Catalytic Enantioselective Conjugate Addition of Stereodefined Di- and Trisubstituted Alkenylaluminum Compounds to Acyclic Enones

Article abstract of DOI:10.1002/adsc.201901435

Catalytic enantioselective conjugate addition (ECA) reactions with readily accessible and stereochemically defined E-, Z-, di- and trisubstituted alkenyl aluminum compounds are disclosed. Transformations are promoted by various NHC-copper catalysts (NHC=N-heterocyclic carbene), which are derived from enantiomerically pure sulfonate imidazolinium salts. The desired products were obtained in up to 89% yield and >99:1 e.r.; the alkenyl moiety was transferred with complete retention of its stereochemical identity in all instances. The scope and limitations of the approach, key mechanistic attributes, and representative functionalization are presented as well. (Figure presented.).

Full text of DOI:10.1002/adsc.201901435

Title: Catalytic Enantioselective Conjugate Addition of Stereodefined
Di- and Trisubstituted Alkenylaluminum Compounds to Acyclic
Enones
Authors: Amir Hoveyda, Kevin McGrath, Aran Hubbell, Yuebiao Zhou,
Damian Padin, Sebastian Torker, and Filippo Romiti
This manuscript has been accepted after peer review and appears as an
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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
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901435
Link to VoR: http://dx.doi.org/10.1002/adsc.201901435

10.1002/adsc.201901435
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Enantioselective Conjugate Addition of Stereodefined
Di- and Trisubstituted Alkenylaluminum Compounds to Acyclic
Enones
Kevin P. McGrath,a Aran K. Hubbell,a Yuebiao Zhou,a Damián Padín Santos,a
Sebastian Torker,b Filippo Romiti,b,* Amir H. Hoveydaa,b,*
a
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United
States
E-mail: amir.hoveyda@bc.edu
Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, 67000 Strasbourg, France
b
E-mail: romiti@unistra.fr, ahoveyda@unistra.fr
Dedicated to our friend, Professor Eric N. Jacobsen, on the occasion of his sixtieth birthday.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201##
catalytic ECA reactions that lead to incorporation of a
select number of alkenyl units have been disclosed,[3–
6] those that allow for the addition of a wider range of
these versatile moieties are yet to be reported. In
2014 we demonstrated that - or -alkenyl–Al
compounds through bisphosphine–Ni-catalyzed Al–H
addition to terminal alkynes, may be used in efficient
ECA reactions that generate a quaternary carbon
stereogenic center (Scheme 1a).[7] However, reactions
with a wider range of alkenyl–Al reagents (i.e., those
bearing a trisubstituted olefin) or those that can
generate a tertiary stereogenic carbon center are yet
to be introduced. Herein, we outline the results of our
investigations to address this deficiency in the state-
of-the-art (Scheme 1b).
Abstract. Catalytic enantioselective conjugate addition
(ECA) reactions with readily accessible and
stereochemically defined di- and E-, or Z-trisubstituted
alkenyl
aluminum
compounds
are
disclosed.
Transformations are promoted by various NHC–copper
catalysts (NHC = N-heterocyclic carbene), which are
derived from enantiomerically pure sulfonate
imidazolinium salts. The desired products were obtained
in up to 89% yield and >99:1 e.r.; the alkenyl moiety
was transferred with complete retention of its
stereochemical identity in all instances. The scope and
limitations of the approach, key mechanistic attributes,
and representative functionalization are presented as
well.
Keywords: aluminum–hydride addition; conjugate
addition; Cu; N-heterocyclic carbenes; Ni
There has been considerable progress in the
development of catalytic enantioselective conjugate
addition (ECA) reactions in recent years, as is evident
from the use of such transformations in a number of
complex molecule total syntheses.[1] However, key
shortcomings remain, one being the availability of
transformations involving acyclic ,-unsaturated
carbonyl
compounds,
substrates
that
are
conformationally less rigid (i.e., addition might occur
via s-cis or s-trans conformer[2]). Furthermore, while
1
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10.1002/adsc.201901435
Advanced Synthesis & Catalysis
3.0 mol % Ni(PPh3)2Cl2
1.3 equiv. dibal–H
thf, 2 h, 22 ºC
Ph
Ph
a. Previous study (2014):
Ar
O
S
O
–
Me
+
O
O
N
N
Ph
Ar
5.0 mol % chiral NHC
G
Me
Al(i-Bu)2
93% b
Me
O
3a
5.0 mol % CuCl2•2H2O
imid-a
up to 77% yield,
99:1 er
Ar
G
Me
b
Al(i-Bu)2
2.0 equiv.
thf, 1 h, 22 °C
Ph
Al(i-Bu)2
4a
Ar
Ph
O
Me
5.0 mol % imid-a, 5.0 mol % CuCl
15 mol % NaOt-Bu
O
O
G
Me
Ph
Me
Ph
Me
thf, 12 h, –30 ºC
5a
6a
63% yield, 95:5 e.r.
b. This study:
R
Al(i-Bu)2
Ph
Ph
N
O
SiHMe2
OMe
CF3
Al(i-Bu)2
S
O
R
N
O
Al(i-Bu)2
R
SiHMe2
Al(i-Bu)2
Ag
Ag
R
O
O
Ph
Me
Ph
Me
O
N
O
O
N
NHC–Cu
catalyst
6b
6c
S
G
Me
(with NHC–Ag-a
+ 10 mol % CuCl)
69% yield, 91:9 e.r.
(with NHC–Ag-a
+ 10 mol % CuCl)
61% yield, 84:16 e.r.
Ph
O
Ph
NHC–Ag-a
R
G
Ph
Ph
Ph
O
O
O
O
Me
R
G
Me
Me
Me
SiHMe2
O
R
high yield
E:Z/Z:E
& e.r.?
O
F3C
Br
MeO
6e
6d
6f
Me
G
Me
R
71% yield, 90:10 e.r.
63% yield, 91:9 e.r.
(at 22 °C)
62% yield, 95:5 e.r.
SiHMe2
O
>98:2 E:Z in all cases
G
Me
Scheme 2. NHC–Cu-catalyzed ECA with 1,2-disubstituted
E-alkenyl–Al compounds. Reactions were carried out
under N2, and yields correspond to isolated and purified
products (±5%). E:Z ratios were determined by analysis of
the 1H NMR spectra of unpurified product mixtures (±2%).
Enantiomeric ratios were determined by HPLC analysis
(±1%). See the Supporting Information for details.
Scheme 1. A reported catalytic ECA method with alkenyl–
Al compounds and the key goals of the present study.
We began by examining the addition of a 1,2-
disubstituted E-alkenyl–Al compound 4a to an
acyclic ,-unsaturated ketone 5a (Scheme 2). To
identify an optimal catalyst, we investigated the
reaction between 4a, which was generated in two
hours at ambient temperature through - and E-
selective bisphosphine–Ni-catalyzed Al–H addition to
phenylacetylene (93:7 :, >98:2 E:Z),[8] and enone
5a. We thus established that, in the presence of 5.0
mol % imid-a and CuCl in thf, after 12 h, and at –30
°C, -alkenyl ketone 6a may be isolated in 63% yield
and 95:5 enantiomeric ratio (e.r.). Reactions with
more electron-rich or electron-deficient alkyl–Al
compounds proceeded with similar efficiency and
enantioselectivity (6b-c, Scheme 2), but yields
improved with NHC–Ag-a as the catalyst precursor
at higher catalyst loading (10 vs. with 5.0 mol %
imid-a: 55% yield, 91:91:0 e.r. and 48% yield, 84:16
e.r. for 6b and 6c, respectively). The precise reason
for this difference has not be rigorously determined;
however, considering the fact that NHC–Ag
complexes are exceptionally efficient carbene transfer
agents, it appears that substrate or product
decomposition was caused by uncoordinated Cu(I)
complexes. In contrast, ECA involving enones
bearing
electron-rich or electron-deficient aryl moieties were
carried out under the same conditions as were used
with 5a, allowing us to isolate 6d-f in up to 71%
yield and 95:5 e.r. There was no loss of
stereochemistry at the alkenyl site (i.e., >98:2 E:Z in
all cases).
A notable aspect of the findings in Scheme 2 is
that that the sense of enantioselectivty is opposite to
that observed when the same set of alkenyl–Al
compounds were used in ECA reactions with
trisubstituted enones (see Scheme 1a).[7a] As will be
described, this trend applies to other additions
involving 1,1-disubstituted enone substrates,
a
mechanistic rationale for which will be provided later
in this disclosure.
Next, we probed the addition of
a 1,1-
disubstituted alkenyl–Al compound, easily prepared
by performing the Al–H addition with Ni(dppp)Cl2
(vs. Ni(PPh3)2Cl2 for high  selectivity) to enone 5a
(Scheme 3).[8] For this initial transformation imid-d
proved to be optimal (vs. 85:15 e.r., 76% yield with
imid-a), affording 8a in 63% yield and 95:5
enantiomeric ratio (e.r.). However, different
sulfonate-containing NHC ligands emerged as the
superior choice in subsequent examples.[9] Thus,
2
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10.1002/adsc.201901435
Advanced Synthesis & Catalysis
3.0 mol % Ni(dppp)Cl2
1.3 equiv. dibal–H
thf, 2 h, 22 ºC
reactions with more electron-rich or electron-
deficient alkenyl–Al compounds proceeded with
similar efficiency and enantioselectivity in the
presence of imid-b or imid-c (8b-d, Scheme 3). This
may be due to the earlier transition state generated
with electron-deficient Al compounds; interaction
between the substrates and catalyst would thus be
diminished, and therefore a more sizable ortho
substituent in the NHC might be needed for high
enantioselectivity (54% yield, 75:25 e.r. and 57%
yield, 84:16 e.r. for 8c and 8d with imid-a). In the
case of an electron-donating alkenyl–Al compound,
on the other hand, tighter catalyst- substrate
association might engender increased steric repulsion
when a more conformationally constrained complex
is involved (imid-d), leading to diminished efficiency
(e.g., 8b was obtained in 34% yield, 91:9 e.r. with
imid-d). 1,3-Diene 8e, derived from a process that
involved an enyne substrate, and alkenyl silane 8f,
generated from silyl-substituted alkyne, were isolated
in 50% and 74% yield and 90.5:9.5 and 99:1 e.r.,
respectively; the higher stereochemical control with
the more sterically hindered alkenyl–Al compound is
mechanistically significant. The exceptionally high
enantioselectivity (>99:1 e.r.) as well as the
possibility of accessing thioester 8i are noteworthy.
The product is sufficiently activated for conversion to
various desirable derivatives, such as carboxylic
ester,[10] which cannot be directly accessed by an ECA
reaction (<5% conv.).
Ph
>98% a
3a
a
Ph
2.0 equiv.
Al(i-Bu)2
7a
5.0 mol % imid-d, 5.0 mol % CuCl
15 mol % NaOt-Bu
Ph
Ph
O
5a
Me
thf, 12 h, –30 ºC
8a
52% yield, 91:9 e.r.
MeO
F3C
F3C
O
O
O
Ph
8b
Me
Ph
8c
Me
Ph
8d
Me
(with 10 mol % imid-b
+10 mol % CuCl)
(with 5.0 mol % imid-c)
81% yield, 86:14 e.r.
(with 10 mol % imid-c
+10 mol % CuCl)
77% yield, 89:11 e.r.
82% yield, 91:9 e.r.
(i-Pr)3Si
O
O
Ph
Me
Ph
Me
8e
8f
(with 5.0 mol % imid-a)
50% yield, 90.5:9.5 e.r.
(with 5.0 mol % NHC–Ag-a
+10 mol % CuCl)
74% yield, 99:1 e.r.
Ph
Ph
Ph
O
O
O
Me
Me
SPh
MeO
F3C
8g
8h
8i
(with 10 mol % imid-c
+10 mol % CuCl)
(with 10 mol % imid-a
+10 mol % CuCl)
(with 10 mol % NHC–Ag-a
+10 mol % CuCl)
63% yield, >99:1 e.r.
Regarding the need for different NHC ligands to
obtain maximum efficiency and/or enantioselectivity,
it is important to note that a key attribute of any class
of catalysts is whether it is readily modifiable and if
different derivatives can be tested for a particular
application. While it is possible to use a single
complex for every transformation, and this would be
the case if the NHC ligand were too cumbersome to
modify and include in screening studies, the
corresponding results would be inferior.[11]
65% yield, 93:7 e.r.
79% yield, 86:14 e.r.
Ph
Ph
Ph
Ph
O
O
–
–
S
S
+
+
N
O
O
O
O
N
N
N
imid-b
imid-c
Ph
Ph
O
S
–
+
O
O
N
N
imid-d
Scheme 3. Catalytic ECA with 1,1-disubstituted alkenyl–
Al compounds. Reactions were carried out under N2, and
yields correspond to isolated and purified products (±5%).
Enantiomeric ratios were determined by HPLC analysis
(±1%). See the Supporting Information for details.
We then turned our attention to examining
catalytic ECA reactions with silyl-substituted
alkenyl–Al compounds. We considered this an
important aspect of these studies for several reasons.
1) Previous investigations had shown that the
presence of a sizeable substituent at the same carbon
as the Al can lead to significantly higher
enantioselectivity.[7b] 2) Subsequent modification of
the alkenyl silane, such as C–Si to C–H conversion to
afford E- or Z-disubstituted alkenyl units[12] or
Hiyama-type cross-coupling[13] to give E- or Z-
3
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10.1002/adsc.201901435
Advanced Synthesis & Catalysis
trisubstituted olefinic products would become
feasible.
NHC–Cu complex derived from imid-e afforded 12a
in 78% yield and >99:1 e.r. As the additional
examples indicate, a variety of different aryl-
substituted enones, including those that contain an
electron-rich or electron-deficient moiety readily
react to afford 12b-g in 57–89% yield and 90:10 to
>99:1 e.r. (Scheme 5). A notable case is the reaction
with an α,β,,-unsaturated ketone that generates 1,4-
diene 12h in 67% yield and 90:10 e.r. As was noted,
while imid-e is typically optimal, with the more
sterically hindered enones (i.e., those that contain an
o-substituted aryl unit), higher yields were obtained
when NHC–Ag–b-c were used as catalyst precursors;
the reason for this trend is not clear at the present
time.
In the event, subjection of silyl-substituted alkyne
9a to dibal–H (5/1 hexanes/thf, 3 h, 55 °C) led to
formation of Z-10a (Scheme 4),[14] which was used
directly for ECA with enone 5a. Screening studies
showed that, in this particular instance, the NHC–Cu
complex derived from imid-a is optimal, allowing us
to isolate 11a in 76% yield and 94:6 e.r. (>98:2 Z:E).
Additional examples provided in Scheme 4 (11b-f),
indicate that e.r. values, while at useful levels (83:17–
93:7), are generally lower than what we observed for
11a. Generation of the trimethylsilyl derivatives of
the alkenyl–Al compounds is similarly facile but the
corresponding ECA reactions afford the expected
products in lower yields (competitive i-Bu addition;
see the Supporting Information for further analysis).
1.0 equiv. dibal–H
hexanes,
3 h, 55 ºC
Ph
O
–
S
+
O
O
N
N
1.3 equiv. dibal–H
5/1 hexanes/thf,
3 h, 55 ºC
Ph
SiHMe2
>98:2 Z:E & r.r.
9a
imid-e
Ph
SiHMe2
SiHMe2
>98:2 Z:E & r.r.
9a
Ph
2.0 equiv.
Al(i-Bu)2
E-10a
Ph
SiHMe2
SiHMe2
O
2.0 equiv.
5.0 mol % imid-e, 5.0 mol % CuCl
15 mol % NaOt-Bu
Ph
Ph
Al(i-Bu)2
Z-10a
5a
Me
Ph
thf, 12 h, –30 ºC
5.0 mol % imid-a, 5.0 mol % CuCl Me2HSi
15 mol % NaOt-Bu
12a
O
78% yield, >99:1 e.r.
5a
Ph
Me
SiHMe2
O
SiHMe2
O
SiHMe2
O
thf, 12 h, –30 ºC
11a
76% yield, 94:6 e.r.
Ph
Ph
Ph
Me
Me
Me
OMe
CF3
MeO
CF3
Br
12b
12c
12d
89% yield, 98.5:1.5 e.r.
78% yield, 99:1 e.r.
78% yield, 99:1 e.r.
SiHMe2
SiHMe2
SiHMe2
Me2HSi
Ph
Me2HSi
Ph
Ph
Ph
Ph
O
O
O
O
O
Br
Me
Me
Me
Me
Me
F
Br
11b
(with imid-b)
71% yield, 90:10 e.r.
11c
12e
75% yield, 95:5 e.r.
12f
12g
(with 5.0 mol % NHC–Ag-a
+10 mol % CuCl)
(with 5.0 mol % NHC–Ag-c,
10 mol % CuCl):
(with 5.0 mol % NHC–Ag-b,
10 mol % CuCl):
68% yield, 98:2 e.r.
57% yield, >99:1 e.r.
67% yield, 86.5:13.5 e.r.
SiHMe2
Ph
Ph
Ph
Ph
O
Me2HSi
Me2HSi
Me2HSi
>98:2 E:Z in all cases
O
O
O
Ph
Me
F3C
Me
12h
67% yield, 90:10 e.r.
Me
Me
MeO
Br
Ph
Ph
11d
11e
11f
O
O
(with 10 mol % imid-c
+10 mol % CuCl)
(with 5.0 mol % NHC–Ag-a
+10 mol % CuCl)
(with 10 mol % NHC–Ag-a
+10 mol % CuCl)
S
S
O
O
N
O
N
N
O
N
63% yield, 83:17 e.r.
61% yield, 85:15 e.r.
83% yield, 93:7 e.r.
Ag
Ag
Ag
Ag
>98:2 Z:E in all cases
O
N
O
N
O
O
N
N
S
S
Scheme 4. Catalytic ECA with Z-trisubstituted alkenyl–Al
compounds. Reactions were carried out under N2, and
yields correspond to isolated and purified products (±5%).
Z:E ratios were determined by analysis of 1H NMR spectra
of unpurified product mixtures (±2%). Enantiomeric ratios
were determined by HPLC analysis (±1%). See the
Supporting Information for details.
O
Ph
O
Ph
NHC–Ag-c
NHC–Ag-b
Scheme 5. Catalytic ECA with E-trisubstituted alkenyl–Al
compounds. Reactions were carried out under N2, and
yields correspond to isolated and purified products (±5%).
Z:E ratios were determined by analysis of 1H NMR spectra
of unpurified product mixtures (±2%). Enantiomeric ratios
were determined by HPLC analysis (±1%). See the
Supporting Information for details.
By carrying out the Al–H addition in pure hexanes
(vs. 5/1 hexanes/thf), silyl-substituted alkyne 9a was
converted to E-10a (Scheme 5);[14d] the corresponding
ECA with 5a in the presence of 5.0 mol % of the
4
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10.1002/adsc.201901435
Advanced Synthesis & Catalysis
A drawback of the present approach is that ECA
of CH/ interaction between the substrate Ph ring
and the NAr moiety, and also due to the fact that an
eclipsing interaction between the substrate’s Me
groups (see IV) can be avoided. Additionally, the
methyl ketone moiety in IV is oriented to the right, as
shown, leading to steric repulsion with the NHC’s o-
i-Pr group, and hence the contracted C1NC2C3
dihedral angle (71.6º).
with alkyl-substituted enones are inefficient; the
example provided in Eq. (1) is representative. The
low yield of the desired product might arise from
diminished electrophilicity of the enone substrates,
rendering alternative reaction pathways too
competitive. Development of catalyst and strategies
that address this issue thus remains an unresolved
issue. However, the present set of transformation are
scalable and do not require rigorous exclusion of air
and moisture (i.e., a glovebox) to be carried, albeit
with some loss in enantioselectivity. For example, 1.0
mmol of 5a was transformed to 6a in 65% yield and
90:10 er.
a. With b-alkyl–Al compounds and disubstituted enones:
Ph
Ph
O
S
O
O
N
N
N
H
Me2Al+
O
Ar
Me
Cu
reduced
repulsion
due to
lack of ortho
substituent
C1
5.0 mol %
Ph
O
SiHMe2
–
S
Ph
+
O
O
Ph
N
N
Ph
Al(i-Bu)2
E-10a
(2.0 equiv.)
SiHMe2
O
Ph
imid-e
I
5.0 mol % CuCl,
C1- Cu- CNHC- N = 102.6º
DGrel = 0.0 kcal/mol
Me
(1)
O
15 mol % NaOt-Bu,
12i
thf, 12 h, –30 ºC
Me
major enantiomer
>98% conv., 20 % yield,
90:10 e.r.
Ph
Ph
O
S
O
O
N
N
To gain insight regarding the basis for the change
in the identity of the major product enantiomer for
reactions between -alkenyl–Al compounds di- (this
work) and tri-substituted enones (reported formerly;
Scheme 1a),[7a] we performed DFT calculations at the
M06L/def2-TZVPP//M06L/ def2-SVP level of
theory (Scheme 6).[15] As suggested previously for
other transformations facilitated by this class of
NHC–Cu complexes, a mode of reaction involving a
salt bridge between the sulfonate and the enone
carbonyl group may be proposed.[16] In the major
pathway (I) for formation of product 5a (see Scheme
2) there is minimal repulsion between the methyl
ketone unit and the ligands NAr moiety (lack of an
ortho substituent; Scheme 6a). Moreover, the enone’s
Ph group is able to avoid generating steric pressure
by interaction with the 3,5-(2,6-diisopropyl-
phenyl)phenyl substituent, an unfavorable association
that is present in the transition state leading to the
minor enantiomer (II).[16a]
N
Me
O
Me2Al+
Ar
steric
repulsion
Cu
steric
repulsion
Ph
C1
II
DGrel = 0.3 kcal/mol
C1- Cu- CNHC- N = 50.8º
minor enantiomer
b. With b-alkyl–Al compounds and trisubstituted enones:
Ph
O
S
C1
O
O
N
N
C3
N
Me
C2
Me2Al+
Cu
C
H/
p
O
interaction
Me
Ph
III
DGrel = 0.0 kcal/mol
C1- N- C2- C3 = 105.4º
The latter steric pressure forces the NHC ligand to
rotate around the CuCNHC bond, engendering
repulsion between the alkenyl and the aryl sulfonate
major enantiomer
ligands,
as
indicated
by
the
contracted
C1CuCNHCN dihedral angle (50.8º in II vs. 102.6º
in I). While the free energy for transition state II is
only marginally larger than that of I (0.3 kcal/mol),
the aforementioned consideration are expected to be
more dominant in the preceding alkene -complex
(contracted C1CuCNHC angle of 106.0º vs. 120.4º in
II), suggesting that, in the pathway leading to the
minor enantiomer, it is olefin coordination that is
turnover-limiting.
Ph
C1
O
S
O
O
C3
N
N
N
C2
O
Me2Al+
steric
repulsion
Me
Cu
eclipsing
Me groups
Me
Ph
Ph
IV
DGrel = 2.9 kcal/mol
In the case of additions to trisubstituted enones[7a]
it is the opposite substrate rotamer which likely reacts
preferentially (III, Scheme 6b vs. I, Scheme 6a). We
expect the mode of addition III to be favored because
C1- N- C2- C3 = 71.6º
minor enantiomer
5
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10.1002/adsc.201901435
Advanced Synthesis & Catalysis
Scheme 6. Rationale for reversal of facial selectivity for
ECA to di- (this work) and trisubstituted enones (see ref.
7a). Calculations were performed at the M06L/def2-
TZVPP//M06L/def2-SVP level in dichloromethane as
solvent with the use of the SMD solvation model.
[1] For relatively recent reviews, see: a) A. Alexakis, N.
Krause, S. Woodward, in Copper-Catalyzed
Asymmetric Synthesis (eds A. Alexakis, N. Krause, S.
Woodward) 33–68 (VCH–Wiley, 2014); b) B. C. Calvo,
J. Buter, A. J. Minaard, in Copper-Catalyzed
Asymmetric Synthesis (eds A. Alexakis, N. Krause, S.
Woodward) 373–448 (VCH–Wiley, 2014).
In conclusion, we have developed a catalytic
method for ECA of a variety of readily accessible
alkyl–Al compounds to acyclic -aryl-substituted,
,-unsaturated methyl ketones. Most products
contain stereochemically defined disubstituted as well
as E-, or Z- trisubstituted alkenyl moieties that may
be functionalized in a number of ways. The latter
attributes are perhaps best highlighted by the
representative diastereoselective reduction/siloxane
formation, shown in Eq. (2).[17]
[2] Z. Gao, S. P. Fletcher, Chem. Sci. 2017, 8, 641–646.
[3] For examples of ECA reactions catalyzed by a
transition metal based complex and involving alkenyl
boronic acids, see: a) T. Hayashi, Synlett 2001, 2001,
879–887; b) D. Muller, A. Alexakis, Chem. Commun.
2012, 48, 12037–12049; c) R. Shintani, Y. Ichikawa, K.
Takatsu, F.-X. Chen, T. Hayashi, J. Org. Chem. 2009,
74, 869–873.
[4] For examples of ECA reactions catalyzed by a
transition metal based complex and involving alkenyl
silanes see: a) Y. Otomaru, T. Hayashi, Tetrahedron:
Asymm. 2004, 15, 2647–2651; b) R. Shintani, Y.
Ichikawa, T. Hayashi, J. Chen, Y. Nakao, T. Hiyama,
Org. Lett. 2007, 9, 4643–4645; c) K. Lee, A. H.
Hoveyda, J. Org. Chem. 2009, 74, 4455–4462.
[5] For examples of ECA reactions catalyzed by a
transition metal based complex involving alkenyl
Experimental Section
zirconocene compounds, see:
a) S. Oi, T. Sato, Y.
Inoue, Tetrahedron Lett. 2004, 45, 5051–5055; b) J.
Westmeier, C. Pfaff, J. Siewert, P. von Zezschwitz, Adv.
Synth. Catal. 2013, 355, 2651–2658.
Procedure for NHC–Cu-catalyzed conjugate addition with
an alkenyl–Al compound: A flame-dried 1-dram vial
containing a magnetic stir bar was charged with imid-e
(2.7 mg, 0.005 mmol), NaOt-Bu (1.4 mg, 0.0150 mmol),
and CuCl (0.5 mg, 0.005 mmol) under N2 atm in a
glovebox. The vessel was sealed (septum), removed from
the glovebox, after which thf (0.5 mL) was added and the
solution was allowed to stir for 15 min. A 1 M solution of
E-10a in hexanes (200 μL, 0.200 mmol) was then added
and the mixture was allowed to cool to −78 °C. A solution
of 4-phenyl-3-buten-2-one 5a (17.6 mg, 0.100 mmol) in thf
(0.5 mL) was added by syringe. The mixture was allowed
to stir at −30 °C for 12 h and then warm to 22 °C. At this
point, the reaction was then quenched by the addition of a
saturated aqueous solution of sodium-potassium tartrate (3
mL) and the mixture was washed with Et2O (3  1 mL).
The combined organic layers were filtered through a short
plug of silica gel (Et2O), the volatiles were removed in
vacuo and the dark oil residue was purified by silica gel
chromatography (hexanes to 20:1 hexanes:Et2O) to afford
12a (24.1 mg, 0.078 mmol, 78% yield, >98:2 E:Z, >99:1
e.r.).
[6] For examples of ECA reactions catalyzed by
enantioenriched diols and involving alkenyl boronic
acids, see: a) T. N. Nguyen, J. A. May, Tetrahedron
Lett. 2017, 58, 1535–1544. b) G.-L. Chai, A.-Q. Sun, D.
Zhai, J. Wang, W.-Q. Deng, H. N. C. Wong, J. Chang,
Org. Lett. 2019, 21, 5040–5045.
[7] a) K. P. McGrath, A. H. Hoveyda, Angew. Chem., Int.
Ed. 2014, 53, 1910−1914. For a related study involving
-substituted cyclic enones, see: b) T. L. May, J. A.
Dabrowski, A. H. Hoveyda, J. Am. Chem. Soc. 2011,
133, 736–739; c) T. L. May, J. A. Dabrowski, A. H.
Hoveyda, J. Am. Chem. Soc. 2014, 136, 10544.
[8] F. Gao, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132,
10961–10962.
[9] See the Supporting Information for details of screening
studies.
[10] For example, see: J. M. O’Brien, K.-s. Lee, A. H.
Hoveyda, J. Am. Chem. Soc. 2010, 132, 10630–10633.
[11] For a more detailed discussion regarding the
advantages of having access to a class of catalysts, see:
A. H. Hoveyda, A. W. Hird, M. A. Kacprzynski, Chem.
Commun. 2004, 16, 1779–1785.
Acknowledgements
This work was supported by the NIH (GM-47480). A. K. H. and Y.
Z. were supported by John Kozarich Summer Undergraduate
Research and LaMattina Graduate Fellow in Organic Synthesis
Fellowships, respectively. D.P. is grateful for a fellowship from
Fondación Barrié (Spain).
[12] For catalytic ECA reactions that lead to the addition
of a Z-alkene moiety, see: a) P. Cottet, D. Müller, A.
Alexakis, Org. Lett. 2013, 15, 828–831; b) D. Müller,
A. Alexakis, Chem. Eur. J. 2013, 19, 15226–15239.
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6
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10.1002/adsc.201901435
Advanced Synthesis & Catalysis
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7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201901435
Advanced Synthesis & Catalysis
COMMUNICATION
R
SiHMe2
R
SiHMe2
O
Catalytic Enantioselective Conjugate Addition of
Stereodefined Di- and Tri-Substituted
Alkenylaluminum Compounds to Acyclic Enones
O
R
R
Al(i-Bu)2
Al(i-Bu)2
Ar
Me
Ar
Me
up to 89% yield,
>99:1 e.r.
up to 71% yield,
95:5 e.r.
O
Adv. Synth. Catal. Year, Volume, Page – Page
Ar
Me
R
R
O
SiHMe2
O
Kevin P. McGrath, Aran K. Hubbell, Yuebiao
Zhou, Damián Padín Santos, Sebastian Torker,
Filippo Romiti,* and Amir H. Hoveyda*
Ar
Me
Ar
Me
R
SiHMe2
up to 83% yield,
95:5 e.r.
up to 82% yield,
>99:1 e.r.
R
Al(i-Bu)2
Al(i-Bu)2
R = aryl, alkenyl, silyl
8
This article is protected by copyright. All rights reserved.