the ste-
reochemical information is retained owing to the fact that the Pd–H
species remains coordinated to one enantiotopic face of the alkene
28 (Fig. 4a), which re-establishes the stereocentre with the same
configuration on migratory insertion. Conversely, if the catalyst dis-
engages from the substrate during chain-walking, the intermediate
alkene leads to two enantiomers by coordination from either enan-
tiotopic face of 30 (Fig. 4b), as was shown to be the case in Mazet and
co-workers’ study23. The factors at play in determining whether the
process is dissociative or associative were explored by both groups.
First and foremost, it appears that the more strongly donating
ligands labilize the alkene ligand due to the trans-effect, in line with
the experimental observations in which a bisphosphine ligand led to
racemization and a pyridine–oxazoline ligand did not. Additionally,
the reaction solvent and its interaction with the metal counter-
ion also plays a substantial role, with more strongly coordinating

Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth 39

Review Article NATure SynThesis

a
4-OMe-C 6H4B(OH) 2 (3 equiv.)
TBSO
TBSO Pd(CH 3CN)2 (OTs) 2 (6 mol%)
TBSO OH
(S)-5-CF 3-t Bu-PyrOx (9 mol%)
2
2 3 Å MS, Cu(OTf)2 (3 mol%) 2
OH O 2 balloon, DMF, r.t., 24 h Ar [Pd] O

F3C
MeO
21 22 23
O
N 61%, 93/7 e.r.
N
t Bu

(S)-5-CF3-tBu-PyrOx

b
HBpin (1.1 equiv.)
ONf Bpin
Pd(OAc)2 (3 mol%) p-MeC6H4CHO
(+)-Taniaphos (3.3 mol%) (1.1 equiv.)

PhNMe 2 (1.1 equiv.) Toluene (1 M), r.t., 16 h

N N N
Boc CPME (0.33 M), r.t., 16 h Boc Boc
OH
PPh2
24 25 26
PPh2 80%, 95.5/4.5 e.r.
Fe
Me2N

(+)-Taniaphos

Fig. 3 | Asymmetric C–C and C–B bond formation at the initiation site. a, The enantioselective redox-relay Heck reaction establishes remote quaternary
stereocentres with excellent stereocontrol. b, Asymmetric borylation–isomerization of alkenyl nonaflates leads to enantioenriched allylboronate esters,
which can be used in stereospecific carbonyl allylation. CPME, cyclopentyl methyl ether; DMF, dimethylformamide; MS, molecular sieves; OTs, tosylate;
OTf, triflate; ONf, nonaflate (perfluorobutanesulfonate); Taniaphos, 1-[(R)-(dimethylamino)[2-(diphenylphosphino)phenyl]methyl]-2-(diphenylphosphino)-
(2R)-ferrocene); TBS, tert-butyldimethylsilyl; (S)-5-CF3-tBu-PyrOx, (S)-4-(tert-butyl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5-dihydrooxazole.

solvents leading to more associative chain-walking, but this effect
has not been conclusively explained yet49. Other reports of remote
functionalization with varying degrees of enantioretention have
accumulated over the years, and also correlate the degree of racemi-
zation with the extent of dissociation during isomerization50–53.
In the case of a quaternary carbon stereocentre along the molec-
ular backbone, a scenario in which chain-walking directly crosses
the stereocentre is, of course, not viable. An alternative way to com-
plete a chain-walking process on a molecule that contains a qua-
ternary carbon would be to ‘skip’ this interfering motif by the ring
opening of a strained ring54.
The first illustration of this concept was reported by our group
using stoichiometric amounts of the Zr-based Negishi reagent (Fig.
4c)55,56. When cyclopropane 32, which features a quaternary carbon
stereocentre and an ω-alkenyl chain, is exposed to the above zircon-
ocene reagent, reversible alkene isomerization is initiated. As soon
as the Zr-coordinated alkene reaches the position adjacent to the
cyclopropane 33, the strained ring is sprung open to give zircona-
cyclobutane 34, which can selectively react with two different elec-
trophiles. The quaternary carbon stereocentre previously contained
in the strained ring is now part of the elaborated acyclic product 35.
An updated demonstration of this concept was developed
using the Pd-catalysed Heck reaction of cyclopropane carbinol 36
as a trigger for the chain-walking process (Fig. 4d)57. Again, this
dynamic process is shifted by cleavage of the strained ring, after
which the catalytic cycle is completed with the oxidation of the ter-
minal alcohol group and release of the Pd catalyst. Notably, the ste-
reochemistry of the tertiary centre in the product 39 is well-defined
thanks to the non-dissociative chain-walking process58. The sub-
strates and catalytic systems used in this reaction can be varied to
create an additional stereocentre at the initiation site and result in
stereodefined acyclic molecules that possess multiple quaternary
and tertiary stereocentres59,60.
Stereocentre formation at the termination site
Allyl- and benzylmetal intermediates. Chain-walking is often ter-
minated by the formation of a stabilized organometallic intermedi-
ate, which is subsequently trapped to regenerate the catalyst.
In an instructive illustration of this concept, Lu and co-workers
reported the Co-catalysed asymmetric remote hydroboration of
the unactivated internal alkene 40 using a newly developed chiral
NNN-pincer ligand 41 (Fig. 5a)51. In the postulated mechanism,
the chain-walking is thermodynamically driven by the forma-
tion of a benzylcobalt intermediate 42, which is trapped by HBpin
(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) to afford the enantioen-
riched product and regenerate the Co–H catalyst.
Zhu and colleagues reported an asymmetric Ni-catalysed
remote hydroalkynylation of allylbenzene derivative 44, which is
proposed to proceed through a similar benzylnickel intermediate
45 (Fig. 5b)61. The alkyne functionality featured in the product
serves as a versatile synthetic handle for further transformations.
This example of remote asymmetric C-C bond formation is, how-
ever, still limited in scope.
Fang and co-workers reported a Ni-catalysed remote hydro-
cyanation reaction of the non-conjugated diene 47 based on the
TADDOL-based bisphosphite ligand 48 (TADDOL, α,α,α′,α′-
tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol), in
which the non-conjugated alkene selectively serves as the initiation
site (Fig. 5c)62. Chain-walking then ensues to result in the allylnickel
intermediate 49, which undergoes reductive elimination to afford
an enantioenriched allylic nitrile. The substrate scope is convinc-
ingly broad, and dienes that feature numerous combinations of
alkenes reacted with high regio- and enantioselectivity.
As early as 1994, Larock et al. reported a beautiful three-com-
ponent process in which the Heck arylation of non-conjugated
dienes is followed by chain-walking to result in allylpalladium
intermediates, which are trapped with nucleophilic amines63.

40 Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth

NATure SynThesis Review Article
a
Retention of a preinstalled stereocentre during chain-walking

Pd(CH3CN2)(OTs)2 (10 mol%)

Ph-B(OH)2 (3 equiv.)
H-[Pd]
OH L (14 mol%) OH O
Ph Ph
3 Å MS, Cu(OTf)2 (4 mol%)
DMF, r.t., 24 h
27 29
(R)-citronellol L: (S)-5-CF3-tBu-PyrOx: 65%
28 >99/1 e.r.
>99/1 e.r.
Strong association between (R)-5-CF3-tBu-PyrOx: 62%
[Pd]-H and alkene leads to retention >99/1 e.r.
b
Racemization of a preinstalled stereocentre during chain-walking

[(dcpe)PdMeCl] (5 mol%) H-[Pd]

OH NaBArF (5.5 mol%) O

OH
Cyclohexene (50 mol%)

27 31
(R)-citronellol 38%
30 1/1 e.r.
>99/1 e.r.
Dissociation from the catalyst
leads to racemization
c
Zr-mediated alkene isomerization-cyclopropane ring-opening as a means to "walk over" quaternary stereocentres

1. Cp2ZrC4H8 (2 equiv.), Et2

Bu
2
3. Acetone OH Bu
32 4. CuI 35
5. Propargyl chloride 53%, 98/2 E/Z, 98/2 d.r.
6. H3O

[Zr]
[Zr] Bu
Bu
2

33 34
d
Pd-catalysed Heck arylation as a trigger for ring-opening

p-MeOC6H4Br (1.2 equiv.)

Bu Pd(OAc)2 (5 mol%), (p-CF3C6H4)3P (15 mol%) Bu
OH
NaHCO3 (2.5 equiv.), TBACl (2 equiv.)

O
MeO 39
36 44%, 98/2 d.r.

Bu Ar
OH [Pd] OH
Ar

[Pd] Bu

37 38

Fig. 4 | Walking ‘over’ tertiary and quaternary stereocentres. a, Chain-walking occurs without dissociation from the substrate, and thus ensures the
retention of stereochemical information. b, Dissociative chain-walking results in the loss of stereochemical information as the intermediate alkene can be
engaged from either enantiotopic face. c, Zr-mediated alkene isomerization–cyclopropane ring-opening. A cyclopropane ring that features a quaternary
stereocentre can allow to ‘walk over’ quaternary centres. The first demonstration of this strategy used Negishi’s zirconocene reagent. Alkene isomerization
followed by cleavage of the cyclopropane results in a bis-nucleophilic organozirconocene and leaves the stereodefined centre untouched. d, Alternatively,
chain-walking can be initiated by a Heck arylation, which culminates in ring opening and alcohol oxidation. This serves as a catalytic counterpart to the
previous transformation. DCE, 1,2-dichlorethane; dcpe, 1,2-bis(dicyclohexylphosphino)ethane; TBA, tetrabutylammonium; THF, tetrahydrofuran; Cp,
cyclopentadienyl.

Even though many examples of both enantioselective Pd-catalysed
Heck arylation and allylic substitution reactions are known, an
enantioselective variant of this process remained elusive until
recently. In 2020, Zhou and colleagues reported that the use of a
bespoke chiral bisphosphite ligand 53 enables the enantioselective
attack of the amine nucleophile onto the allylpalladium intermedi-
ate 54, finally realizing this long-standing goal (Fig. 5d)64.
Alkylmetal intermediates. Instead of trapping a thermodynami-
cally stabilized organometallic intermediate, selectivity can also

Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth 41

Review Article NATure SynThesis

a Co(OAc) 2 (2.5 mol% )

41 (3 mol%) [Co] Bpin
HBpin (1.2 equiv.) Ph
Ph Ph
Ph 3 Ph
Et2 O, r.t., 20 h

40 43
4.1/1Z/E 90%, 99/1 e.r.
42

b NiI2(xH 2O) (5 mol%)

(S)-5-CF3-t Bu-PyrOx (6 mol%) Et
(MeO)3SiH (2.5 equiv.) Br
MeO [Ni] TIPS MeO
Bromoalkyne (1.5 equiv.) MeO
K3PO4·4H2O (2.5 equiv) TIPS
AcO AcO
NaI (2.0 equiv) AcO
44 PhCF3, 0 °C, 12 h 46
45 78%, 95/5 e.r.
90:10 r.r.

c Ni(cod)2 (5 mol%)
48 (5 mol%) CN
[Ni]
Me 2C(OH)CN (3.0 equiv.)
Ph Ph Ph
toluene, 50 °C, 12 h
47 50
49 93%, 95/5 e.r.

d PdCl 2 (5 mol%)
[Pd]
H 53 (6 mol%) Ph
N proton sponge (2 equiv.)
+ NHR2
Ph N
PhI 55
ethylene glycol, 60 °C, 72 h 90%
51 52
54 97/3 e.r.

O
= (R )-BINOL, Ar = 3-CF3 -C6H4 t Bu
O O
O
Ar Ar O
N P
H O O P
N O
O O
N NPh
O O O
P t Bu
2
Ar Ar O

41 48 53

Fig. 5 | Formation of stereocentres at the termination site through allyl- and benzylmetal intermediates. a, In the Co-catalysed enantioselective
remote hydroboration of alkenes, the thermodynamically favoured benzylcobalt intermediate undergoes reductive elimination to afford enantioenriched
alkylboronate esters. b, Ni-catalysed isomerization–hydroalkynylation provides valuable enantioenriched propargylbenzene derivatives and proceeds
through a similar benzylnickel intermediate. c, Ni-catalysed asymmetric remote hydrocyanation of non-conjugated dienes. The terminal alkene selectively
reacts with the Ni–H catalyst, followed by chain-walking to result in a stabilized allylnickel species which furnishes an enantioenriched allylic nitrile.
d, A Pd-catalysed asymmetric three-component Heck arylation–isomerization–amination cascade. The enantiodetermining step is the trapping of the
allylpalladium intermediate with a nucleophilic amine. cod, cyclooctadiene; r.r., regioisomeric ratio; proton sponge, 1,8-bis(dimethylamino)naphthalene.

hinge on kinetic differentiation between the regioisomeric alkyl-
metal intermediates generated during chain-walking.
In an elegant example by Zhang and co-workers, an aldehyde
C–H bond serves as a hydride source for a Rh catalyst (through
C–H oxidative addition), which allowed cyclization onto a pendant
alkene65. The resulting alkylmetal intermediate 57 did not immedi-
ately undergo reductive elimination, but first underwent a single-
position isomerization that led to 58, which underwent reductive
elimination to form a five-membered ring (Fig. 6a). Detailed com-
putational investigations by the authors suggest that rotation along
a C–C bond prior to the β-hydride elimination required for isom-
erization is the turnover-limiting and enantio-determining step65. A
prior study from Dong and colleagues describes the desymmetri-
zation of α,α-diallyl aldehydes by an enantioselective Rh-catalysed
isomerization-cycloisomerization process, affording synthetically
valuable cyclopentanone derivatives66.
In work reported by Nishimura and co-workers in 2017, an
Ir-based catalyst isomerizes ω-alkenyl ethers, for example, 60, into
the corresponding enol ethers, which then undergo an enantiose-
lective hydroarylation reaction catalysed by the same Ir complex
(Fig. 6b)67,68. The authors showed that the enantioselectivity is inde-
pendent of the stereochemical purity of the intermediate enol ether,
and instead proposed that it arises from different rates of reductive
elimination by the different diastereomers of alkyliridium interme-
diate 61.
Kochi and collaborators explored an alternative strategy to shift
the chain-walking equilibrium, by selective cyclization of an alkyl-
metal intermediate 64 onto another alkene present in the molecule

42 Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth

NATure SynThesis Review Article
a (R )-DM-MeO-BIPHEP
(5 mol%)
[Rh(cod)Cl] 2
(2.5 mol%)
O O O
NaBArF (5 mol%) [Rh]
[Rh]
H 1,4-Dioxane H
O H
110 °C, 24 h H Ph
Ph Ph
56 57 58 59
95%, 70/30 d.r.
96/4 e.r.

b Ph
[Ir(cod)Cl] 2 (2.5 mol%)
(R )-BINAP* (5 mol%) MeO
Ph OMe NaBArF (10 mol%) Ph OMe N

2-Phenylpyridine, 80 °C
[Ir] Ar
Toluene, 24 h

60 61 62
87%, 97/3 e.r.

c
(phen)PdMeCl (2.5 mol%)
EtO2C NaBArF (3 mol%) EtO 2C H2 /PtO2 EtO 2C
EtO2C EtO 2C [Pd] EtO 2C
DCE, r.t., 24 h

63 64 65
1/4 E /Z 83%, 95/5 d.r.

d s BuLi(1.2 equiv.)
67 (1.2 equiv.)
H Et2O, –78 °C [Pd]Ph Ph
O O O
nPr
then, ZnCl2 (1.2 equiv.) nPr n
Pr
n N H then, PhBr n N H n N H
Pr Pr Pr
Boc Pd2(dba) 3 (2.5 mol%) Boc Boc
68 (5 mol%)
Toluene, 80 °C
66 69 70
72%, 96.5/3.5 e.r.

MeO PAr2 PAr2

H P(iPr)2
MeO PAr2 PAr2 N

N N
H

(R )-DM-MeO-BIPHEP (R )-BINAP* 67 68
Ar = 3,5-di-Me-C6H3 Ar = 3,5-di- t Bu-4-OMe-C6H2 (–)-Sparteine

Fig. 6 | Formation of stereocentres at the termination site through alkylmetal intermediates. a, Rh-catalysed asymmetric hydroacylation involving
alkene isomerization. The alkylmetal intermediate that leads to five-membered ring formation is selectively trapped. b, Ir-catalysed isomerization–
hydroarylation of a ω-alkenyl ether. Isomerization to an enol ether is followed by enantioselective hydroarylation. c, Pd-catalysed remote
cycloisomerization of 1,n-dienes, for example, 63. Hydropalladation is followed by reversible chain-walking, which is shifted by a 5-exo-trig cyclization. d,
Enantioselective C5 functionalization of Boc-1,3-oxazinanes through Pd-catalysed alkene isomerization and Negishi cross-coupling of an enantioenriched
organozinc species. The enantiospecificity of the isomerization process stems from its non-dissociative nature. dba, dibenzylideneacetone; BIPHEP,
2,2′-bis(diphenylphosphino)biphenyl; phen, phenanthroline; Boc, tert-butyloxycarbonyl; (R)-DM-MeO-BIPHEP, (R)-di-Me-MeO-BIPHEP.

to form a kinetically favoured five-membered ring (Fig. 6c)69,70. The
process is terminated by a non-regioselective β-hydride elimina-
tion, which mandates the hydrogenation of the cycloisomeriza-
tion product to obtain isomerically pure products 65. Similar work
regarding hydrosilylative cycloisomerizations was performed by the
same group71.
A synthetically and mechanistically exciting study by Baudoin
and co-workers demonstrates the preparation of functionalized
β-amino acid derivatives via a sequence of enantioselective lithia-
tion, transmetallation, stereospecific alkene isomerization and
cross-coupling (Fig. 6d)72. Using (−)-sparteine (67) to induce enan-
tioselective lithiation α to the protected amine of 66, followed by
transmetallation with ZnCl2, an enantioenriched alkylzinc spe-
cies was obtained. Immediately following, an electrophile and a
palladium catalyst equipped with the phosphine ligand 68, known
to favour chain-walking, were added. After transmetallation to
palladium, monoisomerization resulted in a new alkylpalladium
species 69, which retained the stereogenic information due to the
non-dissociative nature of the isomerization. Reductive elimination
afforded the final product 70, which can be easily cleaved under
oxidative conditions to afford enantioenriched β-amino acids.
Notably, isomerization can be avoided using a different phosphine
ligand, which gives rise to a different regioisomer of the product.
The authors also demonstrated that enantioselective lithiation can
be performed using substoichiometric amounts of (+)-sparteine
surrogate along with the achiral diamine bispidine. Previous work
from the same group demonstrated an example in which the stereo-
chemistry established by enantioselective lithiation can be retained

Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth 43

Review Article NATure SynThesis
a Ir-catalysed alkene isomerization-asymmetric carbonyl allylation

[Ir(cod)2]BF4 (5 mol%)
OH
PCy3 (12.5 mol%)
H2 activation PhCHO
BPin BPin
(R)-TRIP (5 mol%)
1,2-DCE, 4 Å MS
71 73
72
91%, 98/2 d.r.
98/2 e.r.
b syn-selective allylation through Z-selective Ni-catalysed alkene isomerization

NiCl2(dppp) (10 mol%)

Zn powder (20 mol%) OH
ZnI2 (20 mol %) BPin
PhCHO
Bpin
HPPh2 (5 mol %)
74
4 h to r.t. (o/n) 76
75
72%, 91/9 d.r.
c Ir-catalysed alkene isomerization followed by asymmetric aldol reaction

MesCu (5 mol%)
[Ir(cod)2(PPh2Me)2]PF6 (R)-DTBM-SEGPHOS
(0.5 mol%) (5 mol%) OH OH
O H2 activation O iPrOH (1 equiv.)

B B
O O O O
PhCHO;
77 then LiBH4 79
78
91%, 94/6 d.r.
98.5/1.5 e.r.
d Ir-catalysed alkene isomerization followed by Mukaiyama aldol reaction

[Ir(cod)Cl]2 (0.5 mol%) PhCH(OMe)2 OMe O

PCy3 (3 mol%) Sc(OTf)3
NaBArF (1.25 mol%) H
OSiMe2Ph OSiMe2Ph
H2 activation

80 syn-82
76%, 94/6 d.r.
E-81

OMe O

As above H
OSiMe2Ph
OSiMe2Ph
83 anti-82
Z-81 67%, >95/5 d.r.

Fig. 7 | Formation of stereocentres at the termination site through intermolecular reactions of alkene intermediates. a, Ir-catalysed alkene isomerization
equilibrates readily available vinylboronate esters with their E-allylboron counterparts. The latter are trapped by reaction with an aldehyde present in
situ, catalysed by the chiral phosphoric acid (R)-TRIP, which resulted in diastereo- and enantiomerically enriched allylation products. b, Ni-catalysed Z-
selective isomerization leads to syn-allylation products through a similar pathway. c, Ir-catalysed alkene isomerization affords E-boron enolates, which
are subsequently engaged in a Cu-catalysed asymmetric aldol reaction. d, Ir-catalysed alkene isomerization proceeds through allylmetal intermediates
and allows the stereoselective formation of fully substituted aldehyde-derived silyl enol ethers. The two stereoisomeric silyl enol ethers participate in a
stereospecific Mukaiyama aldol reaction in the same pot. dppp, 1,3-bis(diphenylphosphino)propane; Mes, mesityl; o/n, overnight.

during a haptotropic isomerization process to enable another exam-
ple of an enantioselective remote cross-coupling reaction73.
Alkene intermediates. Rather than directly trapping the organo-
metallic intermediates involved in chain-walking, one can generate
and subsequently trap stereodefined alkenes, which are challenging
to generate otherwise.
This idea is exemplified by the work from the Murakami group,
in which vinylboronate esters, such as 71 (readily prepared through
hydroboration of terminal alkynes), were subjected to isomeriza-
tion with an Ir-based catalyst in the presence of aldehydes74. The
unfavourable isomerization from vinyl- to allylboronate 72 is
driven by the reaction of the latter with the aldehyde (Fig. 7a). As
the reaction proceeds through a cyclic chair-like transition state, the
E-stereochemistry of the allylboronate 72 generated in situ is trans-
lated into complete diastereocontrol over the product homoallylic
alcohols 73. Furthermore, the Ir catalyst is compatible with the chiral
phosphoric acid (R)-TRIP ((R)-3,3′-bis(2,4,6-triisopropylphenyl)-
1,1′-binaphthyl-2,2′-diyl hydrogenphosphate), which exerts enan-
tiocontrol over the allylation. The key E-allylboronates could also
be accessed through long-range isomerization of ω-ene alkylboro-
nates, using the same catalytic system. This concept was extensively
explored by the Murakami group, and resulted in a suite of isom-
erization–allylation reactions, which provided allylated products that
featured various substitution patterns and functionality75–78. Hilt and
co-workers recently reported a complementary method, in which a
Ni catalyst isomerized a remote alkene (74) to stereoselectively gen-
erate Z-allylboronate 75, which furnished syn-homoallylic alcohol 76
(Fig. 7b)79. This study serves as an impressive synthetic application of
the Z-selective isomerization catalysts developed by the Hilt group80.
In a similar vein, Kanai and collaborators developed an ele-
gant stereoselective strategy towards the cross-aldol reaction of

44 Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth

NATure SynThesis Review Article
a
[Ir(coe)2Cl] 2 (1 mol%)
PCy3 (6 mol%), NaBPh 4 (2 mol%) O
O DCE, 75 °C, 60 h O
Bu
Bu Bu

84 85 86
75%, 95/5 d.r.

b O
[Ir(cod)Cl] 2 (1 mol%) PPh 3 (6 mol%)
O PCy3 (6 mol%), NaBArF (2 mol%) O 85 °C, 3 h O

O Ph DCE, r.t, 30 min O Ph or MgBr2 (80 mol%) Ph

Et2O, TBM, 10 min
87 89
88 85 °C: 87%,
2/1 E/Z, 96/4 d.r.
MgBr2: 86%
95/5 E/Z, 89/11 d.r.

c O O O

MeO [Ir(cod)Cl] 2 (1 mol%) MeO

[3,3] Me O
PCy3 (6 mol%), NaBArF (2.5 mol%)
9
DCE, TBM to 85 °C
Ph Ph 9
Ph 9

90 91 92
52%, >95/5 d.r.

d O Ph O Ph
MeO O
[Ir(cod)Cl] 2 (2 mol%) O
PCy3 (12 mol%), NaBArF (5 mol%) Hydrolysis
H
OMe Ph
PhCl, TBM to 140 °C
OMe O
O O
93 94 95
91%, >95/5 d.r. 85%, >95/5 d.r.

Fig. 8 | Accessing sigmatropic rearrangement substrates through alkene isomerization. a, A cationic Ir-based catalyst site- and stereoselectively
isomerizes the primary allyl fragment of bis-allylic ethers, which constitutes a powerful approach towards the aliphatic Claisen rearrangement to
generate quaternary carbon stereocentres. b, Diallyl acetals derived from α,β-unsaturated aldehydes undergo isomerization to the corresponding divinyl
acetals, which serve as substrates for the Coates–Claisen rearrangement. c, In an alkene isomerization–Cope rearrangement, the same Ir-based catalytic
system forms reactive divinyl cyclopropanes which rearrange to yield valuable cycloheptadiene products with complete diastereoselectivity. d, Di-ω-
ene epoxides similarly undergo isomerization and Cope rearrangement that leads to dihydrooxepines, which serve as a source of stereodefined acyclic
1,6-dicarbonyl compounds.

aldehydes81,82. By generating E-configured boron enolate 78 through
Ir-catalysed alkene isomerization, problems of stereoselectivity and
self-condensation typical of aldehyde-derived enolates were side-
stepped. These nascent enolates were reacted with aldehydes in
the presence of a Cu-based chiral catalyst, which resulted in enan-
tio- and diastereopure aldol products, which were isolated as the
respective 1,3-diols 79 (Fig. 7c). As the aldehyde product of the first
aldol reaction is similarly reactive to the initial aldehyde, the authors
found that by variation of additives, double, triple and even qua-
druple aldol products could be obtained with high stereoselectivity.
Alkene isomerization is an attractive strategy to generate enolates
because it can circumvent the issues of regio- and stereoselectivity
often encountered with classical deprotonation-based approaches.
Building on previously reported Ir-based catalytic systems that
operate through allylmetal intermediates83–85, our group developed
an approach towards fully substituted aldehyde-derived silyl enol
ethers86. By virtue of the 1,3-hydride shift mechanism and the con-
formational preferences of the allyliridium hydride intermediate,
either stereoisomer of a given enolate was cleanly generated, with
the stereochemistry determined by the regiochemistry of the start-
ing material, rather than by the steric properties of the substituents
at the α-carbon (Fig. 7d). Thus, two regioisomeric allyl silyl ethers
80 and 83 were isomerized into two stereoisomeric fully substituted
aldehyde-derived silyl enol ethers 81, which underwent a stereo-
specific Sc-catalysed Mukaiyama aldol reaction with benzaldehyde
dimethyl acetal in the same pot87, which resulted in two different
diastereomers of aldehyde 82 that bears adjacent quaternary and
tertiary stereocentres.
[3,3]-Sigmatropic rearrangements, such as those named after
Claisen and Cope, are strikingly general transformations, as the
parent reactive scaffold can be decorated with various substitution
patterns and functionality without compromising the success of the
sigmatropic event. Indeed, the main ‘bottleneck’ when such sigma-
tropic rearrangements are employed in synthesis is often to find an
efficient and selective access to the substrates, as many pose signifi-
cant synthetic challenges that result from the positioning of unsatu-
ration in the molecule. It is therefore fitting that substantial efforts
have been dedicated to access difficult sigmatropic rearrangement
substrates through alkene isomerization of their more readily avail-
able regioisomeric counterparts.
In the case of the Claisen rearrangement, alkene isomerization
can be leveraged to access relatively tricky allyl vinyl ether substrates
from simple diallyl ethers. This idea has been explored in numerous
iterations that utilized various catalytic systems, but the most syn-
thetically relevant example was reported by Nelson, who employed
a highly site- and stereoselective Ir-based isomerization catalyst to

Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth 45

Review Article
isomerize substituted bis-allyl ethers, such as 84, into their reactive
allyl vinyl ether counterparts (85), which then rearranged in the
same pot to selectively and efficiently furnish diastereopure Claisen
rearrangement products that possess quaternary carbon stereo-
centres (86) (Fig. 8a)88–91. The strategic use of alkene isomerization
thus greatly enhances the synthetic appeal of the aliphatic Claisen
rearrangement.
The same concept could be demonstrated to an even greater
effect when diallyl acetals of α,β-unsaturated aldehydes, such as 87,
were employed, which yielded the corresponding divinyl acetals
(88) (Fig. 8b)92. The allylic divinyl acetals thus obtained serve as
substrates for the Coates–Claisen rearrangement93–95, a relatively
little-known variant that has suffered from limited applicabil-
ity owing to the inaccessibility of the key vinyl acetals. The acetal
moiety confers two attractive features to this rearrangement: con-
siderable rate enhancement due to the electron-donating alkoxy
moiety, which also enables the mediation of this rearrangement
by mild Lewis acids, such as MgBr2, as well as the presence of a
vinyl ether in the product 89, which serves as a protected aldehyde
and offers synthetic possibilities distinct from those available with
classical alkenes generated through other variants of the Claisen
rearrangement.
Ir-catalysed alkene isomerization can also be applied to tran-
siently generate stereodefined divinyl cyclopropane intermediates,
such as 91, which immediately undergo a Cope rearrangement
to yield cycloheptadienes that contain two contiguous stereocen-
tres (92) (Fig. 8c)96. Unlike the case of the isomerization–Claisen
rearrangement, which is performed sequentially, the isomeriza-
tion–Cope cascade effectively funnels the equilibrium towards the
divinyl cyclopropane through the ensuing rearrangement, even
when ten different energetically degenerate isomers are present in
equilibrium through isomerization.
A similar transformation can be performed on epoxides, such
as 93, rather than cyclopropanes, to form reactive dialkenyl epox-
ides, which rearrange into stereodefined dihydrooxepines (94) (Fig.
8d)97. The rearrangement products are amenable to hydrolysis, and
yield diastereomerically pure 1,6-dicarbonyl compounds that fea-
ture two adjacent stereocentres. This combined isomerization–rear-
rangement–hydrolysis sequence constitutes an attractive strategy
towards acyclic 1,6-dicarbonyl compounds 95.
Outlook
Work in the area of remote functionalization through alkene isom-
erization is diverse and spans investigations into the mechanistic
intricacies of chain-walking, the design of new catalytic systems
and the application of existing technologies in complex molecular
settings. The development of new remote functionalization systems
can lead to their extensive use in industry, as illustrated by Takasago
industry’s menthol synthesis.
The goal of this review was to highlight an additional facet and
source of opportunity in remote functionalization reactions, namely,
the control and leverage of stereochemical information. Tackling
issues of stereocontrol at all stages of the remote functionalization
process can lead to synthetically and conceptually valuable results,
as well as deepen our mechanistic understanding of such processes.
Specifically, designing isomerization catalysts that can form
highly substituted alkenes with complete stereoselectivity can lead
to control over the diastereoselectivity of subsequent stereospecific
transformations, such as aldol and allylation reactions, sigmatropic
rearrangements and more. Alternatively, the migrating metal cata-
lyst can actively participate in stereocentre-forming steps, such as
migratory insertion and reductive elimination. Identifying chiral
ligands that enable long-distance isomerization and also achieve effi-
cient stereocontrol is thus an important undertaking. Furthermore,
modulating the catalyst to precisely control the position at which
termination occurs can result in products that feature challenging
46
NATure SynThesis
regiochemistry as well as stereochemistry. Finally, the development
of catalytic isomerization systems based on Earth-abundant tran-
sition metals, such as Mn, Fe, Co and Ni, without compromising
efficiency and selectivity is a crucial long-term goal.
One can envisage exciting prospects for stereoselective remote
functionalization reactions. We hope this overview of the topic will
inform and inspire further progress in the field.
Received: 29 June 2021; Accepted: 19 October 2021;
Published online: 12 January 2022
References
1. Vasseur, A., Bruffaerts, J. & Marek, I. Remote functionalization through
alkene isomerization. Nat. Chem. 8, 209–219 (2016).
2. Sommer, H., Juliá-Hernández, F., Martin, R. & Marek, I. Walking metals for
remote functionalization. ACS Cent. Sci. 4, 153–165 (2018).
3. Molloy, J. J., Morack, T. & Gilmour, R. Positional and geometrical
isomerisation of alkenes: the pinnacle of atom economy. Angew. Chem. Int.
Ed. 58, 13654–13664 (2019).
4. Janssen‐Müller, D., Sahoo, B., Sun, S. & Martin, R. Tackling remote sp3 C−H
functionalization via Ni‐catalyzed ‘chain‐walking’ reactions. Isr. J. Chem. 60,
195–206 (2020).
5. Massad, I. & Marek, I. Alkene isomerization through allylmetals as a strategic
tool in stereoselective synthesis. ACS Catal. 10, 5793–5804 (2020).
6. Fiorito, D., Scaringi, S. & Mazet, C. Transition metal-catalyzed alkene
isomerization as an enabling technology in tandem, sequential and domino
processes. Chem. Soc. Rev. 50, 1391–1406 (2021).
7. Zhang, F. G. et al. Remote fluorination and fluoroalkyl(thiol)ation reactions.
Chem. Eur. J. 26, 15378–15396 (2020).
8. Juliá-Hernández, F., Moragas, T., Cornella, J. & Martin, R. Remote
carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide.
Nature 545, 84–88 (2017).
9. Kumobayashi, H., Akutagawa, S. & Otsuka, S. Metal-assisted terpenoid
syntheses. 6. Enantioselective hydrogen migration in prochiral allylamine
systems by chiral cobalt catalysts. J. Am. Chem. Soc. 100, 3949–3950 (1978).
10. Tani, K. et al. Highly enantioselective isomerization of prochiral allylamines
catalyzed by chiral diphosphine rhodium(I) complexes. Preparation of
optically active enamines. J. Am. Chem. Soc. 106, 5208–5217 (1984).
11. Tani, K. Asymmetric isomerization of allylic compounds and the mechanism.
Pure Appl. Chem. 57, 1845–1854 (1985).
12. Akutagawa, S. Asymmetric synthesis by metal BINAP catalysts. Appl. Catal. A
128, 171–207 (1995).
13. Yoshimura, T. et al. Exploring the full catalytic cycle of rhodium(I)–BINAP-
catalysed isomerisation of allylic amines: a graph theory approach for path
optimisation. Chem. Sci. 8, 4475–4488 (2017).
14. Tanaka, K., Qiao, S., Tobisu, M., Lo, M. M.-C. & Fu, G. C. Enantioselective
isomerization of allylic alcohols catalyzed by a rhodium/phosphaferrocene
complex. J. Am. Chem. Soc. 122, 9870–9871 (2000).
15. Tanaka, K. & Fu, G. C. A versatile new catalyst for the enantioselective
isomerization of allylic alcohols to aldehydes: scope and mechanistic studies.
J. Org. Chem. 66, 8177–8186 (2001).
16. Fu, G. C. in Modern Rhodium(I)‐Catalyzed Organic Reactions (ed. Evans, P.
A.) Ch. 4 (Wiley‐VCH, 2005).
17. Mantilli, L., Gerard, D., Torche, S., Besnard, C. & Mazet, C. Iridium‐catalyzed
asymmetric isomerization of primary allylic alcohols. Angew. Chem. Int. Ed.
48, 5143–5147 (2009).
18. Mantilli, L., Gérard, D., Torche, S., Besnard, C. & Mazet, C. Improved
catalysts for the iridium‐catalyzed asymmetric isomerization of
primary allylic alcohols based on Charton analysis. Chem. Eur. J. 16,
12736–12745 (2010).
19. Li, H. & Mazet, C. Iridium-catalyzed selective isomerization of primary allylic
alcohols. Acc. Chem. Res. 49, 1232–1241 (2016).
20. Cahard, D., Gaillard, S. & Renaud, J.-L. Asymmetric isomerization of allylic
alcohols. Tetrahedron Lett. 56, 6159–6169 (2015).
21. Arai, N., Sato, K., Azuma, K. & Ohkuma, T. Enantioselective isomerization of
primary allylic alcohols into chiral aldehydes with the tol-binap/dbapen/
ruthenium(II) catalyst. Angew. Chem. Int. Ed. 52, 7500–7504 (2013).
22. Wu, R., Beauchamps, M. G., Laquidara, J. M. & Sowa, J. R. Ruthenium-
catalyzed asymmetric transfer hydrogenation of allylic alcohols by an
enantioselective isomerization/transfer hydrogenation mechanism. Angew.
Chem. Int. Ed. 51, 2106–2110 (2012).
23. Lin, L., Romano, C. & Mazet, C. Palladium-catalyzed long-range
deconjugative isomerization of highly substituted α,β-unsaturated carbonyl
compounds. J. Am. Chem. Soc. 138, 10344–10350 (2016).
24. Liu, T. L., Ng, T. W. & Zhao, Y. Rhodium-catalyzed enantioselective
isomerization of secondary allylic alcohols. J. Am. Chem. Soc. 139,
3643–3646 (2017).
Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth
NATure SynThesis
25. Huang, R.-Z., Lau, K. K., Li, Z., Liu, T.-L. & Zhao, Y. Rhodium-catalyzed
enantioconvergent isomerization of homoallylic and bishomoallylic secondary
alcohols. J. Am. Chem. Soc. 140, 14647–14654 (2018).
26. Martinez-Erro, S. et al. Base-catalyzed stereospecific isomerization of
electron-deficient allylic alcohols and ethers through ion-pairing. J. Am.
Chem. Soc. 138, 13408–13414 (2016).
27. Frauenrath, H., Reim, S. & Wiesner, A. Asymmetric double-bond
isomerization of cyclic allyl acetals by using diop and chiraphos modified
nickel complexes. Tetrahedron Asymmetry 9, 1103–1106 (1998).
28. Mei, T. S., Patel, H. H. & Sigman, M. S. Enantioselective construction of
remote quaternary stereocentres. Nature 508, 340–344 (2014).
29. Werner, E. W., Mei, T. S., Burckle, A. J. & Sigman, M. S. Enantioselective
Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy.
Science 338, 1455–1458 (2012).
30. Mei, T.-S., Werner, E. W., Burckle, A. J. & Sigman, M. S. Enantioselective
redox-relay oxidative Heck arylations of acyclic alkenyl alcohols using
boronic acids. J. Am. Chem. Soc. 135, 6830–6833 (2013).
31. Xu, L. et al. Mechanism, reactivity, and selectivity in palladium-catalyzed
redox-relay Heck arylations of alkenyl alcohols. J. Am. Chem. Soc. 136,
1960–1967 (2014).
32. Zhang, C., Santiago, C. B., Crawford, J. M. & Sigman, M. S. Enantioselective
dehydrogenative Heck arylations of trisubstituted alkenes with indoles to
construct quaternary stereocenters. J. Am. Chem. Soc. 137, 15668–15671 (2015).
33. Chen, Z. M., Hilton, M. J. & Sigman, M. S. Palladium-catalyzed
enantioselective redox-relay Heck arylation of 1,1-disubstituted homoallylic
alcohols. J. Am. Chem. Soc. 138, 11461–11464 (2016).
34. Race, N. J., Schwalm, C. S., Nakamuro, T. & Sigman, M. S. Palladium-
catalyzed enantioselective intermolecular coupling of phenols and allylic
alcohols. J. Am. Chem. Soc. 138, 15881–15884 (2016).
35. Avila, C. M. et al. Enantioselective Heck–Matsuda arylations through chiral
anion phase‐transfer of aryl diazonium salts. Angew. Chem. Int. Ed. 56,
5806–5811 (2017).
36. Race, N. J., Yuan, Q. & Sigman, M. S. Enantioselective C2-alkylation of
indoles via a redox-relay Heck reaction of 2-indole triflates. Chem. Eur. J. 25,
512–515 (2019).
37. Chen, Z. M., Nervig, C. S., DeLuca, R. J. & Sigman, M. S. Palladium-
catalyzed enantioselective redox-relay Heck alkynylation of alkenols to access
propargylic stereocenters. Angew. Chem. Int. Ed. 56, 6651–6654 (2017).
38. Yuan, Q. & Sigman, M. S. Palladium-catalyzed enantioselective relay Heck
arylation of enelactams: Accessing α, β-unsaturated δ-lactams. J. Am. Chem.
Soc. 140, 6527–6530 (2018).
39. Yuan, Q. & Sigman, M. S. Palladium-catalyzed enantioselective
alkenylation of enelactams using a relay Heck strategy. Chem. Eur. J. 25,
10823–10827 (2019).
40. Liu, J., Yuan, Q., Toste, F. D. & Sigman, M. S. Enantioselective construction of
remote tertiary carbon–fluorine bonds. Nat. Chem. 11, 710–715 (2019).
41. Ross, S. P., Rahman, A. A. & Sigman, M. S. Development and mechanistic
interrogation of interrupted chain-walking in the enantioselective relay Heck
reaction. J. Am. Chem. Soc. 142, 10516–10525 (2020).
42. Prater, M. B. & Sigman, M. S. Enantioselective synthesis of alkyl allyl ethers
via palladium‐catalyzed redox‐relay Heck alkenylation of O‐alkyl enol ethers.
Isr. J. Chem. 60, 452–460 (2020).
43. Zhang, C. et al. Palladium-catalyzed enantioselective Heck alkenylation of
trisubstituted allylic alkenols: a redox-relay strategy to construct vicinal
stereocenters. Chem. Sci. 8, 2277–2282 (2017).
44. Nakamura, H., Yasui, K., Kanda, Y. & Baran, P. S. 11-step total synthesis of
teleocidins B-1–B-4. J. Am. Chem. Soc. 141, 1494–1497 (2019).
45. Lessard, S., Peng, F. & Hall, D. G. α-Hydroxyalkyl heterocycles via chiral
allylic boronates: Pd-catalyzed borylation leading to a formal enantioselective
isomerization of allylic ether and amine. J. Am. Chem. Soc. 131, 9612–9613
(2009).
46. Kim, Y. R. & Hall, D. G. Optimization and multigram scalability of a catalytic
enantioselective borylative migration for the synthesis of functionalized chiral
piperidines. Org. Biomol. Chem. 14, 4739–4748 (2016).
47. Clement, H. A. & Hall, D. G. Synthesis of α-hydroxyalkyl dehydroazepanes
via catalytic enantioselective borylative migration of an enol nonaflate.
Tetrahedron Lett. 59, 4334–4339 (2018).
48. Clement, H. A., Estaitie, M., Kim, Y.-R., Hall, D. G. & Legault, C. Y.
Mechanism of the palladium-catalyzed asymmetric borylative migration of
enol perfluorosulfonates: insights into an enantiofacial-selective
transmetalation. ACS Catal. 11, 8902–8914 (2021).
49. Larionov, E., Lin, L., Guenee, L. & Mazet, C. Scope and mechanism in
palladium-catalyzed isomerizations of highly substituted allylic, homoallylic,
and alkenyl alcohols. J. Am. Chem. Soc. 136, 16882–16894 (2014).
50. Ida, A., Hoshiya, N. & Uenishi, J. Alkene migration to the end-terminal
carbon bearing a phenyl group over a chiral siloxy carbon center in Heck
reaction. Tetrahedron 71, 6442–6448 (2015).
51. Chen, X., Cheng, Z., Guo, J. & Lu, Z. Asymmetric remote CH borylation of
internal alkenes via alkene isomerization. Nat. Commun. 9, 3939 (2018).
Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth
Review Article
52. Kochi, T., Kanno, S. & Kakiuchi, F. Nondissociative chain walking as a
strategy in catalytic organic synthesis. Tetrahedron Lett. 60, 150938 (2019).
53. Li, J., Qu, S. & Zhao, W. Rhodium-catalyzed remote C(sp3)−H borylation of
silyl enol ethers. Angew. Chem. Int. Ed. 59, 2360–2364 (2020).
54. Cohen, Y., Cohen, A. & Marek, I. Creating stereocenters within acyclic systems
by C–C bond cleavage of cyclopropanes. Chem. Rev. 121, 140–161 (2020).
55. Masarwa, A. et al. Merging allylic carbon–hydrogen and selective carbon–
carbon bond activation. Nature 505, 199–203 (2014).
56. Bruffaerts, J. et al. Zirconocene-mediated selective C–C bond cleavage
of strained carbocycles: scope and mechanism. J. Org. Chem. 83,
3497–3515 (2018).
57. Singh, S., Bruffaerts, J., Vasseur, A. & Marek, I. A unique Pd-catalysed
Heck arylation as a remote trigger for cyclopropane selective ring-opening.
Nat. Commun. 8, 14200 (2017).
58. Kou, X., Shao, Q., Ye, C., Yang, G. & Zhang, W. Asymmetric aza-Wacker-type
cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins: synthesis of
pyrazolines bearing one quaternary or two vicinal stereocenters. J. Am. Chem.
Soc. 140, 7587–7597 (2018).
59. Bruffaerts, J., Pierrot, D. & Marek, I. Efficient and stereodivergent synthesis
of unsaturated acyclic fragments bearing contiguous stereogenic elements.
Nat. Chem. 10, 1164–1170 (2018).
60. Cohen, A., Chagneau, J. & Marek, I. Stereoselective preparation of distant
stereocenters (1,5) within acyclic molecules. ACS Catal. 10, 7154–7161 (2020).
61. Jiang, X. et al. Nickel-catalysed migratory hydroalkynylation and
enantioselective hydroalkynylation of olefins with bromoalkynes. Nat.
Commun. 12, 3972 (2021).
62. Yu, R., Rajasekar, S. & Fang, X. Enantioselective nickel‐catalyzed migratory
hydrocyanation of nonconjugated dienes. Angew. Chem. Int. Ed. 59,
21436–21441 (2020).
63. Larock, R. C., Wang, Y., Lu, Y. & Russell, C. A. Synthesis of aryl-substituted
allylic amines via palladium-catalyzed coupling of aryl iodides, nonconjugated
dienes, and amines. J. Org. Chem. 59, 8107–8114 (1994).
64. Zhu, D. et al. Asymmetric three-component Heck arylation/amination of
nonconjugated cyclodienes. Angew. Chem. Int. Ed. 59, 5341–5345 (2020).
65. Liu, C., Yuan, J., Zhang, Z., Gridnev, I. D. & Zhang, W. Asymmetric
hydroacylation involving alkene isomerization for the construction of
C3-chirogenic center. Angew. Chem. Int. Ed. 60, 8997–9002 (2021).
66. Park, J. W., Kou, K. G. M., Kim, D. K. & Dong, V. M. Rh-catalyzed
desymmetrization of α-quaternary centers by isomerization–hydroacylation.
Chem. Sci. 6, 4479–4483 (2015).
67. Ebe, Y., Onoda, M., Nishimura, T. & Yorimitsu, H. Iridium-catalyzed
regio- and enantioselective hydroarylation of alkenyl ethers by olefin
isomerization. Angew. Chem. Int. Ed. 56, 5607–5611 (2017).
68. Ebe, Y. & Nishimura, T. Iridium-catalyzed branch-selective hydroarylation
of vinyl ethers via C–H bond activation. J. Am. Chem. Soc. 137,
5899–5902 (2015).
69. Kochi, T., Hamasaki, T., Aoyama, Y., Kawasaki, J. & Kakiuchi, F. Chain-
walking strategy for organic synthesis: catalytic cycloisomerization of
1,n-dienes. J. Am. Chem. Soc. 134, 16544–16547 (2012).
70. Hamasaki, T., Aoyama, Y., Kawasaki, J., Kakiuchi, F. & Kochi, T. Chain
walking as a strategy for carbon–carbon bond formation at unreactive sites in
organic synthesis: catalytic cycloisomerization of various 1, n-dienes. J. Am.
Chem. Soc. 137, 16163–16171 (2015).
71. Kochi, T., Ichinose, K., Shigekane, M., Hamasaki, T. & Kakiuchi, F.
Metal-catalyzed sequential formation of distant bonds in organic molecules:
palladium-catalyzed hydrosilylation/cyclization of 1,n-dienes by chain
walking. Angew. Chem. Int. Ed. 58, 5261–5265 (2019).
72. Lin, W., Zhang, K.-F. & Baudoin, O. Regiodivergent enantioselective C–H
functionalization of Boc-1, 3-oxazinanes for the synthesis of β2- and β3-amino
acids. Nat. Catal. 2, 882–888 (2019).
73. Royal, T. & Baudoin, O. Pd-catalyzed γ-arylation of γ,δ-unsaturated
O-carbamates via an unusual haptotropic rearrangement. Chem. Sci. 10,
2331–2335 (2019).
74. Miura, T., Nishida, Y., Morimoto, M. & Murakami, M. Enantioselective
synthesis of anti homoallylic alcohols from terminal alkynes and aldehydes
based on concomitant use of a cationic iridium complex and a chiral
phosphoric acid. J. Am. Chem. Soc. 135, 11497–11500 (2013).
75. Miura, T., Oku, N. & Murakami, M. Diastereo- and enantioselective synthesis
of (E)-δ-boryl-substituted anti-homoallylic alcohols in two steps from
terminal alkynes. Angew. Chem. Int. Ed. 58, 14620–14624 (2019).
76. Miura, T., Nishida, Y. & Murakami, M. Construction of homoallylic alcohols
from terminal alkynes and aldehydes with installation of syn-stereochemistry.
J. Am. Chem. Soc. 136, 6223–6226 (2014).
77. Miura, T. et al. Enantioselective synthesis of anti-1,2-oxaborinan-3-enes from
aldehydes and 1,1-di(boryl)alk-3-enes using ruthenium and chiral phosphoric
acid catalysts. J. Am. Chem. Soc. 139, 10903–10908 (2017).
78. Miura, T., Nakahashi, J. & Murakami, M. Enantioselective synthesis of
(E)‐δ‐boryl‐substituted anti homoallylic alcohols using palladium and a chiral
phosphoric acid. Angew. Chem. Int. Ed. 56, 6989–6993 (2017).
47
Review Article
79. Weber, F., Ballmann, M., Kohlmeyer, C. & Hilt, G. Nickel-catalyzed double
bond transposition of alkenyl boronates for in situ syn-selective allylboration
reactions. Org. Lett. 18, 548–551 (2016).
80. Weber, F. et al. Double-bond isomerization: highly reactive nickel catalyst
applied in the synthesis of the pheromone (9Z,12Z)-tetradeca-9,12-dienyl
acetate. Org. Lett. 17, 2952–2955 (2015).
81. Lin, L., Yamamoto, K., Matsunaga, S. & Kanai, M. Rhodium-catalyzed
cross-aldol reaction: in situ aldehyde–enolate formation from allyloxyboranes
and primary allylic alcohols. Angew. Chem. Int. Ed. 51, 10275–10279 (2012).
82. Lin, L. et al. Catalytic asymmetric iterative/domino aldehyde cross-aldol
reactions for the rapid and flexible synthesis of 1,3-polyols. J. Am. Chem. Soc.
137, 15418–15421 (2015).
83. Baudry, D., Ephritikhine, M. & Felkin, H. Isomerisation of allyl ethers
catalysed by the cationic iridium complex [Ir(cyclo-octa-1,5-diene)
(PMePh2)2]PF6. A highly stereoselective route to trans-propenyl ethers. J.
Chem. Soc. Chem. Commun. 1978, 694–695 (1978).
84. Oltvort, J. J., Van Boeckel, C. A. A., De Koning, J. H. & Van Bloom, J. H. Use
of the cationic iridium complex 1,5-cyclooctadiene-
bis[methyldiphenylphosphine]-iridium hexafluorophosphate in carbohydrate
chemistry: smooth isomerization of allyl ethers to 1-propenyl ethers. Synthesis
1981(305), 308 (1981).
85. Moriya, T., Suzuki, A. & Miyaura, N. A stereoselective preparation of
γ-alkoxyallylboronates via catalytic isomerization of pinacol [(E)-3-alkoxy-1-
propenyl] boronates. Tetrahedron Lett. 36, 1887–1888 (1995).
86. Massad, I., Sommer, H. & Marek, I. Stereoselective access to fully substituted
aldehyde-derived silyl enol ethers by iridium-catalyzed alkene isomerization.
Angew. Chem. Int. Ed. 59, 15549–15553 (2020).
87. Wang, P. Y., Massad, I. & Marek, I. Stereoselective Sc(OTf)3-catalyzed aldol
reactions of disubstituted silyl enol ethers of aldehydes with acetals. Angew.
Chem. Int. Ed. 60, 12765–12769 (2021).
88. Nelson, S. G., Bungard, C. J. & Wang, K. Catalyzed olefin isomerization
leading to highly stereoselective Claisen rearrangements of aliphatic allyl
vinyl ethers. J. Am. Chem. Soc. 125, 13000–13001 (2003).
89. Stevens, B. D., Bungard, C. J. & Nelson, S. G. Strategies for expanding
structural diversity available from olefin isomerization−Claisen
rearrangement reactions. J. Org. Chem. 71, 6397–6402 (2006).
90. Wang, K., Bungard, C. J. & Nelson, S. G. Stereoselective olefin isomerization
leading to asymmetric quaternary carbon construction. Org. Lett. 9,
2325–2328 (2007).
91. Kerrigan, N. J., Bungard, C. J. & Nelson, S. G. Pd(II)-catalyzed aliphatic
Claisen rearrangements of acyclic allyl vinyl ethers. Tetrahedron 64,
6863–6869 (2008).
48
NATure SynThesis
92. Massad, I. & Marek, I. Alkene isomerization revitalizes the Coates–Claisen
rearrangement. Angew. Chem. Int. Ed. 60, 18509–18513 (2021).
93. Coates, R. M., Shah, S. K. & Mason, R. W. Stereoselective total synthesis of
(+/–)-gymnomitrol via reduction–alkylation of α-cyano ketones. J. Am.
Chem. Soc. 104, 2198–2208 (1982).
94. Coates, R. M. & Hobbs, S. J. α-Alkoxyallylation of activated carbonyl
compounds. A novel variant of the Michael reaction. J. Org. Chem. 49,
140–152 (1984).
95. Coates, R. M., Rogers, B. D., Hobbs, S. J., Peck, D. R. & Curran, D. P.
Synthesis and Claisen rearrangement of alkoxyallyl enol ethers. Evidence for a
dipolar transition state. J. Am. Chem. Soc. 109, 1160–1170 (1987).
96. Sommer, H., Weissbrod, T. & Marek, I. A tandem iridium-catalyzed
‘chain-walking’/Cope rearrangement sequence. ACS Catal. 9,
2400–2406 (2019).
97. Suresh, R., Massad, I. & Marek, I. Stereoselective tandem iridium-catalyzed
alkene isomerization–Cope rearrangement of ω-diene epoxides: efficient
access to acyclic 1,6-dicarbonyl compounds. Chem. Sci. 12, 9328–9332 (2021).
Acknowledgements
This project has received funding from the European Union’s Horizon 2020 research and
innovation program under grant agreement no. 786976.
Author contributions
I. Massad, R.S., L.S. and I. Marek conceived and wrote the manuscript. All the authors
contributed to discussions.
Competing interests
The authors declare no competing interests.
Additional information
Correspondence should be addressed to Ilan Marek.
Peer review information Nature Synthesis thanks Guangbin Dong, Wanbin Zhang and
the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Alison Stoddart managed the editorial process and peer review in collaboration with the
rest of the editorial team.
Reprints and permissions information is available at www.nature.com/reprints.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
© The Author(s), under exclusive licence to Springer Nature Limited 2022
Nature Synthesis | VOL 1 | January 2022 | 37–48 | www.nature.com/natsynth