Palladium-Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ-Lactams with Aryl Chlorides and Bromides

Article abstract of DOI:10.1002/anie.201814475

Herein, we report the first Pd-catalyzed enantioselective arylation of α-substituted γ-lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron-rich dialkylphosphine ligand we have been able to construct α-quaternary centers in good yields (up to 91 % yield) and high enantioselectivities (up to 97 % ee).

Full text of DOI:10.1002/anie.201814475

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Palladium-Catalyzed Construction of Quaternary Stereocenters
by Enantioselective Arylation of γ-Lactams with Aryl Chlorides
and Bromides
Authors: Carina Jette, Irina Geibel, Shoshana Bachman, Masaki
Hayashi, Shunya Sakurai, Hideki Shimizu, Jeremy B. Morgan,
and Brian Stoltz
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.201814475
Angew. Chem. 10.1002/ange.201814475
Link to VoR: http://dx.doi.org/10.1002/anie.201814475
http://dx.doi.org/10.1002/ange.201814475

Angewandte Chemie International Edition
10.1002/anie.201814475
COMMUNICATION
Palladium-Catalyzed Construction of Quaternary Stereocenters
by Enantioselective Arylation of -Lactams with Aryl Chlorides
and Bromides
[
a]
[a]
[a]
[a]
[a]
Carina I. Jette , Irina Geibel , Shoshana Bachman , Masaki Hayashi , Shunya Sakurai , Hideki
[
a]
[b]
[a]
Shimizu , Jeremy B. Morgan* , Brian M. Stoltz*
Abstract: Herein, we report the first Pd-catalyzed enantioselective
arylation of -substituted -lactams. Two sets of conditions were
developed for this transformation, allowing for the use of either aryl
chlorides or bromides as electrophiles. Utilizing a highly electron-
rich, dialkylphosphine ligand, we have been able to construct -
quaternary centers in good yields (up to 91% yield) and high
enantioselectivities (up to 97% ee).
successfully implemented in Pd-catayzed asymmetric -
arylation chemistry. One of the challenges associated with the
use of lactams in metal-catalyzed enolate arylation is the
necessity for enolization by strong base, which may lead to the
generation of unwanted aryne intermediates from the aryl
halide[9,10] in addition to catalyst decomposition. As a result,
prior reports are limited to either -unsubstituted piperidinones,
which require pre-formation of a basicity-tempered zinc enolate
to generate the desired product, or oxindoles,[11] a special case
Nitrogen heterocycles are ubiquitous structural motifs that
can be found across all areas and applications of organic
chemistry. A particularly important subgroup of this class are
the pyrrolidinones, which along with their saturated counterparts
the pyrrolidines, occur widely in nature,[1,2] possess a wide range
of biological and pharmacological properties,[3] and are
employed in materials and catalysis.[5] For these reasons, the
development of stereoselective approaches to functionalized
five-membered nitrogen-containing heterocycles is a topic of
great interest in the synthesis of small molecules and natural
products.
that does not require high temperatures or strongly basic
[12]
conditions (Figure 1b).
A crucial step in the development of
this transformation would be the identification of a catalyst that
not only possesses optimal steric and electronic properties, but
also exhibits good stability under basic conditions. Taking these
considerations into account, we sought to develop the first
method for the direct transition metal-catalyzed enantioselective
[4]
-arylation of -substituted -lactams to generate all-carbon
quaternary stereocenters.
Our group has
a
long-standing interest in the
stereoselective synthesis of five-membered N-heterocyclic
building blocks, having developed methods for both
[
6]
enantioselective allylic alkylation
and enantioselective -
[
7]
acylation of -butyrolactams. The -aryl pyrrolidinone building
block is of special interest, as it would enable access to the
phenethylbenzylamine structural motif, which is prevalent in a
number of biologically active natural products and drug-like
molecules (Figure 1a).[8] Nevertheless, methods describing the
asymmetric -arylation of substituted pyrrolidinones to produce
-quaternary lactams have previously remained elusive.
Despite the apparent similarities to other known -arylation
reactions, there are a number of subtle challenges that have
potentially precluded -substituted -lactams from having been
Figure 1. Representative benzylphenethylamine-type alkaloids and state of
the art in transition metal-catalyzed -arylation of monocyclic lactams.
[
a]
Carina I. Jette, Irina Geibel, Shoshana Bachman, Masaki Hayashi,
Hideki Shimizu, Brian M. Stoltz
Warren And Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering
Division of Chemistry and Chemical Engineering
California Institute of Technology
We initiated our investigation into the enantioselective -
arylation of N-p-methoxyphenyl (PMP) -methyl pyrrolidinone
(
1a) with chlorobenzene by examining the effect of a number of
different ligands on the reactivity and selectivity of the reaction
(Table 1).[13] With Pd(dmdba)
as the Pd source, commonly
1200 E. California Blvd. MC 101-20, Pasadena CA 91125 (USA)
2
E-mail: stoltz@caltech.edu
Jeremy B. Morgan
Dobo Hall
Department of Chemistry and Biochemistry,
University of North Carolina Wilmington, NC 28403 (USA)
employed ligands (S)-BINAP (entry 1) and Josiphos (entry 2)
resulted in both low yields and low enantiomeric excess. We
found that the ferrocelane class of ligands (L3-L5) was optimal;
both L3 (entry 3) and L4 (entry 4) resulted in the formation of the
desired -quaternary lactam 3aa in equally high yield and high
enantiomeric excess. However, the use of the bulkier L5 led to
[
b]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201814475
COMMUNICATION
both diminished yield and enantioselectivity. Crucially, these
highly electron-rich dialkylphosphine ligands should undergo
rapid oxidative addition to the aryl halide, while the large bite
angle should encourage facile reductive elimination.[14]
Furthermore, since alkyl phosphines are less susceptible to P–C
By changing the Pd source, we were able to produce a more
active pre-catalyst that allowed for a lower catalyst loading and
shorter reaction time with L3 (Table 2, entry 1). We found that
the identity of the base was critical for high yields and
enantioselectivities and dependent on the choice of electrophilic
coupling partner: when chlorobenzene is used, LiHMDS resulted
in the highest yield and enantioselectivity (entries 1, 4, and 5),
whereas with bromobenzene, NaHMDS proved optimal (entries
7 and 8). By employing the less hindered ligand L4, we were
able to isolate 3aa in 86% yield and 92% ee after 12 hours
cleavage[15]
, we believe that these ligands might form a
Pd/ligand complex that is more stable at high temperatures.
Interestingly, we noted that the structurally similar phosphonato
FerroTANE ligand (L6) (entry 6) resulted in low conversion.
(
entry 7).[16] With this new set of conditions, the reaction
proceeds at a lower temperature; the desired product is obtained
in 83% yield and 92% ee (entry 8) after 15 h at 80 °C. Moreover,
at 54 °C the product is still obtained in good yield and high
enantiomeric excess (entry 10).
Table 1. Evaluation of Ligands for Pd-Catalyzed -Arylation of -Lactams.a
[
a] Conditions: 0.1 mmol scale, 1a (1.5 equiv), 2a (1.0 equiv), LiHMDS (1.5
equiv), 10 mol Pd(dmdba) 12 mol ligand, 0.5 mL dioxane. [b]
%
2
,
%
Determined by LC-MS analysis of the crude reaction mixture using 1,3,5–
trimethoxybenzene as a standard. [c] Determined by chiral SFC analysis of the
isolated product. PMP
dimethoxydibenzylideneacetone .
=
p-methoxyphenyl. dmdba
=
3,5,3’,5’–
Table 3. Scope of the N-Protecting Group.a
[
a] Conditions for each method are as follows: Method A: lactam (1.5 equiv),
Ph–Cl (1.0 equiv), Pd (pmdba) (2.5 mol%), L3 (7.5 mol %), LiHMDS (1.5
equiv), dioxane (0.2 M), 100 °C, 20h. Method B: lactam (1.5 equiv), Ph–Br (1.0
equiv), Pd (pmdba) (2.5 mol%), L4 (7.5 mol%), NaHMDS (1.5 equiv), dioxane
0.2 M), 80 °C, 20 h. [b] h. [c] 15 h. pmdba= 4,4’–
dimethoxydibenzylideneacetone.
2
3
2
3
(
6
With optimized conditions for aryl chlorides (Method A, Table
, entry 1) and aryl bromides (Method B, Table 2, entry 9) in
2
hand, the effect of the N-protecting group on the reaction was
examined (Table 3). We were pleased to find that a number of
different N-protecting groups were tolerated in our reaction. Bis-
methoxyphenyl lactam 1b performs just as well as 1a with
Method B, but a slight decrease in yield and enantioselectivity is
observed when subjected to Method A (3ba). Switching to
ortho-methoxy phenyl substituted 1c or electron-deficient
trifluoromethylphenyl 1e led to diminished yield and
enantioselectivity (3ca and 3ea). Although N-phenyl 1d does
not outperform 1a in Method A, it does exhibit higher reactivity
and enantioselectivity when exposed to Method B, furnishing the
desired product in 91% yield and 93% ee (3da). Benzyl-
protected lactam 1f affords -quaternary lactam 3fa in high
levels of enantiomeric excess across both Methods.
Table 2. Optimization of Reaction Conditions.a
[
a] Conditions: 0.1 mmol scale, 1a (1.5 equiv), Ph–X (1.0 equiv), base 1.5
equiv), Pd (pmdba) (2.5 mol %), ligand (7.5 mol %), 0.5 mL dioxane. [b] yield
2
3
determined by LCMS analysis of the crude reaction mixture using 1,3,5–
trimethoxybenzene as a standard. [c] Determined by chiral SFC analysis of the
isolated product. [d] Reaction performed at 80 °C. [e] Reaction performed at
54
°C.
PMP
=
p-methoxyphenyl.
pmdba
=
4,4’
–
dimethoxydibenzylideneacetone.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201814475
COMMUNICATION
Next, we examined the substrate scope of the
enantioselective -arylation (Table 4). We found that aryl
bromides and aryl chlorides with a variety of substitution
patterns are accommodated in the arylation. Aryl halides
possessing electron-deficient (see products 3ab, 3ad, 3ah,[17]
3gb), propyl (3ia), phenethyl (3ja), and 2-naphthylmethyl (3ka)
substitution all furnish the -arylated products in good
enantioselectivity. -Benzyl substituted lactam 1g was also
employed in the reaction with a number of different electrophilic
coupling partners using both Methods. Even with a more
hindered substrate, similar patterns of reactivity and selectivity to
-methyl substituted 1a were observed. When an electron-
deficient aryl chloride coupling partner is used in Method A or m-
bromotoluene is used in Method B with 1g, the desired product
is formed in high enantioselectivity and good yield (3gc and
3gd).
3
ae) and electron-rich (3af, 3ag) substituents at the para
position led to products with excellent enantioselectivites using
Method and respectively. Aryl halides possessing
A
B
substituents at the meta position are also permissible in both
Method A and B, although slightly diminished enantioselectivity
is observed when 3-chloroanisole is used as the electrophile
(
3ai). Unfortunately, only trace product is observed when ortho-
substituted aryl halides are exposed to our reaction
conditions.[18] Gratifiyingly, an N-methyl indole was also
tolerated, as we obtained 5-indolyl lactam 3al in moderate yield
and excellent enantioselectivity.
Table 5. Scope of the Lactam.a
[
a] Conditions for each method are as follows: Method A: lactam (1.5 equiv),
Ar–Cl (1.0 equiv), Pd (pmdba) (2.5 mol %), L3 (7.5 mol %) LiHMDS (1.5
equiv), dioxane (0.2 M), 100 °C, 20 h. Method B: lactam (1.5 equiv), Ar–Br (1.0
equiv), Pd (pmdba) (2.5 mol %), L4 (7.5 mol %) NaHMDS (1.5 equiv),
2
3
2
3
dioxane (0.2 M), 80 °C, 20 h. PMP = p-methoxyphenyl. pmdba = 4,4’ –
dimethoxydibenzylideneacetone.
Recognizing the potential value of these enantioenriched,
quaternary center-containing heterocycles to the synthetic and
pharmaceutical communities, we sought to utilize this new
transformation in the preparation of differentially substitutes five-
membered heterocycles (Scheme 1). -Quaternary lactam 3aa
can be swiftly deprotected with ceric ammonium nitrate (CAN)
providing unprotected lactam 4 in 73% yield. Reduction of the
Table 4. Scope of the Aryl Halide.a
[
a] Conditions for each method are as follows: Method A: 1a (1.5 equiv), Ar–
Cl (1.0 equiv), Pd (pmdba) (2.5 mol %), L3 (7.5 mol %), LiHMDS (1.5 equiv),
dioxane (0.2 M), 100 °C, 6 h. Method B: lactam (1.5 equiv), Ar–Br (1.0 equiv),
Pd (pmdba) (2.5 mol %), L4 (7.5 mol %) NaHMDS (1.5 equiv), dioxane (0.2
M), 80 °C, 15 h. [b] Absolute configuration determined via single crystal X-ray
analysis. PMP p-methoxyphenyl. pmdba 4,4’
dimethoxydibenzylideneacetone.
2
3
lactam carbonyl with lithium aluminum hydride provides the
2
3
corresponding medicinally valuable pyrrolidine (5).[
19]
Partial
=
=
–
reduction of the lactam with lithium triethylborohydride and
trapping of the resulting iminium ion with potassium cyanide
yields chiral aminonitrile 6 in moderate yield but with high
diastereoselectivity.
The scope of substitution at the lactam -carbon was then
examined (Table 5). We found that sterically demanding -
substituents are well tolerated in both Methods. Although the
yields are slightly diminished, the high levels of enantioselectivity
are retained. Examples having ethyl (3ha, 3hb), benzyl (3ga,
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201814475
COMMUNICATION
Scheme 1. Derivatization of Arylation Products.a
98–122. (b) F.-X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 19,
3
693–3712.
O
[
2]
For recent reviews on the synthesis of pyrrolidinone containing
alkaloids: (a) Y. Long-Wu; C. Shu, F. Gagosz, Org. Biomol. Chem.
2014, 12, 1833–1845. (b) F. Rivas, T. Ling, Org. Prep. Proced. Int.
Ph
PMP
N
O
4
Me
a
Ph
Me
HN
3aa
2016, 48, 254−295.
b
[3]
For some examples of biologically active pyrrolidines, see: (a) A. P.
Guzikowski, A. P. Tamiz, M. Acosta-Burruel, S. Hong- Bae, S. X. Cai, J.
E. Hawkinson, J. F. W. Keana, S. R. Kesten, C. T. Shipp, M. Tran, E. R.
Whittemore, R. M. Woodward, J. L. Wright, Z. L. Zhou, J. Med. Chem.
2000, 43, 984–994. (b) C. L. Lynch, J. J. Hale, R. J. Budhu, A. L.
Gentry, S. G. Mills, K.T. Chapman, M. MacCoss, L. Malkowitz, M. S.
Springer, S. L. Gould, J. A. DeMartino, S. J. Siciliano, M. A. Cascieri, A.
Carella, G. Carver, K. Holmes, W. A. Schleif, R. Danzeisen, D. Hazuda,
J. Kessler, J. Lineberger, M. Miller, E. A. Emini, Bioorg. Med. Chem.
Lett. 2002, 12, 3001–3004. (c) M. E. Hensler, G. Bernstein, V. Nizet, A.
Nefzi, Bioorg. Med. Chem. Lett. 2006, 16, 5073–5079. (d) X. Li, J. Li,
Mini-Rev. Med. Chem. 2010, 10, 794–805. (e) K. W. Lexa, H. A.
Carlson, Proteins 2011, 79, 2282–2290. (f) L. R. Whitby, Y. Ando, V.
Setola, P. K. Vogt, B. L. Roth, D. L. Boger, J. Am. Chem. Soc. 2011,
c
CN
Ph
Me
Ph
Me
PMP
PMP
N
N
6
5
[
°
°
a] Conditions: (a) CAN, MeCN/H
C to 23 °C, 16 h, 93% yield; (c) LiBEt
C, 5 h, 43% yield, 93:7 dr.
2
O, 0 °C, 30 min, 73% yield; (b) LAH, Et
2
O, 0
3
H, –78 °C to 23 °C, then AcOH, KCN, 0
In conclusion, we have developed a protocol for the first
transition metal-catalyzed enantioselective -arylation of -
lactams. Two related procedures were developed for this
transformation, allowing for the use of either aryl chlorides or
133, 10184–10194. (g) A. Raghuraman, E. Ko, L. M. Perez, T. R.
i
Ioerger, K. Burgess, J. Am. Chem. Soc. 201 1, 133, 12350–12353. For
select examples of biologically active pyrrolidinones see: (a) J. Caruano,
G.G. Muccioli, R. Robiette, Org. Biomol. Chem., 2016, 14, 10134–
10156. (b) J. J. –W. Duan, L. Chen, Z. R. Wasserman, Z. Lu, R. –Q. Liu,
M. B. Covington, M. Qian, K. D. Hardman, R. L. Magolda, R. C. Newton,
D. D. Christ, R. R. Wexler, C. P. Decicco, J. Med. Chem. 2002, 45,
bromides as electrophiles.
We are able to construct -
quaternary stereocenters in good yield and high enantiomeric
excess (up to 91% yield and 97% ee). Asymmetry is induced
through the use of a chiral, dialkyl bisphosphine ligand that
generates a Pd/ligand complex that is stable under strongly
basic conditions and elevated temperatures. Critical to the
development of these conditions was also the identification of an
appropriate base and electrophile combination. We found that a
broad range of substitution is tolerated on either coupling
partner. We also demonstrated that these -quaternary lactams
4954–4957.
[
4]
M. Teodorescu, M. Bercea, Polym Plast Technol Eng. 2015, 54, 923–
943.
[5]
(a) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840–3864.
Angew. Chem. Int. Ed. 2001, 40, 3726–3748. b) P. I. Dalko, L. Moisan,
Angew. Chem. 2004, 116, 5248–5286. Angew. Chem. Int. Ed. 2004, 43,
5138–5175. c) B. List, Synlett 2001, 11, 1675–1686. d) B. List,
can be efficiently converted to
a
number of different
Tetrahedron 2002, 58, 5573–5590. e) B. List, Acc. Chem. Res. 2004,
37, 548–557. f) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res.
2004, 37, 580–591. (g) S. Zhang, W. Wang, Q.–L. Zhou, Privileged
Chiral Ligands and Catalysts; Ed.; Wiley-VCH: Weinheim, Germany,
enantioenriched nitrogen containing heterocyclic building blocks
via product derivatizations. Finally, we were pleased to find that
in preliminary studies our conditions can be applied to the
enantioselective -vinylation of lactams.[20] A more extensive
report of these investigations will be disclosed in due course.
2011; pp 409−439. (h) A. J. B. Watson, D. W. C. MacMillan, I. Ojima,
Enantioselective Organocatalysis Involving Iminium, Enamine SOMO
and Photoredox Activation. In Catalytic Asymmetric Synthesis, 3rd ed.;
Ed.; Wiley & Sons: Hoboken, NJ, 2010; pp 39−57. (i) C. A. Caputo, N.
D. Jones, Dalton Trans. 2007, 4627.
[
[
6]
7]
D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D. E. White, S. C. Virgil, B. M.
Stoltz, Nat. Chem. 2012, 4, 130–133.
M. Hayashi, S. Bachman, S. Hashimoto, C. C. Eichman, B. M. Stoltz, J.
Am. Chem. Soc. 2016, 138, 8997–9000
Acknowledgements
[
8]
9]
L.–N. Wang, Q. Cui, Z.–X. Yu, J. Org. Chem. 2016, 81, 10165–10171.
(a) J. D. Stewart, S. C. Fields, K. S. Kochhar, H. W. Pinnick, J. Org.
Chem. 1987, 52, 2110–2113. (b) K. H. Shaughnessy, B. C. Hamann, J.
F. Hartwig, J. Org. Chem. 1998, 63, 6546–6553.
[
The NIH-NIGMS (R01GM080269) and Caltech are thanked for
support of our research program. C. I. Jette thanks the National
Science Foundation for
a
predoctoral fellowship.
I. Geibel
acknowledges the Deutsche Forschungsgemeinschaft (DFG) for a
postdoctoral fellowship (GE 3082/1-1). H.S. thanks Shionogi & Co.,
Ltd. for a research grant and fellowship. J. B. Morgan acknowledges
the University of North Carolina Wilmington for research
reassignment and travel funds. Dr. Scott Virgil (Caltech) is thanked
for instrumentation and SFC assistance.
[10] In the presence of strong base and no transition-metal catalyst, the
product was formed in good yield at 23 °C:
[
11] (a) M. J. Durbin, M. C. Willis, Org. Lett., 2008, 10, 1413–1415. (b) R. A.
Altman, A. M. Hyde, X. Huang, S. L. Buchwald, J. Am. Chem. Soc.
2008, 130, 9613–9620. (c) C.–K. Mai, M. F. Sammons, T. Sammakia,
Keywords: Palladium • -arylation • Nitrogen heterocycles •
quaternary stereocenters • asymmetric catalysis
Org. Lett. 2010, 12, 2306–2309. (d) E. Koch, R. Takise, A. Studer, J.
Yamaguchi, K. Itami, Chem. Commun. 2015, 51, 855–857. (e) J. Duan,
F. Y. A Kwong, J. Org. Chem. 2017, 82, 6468–6473. (f) P. K. R.
Panyam, B. Ugale, T. Gandhi, J. Org. Chem. 2018, 83, 7622–7632. (g)
A. Vignesh, W. Kaminsky, N. Dharmaraj, Chem. Cat. Chem. 2017, 9,
[
1]
For pyrrolidine-containing alkaloids, see: (a) T. J. Donohoe, C. J. R.
Bataille, G. W. Churchill, Annu. Rep. Prog. Chem., Sect. B 2006, 102,
910–914. (h) P. Li, S. L. Buchwald, Angew. Chem. 2011, 123, 6520–
524. Angew. Chem. Int. Ed. 2011, 50, 6396–6400. For
6
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201814475
COMMUNICATION
enantioselective examples see: (i) A. M. Taylor, R. A. Altman, S. L.
Buchwald, J. Am. Chem. Soc. 2009, 131, 9900–9901. (j) Y. Jin, M.
Chen, S. Ge, J. F. Hartwig, Org. Lett. 2017, 19, 1390–1393. For
examples of Pd-catalyzed enantioselective -arylation to form
quaternary centers see: (k) T. Hamada, A. Chieffi, J. Åhman, S. L.
Buchwald, J. Am. Chem. Soc. 2002, 124, 1261–1268. (l) J. García-
Fortanet, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 8108–8111.
Angew. Chem. 2008, 120, 8228–8231. (m) X. Liao, Z. Weng, J. F.
Hartwig, J. Am. Chem. Soc. 2008, 130, 195–200.
[
[
12] (a) J. Cossy, A. de Filippis, D. G. Pardo, Org. Lett. 2003, 5, 3037–3039.
b) A. de Filippis, D. G. Pardo, J. Cossy, Tetrahedron, 2004, 60, 9757–
767. Tetrahedron, 2004, 60, 9757–9767. (c) J. Cossy, A. de Filippis, D.
(
9
G. Pardo, Synlett, 2003, 14, 2171–2174.
13] An additional 22 ligands were examined under slightly modified
conditions. See supporting information for details.
[
[
14] J. E. Marcone, K. G. Moloy, J. Am. Chem. Soc. 1998, 120, 8527–8528.
15] (a) F. E. Goodson, T. I. Wallow, B. M. Novak, J. Am. Chem. Soc. 1997,
119, 12441–12453. (b) D. K. Morita, J. K. Stille, J. R. Norton, J. Am.
Chem. Soc. 1995, 117, 8576–8581.
[
[
[
16] We obtained a crystal structure of Pd/L4 complex. See supporting
information for details.
17] A control experiment omitting the Pd catalyst revealed a background
reaction by which the same product was formed in 80% yield.
18] Using Method A, the corresponding ortho-methyl product was obtained
in only 14% yield.
[
[
19] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257–10274.
20] Preliminary experiments showed diminished reactivity but good
selectivity in enantioselective -vinylation.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201814475
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
Carina I. Jette, Irina Geibel, Shoshana
Bachman, Masaki Hayashi, Shunya
Sakurai, Hideki Shimizu, Jeremy B.
Morgan*, Brian M. Stoltz*
Page No. – Page No.
Palladium-Catalyzed Construction of
Quaternary Stereocenters by
Enantioselective Arylation of -
Lactams with Aryl Chlorides and
Bromides
We report the first Pd-catalyzed enantioselective arylation of -substituted -
lactams. Two sets of conditions were developed for this transformation, allowing for
the use of either aryl chlorides or bromides as electrophiles. Utilizing commercially
available ferrocelane ligands, we have been able to construct -quaternary centers
in good yields (up to 91% yield) and high enantioselectivities (up to 97% ee).
ii
This article is protected by copyright. All rights reserved.