N-heterocyclic Carbene-Cu-Catalyzed Enantioselective Conjugate Additions with Alkenylboronic Esters as Nucleophiles

Article abstract of DOI:10.1021/acscatal.7b02132

Catalytic enantioselective conjugate additions with easily accessible alkenylboronic acid pinacol esters as nucleophiles promoted by chiral copper complexes of N-heterocyclic carbenes are presented. These processes constitute an unprecedented instance of conjugate additions of a variety of functionalized alkenyl groups and afford desired products that are otherwise difficult to access in up to 98% yield and 99.5:0.5 enantiomeric ratio. The origins of ligand-controlled enantioselectivity are elucidated with density functional theory (DFT) calculations.

Full text of DOI:10.1021/acscatal.7b02132

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Article
N-Heterocyclic Carbene–Cu-Catalyzed Enantioselective
Conjugate Additions with Alkenylboronic Esters as Nucleophiles
Qinglei Chong, Zhenting Yue, Shuo-Qing Zhang, Chonglei Ji,
Fengchang Cheng, Haiyan Zhang, Xin Hong, and Fanke Meng
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02132 • Publication Date (Web): 18 Jul 2017
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ACS Catalysis
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N-Heterocyclic
Carbene–Cu-Catalyzed
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Enantioselective Conjugate Additions with
Alkenylboronic Esters as Nucleophiles
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Qinglei Chong†, Zhenting Yue†, Shuoqing Zhang‡, Chonglei Ji‡, Fengchang Cheng†, Haiyan
Zhang†, Xin Hong‡* and Fanke Meng†*
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
345 Lingling Road, Shanghai, 200032, China.
‡Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou, 310027, China.
ABSTRACT: Catalytic enantioselective conjugate additions with easily accessible
alkenylboronic acid pinacol esters as nucleophiles promoted by chiral copper complexes of Nꢀ
heterocyclic carbenes are presented. These processes constitute an unprecedented instance of
conjugate additions of a variety of functionalized alkenyl groups and afford desired products that
are otherwise difficultꢀtoꢀaccess in up to 98% yield and 99.5:0.5 enantiomeric ratio. The origins
of ligandꢀcontrolled enantioselectivity are elucidated with density functional theory (DFT)
calculations.
KEYWORDS: Conjugate addition, copper catalysis, alkenylboron, enantioselective catalysis, Nꢀ
heterocyclic carbene
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Introduction
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Copperꢀcatalyzed enantioselective conjugate additions of organometallic reagents to α,βꢀ
unsaturated compounds stand for a powerful method for efficient and selective construction of
C–C bonds.1 Reactions with highly reactive organometallic reagents such as Grignard
reagents,1cꢀf, 1l, 2 organozinc reagents1b, 1g, 1h, 3 and organoaluminum,1cꢀi, 4 organozirconium
reagents1k, 5 have been well established. In contrast, the utility of more robust nucleophiles has
been much less studied. Organoboronic acids and their derivatives are attractive due to their high
functional group tolerance and diversity, low toxicity and ease of access and handling. There are
only two reports regarding Cuꢀcatalyzed enantioselective 1,4ꢀconjugate additions with
arylboronic acid derivatives by Hayashi (Scheme 1a)6 and Zhou (Scheme 1b)7. In addition,
Sawamura disclosed the use of organoboranes as nucleophiles in Cuꢀcatalyzed enantioselective
conjugate additions (Scheme 1c).8
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Scheme 1. Cu-Catalyzed Enantioselective Conjugate Additions with Organoboron
Nucleophiles.
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Introduction of an alkenyl group into α,βꢀunsaturated compounds is desirable in organic
synthesis. Although Rhꢀcatalyzed enantioselective conjugate additions with organoboron
compounds have been well studied,1jꢀk alkenylboron compounds still stands for a class of
challenging nucleophiles. To the best of our knowledge, there is no protocol for highly efficient
and enantioselective conjugate additions of alkenylboron nucleophiles promoted by Cuꢀbased
catalysts.9 Herein, we describe the first catalytic enantioselective 1,4ꢀadditions of alkenylboronic
acid pinacol esters to enoates promoted by Nꢀheterocyclic carbene (NHC)–Cu complexes.
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We envision that a suitable Cu(I) complex could promote transmetallation with alkenyl–
B(pin) to generate alkenyl–Cu complex I, which could coordinate with diethyl
benzylidenemalonate 1a to form a πꢀcomplex II. Transfer of alkenyl group to the πꢀbond would
deliver the Cu(I) complex III, which rapidly collapsed to Cu enolate IV. Exchange of IV with
NaOtꢀBu released addition product V and regenerated the catalyst. (Scheme 1d)
The challenge for reactions with alkenylboron nucleophiles is their lower reactivity. In
addition, the metal salts that are present in the reactions with more reactive Grignard reagents,
organozinc reagents and organoaluminum reagents might work as Lewis acids to activate α,βꢀ
unsaturated compounds and lead to more organized transition states, resulting in higher reactivity
and better control of enantioselectivity.4g, 10 Such activation is significantly diminished in the
case of alkenylboronic esters as nucleophiles due to their weaker Lewis acidity. Therefore,
ligands that are strong σꢀdonor might be necessary to enhance the nucleophilicity of
alkenylcopper intermediate.11
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Results and discussion
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In our initial investigation, reactions of commercially available alkenyl–B(pin) (pin =
pinacolato) 2a with ethyl cinnamate in the presence of NHC–Cu or bisphosphine–Cu complexes
resulted in <2% conversion of starting materials. More electronically deficient ethyl
benzylidenemalonate 1a was tested. Transformation of 1a with alkenyl–B(pin) 2a catalyzed by
racꢀBINAP–Cu complex led to 46% conversion of 1a, indicating σꢀdonation of the bisphosphine
ligand is not strong enough to promote the alkenyl addition (Scheme 2a). Followꢀup studies
revealed that 1a did undergo efficient conjugate addition with 2a in the presence of NHC–Cu
complex derived from imidazolinium salt 4a, affording desired product 3a in 97% yield.
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Having established the viability of Cuꢀcatalyzed conjugate addition of alkenyl–B(pin) to
alkylidene malonates, we turned our attention to the development of an enantioselective variant
(Scheme 2a).
a
O
Cl
B
2a
5.0 mol % Imidazolinium salt,
O
COOEt
COOEt
1.5 equiv.
5.0 mol % CuCl, 1.5 equiv. NaOt-Bu
Cl
THF, 22 oC, 16 h
COOEt
Ph
Ph
COOEt
1a
3a
Me
Me
Me
Et
i-Pr
PF6
Cl
PF6
PF6
rac-BINAP
Ph
Ph
Ph
N
N
N
N
N
N
N
N
Me
Me
Me
Me Me
4a
OH Me
4b
OH
Et
OH i-Pr
4c
4d
97% yield, 94:6 e.r.
92% yield, 91:9 e.r.
93% yield, 83:17 e.r.
46% conv.
97% yield
Me
Me
Me
Me
PF6
PF6
PF6
PF6
PF6
Me
i-Pr
Ph
t-Bu
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
OH Me
OH Me
OH Me
OH Me
OH
Me
4f
4g
4h
4i
4e
92% yield, 95:5 e.r.
95% yield, 77:23 e.r.
90% yield, 97:3 e.r.
96% yield, 87:13 e.r.
89% yield, 90:10 e.r.
c
b
O
B
Cl
Ph
O
B
2a
5.0 mol % 4f,
O
5.0 mol % imidazolinium salt,
COOEt
COOCEt3
CN
2b
O
1.5 equiv.
5.0 mol % CuCl, 1.5 equiv. Base
5.0 mol % CuCl, 1.5 equiv. NaOt-Bu
Ph
Cl
COOEt
Ph
1.5 equiv.
COOCEt3
COOEt
THF, 22 oC, 16 h
THF, 22 oC, 16 h
Ph
Ph
Ph
COOEt
1a
6, d.r. ~1:1
3a
CN
4g: 76% yield, 60:40 e.r.
4i: 65% yield, 78:22 e.r.
LiOt-Bu: 39% yield, 70:30 e.r.
KOt-Bu: 99% yield, 88:12 e.r.
5
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Scheme 2. Optimization of Reaction Conditionsa
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aReactions were performed under N2 atmosphere; enantiomeric ratios (e.r.) were determined by HPLC analysis, see Supporting
Information for details.
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Reaction of enoate 1a with alkenyl–B(pin) 2a was carried out in the presence of NHC–Cu
complex in situ generated from imidazolinium salt 4b. Under these conditions, desired product
3a was delivered in 97% yield and 94:6 e.r.. Modification of the N–aryl moiety by increasing the
size of the 2,6ꢀsubstituents resulted in diminished enantioselectivity (cf. 4cꢀd). Reaction
catalyzed by Cu complex derived from imidazolinium salt 4e bearing 3,5ꢀsubstituents provided
3a in 95% yield and 77:23 e.r.. Followꢀup studies revealed that changing the aminoꢀalcohol
moiety of the ligand from phenylglycinol to valinol and tertꢀleucinol led to improvement of
enantioselectivity (cf. 4fꢀg). Cu complexes derived from imidazolinium salts 4h and 4i
containing two stereogenic centers promoted the reaction to deliver 3a in 87:13 and 90:10 e.r.
respectively. In addition, Na+ is important for high enantioselectivity. Reactions of enoate 1a and
alkenyl–B(pin) 2a in the presence of LiOtꢀBu and KOtꢀBu led to erosion of enantioselectity
(Scheme 2b). Further investigation indicates that reaction of cyanoester 5 that provides high
enantioselectivity in Hayashi’s work in the presence of NHC–Cu complexes derived from
imidazolinium salts 4g and 4i resulted in significantly lower enantioselectivity (Scheme 2c). One
prominent aspect of this protocol is that the imidazolinium salts 4fꢀg are airꢀstable solids, and can
be readily prepared in multiꢀgram quantities from inexpensive materials and without costly silica
gel column chromatography purifications.12 Moreover, the reactions with alkenyl–B(pin)
proceed in high efficiency and enantioselectivity at ambient temperature. Costly and
inconvenient cryogenic conditions are avoided.
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With the optimal conditions in hand, we first investigated the scope of enoates (Scheme 3).
Reactions in the presence of imidazolinium salt 4f or 4g were carried out, providing conjugate
addition products in similar enantioselectivity. Transformations of enoates bearing sterically
hindered aryl groups afforded desired products in high yield and selectivity (cf. 3b and 3f),
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COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt Cl
COOEt
COOEt
COOEt
COOEt
Cl
Cl
Cl
Cl
Cl
Br
Me
O
Br
CF3
3b
3c
3e
3f
3g
3d
with 4f: 88% yield, 96:4 e.r.
with 4g: 82% yield, 97:3 e.r.
wtih 4f: 93% yield, 95:5 e.r.
with 4g: 87% yield, 96:4 e.r.
with 4fb: 47% yield, 98:2 e.r.
with 4gb: 65% yield, 98:2 e.r.
with 4fb: 78% yield, 97:3 e.r.
with 4gb: 60% yield, 95.5:4.5 e.r.
with 4f: 85% yield, 88:12 e.r.
with 4g: 90% yield, 92:8 e.r.
with 4f: 65% yield, 97:3 e.r.
with 4g: 72% yield, 96:4 e.r.
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Ph
Ph
Ph
Ph
Cl
COOEt Cl
COOEt
COOEt
COOEt
COOEt
Me
Me
Me
N
S
3h
3j
3k
3l
3m
3i
with 4fb: 84% yield, 93:7 e.r.
with 4gb: 79% yield, 94.5:5.5 e.r.
with 4f: 83% yield, 84:16 e.r.
with 4g: 83% yield, 93:7 e.r.
with 4f: 86% yield, 83:17 e.r.
with 4g: 96% yield, 94:6 e.r.
with 4f: 27% yield, 75:25 e.r.
with 4g: 62% yield, 90:10 e.r.
with 4f: 78% yield, 90:10 e.r.
with 4g: 71% yield, 91:9 e.r.
with 4f: 62% yield, 95:5 e.r.
with 4g: 65% yield, 97:3 e.r.
MeO
F
F3C
NC
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Ph
COOEt
Ph
COOEt
Me
COOEt
COOEt
Ph
Ph
Ph
Ph
Ph
7a
7b
7c
7d
7e
7f
with 4f: 95% yield, 93:7 e.r.
with 4g: 93% yield, 95:5 e.r.
with 4f: 96% yield, 94.5:5.5 e.r.
with 4g: 89% yield, 96:4 e.r.
with 4f: 85% yield, 92.5:7.5 e.r.
with 4g: 88% yield, 94.5:5.5 e.r.
with 4f: 98% yield, 88:12 e.r.
with 4g: 95% yield, 92:8 e.r.
with 4f: 86% yield, 89:11 e.r.
with 4g: 75% yield, 94:6 e.r.
with 4f: 84% yield, 94:6 e.r.
with 4g: 89% yield, 97:3 e.r.
S
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
TBSO
COOEt
(Boc)2N
COOEt
COOEt
COOEt
Ph
Ph
Ph
Ph
Cl
Ph
OMe
Ph
7j
7k
7l
7g
7h
7i
with 4f: 92% yield, 94:6 e.r.
with 4g: 88% yield, 98:2 e.r.
with 4f: 95% yield, 95:5 e.r.
with 4g: 96% yield, 97:3 e.r.
with 4f: 88% yield, 96:4 e.r.
with 4g: 91% yield, 97:3 e.r.
with 4f: 95% yield, 91:9 e.r.
with 4g: 95% yield, 95:5 e.r.
with 4f: 72% yield, 99.5:0.5 e.r.
with 4g: 89% yield, 98:2 e.r.
with 4f: 94% yield, 95:5 e.r.
with 4g: 95% yield, 95:5 e.r.
COOEt
COOEt
COOEt
Me
COOEt
COOEt
COOEt
O
COOEt
COOEt
COOEt
Me
Me
COOEt
Ph
COOEt
COOEt
Me Ph
Ph
Ph Ph
OMe
OPMB
7m
7n
8a
8b
8c
8d
with 4f: 98% yield, 97:3 e.r.
with 4g: 98% yield, 98:2 e.r.
with 4f: 86% yield, 91:9 e.r.
with 4fb: 54% yield, 82:18 e.r.
with 4fb: 98% yield, 77:23 e.r.
with 4g: 88% yield, 76:24 e.r.
with 4i: 95% yield, 93:7 e.r.
with 4f: 75% yield, 80:20 e.r.
with 4g: 98% yield, 74:26 e.r.
with 4i: 91% yield, 91:9 e.r.
with 4f: 59% yield, 94.5:5.5 e.r.
with 4g: 89% yield, 91:9 e.r.
with 4i: 87% yield, 96:4 e.r.
with 4g: 93% yield, 78.5:21.5 e.r. with 4gb: 55% yield, 84:16 e.r.
with 4i: 93% yield, 92:8 e.r.
Scheme 3. Substrate Scopea
a Same conditions as shown in Scheme 2. b 10 mol % Imidazolinium salts and CuCl were used.
although 10 mol % catalyst loading is necessary in the case of formation of 3f. Arylꢀsubstituted
enoates containing electronꢀwithdrawing groups can be converted into products in 60–93% yield
and 95:5–97:3 e.r. (cf. 3cꢀd, 3f). Halogen substituents are well tolerated in the reaction
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conditions (cf. 3c and 3f). Reactions with both electronꢀrich and electronꢀdeficient heteroꢀaryl
substituents generated products in 62–90% yield and 88:12–97:3 e.r. (cf. 3gꢀi). In these cases, Cu
complex derived from 4g gives slightly higher enantioselectivity. Enoates that contain primary
and secondary alkyl substitutent are also suitable substrates, delivering products without
significant erosion of enantioselectivity (cf. 3jꢀm).
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Next, the scope of alkenyl–B(pin) was studied (Scheme 3). Reactions with alkenylboron
compounds bearing Eꢀ1,2ꢀdisubstituted alkene moieties afforded addition products in 75–98%
yield and 88:12–99.5:0.5 e.r. (cf. 7aꢀn). In most cases, Cu complex derived from imidazolinium
salt 4g induces similar enantioselectivity with that formed from 4f. Transformations of alkenyl–
B(pin) that contain electronꢀdonating (7bꢀc, 7f, 7h) and electronꢀwithdrawing (7dꢀe, 7g) aryl
groups provided products in high yield and enantioselectivity. Heteroarylꢀsubstituted alkenyl–
B(pin) are good substrates (7i). Alkylꢀsubstituted alkenyl–B(pin) were converted into products in
up to 96% yield and 98:2 e.r. (cf. 7jꢀl). Protected amine and alcohol are well tolerated. We also
investigated simple vinyl–B(pin) as nucleophile; product 7m was generated in 98% yield and
97:3 e.r. and 98:2 e.r. in the presence of 4f and 4g respectively. Reactions with commercially
available 1,2,2ꢀtrisubstituted alkenyl–B(pin) afforded addition product 7n in high efficiency,
whereas in this case Cu complex formed from imidazolinium salt 4f induced much higher
enantioselectivity.
Other substitution patterns of alkenyl–B(pin) nucleophiles were investigated. However,
ligands optimized for Eꢀ1,2ꢀdisubstituted alkenyl–B(pin) proved to be not selective. In addition,
reactions with enoates bearing electronꢀdonating groups resulted in lower enantioselectivity
under previous conditions. Therefore, further ligand optimization is necessary for development
of highly enantioselective conjugate additions.
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Reinvestigation of Cu complexes derived from imidazolinium salts shown in Scheme 2a
revealed that NHC–Cu complex in situ generated from imidazolinium salt 4i promoted the
reactions with higher enantioselectivity. As shown in Scheme 3, transformations of 1,1,2ꢀ
trisubstituted and Zꢀ1,2ꢀdisubstituted alkenyl–B(pin) afforded 8a and 8b in much higher
enantioselectivity (92:8 and 93:7 e.r.) in the presence of NHC–Cu complex prepared from
imidazolinium salt 4i. Furthermore, enoates bearing electronꢀdonating aryl groups can be
converted into products in higher selectivity (cf. 8cꢀd). It is worth mentioning that such alkenyl
groups are otherwise difficult to introduce through reactions with Grignard reagents, organozinc
reagents or organoaluminum reagents. These results indicated that the enantioselectivity of
NHC–Cuꢀcatalyzed enantioselective conjugate additions with alkenyl–B(pin) is highly sensitive
to the substitution patterns of the alkenyl groups. Ligand optimization is necessary according to
different substrate combinations.
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To understand the origins of ligandꢀcontrolled enantioselectivity, we studied the determining
olefin insertion transition states with DFT calculations at the ωB97XꢀD/6ꢀ311+G(d,p)ꢀ
SMD(THF)//ωB97XꢀD/6ꢀ31G(d) level.13 The optimized structures and relative enthalpies and
free energies of transition states for the insertion with Eꢀvinyl copper species and ethyl
benzylidenemalonate 1a, TS1 and TS2, are summarized in Scheme 4a.14 The sodium bridge
model is adapted from previous computational studies.9 This is also supported by the results that
reactions in the presence of LiOtꢀBu and KOtꢀBu provide lower enantioselectivity (Scheme 2b).
In addition, the diethyl ester moiety is important for formation of the sodium bridge. This
explains why reaction of cyanoester 5 led to low enantioselectivity (Scheme 2c). For ligand 4g,
TS1, which leads to the major enantiomer product 7a, is 2.0 kcal/mol more favorable than TS2
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in terms of free energy. This is consistent with the experimental enantioselectivity (95:5, Scheme
5
6
3). The favored transition state TS1 has a CHꢀπ interaction15 between the malonate phenyl CꢀH
7
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46
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52
53
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56
57
58
59
60
Scheme 4. Mechanistic Studies
and the mesityl group of ligand 4g (highlighted with green line in TS1). This CHꢀπ interaction
does not exist in the competing TS2, and TS2 has steric repulsions between the malonate phenyl
group and the bulky tBu group of the ligand. Thus, ligand 4g prefers to have the malonate phenyl
group proximal to the mesityl group of the ligand, making TS1 the favorable transition state and
eventually generating enantiomer 7a.
The ligand 4i provided the highest enantioselectivity for reactions with Zꢀ1,2ꢀdisubstituted
alkenyl–B(pin) (cf. 8b, Scheme 3). The computed energy differences of the competing transition
states with Zꢀvinyl copper species and ethyl benzylidenemalonate 1a reproduced the trends in
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experiments (Scheme 4b). TS3 has unique dual CHꢀπ interactions. Both phenyl groups of the
substrates have the appropriate proximity to achieve the CHꢀπ interaction with the ligand. This
significantly stabilizes TS3, making ligand 4i achieve the highest enantioselectivity for Zꢀolefins
among the tested ligands.
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The reaction can be conducted on multiꢀgram scale. As shown in Scheme 5a, reaction of ethyl
benzylidenemalonate 1a (1.12 g) with alkenyl–B(pin) 2a (1.56 g) in the presence of NHC–Cu
complex derived from imidazolinium salt 4f afforded 3a in 98% yield and 95.5:4.5 e.r..
Decarboxylation of the conjugate addition products was studied. Treatment of 8d with NaCl in
o
DMSO and H2O at 155 C generated decarboxylation product 9 in 92% yield, which constitutes
products resulted from a formal enantioselective alkenyl conjugate additions to α,βꢀunsaturated
esters that have been unprecedented (Scheme 5b).16 Ester 10 was transformed into a member of a
family of GPR40 agonists was delivered after several functional group manipulations. Previous
method for installation of the stereogenic center is resolution of racemic mixture.17 The
advantage of such catalytic enantioselective protocol is that diversified alkenyl groups with
various functional groups can be easily introduced, which is of importance in leading compounds
discovery for pharmaceutical molecules.
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a
Me
PF6
O
i-Pr
5.0 mol %
Cl
B
N
N
2a
O
Me
(1.56 g)
1.5 equiv.
OH Me
4f
COOEt
COOEt
5.0 mol % CuCl, 1.5 equiv. NaOt-Bu
Cl
THF, 22 oC, 16 h
COOEt
COOEt
Ph
10
11
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Ph
3a
(1.56 g)
1a
(1.12 g)
98% yield, 95.5:4.5 e.r.
b
O
COOEt
OH
COOEt
ref 17
COOEt
NaCl, DMSO, H2O
155 oC, 10 h
O
t-Bu
F
OPMB
OPMB
MeO
8d
96:4 e.r.
9
92% yield, 98:2 e.r.
member of a family of GPR40 agonists
Scheme 5. Gram Scale Reaction and Application
Conclusion
In conclusion, we have disclosed the first NHC–Cuꢀcatalyzed enantioselective conjugate
additions of readily available alkenyl–B(pin) to α,βꢀunsaturated compounds that can be prepared
in a single step. The reactions are performed at ambient temperature in the presence of NHC–Cu
complexes in situ generated from easily accessible airꢀstable imidazolinium salts. Alkenyl groups
with a variety of substitution patterns and functional groups can be introduced into products in
high efficiency and enantioselectivity. The enantiomerically enriched products may serve as
precursors to other useful derivatives that would otherwise be difficult to prepare. The models
for enantioselective induction were investigated through DFT calculations, illustrating the
selectivity with different catalysts and the unique way of stereogenicity induction of the catalysts
that distinguishes our catalytic system from the previous.6, 12 Development of conjugate additions
with other organoboron nucleophiles is underway.
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ASSOCIATED CONTENT
5
6
7
The Supporting Information is available free of charge on the ACS Publications websites.
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Experimental procedures, spectroscopic data, and the NMR spectra of all the products (PDF)
Crystallographic data for 7a (CIF)
AUTHOR INFORMATION
Corresponding Author
*mengf@sioc.ac.cn
*hxchem@zju.edu.cn
Notes
The authors declare no conflict of interest.
ACKNOWLEDGMENT
This work was financially supported by State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, the “Hundred Talents Plan” of Chinese Academy of
Sciences, Zhejiang University, the “Thousand Youth Talents Plan”, Shanghai Sailing Program
(Grant No. 17YF1424100), Strategic Priority Research Program of the Chinese Academy of
Sciences (Grant No. XDB20000000) and the “Fundamental Research Funds for the Central
Universities”. We thank Prof. Kuiling Ding for the kind help of experimental space, HPLC
analysis and chemical supply.
REFERENCES
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Asymmetric Synthesis; Alexakis, A.; Krause, N.; Woodward, S. Eds; WileyꢀVCH, Weinherm,
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2014, p 33–69. (b) Kotora, M.; Betík, R. in Catalytic Asymmetric Conjugate Reactions; Córdova,
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M.; Campagne, J.ꢀM. Angew. Chem. Int. Ed. 2015, 54, 11830–11834. (g) DrissiꢀAmraoui, S.;
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H.; Mauduit, M.; Campagne, J.ꢀM. Adv. Synth. Catal. 2016, 358, 2519–2540.
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(4) For recent examples, see (a) Cottet, P.; Müller, D.; Alexakis, A. Org. Lett. 2013, 15, 828–
831. (b) Müller, D.; Alexakis, A. Chem. Eur. J. 2013, 19, 15226–15239. (c) GoncalvesꢀContal,
S.; Gremaud, L.; Alexakis, A. Angew. Chem. Int. Ed. 2013, 52, 12701–12704. (d) Willcox, D.;
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A.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 736–739. (f) Dabrowski, J. A.; Villaume, M.
T.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2013, 52, 8156–8159. (g) McGrath, K. P.; Hoveyda,
A. H. Angew. Chem. Int. Ed. 2014, 126, 1910–1914.
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Garrec, K.; Fletcher, S. P. Org. Lett. 2016, 18, 3814–3817. (c) Rideau, E.; Mäsing, F.; Fletcher,
S. P. Synthesis 2015, 47, 2217–2222. (d) Roth, P. M. C.; Fletcher, S. P. Org. Lett. 2015, 17, 912–
915. (e) Oi, S.; Sato, T.; Inoue, Y. Tetrahedron Lett. 2004, 45, 5051–5055. (f) Nicolaou, K. C.;
Tang, W.; Dagneau, P.; Faraoni, R. Angew. Chem. Int. Ed. 2005, 44, 3874–3879.
(6) Takatsu, K.; Shintani, R.; Hayashi, T. Angew. Chem. Int. Ed. 2011, 50, 5548–5552.
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6
(7) Wu, C.; Yue, G.; Nielsen, C. D.ꢀT.; Xu, K.; Hirao, H.; Zhou, J. J. Am. Chem. Soc. 2016,
138, 742–745.
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(8) Yoshida, M.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2012, 134, 11896–11899.
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(9) For Cuꢀcatalyzed 1,4ꢀconjugate additions of in situ generated allylcopper intermediates,
see: (a) Li, X.; Meng, F.; Torker, S.; Shi, Y.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2016, 55,
9997–10002. For Cuꢀcatalyzed 1,6ꢀconjugate additions of allenyl–B(pin) and in situ generated
allylcopper complexes, see: (b) Meng, F.; Li, X.; Torker, S.; Shi, Y.; Shen, X.; Hoveyda, A. H.
Nature 2016, 537, 387–393.
(10) (a) Harutyunyan, S. R.; López, F.; Browne, W. R.; Correa, A.; Peña, D.; Badorrey, R.;
Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103–9118. (b)
Wang, S. Y.; Ping, S.; Loh, T. P. Adv. Synth. Catal. 2010, 352, 3185–3189.
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367–374.
(13) The computational details are included in the supplementary information.
(14) Extensive conformational searches have been conducted on the transition states. Only the
most stable conformers are shown in the figures. The optimized structures and relative energies
of all conformers are included in the supplementary information.
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(15) For selected studies on arylꢀaryl interaction, see: (a) Hobza, P.; Selzle, H. L.; Schlag, E. W.
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Chem. A 2007, 111, 3446–3457. (d) Singh, N. J.; Min, S. K.; Kim, D. Y.; Kim, K. S. J. Chem.
Theory Comput. 2009, 5, 515–529.
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(16) Lanners, S.; NorouziꢀArasi, H.; Khiri, N.; Hanquet, G. Eur. J. Org. Chem. 2007, 4065–
4075.
(17) (a) Houze, J. B.; Zhu, L.; Sun, Y.; Akerman, M.; Qiu, W.; Zhang, A. J.; Sharma, R.;
Schmitt, M.; Wang, Y.; Liu, J.; Liu, J.; Medina, J. C.; Reagan, J. D.; Luo, J.; Tonn, G.; Zhang, J.;
Lu, J. Y.ꢀL.; Chen, M.; Lopez, E.; Nguyen, K.; Yang, L.; Tang, L.; Tian, H.; Shuttleworth, S. J.;
Lin, D. C.ꢀH. Bioorg. Med. Chem. Lett. 2012, 22, 1267–1270. (b) Brown, S. P.; Dransfield, P.;
Fu, Z.; Houze, J.; Jiao, X. Y.; Kohn, T. J.; Pattaropong, V.; Vimolratana, M.; Schmitt, M. J.;
Patent WO2008/130514 A1, 2008.
TOC
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a
d
Page 17 of 22
COOCEt3
ACS Catalysis
R'
R1
NHC–Cu complex,
KOt-Bu, dioxane
R2
COOCEt3
CN
R2
R
R
(pin)B
R1
O
R3
ONa
Me
1
2
3
4
LCu(I) Ot-Bu
CN
R3
NaOt-Bu
R'
B
O
2
Me
Ph
OEt
R' = aryl
CO2Et
V
5
6
7
8
9
(pin)B Ot-Bu
R2
R1
R3
OCu(I)L
R1
R2
10
Ph
OEt
CO2Et
LCu(I)
b
11
12
phosphoramidite–Cu complex
KOAc, toluene
O
R'
R
O
CO2Et
CO2Et
I
R3
IV
Ph
This work:
R
Ar
13
Ar
R'
B
1a
14
15
16
17
18
19
20
21
22
∗ Efficiency?
O
B
O
B
R' = aryl
∗ Enantioselectivity?
∗ Scope of Alkenyl–B(pin)?
R'
O
R'
R2
R1
R2
L
I
R1
Cu(I)L
R3
R3
Ph
II
Cu
CO2Et
CO2Et
Ph
CO2Et
CO2Et
c
III
ACS Paragon Plus Environment
R'
R
O
O
23
24
Me
Me
NHC–Cu complex,
PhOK, toluene
N
N
R
25
BBN
R'
26
27
N
N

a
ACS Catalysis
Page 18 of 22
O
Cl
B
2a
5.0 mol % Imidazolinium salt,
O
1
2
3
4
5
6
7
COOEt
COOEt
1.5 equiv.
5.0 mol % CuCl, 1.5 equiv. NaOt-Bu
Cl
THF, 22 oC, 16 h
COOEt
Ph
Ph
COOEt
1a
3a
8
9
Me
Me
Me
Et
i-Pr
PF6
Cl
PF6
PF6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
rac-BINAP
Ph
Ph
Ph
N
N
N
N
N
N
N
N
Me
Me
Me
Me Me
4a
OH Me
OH
Et
OH i-Pr
4d
4b
4c
93% yield, 83:17 e.r.
97% yield, 94:6 e.r.
92% yield, 91:9 e.r.
46% conv.
97% yield
Me
Me
Me
Me
PF6
PF6
PF6
PF6
PF6
Me
i-Pr
t-Bu
Ph
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
OH Me
OH Me
OH Me
OH Me
OH
Me
4f
4g
4h
4i
4e
92% yield, 95:5 e.r.
90% yield, 97:3 e.r.
96% yield, 87:13 e.r.
89% yield, 90:10 e.r.
95% yield, 77:23 e.r.
c
b
O
B
Cl
31
Ph
O
B
2a
5.0 mol % 4f,
32
33
34
35
36
37
38
39
40
41
5.0 mol % imidazolinium salt,
O
COOEt
COOCEt3
CN
2b
O
1.5 equiv.
COOEt
5.0 mol % CuCl, 1.5 equiv. Base
5.0 mol % CuCl, 1.5 equiv. NaOt-Bu
Ph
Cl
COOEt
Ph
1.5 equiv.
COOCEt3
THF, 22 oC, 16 h
THF, 22 oC, 16 h
Ph
Ph
Ph
COOEt
1a
6, d.r. ~1:1
3a
CN
ACS Paragon Plus Environment
LiOt-Bu: 39% yield, 70:30 e.r.
KOt-Bu: 99% yield, 88:12 e.r.
4g: 76% yield, 60:40 e.r.
4i: 65% yield, 78:22 e.r.
5

COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt Cl
COOEt
COOEt
COOEt
ACS Catalysis
Page 19 of 22
Cl
Cl
Cl
Cl
Cl
COOEt
Br
Me
1
2
3
4
5
6
7
8
9
O
Br
CF3
3b
3c
3e
3f
3g
3d
with 4f: 88% yield, 96:4 e.r.
with 4g: 82% yield, 97:3 e.r.
wtih 4f: 93% yield, 95:5 e.r.
with 4g: 87% yield, 96:4 e.r.
with 4fb: 47% yield, 98:2 e.r.
with 4gb: 65% yield, 98:2 e.r.
with 4fb: 78% yield, 97:3 e.r.
with 4gb: 60% yield, 95.5:4.5 e.r.
with 4f: 85% yield, 88:12 e.r.
with 4g: 90% yield, 92:8 e.r.
with 4f: 65% yield, 97:3 e.r.
with 4g: 72% yield, 96:4 e.r.
10
11
COOEt
COOEt Cl
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Ph
Ph
Ph
Ph
12
Cl
COOEt
COOEt
COOEt
COOEt
13
14
15
16
17
18
Me
Me
Me
N
S
3h
3j
3k
3l
3m
3i
with 4fb: 84% yield, 93:7 e.r.
with 4f: 83% yield, 84:16 e.r.
with 4g: 83% yield, 93:7 e.r.
with 4f: 86% yield, 83:17 e.r.
with 4g: 96% yield, 94:6 e.r.
with 4f: 27% yield, 75:25 e.r.
with 4g: 62% yield, 90:10 e.r.
with 4f: 78% yield, 90:10 e.r.
with 4g: 71% yield, 91:9 e.r.
with 4f: 62% yield, 95:5 e.r.
with 4g: 65% yield, 97:3 e.r.
19
b
20
with 4g : 79% yield, 94.5:5.5 e.r.
21
22
23
F
NC
MeO
F3C
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
24
Ph
COOEt
Ph
COOEt
Me
COOEt
COOEt
25
26
27
28
29
Ph
Ph
Ph
Ph
Ph
7c
7d
7e
7f
7a
7b
with 4f: 84% yield, 94:6 e.r.
with 4g: 89% yield, 97:3 e.r.
with 4f: 95% yield, 93:7 e.r.
with 4f: 96% yield, 94.5:4.5 e.r.
with 4g: 89% yield, 96:4 e.r.
with 4f: 85% yield, 92.5:7.5 e.r.
with 4g: 88% yield, 94.5:5.5 e.r.
with 4f: 98% yield, 88:12 e.r.
with 4g: 95% yield, 92:8 e.r.
with 4f: 86% yield, 89:11 e.r.
with 4g: 75% yield, 94:6 e.r.
30
with 4g: 93% yield, 95:5 e.r.
31
32
33
34
35
36
37
38
39
S
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
TBSO
COOEt
(Boc)2N
COOEt
COOEt
COOEt
Ph
Ph
Ph
Ph
Cl
Ph
OMe
Ph
7j
7k
7l
7g
7h
7i
with 4f: 92% yield, 94:6 e.r.
with 4g: 88% yield, 98:2 e.r.
with 4f: 95% yield, 95:5 e.r.
with 4g: 96% yield, 97:3 e.r.
with 4f: 88% yield, 96:4 e.r.
with 4g: 91% yield, 97:3 e.r.
with 4f: 95% yield, 91:9 e.r.
with 4f: 72% yield, 99.5:0.5 e.r.
with 4g: 89% yield, 98:2 e.r.
with 4f: 94% yield, 95:5 e.r.
with 4g: 95% yield, 95:5 e.r.
40
with 4g: 95% yield, 95:5 e.r.
41
42
43
44
45
46
47
48
49
50
51
COOEt
COOEt
COOEt
Me
COOEt
COOEt
COOEt
COOEt
O
COOEt
COOEt
COOEt
Me
Me
COOEt
COOEt
Ph
Me Ph
Ph
Ph Ph
OMe
OPMB
7m
7n
8a
8b
8c
8d
with 4fb: 54% yield, 82:18 e.r.
with 4fb: 98% yield, 77:23 e.r.
with 4f: 75% yield, 80:20 e.r.
with 4g: 98% yield, 74:26 e.r.
with 4i: 91% yield, 91:9 e.r.
52
with 4f: 98% yield, 97:3 e.r.
with 4f: 86% yield, 91:9 e.r.
with 4g: 93% yield, 78.5:21.5 e.r. with 4gb: 55% yield, 84:16 e.r.
with 4f: 59% yield, 94.5:5.5 e.r.
with 4g: 89% yield, 91:9 e.r.
with 4i: 87% yield, 96:4 e.r.
ACS Paragon Plus Environment
53
with 4g: 98% yield, 98:2 e.r.
54
55
with 4g: 88% yield, 76:24 e.r.
with 4i: 93% yield, 92:8 e.r.
with 4i: 95% yield, 93:7 e.r.

a.
b.
ACS Catalysis
Page 20 of 22
insertion
insertion
transition states
transition states
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
1
2
3
4
CuL
CuL
Ph
Ph
Ph
+
+
Ph
Ph
COOMe
1a
COOMe
1a
Ph
Ph Ph
L = 4g and 4i
7a and its enantiomer
L = 4g and 4i
8b and its enantiomer
5
6
7
Ligand = 4g
Ligand = 4g
8
9
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
O
O
Me
Me
Me
O
Me
O
Na
Na
O
O
Cu
Cu
MeO
MeO
OMe
OMe
H
H
Ph
Ph
TS1
TS5
ΔΔH = 0.0
ΔΔG = 0.0
ΔΔH = 0.0
ΔΔG = 0.0
Favored
Disfavored
Me
Me
N
O
Na
N
N
O
Na
N
Me
Me
Me
O
Me
O
O
Cu
O
Cu
MeO
MeO
OMe
Ph
OMe
H
H
Ph
TS6
TS2
ΔΔH = -2.3
ΔΔG = -2.2
ΔΔH = 1.0
ΔΔG = 2.0
Disfavored
Favored
Ligand = 4i
Ligand = 4i
Me
N
O
Na
N
Me
Me
N
O
Na
N
Me
O
Me
Me
O
O
Cu
MeO
Ph
OMe
Cu
O
Ph
MeO
OMe
H
H
TS3
ΔΔH = 0.0
ΔΔG = 0.0
TS7
Favored
Favored
ΔΔH = 0.0
ΔΔG = 0.0
Me
Me
N
N
N
N
O
Me
O
Me
O
Na
Me
Me
O
Na
O
Cu
O
Cu
MeO
OMe
MeO
OMe
Ph
H
Ph
H
TS4
TS8
ACS Paragon Plus Environment
ΔΔH = 0.0
ΔΔG = 1.0
ΔΔH = 4.0
ΔΔG = 2.2
Disfavored
Disfavored

a
Page 21 of 22
ACS Catalysis
Me
PF6
O
i-Pr
5.0 mol %
Cl
B
N
N
2a
1
2
3
4
5
6
7
8
9
O
Me
(1.56 g)
1.5 equiv.
OH Me
4f
COOEt
COOEt
5.0 mol % CuCl, 1.5 equiv. NaOt-Bu
Cl
THF, 22 oC, 16 h
COOEt
COOEt
Ph
Ph
3a
(1.56 g)
1a
10
11
12
13
14
(1.12 g)
98% yield, 95.5:4.5 e.r.
b
15
16
17
18
19
20
21
22
23
24
25
26
27
O
COOEt
OH
COOEt
ref 17
COOEt
NaCl, DMSO, H2O
155 oC, 10 h
O
t-Bu
F
OPMB
ACS Paragon Plus Environment
OPMB
MeO
8d
96:4 e.r.
9
92% yield, 98:2 e.r.
member of a family of GPR40 agonists

ACS Catalysis
Page 22 of 22
R2
R1
O
B
R3
O
R2
1
R1
5–10 mol % NHC–Cu complex
R3
COOEt
R
1.5 equiv NaOt-Bu
2
3
COOEt
COOEt
THF, 22 oC, 16 h
COOEt
R
4
28 examples
5
6
7
8
ACS Paragon Plus Environment
up to 98% yield
up to 99.5:0.5 e.r.