PdII-Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

Article abstract of DOI:10.1002/anie.202000532

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II-catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II-catalyzed enantioselective β-C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.

Full text of DOI:10.1002/anie.202000532

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Pd(II)-Catalyzed Enantioselective C(sp3)−H Arylation of
Cyclobutyl Ketones Using a Chiral Transient Directing Group
Authors: Jin-Quan Yu, Li-Jun Xiao, Kai Hong, Fan Luo, Liang Hu,
William R. Ewing, and Kap-Sun Yeung
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000532
Angew. Chem. 10.1002/ange.202000532
Link to VoR: http://dx.doi.org/10.1002/anie.202000532
http://dx.doi.org/10.1002/ange.202000532

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
Pd(II)-Catalyzed Enantioselective C(sp3)−H Arylation of Cyclobutyl
Ketones Using a Chiral Transient Directing Group
Li-Jun Xiao,[a] Kai Hong,[a] Fan Luo,[a] Liang Hu,[a] William R. Ewing,[b] Kap-Sun Yeung,[c] Jin-Quan Yu*[a]
[a]
Dr. L.-J. Xiao, Dr. K. Hong, Dr. F. Luo, Dr. L. Hu, Prof. Dr. J.-Q. Yu
Department of Chemistry
The Scripps Research Institute
10550 N. Torrey Pines Road, La Jolla, California 92037, United States
E-mail:
[b]
[c]
Dr. W. R. Ewing
Discovery Chemistry
Bristol-Myers Squibb
PO Box 4000, Princeton, New Jersey 08543, United States
Dr. K.-P. Yeung
Discovery Chemistry
Bristol-Myers Squibb Research and Development
100 Binney Street, Cambridge, MA 02142, United States
Supporting information for this article is given via a link at the end of the document.
Abstract: The utilization of chiral transient directing groups (TDGs)
has recently emerged as a promising approach for developing Pd(II)-
catalyzed enantioselective C(sp3)−H activation reactions. However,
this strategy is particularly challenging because the stereogenic
The second strategy employs chiral transient directing groups
attached to substrates via a reversible imine linkage (Scheme
1b).[8,9] The transient directing groups have a dual role: (1) to
direct C–H activation through a reversible linkage with aldehydes,
center present on the TDG is often far from the C–H bond. Additionally, ketones or amines, and (2) to induce chirality by generating chiral
the TDG covalently attached to the substrate and the free TDG are
both capable of coordinating to Pd(II) centers, which can result in a
mixture of reactive complexes that may lead to opposite asymmetric
induction. To date, the single example of TDG-enabled
enantioselective C(sp3)−H activation is limited to the functionalization
of benzylic C–H bonds. Herein we report the first example of a Pd(II)-
catalyzed enantioselective β-C(sp3)−H arylation reaction of aliphatic
ketones using a chiral transient directing group. A chiral trisubstituted
cyclobutane is efficiently synthesized from a mono-substituted
cyclobutane via sequential C–H arylation reactions, demonstrating
the ability of this method to access structurally complex products from
simple starting materials. The use of an electron-deficient pyridone
ligand is also crucial for the observed high enantioselectivity.
Interestingly, employing different silver salts can reverse the
enantioselectivity in the C(sp3)−H arylation reaction. These key
mechanistic findings will provide insight for future development of
Pd(II)-catalyzed enantioselective C(sp3)−H activation reactions with
chiral TDGs.
Pd(II) intermediates.
Scheme 1. Two strategies for Pd(II)-catalyzed directed asymmetric C(sp3)–H
activation
The employment of chiral transient directing groups allows for
enantioselective C−H activation without the need to install, and
later remove, a directing group. Nonetheless, this strategy still has
intrinsic limitations. In C–H activation reactions utilizing well-
established chiral ligands bearing privileged acetyl-protected
amino groups (NHAc), the ligand plays a crucial role in the C−H
]
cleavage transition state.[2-5 However, in reactions instead
employing chiral TDGs, another external base will be needed to
perform this function (Scheme 1). Secondly, the stereogenic
center in the transient directing groups is distal from the site of
C−H bond cleavage, rendering the asymmetric induction more
difficult. Finally, both the free TDG and the TDG-substrate adduct
could coordinate with Pd(II) center and lead to a mixture of
reactive and unreactive complexes. Despite extensive efforts on
developing non-enantioselective C–H activation reactions using
this TDG strategy,[8] asymmetric variants are limited to benzylic
Introduction
Transition metal-catalyzed enantioselective activation of prochiral
C(sp3)–H bonds has emerged as a valuable avenue for
asymmetric catalysis. Notably, a wide range of Pd(II)-catalyzed
enantioselective C–H activation/C–C bond and C–heteroatom
bond forming reactions have been realized in the past decade.[1]
Two fundamental strategies have been established for achieving
intermolecular catalytic asymmetric C–H activation reactions. The
first involves the design and development of various chiral
bidentate ligands,[2-7] including mono-N-protected amino acids
(MPAA),[2] quinolines,[3] oxazolines,[4] and amines[5] (Scheme 1a).
C(sp3)−H (Scheme 2a)[9] and C(sp2)–H bonds.[10]
.
Cyclobutanes are prevalent motifs in naturally occurring
alkaloids and important synthetic intermediates for the synthesis
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
of biologically active molecules.[11,12] Although progress has been
made on enantioselective functionalization of cyclobutyl
carboxylic acids and amides using chiral NHAc-containing
ligands,[2c,e,4c] the C–H activation of cyclobutyl ketones has not yet
been realized. We envision that the chiral TDG strategy via a
reversible imine linkage could fill this significant gap in
enantioselective C–H activation. Herein, we report the first
example of an enantioselective C–H arylation of aliphatic ketones
using an α-amino acid as a chiral transient directing group
responsible for chiral induction. Both the electron-deficient 2-
pyridone ligand and Ag3PO4 additive are crucial in order to attain
high enantioselectivity (Scheme 2b). Mechanistic experiments
using deuterium incorporation indicate that the use of different Ag
salts might switch the rate-limiting step by impacting the reductive
elimination, hence reversing the enantioselectivity.
Scheme 2. Enantioselective C(sp3)‒H arylation using a transient directing group
strategy
Results and Discussion
On the basis of our laboratory’s previous β-C−H arylation of
ketones with aryl iodides,[8e,9a] we began our investigation by
conducting the enantioselective β-C−H arylation of cyclobutyl
ketone 1a with methyl 4-iodobenzoate 2a in the presence of
Pd(OAc)2, D-cyclopentyl glycine TDG1 and AgTFA (Table 1).
Under our previous reaction conditions which utilize OAc as an X-
type ligand that can accelerate the C−H activation step, only 30%
yield of the desired product with 33:67 er was observed. We
envisioned that using a bulkier X-type ligands to accelerate the
C(sp3)−H bond cleavage would enchance the enantioselectivity.
First, we tried PivOH L2, N-protected amino acids L3 and L4, and
phosphoric acid L5, as these ligands have been previously
utilized to promote enantioselective C–H activation.[1] However,
none of these ligands increased the enantioselectivity,
presumably because they failed to replace OAc/OTFA and
coordinate to the palladium catalyst. Therefore, we moved on to
stronger binding X-type ligands. 2-Pyridones were recently
identified as exceptionally efficient ligands that can accelerate
C−H activation.[13,14] We evaluated various ligands of this type and
were encouraged to find that electron-deficient pyridone ligands
(L7–L13) not only promote the C–H activation to afford a higher
yield of diarylation product but also increase the enantioselectivity
up to 15:85 er, with 5-nitropyridone L9 generating the highest
enantioselectivity. The enantioselectivity of this reaction could be
further optimized to 14:86 er by adding 1.5 equiv of TFA (see the
Supporting Information for optimization of reaction conditions).
Table 1. Ligand Evaluation for Enantioselective β-C(sp3)‒H Arylation of Cyclobutyl Ketones with AgTFA[a,b]
[a] Conditions: 1a (0.2 mmol, 2.0 equiv), methyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (10 mol %), TDG1 (30 mol %), ligand (40 mol %), AgTFA (2.0 equiv), HFIP
(0.6 mL), 100 °C, under air, 24 h. [b] Yield determined by 1H NMR analysis of the crude product using CH2Br2 as internal standard.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
Although we found pyridone ligands are capable of promoting
the C–H activation reaction, the yield and enantioselectivity of the
desired product 3a required further improvement. With the best
pyridone ligand in the presence of AgTFA identified, we next
evaluated other Ag salts with the ligand L9 (Table 2). A control
experiment without a silver salt additive afforded no desired
product, indicating that silver salts are crucial to this reaction.
Notably, most of the silver salts evaluated, such as AgOAc,
enantioselectivities (15:85–10:90 er), with the exception of AgNO3
or AgF. Surprisingly, a reversal of enantioselectivity (96:4 er) of
the desired product was observed when Ag3PO4 was employed.
Moreover, the undesired di-arylation product was also reduced. A
moderate and reversed enantioselectivity (75:25 er) of the desired
product was observed when K3PO4 and AgTFA was employed.
Lastly, control experiment show both Ag3PO4 and the pyridone
ligand are essential for the observed reversal of the
enantioselectivity (Table 2).
Ag2CO3,
and
Ag2O,
afforded
moderate
to
good
Table 2. The Dramatic Effects of Silver Salts in the Presence of Pyridone Ligands[a,b]
[a] Conditions: 1a (0.2 mmol, 2.0 equiv), methyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (10 mol %), TDG1 (30 mol %), L9 (40 mol %), TFA (1.5 equiv), silver salt (2.0
equiv), HFIP (0.6 mL), 100 °C, under air, 24 h. [b] Yield determined by 1H NMR analysis of the crude product using CH2Br2 as internal standard. [c] Ag3PO4 (1.0
equiv). [d] K3PO4 (1.0 equiv).
With the best silver salt in the presence of L9 established, we
next systematically evaluated a series of chiral transient directing
groups (Table 3). We found that substituents at the α-position of
free amino acids has a significant effect on the enantioselectivity.
Bulkier substituents at the α-position of amino acids afforded
higher enantioseletivities (TDG3 vs TDG8, TDG3 vs TDG6).
Although TDG6 generates the highest enantioselectivity, a lower
yield was delivered presumably because of sluggish imine
formation. Therefore, we selected TDG3 as the optimal transient
directing group, which affords the best yield and a high
enantioselectivity of 82% and 97:3 er, respectively. The control
experiment with TDG4 (ent-TDG3) was also conducted to verify
the role of an amino acid as a chiral transient directing group to
predominantly determine the stereochemistry. The reaction could
be further optimized to 82% NMR yield and 98:2 er by using L12
in the presence of TDG3 and Ag3PO4 (see the Supporting
Information for optimization of reaction conditions).
Table 3. Transient directing group evaluation for enantioselective β-C(sp3)‒H Arylation of cyclobutyl ketones[a,b]
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
[a] Conditions: 1a (0.2 mmol, 2.0 equiv), methyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (10 mol %), TDG (30 mol %), L9 (40 mol %), TFA (1.5 equiv), Ag3PO4 (1.0
equiv), HFIP (0.6 mL), 100 °C, under air, 24 h. [b] Yield determined by 1H NMR analysis of the crude product using CH2Br2 as internal standard.
With the optimal reaction conditions established, we next
investigated the scope of the aryl iodides and heteroaryl iodides
using cyclobutyl ketone (1a) as the substrate (Table 4). The
reaction of 1a with various aryl iodides furnished mono-arylated
products in good yields and high enantioselectivities, exhibiting
excellent functional group compatibility (3a−l). Various electron-
withdrawing groups and coordinative cyano, nitro, acetyl, and
benzoyl groups were well-tolerated. Ortho-fluorine substituted
aryl iodide showed comparable reactivity and high
enantioselectivity (3l). More importantly, to install diverse
pyridines at β-position through asymmetric β-C(sp3)–H activation
remains challenging, due to strong binding of iodopyridine to
palladium. We optimized the reaction conditions for
heteroarylation of 1a by increasing the pyridone ligand loading to
one equivalent. Heteroarylation of 1a with a diverse range of 2-
substituted iodopyridines proceeded smoothly in moderate yields
and high enantioselectivities (3m–s). However, electron-neutral
and electron-rich aryl iodides, such as iodobenzene and 4-
iodoanisole, showed low activity affording around 5–10% yield of
the desired products under our standard conditions.
Table 4. Scope of ArI[a,b]
[a] Conditions: 1a (0.2 mmol, 2.0 equiv), aryl iodide 2 (1.0 equiv), Pd(OAc)2 (10 mol %), TDG3 (30 mol %), L12 (40 mol %), TFA (1.5 equiv), Ag3PO4 (1.0 equiv),
HFIP (0.6 mL), 100 °C, under air, 24 h. [b] Isolated yields. [c] 1a (0.1 mmol, 1.0 equiv), aryl iodide 2 (2.0 equiv). [d] TDG6. [e] L12 (1.0 equiv), 48 h. [f] TFA (0.5
equiv).
Next, we examined the scope of ketones (Table 5). Cyclobutyl
alkyl ketones 5a−h were functionalized at the α-position in
moderate yields and with good to excellent enantioselectivities
(6a−h, 96:4–98:2 er). Notably, an array of functional groups,
including phenyl, methoxy, cyclobutyl, and cyclohexyl groups
were well tolerated. Interestingly, the C–H activation reaction also
worked well with the spiro cyclobutyl ketone, affording a good
yield and high enantioselectivity (6i). Although this catalytic
system offers high enantioselectivity for C–H arylation of
numerous cyclobutyl ketones where the enantiomer of product
can be controlled by the choice of silver salt, it is not without
limitations. For instance, cyclopentyl ketones and open chain
ketones are reactive, but the enantioselectivities are lower (6j, 6k).
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
For the cyclopentyl ketone, using AgTFA and Ag3PO4 did not
generate inverse enantioselectivities.
Table 5. Scope of ketones[a,b]
Scheme 3. Diverse chiral cyclobutanes via sequential C–H arylation
To obtain some mechanistic insight into the reversed
enantioselectivity observed when two different silver salts were
employed in the reaction, we conducted deuterium incorporation
experiments with 1a under the standard conditions with different
silver salts in the presence of TFA-D and HFIP-ol-D (Scheme 4).
No deuterium incorporation with AgTFA at the C-4 position on the
cyclobutyl ring of the arylated product 3a suggests that the AgTFA
conditions give rise to the irreversible C–H cleavage as the rate-
limiting step (Scheme 4a). The distinct presence of 88%
deuterium incorporation with Ag3PO4 at the C-4 position on the
cyclobutyl ring of the arylated product 3a suggests that in these
conditions C–H bond cleavage is a rapid, reversible step and the
rate-limiting step might involve the Pd(IV) intermediate after C–H
bond cleavage (Scheme 4b). Additionally, the lack of deuterium
incorporation at the C-5 position on the cyclopentyl ring of the
arylated product 6j with both AgTFA (Scheme 4c) and Ag3PO4
(Scheme 4d) additives suggests that the irreversible C–H
cleavage is always the rate-limiting step for the arylation reaction
of cyclopentyl ketones, regardless of the identity of the silver salt.
These results could rationalize the lack of reverse
enantioselectivity in C–H arylation reactions of cyclopentyl
ketones with different silver salts (Table 5, 6j).
[a] Conditions: 5 (0.2 mmol, 2.0 equiv), methyl 4-iodobenzoate (1.0 equiv),
Pd(OAc)2 (10 mol %), TDG3 (30 mol %), L12 (40 mol %), TFA (1.5 equiv),
Ag3PO4 (1.0 equiv), HFIP (0.6 mL), 100 °C, under air, 24 h. [b] Isolated yields.
[c] Numbers in parentheses indicate the ratio of the arylation of the cyclobutane
and terminal methyl group. [d] AgTFA (2.0 equiv).
To demonstrate the robustness and the utility of this reaction, a
gram-scale reaction and a sequential C−H activation were
performed (Scheme 3). Arylation of 1a under the standard
conditions with 3-iodo-4-fluorobromobenzene as the coupling
partner afforded 1.2 g of enantioenriched product 3l in 75%
isolated yield and 99:1 er. Cyclobutane 3l was then subjected to
a second C−H arylation reaction employing simple glycine as the
transient directing group and methyl 4-iodobenzoate as the
coupling partner. This reaction afforded two enantiopure
cyclobutanes bearing three contiguous stereogenic centers.
Interestingly, the cis-mono-arylated ketone intermediate was
epimerized to give the trans-isomer which readily form imine with
TDG to direct subsequent diarylation.[15] The absolute
configuration of these two products (7a, 7b) was confirmed by X-
ray crystallographic analysis. This method allows rapid access to
diverse chiral cyclobutanes which cannot be readily accessed by
the previously reported asymmetric approaches.[12]
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 4. Deuterium-labeling experiments
On the basis of previous works from our laboratory[9,13,14] and the
above-described experimental results, we propose a possible
mechanism for the reversed enantioselectivity observed when
two different silver salts, AgTFA and Ag3PO4, are employed as
additives (Scheme 5). First, the pyridone ligand accelerates the
C−H bond cleavage step and facilitates the generation of
cyclometalated Pd(II)-complexes B and B’. Next, oxidative
addition of the aryl iodide occurs to afford Pd(IV) complexes C
and C’. A previous computational study suggests that abstraction
of the iodide of this Pd(IV) intermediate by the silver additive
triggers the reductive elimination to give the final arylation
product.[16] Since AgTFA is an efficient additive that rapidly
abstracts the iodide from Pd(IV) intermediates to promote C−C
reductive elimination, the initial C–H bond cleavage will be the
rate-limiting step, therefore, the chiral TDG-induced asymmetric
C–H palladation controls the enantioselectivity. In contrast, when
reductive elimination becomes the rate-limiting step with Ag3PO4
as the additive, the product formation from the chiral Pd(IV)
intermediates is responsible for the chiral induction.
Scheme 5. Proposed mechanism: combinations of pyridone ligands with silver salts to switch the rate-limiting steps (RLS)
to achieve Pd-catalyzed enantioselective arylation of other alkyl
C−H bonds using chiral transient directing groups.
Conclusion
Acknowledgements
We have developed the first example of a Pd(II)-catalyzed
enantioselective C(sp3)−H arylation of ketones using an α-amino
acid as a chiral transient directing group. A chiral trisubstituted
cyclobutane is efficiently synthesized from a mono-substituted
cyclobutane via sequential C–H arylation reactions,
demonstrating the ability of this method to access structurally
complex products from simple starting materials. The 3-nitro-5-
trifluoromethyl-2-pyridone was identified as an effective ligand,
serving as an acetate surrogate to accelerate C–H bond cleavage
in the transient directing group strategy. The combination of an
electron-deficient 2-pyridone ligand with different silver salts
offers an effective method for controlling the rate-limiting steps
which enables the high enantioselectivity and yield of this reaction.
Our laboratory is currently applying these fundamental principles
We gratefully acknowledge The Scripps Research Institute, NIH
(NIGMS, R01 GM084019), and Bristol-Myers Squibb for financial
support. We thank Jiangsu Industrial Technology Research
Institute (JITRI) for a postdoctoral fellowship (L.J.X). We thank Dr.
Jason Chen, Ms. Brittany Sanchez, and Ms. Emily Sturgell from
Automated Synthesis Facility (TSRI) for their assistance with
HRMS analysis. We thank Arnie Rheingold, Jake Bailey and Milan
Gembicky from X-ray Crystallography Facility (UCSD) for X-ray
crystallography.
Keywords: pyridone ligand• arylation • C–H activation • transient
directing group • palladium
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
[1] For selected reviews of enantioselective C−H functionalization, see: a) R.Giri,
B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38,
3242. b) C. G. Newton, S.-G. Wang, C. C. Oliveira, N. Cramer, Chem. Rev.
2017, 117, 8908. c) T. G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F. Wu, J.-Q.
Yu, Science 2018, 359, eaao4798.
Shi, Angew. Chem. Int. Ed. 2017, 56, 6617; Angew. Chem. 2017, 129, 6717.
b) J. Xu, Y. Liu, J. Zhang, X. Xu, Z. Jin, Chem. Commun. 2018, 54, 689.
[11] a) T. V. Hansen, Y. Stenstrøm, Naturally Occurring Cyclobutanes. In
Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; Elsevier
Science: Oxford, U.K., 2001; Vol. 5, p 1. b) V. M. Dembitsky, J. Nat. Med.
2008, 62, 1. c) Y. M. Chi, M. Nakamura, X. Y. Zhao, T. Yoshizawa, W. M.
Yan, F. Hashimoto, J. Kinjo, T. Nohara, Chem. Pharm. Bull. 2005, 53, 1178.
d) K. Kurosawa, K. Takahashi, E. Tsuda, J. Antibiot. 2001, 54, 541. e) W.
R. Gutekunst, P. S. Baran, J. Am. Chem. Soc. 2011, 133, 19076. f) W. R.
Gutekunst, R. Gianatassio, P. S. Baran, Angew. Chem. Int. Ed. 2012, 51,
7507; Angew. Chem. 2012, 124, 7625. g) W. R. Gutekunst, P. S. Baran, J.
Org. Chem. 2014, 79, 2430. h) R. A. Panish, S. R. Chintala, J. M. Fox,
Angew. Chem. Int. Ed. 2016, 55, 4983; Angew. Chem. 2016, 128, 5067.
[12] For selected recent examples of enantioselective synthesis of cyclobutane
derivatives, see: a) E. Canales, E. J. Corey, J. Am. Chem. Soc. 2007, 129,
12686. b) F. Kleinbeck, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 9178.
c) C. Müller, A. Bauer, M. M. Maturi, M. C. Cuquerella, M. A. Miranda, T.
Bach, J. Am. Chem. Soc. 2011, 133, 16689. d) Ł. Albrecht, G. Dickmeiss,
F. C. Acosta, C. Rodriguez-Escrich, R. L. Davis, K. A. Jørgensen, J. Am.
Chem. Soc. 2012, 134, 2543. e) M. Reeves, C. Eidamshaus, J. Kim, B. M.
Stoltz, Angew. Chem. Int. Ed. 2013, 52, 6718; Angew. Chem. 2013, 125,
6850. f) R. Panish, S. R. Chintala, D. T. Boruta, Y. Fang, M. T. Taylor, J. M.
Fox, J. Am. Chem. Soc. 2013, 135, 9283. g) J. N. Du, K. L. Skubi, D. M.
Schultz, T. P. Yoon, Science 2014, 344, 392. h) M. L. Conner, Y. Xu, M. K.
Brown, J. Am. Chem. Soc. 2015, 137, 3482. i) M. Guisán-Ceinos, A. Parra,
V. Martín-Heras, M. Tortosa, Angew. Chem. Int. Ed. 2016, 55, 6969; Angew.
Chem. 2016, 128, 7083. j) J.-L. Hu, L.-W. Feng, L. Wang, Z. Xie, Y. Tang,
X. Li, J. Am. Chem. Soc. 2016, 138, 13151.
[2] a) B.-F. Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. Int. Ed. 2008,
47, 4882; Angew. Chem. 2018, 120, 4960. b) M. Wasa, K. M. Engle, D. W.
Lin, E. J. Yoo, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 19598. c) K.-J. Xiao,
D. W. Lin, M. Miura, R.-Y. Zhu, W. Gong, M. Wasa, J.-Q. Yu, J. Am. Chem.
Soc. 2014, 136, 8138. d) K. S. L. Chan, H.-Y. Fu, J.-Q. Yu, J. Am. Chem.
Soc. 2015, 137, 2042. e) L. Hu, P.-X. Shen, Q. Shao, K. Hong, J. X. Qiao,
J.-Q. Yu, Angew. Chem. Int. Ed. 2019, 11, 2134; Angew. Chem. 2019, 131,
2156.
[3] G. Chen, W. Gong, Z. Zhuang,; M. S. Andra,; Y.-Q. Chen, X. Hong, Y.-F.
Yang, T. Liu, K. N. Houk,; J.-Q. Yu, Science 2016, 353, 1023.
[4] a) Q.-F. Wu, P.-X. Shen, J. He, X.-B. Wang, F. Zhang, Q. Shao, R.-Y. Zhu,
C. Mapelli, J. X. Qiao, M. A. Poss, J.-Q. Yu, Science 2017, 355, 499. b) Q.
Shao, Q.-F. Wu, J. He, J.-Q. Yu, J. Am. Chem. Soc. 2018, 140, 5322. c)
Q.-F. Wu, X.-B. Wang, P.-X. Shen, J.-Q. Yu, ACS Catal. 2018, 8, 2577.
[5] Shen, P.-X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. J. Am. Chem. Soc. 2018,
140, 6545.
[6] For Pd (II)-catalyzed enantioselective C−H functionalization using
phosphoric acid/amide and BINOL ligands, see: a) S.-B. Yan, S. Zhang,
W.-L. Duan, Org. Lett. 2015, 17, 2458. b) H. Wang, H.-R. Tong, G. He, G.
Chen, Angew. Chem. Int. Ed. 2016, 55, 15387; Angew. Chem. 2019, 128,
15613. c) P. Jain, P. Verma, G. Xia, J.-Q. Yu, Nat. Chem. 2017, 9, 140. d)
Y.-Q. Han, Y. Ding, T. Zhou, S.-Y. Yan, H. Song, B.-F. Shi, J. Am. Chem.
Soc. 2019, 141, 4558.
[13] For selected examples of 2-pyridone-accelerated C(sp2)–H activation
reactions: a) P. Wang, M. E. Farmer, X. Huo, P. Jain, P.-X. Shen, M. Ishoey,
J. E. Bradner, S. R. Wisniewski, M. E. Eastgate, J.-Q. Yu, J. Am. Chem.
Soc. 2016, 138, 9269. b) P. Wang, P. Verma, G. Xia, J. Shi, J. X. Qiao, S.
Tao, P. T. W. Cheng, M. A. Poss, M. E. Farmer, K. S. Yeung, J.-Q. Yu,
Nature 2017, 551, 489. c) G. C. Li, P. Wang, M. E. Farmer, J.-Q. Yu, Angew.
Chem. Int. Ed. 2017, 56, 6874; Angew. Chem. 2017, 129, 6978. d) M. E.
Farmer, P. Wang, H. Shi, J.-Q. Yu, ACS Catal. 2018, 8, 7362.
[7] For selected Pd(0)-catalyzed intramolecular enantioselective C−H
functionalization, see: a) M. Nakanishi, D. Katayev, C. Besnard, E. P.
Kündig, Angew. Chem. Int. Ed. 2011, 50, 7438; Angew. Chem. 2011, 123,
7576. b) S. Anas, A. Cordi, H. B. Kagan, Chem. Commun. 2011, 47, 11483.
c) T. Saget, N. Lémouzy, N. Cramer, Angew. Chem. Int. Ed. 2012, 51,
2238; Angew. Chem. 2012, 124, 2281. d) N. Martin, C. Pierre, M. Davi, R.
Jazzar, O. Baudoin, Chem. Eur. J. 2012, 18, 4480. e) C. Zhu, D. Wang, Y.
Zhao, W.-Y. Sun, Z. Shi, J. Am. Chem. Soc. 2017, 139, 16486.
[14] For selected examples of 2-pyridone-accelerated C(sp3)–H activation
reactions: a) R.-Y. Zhu, Z.-Q. Li, H. S. Park, C. H. Senanayake, J.-Q. Yu,
J. Am. Chem. Soc. 2018, 140, 3564. b) ref 8i.
[8] For non-enantioselective examples of C(sp3)–H functionalization using a
transient directing group, see: a) Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate,
J.-Q. Yu, J. Am. Chem. Soc. 2016, 138, 14554. b) F. Ma, M. Lei, L. Hu, Org.
Lett. 2016, 18, 2708. c) K. Yang, Q. Li, Y. Liu, G. Li, H. Ge, J. Am. Chem.
Soc. 2016, 138, 12775. d) Y. Xu, M. C. Young, C. Wang, D. M. Magness,
G. Dong, Angew. Chem. Int. Ed. 2016, 55, 9084; Angew. Chem. 2016, 128,
9230. e) K. Hong, H. Park, J.-Q. Yu, ACS Catal. 2017, 7, 6938. f) Y. Liu, H.
Ge, Nat. Chem. 2017, 9, 26. g) A. Yada, W. Liao, Y. Sato, M. Murakami,
Angew. Chem. Int. Ed. 2017, 56, 1073; Angew. Chem. 2017, 129, 1093. h)
S. St John-Campbell, A. J. P. White, J. A. Bull, Chem. Sci. 2017, 8, 4840.
i) Y.-Q. Chen, Z. Wang, Y. Wu, S. R. Wisniewski, J. X. Qiao, W. R. Ewing,
M. D. Eastgate, J.-Q. Yu, J. Am. Chem. Soc. 2018, 140, 17884. j) L. Pan,
K. Yang, G. Li, H. Ge, Chem. Commun. 2018, 54, 2759. k) C. Dong, L. Wu,
[15] For proposed mechanism of the sequential C−H activation see SI, Scheme
S3.
[16] W. Feng, T. Wang, D. Liu, X. Wang, Y. Dang, ACS Catal. 2019, 9, 6672.
J. Yao, K. Wei, Org. Lett. 2019, 21, 2085.
[9] For enantioselective examples of C(sp3)–H functionalization using a transient
directing group, see: a) F.-L. Zhang, K. Hong, T.-J. Li, H. Park, J.-Q. Yu,
Science 2016, 351, 252. b) H. Park, P. Verma, K. Hong, J.-Q. Yu, Nat.
Chem. 2018, 10, 755.
[10] For selected enantioselective examples of C(sp2)–H functionalization using
a transient directing group, see: a) Q.-J. Yao, S. Zhang, B.-B. Zhan, B.-F.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202000532
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
A Pd(II)-catalyzed enantioselective C(sp3)−H arylation of ketones using an α-amino acid as a chiral transient directing group is reported.
The 3-nitro-5-trifluoromethyl-2-pyridone was identified as an effective ligand, serving as an acetate surrogate to accelerate C–H bond
cleavage in the transient directing group strategy. The combination of an electron-deficient 2-pyridone ligand with different silver salts
offers an effective method for controlling the rate-limiting steps which enables the high enantioselectivity and yield of this reaction.
Li-Jun Xiao, Kai Hong, Fan Luo, Liang Hu, William R. Ewing, Kap-Sun Yeung, Jin-Quan Yu*
Pd(II)-Catalyzed Enantioselective C(sp3)−H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group
8
This article is protected by copyright. All rights reserved.