Highly enantioselective cyclopropanation of trisubstituted olefins

Article abstract of DOI:10.1007/s11426-017-9200-9

A highly efficient asymmetric cyclopropanation of trisubstituted olefins with methyl diazoacetate has been developed in terms of an elaborate modified chiral bisoxazoline/copper complex as a catalyst. A broad scope of substrates is compatible with this catalyst system, including various trisubstituted olefins bearing different aryl-, fused aryl- and alkyl-substituents, providing an easy access to optically active 1,1-dimethyl cyclopropanes in good yields with excellent diastereo- and enantio-selectivity.

Full text of DOI:10.1007/s11426-017-9200-9

SCIENCE CHINA
Chemistry
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Highly enantioselective cyclopropanation of trisubstituted olefins
Jun Li1†, Long Zheng1†, Hao Chen1, Lijia Wang1*, Xiu-Li Sun1, Jun Zhu1 & Yong Tang1,2*
1The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of
Chinese Academy of Sciences, Shanghai 200032, China;
2Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
Received November 3, 2017; accepted December 24, 2017; published online January 24, 2018
A highly efficient asymmetric cyclopropanation of trisubstituted olefins with methyl diazoacetate has been developed in terms of
an elaborate modified chiral bisoxazoline/copper complex as a catalyst. A broad scope of substrates is compatible with this
catalyst system, including various trisubstituted olefins bearing different aryl-, fused aryl- and alkyl-substituents, providing an
easy access to optically active 1,1-dimethyl cyclopropanes in good yields with excellent diastereo- and enantio-selectivity.
cyclopropanation, enantioselective, bisoxazoline, copper, diazoacetate
Citation:
Li J, Zheng L, Chen H, Wang L, Sun XL, Zhu J, Tang Y. Highly enantioselective cyclopropanation of trisubstituted olefins. Sci China Chem, 2018, 61,
https://doi.org/10.1007/s11426-017-9200-9
1,1-Dimethyl cyclopropanes are a class of important scaf-
folds, which widely exist in natural products, such as Δ3-
(+)-carene, jatropholone B and pyrethrin I (Figure 1). Those
natural products were usually found to be biologically useful
compounds [1]. For example, since optically active pyrethrin
and its analogs exhibited impressive insecticidal activity,
many insecticides that are effective, low toxicity and low
residue have been developed base on the 1,1-dimethyl cy-
clopropane skeleton [2]. Besides, enantiopure artificial mo-
lecules containing the 1,1-dimethyl cyclopropane backbone,
such as BMS-2846-40, was also found significant NHE-1
inhibitory activity [3]. Asymmetric catalytic cyclopropana-
tion of trisubstituted olefins bearing 1,1-dimethyl moiety
with metal carbene generated from diazo acetates [4] pro-
vides a straightforward access to the optically active 1,1-
dimethyl cyclopropanes. Therefore, developing highly effi-
cient methods for the stereospecific cyclopropanation in-
creasingly becomes of great interests to many chemists.
Aratani and co-workers [5] demonstrated their pioneering
study on the double asymmetric induction of Schiff base/
copper catalyzed asymmetric cyclopropanation of 2,5-di-
methylhexa-2,4-diene with optically active l-menthyl dia-
zoacetate in 1977, affording the mono cyclic product in 75%
yield with 93/7 dr and 94% ee. Since then, a variety of ef-
ficient catalyst systems have been developed for the cyclo-
propanation of 2,5-dimethylhexa-2,4-diene, such as chiral
bisoxazoline (BOX)/copper catalysts developed by Ma-
sammune et al. [6b] and Itagaki et al. [6e,6f] respectively,
and chiral diamine/copper catalyst reported by Kanemasa et
al. [6c]. However, for other trisubstituted alkenes in the en-
antioselective cyclopropanation, relatively less studies have
been reported. Aratani et al. [7] studied the double asym-
metric induction of cyclopropanation with 2-alkyl-1,1-di-
methyl olefins, resulted in 47%–73% yield with 85%–95%
ee for major cis isomer. Recently, Tanner et al. [8] reported
the BOX/copper catalyzed asymmetric cyclopropantion of
allyl alcohol derivatives with ethyl diazoacetate, obtaining
10%–95% ee and 50/50–88/12 dr. Although many asym-
metric catalytic methodologies have been developed, the
trisubstituted olefin substrates are limited to the aforemen-
tioned three types (Scheme 1) [9,10]. Furthermore, with re-
gard to the substrate scope generality, those reported
†These authors contributed equally to this work.
*Corresponding authors (email: wanglijia@sioc.ac.cn; tangy@sioc.ac.cn)
© Science China Press and Springer-Verlag GmbH Germany 2018 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . chem.scichina.com link.springer.com

2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Li et al. Sci China Chem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
donor-acceptor carbenes [12a], carbene acetates [12b] and
carbene malonates [12c]. Our study began with the screening
of a number of BOX and TOX ligands. As shown in Table 1,
BOX ligands L1–L4 bearing different chiral backbones were
initially examined, and L-tert-Leucine derivatives L4 proved
to be the optimal ligand, giving the desired cyclopropane 3a
in 56% yield with 88/12 dr and 79% ee (entry 5). Based on
our previous study on the complex structures of TOX/nickel
[13a] and SaBOX/copper [12c,13b], the pandent side-arm
groups swing towards the copper center, which may force the
coordinated parent oxazoline groups and allow a more sui-
table space to accommodate the substrates and release the
products. However, in this reaction, when TOX ligand L5
Figure 1 Useful biologically active compounds bearing 1,1-dimethyl
cyclopropane scaffold (color online).
and SaBOX ligand L6 were employed, both the yields and
enantioselectivity declined (entries 6 and 7).
Based on the previously reported works, the bridge angle
of the two oxazolines in a chiral BOX ligand has significant
effects on the enantioselectivity of a reaction. For example,
Davies et al. [14a] found that the increasing bridge angles of
the chiral BOX ligands led to the increasing enantioselec-
tivity in the In-BOX/Cu(II) catalyzed asymmetric Diels-
Alder reaction. Denmark and coworkers [14b,14c] also de-
monstrated that when bulkier substituents were installed on
the bridge carbon of the chiral BOX ligands, the corre-
sponding bridge angles were smaller, and the enantioselec-
tivities of the asymmetric reactions promoted by these chiral
BOX ligands were increased, for some substrates in the en-
antioselective additions of organolithium to imines. In our
recent studies on the catalytic asymmetric [2+2+2] tandem
cyclization reactions, we utilized a strong Thorpe-Ingold
effect to modify the chiral ligands, which by means of in-
creasing the steric hindrance of the substituents on the bridge
Scheme 1 Trisubstituted olefins in asymmetric 1,1-dimethyl cyclopro-
pantion.
carbon of chiral BOX ligand, the enantioselectivity of the
reaction could be improved [14d]. In this cyclopropanation,
we noticed that, in comparison of L2a with L2b, L2b with a
methods are specific to one or one type of olefins. Moreover,
due to the high sensitivity of metallocarbenes to the steric
hindrance and geometry of the alkenes, for more steric bulky
trisubstituted olefins bearing different aryl groups, the en-
antioselective cyclopropanation has rarely been realized yet.
Accordingly, in consideration of the versatility of 1,1-di-
methyl cyclopropanes in drugs development, a new chiral
catalyst system, that is highly efficient on both reactivity and
enantioselectivity, as well as with abroad substrate scopes, is
still in eager demand. Here, we report our efforts on this
subject.
In a metal complex involved asymmetric catalysis, the
chiral ligands usually proved to be crucial for both the re-
activity and the stereo selectivity. Recently, we have devel-
oped a series of side arm modified chiral bisoxazoline
ligands [11], which were successfully applied in the en-
antioselective cyclopropanation of terminal olefins and 1,2-
disubstituted olefins with different copper carbenes such as
cyclopropyl group led to an obviously drop on both the yield
and ee value (entry 2 vs. entry 3, Table 1). These results
suggested that the reaction was quite sensitive to the steric
demand of R1 and R2, and that drove us to the screening of
ligands with different R1 and R2 groups. With L7 and L8,
containing less hindered R1 and R2 groups, 38% and 50%
yields with 77/23 dr as well as 73% ee and 72% ee were
obtained respectively (entries 8 and 9). Inspiringly, 91/9 dr
and 87% ee were achieved with a diethyl substituted ligand
L9 (entry 10). Further increasing the steric hindrance with
diisopropyl substituents (L10) allowed the current reaction
to give an 89/11 dr with 91% enantioselectivity (entry 11).
However, with diisobutyl substituted ligand L11, the stereo
control of this reaction was destroyed (entry 12). To our
delight, both the yield and enantioselectivity of the desired
cyclopropane could be increased in terms of lowering the
reaction temperature to 0 °C, and gave 76% yield, 95/5 dr
and 95% ee (entry 13), probably due to the lower temperature

3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Li et al. Sci China Chem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
a)
Table 1 Screening of ligands
spiro products 3h and 3i in 95/5 dr and excellent ee value
(entries 8, 9). In addition, aliphatic olefin substrate 1j was
also tolerated in the current catalytic system, affording the
product 3j in 41% yield with 95/5 dr and 85% ee (entry 10).
The enantioinduction model shown in Figure 2 was pro-
posed to explain the accomplished high enantioselectivity.
According to our previous studies on the structure of a di-
isopropyl substituted L-phenylglycine derived BOX ligand/
copper complex (for details, see the Supporting Information
online), the isopropyl groups on the bridge carbon are always
far away from the metal center. In this model, effected by the
steric hindrance from the two methyl groups of the olefin
substrates, the less hindered mono-substituted carbon of the
olefin substrate keep close to the copper complex. Owing to
the steric repulsion between the ester group of the metal
carbene and the aryl group of the olefin substrate, these two
groups adopt the opposite direction. In addition, the observed
enantioselectivity of the cyclopropanation could be attrib-
uted to the steric hindrance between the aryl group of the
olefin and the bulky tert-butyl group on the chiral ligand.
This model is consistent with stereochemical results and the
configuration of the cyclopropane determined by X-ray
crystallographic analysis [15].
b)
c)
d)
Entry
1
L
Yield (%)
54
Time (h)
12
dr
ee (%)
26
L1
82/18
86/14
90/10
82/18
88/12
70/30
75/25
77/23
77/23
91/9
2
L2a
L2b
L3
34
12
64
3
22
11
30
4
31
12
47
5
L4
56
22
79
6
L5
18
12
47
7
L6
23
13
73
In conclusion, we developed a highly efficient asymmetric
cyclopropanation of trisubstituted olefins with methyl dia-
zoacetate in terms of an elaborate modified chiral bisox-
azoline/copper complex as catalyst. A broad scope of
substrates was compatible with this catalyst system, includ-
ing various trisubstituted olefins bearing different aryl-,
fused aryl- and alkyl-substituents, providing a number of
optically active multi-functionalized cyclopropanes in good
8
L7
38
12
73
9
L8
50
12
72
10
11
12
13 e)
14 f)
L9
35
12
87
L10
L11
L10
L10
24
13
89/11
80/20
95/5
91
25
12
78
76
12
95
49
13
95/5
96
a)
Performed
with
1-bromo-4-(2-methylprop-1-enyl)benzene
(0.5 mmol), methyl 2-diazoacetate (1.0 mmol), CuPF6(CH3CN)4
(0.025 mmol), L (0.0275 mmol), at 30 °C, in DCM (4.5 mL); b) isolated
1
yield; c) determined by H NMR of the crude products; d) determined by
Chiral HPLC; e) at 0 °C; f) at −20 °C.
diminishing the side reactions in this catalytic system. When
the reaction was carried out at −20 °C, the reaction was slow
down and resulted in 49% yield with 95/5 dr in 96% ee (entry
14).
Under the optimized reaction conditions, a variety of tri-
substituted olefins bearing different functional groups were
subjected to the current catalytic system. As shown in Table
2, both the electron rich and poor alkenes proceeded
smoothly, providing the corresponding multisubstituted cy-
clopropanes 3a–3e in good yields with excellent diaster-
eoselectivity and enantioselectivity (76%–85% yields, 91/9–
95/5 dr and 94%–97% ee, entries 1–5). Remarkably, 1-
naphthyl substituted cyclopropane 3f and 2-naphthyl sub-
stituted cyclopropane 3g could also be obtained in 81%–83%
yield with 96/4–93/7 dr and 95%–99% ee (entries 6 and 7).
The catalyst also proved to be highly efficient for the five-
and six-membered cyclic substrates, furnishing the rigid
Figure 2 Proposed enantioinduction model and crystal structure of 3a
(color online).

4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Li et al. Sci China Chem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
a)
Table 2 Substrate scope
a) Performed with 1-bromo-4-(2-methylprop-1-enyl)benzene (0.5 mmol), methyl 2-diazoacetate (1.0 mmol), CuPF6(CH3CN)4 (0.025 mmol),
L
(0.0275 mmol), at 30 °C, in DCM (4.5 mL); b) isolated yield; c) determined by 1H NMR of the crude products; d) determined by Chiral HPLC; e) the absolute
configuration of 3a was determined by X-ray diffraction analysis as 1R, 3R, as shown in Figure 2 [15]; f) at −20 °C, with 1.5 mmol of methyl 2-diazoacetate.
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Further study on asymmetric cyclopropanation involving
diacceptor diazo compounds as carbene precursor is still in
progress in our laboratory.
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Acknowledgements This work was supported by the National Natural
Science Foundation of China (21432011, 21772224), Key Research Pro-
gram of Frontier Sciences of Chinese Academy of Sciences (QYZDY-SSW-
SLH016), the Strategic Priority Research Program of the Chinese Academy
of Sciences (XDB20000000), the Youth Innovation Promotion Association
CAS (2017301) and the National Basic Research Program of China
(2015CB856600). We thank Dr. Xue-Bing, Leng (SIOC) and Mr. Jie, Sun
(SIOC) for X-ray crystal analysis.
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
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