Highly diastereo- and enantioselective cyclopropanation of 1,2-disubstituted alkenes

Article abstract of DOI:10.1002/anie.201203218

A helping hand: A series of bis(oxazoline) ligands, which contain pendant C₂-symmetry-breaking groups, for the Cu-catalyzed asymmetric cyclopropanation of 1,2-disubstituted alkenes has been developed. Under mild reaction conditions, both cis- and trans-1,2-substituted alkenes can be converted into the corresponding 1,2,3-trisubstituted cyclopropanes with high levels of diastereo- and enantioselectivity (see scheme). Copyright

Full text of DOI:10.1002/anie.201203218

Angewandte
Chemie
DOI: 10.1002/anie.201203218
Asymmetric Cyclopropanation
Highly Diastereo- and Enantioselective Cyclopropanation of
1,2-Disubstituted Alkenes**
Jun Li, Sai-Hu Liao, Hu Xiong, You-Yun Zhou, Xiu-Li Sun,* Yue Zhang, Xiao-Guang Zhou,
and Yong Tang*
Since Nozaki et al. reported the first enantioselective syn-
thesis of cyclopropanes, a reaction that involved copper-
catalyzed transfer of a carbene moiety from diazo compounds
to alkenes,[1] much effort has been devoted to the area of
transition-metal-catalyzed asymmetric cyclopropanation
reactions because it is a straightforward method for accessing
optically active cyclopropanes.[2–7] However, there are only
a few examples where 1,2-disubstituted alkenes have been
transformed through a transition-metal-catalyzed asymmetric
cyclopropanation reaction with high levels of diastereo- and
enantioselectivity;[8] these reactions usually involve cyclic
alkenes[8c] and trisubstituted alkenes.[8a,e] In 1991, Masamune
et al. reported a double-asymmetric-induction approach in
of bis(oxazoline) (BOX) ligands that contain C2-symmetry-
breaking pendant groups in the copper-catalyzed cyclopropa-
nation of both cis- and trans-1,2-disubstituted alkenes can
lead to high levels of diastereo- and enantioselectivity.
We commenced our study by screening copper salts in
combination with several BOX ligands in the cyclopropana-
tion reaction of cis-b-methyl styrene (Table 1). When using
Table 1: Screening of ligands for the copper-catalyzed cyclopropanation
reaction.[a]
which cis-b-methyl styrene was transformed using
a
CuI/BOX-catalyzed cyclopropanation reaction involving
l-menthol-derived diazoacetate to give product in 92% ee
and 76% de.[8a] High enantioselectivity was achieved by Ito
and Katsuki when they used chiral bipyridine ligands in the
cyclopropanation of trans-b-methyl styrene, although the
diastereoselectivity was low (trans/cis 40:60).[8b] Recently,
Katsuki and co-workers reported the use of an aryliridium/
salen catalyst, which led to remarkably high levels of enantio-
and diastereoselectivity (favoring the cis product) in the
cyclopropanation of terminal and cyclic alkenes. However,
when cis-b-methyl styrene was used as a substrate, a relatively
low yield of product (29%) was obtained and for trans-b-
methyl-styrene only a trace amount of cyclopropanation
product was obtained.[8c] The unsatisfactory results obtained
in the cases of 1,2-disubstituted alkenes can be mainly
ascribed to the high sensitivity of metallocarbenes to the
steric hindrance and geometry of the alkene.[8] Therefore,
a cyclopropanation catalyst that is efficient and applicable to
the highly stereoselective cyclopropanation of both cis- and
trans-1,2-disubstituted alkenes, especially simple trans al-
kenes, is still in high demand. Herein, we report that the use
Entry
Ligand
Yield [%][b]
Trans/cis[c]
eetrans [%][d]
1
2
3
4
5
6
L1
L2
L3
L4a
L5a
L6a
25
0
45
61
53
50
75/25
–
86/14
95/5
97/3
94/6
7
–
7
89
87
80
[a] 1a (0.5 mmol), CH3CO2iBu (3.5 mL). [b] Yield of isolated product.
[c] Determined by H NMR analysis. [d] Determined by HPLC using
a chiral stationary phase.
1
[*] J. Li, Dr. S.-H. Liao, H. Xiong, Dr. Y.-Y. Zhou, Dr. X.-L. Sun, Y. Zhang,
X.-G. Zhou, Prof. Dr. Y. Tang
2,6-dimethylphenyl diazoacetate as the carbene source,[9] all
ligands tested exhibited the required activity, except Ph-
DBFOX (L2; Table 1, entry 2); only low levels of enantiose-
lectivity were obtained with L1 and L3 (Table 1, entries 1 and
3). Because iPr-BOX (L4a) gave the most promising enan-
tioselectivity (89% ee; Table 1, entry 4), we prepared and
tested ligands L5a and L6a, which have different substituents
on the C4 atom. Unfortunately, the levels of enantioselectiv-
ity that were obtained using these ligands were not an
improvement on that obtained using L4a and were thus
impractical (Table 1, entries 5 and 6).
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P.R. China)
E-mail: xlsun@sioc.ac.cn
tangy@mail.sioc.ac.cn
[**] We are grateful for the financial support from the National Natural
Sciences Foundation of China (No. 21121062, 20932008, and
21072207), the Major State Basic Research Development Program
(Grant No. 2009CB825300) and the Chinese Academy of Sciences.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203218.
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Table 2: The effect of ligand on the Cu-catalyzed asymmetric cyclo-
propanation reaction.
It is well known that the origin of enantioselectivity in
these reactions lies in the interaction between the ester group
of the carbene and the C4 substituent of the BOX ligand.[10]
Recently, Garcꢀa, Salvatella, and co-workers reported that the
copper atom of the carbene complex has a distorted trigonal
arrangement of ligands and that the metal–carbon bond of the
complex deviates from the symmetry axis of the catalyst
ligand.[11] During their elegant studies on asymmetric catal-
ysis, Gade and co-workers observed that the pendant groups
of BOX–metal complexes bend toward and cover the metal
center;[12] a similar orientation of pendant groups is evident in
the X-ray structure of the L6d/CuBr2 complex (Figure 1);[13]
Entry[a]
Alkene
Ligand
Yield [%][b]
Trans/cis[c]
eetrans [%][d]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
L5b
L6b
L6c
L6d
L6e
L6 f
L6g
L6h
L4b
L4c
L7b
L4d
L4b
L4c
L7a
L7b
52
75
65
81
39
74
76
78
84
43
53
43
43
68
58
89
96/4
82/18
88/12
94/6
89/11
93/7
94/6
94/6
96/4
92/8
93/7
95/5
>99/1
>99/1
>99/1
>99/1
93
47
71
89
89
89
89
84
92
84
89
83
89
85
60
96
9
10
11
12
13
14
15
16
Figure 1. Crystal structure of L6d/CuBr2. Thermal ellipsoids are shown
at 30% probability and hydrogen atoms are omitted for clarity.[13]
[a] 1a or 1b (0.5 mmol), CH3CO2iBu (3.5 mL). [b] Yield of isolated
product. [c] Determined by 1H NMR analysis. [d] Determined by HPLC
using a chiral stationary phase.
such an orientation can tune both the steric interaction
between the groups on the BOX and the carbene moieties
and the level of deviation of the metal–carbene bond from the
symmetry axis of the complex, thus influencing the stereose-
lectivity. Therefore, it should be possible to further improve
the stereoselectivity by using a BOX ligand containing
a suitable pendant group.[14]
With this concept in mind, a number of BOX ligands with
different pendant groups were synthesized (Figure 2). The
replacement of one the methyl groups of L5a with an aryl
group, that is, tBu-BOX L5b, led to a slight increase in
enantioselectivity, although the yield of product was lower
(Table 2, entry 1 versus Table 1, entry 5). The replacement of
one of the methyl groups of L6a with an oxazoline group led
to a 9% decrease in enantioselectivity (Table 1, entry 6 versus
Table 2, entry 3). The use of ligand L6d, which contains
a pendant benzyl group, led to higher enantioselectivity
(89% ee; Table 2, entry 4), although further variation of the
aryl group led to no improvement in the enantioselectivity
(Table 2, entries 4–8). iPr-BOX L4b, which contains a pendant
benzyl group, was the best ligand for this reaction (Table 1,
entry 4 versus Table 2, entry 9); the use of this ligand gave the
desired cyclopropane 2a in 84% yield and with 92% ee,
together with high trans selectivity (trans/cis 96:4). Ligand
L4d, which contains two identical pendant groups, gave lower
selectivity (Table 2, entry 12). Further studies showed that
these modified BOX ligands also worked extraordinarily well
when applied to the cyclopropanation of trans-b-methyl
styrene (Table 2, entries 13–16). For example, when L4b
was employed, the desired cyclopropane 2b was obtained in
43% yield with high diastereoselectivity (trans/cis greater
than 99:1), the major diastereomer having an ee value of 89%
(Table 2, entry 13). When ligand L7b was used, the ee value of
the product was further increased to 96% and the diastereo-
selectivity remained very high (Table 2, entry 16).
With the optimum ligands for the cyclopropanation
reaction of both cis- and trans-b-methyl styrenes in hand,
we then explored the scope of the reaction. The cyclo-
propanation of a series of cis-b-methyl styrenes proceeded
smoothly regardless of their electronic nature (Table 3,
entries 1–4). The desired cyclopropanes were obtained in
high yields (72–84%) with high levels of diastereoselectivity
(trans/cis from 95:5 to 97:3) and enantioselectivity (92–
94% ee). A dihydronaphthalene- and an indole-derived
alkene were good substrates for this reaction (Table 3,
Figure 2. BOX ligands containing pendant groups.
2
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Table 3: Asymmetric cyclopropanation of Z alkenes.[a]
Table 4: Asymmetric cyclopropanation of E alkenes.[a]
Yield [%][b] Trans/cis[c] eetrans [%][d]
Entry Alkene
Yield [%][b] Trans/cis[c] eetrans [%][d]
Entry Alkene
1
1b:
1j:
89
99
96
96
73
>99/1
>99/1
>99/1
>99/1
>99/1
96
96
94
97
96
1
2
3
4
5
1a:
1c:
1d:
1e:
1 f:
84
78
72
72
60
96/4
96/4
95/5
95/5
97/3
92
93
94
93
89
2
3
1k:
1l:
4
5[e]
1m:
6
7
8
9
1n:
1o:
1p:
1q:
60
97
64
84
>99/1
93/7
96
96
98
97
>99/1
>99/1
6
1g:
1h:
1i:
95
60
66
97/3
97/3
93/7
89
86
86
10
1r:
82
>99/1
96
7
[a] Alkene (0.5 mmol), CH3CO2iBu (3.5 mL). [b] Yield of isolated product.
[c] Determined by H NMR analysis. [d] Determined by HPLC using
1
8[e]
a chiral stationary phase. [e] The absolute configuration was determined
to be (1R,2R,3R) by X-ray crystallography.[14]
[a] Alkene (0.5 mmol), CH3CO2iBu (3.5 mL). [b] Yield of isolated product.
1
[c] Determined by H NMR analysis. [d] Determined by HPLC using
a chiral stationary phase. [e] 4 equivalents of diazo acetate were used.
entries 6 and 7). Although a relatively low yield was obtained
in the reaction of the more sterically demanding cis-b-ethyl
styrene, high diastereoselectivity (93:7) and enantioselectivity
(86% ee) were observed (Table 3, entry 8).
Scheme 1. Reactions with reduced catalyst loading.
The cyclopropanation reaction of 1,2-trans-disubstituted
alkenes had broad substrate scope and high levels of
stereoselectivity (Table 4). Using L7b/CuOTf as the catalyst,
various trans b-methyl styrene derivatives bearing electron-
donating and electron-withdrawing substituents on the phenyl
ring, underwent cyclopropanation with perfect levels of
diastereoselectivity (> 99:1) and high levels of enantioselec-
tivity (94–97% ee; Table 4, entries 1–5). 1-Naphthyl and
1-cinnamyl alkene were also suitable substrates and were
transformed into the corresponding cyclopropanes with high
levels of trans selectivity and enantioselectivity (Table 4,
entries 6–7). Notably, under the optimized reaction condi-
tions, more hindered trans alkenes, such as cinnamyl-alcohol
derivative 1p and b-ethyl styrene 1q, can also be converted
into the desired cyclopropanes with high levels of stereose-
lectivity (Table 4, entries 8 and 9), and a Sommelet–Hauser
rearrangement product was not observed in the reaction of
1p. Moreover, the reaction of trisubstituted alkene 1r also
proceeded well, affording fused bicyclic product 2r in 82%
yield with greater than 99:1 trans/cis and 96% ee (Table 4,
entry 10).
in 44% yield with 98% ee. To our knowledge, 0.05 mol% is
the lowest catalyst loading used in a copper-catalyzed cyclo-
propanation reaction.
In summary, an efficient BOX/CuI-catalyzed cyclopropa-
nation reaction has been designed and developed. Cis- and
trans-1,2-substituted alkenes can be converted into the
corresponding trisubstituted cyclopropanes with high levels
of diastereo- and enantioselectivity (> 99:1 trans/cis and up to
98% ee). The effect of the pendant group of BOX ligands was
investigated, thus leading to the discovery of the BOX ligand
L4b and L7b, the copper complexes of which were the best
catalysts. This reaction features high catalytic efficiency and
excellent stereoselectivity, especially for trans alkenes, the
generality and high diastereoselectivity of which are unpre-
cedented. Further investigations of this catalytic reaction are
underway.
Considering the high efficiency of the L7b/CuOTf cata-
lyzed cyclopropanation of trans alkenes, a scaled-up reaction
(50 mmol) was performed. In the event, high yields and high
levels of enantioselectivity were obtained when 0.5 mol% of
catalyst was used (Scheme 1). The cyclopropanation of trans-
b-methyl styrene also proceeded well even with only
0.05 mol% catalyst loading, giving the desired propane 2b
Experimental Section
A typical procedure using the reaction that gives the product 2a as an
example:
a mixture of CuOTf·0.5PhCH3 (0.025 mmol), L4b
(0.0275 mmol), and activated 4 ꢁ MS (300 mg) in CH3CO2iBu
(1 mL) was stirred at 308C for 1 h under N2 atmosphere. 1a
(0.5 mmol) in CH3CO2iBu (0.5 mL) were added, followed by the
diazo acetate (1.0 mmol) in CH3CO2iBu (0.5 mL) which was added
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dropwise using a syringe pump over 8 h. After the reaction was
complete, the mixture was filtered through a thin layer of silica gel,
eluting with CH2Cl2, and the filtrate was concentrated. The residue
was purified by column chromatography over silica gel using CH2Cl2/
petroleum ether 6:1 as eluent to afford 2a (118 mg, 84% yield).
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Received: April 26, 2012
Revised: July 2, 2012
Published online: && &&, &&&&
Keywords: alkenes · copper · cyclopropanation ·
.
diazo compounds · homogeneous catalysis
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Asymmetric Cyclopropanation
J. Li, S.-H. Liao, H. Xiong, Y.-Y. Zhou,
X.-L. Sun,* Y. Zhang, X.-G. Zhou,
Y. Tang*
&&&& — &&&&
Highly Diastereo- and Enantioselective
Cyclopropanation of 1,2-Disubstituted
Alkenes
A helping hand: A series of bis(oxazoline)
ligands, which contain pendant C2-sym-
metry-breaking groups, for the Cu-cata-
lyzed asymmetric cyclopropanation of
1,2-disubstituted alkenes has been
tions, both cis- and trans-1,2-substituted
alkenes can be converted into the corre-
sponding 1,2,3-trisubstituted cyclopro-
panes with high levels of diastereo- and
enantioselectivity (see scheme).
developed. Under mild reaction condi-
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!