Tandem Iridium Catalysis as a General Strategy for Atroposelective Construction of Axially Chiral Styrenes

Article abstract of DOI:10.1021/jacs.1c04400

Axially chiral styrenes are of great interest since they may serve as a class of novel chiral ligands in asymmetric synthesis. However, only recently have strategies been developed for their enantioselective preparation. Thus, the development of novel and efficient methodologies is highly desirable. Herein, we reported the first tandem iridium catalysis as a general strategy for the synthesis of axially chiral styrenes enabled by Asymmetric Allylic Substitution-Isomerization (AASI) using cinnamyl carbonate analogues as electrophiles and naphthols as nucleophiles. In this approach, axially chiral styrenes were generated through two independent iridium-catalytic cycles: iridium-catalyzed asymmetric allylic substitution and in situ isomerization via stereospecific 1,3-hydride transfer catalyzed by the same iridium catalyst. Both experimental and computational studies demonstrated that the isomerization proceeded by iridium-catalyzed benzylic C-H bond oxidative addition, followed by terminal C-H reductive elimination. Amid the central-to-axial chirality transfer, the hydroxyl of naphthol plays a crucial role in ensuring the stereospecificity by coordinating with the Ir(I) center. The process accommodated broad functional group compatibility. The products were generated in excellent yields with excellent to high enantioselectivities, which could be transformed to various axially chiral molecules.

Full text of DOI:10.1021/jacs.1c04400

pubs.acs.org/JACS
Article
Tandem Iridium Catalysis as a General Strategy for Atroposelective
Construction of Axially Chiral Styrenes
Jie Wang, Xiaotian Qi, Xiao-Long Min, Wenbin Yi,* Peng Liu,* and Ying He*
Cite This: J. Am. Chem. Soc. 2021, 143, 10686−10694
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Axially chiral styrenes are of great interest since they
may serve as a class of novel chiral ligands in asymmetric synthesis.
However, only recently have strategies been developed for their
enantioselective preparation. Thus, the development of novel and
efficient methodologies is highly desirable. Herein, we reported the
first tandem iridium catalysis as a general strategy for the synthesis
of axially chiral styrenes enabled by Asymmetric Allylic Substitution-
Isomerization (AASI) using cinnamyl carbonate analogues as
electrophiles and naphthols as nucleophiles. In this approach,
axially chiral styrenes were generated through two independent
iridium-catalytic cycles: iridium-catalyzed asymmetric allylic substitution and in situ isomerization via stereospecific 1,3-hydride
transfer catalyzed by the same iridium catalyst. Both experimental and computational studies demonstrated that the isomerization
proceeded by iridium-catalyzed benzylic C−H bond oxidative addition, followed by terminal C−H reductive elimination. Amid the
central-to-axial chirality transfer, the hydroxyl of naphthol plays a crucial role in ensuring the stereospecificity by coordinating with
the Ir(I) center. The process accommodated broad functional group compatibility. The products were generated in excellent yields
with excellent to high enantioselectivities, which could be transformed to various axially chiral molecules.
or acylation at sites proximal to the C−C axes (Scheme 1A,
bottom).6 While these methods have offered elegant and
innovative routes to axially chiral styrenes, a vast majority of
them require specialized substrates whose syntheses need
multistep synthetic procedures, thus hampering the develop-
ment of this important class of molecules. A versatile method
for the catalytic synthesis of axially chiral styrenes still needs to
be addressed.
Recently, our group developed an asymmetric allylic
substitution-isomerization (AASI) strategy for the synthesis of
axially chiral enamides (Scheme 1B).7 In our mechanistic
proposal, enantioenriched product I was formed via the
iridium-catalyzed asymmetric allylic substitution,8 followed by
base-promoted in situ isomerization to axially chiral products II
via central-to-axial chirality transfer (Scheme 1C, left).9 In this
context, 1,3-proton (H+) transfer occurs via a stepwise
deprotonation/reprotonation pathway through a chiral ion-
pair intermediate. Meanwhile, the hydrogen-bonding inter-
actions between the proton and enamide carbonyl played a
significant role in promoting both the reactivity and the
1. INTRODUCTION
New strategies toward the construction of axially chiral
compounds have been targeted in recent years due to their
widespread appearance in natural products, biologically active
compounds, and useful chiral ligands in asymmetric catalysis.1
However, synthetic studies of axially chiral compounds beyond
biaryl and heterobiaryl derivatives have been sparse. Axially
chiral styrenes are one family of chiral compounds whose
synthesis represents a major synthetic challenge due to their
relatively low configurational stability.2 In this context, the
pioneering work of catalytic enantioselective construction of
axially chiral arylcyclohexenes was reported by the Gu and
Smith groups.3 These kinds of styrene atropisomers have
similar skeletons to biaryls, which enabled them high rotational
barriers around the C−C axes.
However, the enantioselective preparation of axially chiral
styrenes with an acyclic alkene is more challenging. Such
synthetic methodologies have been realized very recently, and
a significant process is achieved in this realm. One of the most
widely used methods for preparing axially chiral styrenes is
atroposelective organocatalysis. Key to this transformation was
the generation of activated chiral allene intermediates, which
are trapped by various nucleophiles, affording axially chiral
styrenes (Scheme 1A, top).4 The other reliable method is
asymmetric C−H functionalization of pro-axially chiral
styrenes by using palladium as catalysts and amino acid
derivatives as ligands (Scheme 1A, middle).5 A complementary
approach to these methods is the stereoselective N-alkylation
Received: April 28, 2021
Published: July 6, 2021
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694
© 2021 American Chemical Society
10686

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Scheme 1. Strategies for the Synthesis of Axially Chiral Styrenes with an Open-Chain Alkene
stereospecificity of the stepwise 1,3-proton transfer. Despite
this achievement, this transformation would be challenging if
the allylic compound I possesses a less acidic allylic C−H bond
due to low reactivity in the base-promoted 1,3-proton transfer.
As an alternative strategy for the central-to-axial chirality
transfer, transition-metal (TM)-catalyzed olefin isomerization
is an exceptional technique for the construction of 1-propen-1-
yl units.10 However, TM-catalyzed C(sp3)−H bond oxidative
cleavage for stereospecific 1,3-hydride (H−) transfer remains
largely unexplored so far. In our effort to develop the AASI
strategy, we recognized that merging a transition-metal-
catalyzed allylic substitution and catalytic olefin isomer-
ization,10d10m might be an efficient approach for accessing
axially chiral styrenes (Scheme 1C, right). Furthermore, it
would be highly desirable that this cascade reaction process
could be catalyzed by an identical TM complex in one pot. We
hypothesized that this catalytic 1,3-hydride transfer can
potentially give higher stereospecificity in the central-to-axial
chirality transfer step.11 If successful, it would represent a
versatile method for the construction of axially chiral styrenes
using easily accessible aryl allylic carbonates and naphthols.
Although naphthols have been used as nucleophiles in
asymmetric allylic substitution, they usually proceeded with
dearomatization12a−d and allylic alkylation.12e The direct
asymmetric vinylation of naphthols to atropisomers is yet to
be explored. To this end, we herein demonstrate an iridium-
catalyzed Asymmetric Allylic Substitution-Isomerization (AASI)
as a general method for the synthesis of axially chiral styrenes
(Scheme 1D).
prepared by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) accord-
ing to the literature.13 The experiment was performed in an
argon-filled glovebox. [Ir(cod)Cl]2 (2.1 mg, 3 mol %), ligand
(6 mol %), and TBD (2.1 mg, 15 mol %) were added to a vial
equipped with a magnetic stirring bar. The vial was then
charged with solvent (0.5 mL) and stirred at 25 °C for 30 min,
generating an orange solution. The iridacycle catalyst
containing the solvent was used directly for the catalysis
system (taking L1, for example, see eq “a”) (see the SI for
details).
Optimization. We initially carried out the reaction of
cinnamyl carbonates 1a and 8-bromonaphthalen-2-ol 2a in the
presence of the in situ generated iridacycle catalyst (Table 1).
In order to ensure the configurational stability of the products,
introducing p-toluenesulfonyl chloride onto the naphthyl
backbone was conducted in one pot after the AASI process.
As expected, axially chiral styrenes 3a was isolated in Z-
selectivity with 92% ee in the presence of 3 mol %
[Ir(cod)Cl]2, 6 mol % L1, and 3.0 equiv of DBU in THF at
35 °C, albeit with a moderate yield of 61% (entry 1). The use
of L2−L5 gave us trace amounts of products (entries 2−5).
The reaction with L6 gave 3a in 90% ee, but the yield was
much lower (entry 6). Reactions conducted with other bases
afforded 3a in either lower yield or lower ee (entries 7−10).
Examination of solvents revealed that reactions carried out in
dioxane or toluene afforded 3a in good yields and slightly
2. RESULTS AND DISCUSSIONS
2.1. Reaction Development and Optimizations.
Catalyst Preparation. The iridacycle catalyst was in situ
10687
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
a
Table 1. Optimized Conditions
Table 2. Substrate Scope of Allylic Carbonates
a
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), [Ir(cod)Cl]2 (3
mol %), L1 (6 mol %), TBD (15 mol %), DBU (3.0 equiv), toluene
(1.0 mL); then TsCl (3.0 equiv), 1.0 h. Isolated yield. ee determined
by chiral HPLC. Unless noted, products were obtained with more
b
than 19:1 of Z/E. 3g was isolated without Ts protection.
Difunctionalized cinnamyl carbonate 1l was compatible with
the reaction, generating 3l in 92% ee and 68% yield.
The fused rings of the R group in 1 were also
accommodated, affording 3m and 3n in 96% and 93% ee,
respectively. The examination of heteroarenes disclosed wide
compatibility, for example, thienyl (1o), furyl (1p), and
protected indolyl (1q) reacted smoothly, providing the
corresponding products in 92% ee with 72−84% yields.
With respect to the β-naphthol scope, various substituted
naphthols were investigated to showcase the generality of the
reaction (Table 3). Replacement of −Br in 2 with other halo
groups such as −Cl and −I resulted in both high
enantioselectivities (94% ee) with 62% and 56% yield,
respectively (3r and 3s). Removal of the substituent at the
8-position was proved to have dramatic effects on the
enantioselectivities of the reaction. Under optimized con-
ditions, axially chiral styrenes 3t−3x were effectively generated
in 78−89% ee with 72−81% yield. The reaction of
disubstituted β-naphthol provided the corresponding product
3y in 85% ee and 72% yield. The slight lower ee’s of 3t−3y
may be attributed to their racemization because of the lower
conformational stability prior to the −tosyl protection. It is
noteworthy that phenanthren-3-ol was also tolerated under the
reaction conditions, affording 3z in 92% ee, albeit with a
moderate yield of 52%.
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), [Ir(cod)Cl]2 (3
mol %), ligand (6 mol %), TBD (15 mol %), DBU (3.0 equiv),
toluene (1.0 mL); then TsCl (3.0 equiv), 1.0 h. Isolated yield. ee
determined by chiral HPLC. Changing amount of 2a from 0.1 to
0.15 mmol; reaction temperature from 35 to 33 °C.
b
c
d
lower ee (entries 11 and 12). Other leaving groups such as
−Cl, −OBz, −OBoc, and −OPO(OEt)2 had a detrimental
impact on reactivity (entries 13−16). A final round of
optimization enabled us to substantially increase the
stoichiometry in 2a and precisely control the temperature to
33 °C, gratefully, generating 3a in 84% yield and 95% ee (entry
17).
Substrate Scope. With the optimized conditions in hand,
we then studied the substrate scope of the reaction with
respect to allylic carbonates (Table 2). Aryl allylic carbonates
bearing both electron-rich and electron-poor groups at the
para position were well tolerated, affording 3b−3g in moderate
to good yields (42−86%) with high enantioselectivities (90−
95% ee). The absolute configuration of 3f was determined by
single-crystal X-ray crystallographic analysis, and others were
assigned by analogy to 3f. Substrates with meta substituents
such as −Me, −MeO, −Cl, and −F all proceeded well,
generating 3h−3k in 58−88% yield and 92−99% ee.
It is obvious that β-naphthols bearing 8-substituents are
crucial for generating axially chiral styrenes with high
enantioselectivities. After a slight adjustment of the reaction
temperature, a broad range of 8-substituted β-naphthols
proceeded smoothly with good results (Table 4). When 8-
Me substituted β-naphthol was employed, 3a′ was afforded in
a high ee of 95% with 76% yield. Notably, N-substituted β-
naphthols at the 8-position were compatible with reaction
conditions, giving the corresponding products in 93% and 90%
10688
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
ee, respectively (3b′ and 3c′). The reaction was efficient
regardless of the aromatic substitution explored, providing the
products in 92−95% ee (3d′−3g′). Other functionalizable
groups such as 8-alkene or 8-alkyne units underwent AASI
efficiently, resulting in the desired products in 94% and 99%
ee, respectively (3h′ and 3i′). It is worthwhile to mention that
complex substrates derived from L-menthol and vitamin E
could also be used in the reaction, yielding the products 3j′
and 3k′ in beyond 20/1 dr with 46% and 37% yield,
respectively.
Table 3. Substrate Scope of β-Naphthols
Having established the AASI of β-naphthols, we hypothe-
sized that 3-substituted α-naphthols may also be suitable as
nucleophiles for preparation of axially chiral styrenes. If the
reaction works, it would represent a rare example for accessing
axially chiral molecules by using α-naphthols as substrates
(Table 5). To our delight, using cinnamyl carbonates 1a and
a
Table 5. Substrate Scope of 3-Substituted α-Naphthols
a
Reaction conditions: 1f (0.1 mmol), 2 (0.15 mmol), [Ir(cod)Cl]2 (3
mol %), L1 (6 mol %), TBD (15 mol %), DBU (3.0 equiv), toluene
(1.0 mL); then TsCl (3.0 equiv), 1.0 h. Isolated yield. ee determined
by chiral HPLC. Unless noted, products were obtained with more
b
than 19:1 of Z/E. 3z was isolated without Ts protection.
a
Table 4. Substrate Scope of 8-Substituted β-Naphthols
a
Reaction conditions: 1 (0.1 mmol), 4 (0.15 mmol), [Ir(cod)Cl]2 (3
mol %), L1 (6 mol %), TBD (15 mol %), DBU (3.0 equiv), toluene
(1.0 mL). Isolated yield. ee determined by chiral HPLC. Unless
b
noted, products were obtained with more than 19:1 of Z/E. 5b was
isolated with Ts protection.
3,4-dimethylnaphthalen-1-ol 4a as substrates, conditions
similar to the optimized protocol, afforded 5a in 85% ee
with 75% yield. Several representative allylic carbonates were
examined, generating products in 85−92% ee with 55−81%
yield (5b−5g). The removal of the methyl group at the 4-
position in α-naphthols was also tested. As a result, 5h was
obtained in 84% ee and 62% yield with high regioselectivity of
vinylation in the 2-position rather than the 4-position.
2.2. Racemization Experiment. The configurational
stability of axially chiral styrenes was one of the key factors
for their utility. No diminished ee’s of 3 were observed after
storing in a freezer for a couple of months. Next, we selected
representative examples and conducted the racemization
a
Reaction conditions: 1f (0.1 mmol), 2 (0.15 mmol), [Ir(cod)Cl]2 (3
mol %), L1 (6 mol %), TBD (15 mol %), DBU (3.0 equiv), toluene
(1.0 mL). Isolated yield. ee determined by chiral HPLC. Unless
b
noted, products were obtained with more than 19:1 of Z/E. 3a′ was
isolated with Ts protection.
10689
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
experiments in toluene at 50 °C. As shown in Figure 1,
comparison of the half-lives (6 vs 7) indicated that the non-8-
Scheme 2. Derivatization of the Products
a
See the Supporting Information for details. Py = pyridine.
acetyl, or TBS were used for the reaction, but no vinylation
products were obtained and the starting materials recovered
(Scheme 3A, eq 1). This result indicated that the −OH group
Figure 1. Racemization experiments. Measured at 50 °C in toluene;
ee determined by chiral HPLC. See the Supporting Information (SI)
for details.
Scheme 3. Control Experiments and Deuterium Labeling
Experiments
substituted axially chiral styrene 6 has a lower configurational
stability than the 8-substituted compound 7 (53.5 vs 138.38
h). This may be attributed to the fact that 8-substituted axially
chiral styrene possesses a bigger steric hindrance that restricted
the rotation about the C−C axes (red arrow in molecules).
The importance of the steric hindrance on configurational
stability was further demonstrated by comparing the half-lives
of 7 and 3a, in which the half-life of 3a was 2444.15 h. These
experiments suggested that the use of bulky naphthols as
substrates was one of the essential criteria for the construction
of high enantioselective axially chiral styrenes in AASI. When
non-8-substituted β-naphthols were used for the reaction, the
protection of the hydroxyl group is necessary to maintain the
high enantioselectivities of axially chiral styrenes.
2.3. Derivatization of the Products. The synthetic utility
of AASI was then demonstrated by conducting a series of
derivatizations (Scheme 2). First, we performed the reaction in
a 1.0 mmol scale, from which 3f was obtained in 72% yield
with 94% ee. According to the “standard conditions” in Table
4, compound 8 was readily isolated in 95% ee that can be easily
transformed to 9 in 94% ee with 82% yield. Using 9 as a
substrate, the cross-coupling with methyl Grignard reagent by
palladium catalysis afforded 10 in 76% yield while maintaining
the ee of 93%. In addition, deprotection of 11 (derived from
3b′) delivered 12 in 82% yield with preservation of the initial
ee of 91%. The free amino group in 12 could be further
transformed to 13 via a two-step reaction in 62% yield with
10:1 dr. The sulfonamide 14 could also be efficiently generated
in 78% yield with >20:1 dr. The facile synthesis of compounds
13 and 14 may provide a new type of axially chiral catalyst or
ligand for asymmetric synthetic chemistry.
in 2 was crucial for the reaction. We next examined the
reactivity of naphthalen-2-amine analogues for AASI. Still,
there were no desired products obtained, and the allylic
amination at the N site was observed in some cases (Scheme
3A, eq 2). To further understand the isomerization for the
central-to-axial chirality transfer, several control experiments
and deuterium labeling experiments were conducted. First,
compound 15 was prepared in 70% ee via rhodium-catalyzed
2.4. Mechanistic Studies. In order to explore the
limitation to the strategy, a series of experiments were carried
out. First, β-naphthols with protecting groups such as methyl,
10690
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
asymmetric allylic arylation.12e Surprisingly, by using DBU or
TBD as the catalyst, only a trace amount of 16 was obtained
for the isomerization of 15 in the absence of Ir catalyst (eq 3).
This result indicated that the base-catalyzed 1,3-proton transfer
is not involved in the isomerization process.
with the naphthol OH group, this process still requires a
relatively high activation free energy of 24.0 kcal/mol.
Subsequent protonation of the terminal allylic carbon in 19
takes place through TS-2, leading to the (P)-enantiomer of the
axially chiral styrene product (P)-20. On the other hand, a
more stable conformer of (R)-18 could be located as 18a
through rotation around the C−C axes (via TS-3). The
analogous 1,3-proton transfer from 18a would lead to the (M)-
product (M)-20. However, the deprotonation of 18a via TS-1a
requires a higher activation free energy than TS-1 due to the
steric repulsion between the bromine atom and the DBU.
Computational results of the 1,3-proton transfer pathway show
that the rate-determining step is the benzylic C−H
deprotonation and the formation of (P)-20 is more favorable
from (R)-18. These results are consistent with the
experimentally observed chirality of the product. Moreover,
computational studies indicate that the racemization of (P)-20
to form (M)-20 is less likely because of a high energy barrier of
28.9 kcal/mol (via TS-4), which is consistent with the
experimentally observed activation free energy of racemization
of compound 7 (Figure 1).
Interestingly, further control experiments showed that the
isomerization proceeded smoothly under iridium catalysis
which afforded axially chiral styrene 16 with full conversion
(eq 4). The reaction was even faster if the iridium-catalyzed
isomerization was performed under basic conditions (eq 4).
More importantly, product 16 could be readily isolated beyond
90% yield in all cases with 67−69% ee (95−98% es).14 These
results indicated that the iridium-catalyzed stereospecific 1,3-
hydride transfer may be involved for central-to-axial chirality
transfer. In order to gain more mechanistic insights, a
deuterium labeling experiment was then carried out. Using
substrate 1a-D labeling with deuterium next to the aryl ring led
to product 17 with ∼80% D incorporation at the methyl group
(Scheme 3, B). The incomplete D migration in the course of
the transformation was attributed to H/D exchange of iridium
hydride with solvent or water during the reaction process.15
The high level central-to-axial chirality transfer maybe
attributed to the coordination between allylic iridium hydride
and the hydroxyl group which restricts the rotation of the
reaction intermediate via chiral C−C axes during the chiral
transfer process.
Next, we considered the iridium(I)-catalyzed stereospecific
1,3-hydride transfer pathway, which involves benzylic C−H
oxidative addition to iridium(I) and C−H reductive
elimination (Figure 3).16 Because experimentally, the 1,3-H
In order to gain more mechanistic insights into the central-
to-axial chirality transfer process, density functional theory
(DFT) calculations were performed to investigate whether the
1,3-H transfer process is catalyzed by the base (DBU) or the
iridium catalyst. As shown in Figure 2, from the allylation
product (R)-18, the DBU-catalyzed benzylic C−H deproto-
nation occurs through transition state TS-1. Although being
assisted by the intramolecular hydrogen-bonding interaction7
Figure 3. Free energy profile of the iridium(I)-catalyzed 1,3-hydride
transfer pathway for central-to-axial chirality transfer. All energies
were calculated at the M06-2X/6-311++G(d,p)−SDD/SMD-
(toluene)//M06-2X/6-31G(d)−LANL2DZ level of theory.
transfer was observed using either [Ir(cod)Cl]2 catalyst or the
iridacycle catalyst generated from [Ir(cod)Cl]2, L1, and TBD
(see Figure S6 of the Supporting Information for details), we
used [Ir(cod)Cl]2 in the DFT calculations for simplicity. First,
complex 21 was generated through the coordination of the
allylation product (R)-18 to the iridium catalyst. From 21, the
iridium(I)-promoted deprotonation of naphthol with DBU
leads to a naphthoxide iridium(I) intermediate 23, which is 4.5
kcal/mol more stable than the naphthol complex 21. The
following benzylic C−H oxidative addition (via TS-6) and the
C−H reductive elimination (via TS-7) then take place to
accomplish the central-to-axial chirality transfer to form the
Figure 2. Free energy profile of the DBU-catalyzed 1,3-proton
transfer pathway for central-to-axial chirality transfer. All energies
were calculated at the M06-2X/6-311++G(d,p)/SMD(toluene)//
M06-2X/6-31G(d) level of theory.
10691
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(P)-enantiomer of the styrene (26). The overall activation free
energy of this pathway is 22.7 kcal/mol, which is 1.3 kcal/mol
lower than that of the DBU-promoted 1,3-proton transfer
pathway. Therefore, our computational results suggested that
the central-to-axial chirality transfer is achieved through the
iridium(I)-catalyzed 1,3-hydride transfer mechanism, instead
of the 1,3-proton transfer mechanism. The benzylic C−H
oxidative addition transition state (TS-6a) leading to the (M)-
product [(M)-20] has a much higher activation free energy
due to the lack of naphthoxide O-coordination to the Ir. The
hydroxyl of naphthol plays a crucial role in ensuring the
stereospecificity because the deprotonated naphthoxide can
coordinate with the iridium(I) catalyst in the pathway leading
to the favored (P)-product, which prevents the rotation around
the C−C axes.
studies of the isomerization process indicated that the
stereospecific 1,3-hydride transfer takes place via iridium-
catalyzed benzylic C−H oxidative addition and C−H reductive
elimination. The hydroxyl of naphthol is critical for the
stereospecificity during the central-to-axial chirality transfer
because the coordination of the deprotonated hydroxyl with
Ir(I) prevents rotation about the C−C axes. We expect that the
AASI strategy by iridium catalysis would open a broader
avenue for efficient access to various types of axially chiral
molecules efficiently.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04400.
■
sı
On the basis of the experimental and DFT results, a
proposed mechanism for AASI is outlined which contained two
independent iridium-catalytic cycles (Scheme 4). In catalytic
Materials and methods; experimental procedures;
optimization studies; characterization data; 1H, 13C,
and 19F NMR; HPLC spectra; and mass spectrometry
data of new compounds (PDF)
Scheme 4. Proposed Catalytic Cycle of the Ir-Catalyzed
Asymmetric Allylic Substitution-Isomerization for the
Formation of Axially Chiral Styrenes
Accession Codes
CCDC 2039913 and 2039920 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Ying He − School of Chemistry and Chemical Engineering,
Nanjing University of Science & Technology, Nanjing
210094, China; orcid.org/0000-0001-9159-4606;
Email: yhe@njust.edu.cn
Wenbin Yi − School of Chemistry and Chemical Engineering,
Nanjing University of Science & Technology, Nanjing
210094, China; orcid.org/0000-0003-4606-7668;
Email: yiwb@njust.edu.cn
Peng Liu − Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States; orcid.org/
0000-0002-8188-632X; Email: pengliu@pitt.edu
cycle 1, the classic iridium-catalyzed asymmetric allylic
substitution occurs via intermediates I and II, generating
compound III in high enantioselectivities. Catalytic cycle 2
then initiates through the coordination of naphthol of III to
the iridium catalyst. A base-facilitated deprotonation of
naphthol generates the chelating O-bound π-alkene iridium
complex IV. The following benzylic C−H oxidative addition
forms the iridium(III) hydride complex (V). Subsequently, the
C−H reductive elimination and protonation of VI lead to the
formation of product VII and regenerated the iridium
catalyst.9d It should be noted that the origin of stereoselectivity
of VII is attributed to the asymmetric allylic substitution step
since [Ir(cod)Cl]2 without ligand could also accomplish the
stereospecific 1,3-hydride transfer (see the SI for details).
Authors
Jie Wang − School of Chemistry and Chemical Engineering,
Nanjing University of Science & Technology, Nanjing
210094, China
Xiaotian Qi − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
orcid.org/0000-0001-5420-5958
Xiao-Long Min − School of Chemistry and Chemical
Engineering, Nanjing University of Science & Technology,
Nanjing 210094, China
3. CONCLUSIONS
In summary, we have developed the first example of tandem
iridium catalysis to control the enantioselectivity and stereo-
specificity of the chirality transfer step in an atroposelective
synthesis of axially chiral styrenes. This transformation was
facilitated by two independent iridium catalytic cycles of
asymmetric allylic substitution-isomerization (AASI) using
easily accessible allylic carbonates and naphthols as substrates.
The reaction tolerated a broad substrate scope for both 1-
naphthols and 2-naphthols, affording corresponding products
in excellent yields and enantioselectivities. The racemization
experiments exhibited the importance of the steric hindrance
of naphthols for the preservation of enantiopurities. DFT
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04400
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
Natural Science Foundation of Jiangsu Province (BK2018-
0447), the Fundamental Research Funds for the Central
Universities (30918011313, 30919011404), and the NSF
10692
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
2020, 6, 497. (b) Song, H.; Li, Y.; Yao, Q.-J.; Jin, L.; Liu, L.; Liu, Y.-
H.; Shi, B.-F. Synthesis of Axially Chiral Styrenes via Pd-Catalyzed
Asymmetric C-H Olefination Enabled by an Amino Amide Transient
Directing Group. Angew. Chem., Int. Ed. 2020, 59, 6576. (c) Yang, C.;
Wu, T.-R.; Li, Y.; Wu, B.-B.; Jin, R.-X.; Hu, D.-D.; Li, Y.-B.; Bian, K.-
J.; Wang, X.-S. Facile Synthesis of Axially Chiral Styrene-Type
Carboxylic Acids via Palladium-Catalyzed Asymmetric C−H
Activation. Chem. Sci. 2021, 12, 3726.
(CHE-1654122). DFT calculations were performed at the
Center for Research Computing at the University of
Pittsburgh, TACC Frontera, and the Extreme Science and
Engineering Discovery Environment (XSEDE). We especially
thank Prof. Yi-Ming Wang (University of Pittsburgh) for
helpful suggestions in the preparation of the manuscript.
(6) (a) Wang, Y.-B.; Wu, Q.-H.; Zhou, Z.-P.; Xiang, S.-H.; Cui, Y.;
Yu, P.; Tan, B. Asymmetric Construction of Axially Chiral 2-
Arylpyrroles by Chirality Transfer of Atropisomeric Alkenes. Angew.
Chem., Int. Ed. 2019, 58, 13443. (b) Ma, C.; Sheng, F.-T.; Wang, H.-
Q.; Deng, S.; Zhang, Y.-C.; Jiao, Y.-C.; Tan, W.; Shi, F.
Atroposelective Access to Oxindole-Based Axially Chiral Styrenes
via the Strategy of Catalytic Kinetic Resolution. J. Am. Chem. Soc.
2020, 142, 15686.
(7) Sun, C.; Qi, X.; Min, X.-L.; Bai, X.-D.; Liu, P.; He, Y.
Asymmetric Allylic Substitution-Isomerization to Axially Chiral
Enamides via Hydrogen-Bonding Assisted Central-to-Axial Chirality
Transfer. Chem. Sci. 2020, 11, 10119.
(8) For selected reviews on iridium-catalyzed asymmetric allylic
substitution, see: (a) Takeuchi, R.; Kezuka, S. Iridium-Catalyzed
Formation of Carbon-Carbon and Carbon-Heteroatom Bonds.
Synthesis 2006, 2006, 3349. (b) Hartwig, J. F.; Stanley, L. M.
Mechanistically Driven Development of Iridium Catalysts for
Asymmetric Allylic Substitution. Acc. Chem. Res. 2010, 43, 1461.
(c) Tosatti, P.; Nelson, A.; Marsden, S. P. Recent Advances and
Applications of Iridium-Catalysed Asymmetric Allylic Substitution.
Org. Biomol. Chem. 2012, 10, 3147. (d) Liu, X.-J.; Zheng, C.; Yang, Y.-
H.; Jin, S.; You, S.-L. Iridium-Catalyzed Asymmetric Allylic
Aromatization Reaction. Angew. Chem., Int. Ed. 2019, 58, 10493.
(e) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Iridium-Catalyzed
Diastereo-, Enantio-, and Regioselective Allylic Alkylation with
Prochiral Enolates. ACS Catal. 2016, 6, 6207. (f) Qu, J.; Helmchen,
G. Applications of Iridium-Catalyzed Asymmetric Allylic Substitution
Reactions in Target-Oriented Synthesis. Acc. Chem. Res. 2017, 50,
2539. (g) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.;
You, S.-L. Iridium-Catalyzed Asymmetric Allylic Substitution
Reactions. Chem. Rev. 2019, 119, 1855. (h) Rössler, S. L.; Petrone,
D. A.; Carreira, E. M. Iridium-Catalyzed Asymmetric Synthesis of
Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin)
Ligands. Acc. Chem. Res. 2019, 52, 2657.
REFERENCES
■
(1) (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Total
Synthesis of Chiral Biaryl Natural Products by Asymmetric Biaryl
Coupling. Chem. Soc. Rev. 2009, 38, 3193. (b) Bringmann, G.; Gulder,
T.; Gulder, T. A. M.; Breuning, M. Atroposelective Total Synthesis of
Axially Chiral Biaryl Natural Products. Chem. Rev. 2011, 111, 563.
(c) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F.
Recent Advances and New Concepts for The Synthesis of Axially
Stereoenriched Biaryls. Chem. Soc. Rev. 2015, 44, 3418. (d) Bring-
mann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Atroposelective Synthesis of Axially Chiral Biaryl
Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384. (e) Renzi, P.
Organocatalytic Synthesis of Axially Chiral Atropisomers. Org. Biomol.
Chem. 2017, 15, 4506. (f) Kumarasamy, E.; Raghunathan, R.; Sibi, M.
P.; Sivaguru, J. Nonbiaryl and Heterobiaryl Atropisomers: Molecular
Templates with Promise for Atropselective Chemical Transforma-
tions. Chem. Rev. 2015, 115, 11239. (g) Wang, Y.-B.; Tan, B.
Construction of Axially Chiral Compounds via Asymmetric Organo-
catalysis. Acc. Chem. Res. 2018, 51, 534.
(2) (a) Yoshimura, T.; Tomohara, K.; Kawabata, T. Asymmetric
Induction via Short-Lived Chiral Enolates with a Chiral C−O Axis. J.
Am. Chem. Soc. 2013, 135, 7102. (b) Mori, K.; Ohmori, K.; Suzuki, K.
Hydrogen-Bond Control in Axially Chiral Styrenes: Selective
Synthesis of Enantiomerically Pure C2-Symmetric Paracyclophanes.
Angew. Chem., Int. Ed. 2009, 48, 5638.
(3) (a) Jolliffe, J. D.; Armstrong, R. J.; Smith, M. D. Catalytic
Enantioselective Synthesis of Atropisomeric Biaryls by a Cation-
Directed O-Alkylation. Nat. Chem. 2017, 9, 558. (b) Feng, J.; Li, B.;
He, Y.; Gu, Z. Enantioselective Synthesis of Atropisomeric Vinyl
Arene Compounds by Palladium Catalysis: A Carbene Strategy.
Angew. Chem., Int. Ed. 2016, 55, 2186. (c) For others, see: Liang, Y.;
Ji, J.; Zhang, X.; Jiang, Q.; Luo, J.; Zhao, X. Enantioselective
Construction of Axially Chiral Amino Sulfide Vinyl Arenes via Chiral
Sulfide-Catalyzed Electrophilic Carbothiolation of Alkynes. Angew.
Chem., Int. Ed. 2020, 59, 4959.
(9) (a) Molleti, N.; Martinez-Erro, S.; Cerdán, A. C.; Sanz-Marco,
A.; Gomez-Bengoa, E.; Martín-Matute, B. Base-Catalyzed [1,n]-
Proton Shifts in Conjugated Polyenyl Alcohols and Ethers. ACS Catal.
2019, 9, 9134. (b) Bai, X.-d.; Wang, J.; He, Y. Iridium-Catalyzed
Propenylation Reactions for the Synthesis of 4-Pyridone Derivatives.
Adv. Synth. Catal. 2019, 361, 496. (c) Huang, J.; Wang, W.; He, H.-Y.;
Jian, L.; Fu, H.-Y.; Zheng, X.-L.; Chen, H.; Li, R.-X. An Approach to
the Synthesis of 1-Propenylnaphthols and 3-Arylnaphtho[2,1-b]-
furans. J. Org. Chem. 2017, 82, 2523. (d) Xu, Q.-L.; Dai, L.-X.; You,
S.-L. Tandem Ir-Catalyzed Allylic Substitution Reaction of Allyl
Sulfinates and Isomerization. Org. Lett. 2010, 12, 800. For selective
reports on stereospecific [1,3]-H transfer, see: (e) Ascough, D. M. H.;
Duarte, F.; Paton, R. S. Stereospecific 1,3-H Transfer of Indenols
Proceeds via Persistent Ion-Pairs Anchored by NH···π Interactions. J.
Am. Chem. Soc. 2018, 140, 16740. (f) Martinez-Erro, S.; Sanz-Marco,
A.; Gómez, A. B.; Vázquez-Romero, A.; Ahlquist, M. S. G.; Martín-
Matute, B. Base-Catalyzed Stereospecific Isomerization of Electron-
Deficient Allylic Alcohols and Ethers through Ion-Pairing. J. Am.
Chem. Soc. 2016, 138, 13408. (g) Dabrowski, J. A.; Haeffner, F.;
Hoveyda, A. H. Combining NHC-Cu and Brønsted Base Catalysis:
Enantioselective Allylic Substitution/Conjugate Additions with
Alkynylaluminum Reagents and Stereospecific Isomerization of the
Products to Trisubstituted Allenes. Angew. Chem., Int. Ed. 2013, 52,
7694. (h) Bizet, V.; Pannecoucke, X.; Renaud, J.-L.; Cahard, D.
Ruthenium-Catalyzed Redox Isomerization of Trifluoromethylated
Allylic Alcohols: Mechanistic Evidence for an Enantiospecific
Pathway. Angew. Chem., Int. Ed. 2012, 51, 6467. (i) Martinez-Erro,
(4) (a) Zheng, S.-C.; Wu, S.; Zhou, Q.; Chung, L. W.; Ye, L.; Tan, B.
Organocatalytic Atroposelective Synthesis of Axially Chiral Styrenes.
Nat. Commun. 2017, 8, 15238. (b) Tan, Y.; Jia, S.; Hu, F.; Liu, Y.;
Peng, L.; Li, D.; Yan, H. Enantioselective Construction of Vicinal
Diaxial Styrenes and Multiaxis System via Organocatalysis. J. Am.
Chem. Soc. 2018, 140, 16893. (c) Jia, S.; Chen, Z.; Zhang, N.; Tan, Y.;
Liu, Y.; Deng, J.; Yan, H. Organocatalytic Enantioselective
Construction of Axially Chiral Sulfone-Containing Styrenes. J. Am.
Chem. Soc. 2018, 140, 7056. (d) Huang, A.; Zhang, L.; Li, D.; Liu, Y.;
Yan, H.; Li, W. Asymmetric One-Pot Construction of Three
Stereogenic Elements: Chiral Carbon Center, Stereoisomeric Alkenes,
and Chirality of Axial Styrenes. Org. Lett. 2019, 21, 95. (e) Li, S.; Xu,
D.; Hu, F.; Li, D.; Qin, W.; Yan, H. Organocatalytic Asymmetric
Atroposelective Construction of Axially Chiral 1,4-Distyrene 2,3-
Naphthalene Diols. Org. Lett. 2018, 20, 7665. (f) Li, D.; Tan, Y.;
Peng, L.; Li, S.; Zhang, N.; Liu, Y.; Yan, H. Asymmetric Mannich
Reaction and Construction of Axially Chiral Sulfone-Containing
Styrenes in One Pot from α-Amido Sulfones Based on the Waste-
Reuse Strategy. Org. Lett. 2018, 20, 4959. (g) Wang, C.-S.; Li, T.-Z.;
Liu, S.-J.; Zhang, Y.-C.; Deng, S.; Jiao, Y.; Shi, F. Axially Chiral Aryl-
Alkene-Indole Framework: A Nascent Member of the Atropisomeric
Family and Its Catalytic Asymmetric Construction. Chin. J. Chem.
2020, 38, 543.
(5) (a) Jin, L.; Yao, Q.-J.; Xie, P.-P.; Li, N.; Zhan, B.-B.; Han, Y.-Q.;
Hong, X.; Shi, B.-F. Atroposelective Synthesis of Axially Chiral
Styrenes via an Asymmetric C−H Functionalization Strategy. Chem.
10693
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
S.; García-Vázquez, V.; Sanz-Marco, A.; Martín-Matute, B. Stereo-
specific Isomerization of Allylic Halides via Ion Pairs with Induced
Noncovalent Chirality. Org. Lett. 2020, 22, 4123. (j) Golec, J. C.;
Carter, E. M.; Ward, J. W.; Whittingham, W. G.; Simon, L.; Paton, R.
S.; Dixon, D. J. BIMP-Catalyzed 1,3-Prototropic Shift for the Highly
Enantioselective Synthesis of Conjugated Cyclohexenones. Angew.
Chem., Int. Ed 2020, 59, 17417. (k) Saga, Y.; Motoki, R.; Makino, S.;
Shimizu, Y.; Kanai, M.; Shibasaki, M. Catalytic Asymmetric Synthesis
of R207910. J. Am. Chem. Soc. 2010, 132, 7905. (l) Wu, Y.; Singh, R.
P.; Deng, L. Asymmetric Olefin Isomerization of Butenolides via
Proton Transfer Catalysis by an Organic Molecule. J. Am. Chem. Soc.
2011, 133, 12458. (m) Wu, Y.; Deng, L. Asymmetric Synthesis of
Trifluoromethylated Amines via Catalytic Enantioselective Isomer-
ization of Imines. J. Am. Chem. Soc. 2012, 134, 14334. (n) Zhou, X.;
Wu, Y.; Deng, L. Cinchonium Betaines as Efficient Catalysts for
Asymmetric Proton Transfer Catalysis: The Development of a
Practical Enantioselective Isomerization of Trifluoromethyl Imines.
J. Am. Chem. Soc. 2016, 138, 12297. (o) Xue, X.-S.; Li, X.; Yu, A.;
Yang, C.; Song, C.; Cheng, J.-P. Mechanism and Selectivity of
Bioinspired Cinchona Alkaloid Derivatives Catalyzed Asymmetric
Olefin Isomerization: A Computational Study. J. Am. Chem. Soc. 2013,
135, 7462.
(10) For selected transition-metal-catalyzed olefin isomerization,
see: (a) Chen, C.; Dugan, T. R.; Brennesse, W. W.; Weix, D. J.;
Holland, P. L. Z-Selective Alkene Isomerization by High-Spin
Cobalt(II) Complexes. J. Am. Chem. Soc. 2014, 136, 945. (b) Trost,
B. M.; Cregg, J. J.; Quach, N. Isomerization of N-Allyl Amides To
Form Geometrically Defined Di-, Tri-, and Tetrasubstituted
Enamides. J. Am. Chem. Soc. 2017, 139, 5133. (c) Larsen, C. R.;
Grotjahn, D. B. Stereoselective Alkene Isomerization over One
Position. J. Am. Chem. Soc. 2012, 134, 10357. (d) Biswas, S.; Huang,
Z.; Choliy, Y.; Wang, D. Y.; Brookhart, M.; Krogh-Jespersen, K.;
Goldman, A. S. Olefin Isomerization by Iridium Pincer Catalysts.
Experimental Evidence for an η3-Allyl Pathway and an Unconven-
tional Mechanism Predicted by DFT Calculations. J. Am. Chem. Soc.
2012, 134, 13276. (e) Schmidt, A.; Nödling, A. R.; Hilt, G. An
Alternative Mechanism for the Cobalt-Catalyzed Isomerization of
Terminal Alkenes to (Z)-2-Alkenes. Angew. Chem., Int. Ed. 2015, 54,
801. (f) Lombardo, V. M.; Thomas, C. D.; Scheidt, K. A. A Tandem
Isomerization/Prins Strategy: Iridium(III)/Brønsted Acid Coopera-
tive Catalysis. Angew. Chem., Int. Ed. 2013, 52, 12910. (g) Kita, M. R.;
Miller, A. J. M. An Ion-Responsive Pincer-Crown Ether Catalyst
System for Rapid and Switchable Olefin Isomerization. Angew. Chem.,
Int. Ed. 2017, 56, 5498. (h) Tian, Y.-C.; Jakoobi, M.; Boulatov, R.;
Sergeev, A. Selective Cleavage of Unactivated Arene Ring C-C Bonds
by Iridium: Key Roles of Benzylic C-H Activation and Metal-Metal
Cooperativity. Chem. Sci. 2021, 12, 3568. For selected reviews, see:
(i) Hassam, M.; Taher, A.; Arnott, G. E.; Green, I. R.; van Otterlo, W.
A. L. Isomerization of Allylbenzenes. Chem. Rev. 2015, 115, 5462.
(j) Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Double
Bond Migration in N-Allylic Systems Catalyzed by Transition Metal
Complexes. Coord. Chem. Rev. 2008, 252, 1819. (k) Larionov, E.; Li,
H.; Mazet, C. Well-Defined Transition Metal Hydrides in Catalytic
Isomerizations. Chem. Commun. 2014, 50, 9816. (l) Li, M.; Sanz-
Marco, A.; Martinez-Erro, S.; García-Vázquez, V.; Mai, B. K.;
Fernández-Gallardo, J.; Himo, F.; Martín-Matute, B. Unraveling the
Mechanism of the IrIII-Catalyzed Regiospecific Synthesis of α-
Chlorocarbonyl Compounds from Allylic Alcohols. Chem.Eur. J.
2020, 26, 14978. (m) Hu, L.; Wu, Z.; Huang, G. Mechanism and
Origins of Regio- and Stereoselectivities in Iridium-Catalyzed
Isomerization of 1-Alkenes to trans-2-Alkenes. Org. Lett. 2018, 20,
5410.
centrochirality of a 3,4-Dihydro-2H-1,1’-binaphthalen-1-ol into Axial
Chirality of a 3,4-Dihydro-1,1’-binaphthalene. Tetrahedron Lett. 2001,
42, 8035. (c) Mori, K.; Ohmori, K.; Suzuki, K. Stereochemical Relay
via Axially Chiral Styrenes: Asymmetric Synthesis of the Antibiotic
TAN-1085. Angew. Chem., Int. Ed. 2009, 48, 5633.
(12) For selected reports on TM-catalyzed asymmetric allylic
dearomatization of naphthols, see: (a) Zhuo, C.-X.; You, S.-L.
Palladium-Catalyzed Intermolecular Asymmetric Allylic Dearomatiza-
tion Reaction of Naphthol Derivatives. Angew. Chem., Int. Ed. 2013,
52, 10056. (b) Tang, S.-B.; Tu, H.-F.; Zhang, X.; You, S.-L. Rhodium-
Catalyzed Asymmetric Allylic Dearomatization of β-Naphthols:
Enantioselective Control of Prochiral Nucleophiles. Org. Lett. 2019,
21, 6130. (c) Tu, H.-F.; Zheng, C.; Xu, R.-Q.; Liu, X.-J.; You, S.-L.
Iridium-Catalyzed Intermolecular Asymmetric Dearomatization of β-
Naphthols with Allyl Alcohols or Allyl Ethers. Angew. Chem., Int. Ed.
2017, 56, 3237. (d) Shen, D.; Chen, Q.; Yan, P.; Zeng, X.; Zhong, G.
Enantioselective Dearomatization of Naphthol Derivatives with Allylic
Alcohols by Cooperative Iridium and Brønsted Acid Catalysis. Angew.
Chem., Int. Ed. 2017, 56, 3242. For reports on TM-catalyzed
asymmetric allylic alkylation of naphthols, see: (e) Li, C.; Breit, B.
Rhodium-catalyzed Dynamic Kinetic Asymmetric Allylation of
Phenols and 2-Hydroxypyridines. Chem.Eur. J. 2016, 22, 14655.
(13) (a) Spiess, S.; Raskatov, J. A.; Gnamm, C.; Brodner, K.;
Helmchen, G. Ir-Catalyzed Asymmetric Allylic Substitutions with
(Phosphoramidite)Ir ComplexesResting States, Synthesis, and
Characterization of Catalytically Active (π-Allyl)Ir Complexes.
Chem.Eur. J. 2009, 15, 11087. (b) Liu, W.-B.; Reeves, C. M.;
Stoltz, B. M. Enantio-, Diastereo-, and Regioselective Iridium-
Catalyzed Asymmetric Allylic Alkylation of Acyclic β-Ketoesters. J.
Am. Chem. Soc. 2013, 135, 17298. (c) Liu, W.-B.; Reeves, C. M.;
Virgil, S. C.; Stoltz, B. M. Construction of Vicinal Tertiary and All-
Carbon Quaternary Stereocenters via Ir-Catalyzed Regio-, Diastereo-,
and Enantioselective Allylic Alkylation and Applications in Sequential
Pd Catalysis. J. Am. Chem. Soc. 2013, 135, 10626. (d) Liu, W.-B.;
Okamoto, N.; Alexy, E. J.; Hong, A. Y.; Tran, K.; Stoltz, B. M.
Enantioselective γ-Alkylation of α,β-Unsaturated Malonates and
Ketoesters by a Sequential Ir-Catalyzed Asymmetric Allylic
Alkylation/Cope Rearrangement. J. Am. Chem. Soc. 2016, 138,
5234. (e) Bai, X.-D.; Zhang, Q.-F.; He, Y. Enantioselective Iridium
Catalyzed α-Alkylation of Azlactones by a Tandem Asymmetric
Allylic Alkylation/Aza-Cope Rearrangement. Chem. Commun. 2019,
55, 5547.
(14) See the SI for details. es = eeprd/eesm∗100%.
(15) (a) Zhou, J.; Hartwig, J. F. Iridium-Catalyzed H/D Exchange at
Vinyl Groups without Olefin Isomerization. Angew. Chem., Int. Ed.
2008, 47, 5783. (b) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman,
R. G. Iridium-Catalyzed H/D Exchange into Organic Compounds in
Water. J. Am. Chem. Soc. 2002, 124, 2092. (c) Iluc, V. M.; Fedorov,
A.; Grubbs, R. H. H/D Exchange Processes Catalyzed by an Iridium-
Pincer Complex. Organometallics 2012, 31, 39.
(16) For selective computational studies about Ir-catalyzed C−H
oxdative addition and reductive elimination processes, see: (a) Xing,
D.; Qi, X.; Marchant, D.; Liu, P.; Dong, G. Branched-Selective Direct
alpha-Alkylation of Cyclic Ketones with Simple Alkenes. Angew.
Chem., Int. Ed. 2019, 58, 4366. (b) Li, X.; Wu, H.; Lang, Y.; Huang,
G. Mechanism, Selectivity, and Reactivity of Iridium- and Rhodium-
Catalyzed Intermolecular Ketone α-Alkylation with Unactivated
Olefins via an Enamide Directing Strategy. Catal. Sci. Technol. 2018,
8, 2417. (c) Huang, G.; Liu, P. Mechanism and Origins of Ligand-
Controlled Linear Versus Branched Selectivity of Iridium-Catalyzed
Hydroarylation of Alkenes. ACS Catal. 2016, 6, 809.
(11) For selected early reports on central-to-axial chirality transfer,
see: (a) Baker, R. W.; Hambley, T. W.; Turner, P.; Wallace, B. J.
Central to Axial Chirality Transfer via Double Bond Migration:
Asymmetric Synthesis and Determination of the Absolute Config-
uration of Axially Chiral 1-(3′-Indenyl)naphthalenes. Chem. Commun.
1996, 2571. (b) Hattori, T.; Date, M.; Sakurai, K.; Morohashi, N.;
Kosugi, H.; Miyano, S. Highly Stereospecific Conversion of C-
10694
https://doi.org/10.1021/jacs.1c04400
J. Am. Chem. Soc. 2021, 143, 10686−10694