Catalytic enantioselective 1,6-conjugate addition of Grignard reagents to linear dienoates

Article abstract of DOI:10.1002/anie.200703702

(Chemical Equation Presented) Dual function of catalyst: Both regio- and enantioselectivity are dictated by Cu catalysis using the reversed josiphos ligand. This allows enantioselective 1,6-addition of Grignard reagents to acyclic α,β,γ,δ-unsaturated este

Full text of DOI:10.1002/anie.200703702

Communications
DOI: 10.1002/anie.200703702
Asymmetric Catalysis
Catalytic Enantioselective 1,6-Conjugate Addition of Grignard
Reagents to Linear Dienoates**
Tim den Hartog, Syuzanna R. Harutyunyan, Daniel Font, Adriaan J. Minnaard,* and
Ben L. Feringa*
Dedicated to Prof. Dr. HansWynberg on the occasion of his85th birthday.
Achieving selectivity (chemo- and regio- as well as stereose-
lectivity) has always been a major challenge in organic
synthesis.[1] This is particularly evident for conjugate addition
(CA).[2] In asymmetric conjugate addition[3] (ACA), besides
high regioselectivity (1,4- vs. 1,2-addition), excellent control
of stereoselectivity has been achieved.
the first Cu-catalyzed ACA of simple alkyl Grignard reagents
to linear d-substituted 2,4-dienoates.[14]
Recently, an extensive study on the mechanism of the 1,4-
ACA of Grignard reagents was reported from our labora-
tory.[15] Noting the proposed mechanistic similarities between
the 1,4-ACA and 1,6-CA,[16] we decided to further expand our
catalytic system[17] towards 1,6-ACA. As an initial model
reaction we chose the addition of EtMgBr to ethyl sorbate
(4).[18] The reversed josiphos ligand (+)-3 (Scheme 1, (À)-3
Compared to 1,4-ACA, conjugate addition to extended
Michael acceptors[4] requires additional control of regiose-
lectivity. For a,b,g,d-unsaturated Michael acceptors, tuning of
the electron density on the Cu reagent allows regioselective
1,4-[5] or 1,6-addition[6–8] as shown in pioneering work by
Yamamoto et al. (for dienoates) and Krause et al. (for
enynes). Only modest progress has been made in enantiose-
lective conjugate additions to extended dienones and dien-
oates.[9] In 2005 Hayashi et al.[10] succeeded in the arylation of
selected (b-substituted)[11] dienones in an asymmetric fashion
(up to 98% ee) employing Rh catalysis. In 2006 Fillion et al.[12]
reported the 1,6-ACA of dialkylzinc reagents to Meldrumꢀs
acids with good selectivity (up to 84% ee). Recently, Jørgen-
sen et al.[13] disclosed the ACA of different nucleophiles (b-
ketoesters and glycine imine) to a variety of d-unsubstituted
dienones and dienoates employing an organocatalyst (up to
99% ee). In all of these methodologies the excellent regiose-
lectivity is associated with specific structural features of the
substrate. Enantioselective conjugate addition to particularly
challenging acyclic dienones or dienoates monosubstituted at
the b and d position has not been reported yet. In particular
the addition of simple alkyl groups to dienoates is highly
warranted owing to the synthetic versatility of the chiral
multifunctional building blocks obtained. Herein, we report
Scheme 1. Chiral ferrocenyl-based phosphines used in ACA of Grignard
reagents. Cy=cyclohexyl.
shown) was employed at À788C, and the b,g-unsaturated 1,6-
addition product 5 was obtained with excellent regio- and
enantioselectivity (Table 1, entries 4 and 5). Remarkably, only
Table 1: Results of initial catalyst screeningfor the enantioselective 1,6-
addition of EtMgBr to ethyl sorbate (4).[a]
Entry
Ligand
Conv. [%]
5/7[b]
ee [%][b,c]
1
2
3
–
>99
ꢀ80
ꢀ35
>99
>99
34:66
–
–
98:2
99:1
0
–
–
[*] T. den Hartog, Dr. S. R. Harutyunyan, D. Font,
Prof. Dr. A. J. Minnaard, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry
University of Groningen
(À)-1
(À)-2
(+)-3
(À)-3
4
95 (R)
95 (S)
5[d]
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: a.j.minnaard@rug.nl
b.l.feringa@rug.nl
Homepage: feringa.fmns.rug.nl
[a] Conditions: 4 was added to a solution of EtMgBr (3.0m in Et2O,
2.0 equiv), ligand (5.25 mol%), and CuBr·SMe2 (5 mol%) in CH2Cl2
(0.2m in 4). [b] The product ratio 5/7 and ee values were determined
by GC on a chiral phase. [c] The absolute configuration of 5 was
determined by conversion into a known compound (see the Supporting
Information). [d] The reaction was performed at À708C for 16 h.
[**] We thank T. D. Tiemersma-Wegman (GC and HPLC) and A. Kiewiet
(MS) for technical support (Stratingh Institute, University of
Groningen). Financial support from the Netherlands Organization
for Scientific Research (NWO-CW) and a generous gift of josiphos
ligands from Solvias (Basel) is gratefully acknowledged.
a trace (< 2%) of the 1,4-addition product 7 and no 1,2-
addition product were detected by GCanalysis. Furthermore,
we did not obtain any of the a,b-unsaturated 1,6-addition
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
398
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Angew. Chem. Int. Ed. 2008, 47, 398 –401

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product 6; in situ quenching of the magnesium bromide
dienolate by ethanol gives the kinetic product 5.
The asymmetric 1,6-addition is remarkably sensitive to
the structure of the catalyst. The use of either josiphos (À)-1
[19]
or taniaphos (À)-2 at À788Cled to less than 5% yield
in
64 h (Table 1, entries 2 and 3). In contrast, the use of a
catalytic amount of a simple copper salt at À788Cled to
formation of a mixture of regioisomers with a preference for
the 1,4-addition product 7 (Table 1, entry 1).
Since the reaction is slow at À788Cwe investigated the
influence of the temperature. Increasing the temperature of
the reaction mixture up to À608Callowed shorter reaction
times (4 h) without loss of regio- or stereoselectivity (Table 2,
entry 2). However, the use of higher temperatures led to
gradual loss of both regio- and stereoselectivity (Table 2,
Scheme 2. Proposed catalytic cycle for the 1,6-ACA of EtMgBr to ethyl
sorbate (4).
Table 2: Optimization for the enantioselective 1,6-addition of EtMgBr to
ethyl sorbate (4).[a]
plex 12 to the remote position.[22] The catalytic cycle ends by
reductive elimination to form product 13 and reformation of
complex 9. Preference for the formation of the 1,6-addition
product over the 1,4-product in view of the proposed
mechanism can be explained by a lower activation energy
for migration of the Cu complex compared to that of alkyl
addition at the 4-position, since this addition would disturb
the conjugation system.[16b]
Following optimization of the reaction conditions and
having achieved excellent regio- and enantioselectivity, we
examined the scope of 1,6-ACA with respect to addition of
different Grignard reagents.[23] Grignard reagents possessing
longer alkyl chains (Table 3, entry 2) and a homoallylic
Grignard (Table 3, entry 3) also gave excellent enantio- and
regioselectivity. Addition of the hindered Grignard iPrMgBr
yields a respectable stereoselectivity (72% ee) (Table 3,
entry 4). However, addition of other hindered and aromatic
Grignard reagents resulted in very low conversion even at
À608Cin 16 h (Table 3, entries 5 and 6).
Entry
T [8C]
t [h]
Conv. [%]
5/7[b]
ee [%][b,c]
1
2
3
À78
À60
À55
À40
À70
64
4
3
2.5
24
>99
>99
>99
98:2
99:1
98:2
77:23
99:1
95 (R)
95 (R)
92 (R)
67 (R)
95 (R)
4
>99
5[d]
98 (77)[e]
[a] Conditions: 4 was added to a solution of EtMgBr (3.0m in Et2O,
2.0 equiv), (+)3 (5.25 mol%), and CuBr·SMe2 (5 mol%) in CH2Cl2 (0.2m
in 4). [b] The product ratio 5/7 and ee values were determined by GC on a
chiral phase. [c] The absolute configuration was determined by con-
version into known compound (see the SupportingInformation). [d] The
reaction was performed with 2 mol% CuBr·SMe2, 2.1 mol% (+)-3, and
1.5 equiv EtMgBr. [e] Yield of isolated product.
entries 3 and 4). To demonstrate the
synthetic potential of this method-
Table 3: Enantioselective 1,6-addition of several Grignard reagents RMgBr to ethyl sorbate (4).[a]
ology we performed the reaction on
a 0.5-g scale with only 2% catalyst;
product 5 was obtained in good
yield with excellent regio- (99:1)
and enantioselectivity (95% ee;
Table 2, entry 5).
Entry
R
Product
Yield [%]
84
15/16[b]
98:2
99:1
97:3
99:1
–
ee [%][b,c]
95 (R)
97 (À)
92 (À)
72 (À)
–
Based on our recent mechanis-
tic studies on CA of Grignard
reagents[15] and the mechanism pro-
posed by Krause and Nakamura for
1,6-CA,[16] we propose the catalytic
cycle depicted in Scheme 2 for our
system. The cycle starts with for-
mation of reactive complex 9 from
the dimeric resting state 8 of the
catalyst. Presumably, 9 forms a p
complex 10 with substrate 4, fol-
lowed by formation of the copper-
(III)[20] s complex 11.[21] Next, 11
undergoes sequential copper migra-
tion via s/p-allylcopper(III) com-
1
2
3
4
5
6
Et
5
Bu
15a
15b
15c
15d
15e
85
but-3-enyl
57
iPr
iBu
Ph
54
<5[d]
<5[d]
–
–
[a] Conditions: 4 was added to a solution of RMgBr (1.5–3.0m in Et2O, 2.0 equiv), (+)-3 (5.25 mol%),
and CuBr·SMe2 (5 mol%) in CH2Cl2 (0.2m in 4). [b] The product ratio 15/16 and ee values were
determined by GC on a chiral phase. [c] The absolute configuration was determined by conversion into a
known compound (see the SupportingInformation). [d] Conversion (degradation) was ca. 35%.
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Communications
Table 4: Enantioselective 1,6-addition of Grignard reagents RMgBr to dienoates 17.[a]
particularly important synthetic
methodology.[17d,26] In our earlier
work we used a,b-unsaturated thio-
esters to overcome the intrinsically
low reactivity of ester substrates to
MeMgBr.[27] In this context ester
substrate 17a gave, as expected, a
low yield (Scheme 3); however, the
use of thioester 22 instead yielded
the anticipated product 23 in high
yield and excellent regio- and enan-
tioselectivity.
To illustrate the potential of this
new method we performed a short
total synthesis of the sulfated
alkene 26, which was isolated from
the Echinus Temnopleurushard-
wickii.[28] As shown in Scheme 4
this synthesis features a 0.5-g scale
asymmetric 1,6-addition of a func-
tionalized Grignard reagent to ethyl
sorbate with high enantioselectivity,
followed by LiAlH4 reduction of
the ester and sulfation of the alco-
Entry
Substrate
R2
Bu
Et
Et
Et
Et
Et
Et
Product
18a
Yield [%]
18/20[b]
99:1
ee [%][b]
96 (À)
93 (+)
79 (À)
93 (+)
90 (+)
73 (À)
90 (À)
1
2
3
4
5
6
7
17a
17b
17c
17d
17e
17 f
17g
88
80
82
77
73
82
69
18a
99:1
18c + 19c
18d
96:4
98:2
18e
98:2
18 f
96:4
18g
>95:5[c]
[a] Conditions: 17 was added to a solution of RMgBr (3.0m in Et2O, 2.0 equiv), (+)-3 (5.25 mol%), and
CuBr·SMe2 (5 mol%) in CH2Cl2 (0.2m in 17). [b] The product ratio 18/206 and ee values were
determined by GC on a chiral phase. [c] Ratio 18g/20g was determined by NMR spectroscopy.
To further examine the scope of the 1,6-ACA with respect
to d substitution in the substrate, we applied our optimized
conditions to the reactions of several extended dienoates.
Substrates with linear aliphatic chains at the d position
provided similar high levels of selectivity (Table 4, entries 1
and 2). Bulky substituents at the e position (Table 4, entry 3)
caused a drop in regio- and enantioselectivity. In addition to
the anticipated b,g-unsaturated product 18c, the a,b-unsatu-
rated product 19c was obtained.[24] Excellent control of regio-
and stereoselectivity was also achieved when bulky substitu-
ents are separated by an additional CH2 spacer (Table 4,
entry 4). High enantiomeric excess was obtained as well for
the substrate functionalized with a phenyl moiety (Table 4,
entry 5). However, functionalization by a bulky TBDPS-
protected hydroxy group at the e position caused a drop in
regio- and enantioselectivity (Table 4, entry 6). Replacing the
TBDPS protectng group by a Bn group provided high regio-
and stereocontrol again (Table 4, entry 7).
Scheme 4. A short total synthesis of a the sulfated alkene 26, which
was isolated from the Echinus Temnopleurus hardwickii.
Since chiral methyl-substituted alkyl chains are abundant
hol to obtain 26 in good yield and stereoselectivity (three
steps, 17% overall yield, 86% ee).
in natural products[25] the ACA of MeMgBr comprises
In conclusion, we have developed a highly enantioselec-
tive 1,6-ACA (with up to 97% ee) to a,b,g,d-unsaturated
esters, providing valuable multifunctional building blocks.
This is also the first example of a 1,6-ACA for which
regioselectivity is primarily dictated by the catalyst.
Received: August 13, 2007
Published online: November 28, 2007
Keywords: 1,6-conjugate addition · asymmetric catalysis ·
copper · enantioselectivity · Grignard reaction
Scheme 3. Enantioselective 1,6-addition of MeMgBr to dienoate 17a
and thioester 22.
.
400
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