On the mechanism of Cu-catalyzed enantioselective extended conjugate additions: A structure-based approach

Article abstract of DOI:10.1021/cs501297s

The enantioselective 1,6-addition to unsaturated carbonyl compounds offers unique opportunities to study the range of selectivities one can obtain using Cu catalysis. Here, a substrate-reagent approach to obtain structural information on the mechanism of extended conjugate additions is reported. By studying the influence of several halides in the Grignard reagent and in the Cu source on the enantioselective 1,6-addition, it was shown that it is advantageous to use a combination of EtMgBr as Grignard reagent and CuI as Cu source. Furthermore, exploring substrates bearing several alkyl esters revealed that tBu-ester substrates enhance the enantiodiscrimination in the 1,6-addition and allow the addition of BnCH₂MgBr. Substrates with a variety of electron-withdrawing groups were investigated as well, identifying that ester substrates are optimal for the 1,6-addition. Two other investigations feature Me-substituted olefin substrates and substrates with all possible olefin geometries. These studies show unprecedented high enantioselectivity in the 1,6-addition when α-Me substrates are used and give relevant insight into the 1,6-addition mechanism. Finally, substrates with three or four olefins in conjugation with the electron-withdrawing groups were studied. Here, a 1,8-addition is reported that gives the corresponding products in reasonable yield, regio- and stereoselectivity. With the combined results of these studies, elucidating key substrate and reagent parameters, an adapted mechanism for the enantioselective 1,6-addition is proposed. This mechanism features the activation of a dimeric precatalyst by an equivalent of Grignard reagent, active catalyst coordination to the internal olefin of the substrate in a Cu^I-π-complex, followed by coordination of the catalyst to the remote olefin forming another Cu^I-π-complex. From the latter Cu^I-complex, an oxidative addition gives a Cu^III-σ-complex at the δ-carbon, followed by transfer of the alkyl moiety to the δ-position. This reductive elimination yields the product and reforms the active Cu^I catalyst via transmetalation with another molecule of Grignard reagent.

Full text of DOI:10.1021/cs501297s

Research Article
pubs.acs.org/acscatalysis
On the Mechanism of Cu-Catalyzed Enantioselective Extended
Conjugate Additions: A Structure-Based Approach
Tim den Hartog, Yange Huang, Martín Fananas-Mastral, Anne Meuwese, Alena Rudolph, Manuel Perez,
́
́
̃
Adriaan J. Minnaard,* and Ben L. Feringa*
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
S
* Supporting Information
ABSTRACT: The enantioselective 1,6-addition to unsatu-
rated carbonyl compounds offers unique opportunities to
study the range of selectivities one can obtain using Cu
catalysis. Here, a substrate−reagent approach to obtain
structural information on the mechanism of extended
conjugate additions is reported. By studying the influence of
several halides in the Grignard reagent and in the Cu source
on the enantioselective 1,6-addition, it was shown that it is
advantageous to use a combination of EtMgBr as Grignard
reagent and CuI as Cu source. Furthermore, exploring substrates bearing several alkyl esters revealed that tBu-ester substrates
enhance the enantiodiscrimination in the 1,6-addition and allow the addition of BnCH2MgBr. Substrates with a variety of
electron-withdrawing groups were investigated as well, identifying that ester substrates are optimal for the 1,6-addition. Two
other investigations feature Me-substituted olefin substrates and substrates with all possible olefin geometries. These studies
show unprecedented high enantioselectivity in the 1,6-addition when α-Me substrates are used and give relevant insight into the
1,6-addition mechanism. Finally, substrates with three or four olefins in conjugation with the electron-withdrawing groups were
studied. Here, a 1,8-addition is reported that gives the corresponding products in reasonable yield, regio- and stereoselectivity.
With the combined results of these studies, elucidating key substrate and reagent parameters, an adapted mechanism for the
enantioselective 1,6-addition is proposed. This mechanism features the activation of a dimeric precatalyst by an equivalent of
Grignard reagent, active catalyst coordination to the internal olefin of the substrate in a CuI-π-complex, followed by coordination
of the catalyst to the remote olefin forming another CuI-π-complex. From the latter CuI-complex, an oxidative addition gives a
CuIII-σ-complex at the δ-carbon, followed by transfer of the alkyl moiety to the δ-position. This reductive elimination yields the
product and reforms the active CuI catalyst via transmetalation with another molecule of Grignard reagent.
KEYWORDS: asymmetric catalysis, mechanism, copper, Grignard reagent, extended conjugate addition
investigations on the stoichiometric addition of Gilman reagents
to 2-en-4-ynoates by Krause16 and Nakamura17,18 are the most
extensive studies reported to date. The proposed mechanism by
Nakamura and co-workers17 shown in Scheme 2, based on
experimental data and computational studies, comprises the
following: (1) formation of a CuI-π-complex by coordination of
Me2CuLi to substrate 5, (2) an oxidative addition to give the
CuIII-σ-complex 7 (Cu-coordination to the β-position), (3)
copper migration to yield σ/π-allenyl-CuIII-complex 8 (Cu-
coordination to the δ-position), and (4) a reductive elimination
forming a CuI-species and the product 9.
In this paper, we describe the results of a largely structural
study toward the mechanism of the Cu-catalyzed enantiose-
lective 1,6-addition of Grignard reagents to dienoates using the
“reversed JosiPhos” ligand L2.7b,c Furthermore, we have
compared the observed parameters and trends for 1,6-ECA
INTRODUCTION
■
Methods for the Cu-catalyzed enantioselective formation of C−
C bonds using organometallic reagents are among the key
transformations of high importance for the synthesis of complex
molecules.1,2 Among them, enantioselective 1,4-addition (1,4-
ECA, Scheme 1a) using Grignard reagents3−5 has proven to be
valuable in numerous syntheses in recent years.6 A special case of
ECA is the enantioselective 1,6-addition (1,6-ECA, Scheme 1b)
in which substrates 3 bearing two olefins in conjugation with an
electron-withdrawing group are selectively converted into
valuable products 4.7−10 The 1,6-ECA not only yields
enantioenriched multifunctional building blocks,11−13 but this
reaction is also an intriguing example of the high chemo-, regio-,
and enantioselectivity one can obtain using enantioselective Cu
catalysis.
Although many synthetic methods have been designed for the
enantioselective construction of C−C bonds using organo-
metallic reagents employing Cu catalysis,1−5 only a limited
number of mechanistic studies toward these reactions has been
conducted.14,15 With respect to the use of organometallic
reagents for extended conjugate additions, the mechanistic
Received: August 30, 2014
Revised: November 11, 2014
© XXXX American Chemical Society
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Scheme 1. Cu-Catalyzed Enantioselective 1,4-3b−d and 1,6-
ECA7b,c of Grignard Reagents
1). The 1,6-ECA of EtMgBr to substrate 10 using CuBr·SMe2
and L2 (Table 1, entry 1) yielded product 11 in excellent
regioselectivity (ratio of 1,6-:1,4-addition = 99:1) and
enantioselectivity (96% ee). When CuCl was used as Cu source
instead of CuBr·SMe2, 11 was obtained in lower regioselectivity
and the same enantioselectivity (entry 2). When CuI replaced
CuBr·SMe2, 11 was obtained with similar regioselectivity and
higher enantioselectivity (98% ee, entry 3). The use of EtMgCl,
instead of EtMgBr, gave a low conversion when CuCl was used as
Cu source (entry 4). When a combination of EtMgCl and CuBr·
SMe2 was used, 11 was obtained in lower regio- and
enantioselectivity (entry 5 vs entry 1). The use of EtMgI in
combination with either CuBr·SMe2 or CuI (entry 6 and 7) gave
lower conversion, lower regioselectivity and slightly lower
(CuBr·SMe2) or the same (CuI) enantioselectivity compared
to the use of EtMgBr and CuBr·SMe2. In conclusion, a
combination of EtMgBr with either CuBr·SMe2 or CuI gives
the best results in terms of conversion, regio- and enantiose-
lectivity. Furthermore, the use of the Grignard reagent derived
from the organobromide is important to obtain high conversion
and selectivity to product 11.
When the regioselectivity of the reaction was lower, we were
able to identify the ee of the obtained 1,4-addition product 12
(entries 2, and 5 to 7). Interestingly, in all cases the 1,4-addition
product was obtained with low ee compared to the 1,6-addition
product (12 in all cases <26% ee vs 11 consistently ≥90% ee).
Finally, a comparison of the halide dependency for the 1,4-
ECA15a (to enoates) and 1,6-ECA (to dienoates) reveals similar
trends, even when these studies were conducted using different
catalysts (L1 for 1,4-ECA, L2 for 1,6-ECA); with a bromide in
either the Cu source or the Grignard reagent high conversions
and selectivities are obtained, while the use of EtMgI, or the
combination of EtMgCl and CuCl, gives lower conversions and
selectivities. The enantioselectivity for the 1,6-addition seems to
be less dependent on the nature of the halide than for the 1,4-
addition.
Scheme 2. Proposed Mechanism by Nakamura et al.17 for
Cuprate 1,6-Addition to an Enynoate
Ester Size Dependency. In a previous study, we found that
the size of the ester has a profound influence on the 1,4-ECA to
crotonates3c (Table 2, far right columns). Therefore, we studied
the influence of the different esters on the 1,6-ECA (Table 2).
Using methyl sorbate (13a), the 1,6-addition product 14a was
obtained with high regioselectivity and 75% ee (entry 1). The
enantioselectivity of the 1,6-ECA increased progressively when
bulkier esters were used (entry 2 to 4), yielding the 1,6-addition
with those obtained for the corresponding enantioselective 1,4-
addition.3a−d,15a
RESULTS
■
Halide Dependency. First, the halide dependency of the
1,6-ECA was studied using the same conditions that we
identified7b as optimal for the addition of ethyl Grignard
reagents to bisunsaturated ester substrates (3, R5 = alkyl, Scheme
Table 1. Halide Dependency of the 1,6-ECA
a
a c
−
1,6-addition
1,4-addition
conv. (%)
d
e
e
entry
EtMgX
CuX
conv. (%)
11:12
ee 11 {ee 1,4 (12)} (%)
ee (%)
1
2
3
4
5
6
7
EtMgBr
EtMgBr
EtMgBr
EtMgCl
EtMgCl
EtMgI
CuBr·SMe2
CuCl
>95%
>95%
>95%
<5%
99:1
96%
92%
90%
90%
80%
96%
40%
50%
94%
95%
95%
70%
80%
40%
88%
83:17
98:2
96% {20%}
98%
CuI
CuCl
n. d.
n. d.
CuBr·SMe2
CuBr·SMe2
CuI
>95%
57%
80:20
79:21
82:18
94% {26%}
90% {13%}
96% {9%}
EtMgI
51%
a
b
c
Conditions: see Supporting Information (SI), 5% Cu, 5.25% L2. Data can also be found in SI Table S6 of ref 15a. Substrate: methyl crotonate;
d
e
product: methyl 3-methylpentanoate. Conversion was determined by GC-MS. Ratio of 1,6:1,4 and ee’s were determined by chiral GC.
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Table 2. Dependency on the Size of the Ester in 1,6-ECA
a
a,b
1,6-addition
1,4-addition
conv. (%)
c
c
entry
R1
13
R2
14
isolated yield (%)
64%
1,6:1,4
ee 1,6 (%)
75%
ee (%)
d
d
d
d
1
2
3
4
5
6
Me
Et
13a
13b
13c
13d
13d
13d
Et
Et
Et
Et
14a
14b
14c
14d
14e
14f
>99:1
>95%
>95%
>95%
92%
e
e
e
d
84%
98:2
95%
78%
d
iPr
tBu
tBu
tBu
82%
88%
72%
77%
99:1
98:2
98:2
99:1
97%
98%
98%
99%
54%
f
<5%
n. d.
nhexyl
ipentyl
a
b
Conditions: see SI, 5% Cu, 5.25% L2. Substrates: methyl, ethyl, iso-propyl or tert-butyl crotonate; products: methyl, ethyl, iso-propyl or tert-butyl 3-
c
d
e
methylpentanoate. Ratio of 1,6:1,4 and ee’s were determined by chiral GC. Data can also be found in Scheme 1 of ref 3c (in parentheses). Data
can also be found in Table 3 of ref 7b [enantiomer of ligand was used and enantiomer of product was obtained]. Unreported data.
f
products in 95% ee (R1= Et, 14b), 97% ee (R1= iPr, 14c), and
98% ee (R1= tBu, 14d), respectively, while the regioselectivity
remained constant. The addition of several other alkyl Grignard
reagents to 13d (R1= tBu) gives the corresponding 1,6-addition
products with high enantioselectivity as well (entries 5 and 6).
The observed trend is in sharp contrast to the one found for 1,4-
ECA to crotonates.3c In the 1,4-ECA the highest enantiose-
lectivity is obtained using methyl crotonate, bearing a small
methyl ester, while the iso-propyl ester gives low ee, and the
bulkier tert-butyl crotonate gives very low conversion to the 1,4-
addition product.3c
It is especially interesting that the 1,6-addition of phenethyl
magnesium bromide to tert-butyl sorbate 13d proceeds with low
conversion and high regio- and stereoselectivity, while the
addition of this Grignard reagent to ethyl sorbate 13b gave no
conversion (Scheme 3).
15c, the 1,6-ECA proceeded with low regio- and enantiose-
lectivity (entry 3). In contrast, the 1,4-ECA to either
monounsaturated thioesters3d or ketones3b gives the 1,4-addition
products in high yield, regio- and enantioselectivity.
Substrates with an EWG group featuring a possible second
coordination site for Mg were tested as well. Addition of EtMgBr
to sulphone3f,19 15d gave the 1,6-addition product 16d in low
yield, high regioselectivity, and negligible enantioselectivity
(entry 4). Use of dienoyloxazolidinone 15e gave the 1,6-addition
product 16e in modest yield and regioselectivity as well as
negligible ee (entry 5). The use of imidazolyldienone substrate
15f gave the 1,4-addition product 17f in low yield, high
regioselectivity, and negligible ee (entry 6).
Finally, we studied the 1,6-addition of the less reactive
MeMgBr to substrates bearing an ester, thioester, and ketone as
EWG. As reported in our previous studies, use of ester 15a gave
low conversion to the 1,6-addition product 16g (entry 7).7b
However, the use of thioester 15g or 15b allowed the isolation of
1,6-addition products, 16h and 16i, respectively, in high yield,
regio- and enantioselectivity (entry 8, 9), emphasizing the
remarkable difference between ester and thioester EWG in these
transformations.7c Addition of MeMgBr to ketone 15c gave 1,6-
addition product 16j in modest yield, regioselectivity, and ee
(entry 10).
Scheme 3. Enantioselective 1,6-Addition of Phenethyl
a
Magnesium Bromide to Sorbates
In conclusion, a fine-tuning of the Michael acceptor properties
of the substrate, with respect to the reactivity of the Grignard
reagent, is required to obtain the 1,6-addition products in high
yield with excellent regio- and enantioselectivities. Furthermore,
when the substrate possesses two heteroatom coordination sites
for Mg, the 1,6-ECA (or 1,4-ECA to bisunsaturated Michael
acceptors) proceeds with negligible enantioselectivity.
a
Conditions: a solution of 13 in CH2Cl2 was added in 2 h to a solution
Influence of the Olefin Substitution Pattern. Methyl
substitution of the olefins has a major impact on the 1,4-ECA of
Grignard reagents to α,β-unsaturated ketone,20 ester, and
thioester substrates. Using standard reaction conditions for the
1,4-ECA using L2, the addition of EtMgBr to the α-Me
substituted ester ethyl tiglate (Table 4, entry 1, far right
columns), the β-Me substituted ester ethyl 3-methyl-2-butenoate
(Table 4, entry 2, far right columns), and β-Me substituted
thioester substrate (S)-ethyl (E)-3-phenylbut-2-enethioate 18
(Scheme 4) gave low conversion. The EtMgBr 1,4-ECA to the α-
Me substituted thioester substrate (S)-ethyl (E)-2-methylbut-2-
enethioate 19 gives full conversion to 1,4-addition product 20,
although the ee of 20 is negligible. The impact of α-Me
substitution on the 1,4-ECA to ketone substrates is even more
of EtMgBr (solution in Et2O, 2.0 equiv), (−)-(R,S)-L2 (5.25 mol %)
and CuBr·SMe2 (5 mol %) in CH2Cl2 (0.2 M final concentration in
13) at −70 °C, 16 or 48 h total reaction time.
Michael Acceptor Dependency. Next, we studied the 1,6-
ECA to several substrates bearing various electron-withdrawing
groups (Table 3). As reported earlier,7b the use of ethyl ester 15a
gave the 1,6-addition product in 80% yield, 99:1 regioselectivity,
and 93% ee (entry 1). The 1,6-ECA of EtMgBr to the more
electron-poor Michael acceptor 15b, incorporating an ethyl
thioester as electron-withdrawing group (EWG), gave the 1,6-
addition product 16b in high regioselectivity, modest yield and
low enantioselectivity (entry 2). When EtMgBr was reacted with
the even more electron-poor Michael acceptor methyl ketone
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Table 3. Michael Acceptor Dependency of the 1,6-ECA
a
1,6-addition
R2
b
b
entry
R1
EWG
15
16/17
yield (%)
1,6:1,4
ee 1,6 (%)
c
1
nBu
nBu
nBu
nBu
Me
Me
Et
CO2Et
COSEt
COMe
15a
15b
15c
15d
15e
15f
Et
Et
Et
Et
Et
16a
16b
16c
16d
16e
17f
16g
16h
16i
80%
58%
99:1
93%
d
2
3
4
5
6
>95:5
63:37
98:2
≈ 40%
≈ 30%
2%
d
d
≈ 60%
sulphone
26%
64%
34%
<10%
85%
83%
54%
e
(CO)oxazolidinone
(CO)imidazole
CO2Et
75:25
<5:95
n. d.
3%
e
BnCH2
Me
2%
f
7
15a
15g
15b
15c
n. d.
93%
89%
66%
f
8
g
Et
COSEt
Me
99:1
9
nBu
nBu
COSEt
Me
99:1
10
COMe
Me
16j
63:37
a
b
c
Conditions: see SI, 5% Cu, 5.25% L2. Ratio 1,6:1,4 and ee’s were determined by chiral GC. Data can also be found in Table 4 of ref 7b [the
d
enantiomer of the ligand was used and the enantiomer of the product was obtained]. Signals corresponding to the two enantiomers on chiral GC
were partly overlapping. Ratio of 1,6:1,4 was determined by NMR. Data can also be found in Scheme 3 of ref 7b. Data can also be found in Table
e
f
g
2 of ref 7c.
Scheme 4. Influence of Methyl Substituted Olefins on the
Enantioselective 1,4-Addition to Unsaturated Thioesters
Scheme 5. Influence of Methyl Substituted Olefins on the
Enantioselective 1,4-Addition to Unsaturated Ketones
a
a
a
Conditions: 1,4-addition to 18: a solution of 18 in CH2Cl2 was added
in 2 h to a solution of EtMgBr (solution in Et2O, 2.0 equiv),
(−)-(R,S)-L2 (5.25 mol %) and CuBr·SMe2 (5 mol %) in CH2Cl2 (0.2
M final concentration in 18) at −78 °C, 16 h total reaction time. 1,4-
addition to 19: a solution of 19 in CH2Cl2 was added in 2 h to a
solution of EtMgBr (solution in Et2O, 2.0 equiv), (−)-(R,S)-L2 (5.25
mol %) and CuBr·SMe2 (5 mol %) in CH2Cl2 (0.2 M final
concentration in 19) at −78 °C, 16 h total reaction time.
a
Conditions: 1,4-addition to 21: a solution of iBuMgBr (solution in
Et2O, 1.15 equiv) was added to a solution of 21, (−)-(R,S)-L1 (6 mol
%) and CuBr·SMe2 (5 mol %) in tBuOMe (0.1 M final concentration
in 21) at −75 °C, 2 h total reaction time. 1,4-addition to 23: a solution
of iBuMgBr (solution in Et2O, 1.2 equiv) in tBuOMe was added over
15 min to a solution of 23, (+)-(S,R)-L2 (6 mol %) and CuBr·SMe2 (5
mol %) in tBuOMe (0.075 M final concentration in 23) at −60 °C, 10
h total reaction time.
dramatic (for an example, see Scheme 5). When α,β-unsaturated
α-Me substituted ketone substrates are treated with alkyl
Grignard reagents at low temperature in the presence of a
catalytic amount of Cu-L2, instead of 1,4-addition products, the
1,2-addition products are obtained in high yield, regio- and
stereoselectivity in most cases.20
We were interested in the effect that methyl substitution at
various positions of the diene moiety in the sorbates 25 would
have on the 1,6-ECA (Table 4). The 1,6-ECA of EtMgBr to α-
Me substituted substrate 25a gave the corresponding 1,6-
addition product 26a in similar yield, regioselectivity, and even
higher enantioselectivity (entry 1) than the corresponding 1,6-
ECA to α-H substituted substrate 15a (Table 3, entry 1). With
respect to the α-stereogenic center, 1,6-addition product 26a was
obtained as a mixture of anti- and syn-isomers; this suggests that
the stereogenic center at the δ-position does not induce any
diastereoselectivity in the trapping of the vinyl enolate
intermediate at the α-position by a proton. Addition of EtMgBr
to the β-Me substituted substrate 25b gave a low conversion and
low yield of a mixture of 1,4- and 1,6-addition products (Table 4,
entry 2). The conversion was low for the 1,6-ECA to the γ-Me
substituted substrate 25c at −70 °C (entry 3, for a corresponding
experiment at −60 °C see SI footnote F1). This is reminiscent of
the 1,4-ECA to the α-Me substituted thioester substrate (entry 1,
far right columns). Finally, at −70 °C the 1,6-ECA to the δ-Me
substituted substrate 25d gave low conversion to the 1,4-addition
product 27d (entry 4, for a corresponding experiment at −60 °C
see SI, footnote F2). In conclusion, while β-, γ-, and δ-Me
substitution of sorbates give worse results for the 1,6-ECA, the
use of the α-Me substituted substrate gives even better results
than the α-H substrate.
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Table 4. Influence of Methyl-Substituted Olefins on the Enantioselective 1,6-Addition
a
b
c
d
Conditions: see SI, 5% Cu, 5.25% L2. Conversion was determined by GC-MS. Ratio of 1,6:1,4 and ee’s were determined by chiral GC.
A
e
f
mixture of syn- and anti-products was obtained. ≈ 55% of substrate 25b was recovered. Mixture of products with MS fragmentation patterns
g
h
corresponding to 1,6- and 1,4-addition products was found. ≈ 55% of substrate 25c was recovered. A mixture of 1,6- and 1,4-products was
i
obtained; overlap of the peaks corresponding to substrate and 1,4-addition product on chiral GC did not allow determination of these ratios. ee for
j
k
the 3Z-1,6-addition product was 5%. ≈ 60% of substrate 25d was recovered. Value between brackets corresponds to ee of 1,4-addition product.
Table 5. Dependency of the Enantioselective 1,6-Addition on the Olefin Geometry of the Sorbates
a
b
c
d
Conditions: see SI, 5% Cu, 5.25% L2. Data can also be found in Table 4 of ref 15a. For footnote F3 see SI. Conversion was determined by GC-
e
f
g
MS. Ratio of 1,6:1,4 and ee’s were determined by chiral GC. Isolated yield. Substrate: E-methyl cinnamate; product: methyl 3-phenylpentanoate.
h
i
j
Please note: enantiomer of catalyst was used. Substrate: Z-methyl cinnamate; product: methyl 3-phenylpentanoate. Total reaction time: 2 h 10
k
l
min to 3 h. Remaining starting material was recovered without isomerization. Overlap of the peaks corresponding to substrate and 1,6-addition
product on chiral GC did not allow determination of this ee. Reaction was quenched after 10% conversion. Recovered starting material Z-: E-
m
n
methyl cinnamate= 94:6.
Olefin Geometry Dependency. We also studied the
influence of the geometry of the two olefinic moieties in the
dienoates on the 1,6-ECA (Table 5). Enantioselective 1,6-
addition of EtMgBr to all-E substrate 10 affords the R-
enantiomer of the corresponding product 11 in high yield,
regioselectivity and 96% ee (entry 1). As expected, the opposite
enantiomer of the 1,6-addition product, S-11, is obtained when
the 2E,4Z-substrate 28a is used in the 1,6-ECA in high yield,
regioselectivity and 96% ee (entry 2). This result contrasts to the
1,4-ECA of E- and Z-cinnamates (entry 1 and 2, far right
columns, for footnote F3 see SI). For the 1,4-ECA, the opposite
enantiomer of the 1,4-addition product is obtained with lower
enantioselectivity due to isomerization of the Z-substrate under
the reaction conditions (vide infra).15a The 1,6-ECA to the
2Z,4E-substrate 28b gave S-11 but with low ee (entry 3). Using
the 2Z,4Z-substrate 28c, compared to the use of 28b, the
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Table 6. Enantioselective 1,8- and 1,10-Addition
a
1,8-addition
cat (%)
b
c
c
c
entry
n
X
29
R
conv. (%)
>95%
yield
1,8:1,6:1,4
ee 1,8-product (%)
1
2
1
1
OEt
SEt
29a
29b
Et
5%
47%
63%
63:8:29
86:0:14
7%
Me
7.5%
92%
72%
a
1,10-addition
b
c
entry
n
X
29
R
cat (%)
conv. (%)
yield
1,10:1,8 + 1,6:1,4
ee 1,10-product (%)
3
4
2
2
OEt
SEt
29c
29d
Et
5%
85%
82%
22%
44%
49:8:43
59:0:41
12%
45%
Me
10%
a
b
c
Conditions: see SI. Conversion was determined by GC-MS. Ratio of 1,6:1,4 and ee’s were determined by chiral GC.
a
Scheme 6. Mechanism of the Enantioselective 1,6-Addition
a
For footnotes F4, F10, and F12, see SI.
opposite enantiomer R-11 was obtained, however, with a higher
enantioselectivity (entry 4).
conjunction with the 1,8-addition product also 1,4-addition
product 31a, and only traces of the 1,6-addition product were
obtained. The 1,8-addition product 30b was the main product
when the 1,8-ECA of MeMgBr to thioester substrate 29b was
performed (entry 2). The product 30b was obtained in
reasonable yield, regio- and enantioselectivity; however, a higher
catalyst loading (7.5 mol %) was required to achieve high
conversion. Again, the main side-product was the 1,4-addition
product 31b, although in this case the 1,6-addition product was
absent.
For 1,10-ECA to ester substrate 29c, a mixture of 1,4- and
1,10-addition product was obtained, in combination with traces
of 1,6- and 1,8-addition products (entry 3). The 1,10-addition
product 30c was obtained in a comparable ee with the 1,8-
addition product (entry 1). The use of MeMgBr and thioester
substrate 29d gave the 1,10-addition product 30d as the main
product in reasonable yield and modest ee using 10 mol % of Cu-
L2 (entry 4). The 1,4-addition product was obtained as well,
while the 1,6- and 1,8-addition products were absent.
The difference in the ee’s obtained using 28b and 28c could
possibly arise from isomerization of the substrate under the
reaction conditions.15a,21 Therefore, we performed several 1,6-
ECA reactions where we did not allow the reaction to proceed
until completion, in order to study the integrity of the olefins. For
none of the substrates 28a, 28b, or 28c, olefin isomerization was
observed under the reaction conditions (entries 5 to 8). This is
again in contrast to the 1,4-ECA to cinnamates,15a where
isomerization of the Z-cinnamate to the E-cinnamate was
observed under the reaction conditions (entry 6, far right
columns). The relatively high stereoselectivity observed for the
1,6-ECA to 28c, compared to the 1,6-ECA to 28b, is thus most
likely the result of a different coordination mode of the Cu-L2
catalyst to this less space-requiring substrate.
Enantioselective 1,8- and 1,10-Addition. Finally, we
explored the enantioselective extended conjugate additions to
substrates that either possess three conjugated olefins in
conjugation with the EWG being a substrate for an
enantioselective 1,8-addition22 (Table 6, 1,8-ECA) or four
conjugated olefins, a substrate for an enantioselective 1,10-
addition (1,10-ECA). The Cu-catalyzed addition of EtMgBr to
the 1,8-ECA substrate 29a mainly gave rise to the 1,8-addition
product 30a, although in modest yield and low ee (entry 1). In
In conclusion, the 1,6-, 1,8- and 1,10-ECA to their
corresponding thioester substrates (15b, 29b and 29d,
respectively) give the products in decreasing regio- and
stereoselectivity the more remote the olefin (and thus the
newly formed stereogenic center) is from the thioester
functionality. Furthermore, 1,8- and 1,10-ECA gives a low
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a
Scheme 7. Mechanism for Enantioselective 1,8-Additions
a
For footnotes F12 and F14, see SI.
stereodiscrimination when ester substrates are used. It is striking
that in all the cases of 1,8- and 1,10-ECA studied, the 1,4-addition
products or the addition product, for which the alkyl is
transferred to the most remote olefinic carbon of the π-system,
are exclusively formed.
the stereochemistry is already established at this stage (also see
SI, footnotes F8 and F9). Second, the opposite trends on
stereoselectivity as a function of the ester size (Table 2) for the
1,4- (for enoates) and 1,6-addition (for dienoates), as well as the
high stereoselectivity obtained for the α-Me substrate (Table 4,
entry 1) similarly argue against hypothetical intermediate 39.
Third, for strong Michael acceptors, for which the formation of
CuIII-σ-intermediate 39 should be more facile, the observed low
regio- and stereoselectivity for the formation of the 1,6-addition
product (e.g., for thioester substrate 15b and ketone substrate
15c, Table 3, entries 2 and 3) is an indication that intermediate
39 is unlikely to be involved in the formation of the 1,6-addition
product for ester substrates (for footnote F10, see SI). Finally,
the fact that no isomerization of any of the Z-olefins was observed
under the reaction conditions for the 2Z,4E-substrate 28b, and
the 2Z,4Z-substrate 28c (Table 5, entries 6 and 7) makes it
unlikely that a CuIII-σ-intermediate on the β-position is involved
in the mechanism of the 1,6-addition (for footnote F11, see SI).
From the second CuI-π-intermediate 36, an oxidative addition
gives CuIII-σ-intermediate 37 at the δ-position. A subsequent
reductive elimination, transferring the alkyl group from the CuIII-
σ-intermediate to the δ-position of the dienoate yields the 1,6-
addition product 38. Alkyl transfer to the resulting CuI-
intermediate by a new equivalent of the Grignard reagent then
allows the reformation of the active catalyst 33.
For the β-Me substituted substrate 25b, the low conversion
that is observed (Table 4, entry 2) can be explained by the steric
repulsion in an intermediate similar to 35. However, the low
conversion for γ-Me-substituted substrate 25c and δ-Me-
substituted substrate 25d (Table 4, entries 3 and 4, respectively)
is caused by the steric hindrance in the corresponding
intermediates 36 or 37.
Stereochemical Course of the 1,6-Addition. The results
we have obtained with our structural study toward the 1,6-
addition mechanism give some insight in the requirements for
the formation of the δ-substituted product with high stereo-
selectivity. The 1,6-addition products are obtained with high
enantiomeric excess when the Mg, which we propose is
coordinating to the carbonyl in the stereodiscriminating step, is
forced toward the Cu in any of the intermediates involving Cu
DISCUSSION
■
Mechanism of the Enantioselective 1,6-Addition. A
mechanism that is consistent with our results is depicted in
Scheme 6 (for footnote F4, see SI). In our proposed mechanism,
the precomplex 3215a is converted by the Grignard reagent (alkyl
transfer) to form the active binuclear Cu,Mg-catalyst 33. Such an
activation was observed during the studies toward the
mechanism of the 1,4-addition of Grignard reagents.15a
Analogous to the first CuI-π-intermediate in the 1,4-addition
mechanism,15a this precomplex 33 coordinates to the internal
olefin of substrate 34, forming CuI-π-intermediate 35.16b,c,f,23
The low conversion observed for the β-Me substituted substrate
25b under the standard reaction conditions (−70 °C, Table 4,
entry 2) supports the involvement of the internal olefin in the
1,6-addition mechanism (for footnote F5, see SI).
After formation of the initial CuI-π-intermediate 35, the Cu
catalyst coordinates to the remote olefin giving a second CuI-π-
intermediate 36; this step is most likely reversible. This
intermediate 36 is, for several reasons, more likely than a first
CuIII-σ-complex 39 (for footnote F6, see SI), a hypothetical
intermediate that would be analogous to 7 in the mechanism for
1,6-addition of Me2CuLi to 2-en-4-ynoates proposed17 by
Nakamura et al. (Scheme 2). First of all, the lower enantiomeric
excess observed for the 1,4-addition products compared to the
1,6-addition products using the same reagents and substrates
(Table 1, entries 2, 5−7) supports the involvement of a second
CuI-π-intermediate 36, since we assume that from the hypo-
thetical CuIII-σ-complex 39 at the β-position the stereochemical
information is transferred to the δ-position, and subsequently to
the 1,6-addition product (for footnote F7 and for Figure S1; for a
graphical depiction of this transfer, see SI). This would mean that
the 1,4-addition product (e.g., 12, Table 1) and the 1,6-addition
product (e.g., 11) would be formed with similar enantiomeric
excess if intermediate 39 would be involved in the mechanism as
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coordination to the olefins (35 or 36). This is achieved either by
the use of a bulky tBu-ester (Table 2, entry 4) or by the use of the
α-Me-substituted dienoate (Table 4, entry 1). In contrast, when
there is a possibility for the Mg to be doubly coordinated to the
electron-withdrawing group (e.g., in the CO-oxazolidinone,
Table 3, entry 5 and the pyridine sulphone, Table 3, entry 4) and
is thus not in the vicinity of the Cu, the 1,6-addition proceeds
without any stereodivergence (for footnote F13, see SI).
Furthermore, our study of the use of the various halides in both
catalyst and Grignard reagent shows that the choice of halide
influences the stereoselectivity of the 1,6-addition, as well as the
conversion (Table 1). The dependency on the halide can be
explained in two possible ways. First of all, a coordination of the
Cu-(halide)-Mg-halide to both the carbonyl and the olefin in a
pseudo 8-membered ring in CuI-π-complex 36, in which the
halide is required to have the right size, might furnish the high
stereodiscrimination. Alternatively, the bulky P-substituents of
the ligand (two phenyl and two cyclohexyl groups) might force a
(rigid) conformer in the stereodiscriminating step, especially
when the Mg-halide coordinated to the carbonyl has the right
size. A nine-membered intermediate in the CuIII-σ-complex 37 is
unlikely, due to the investigation of similar CuIII-σ-complexes at
low temperatures by NMR spectroscopy.24 These CuIII-σ-
complexes have been identified to possess a square planar
geometry.24 Unfortunately, the aforementioned studies of CuIII-
σ-complexes do not include any bidentate ligands coordinating
the Cu.
mechanism the enantioselectivity will have been predetermined
at the formation of the CuIII-σ-intermediate at the δ-position (i.e.,
addition of the Cu at either the re- or si-face of the olefin). The
stereochemical information would then be transferred along the
carbon-chain, with some racemization, explaining the decreasing
enantioselectivity for 1,6- > 1,8- > 1,10-addition.
Formation of 1,4-Addition Products by the Reaction of
a Grignard Reagent with Dienoates. A mechanism for the
formation of the 1,4-addition products (Scheme 8) involves the
Scheme 8. Mechanism for the Catalytic Formation of the 1,4-
a
Addition Product in Dienoates
a
For footnote F12 see SI.
Mechanism of the 1,8- and 1,10-Addition. A plausible
mechanism for the formation of 1,8- and 1,10-addition products
using the appropriate substrate (29a,b or 29c,d, Table 6)
involves, analogous to the 1,6-addition mechanism, active
catalyst 33, CuI-π-complex 1 41, and CuI-π-complex 2 42
(Scheme 7). When an oxoester is used as electron-withdrawing
group, from intermediate 42, CuI-π-complexes with the third
olefin (43, 1,8-addition), or, subsequently, the third and the
fourth olefin (1,10-addition) are accessible. These intermediates
with the CuI-π-complex coordinated to the remote olefin (e.g.,
43), then form a CuIII-σ-complex at the remote C atom of the π-
system (the ζ-position for 1,8-addition (45), the θ-position for
1,10-addition). Analogous to the 1,6-addition from this CuIII-σ-
intermediate, the alkyl group is transferred to the ζ- or the θ-
position to yield the product, while simultaneously, complex-
ation of another Grignard reagent allows the reformation of the
active catalyst.
The low stereoselectivity observed for the 1,8- and 1,10-
addition to oxoester substrates strengthens our proposal that in
the stereodiscriminating step the distance between the Cu and
the Mg, coordinated to the enolate, is highly important for high
enantioselectivity in extended conjugate additions. It is striking
that for the 1,8- and 1,10-addition using the oxoester substrates
the reaction proceeds with low stereoselectivity, while for the
thioester substrates the 1,8- and 1,10-addition products are
obtained with high and modest enantioselectivity, respectively.
This difference points at a different mechanism for 1,8- and 1,10-
addition when a thioester (vs the oxoester) is used as electron-
withdrawing group, although further studies are necessary. In this
alternative mechanism after the first CuI-π-intermediate 41 an
oxidative addition gives the CuIII-σ-complex at the β-position
(44), due to the better Michael acceptor properties of the
thioester functionality (for footnote F14 and F15 see SI). From
intermediate 44 the CuIII is then transferred from the β- to
consecutively, the δ- and the ζ-position (for 1,8-ECA, 45), or
subsequently to the δ-, ζ- and θ-position (for 1,10-ECA). In this
active catalyst 33 and CuI-π-complex 35, both present in the
proposed 1,6-addition mechanism. The increased formation of
1,4-addition product vs 1,6- < 1,8- < 1,10-addition product, the
more extended the conjugation is, most probably indicates that
these reactions share common intermediates. From CuI-π-
complex 35, oxidative addition gives CuIII-σ-complex 39, in
which the Cu is coordinated to the β-position. Subsequently, a
reductive elimination, transferring the alkyl group from the CuIII-
σ-intermediate to the β-position of the dienoate, gives the 1,4-
addition product. From our results showing dramatic differences
in the ee of the 1,4- and 1,6-adducts of the dienoates (see Table
1) it is evident that the 1,6-ECA and 1,4-ECA have a diverging
stereodefining step.
The low regioselectivity for the 1,6-ECA of EtMgBr to
thioester and ketone substrates (15b and 15c, Table 3, entries 2
and 3, respectively) can be explained by a higher rate for the
oxidative addition at the β-position, in comparison with the rate
for isomerization to the δ-position.
CONCLUSIONS
■
The structure-based mechanistic studies that we have conducted
for this research have allowed us to identify substrates (α,β,γ,δ-
bisunsaturated tert-butyl esters and α-Me substituted α,β,γ,δ-
bisunsaturated ethyl esters) for which the stereodiscrimination of
the 1,6-addition to dienoates using Grignard reagents is even
better (up to 99% ee) than for previously reported substrates.
Furthermore, use of the α,β,γ,δ-bisunsaturated tert-butyl esters in
the 1,6-ECA allows the addition of a Grignard reagent that did
not display the desired reactivity7b before. Additionally, we show
that 1,8-addition products can be obtained in reasonable yield,
regio- and stereoselectivity. With the combined studies described
here, we have obtained further insight in the mechanism of the
1,6-addition. This has led to an adapted proposal for the 1,6-
addition mechanism (Scheme 6). Finally, our results make it
likely that there is a different mechanism for the 1,8- and 1,10-
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+
addition to either oxoester or thioester substrates (Scheme 7).
Further research, including extensive kinetic studies (combining
in situ and quenching experiments) and high level quantum
chemical calculations (for which the exact description of the
Grignard reagent in solution25 remains a big challenge), will shed
more light on the mechanism for 1,6-addition using Grignard
reagents.
(57) [C3H3O+]; HRMS calcd for C15H29O2 241.2162; found,
241.2160; ee and regioselectivity were determined by chiral GC
analysis, column: Chiraldex-B-PM, 40 to 110 °C in 7 min, 110 °C
for 90 min; retention times (min): 68.1 (an enantiomer of the
1,4-addition product), 69.0 (other enantiomer of the 1,4-
addition product), 75.0 (S-11), 75.9 (R-11).
Ester Size Dependency. (S,E)-methyl 5-methylhept-3-
enoate (14a) was prepared via the general procedure for the
enantioselective 1,6-conjugate addition using (2E,4E)-methyl
hexa-2,4-dienoate (13a) and EtMgBr. Results: [0.5 mmol scale,
64% yield, (The low yield can be explained either by volatility of
the products or by a substantial degradation of methyl sorbate
under the reaction conditions) 75% ee, 1,6:1,4 = >99:1, colorless
EXPERIMENTAL SECTION
■
The general procedure for the enantioselective 1,6-conjugate
addition is as follows. In a dried Schlenk tube equipped with a
septum and a stir bar under a N2 atmosphere, CuBr·SMe2 (5.0
mol %) and (R,S)-reversed JosiPhos (L2, 5.25 mol %) were
dissolved in anhydrous CH2Cl2 (4 mL/mmol substrate). After
the mixture was stirred for 5 min at room temperature, it was
cooled to −70 °C, and the Grignard reagent (solution in Et2O,
2.0 equiv) was added. After it was stirred for an additional 10 min,
a solution of the substrate (1.0 equiv) in anhydrous CH2Cl2
(additional 1.0 mL/mmol substrate) was added with syringe
pump over 2 h. The reaction mixture was stirred overnight (16 h
including addition) at −70 °C, and subsequently, EtOH (0.2
mL/mmol substrate) and an aq. NH4Cl-solution (1 M, 1.0 mL/
mmol substrate) were added. The mixture was warmed to room
temperature, and an additional 10 mL/mmol substrate of the
NH4Cl-solution and 10 mL/mmol substrate of CH2Cl2 were
added, and the layers were separated. After extraction with
CH2Cl2 (2 × 10 mL/mmol substrate), the combined organic
extracts were dried, and in view of the volatility, they were
carefully concentrated to a yellow oil. Flash column chromatog-
raphy (3:97 Et2O/pentane) yielded the product as a colorless oil.
(Occasionally the product was polluted by traces of a yellow
colored side product undetectable by GC/MS or NMR.)
1
oil]. Data: [α]D20 = +14.9 (c = 1.0 in CH2Cl2); H NMR (400
MHz, CDCl3, 25 °C, TMS): δ = 5.55−5.34 (m, 2H), 3.66 (s,
3H), 3.02 (d, J = 5.9 Hz, 2H), 2.02 (dt, J = 13.5, 6.8 Hz, 1H), 1.28
(p, J = 7.3 Hz, 2H), 0.95 (d, J = 6.7 Hz, 3H), 0.83 ppm (t, J = 7.4
Hz, 3H); 13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ 172.8
(C), 140.6 (CH), 120.0 (CH), 51.8 (CH3), 38.4 (CH), 38.1
(CH2), 29.7 (CH2), 20.0 (CH2), 11.8 ppm (CH3); MS (m/z)
+
156 (5) [M+], 85 (100) [C4H5O2 ], 82 (80) [C5H6O+], 67 (45)
[C4H3O+], 59 (44) [C2H3O2 ], 55 (95) [C3H3O+]; HRMS calcd
+
for C9H16O2Na+ 179.1043; found, 179.1039; ee was determined
by chiral GC analysis for 2-methylbutanoic acid,26,27 column:
Chiraldex-B-PM, 50 to 60 °C in 1 min, 60 °C for 70 min, 60 to
160 °C in 10 min, 160 °C for 4 min, retention times (min): 81.5
(major), 82.0 (minor). Regioselectivity was determined by chiral
GC analysis, column: Chiraldex-B-PM, 50 to 60 °C in 1 min, 60
°C for 140 min, retention times (min): 112.6 (1,4-product),
119.6 (14a).
(S,E)-iso-propyl 5-methylhept-3-enoate (14c) was prepared
via the general procedure for the enantioselective 1,6-conjugate
addition using (2E,4E)-iso-propyl hexa-2,4-dienoate (13c) and
EtMgBr. Results: [0.5 mmol scale, 82% yield, 97% ee, 1,6:1,4 =
99:1, colorless oil]. Data: [α]D20 = +13.7 (c = 1.0 in CH2Cl2); 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 5.52−5.34 (m, 2H),
5.05−4.93 (m, 1H), 2.96 (d, J = 6.6 Hz, 2H), 2.01 (dt, J = 13.5,
6.7 Hz, 1H), 1.34−1.15 (m, 8H), 0.95 (dd, J = 6.7, 1.6 Hz, 3H),
0.83 ppm (td, J = 7.3, 1.4 Hz, 3H); 13C NMR (100.59 MHz,
CDCl3, 25 °C, TMS): δ = 171.9 (C), 140.3 (CH), 120.3 (CH),
67.8 (CH), 38.6 (CH2), 38.5 (CH), 29.7 (CH2), 21.9 (CH3),
20.2 (CH3), 11.8 ppm (CH3); MS (m/z) 184 (2) [M+], 142 (21)
[M+ − iPr+H], 124 (31) [C8H12O+], 113 (22), 97 (44) [M+ −
CO2iPr], 82 (52) [C6H10+], 67 (22) [C4H3O+], 55 (100)
[C3H3O+]; HRMS calcd for C11H20O2Na+ 207.1356; found,
207.1351; ee was determined by chiral GC analysis for 2-
methylbutanoic acid,26,27 column: Chiraldex-B-PM, 50 to 60 °C
in 1 min, 60 °C for 70 min, 60 to 160 °C in 10 min, 160 °C for 4
min; retention times (min): 81.3 (major), 82.1 (minor).
Regioselectivity was determined by chiral GC analysis, column:
Chiraldex-B-PM, 50 to 60 °C in 1 min, 60 °C for 140 min, 60 to
160 °C in 10 min, retention times (min): 149.0 (1,4-product,
minor), 149.1 (1,4-product, major), 149.9 (14c).
(S,E)-tert-butyl 5-methylhept-3-enoate (14d) was prepared
via the general procedure for the enantioselective 1,6-conjugate
addition using (2E,4E)-tert-butyl hexa-2,4-dienoate (13d) and
EtMgBr. Results: [0.5 mmol scale, 88% yield, 98% ee, 1,6:1,4 =
98:2, colorless oil]. Data: [α]D20 = +15.3 (c = 1.0 in CH2Cl2); 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 5.56−5.30 (m, 2H),
2.90 (d, J = 6.4 Hz, 2H), 2.01 (dt, J = 13.6, 6.8 Hz, 1H), 1.43 (s,
9H), 1.37−1.20 (m, 2H), 0.95 (d, J = 6.7 Hz, 3H), 0.83 ppm (t, J
= 7.4 Hz, 3H); 13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ
= 171.7 (C), 140.0 (CH), 120.7 (CH), 80.4 (C), 39.5 (CH2),
Halide Dependency. (R,E)-Ethyl 5-ethylundec-3-enoate
(11) was prepared via the general procedure for the
enantioselective 1,6-conjugate addition using (2E,4E)-ethyl
undeca-2,4-dienoate (10) and EtMgBr. In the experiments
using EtMgCl (2.0 equiv) or EtMgI (2.0 equiv), these reagents
replaced EtMgBr (2.0 equiv). In the experiments using CuI (5
mol %) or CuCl (5 mol %), these reagents replaced CuBr·SMe2
(5 mol %). Results: [Using EtMgCl and CuCl, 0.25 mmol scale,
no conversion]; [Using EtMgCl and CuBr·SMe2, 0.25 mmol
scale, full conversion, 94% ee (R-enantiomer), 1,6:1,4 = 80:20,
(ee 1,4-addition product: 26%)]; [Using EtMgBr and CuCl, 0.25
mmol scale, full conversion, 96% ee (R-enantiomer), 1,6:1,4 =
83:17, (ee 1,4-addition product: 20%)]; [Using EtMgBr and
CuBr·SMe2, 0.25 mmol scale, full conversion, 96% ee (R-
enantiomer), 1,6:1,4 = 99:1]; [Using EtMgBr and CuI, 0.25
mmol scale, full conversion, 98% ee (R-enantiomer), 1,6:1,4 =
98:2]; [Using EtMgI and CuBr·SMe2, 0.25 mmol scale, 57%
conversion, 90% ee (R-enantiomer), 1,6:1,4 = 79:21, (ee 1,4-
addition product: 13%)]; [Using EtMgI and CuI, 0.25 mmol
scale, 51% conversion, 96% ee (R-enantiomer), 1,6:1,4 = 82:18,
20
(ee 1,4-addition product: 9%)]. Data: [α]D = −2.4 (R-
1
enantiomer, c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3,
25 °C, TMS): δ = 5.45 (dt, J = 15.3, 6.9 Hz, 1H), 5.26 (dd, J =
15.3, 8.8 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.01 (d, J = 6.9 Hz,
2H), 1.89−1.80 (m, 1H), 1.43−1.15 (m, 15H), 0.86 (t, J = 6.8
Hz, 3H), 0.82 ppm (t, J = 7.4 Hz, 3H); 13C NMR (100.59 MHz,
CDCl3, 25 °C, TMS): δ 172.2 (C), 139.0 (CH), 121.4 (CH),
60.4 (CH2), 44.4 (CH), 38.2 (CH2), 34.8 (CH2), 31.8 (CH2),
29.4 (CH2) 27.8 (CH2), 27.1 (CH2), 22.6 (CH2), 14.2 (CH3),
14.1 (CH3), 11.6 ppm (CH3); MS (m/z) 240 (7) [M+], 124
(100) [C8H12O+], 81 (79) [C5H5O+], 67 (56) [C4H3O+], 55
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38.5 (CH), 29.7 (CH2), 28.2 (CH3), 20.2 (CH3), 11.8 ppm
(1) [M+], 218 (32) [M+ − tBu+H], 131 (43) [C10H11+], 104
(CH3); MS (m/z) 198 (1) [M+], 142 (15) [M+ − tBu + H], 97
(33) [C8H8 ], 191 (51) [C7H7 ], 57 (100) [C4H9 ]; HRMS
calcd for C18H26O2Na+ 297.1825; found, 297.1827; ee was
determined by chiral HPLC analysis, column: (R,R)-Whelk-01,
(99.9:0.1 heptane:iPrOH); retention times (min): 17.3 (major
peak, 1,4-addition product), 16.8 (minor peak, 1,4-addition
product), 19.1 (S-14g), 19.1 (R-14g).
+
+
+
(17) [M+-CO2tBu], 57 (100) [C4H9 ]; HRMS (APCI+) calcd
+
for C12H22O2Na+ 221.1512; found, 251.1503; ee was determined
by chiral GC analysis for 2-methylbutanoic acid,26,27 column:
Chiraldex-B-PM, 50 to 60 °C in 1 min, 60 °C for 70 min, 60 to
160 °C in 10 min, 160 °C for 4 min, retention times (min): 81.6
(major), 82.1 (minor). Regioselectivity was determined by chiral
GC analysis, column: Chiraldex-B-PM, 50 to 60 °C in 1 min, 60
°C for 140 min, 60 to 160 °C in 10 min, 160 °C for 4 min,
retention times (min): 150.6 (1,4-product, minor), 150.7 (1,4-
product, major), 151.2 (14d).
Michael Acceptor Dependency. E-2-(4-ethyloct-2-
enylsulfonyl)pyridine (16d) was prepared via the general
procedure for the enantioselective 1,6-conjugate addition using
2-([1E,3E]-octa-1,3-dienylsulfonyl)pyridine (15d) and EtMgBr;
upon addition of the substrate the solution turns bright red, upon
quenching the solution becomes orange. Results: [0.25 mmol
(S,E)-tert-butyl 5-methylundec-3-enoate (14e) was prepared
via the general procedure for the enantioselective 1,6-conjugate
addition using (2E,4E)-tert-butyl hexa-2,4-dienoate (13d) and
hexylMgBr. Results: [0.5 mmol, 72% yield, 98% ee, 1,6:1,4 =
98:2, colorless oil]. Data: [α]D20 = +9.6 (c = 1.0 in CH2Cl2); 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 5.50−5.33 (m, 2H),
2.91 (d, J = 6.1 Hz, 2H), 2.15−2.04 (m, 1H), 1.44 (s, 9H), 1.32−
1.19 (m, 10H), 0.96 (d, J = 6.7 Hz, 3H), 0.87 ppm (t, J = 6.8 Hz,
3H); 13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ = 171.8
(C), 140.4 (CH), 120.5 (CH), 80.4 (C), 39.6 (CH2), 37.1
(CH2), 36.8 (CH), 32.0 (CH2), 29.6 (CH2), 28.2 (CH3), 27.4
(CH2), 22.8 (CH2), 20.7 (CH3), 14.3 ppm (CH3); MS (m/z)
1
scale, 26% yield, 2% ee, 1,6:1,4 = 98:2, colorless oil]. Data: H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 8.81−8.73 (m, 1H),
8.04 (dd, J = 7.8, 1.0 Hz, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 7.52
(ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 5.31 (dd, J = 5.1, 2.1 Hz, 2H), 4.11
(dd, J = 4.1, 2.0 Hz, 2H), 1.83−1.69 (m, 1H), 1.33−0.89 (m,
8H), 0.81 (t, J = 7.3 Hz, 3H), 0.63 ppm (t, J = 7.4 Hz, 3H);
GCOSY 1H NMR (400 MHz, CDCl3, 25 °C, TMS): Coupling
between the NMR signals at δ = 5.31 and 4.11 ppm indicate 1,6-
addition product; ee and regioselectivity were determined by
chiral HPLC analysis, column: chiralcel OD-H, (98:2 heptane/
iPrOH); retention times (min): 33.0 (1,4-addition product),
34.3 (1,4-addition product), 37.2 (16d), 39.4 (16d).
+
+
254 (1) [M+], 128 (30) [C7H12O2 ], 57 (100) [C4H9 ]; HRMS
+
calcd for C16H31O2 255.2318; found, 255.2318. Regio- and
E-3-(5-methylhept-3-enoyl)oxazolidin-2-one (16e) was pre-
pared via the general procedure for the enantioselective 1,6-
conjugate addition using 3-(2E,4E)-hexa-2,4-dienoyloxazolidin-
2-one (15e) and EtMgBr. Results: [0.25 mmol scale, 64% yield,
enantioselectivity were determined by conversion into the ethyl
ester28 and subsequent chiral GC analysis, column: Chiraldex-B-
PM, 80 °C, retention times (min): 118.4 (1,4-product, minor),
122.4 (1,4-product, major), 132.6 (14e, major), 139.3 (14e,
minor).
20
3% ee for 1,6-product, 1,6:1,4 = 75:25, colorless oil]. Data: [α]D
= +0.9 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 5.62−5.41 (m, 2H), 4.45−4.34 (m, 3H), 4.07−3.94
(m, 3H), 3.64 (d, J = 5.8 Hz, 2H), 2.04 (dt, J = 13.5, 6.8 Hz, 1H),
1.37−1.22 (m, 2H), 0.96 (d, J = 6.7 Hz, 3H), 0.84 ppm (t, J = 7.4
Hz, 3H). Residual absorptions 1,4-addition product: δ = 5.40−
5.20 (m, 2H), 4.45−4.34 (m, 3H), 4.07−3.94 (m, 3H), 3.70 (dt, J
= 7.0, 1.7 Hz, 1H), 2.93 (qd, J = 15.7, 7.1 Hz, 2H), 2.50−2.41 (m,
1H), 1.63 ppm (dd, J = 6.3, 1.5 Hz, 2H); GCOSY 1H NMR (400
MHz, CDCl3, 25 °C, TMS): Coupling between the NMR signals
at δ = 5.30 and 3.64 ppm indicate 1,6-addition product; 13C
NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ = 172.2 (C), 153.6
(C), 141.2 (CH), 119.4 (CH), 62.2 (CH2), 42.7 (CH2), 38.9
(CH2), 38.5 (CH), 29.7 (CH2), 20.1 (CH3), 11.8 ppm (CH3);
MS (m/z) 211 (8) [M+], 182 (35) [M+ − Et], 96 (36)
[C6H8O+], 95 (100) [C6H7O+], 55 (24) [C3H3O+]; HRMS
calcd for C11H17NO3Na+ 234.1101; found, 234.1097; regiose-
(S,E)-tert-butyl 5,8-dimethylnon-3-enoate (14f) was prepared
via the general procedure for the enantioselective 1,6-conjugate
addition using (2E,4E)-tert-butyl hexa-2,4-dienoate (13d) and
iso-pentylMgBr. Results: [0.5 mmol, 77% yield, 99% ee, 1,6:1,4 =
99:1, colorless oil]. Data: [α]D20 = +7.0 (c = 1.0 in CH2Cl2); 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 5.52−5.32 (m, 2H),
2.91 (d, J = 6.0 Hz, 2H), 2.14−1.99 (m, 1H), 1.56−1.39 (m,
10H), 1.25 (dd, J = 12.6, 7.1 Hz, 2H), 1.19−1.07 (m, 2H), 0.96
(d, J = 6.7 Hz, 3H), 0.85 ppm (dd, J = 6.6, 0.6 Hz, 6H); 13C NMR
(100.59 MHz, CDCl3, 25 °C, TMS): δ = 171.8 (C), 140.4 (CH),
120.5 (CH), 80.4 (C), 39.6 (CH2), 37.1 (CH), 36.7 (CH2), 34.8
(CH2), 28.3 (CH), 28.2 (CH3), 22.9 (CH3), 22.8 (CH3), 20.7
+
ppm (CH3); MS (m/z) 240 (1) [M+], 128 (35) [C7H12O2 ], 57
+
+
(100) [C4H9 ]; HRMS calcd for C15H29O2 241.2162; found,
241.2162. Regio- and enantioselectivity were determined by
conversion into the ethyl ester28 and subsequent chiral GC
analysis, column: Chiraldex-B-PM, 90 °C, retention times (min):
117.6 (1,4-product, minor), 123.5 (1,4-product, major), 131.5
(14f, major), 139.8 (14f, minor).
1
lectivity was determined by H NMR with d1= 10 s; ee was
determined by chiral GC analysis for 2-methylbutanoic acid,26,27
column: Chiraldex-B-PM, 50 to 60 °C in 1 min, 60 °C for 70 min,
60 to 160 °C in 10 min, 160 °C for 4 min; retention times (min):
81.6 (major), 82.0 (minor).
(S,E)-tert-butyl 5-methyl-7-phenylhept-3-enoate (14g) was
prepared via the general procedure for the enantioselective 1,6-
conjugate addition using (2E,4E)-tert-butyl hexa-2,4-dienoate
(13d) and phenethylMgBr; reaction time: 48 h. Results: [47%
conversion, 30% yield, 88% ee, 1,6:1,4 = 93:7, colorless oil].
Data: [α]D20 = +6.3 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 7.31−7.13 (m, 5H), 5.58−5.41 (m,
2H), 2.97 (d, J = 6.6 Hz, 2H), 2.63−2.53 (m, 2H), 2.24−2.14 (m,
1H), 1.67−1.58 (m, 2H), 1.47 (s, 9H), 1.04 ppm (d, J = 6.7 Hz,
3H); 13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ = 171.7
(C), 142.9 (C), 139.8 (CH), 128.5 (CH), 128.4 (CH), 125.7
(CH), 121.3 (CH), 80.5 (C), 39.6 (CH2), 38.8 (CH2), 36.5
(CH), 33.7 (CH2), 28.2 (CH3), 20.8 ppm (CH3); MS (m/z) 274
E-1-(1-methyl-1H-imidazol-2-yl)-3-phenethylhex-4-en-1-one
(17f) was prepared via the general procedure for the
enantioselective 1,6-conjugate addition using (2E,4E)-1-(1-
methyl-1H-imidazol-2-yl)hexa-2,4-dien-1-one (15f) and phene-
thylMgBr. Results: [0.5 mmol scale, 98% conversion, 34% yield,
2% ee, 1,6:1,4 = <5:95, colorless oil]. Data: [α]D20 = +0.5 (c = 1.0
1
in CH2Cl2); H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
7.34−7.13 (m, 5H), 7.11 (s, 1H), 6.98 (s, 1H), 5.47 (dq, J = 15.2,
6.2 Hz, 1H), 5.34 (ddd, J = 15.2, 8.4, 1.4 Hz, 1H), 3.95 (s, 3H),
3.16 (ddd, J = 21.8, 15.8, 7.1 Hz, 2H), 2.77 (dt, J = 8.5, 5.5 Hz,
1H), 2.62 (dddd, J = 19.9, 13.8, 10.7, 5.7 Hz, 2H), 1.83−1.72 (m,
1H), 1.70−1.58 (m, 1H), 1.70−1.58 ppm (m, 2H). Residual
569
dx.doi.org/10.1021/cs501297s | ACS Catal. 2015, 5, 560−574

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absorptions phenethyl alcohol: δ = 7.34−7.13 (m, 5H), 3.85 (t, J
= 6.7 Hz, 2H), 2.87 ppm (t, J = 6.7 Hz, 2H); GCOSY 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): Coupling between the NMR
signals at δ = 3.85 and 1.65 ppm and the coupling between the
NMR signals at δ = 3.16 and 2.77 ppm indicate 1,4-addition
product; 13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ =
192.3 (C), 142.7 (C), 134.0 (CH), 129.1 (CH), 128.6 (CH),
128.5 (CH), 128.3 (CH), 126.9 (C), 125.8 (CH), 125.7 (CH),
44.7 (CH2), 38.8 (CH3), 37.1 (CH2), 36.2 (CH), 33.6 (CH2),
18.0 ppm (CH3). Residual absorptions phenethyl alcohol: δ =
138.65 (C), 128.9 (CH), 128.3 (CH), 126.5 (CH), 63.7 (CH2),
39.3 ppm (CH2); MS (m/z) 282 (1) [M+], 254 (52) [M+-
MeCH], 191 (61) [M+-Bn], 163 (69) [M+-MeCH-Bn], 150 (58)
[C9H11N2O+], 149 (62) [C9H10N2O+], 109 (93) [C5H5N2O],
91 (100) [Bn+], 83 (60) [C5H7O+], 82 (81) [C5H6O+]; HRMS
calcd. for C18H23N2O+ 283.1805, found 283.1805; regioselectiv-
ity was determined by 1H NMR with d1= 10 s; ee was
determined by chiral HPLC analysis, column: chiralcel OJ-H,
(95:5 heptane:iPrOH); retention times (min): 17.0 (minor),
18.4 (major).
addition diastereomer)), 52.9 (minor enantiomer of the second
1,6-addition diastereomer), 54.1 (major enantiomer of the
second 1,6-addition diastereomer)).
A mixture of 27% Z-ethyl 4,5-dimethylhept-3-enoate (Z-26c)
and 73% E-ethyl 4,5-dimethylhept-3-enoate (E-26c) was
prepared via the general procedure for the enantioselective 1,6-
conjugate addition using (2E,4E)-ethyl 4-methylnona-2,4-
dienoate (25c) and EtMgBr; reaction time 40 h, reaction
temperature −60 °C. Results: [0.5 mmol scale, 94% conversion,
59% yield, 0% ee, > 92% 1,6-addition product, colorless oil].
Data: [α]D20 = +1.3 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 5.38−5.28 (m, 1H), 4.12 (qd, J = 7.1,
1.6 Hz, 2H), 3.09−2.98 (m, 2H), 2.45 (E-26c, dt, J = 13.9, 7.0 Hz,
1H), 2.03 (Z-26c, dd, J = 14.1, 7.0 Hz, 1H), 1.60 (E-26c, d, J = 1.3
Hz, 3H), 1.52 (Z-26c, s, 5H), 1.49 (27c, s, 1H), 1.38−1.27 (m,
2H), 1.24 (t, J = 7.1 Hz, 3H), 0.96 (E-26c, t, J = 7.3 Hz, 3H), 0.87
(Z-26c, t, J = 7.0 Hz, 3H), 0.79 ppm (td, J = 7.4, 1.6 Hz, 3H);
GCOSY 1H NMR (400 MHz, CDCl3, 25 °C, TMS): Coupling of
the overlapping NMR signals for both the E- and Z-product at δ =
5.38−5.28 and 3.09−2.98 ppm indicate Z- and E-1,6-addition
product;13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ =
172.64 (C), 143.0 (C), 116.4 (E-26c, CH), 115.4 (Z-26c, CH),
60.6 (E-26c, CH2), 60.5 (Z-26c, CH2), 44.5 (Z-26c, CH), 36.2
(E-26c, CH), 33.8 (Z-26c, CH2), 33.3 (E-26c, CH2), 27.8 (Z-
26c, CH2), 27.6 (E-26c, CH2), 19.3 (Z-26c, CH3), 18.9 (E-26c,
CH3), 18.0 (Z-26c, CH3), 14.3 (E-26c, CH3), 12.3 (E-26c,
CH3), 12.1 ppm (Z-26c, CH3); MS (m/z) 184 (27) [M+], 110
(S,E)-S-ethyl 5-methylnon-3-enethioate (16i) was prepared
via the general procedure for the enantioselective 1,6-conjugate
addition using (2E,4E)-S-ethyl nona-2,4-dienethioate (15b) and
MeMgBr. Results: [0.5 mmol scale, 83% yield, 89% ee, 1,6:1,4 =
99:1, colorless oil]. Data: [α]D20 = +9.0 (c = 1.0 in CHCl3); 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 5.50−5.39 (m, 2H),
3.19 (d, J = 5.7 Hz, 2H), 2.84 (q, J = 7.4 Hz, 2H), 2.18−2.04 (m,
1H), 1.31−1.16 (m, 9H), 0.96 (d, J = 6.7 Hz, 3H), 0.86 ppm (t, J
= 6.7 Hz, 3H); 13C NMR (100.59 MHz, CDCl3, 25 °C, TMS): δ
= 198.7 (C), 142.6 (CH), 119.6 (CH), 47.9 (CH2), 36.9 (CH),
36.7 (CH2), 29.7 (CH2), 23.5 (CH2), 23.0 (CH2), 20.6 (CH3),
14.9 (CH3), 14.3 ppm (CH3); MS (m/z) 214 (10) [M+], 124
(40) [C7H10O+], 97 (43) [C5H5O2 ], 96 (68) [C6H8O+], 81
+
(47) [C5H5O+], 69 (93) [C5H9 ], 55 (100) [C3H3O+]; HRMS
+
calcd for C11H21O2+ 185.1536; found, 185.1535; Ratio E- and Z-
1
product was determined by H NMR with d1= 10 s; ee and
regioselectivity were determined by chiral GC analysis, column:
Chiraldex-B-PM, 50 to 110 °C in 6 min, 110 °C for 90 min;
retention times (min): 84.2 (an enantiomer of E-26c), 95.1 (an
enantiomer of E-26c), 100.1 (an enantiomer of Z-26c) 102.4 (an
enantiomer of Z-26c).
+
(34) [M+-SEt-Et], 83 (46) [C6H11+], 69 (100) [C5H9 ]; HRMS
calcd for C12H22OS+ 214.1391; found, 214.1401; ee and
regioselectivity were determined by chiral GC analysis, column:
Chiraldex-B-PM, 50 to 98 °C in 4.8 min, 98 °C for 200 min;
retention times (min): 163.8 (an enantiomer of the 1,4-addition
product), 191.1 (R-16i), 192.3 (S-16i).
Olefin Geometry Dependency. E-Ethyl 5-ethylundec-3-
enoate (11) was prepared via the general procedure for the
enantioselective 1,6-conjugate addition using EtMgBr and
(2E,4E)-ethyl undeca-2,4-dienoate (10), or EtMgBr and
(2E,4Z)-ethyl undeca-2,4-dienoate (28a), or EtMgBr and
(2Z,4E)-ethyl undeca-2,4-dienoate (28b), or EtMgBr and
(2Z,4Z)-ethyl undeca-2,4-dienoate (28c) (including 8%
((2Z,4E)-ethyl undeca-2,4-dienoate). Results: [Using the
(2E,4E)-enantiomer, 0.25 mmol scale, 77% yield, full conversion,
96% ee (R-enantiomer), 1,6:1,4 = 99:1]; [Using the (2E,4Z)-
enantiomer, 0.25 mmol scale, full conversion, 96% ee (S-
enantiomer), 1,6:1,4 = 98:2]; [Using the (2Z,4E)-enantiomer,
0.25 mmol scale, full conversion, 12% ee (S-enantiomer), 1,6:1,4
= 94:6]; [Using the (2Z,4Z)-enantiomer, 0.25 mmol scale, full
conversion, 66% ee (R-enantiomer), 1,6:1,4 = 99:1]. Data: see
Halide dependency section.
Isomerization study: To observe possible isomerization under
reaction conditions the general procedure for the enantiose-
lective 1,6-conjugate addition using EtMgBr and (2E,4E)-ethyl
undeca-2,4-dienoate (10), or EtMgBr and (2E,4Z)-ethyl undeca-
2,4-dienoate (28a), or EtMgBr and (2Z,4E)-ethyl undeca-2,4-
dienoate (28b), or EtMgBr and (2Z,4Z)-ethyl undeca-2,4-
dienoate (28c) was followed. Before completion (after 2 h
addition and an additional 10 min-1 h stirring) the reaction
mixture was quenched at −70 °C using EtOH (0.2 mL/mmol
substrate) and an aq. NH4Cl-solution (1 M, 1.0 mL/mmol
substrate). The olefin geometry was established using 1H NMR,
Influence of the Olefin Substitution Pattern. (5R,E)-
ethyl 5-ethyl-2-methylnon-3-enoate (26a) was prepared via the
general procedure for the enantioselective 1,6-conjugate addition
using (2E,4E)-ethyl 2-methylnona-2,4-dienoate (25a) and
EtMgBr. Results: [0.5 mmol scale, 94% conversion, 83% yield,
1:1 mixture of cis and trans diastereomers, 97% ee, 1,6:1,4 =
>99:1, colorless oil]. Data: [α]D20 = +2.9 (c = 1.0 in CH2Cl2); 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 5.42 (dd, J = 15.3,
7.8 Hz, 1H), 5.23 (dd, J = 15.3, 8.8 Hz, 1H), 4.23−3.99 (m, 2H),
3.22−2.89 (m, 1H), 1.88−1.72 (m, 1H), 1.53−1.02 (m, 13H),
0.99−0.64 ppm (m, 6H); 13C NMR (100.59 MHz, CDCl3, 25
°C, TMS): δ = 175.3 (C), 136.6 (CH), 129.0 (CH), 60.5 (CH2),
44.5 (CH), 43.1 (CH), 34.8 (first diastereomer CH2), 34.7
(second diastereomer CH2), 29.6 (CH2), 28.1 (CH2), 22.9
(CH2), 17.7 (CH3), 14.3 (CH3), 14.2 (CH3), 11.8 ppm (CH3);
MS (m/z) first diastereomer: 226 (10) [M+], 102 (100)
+
+
[C5H10O2 ], 95 (44) [C6H7O+], 69 (47) [C5H9 ], 55 (69)
[C3H3O+], second diastereomer: 226 (10) [M+], 102 (100)
[C5H10O2 ], 95 (45) [C6H7O+], 69 (47) [C5H9 ], 55 (70)
[C3H3O+]; HRMS calcd for C14H26O2Na+ 249.1825; found,
249.1822; ee and regioselectivity were determined by chiral GC
analysis, column: Chiraldex-B-PM, 50 to 110 °C in 6 min, 110 °C
for 90 min; retention times (min): 38.4 (an enantiomer of the
1,4-addition product), 51.3 (major enantiomer of the first 1,6-
addition diastereomer), 52.0 (minor enantiomer of the first 1,6-
+
+
570
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GC (column: Chiraldex-B-PM, 40 to 110 °C in 7 min, 110 °C for
90 min; retention times (min): 2E,4E = 65.4; 2Z,4E = 72.1;
2E,4Z = 75.1; 2Z,4Z = 83.2, and GC-MS. Results: [Using the
(2E,4E)-enantiomer, 0.25 mmol scale, 95% conversion, 96% ee
(R-enantiomer), 1,6:1,4 = 99:1, no isomerization of the starting
material]; [Using the (2E,4Z)-enantiomer, 0.20 mmol scale, 26%
conversion, ee not determined (overlap of GC peaks with
starting material), 1,6:1,4 = 98:2, no isomerization of the starting
material]; [Using the (2Z,4E)-enantiomer, 0.20 mmol scale, 40%
conversion, 19% ee (S-enantiomer), 1,6:1,4 = 99:1, no
isomerization of the starting material]; [Using the (2Z,4Z)-
enantiomer, 0.25 mmol scale, 55% conversion, 60% ee (R-
enantiomer), 1,6:1,4 = 99:1, no isomerization of the starting
material]
(m, 1H), 1.05 ppm (d, J = 6.7 Hz, 3H); GCOSY 1H NMR (400
MHz, CDCl3, 25 °C, TMS): Coupling between the NMR signals
at δ = 2.75 and 2.53 ppm and the coupling between the NMR
signals at δ = 5.48 and 2.75 ppm indicate 1,4-addition product,
coupling between the NMR signals at δ = 5.60 and 3.27 ppm and
the coupling between the NMR signals at δ = 5.56 and 2.12 ppm
indicate 1,8-addition product; 13C NMR (100.59 MHz, CDCl3,
25 °C, TMS): δ = 198.0 (C), 141.6 (CH), 135.5 (CH), 127.7
(CH), 122.0 (CH), 47.7 (CH2), 36.9 (CH), 36.8 (CH2), 29.7
(CH2), 23.5 (CH2), 23.0 (CH2), 20.6 (CH3), 14.8 (CH3), 14.2
ppm (CH3); Residual absorptions side-product 31b: δ = 135.1
(CH), 133.9 (CH), 130.1 (CH), 129.7 (CH), 51.1 (CH2), 34.3
(CH), 32.4 (CH2), 31.6 (CH2), 23.5 (CH2), 22.4 (CH2), 20.0
(CH3), 14.9 (CH3), 14.1 ppm (CH3); MS (m/z) 240 (11) [M+],
+
95 (64) [C6H7O+], 81 (69) [C5H5O+], 79 (39) [C6H7 ], 67
Enantioselective 1,8- and 1,10-Addition. (R,3E,5E)-ethyl
7-ethylundeca-3,5-dienoate (30a) was prepared via the general
procedure for the enantioselective 1,6-conjugate addition using
(2E,4E,6E)-ethyl undeca-2,4,6-trienoate (29a) and EtMgBr, 48 h
reaction time. Results: [0.5 mmol scale, 47% yield (combined
yield 1,8-, 1,6- and 1,4-addition products), 7% ee, 1,8:1,6:1,4 =
63:8:29, colorless oil]. Data: [α]D20 = +1.5 (c = 1.0 in CH2Cl2);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 6.10 (dd, J = 15.1,
10.3 Hz, 1H), 6.02−5.94 (m, 1H), 5.63 (dt, J = 22.5, 7.3 Hz, 1H),
5.38 (dd, J = 14.8, 8.9 Hz, 1H), 4.20−4.05 (m, 3H), 3.08 (dd, J =
7.2, 1.0 Hz, 2H), 1.92−1.80 (m, 1H), 1.48−1.12 (m, 11H),
0.91−0.78 ppm (m, 6H). Residual absorptions side-products: δ =
3.24−3.19 (1,6-add. product, m, 2H), 2.43 (1,6-add. product, dd,
J = 8.3, 5.4 Hz, 1H), 2.30 (31a, ddd, J = 22.7, 14.5, 7.2 Hz, 2H),
2.04 ppm (31a, q, J = 7.0 Hz, 1H); GCOSY 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): Coupling between the NMR signals at δ =
2.25 and 2.05 ppm and the coupling between the NMR signals at
δ = 5.58 and 2.05 ppm indicate 1,4-addition product, Coupling
between the NMR signals at δ = 5.63 and 3.08 ppm and the
coupling between the NMR signals at δ = 5.39 and 1.85 ppm
indicate 1,8-addition product; 13C NMR (100.59 MHz, CDCl3,
25 °C, TMS): δ = 172.0 (C), 139.5 (CH), 134.2 (CH), 129.5
(CH), 122.4 (CH), 60.8 (CH2), 44.7 (CH), 38.3 (CH2), 34.8
(CH2), 29.7 (CH2), 28.2 (CH2), 23.0 (CH2), 14.3 (CH3), 14.2
(CH3), 11.9 ppm (CH3); Residual absorptions side-product 31a:
δ = 172.8 (C), 133.8 (CH), 133.6 (CH), 131.2 (CH), 130.2
(CH), 60.3 (CH2), 41.2 (CH), 40.3 (CH2), 32.4 (CH2), 31.6
(CH2), 27.9 (CH2), 22.4 (CH2), 14.4 (CH3), 14.1 (CH3), 11.7
ppm (CH3); MS (m/z) 238 (25) [M+], 135 (68) [C9H11O+],
(100) [C4H3O+]; HRMS calcd for C14H25OS+ 241.1621; found,
1
214.1621; Regioselectivity was determined by H NMR with
d1=10 s; ee was determined by chiral GC analysis for 2-
methylhexanoic acid,27 column: Chiraldex-B-PM, 50 to 130 °C
in 8 min, 130 °C for 70 min; retention times (min): 22.6 (minor),
23.8 (major).
(R,3E,5E,7E)-ethyl 9-ethyltrideca-3,5,7-trienoate (30c) was
prepared via the general procedure for the enantioselective 1,6-
conjugate addition using (2E,4E,6E,8E)-ethyl trideca-2,4,6,8-
tetraenoate (29c) and EtMgBr, 48 h reaction time. Results: [0.5
mmol scale, 85% conversion, 22% yield (combined yield 1,10-,
1,8-/1,6- and 1,4-addition products), 1,10-product 12% ee,
1,10:1,8/1,6:1,4 = 49:8:43, colorless oil]. Data: [α]D20 = +1.4 (c =
1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
6.24−5.94 (m, 4H), 5.69 (qd, J = 14.0, 6.7 Hz, 1H), 5.44 (dd, J =
15.0, 9.0 Hz, 1H), 4.20−4.05 (m, 2H), 3.11 (d, J = 7.2 Hz, 2H),
1.96−1.83 (m, 1H), 1.52−1.12 (m, 11H), 0.96−0.77 ppm (m,
6H). Residual absorptions side-products: δ = 3.22 (1,6- or 1,8-
addition, dd, J = 7.5, 1.6 Hz, 2H), 2.54−2.43 (31c, m, 1H), 2.43−
2.22 (31c, m, 2H), 2.08 ppm (31c, q, J = 6.8 Hz, 2H); GCOSY
1H NMR (400 MHz, CDCl3, 25 °C, TMS): Coupling between
the NMR signals at δ = 2.52 and 2.30 ppm and the coupling
between the NMR signals at δ = 5.43 and 2.52 ppm indicate 1,4-
addition product, Coupling between the NMR signals at δ = 5.55
and 3.21 ppm indicate either 1,6- or 1,8-addition product,
Coupling between the NMR signals at δ = 5.44 and 1.80 ppm and
the coupling between the NMR signals at δ = 5.77 and 3.10 ppm
indicate 1,10-addition product; 13C NMR (100.59 MHz, CDCl3,
25 °C, TMS): δ = 171.6 (C), 140.4 (CH), 133.9 (CH), 133.0
(CH), 130.0 (CH), 129.5 (CH), 124.1 (CH), 60.7 (CH2), 44.8
(CH), 38.3 (CH2), 34.7 (CH2), 29.5 (CH2), 28.1 (CH2), 22.8
(CH2), 14.2 (CH3), 14.1 (CH3), 11.7 ppm (CH3); Residual
absorptions side-product 31c: δ = 172.5 (C), 135.7 (CH), 135.0
(CH), 131.8 (CH), 131.1 (CH), 130.3 (CH), 130.3 (CH), 60.2
(CH2), 41.2 (CH), 40.1 (CH2), 32.5 (CH2), 31.5 (CH2), 27.7
(CH2), 22.2 (CH2), 14.3 (CH3), 13.9 (CH3), 11.5 ppm (CH3);
MS (m/z) 264 (40) [M+], 133 (82) [C10H13+], 119 (77)
121 (48) [C8H9O+], 107 (100) [C7H7O+], 93 (85) [C7H9 ], 79
+
(91) [C6H7 ], 67 (64) [C4H3O+]; HRMS calcd for
+
C15H26O2Na+ 261.1825; found, 261.1820; Regioselectivity was
1
determined by H NMR with d1=10 s; ee was determined by
chiral GC analysis for 2-ethylhexanoic acid,27 column: Chiraldex-
B-PM, 50 to 120 °C in 7 min, 120 °C for 70 min; retention times
(min): 41.2 (major), 43.2 (minor).
(R,3E,5E)-S-ethyl 7-methylundeca-3,5-dienethioate (30b)
was prepared via the general procedure for the enantioselective
1,6-conjugate addition using (2E,4E,6E)-S-ethyl undeca-2,4,6-
trienethioate (29b) and MeMgBr, 48 h reaction time, 7.5%
catalyst. Results: [0.5 mmol scale, 91% conversion, 63% yield
(combined yield 1,8- and 1,4- product), 72% ee, 1,8:1,6:1,4 =
86:0:14, colorless oil]. Data: [α]D20 = −13.4 (c = 1.0 in CH2Cl2);
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 6.13 (dd, J = 15.0,
10.4 Hz, 1H), 5.99 (dd, J = 15.2, 10.3 Hz, 1H), 5.69−5.52 (m,
2H), 3.28 (dd, J = 7.3, 0.9 Hz, 2H), 2.87 (q, J = 7.4 Hz, 2H),
2.19−2.08 (m, 1H), 1.36−1.18 (m, 9H), 0.98 (d, J = 6.7 Hz, 3H),
0.91−0.84 ppm (m, 3H); Residual absorptions 31b: δ = 2.80−
2.71 (m, 1H), 2.52 (ddd, J = 22.1, 14.5, 7.2 Hz, 2H), 2.08−2.01
+
+
[C9H11++], 105 (67) [C8H9 ], 93 (50) [C7H9 ], 91 (100)
+
[C7H7 ]; HRMS calcd for C17H29O2 265.2162; found,
265.2163; ee was determined by chiral GC analysis for 2-
ethylhexanoic acid,27 column: Chiraldex-B-PM, 50 to 120 °C in 7
min, 120 °C for 70 min; retention times (min): 42.0 (major),
44.0 (minor).
(R,3E,5E,7E)-S-ethyl 9-methyltrideca-3,5,7-trienethioate
(30d) was prepared via the general procedure for the
enantioselective 1,6-conjugate addition using (2E,4E,6E,8E)-S-
ethyl trideca-2,4,6,8-tetraenethioate (29d) and MeMgBr, 48 h
reaction time, 10% catalyst. Results: [0.5 mmol scale, 82%
571
dx.doi.org/10.1021/cs501297s | ACS Catal. 2015, 5, 560−574

ACS Catalysis
Research Article
Chem. Rev. 2008, 108, 2796−2823. (c) Muller, D.; Alexakis, A. Chem.
̈
conversion, 44% yield (combined yield 1,10- and 1,4-addition
products), 1,10-product 45% ee, 1,10:1,8/1,6:1,4 = 59:0:41,
Commun. 2012, 48, 12037−12049. (d) Howell, G. P. Org. Process Res.
̌
1
colorless oil]. Data: [α]D20 = −13.4 (c = 1.0 in CH2Cl2); H
Dev. 2012, 16, 1258−1272. (e) Galest
̌
okova,
́
Z.; Sebesta, R. Eur. J. Org.
Chem. 2012, 6888−6695. (f) Wang, S.-Y.; Loh, T.-P. Chem. Commun.
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 6.23−5.96 (m, 4H),
5.76−5.51 (m, 2H), 3.30 (d, J = 7.3 Hz, 1H), 2.91−2.82 (m, 2H),
2.21−2.12 (m, 1H), 1.41−1.17 (m, 9H), 0.99 (d, J = 6.7 Hz, 3H),
0.93−0.84 ppm (m, 3H), Residual absorptions 31d: δ = 2.82−
2.74 (m, 1H), 2.53 (ddd, J = 36.9, 14.5, 7.2 Hz, 2H), 2.12−2.04
(m, 2H), 1.06 (d, J = 6.7 Hz, 1H); GCOSY 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): Coupling between the NMR signals at δ =
2.78 and 2.52 ppm and the coupling between the NMR signals at
δ = 5.54 and 2.78 ppm indicate 1,4-addition product, coupling
between the NMR signals at δ = 5.61 and 2.16 ppm and the
coupling between the NMR signals at δ = 5.65 and 3.30 ppm
indicate 1,10-addition product; 13C NMR (100.59 MHz, CDCl3,
25 °C, TMS): δ = 197.7 (C), 142.1 (CH), 135.2 (CH), 133.6
(CH), 129.5 (CH), 128.3 (CH), 123.4 (CH), 47.7 (CH2), 36.9
(CH), 36.7 (CH2), 29.5 (CH2), 23.4 (CH2), 22.8 (CH2), 19.9
(CH3), 14.6 (CH3), 14.1 ppm (CH3); Residual absorptions side-
product 31d: δ = 198.3 (C), 136.8 (CH), 135.1 (CH), 132.0
(CH), 130.3 (CH), 130.2 (CH), 129.6 (CH), 50.9 (CH2), 34.3
(CH), 32.5 (CH2), 31.4 (CH2), 23.3 (CH2), 22.2 (CH2), 20.5
(CH3), 14.8 (CH3), 13.9 ppm (CH3); Residual absorption: δ =
2010, 46, 8694−8703. (g) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295−7306. (h) Tietze, L. F.; Dufert, A. In Catalytic
̈
Asymmetric Conjugate Reactions; Cor
GmbH & Co. KgaA: Weinheim, 2010; p 321−350;. (i) Zhao, G.-L.;
Cordova, A. In Catalytic Asymmetric Conjugate Reactions; Cordova, A.,
́
dova, A., Ed.; Wiley-VCH Verlag
́
́
Ed.; Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, 2010; p 145−
168;. (j) Ji, J.-X.; Chan, A. S. C. In Catalytic Asymmetric Synthesis, 3rd ed.;
Ojima, I., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2010; pp 439−
́
496. (k) Nguyen, B. N.; Hii, K. K.; Szymanski, W.; Janssen, D. B. In
Science of Synthesis Stereoselective Synthesis; de Vries, J. G., Ed.; Thieme
Publishing Group: Stuttgart, 2010; Vol. 1, p 571−687. (l) Jerphagnon,
T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009,
38, 1039−1075. (m) Polet, D.; Alexakis, A. In The Chemistry of
Organocopper Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
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́
ez, F.; Feringa, B. L. In
Asymmetric Synthesis − The Essentials, 2nd ed.; Christmann, M., Brase, S.,
̈
Eds.; Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, 2008; p 83−
́
89. (o) Lopez, F.; Minnaard, A. J.; Feringa, B. L. In The Chemistry of
Organomagnesium Compounds; Rappoport, Z., Marek, I., Eds.; John
Wiley & Sons Ltd.: Chichester, 2008; p 771−802;. (p) Lopez, F.;
́
Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179−188.
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2012, 38, 321−340. (b) Langlois, J.-B.; Alexakis, A. Top. Organomet.
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Chirality 2011, 23, 703−710. (d) Crawley, M. L. In Science of Synthesis
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Stuttgart, 2011; Vol. 3, pp 403−442;. (e) Spino, C. In The Chemistry of
Organocopper Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
Sons Ltd.: Chichester, 2009; pp 603−692. (f) Falciola, C. A.; Alexakis, A.
Eur. J. Org. Chem. 2008, 3765−3780. (g) Geurts, K.; Fletcher, S. P.; van
Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Pure Appl. Chem. 2008, 80,
1025−1037.
22.3 ppm; MS (m/z) 266 (22) [M+], 93 (100) [C7H9 ], 91 (53)
+
+
+
+
[C7H7 ], 79 (44) [C6H7 ], 77 (33) [C6H5 ]; HRMS calcd for
C16H27OS+ 267.1777; found, 267.1779; Regioselectivity was
1
determined by H NMR with d1=10 s; ee was determined by
chiral GC analysis for 2-methylhexanoic acid,27 column:
Chiraldex-B-PM, 50 to 130 °C in 8 min, 130 °C for 70 min;
retention times (min): 22.6 (minor), 23.8 (major).
ASSOCIATED CONTENT
* Supporting Information
The following file is available free of charge on the ACS
■
S
(3) For selected and recent publications on enantioselective conjugate
additions using Grignard reagents, see: (a) Feringa, B. L.; Badorrey, R.;
Publications website at DOI: 10.1021/cs501297s.
Footnotes, experimental protocols for the synthesis of
substrates, and spectral data (PDF)
Pena, D.; Harutyunyan, S. R.; Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A.
̃
2004, 101, 5834−5838. (b) Lop
́
ez, F.; Harutyunyan, S. R.; Minnaard, A.
ez,
J.; Feringa, B. L. J. Am. Chem. Soc. 2004, 126, 12784−12785. (c) Lop
F.; Harutyunyan, S. R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L.
́
AUTHOR INFORMATION
Corresponding Authors
*E-mail: a.j.minnaard@rug.nl. Tel.: (+31)-50-363 4258. Fax:
(+31)-50-363 4296 (A.J.M.).
■
Angew. Chem., Int. Ed. 2005, 44, 2752−2756. (d) Des Mazery, R.; Pullez,
́
M.; Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2005, 127, 9966−9967. (e) Macia
Fernandez-Ibanez, M. A.; ter Horst, B.; Minnaard, A. J.; Feringa, B. L.
Org. Lett. 2007, 9, 5123−5126. (f) Bos, P. H.; Minnaard, A. J.; Feringa, B.
L. Org. Lett. 2008, 10, 4219−4222. (g) Macia, B.; Fernandez-Ibanez, M.
A.; Mrsic, N.; Minnaard, A. J.; Feringa, B. L. Tetrahedron Lett. 2008, 49,
1877−1880. (h) Teichert, J. F.; Feringa, B. L. Chem. Commun. 2011, 47,
2679−2681. (i) Vila, C.; Hornillos, V.; Fananas-Mastral, M.; Feringa, B.
L. Chem. Commun. 2013, 49, 5933−5935. (j) Mao, B.; Fananas-Mastral,
́
Ruiz, B.; Geurts, K.;
́
́
̃
*E-mail: b.l.feringa@rug.nl. Tel.: (+31)-50-363 8569. Fax:
(+31)-50-363 4296 (B.L.F.).
Notes
́
́
́
̃
̌
́
The authors declare no competing financial interest.
́
̃
́
̃
ACKNOWLEDGMENTS
■
M.; Feringa, B. L. Org. Lett. 2013, 15, 286−289. (k) Calvo, B. C.;
Madduri, A. V. R.; Harutyunyan, S. R.; Minnaard, A. J. Adv. Synth. Catal.
2014, 356, 2061−2069. (l) Martin, D.; Kehrli, S.; d’Augustin, M.;
Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128,
8416−8417. (m) Kehrli, S.; Martin, D.; Rix, D.; Mauduit, M.; Alexakis,
A. Chem. − Eur. J. 2010, 16, 9890−9904. (n) Germain, N.; Magrez, M.;
Kehrli, S.; Mauduit, M.; Alexakis, A. Eur. J. Org. Chem. 2012, 5301−
5306. (o) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129,
276−277. (p) Wang, S.-Y.; Lum, T.-K.; Ji, S.-J.; Loh, T.-P. Adv. Synth.
Catal. 2008, 350, 673−677. (q) Robert, T.; Velder, J.; Schmalz, H.-G.
Angew. Chem., Int. Ed. 2008, 47, 7718−7721. (r) Naeemi, Q.; Robert, T.;
Kranz, D. P.; Velder, J.; Schmalz, H.-G. Tetrahedron: Asymmetry 2011,
T. D. Tiemersma-Wegman and M. J. Smith are thanked for
technical support (GC, HPLC, MS). The Netherlands
Organization for Scientific Research (NWO-CW), the National
Research School Catalysis (NRSC-C), the European Research
Council (ERC advanced grant 227897 to B.L.F.), the Royal
Netherland Academy of Arts and Sciences (KNAW), and the
Ministry of Education Culture and Science (Gravitation program
024.601035) are acknowledged for financial support.
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