Copper-Catalyzed Enantioselective Allylic Alkylation with a γ-Butyrolactone-Derived Silyl Ketene Acetal

Article abstract of DOI:10.1002/anie.201912618

Herein, we report a Cu-catalyzed enantioselective allylic alkylation using a γ-butyrolactone-derived silyl ketene acetal. Critical to the development of this work was the identification of a novel mono-picolinamide ligand with the appropriate steric and electronic properties to afford the desired products in high yield (up to 96 %) and high ee (up to 95 %). Aryl, aliphatic, and unsubstituted allylic chlorides bearing a broad range of functionality are well-tolerated. Spectroscopic studies reveal that a Cu^I species is likely the active catalyst, and DFT calculations suggest ligand sterics play an important role in determining Cu coordination and thus catalyst geometry.

Full text of DOI:10.1002/anie.201912618

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Cu-Catalyzed Enantioselective Allylic Alkylation with a γ-
Butyrolactone-Derived Silyl Ketene Acetal.
Authors: Carina Jette, Zhengjia Tong, Ryan Hadt, 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.201912618
Angew. Chem. 10.1002/ange.201912618
Link to VoR: http://dx.doi.org/10.1002/anie.201912618
http://dx.doi.org/10.1002/ange.201912618

10.1002/anie.201912618
Angewandte Chemie International Edition
COMMUNICATION
γ
Cu-Catalyzed Enantioselective Allylic Alkylation with a -
Butyrolactone-Derived Silyl Ketene Acetal.
Carina I. Jette,1 Z. Jaron Tong,2 Ryan G. Hadt,*2 and Brian M. Stoltz*1
A. Pd-Catalyzed Enantioselective α-Allylation (Braun, 2011):
Abstract Herein, we report a Cu-catalyzed enantioselective allylic
O
R
O
H
alkylation using a γ-butyrolactone-derived silyl ketene acetal. Critical
to the development of this work was the identification of a novel mono-
picolinamide ligand with the appropriate steric and electronic
properties to afford the desired products in high yields (up to 96%)
and high ee (up to 95%). Aryl, aliphatic, and unsubstituted allylic
chlorides bearing a broad range of functionality are well-tolerated.
Spectroscopic studies reveal that a CuI species is likely the active
catalyst, and DFT calculations suggest ligand sterics play an
important role in determining Cu coordination and thus catalyst
geometry.
1. LiN(iPr)2, –78 °C
O
R
O
2. [PdL*], –78 °C, 40 h
OCO2Me
R = Me, 73% yield, 3:1 dr, 88% ee
R = H, 97% yield, 13% ee
R
R
B. Cu-Catalyzed α-Allylation with Silyl Ketene Acetals (Sawamura, 2011):
Me
OTMS
O
OP(O)(OEt)2
[CuL]
Ph
O
O
Ph
Me
Cs2CO3 , 23 °C
37% yield
3:1 dr
C. Traditional Cu-Catalyzed Enantioselective Allylic Alkylation
R2
R2
R3
[CuL*]
γ-Butyrolactones are important structural motifs present in
numerous natural products and pharmaceutically-relevant
molecules, and are also useful synthetic building blocks that serve
as precursors for other highly functionalized molecules.1 Although
there are a number of reports on the α-functionalization of γ-
butyrolactones to form chiral quaternary centers, only a limited
number of examples have demonstrated the construction of chiral
α-tertiary γ-butyrolactones. Some previously disclosed strategies
include chiral auxiliary-directed alkylation and subsequent
cyclization1b, Claisen-type rearrangements1c and catalytic
hydrogenation approaches.1d However, reports on the
construction of these molecules via enantioselective α-
functionalization remain limited, as the potential for racemization
of the product necessitates the development of exceptionally mild
reaction conditions.2
Since the seminal report by Tsuji,3 transition-metal catalyzed
allylic alkylation of enolate-derived nucleophiles continues to be a
powerful approach for α-functionalization of carbonyl-containing
compounds, as the alkene may be easily converted to a diverse
array of functional groups. Nonetheless, the use of γ-
butyrolactones in this transformation remains underdeveloped.4
R1
X
R1
with prochiral electrophiles
*
R3M
R1 = alkyl, aryl, heteroatoms
R2 = alkyl, aryl, H
M = ZnX, MgX, AlX2, Li, B(OR)3
D. This Research: Cu-Catalyzed Enantioselective Allylic Alkylation with Silyl Ketene Acetals
OTMS
O
[CuL*]
O
R1
R1
Cl
O
CsOAc , 30 °C
R2
R2
up to 95% yield
and 95% ee
R1 = aryl, heterocyclic, alkyl, H
R2 = H, Me
22 examples
with a prochiral nucleophile
O
O
L* =
NH
HN
N
Figure 1. Transition-metal catalyzed α-allylation of γ-butyrolactones.
More specifically, there is only one example on the use of this
transformation to produce enantioenriched α-tertiaryl lactones. 4c
Although the desired product is obtained in moderate
diastereoselectivity and good ee when an electrophile possessing
terminal substitution is used, the ee is extremely low when simple
allyl carbonate is employed (Figure 1A). As part of our ongoing
interest in exploring first row transition metals in enantioselective
catalysis,5 we became interested in a system reported by
Sawamura, wherein a Cu catalyst was used to obtain the desired
α-allyl γ-butyrolactone in a racemic fashion by reaction of silyl
ketene acetals with allylic phosphates (Figure 1B).6 It should be
noted that Cu as a catalyst in allylic substitutions with hard,
organometallic nucleophiles (pka >40) has been extensively
studied, and the desired branched products can be accessed in
high yields and enantioselectivities (Figure 1C).7 However, the
use of Cu with softer, enolate derived nucleophiles (pka < 30),
remains underdeveloped.8,9
1.
2.
Carina I. Jette, Brian M. Stoltz
Warren And Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering,
E-mail: stoltz@caltech.edu
Z. Jaron Tong, Ryan G. Hadt
Arthur Amos Noyes Laboratory of Chemical Physics
E-mail: rghadt@caltech.edu
California Institute of Technology, Pasadena CA 91125 (USA)
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.

10.1002/anie.201912618
Angewandte Chemie International Edition
COMMUNICATION
One challenge associated with the development of the
enantioselective variant of this transformation is that it involves a
prochiral nucleophile, which, to our knowledge, is unprecedented
in Cu-allylic alkylations. For this reason, we believed that we
would not be able to rely on chiral ligand scaffolds previously used
in this type of transformation. Herein, we report a Cu-catalyzed
Table 1. Evaluation of Ligands for Enantioselective Cu-
Catalyzed Allylic Alkylationa
Cu source (10 mol %)
OTMS
ligand (12 mol %)
base (0–26 mol %)
O
Ph
Cl
O
Ph
O
CsOAc (1 equiv)
THF (0.08 M), 30 °C, 14 h
1a
1 equiv
2
3a
1.5 equiv
asymmetric allylic alkylation with
enolate.
a γ-butyrolactone-derived
entry
Cu source
ligand yield (%)b ee (%)c
base
none
[Cu(MeCN)4]PF6
L1
74
22
1
Upon examination of more than 20 commercially available
ligands, we found cyclohexyl bis-picolinamide ligand L1 (Table 1,
entry 1) was the only ligand to impart any degree of
stereocontrol.10 Although encouraged by these results, we soon
found that the reaction outcome was highly variable, and after
careful examination of all the reaction parameters, we concluded
that the source of variability was the ligand itself. As a
consequence of the large number of coordinating atoms present
and its high flexibility, we believed L1 could bind to Cu in a variety
of conformations. As a result, small changes in the reaction set-
up could alter the distribution of different Cu complexes in
solution. We found that by employing mono-picolinamide L2 as
the ligand, CuCl2 as the Cu source, and by deprotonation of both
amide hydrogens on the ligand with n-BuLi, we were able to
consistently obtain our product in moderate yields and ee (entry
2).
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
n-BuLi (24 mol %)
n-BuLi (12 mol %)
n-BuLi (12 mol %)
n-BuLi (24 mol %)
n-BuLi (24 mol %)
n-BuLi (24 mol %)
LiHMDS (26 mol %)
LiHMDS (26 mol %)
L2
L3
L4
L5
L6
L7
L8
L9
44
60
64
44
54
33
90
73
62
11
14
40
62
62
92
91
2
3
4
5
6
7
8
9
CuCl2
CuCl2
CuCl2
CuCl2
LiHMDS (26 mol %)
LiHMDS (26 mol %)
LiHMDS (13 mol %)
NaHMDS (13 mol %)
10
11
12d
13d,e
L10
L11
L8
83
80
90
94
89
87
94
87
L8
14d,e
CuCl2
KHMDS (13 mol %)
L8
95
85
O
O
O
O
O
O
O
NH HN
NH HN
NH
O
NH
N
N
N
N
N
N
L4
L1
L2
L3
O
O
O
O
O
O
O
O
S
HN
HN
NH HN
NH
NH
To determine whether the benzamide moiety was critical for
reactivity and selectivity, we tested ligands bearing a mono-imine
(L3), an ester moiety (L4) and a sulfonamide (L5). The anionic
benzamide appears to be especially important for stereocontrol,
as removing this moiety led to a drastic decrease in ee (L3 and
L4, entries 3 and 4). In comparison, anionic sulfonamide-
containing L5 performed most similarly to L2 (entry 5).
Interestingly, we found the ee was insensitive to the identity of the
organic substituent on the amide; although the use of
naphthylamide L6 and pivalamide L7 resulted in very different
yields, the ee’s were identical (entries 6 and 7).
NH
HN
O
N
N
N
N
L8
L5
L6
L7
Me
O
O
O
O
O
O
NH
HN
NH
HN
NH
HN
N
N
F3C
N
MeO
L11
L9
L10
(a) 0.1 mmol scale. (b) Determined by 1HNMR analysis of the crude reaction mixture
using 1,3,5–trimethoxybenzene as a standard. (c) Determined by chiral SFC
analysis. (d) 5 mol% CuCl2, 6 mol% ligand, 0.042 M, 6 h. (e) 3 h reaction time.
After synthesizing and testing a number of chiral mono-
picolinamide ligands, we found that a bulkier backbone (L8, entry
8) was crucial for consistently high levels of reactivity and
selectivity. We also noted that altering the electronics at the
position para- to the nitrogen (L9 and L10, entries 9 and 10) or
increasing the steric bulk of the pyridine moiety (L11, entry 11) led
to no improvement in yield or ee.
group (3g) led to products in high yield and ee. Electrophiles
possessing substituents at the para-phenyl position such as
halogens (3i, 3j, 3k) a trifluoromethyl (3l) and a nitrile (3m) were
were also well-tolerated. Even heterocyclic compounds (3n and
3o), a diene substrate (3p), an aliphatic allylic chloride (3q) and
unsubstituted allyl chloride (3r) led to product formation in good
yields and ee’s.
Upon more extensive optimization we found that lowering the
reaction concentration from [0.08 M] to [0.042 M] led to a slight
increase in ee, and with 5 mol % Cu, the reaction was complete
in 6 h (entry 12).11 Furthermore, we noted that the counterion on
the catalytic base did have an effect on the overall outcome of the
reaction: when NaHMDS (entry 13) or KHMDS (entry 14) is used
instead of LiHMDS, the ee is slightly reduced but the reaction is
complete in only 3 hours.
Although trisubstituted olefin 1s (Scheme 1) led to the desired
product 3s in good selectivity and yield, the product formed from
α-,α-substituted olefin 1t was obtained in significantly lower yield
and ee. Intrigued by this result, we exposed Z-olefin substrate 1u
to our reaction conditions. Interestingly, we obtained the
corresponding Z-olefin product 3u in good yield, but in only
moderate ee. Furthermore, we also noted that even when a
mixture of linear and branched electrophiles is used, only the
linear product is obtained (3v). Taking these results into account,
and also considering that other electrophiles such as benzyl or
phenethyl chloride result in no product formation, we believe the
reaction is proceeding through a CuIII[σ+π] allyl species (Scheme
2, D).12
With optimized conditions in hand, we examined the scope of
the electrophile (Table 2). We were pleased to find 2-naphthyl 3c
and ortho- methylphenyl (3d) substituents were well tolerated.
Meta-phenyl substituted electrophiles (3b, 3e) also fared well, and
even a sensitive triflate (3f) and a bulky 3,5-dimethoxy phenyl
This article is protected by copyright. All rights reserved.

10.1002/anie.201912618
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Scope of the Allylic Chloridea
CuCl2 (5 mol %)
L8 (6 mol %), LiHMDS (13 mol %)
Scheme 1. Importance of Olefin Substitution Patterna
O
CuCl2 (5 mol %)
OTMS
O
L8 (6 mol %), LiHMDS (13 mol%)
Cl
O
O
R
Cl
R
O
Me
CsOAc (1 equiv)
M
Me
3s
2 (1.5 equiv), CsOAc (1 equiv)
THF (0.042 M), 30 °C, 6 h
THF (0.042
), 30 °C, 6 h
1a-t
2
3a-r
1s
87% yield, 89% ee
1.5 equiv
1 equiv
Me
Me
O
O
O
O
O
CuCl2 (5 mol %)
L8 (6 mol %), LiHMDS (13 mol%)
Cl
O
O
O
2 (1.5 equiv), CsOAc (1 equiv)
THF (0.042 M), 30 °C, 6 h
1t
3t
3a
90% yield, 94% ee
3bb
86% yield, 91% ee
3c
84% yield, 91% ee
65% yield, < 5% ee
Me
CuCl2 (5 mol %)
L8 (6 mol %), LiHMDS (13 mol%)
O
O
O
O
Me
TfO
Cl
O
O
O
2 (1.5 equiv), CsOAc (1 equiv)
THF (0.042 M), 30 °C, 6 h
O
1u
3u
3d
63% yield, 94% ee
3ed
80% yield, 90% ee
3fd
60% yield, 88% ee
97:3 Z/E
Cl
84% yield, 73% ee
Z/E = 89:11
O
O
O
O
CuCl2 (5 mol %)
L8 (6 mol %), LiHMDS (13 mol%)
MeO
O
O
O
O
2 (1.5 equiv), CsOAc (1 equiv)
THF (0.042 M), 30 °C, 6 h
Me
F
1v
3v
OMe
3g
74% yield, 86% ee
3h
90% yield, 93% ee
3i
85% yield, 92% ee
2.8:1 branched/linear
90% yield, 88% ee
(100% linear)
O
O
O
O
O
O
(a) Isolated yields on 0.2 mmol scale. SFC analysis was used to determine ee.
Cl
Br
F3C
3j
94% yield, 88% ee
3k
77% yield, 90% ee
3ld
83% yield, 90% ee
O
DFT calculations indicate L8 preferentially binds to Cu in a
tridentate fashion, via Npyridine, Npicolinamide, and Obenzamide atoms
(L8NNO•CuCl2, Table 3, entry 1). Regardless of the level of theory
employed, the alternative tridentate binding mode via the
benzamide nitrogen (L8NNN•CuCl2) is disfavored by 14-23
kcal/mol (entry 2 and Table S2). This large energy difference
renders the thermal interconversion between the two binding
modes unlikely; for this reason, we postulate only one conformer
of the pre-catalyst accounts for the observed asymmetric catalytic
activity.
O
O
O
O
O
S
O
NC
3mc,d
96% yield, 86% ee
3n
56% yield, 95% ee
3o
71% yield, 90% ee
O
O
O
O
O
O
3p
76% yield, 83% ee
3q
95% yield, 87% ee
3rc
95% yield, 80% ee
(a) Isolated yields on 0.2 mmol scale. SFC analysis was used to determine ee. (b)
Absolute stereochemistry was determined by X-ray diffraction. (c) With 10 mol %
CuCl2, 12 mol % L8, and 26 mol % LiHMDS. (d) synthesized from a mixture of linear
and branched allylic chlorides (see the SI for more details).
a
Table 3. DFT Calculations on L8 and L8•CuCl2
Given the novelty of the Cu/L8 complex, we chose to examine
it using continuous wave (CW) X-band electron paramagnetic
resonance (EPR), UV-vis spectroscopies, and density functional
theory (DFT) calculations. Although the crystal structure of a
planar CuII complex with a tetradentate, deprotonated L1 has
been reported,13 it was unclear how exclusion of one of the
pyridine moieties, and the presence of a large, bulky backbone
would affect the binding mode of the ligand. For this reason, we
aimed to determine whether our best performing ligand L8
coordinates through the two amide nitrogens, or if it adopts an
alternative binding mode through the benzamide oxygen, similarly
to the previously disclosed Mo/L2 complex.14
C1
C2
C1
C2
L8NNO•CuCl2
L8NNN•CuCl2
Egas phase
(kcal/mol)
Esolvent corrected
(kcal/mol)c
ligand binding
mode
entry
τ4’ C1
τ4’ C2
Preparing the pre-catalyst in THF afforded a green solution
with low intensity d-d transitions ranging from 560 to 1400 nm
(Figure 2 and S4). Spin quantification of the 77 K X-band EPR
spectra revealed a monomeric CuII center was the major species
at the reaction concentration.15 Negative ion mode ESI-MS
generated product ions and isotope patterns consistent with the
ionization of the fully deprotonated [L8•CuCl2]2- species,
indicating that the Cl- counter-ions may be playing a role in the
generation of a consistent complex.
with CuCl2
L8NNO•CuCl2
L8NNN•CuCl2
1
2
0
0
0.93
0.86
0.95
0.85
22.5
19.5
b
without CuCl2
3
relaxed L82-
L8NNO
L8NNN
0
0
0.96
0.93
0.86
0.97
0.95
0.85
4
5
18.7
39.5
13.6
30.0
(a) Obtained using B3LYP density functional with 38% Hartree-Fock exchange.
(b) Ligand coordination geometry was obtained by removing CuCl2 from the
optimized geometry of the corresponding complex.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912618
Angewandte Chemie International Edition
COMMUNICATION
To further probe the origin for this binding preference, we
performed single-point calculations on L8 in the absence of CuCl2
(entries 3-5). Interestingly, we found the energy gap between the
two conformations L8NNO and L8NNN is still retained (entries 4 and
5), implying ligand sterics affect the binding preference and tune
the metal coordination geometry. As demonstrated by the
geometry index τ4’,16 the two sp3 ring carbons C1 and C2 exhibit
a stronger deviation from the ideal tetrahedral geometry (τ4’ = 1)
Scheme 2. Proposed Reaction Mechanism
Li
O
N
OSiMe3
Ph
O
+
CsOAc
Silyl Ketene Acetal
Coordination
O
O
N
N
O
Ph
CuI
Reductive
Elimination
A
O
N
N
Ph
O
Ph
in L8NNN relative to L8NNO 17
. Thus, in addition to providing steric
H
Li
O
OSiMe3
LiO
CuIII
N
N
O
N
N
-OAc
O
CuI
bulk to assist in stereocontrol, the rigid backbone of L8 likely plays
O
an important role in enforcing NNO binding.
Ph
B
D
CsCl
Enantiodetermining
Cu Enolate Formation
Cs
N
Ph
Oxidative
Addition
LiO
CuI
N
O
Ph
Cl
Me3SiOAc
O
H
N
O
C
In order to demonstrate the synthetic utility of these products,
we subjected α-allyl γ-butyrolactone 3a and 3r to a number of
transformations (Scheme 3).23 Lactone 3a was reduced to the
corresponding lactol 4 using DIBAL-H. Lactol 4 was then
converted to the unsaturated ester, which spontaneously cyclized
to the corresponding tetrahydrofuran 5 in high yield and high
diastereoselectivity. Lactone 3a was also converted to the
corresponding chiral diol 6 in good yields using lithium aluminum
hydride. We also found 3r could be swiftly converted to the
corresponding methyl acrylate species via cross metathesis.
Scheme 3. Derivatization of Allyl
γ
-Butyrolactone Products
OH
O
Figure 2. Room temperature UV-vis and 77
K X-band EPR (inset)
A.
spectroscopic monitoring of the reaction of 5 mol% of L8•CuCl2 with silyl
ketene acetal 2.
O
O
4
3a
94% ee
96% yield,
anti:syn = 68:32
The characteristic d-d transitions and 77 K X-band EPR signal
of the starting L8•CuCl2 complex disappear at the start of the
reaction, signifying the CuII precatalyst is reduced to a CuI
complex (Figure 2).18 We found reduction occurs even in the
absence of CsOAc, indicating the silyl ketene acetal 2 is the
reductant.19 Consequently, we propose the reaction follows a CuI-
CuIII catalytic cycle as shown in Scheme 2.20
C.
B.
OEt
OH
O
OH
O
6
5
84% yield
95:5 anti:syn
92% ee
95% yield
94% ee
O
O
Grubbs II
MeO
O
methyl acrylate
DCM, 40°C , 3 h
O
We believe the catalytic cycle commences with coordination
of the electron-rich olefin of the silyl ketene acetal to CuI bis-
amidate complex A, forming B. The Si-O bond is then cleaved via
outer sphere attack by the acetate anion2d to afford the desired C-
bound Cu enolate C.21 We envision this could be the
enantiodetermining step, during which the lithium counter-ion may
assist through electrostatic interactions, preventing rotation of the
silyl ketene acetal. Dissociation of the benzamide then allows for
the coordination and subsequent oxidative addition of the allyl
chloride, generating CuIII[σ+π] species D.12,22 The sterically
encumbered CuIII species can then undergo reductive elimination
to generate the desired α-allyl γ-butyrolactone and the starting CuI
species A.
O
3r
7
95% yield
80% ee
A. DIBAL-H, CH2Cl2, –78 °C, 30 min. (b). NaH, triethylphosphonoacetate,
THF, 0 °C to 23 °C, 3 h. C. LiAlH4, Et2O, reflux, 3 h.
In conclusion, we have developed
a
Cu-catalyzed
enantioselective allylic alkylation with a non-stabilized enolate-
derived nucleophile. Critical to the development of this reaction
was the identification of a novel mono-picolinamide ligand that led
to product formation in high yields (up to 96%) and ee (up to 95%).
A number of electrophiles with a broad range of functionality were
well-tolerated in this reaction, including aryl, heteroaryl, and
aliphatic allylic chlorides. DFT calculations suggest ligand sterics
This article is protected by copyright. All rights reserved.

10.1002/anie.201912618
Angewandte Chemie International Edition
COMMUNICATION
9.
The use of first row transition metals in allylation is mainly limited to 1,3-
dicarbonyls: (a) Alexakis, A.; Begouin, J. M.; Crawley, M. L.; Guiry, P. J.;
Kammerer-Pentier, C.; Kleimark, J.; Klein, J. E M. N.; Langlois, J. –B.; Liron, F.;
Liu, W. –B.; Milhau, L.; Moberg, C.; Norrby, P. –O.; Plietker, B.; Poli, G.; Prestat,
G.; Trost, B. M. Weickmann, D.; Xia, J.–B.; You, S. –L. Transition Metal
Catalyzed Enantioselective Allylic Substitution in Organic Synthesis; Kazmeier,
U., Eds.; Springer, New York, 2012, vol. 38, pp1-341.To our knowledge, there
is only one report with Ni: (b) Wang, J.; Wang, P.; Wang, L.; Li, D.; Wang, K.;
Wang, Y.; Zhu, H.; Yang, D.; Wang, R. Org. Lett. 2017, 19, 4826–4829.
play an important role in determining metal coordination
geometry, leading to tri-dentate NNO Cu coordination by the
ligand. Preliminary mechanistic investigations indicate that a CuI
species is likely the active catalyst, and that the reaction may
proceed through a CuIII[σ+π] intermediate. Future work will focus
on gaining a deeper understanding of the reaction mechanism
and expanding the scope of this reaction to include other enolate
derived nucleophiles.24
10. For other ligands, bases, and copper salts tested, see S6-8, 22.
11. With LiHMDS as the base, the complexation could be carried out at room
temperature, allowing for an operationally simpler reaction set-up. For Cu/L
complexation using different bases, see S8.
Acknowledgements
The NIH-NIGMS (R01GM080269) and Caltech are thanked
for support of our research program. Financial support from
Caltech and the Dow Next Generation Educator Fund is gratefully
acknowledged (R. G. Hadt). C. I. Jette thanks the National
Science Foundation for a predoctoral fellowship. Alexander Q.
Cusumano is thanked for assistance and helpful discussions. Dr.
Scott Virgil is thanked for instrumentation and SFC assistance.
We thank Lawrence Henling for assistance with X-Ray Analysis.
Dr. Mona Shahgholi is acknowledged for mass spectrometry
assistance. Dr. Paul H. Oyala is thanked for his assistance with
EPR spectroscopy. We acknowledge Prof. H. B. Gray for the use
of the Cary 500 UV-vis-NIR spectrophotometer.
12.
(a) Harada, A.; Makida, Y.; Sato, T.; Ohmiya, H.; Sawamura, M. J. Am. Chem.
Soc. 2014, 136, 13932–13939. (b) Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J.
Am. Chem. Soc. 2008, 130, 12862–12863. (c) Yamanaka, M.; Kato, S.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 6287–6293. (d) Yoshikai, N.;
Nakamura, E. Chem. Rev. 2012, 112, 2339–2372.
13. (a) Mulqi, M.; Stephens, F. S.; Vagg, R. S. Inorg. Chim. Acta, 1981, 51, 9–14.
(b) Mulqi, M.; Stephens, F. S.; Vagg, R. S. Inorg. Chim. Acta, 1981, 52, 177–
182. (c) Fan, X.; Zhang, X.; Li, C.; Gu, Z. ACS Catal. 2019, 9, 2286–2291. (d)
Carlo Sambiagio. Investigations on the use of Amidic Ligands in Copper-
Catalyzed Arylation Reactions, Ph.D. Dissertation, University of Leeds, Leeds,
West Yorkshire, England, 2015.
14. (a) Trost, B. M.; Dogra, K.; Hachiya, I.; Emura, T.; Hughes, D. L.; Krska, S.;
Reamer, R. A.; Palucki, M.; Yasuda, N.; Reider, P. Angew. Chem. Int. Ed. 2002,
41, 1929–1932, Angew. Chem. 2002, 114, 2009–2012.
15. See S51 for more information.
Keywords: Copper • Allylic Alkylation • Enolate Nucleophiles• γ-
16. Okuniewski, A.; Rosiak, D.; Chojnacki, J.; Becker, B. Polyhedron. 2015, 90, 47–
57.
butyrolactones• Asymmetric Catalysis
17. Although the energy gap between the two binding modes of L2 was smaller
than that of L8, the energy difference was still too large for thermal
interconversion (Table S3).
References
18. We also observed a diamagnetic species by 1HNMR (S234)
19. (a) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 2912–2914.
(b) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2013, 135, 16074–16077. (c) Rathke, M.; Lindert, A. J. Am. Chem. Soc.
1971, 93, 4605–4606. (d) Kochi, J. K. J. Am. Chem. Soc. 1955, 77, 5724–5728.
(e) Kosower, E. M.; Cole, W. J.; Wu, G. –S, Cardy, D. E.; Meisters, G. J. Org.
Chem. 1963, 28, 630–633. (f) Kosower, E. M.; Wu, G. –S. J. Org. Chem. 1963,
28, 633–638.
1.
2.
(a) Seitz, M.; Reiser, O. 2005, 9, 285–292. (b) Meyers, A. I.; Yamamoto, Y.;
Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792–2796. (c) Madelaine,
C.; Valerio, V.; Maulide, N. Angew. Chem. Int. Ed. 2010, 49, 1583–1586,
Angew. Chem. 2010, 122, 1628–1631. (d) Mao, B.; Fañanás-Mastral, M.;
Feringa, B. L. Chem. Rev. 2017, 117, 10502–10566.
(a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.;
Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669–685. (b) Evans,
D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814–5815.
(c) Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jørgensen, K. A. Chem.
Eur. J. 2003, 9, 6145−6154. (d) Huang, Z.; Chen, Z.; Lim, L. H.; Quang, G. C.
P.; Hirao, H.; Zhou, J. Angew. Chem. Int. Ed. 2013, 52, 5807–5812, Angew.
Chem. 2013, 125, 5919 –5924.
20. The NNO binding preference was retained in a number of CuII and CuI
intermediates (Table S4).
21. IR data of our CuI catalyst indicates that the benzamide dissociates upon
exposure to 2. DFT data indicates that a C-bound CuI enolate is lower in energy
than the O-bound enolate (S50).
3.
4.
Tsuji, J.;Takahashi, H.; Morikawa, M. Tetrahedron Lett., 1965, 6, 4387–4388.
(a) James, J.; Guiry, P. J. ACS Catal. 2017, 7, 1397–1402. (b) Nascimiento de
Oliveira, M.; Fournier, J.; Arseniyadis, S.; Cossy, J. A. Org. Lett. 2017, 19, 14–
17. (c) Meletis, P.; Patil, M.; Thiel, W.; Frank, W.; Braun, M. Chem. Eur. J. 2011,
17 , 11243–11249. (d) Jiang, X.; Hartwig, J. F. Angew, Chem. Int. Ed. 2017, 56,
8887–8891. Angew, Chem. 2017, 129, 9013–9017.
22. We believe that oxidative addition to 1v generates a sterically congested
CuIII[σ+π] allyl species which undergoes a 1,3 allyl migration:12a
O
O
Cs
Cs
N
Ph
O
N
Ph
O
H
H
H
Cy
LiO
N
N
O
LiO
N
N
O
CuIII
CuIII
1,3 allyl migration
5.
(a) Ngamnithiporn, A.; Jette, C.; Bachman, S.; Virgil, S.; Stoltz, B. M. Chem.
Sci. 2018, 9, 2547–2551. (b) Hayashi, M.; Bachman, S.; Hashimoto, S.;
Eichman, C. C.; Stoltz, B.M. J. Am. Chem. Soc. 2016, 138, 8997–9000. (c) Han,
S.–J.; Doi, R.; Stoltz, B. M. Angew. Chem. Int. Ed. 2016, 55, 7437–7440,
Angew. Chem. 2016, 128, 7563 –7566.
Cy
23. For other potential applications of chiral α-allyl γ-butyrolactones, see S76.
24. For other nucleophiles tested, see S23.
6.
7.
Li, D.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2011, 133, 5672–5675.
(a) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 3765–3780. (b)
Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev.
2008, 108, 2796–2823. (c) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852.
8.
For Cu(II) catalysts with 1,3-dicarbonyls see (a) Trillo, P.; Baeza, A. Adv. Synth.
Catal. 2017, 359, 1735–1741. (b) Deng, Q.–H.; Wadepohl, H.; Gade, L. H. J.
Am. Chem. Soc. 2012, 134, 2946–2949. Given the large difference in sterics
and reactivity between stabilized and non-stabilized enolates, it is unlikely that
γ-butyrolactones would undergo allylation via a similar pathway.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912618
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
.
OTMS
[CuL*]
O
O
R1
R1
Cl
O
CsOAc , 30 °C
R2
R2
Carina I. Jette, Z. Jaron
Tong, Ryan G. Hadt, and
Brian M. Stoltz
up to 95% yield
and 95% ee
R1 = aryl, heterocyclic, alkyl, H
R2 = H, Me
22 examples
Page No. – Page No
O
O
Cu-Catalyzed
Enantioselective Allylic
L* =
NH
HN
Alkylation with a -
γ
Butyrolactone-Derived S
Ketene Acetal.
N
We report a Cu-catalyzed enantioselective allylic alkylation using a γ-butyrolactone-derived silyl
ketene acetal as a nucleophile. Critical to the development of this work was the identification of a
novel mono-picolinamide ligand with the appropriate steric and electronic properties to afford the
desired alkylation products in high yields (up to 96%) and high levels of enantiomeric excess (up
to 95%). DFT calculations suggest ligand sterics play an important role in determining Cu
coordination and thus catalyst geometry.
COMMUNICATION
This article is protected by copyright. All rights reserved.