Copper-catalyzed asymmetric conjugate addition to challenging michael acceptors and synthesis of relevant target molecules

Article abstract of DOI:10.2533/chimia.2012.196

We report herein the enantioselective Cu-catalyzed conjugate addition of organometallic reagents to sensitive Michael acceptors and their application to the synthesis of relevant target molecules. This is one of the most important methodologies to form a C-C bond in an enantioselective manner. A wide range of α,β-unsaturated aldehydes and β,γ-unsaturated-α- ketoesters has been successfully used. Reactivity, regioand enantioselectivities were strongly dependent on the reaction conditions, therefore moderate to very good results were obtained. Furthermore, γ-substituted-α-ketoesters were used as chiral building blocks for further derivatization with complete retention of the chiral information to obtain key compounds. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2012.196

196 CHIMIA 2012, 66, No. 4
doi:10.2533/chimia.2012.196
Laureates: awards and Honors, sCs FaLL Meeting 2011
Chimia 66 (2012) 196–200 © Schweizerische Chemische Gesellschaft
Copper-catalyzed Asymmetric Conjugate
Addition to Challenging Michael
Acceptors and Synthesis of Relevant
Target Molecules
Ludovic Gremaud§, Laëtitia Palais, and Alexandre Alexakis*
§SCS-Metrohm Foundation Award for best oral presentation
Abstract: We report herein the enantioselective Cu-catalyzed conjugate addition of organometallic reagents
to sensitive Michael acceptors and their application to the synthesis of relevant target molecules. This is one
of the most important methodologies to form a C–C bond in an enantioselective manner. A wide range of
α,β-unsaturated aldehydes and β,γ-unsaturated-α-ketoesters has been successfully used. Reactivity, regio-
and enantioselectivities were strongly dependent on the reaction conditions, therefore moderate to very good
results were obtained. Furthermore, γ-substituted-α-ketoesters were used as chiral building blocks for further
derivatization with complete retention of the chiral information to obtain key compounds.
Keywords: Asymmetric conjugate addition · Copper · Organometallic reagents · α,β-Unsaturated aldehydes ·
β,γ-Unsaturated-α-ketoesters
for example, as additives in perfume- or new families of chiral building blocks of
flavor chemistry as well as pharmaceuti- β-substituted aldehydes. β,γ-Unsaturated-
Introduction
cal drugs for anti-cancer, antimicrobial α-ketoesters pose the same problem as the
and bladder disorder treatment in medici- corresponding aldehyde because the ester
nal chemistry. Bräse et al. developed the functionality activates the α-keto position
first asymmetric conjugate addition (ACA) to generate an undesired mixture of 1,4-
to enals through an enantioselective Cu- and 1,2-addition products. During the last
free 1,4-addition methodology, using decade, a wide range of organocatalytic
[2.2]-paracyclophaneketimine ligands.[3] additions to β,γ-unsaturated-α-ketoesters
On the other hand, prior to our work, only were published in the literature.[11] Very
indirect methodologies have been devel- recently, Zhang et al. developed an en-
oped for Cu-catalyzed ACA to enals. In antioselective synthesis of chiral γ-aryl
2003, Hoveyda et al. published the ACA α-ketoesters by ACA to the corresponding
to N-acyloxazolidinones[4] and a few years β,γ-unsaturated-α-ketoesters catalyzed by
later, Feringa et al. reported on the ACA copper and using D2-symmetric biphenyl
with thioesters and allylic α-chloroacetate phosphoroamidite ligands.[12] During the
Enantioselective Cu-catalyzed conju-
gate addition of organometallic reagents
to Michael acceptors has been one of the
strongest methods to create enantioen-
riched products through C–C bond for-
mation.[1] In this field, a wide range of
nitrodienes, nitroenynes, sulfones, α,β-
and β,γ-unsaturated carbonyl compounds
has been used successfully. However,
the direct asymmetric conjugate addition
with organometallic reagents and cop-
per as transition metal catalyst to much
more challenging substrates, such as α,β-
unsaturated aldehydes or β,γ-unsaturated-
α-ketoesters, has not been reported in the
using
a
one-pot
procedure.[5] same time, we reported the successful Cu-
literature before our work.[2] Their very
Finally, in 2008, Palomo et al. described catalyzed asymmetric conjugate addition
the 1,4-addition to α’-oxy enones followed to several β,γ-unsaturated-α-ketoesters
by a reduction–oxidation procedure to ob- with trimethylaluminum as organometallic
tain the chiral β-substituted aldehydes.[6] reagent and their derivatization to access
high reactivity can easily lead to the for-
mation of an undesired mixture of 1,4- and
1,2-addition products as well as the aldol
Other methods with transition metals, like natural and unnatural target compounds.[2b]
by-product. The resulting β-substituted
aldehydes or γ-substituted-α-ketoesters
have valuable properties and can be used,
Pd,[7] Rh,[8] Ir,[9] or organocatalyzed meth- Herein, we report recent progress in Cu-
odologies have been developed to access catalyzed asymmetric conjugate addition
β-substituted aldehydes.[10] In 2010, based to challenging Michael acceptors and their
upon the literature results, we developed derivatization in order to simultaneously
the challenging ACA to α,β-unsaturated access new families of chiral and complex
aldehydes. We obtained promising results building blocks.
but unfortunately, we could never achieve
high ees and high regioselectivities at the
*Correspondence: Prof. Dr. A. Alexakis
University of Geneva
Department of Organic Chemistry
Quai Ernest-Ansermet, 30
CH-1211 Genève 4
sametime.[2a] To obtainβ-andγ-substituted
Results and Discussion
compounds with high selectivities, we de-
veloped the 1,4-addition to a new class of
substrate catalyzed by a transition metal. ric conjugate addition to α,β-unsaturated
Following a minor derivatization, the aldehydes with various types of organo-
We initially investigated the asymmet-
Tel.: +41 22 379 6522
Fax: +41 22 379 3215
product can then be transformed to access metallic reagents. The first attempts were
E-mail: alexandre.alexakis@unige.ch

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 197
done with trans-2-decenal in presence entry 8–12). Normant et al. discovered this fully in favor of the 1,4-addition product.
of copper(i) thiophene-2-carboxylate beneficial effect in 1980 for the 1,4-addi- No traces of 1,2-addition products or aldol
(CuTC) or copper(ii) triflate (Cu(OTf) )
and mono- or bidentate phosphorus l2i- et al. and Nakamura et al. confirmed this enabled full conversion to be obtained
gands. As expected, an undesired mixture discovery a few years later.[14] The additive
with moderate ees (Table 2, entries 6–9).
of 1,4- and 1,2-addition products as well amounts of TMSCl contributed to acceler- However, with dimethylzinc, a poorly re-
as the aldol by-product were obtained ating cuprate-enone conjugate addition by active organometallic reagent, the reac-
(Table 1). With dialkylzinc reagents only trapping the copper (iii) complex and forc- tions must be performed at 0 °C. A small
tion on enals.[13] Corey and Boaz, Alexakis by-products were observed. Diethylzinc
the 1,4-addition products and aldol de- ing the conversion towards the β-adduct. drop in conversions was observed but mod-
rivatives were observed. After reductive The use of trialkylaluminum reagents were
erate to good ees were achieved (Table 2,
elimination of the Cu(iii) intermediate, also envisaged because they are mild or- entries 1–5).
the resulting zinc enolate reacted quickly ganometallic reagents equally very well
The commercial diversity of dialkyl-
with the highly reactive α,β-unsaturated known to access methyl-substituted ad- zinc remains limited and the self-prepara-
aldehydes to give undesired byproducts ducts. Unfortunately, the regioselectivity tion quite demanding. For these reasons,
(Table 1, entries 1–7). Due to the high re-
activity of Grignard reagents, and the enals entry 13). for the ACA to α,β-unsaturated aldehydes.
themselves, reactions were performed at With these experimental conditions As mentioned previously, the key factor
and enanstioselectivity dropped (Table 1, the use of Grignard reagents was envisaged
low temperature with these organometal- in hand, we screened the ACA to various when using Grignard reagents was the
lic reagents. Unfortunately, large amounts α,β-unsaturated aldehydes. Dialkylzinc positive effect of TMSCl. Unfortunately,
of 1,2-addition products were obtained. reagents are soft organometallic reagents despite the improvement provided with
By addition of trimethylsilyl chloride with substantial advantages and one of this additive, the regioselectivities were
(TMSCl) as additive the regioselectivity
was increased by more than 50% without tional groups. Thereby, with Et Zn or (Table 3, entry 5), with regards to organo-
affecting the enantiomeric excess (Table 1,
Me2Zn the regioselectivities were 2always zinc reagents. However, the enantioselec-
them is the high tolerance toward func- moderate, particularly with aryl derivatives
tivities were better, ranging from 74 to
90%, whether with MeMgBr or EtMgBr
(Table 3, entries 1–9).
Direct addition of organometallic re-
agents to α,β-unsaturated aldehydes ap-
pears to be a very challenging concept
to obtain chiral β-substituted aldehydes
with high regio- and enantioselectivities.
To achieve this goal, we investigated a
new Cu-catalyzed asymmetric conjugate
Table 1. Screening of reaction conditions with various organometallic
reagents and chiral ligand
R
2eq. R
M
∗
R
R
∗
L* /Cu
X
∗
O
O
6
∗
O
H
O
6
Solvent /T°C /3to8h
6
6
OH
6
1
2: R=Et
5: R=Me
3: R=Et
4: R=Et
6: R=Me
7: R=Me
Ph
O
Ph
2-Naphtyl
Ph
Ph
O
O
addition of organometallic reagents to
P N
P N
P N
β,γ-unsaturated-α-ketoesters. The result-
O
O
O
Ph
Ph
2-Naphtyl
ing γ-substituted-α-ketoesters can be eas-
ily transformed into the corresponding
β-substituted aldehydes by a simple one-
Ph
Ph
(S,S)
(R,S,S)
(R,S,S)
L
1
L
2
L
3
Ph
2-Na
PN
2-Na
(S,S)
phtyl
Ph
O
PAr2
PAr2
Table 2. Screening of α,β-unsaturated aldehydes with R2Zn
P N
O
Ph
phtyl
Ph
(R,S,S)
2eqRZn
(R)
5 : R=Ph
7 : R=Tol
5mol%2CuTC
L
6
R
L4
L
L
R'
O
∗
R'
O
Entry Ligand
RM
Conv. [%]a 1,4:1,2:aldola ee [%]b
5.25 mol% (R)-BINA
P
Et O/-20°C/6h
2
13-17
8: R' = n-Bu
1c
2c
L1
L2
L3
L4
L5
L5
L6
L1
L4
L5
L7
L7
L5
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
Me3Al
>99
99
99
99
59
>99
88
>99
>99
98
99
>99
83
>99
>98
>99
50
57
64
73
72
75
79
50
44
89
92
90
66
9: R' = i-Bu
10: R' = i-Pr
11:R'=c-Hex
>99% Regioselectivity
3c
12: R' =CH
6 5
4c
93:0:7
87:0:13
>99
95:0:5
24:76:0
21:79:0
62:30:0
32:42:26
85:15:0
65:19:16
5c
Conv. [%]a,b
ee [%]c
6c
Entry
R
RM
7d
1d
2d
3d
4d
5d
6
7
8
9
1
8
10
11
12
8
9
10
11
Me Zn
Me22Zn
85(79)
87
68
76
8e
9e
Me2Zn
Me2Zn
Me2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
>99
87(61)
50
>99(60)
>99
70
60
64
64
70
27
52
10e
11e
12f
13g
aDetermined by 1H NMR. bDetermined by chiral GC. C5 mol% Cu(OTf)2, 10
>99
>99
mol% L*, Toluene, 0 °C, 3 h. d5 mol% CuTC, 5.25 mol% L*, Et2O, -20 °C,
e
6 h. 5 mol% Cu(OTf)2, 5.25 mol% L*, Et2O, -78 °C, 8 h. f1.3 eq TMSCl,
g
5 mol% Cu(OTf)2, 5.25 mol% L*, Et2O, -78 °C, 8h. 5 mol% Cu(OTf)2, 5 aDetermined by 1H NMR. bIsolated yield for 1,4-addition product in paren-
mol% L*, THF, -78°C, 13 h.
theses. cDetermined by chiral GC. dReaction performed at 0 °C over 16 h.

198 CHIMIA 2012, 66, No. 4
Laureates: awards and Honors, sCs FaLL Meeting 2011
Table 3. Screening of α,β-unsaturated aldehydes with RMgBr
Table 4. Screening of organometallic reagents to β,γ-unsaturated-α-
ketoesters
5mol% Cu
TC
1.2 eq. R
5mol% CuT
5.25 mol% (R)-BIN
M
5.25 mol% (R)-tol-BIN
A
P
C
R
R
R
O
O
H
O R
∗
1.5 eq RMgBr
AP
R'
O
∗
∗
OEt
1.3 eq. TMSCl
R'
R'
O
H
OEt
OEt
O
∗
Ph
Ph
Ph
Et O/-78°C/8h
2
Et O, T°C, o.n.
2
9-12
18-2
2
2
3-27
O
O
O
Entry
R
RM
Conv. [%]a,b 1,4:1,2a ee [%]c Entry
RM
T [°C]
Conv. [%]a 1,4:1,2a ee [%]b,c
1
2
1
8
MeMgBr
MeMgBr
>99(40)
>99
65:35
40:60
81
86
1d
2
MeMgBr
MeMgBr
-78
-78
>99
>99
1:99
1:99
n.d.
n.d.
3
4
5
6
7
8
9
10
11
12
8
9
10
11
MeMgBr
MeMgBr
MeMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
86
>99(49)
>99
>99(46)
>99(44)
>99
43:57
63:37
10:90
60:40
71:29
36:64
63:37
84
80
n.d.
90
90
74
3
4e
5
Me2Zn
Me2Zn
Me3Al
Me3Al
Me3Al
0
0
-20
-78
-78
0
n.d.
99:1
43:57
70:30
>99:1
n.d.
93
55
94
>99.5
>99(14)f
>99(40)f
>99
6g
7h
>99
aDetermined by 1H NMR spectroscopy. bDetermined by GC analysis using
a chiral stationary phase. Enantiomeric excess for 1,4-addition product.
>99(51)
80
c
dReaction performed with 1.3 equiv TMSCl. eReaction performed with 2
equiv Me2Zn, 5 mol% CuTC, and (R)-binap in THF. fYield of isolated prod-
uct. gReaction performed with 1.2 equiv Me3Al, 5 mol% CuTC, and (R)-
binap in Et2O. gReaction performed with 2 equiv Me3Al, 5 mol% CuTC, and
(R)-binap in THF. binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl,
TMS = trimethylsilyl.
aDetermined by 1H NMR. bIsolated yield for 1,4-addition product in paren-
theses. cDetermined by chiral GC.
out furnishing by-products (Table 5, entries
6,8). For R = o-OMePh we also noticed an
importantdropofenantioselectivityto27%
(Table 5, entry 8). It is interesting to notice
R'
O
∗
R'M
CuX, L*
Et O, T°C, o.n.
2
2
O
O
R'
R
H
H
O R'
1
1
1
R O
R O
R O
2
2
2
R
R
R
MeO
O
R'
O
O
O
∗
∗
that β,γ,δ,ε-unsaturated-α-ketoesters, a di-
enic substrate, provided purely the chiral
γ-substituted-α-ketoesters, without any
2
HN
R
1,4 addition
1,2 addition
R' =Me, Et, n-Pr, i-Bu
1
R =Me, Et, i-Pr, t-Bu
traces of the 1,6-addition adduct (Table 5,
2
R =Alkyl, Aryl
entry 15).
OH
M=MgX, Al, Zn
The sweeping scope of the ACA was
finally explored using various organoalu-
minum, organozinc and Grignard reagents,
but unfortunately a mixture of 1,4- and
1,2-additon products, low yield and/or en-
antioselectivities were obtained under our
Scheme 1. Cu-catalyzed ACA to β,γ-unsaturated-α-ketoesters.
roughly a 1:1 ratio for the 1,4- and 1,2-ad-
duct selectivity achieving a promising 55%
pot reduction-oxidation or to α-amino
acid precursors by reductive amination
(Scheme 1).
ee for the γ-substituted-α-ketoesters (Table
reaction conditions.
4, entry 5).
By decreasing the reaction temperature
to –78 °C and increasing the reaction time
The ester functionality of β,γ-
unsaturated-α-ketoesters gives access to
a wide range of chiral building blocks af-
We initially investigated the ACA with
the simplest (E)-ethyl 2-oxo-4-phenylbut-
3-enoate, 28. This first attempt was done
to 17 hours, the regioselectivity was in-
creased in favor of the 1,4-addition adduct
and the enantioselectivity could equally be
ter further small and easy derivatization.
As mentioned in the introduction, direct
addition of organometallic reagents to
using the reaction conditions previously
developed for α,β-unsaturated aldehydes:
1.2 equivalents of an organometallic re-
improved (Table 4, entry 6).Various copper
aldehydes or alternative methodologies
agent, 5mol% of CuTC, 5.25 mol% of
salts, solvents and catalyst loadings were
to obtain chiral β-substituted aldehydes
left room for improvement. For this rea-
son we developed a one-pot, reduction-
oxidation procedure,[15] for the synthesis
of (S)-Florhydral.[16] With this strategy, we
were able to obtain the desired compound
with high yield and complete retention of
the chiral information (Scheme 2). We can
also easily prepare chiral α-amino acid
precursors through a one-step procedure.
By a simple reductive amination on chiral
γ-substituted-α-ketoesters we obtained,
under non-optimized reaction condi-
(R)-binap in diethyl ether (Et2O) at –78°C
screened revealing CuTC, tetrahydrofuran
(Table 4).
(THF) and 5 mol% of ligand and transi-
With the Grignard reagent, we ob-
tained full conversion of the substrate, but
unfortunately, we observed exclusively
the 1,2-addition product as well as in the
tion metal catalyst as the reaction condi-
tions of choice. However, an excess of tri-
methylaluminum (2 equiv.) was required
to get full conversion and complete regio-
presence of TMSCl as an additive (Table
selectivity in favor of the γ-substituted-α-
4, entries 1,2). The use of the less reac-
ketoesters (Table 4, entry 7).
tive organometallic reagent Me Zn under
similar reaction conditions resu2lted in no
conversion. However, under the best reac-
tion conditions developed later, 14% of
isolated γ-substituted-α-ketoesters could
With these reaction conditions in
hand, the substrate scope was investigated
with aromatic, aliphatic as well as linear
and cyclic β,γ-unsaturated-α-ketoesters.
Halogenated, nitro, methoxy aryl and ali-
tions, the corresponding unnatural chiral
be isolated with 93% ee (Table 4, entries
phatic derivatives are compatible under the
α-amino acid precursors also with com-
3,4). The use of trimethylaluminum, a well
reactionconditions(Table5).Onlystrongly
plete retention of the chiral information
and with a promising diastereoselectivity
of up to 3:1 (Scheme 2).
known mild organometallic reagent to in-
troduce methyl groups, was considered. At
–20 °C, full conversion was observed with
electron-donating groups (o, m, p-OMePh)
generated lower conversion and yield with-

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 199
Table 5. Scope of substrate
[1] For reviews on asymmetric conjugate additions,
see: a) M. P. Sibi, S. Manyem, Tetrahedron
2000, 56, 8033; b) T. Hayashi, Acc. Chem. Res.
2000, 33, 354; c) N. Krause, A. Hoffmann-
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C. Benhaim, Eur. J. Org. Chem. 2002, 3221;
e) T. Hayashi, K. Yamasaki, Chem. Rev. 2003,
103, 2829; f) A. Alexakis in ‘Methodologies
in Asymmetric Catalysis’, American Chemical
2.0 eq. Me Al
3
5mol% CuT
C
O
Me O
5mol% (R)-BIN
AP
OEt
OEt
R
R ∗
THF,-78°C, 17h
O
O
>99% regio.
31-45
46-60
Society, Washington DC, 2004, 43; g) J.
Christoffers, G. Koripelly, A. Rosiak, M.
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Harutyunyan, T. den Hartog, K. Geurts, A. J.
Entry
Sub.
R
Prod.
Yield
[%]
ee [%]a
1
2
31
32
p-FC6H4
p-ClC6H4
46
47
68
87
97
97
Minnard, B. L. Feringa, Chem. Rev. 2008, 108,
2824.
[2] a) L. Palais, L. Babel, A. Quintard, S. Belot,
3
4
5
6
7
33
34
35
36
37
38
39
40
41
42
43
44
45
p-BrC6H4
m-BrC6H4
o-BrC6H4
48
49
50
51
52
53
54
55
56
57
58
59
60
91
85
89
55
35
27
88
91
90
93
93
90
92
98
>99.5
99
97
94
27
96
88
92
98
91
82
98
A. Alexakis, Org. Lett. 2010, 12, 1988; b) L.
Gremaud, A. Alexakis, Angew. Chem. Int. Ed.,
DOI: 10.1002/anie.201107324.
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-NO2C6H4
m-NO2C6H4
o-NO2C6H4
m-iPrC6H4
C7H15
[3] a) S. Brase, S. Hofener, Angew. Chem. Int. Ed.
8
9
2005, 44, 7879; b) S. Ay, M. Nieger, S. Brase,
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10
11
12
13
14
15
[4] A. W. Hird, A. H. Hoveyda, Angew. Chem. Int.
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[5] a) R. Des Mazery, M. Pullez, F. Lopez, S. R.
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cyclohexyl
C6H4CH=CH
aDetermined by either GC, SFC or HPLC using chiral stationary phase. bNo
1,6-addition product was observed.
[6] J. M. Garcia, A. Gonzalez, B. G. Kardak, J. M.
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In conclusion, by direct addition of or- tives was observed, and resulted in a de-
ganometallic reagents to α,β-unsaturated crease of reactivity and enantioselectivity.
aldehydes we obtained good regio- or Furthermore, γ-substituted-α-ketoesters
enantioselectivities but never both at the were used as chiral building blocks for
same time. With both Grignard reagents further derivatization. We obtained the
corresponding β-substituted aldehydes
per (iii) complex and forcing conversion and unnatural chiral α-amino acid precur-
to β-adduct, the regioselectivities are not sors with high yield, complete retention of
flawless. In contrast, alternative method- the chiral information and with promising
ologies are complementary and more se- diastereoselectivity.
P. Eidam, Org. Lett. 2006, 8, 5505.
[8] T. Nishikata, Y. Yamamoto, N. Miyaura, Chem.
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Received: January 5, 2012
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DOI: 10.1002/anie.201105458.
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Scheme 2. Synthesis of unnatural α-amino acid precursors and (S)-Florhydral.

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