Oxazaborolidinium ion-catalyzed cyclopropanation of α-substituted acroleins: Enantioselective synthesis of cyclopropanes bearing two chiral quaternary centers

Article abstract of DOI:10.1021/ja209270e

A catalytic synthetic route to highly functionalized chiral cyclopropane derivatives was developed by Michael-initiated cyclopropanation of α-substituted acroleins with aryl- and alkyl diazoacetates. In the presence of chiral (S)-oxazaborolidinium cation

Full text of DOI:10.1021/ja209270e

COMMUNICATION
pubs.acs.org/JACS
Oxazaborolidinium Ion-Catalyzed Cyclopropanation of α-Substituted
Acroleins: Enantioselective Synthesis of Cyclopropanes Bearing Two
Chiral Quaternary Centers
Lizhu Gao,† Geum-Sook Hwang,*,‡ and Do Hyun Ryu*,†
†Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
‡Korea Basic Science Institute and Graduate School of Analytical Science and Technology, Chungnam National University,
Seoul 136-713, Korea
S Supporting Information
b
ABSTRACT: A catalytic synthetic route to highly func-
tionalized chiral cyclopropane derivatives was developed by
Michael-initiated cyclopropanation of α-substituted acro-
leins with aryl- and alkyl diazoacetates. In the presence of
chiral (S)-oxazaborolidinium cation 1b as a catalyst, the
reaction proceeded in high yield (up to 93%) with high to
excellent diastereoselectivity (up to 98% de) and enantios-
Figure 1. Structures of catalysts 1.
electivity (up to 95% ee).
date. However, Maruoka and co-workers reported titanium
BINOLate-catalyzed asymmetric cyclopropanation with moder-
ate enantioselectivity.7c
he cyclopropane ring is a common unit in a diverse range of
both naturally occurring and artificial compounds. Many
T
biologically active compounds contain complex cyclopropane
moieties.1 Because of their unique combination of a rigid struc-
ture with inherent electrophilic reactivity, cyclopropane rings can
constitute the key step in complex molecular syntheses.2 Thus,
over the past few decades considerable attention has been
devoted to the development of asymmetric methodologies for
the synthesis of highly functionalized cyclopropane derivatives.3,4
Among these methods, catalytic enantioselective SimmonsÀ
Smith-type reactions3 and transition-metal-catalyzed reactions5
utilizing metal carbenoid intermediates have been studied
extensively.
Catalysts 1 (Figure 1) are generated from the corresponding
oxazaborolidines by protonation with trifluoromethanesulfonic
acid (triflic acid). They have been proven as effective catalysts for
enantioselective DielsÀAlder reactions,10a cyanosilylations,10b
three-component coupling reactions,10c 1,3-dipolar cycloaddi-
tions,10d and the Mukaiyama aldol reaction.10e In addition, much
evidence exists in support of the formation of complexes between
1 and aldehydes.10a In view of these powerful catalytic activities,
we became interested in evaluating chiral oxazaborolidinium ions
1 as Lewis acid catalysts for asymmetric cyclopropanation. In this
communication, we present the first case of highly enantiocon-
trolled catalytic cyclopropanation of α-substituted acroleins with
diazoacetates.
Initially, an asymmetric cyclopropanation reaction between
methyl phenyldiazoacetate and methacrolein was examined in
the presence of 20 mol % oxazaborolidinium ion 1a (Figure 1),
which was activated by triflic acid. When the reaction was carried
out at À45 °C in propionitrile, the desired optically active
cyclopropane 2a was formed in 35% yield with 76% ee and a
high level of trans selectivity.11 At the same time, a 45% yield of
1-pyrazoline 3 (mixture of trans and cis isomers) was isolated.
The effect of changing the catalyst boracycle substituent was then
investigated, and the best boron aryl substituent was found to be
1-naphthyl (Table 1, entries 2À4). To improve the yield and
A Michael-initiated ring-closure reaction using ylides6 is
complementary to these variants and proceeds chemoselectively
with electron-deficient olefins. Aggarwal6f and Gaunt6l reported
pioneering studies on catalytic enantioselective cyclopropana-
tions via chiral sulfonium and ammonium ylides. Although
cyclopropanation of diazo reagents and olefins represents one
of the most general methods for constructing cyclopropane
derivatives, there are a few reports using diazoacetate as the
ylide.7 Enantioselective cyclopropanation reactions via Michael-
initiated ring closure between α,β-unsaturated aldehydes and
diazoacetates (eq 1) are highly desirable. This is because the
corresponding cyclopropanes contain two or more electron-
withdrawing groups that have the potential to be highly valuable
synthetic intermediates for various applications.8 In addition, this
asymmetric process with α-substituted acroleins results in the
construction of two chiral quaternary stereocenters. This remains
a challenging area, and new procedures are necessary.9 Highly
enantioselective catalytic methods have not been reported to
Received: October 1, 2011
Published: November 07, 2011
r
2011 American Chemical Society
20708
dx.doi.org/10.1021/ja209270e J. Am. Chem. Soc. 2011, 133, 20708–20711
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Asymmetric Cyclopropanation of Methacrolein with
Phenyldiazoacetates Catalyzed by Oxazaborolidinium Ions 1
Table 2. Asymmetric Cyclopropanation of tert-Butyl Phenyldia-
zoacetate with α- or α,β-Substituted Acroleins Catalyzed by 1b
entrya
cat.
R
2
trans:cisb
yield (%)c
ee (%)d
entry
R1, R2
Me, H
2
T (°C), t
trans:cisa yield (%)b ee (%)c
1
2
3
4
5
6
7
1a
1b
1c
1d
1b
1b
1b
Me
Me
Me
Me
Et
2a
2a
2a
2a
2b
2c
2c
89:11
91:9
35
57
35
43
65
63
71
76
84
79
59
87
91
91
1
2d
3d
4
2c À45, 0.5 h
2d À45, 0.5 h
2e À45, 0.5 h
2f À45, 0.5 h
2g À45, 0.5 h
2h À78, 9 h
89:11
88:12
95:5
71
75
52
87
91
64
91
70
51
91
93
90
92
95e
85
92f
82
94
88:12
97:3
Et, H
i-Pr, H
Cl, H
95:5
99:1
t-Bu
91:9
5
Br, H
93:7
t-Bu
89:11
6
Bn, H
Me, Me
Me, Et
86:14
92:8
a Except for entry 7, the reactions were performed with 1.2 equiv of
methacrolein and 1.0 equiv of phenyldiazoacetate at À45 °C for 30 min.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of the trans isomer. d The ee of 2 was determined by
chiral HPLC.
7
2i À20, 20 h
2j À50, 5 days
8g
9g
91:9
À(CH2)4À 2k À20, 5 days
90:10
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield of the trans isomer. c The ee of the trans isomer was
determined by chiral HPLC. d For detailed conditions, see the Support-
ing Information. e The (1S,2R) absolute configuration was determined
enantioselectivity further, the methyl group of the diazoacetate
was replaced by a more sterically hindered ethyl group. The yield
was enhanced to 65% with a diastereomeric ratio of 95:5 and an
enantiomeric excess of up to 87% (entry 5). An increase in
enantioselectivity was observed in the subsequent reaction when
tert-butyl phenyldiazoacete was used, although the diastereos-
electivity decreased slightly and the yield was still moderate
(entry 6). In another experiment under the same conditions and
at À45 °C, the diazoacetate was consumed in 30 min, and the
reaction mixture was then stirred for 8 h at 0 °C.12 The desired
cyclopropane 2c was obtained in a higher yield of 71% and with
similar diastereo- and enantioselectivties without any pyrazolines
(entry 7).
f
by X-ray analysis. The (1R,2S,3S) absolute configuration was deter-
mined by reduction with NaBH4, p-bromobenzoylation, and X-ray
analysis. g Using 40 mol % catalyst.
Table 3. Asymmetric Cyclopropanation of Various Diazoa-
cetates and α-Substituted Acroleins Catalyzed by 1b
entry
R1, R2
2
T (°C), t (h) trans:cisa yield (%)b ee (%)c
After the optimization of the asymmetric cyclopropanation
conditions, the scope of this methodology was investigated using
a range of substituted acroleins with 1b as the catalyst. As
summarized in Table 2, the steric properties of the α-substituents
had different effects on the acroleins. In spite of this, the results
included moderate to good yields, high diastereoselectivities, and
excellent enantioselectivities (entries 1À3). Cyclopropanation
involving electron-deficient olefins is a more challenging
process,1,3,13 but under our catalytic reaction conditions, elec-
tron-deficient olefins bearing electron-withdrawing groups were
more favored. For example, cyclopropanations involving α-
chloro- and α-bromoacrolein produced corresponding halo-
cyclopropanes14 2f and 2g in excellent yields and enantioselec-
tivities with nearly complete control of the diastereoselectivity
(entries 4, 5). Asymmetric cyclopropanation with the benzyl
group also proceeded with good enantiocontrol, although the
yield and diastereocontrol were not as high (entry 6). Absolute
configurations were assigned on the basis of the structure of 2g,
which was confirmed unambiguously by an X-ray crystallo-
graphic study.
1
2
3
4
5
6
7
8
9
Me, 4-BrPh
Br, 4-BrPh
Cl, 4-BrPh
2l
À45, 1
À25, 5
À25, 5
À45, 6
À45, 0.5
À45, 0.5
À45, 0.5
À78, 6
À45, 1
À78, 2
0, 18
80:20
95:5
72
93
89
95
92
90
94
93
95
95
95
95
92
95
95
2m
2n
96:4
93
Me, 2-MePh 2o
92:8
83
Br, 2-MePh
Cl, 2-MePh
Cl, 3-MePh
Cl, 4-MePh
2p
2q
2r
2s
90:10
90:10
92:8
88
87 d
88 d
85
93:7
Cl, 3-MeOPh 2t
90:10
55:45
92:8
87
10 Cl, 4-MeOPh 2u
11 Br, 4-NO2Ph 2v
51 e
71d
85 d
80 d
12 Cl, H
2w
À78, 1
À78, 2
91:9
13 Br, H
2x
91:9
a Determined by 1H NMR analysis of the crude reaction mixture.
b Isolated yield of the trans isomer. c The ee of the trans isomer was
determined by chiral HPLC or GC. d Yield of the trans isomer was
calculated by 1H NMR analysis of the isolated mixture of isomers. e The
cis isomer was obtained in 43% yield with 94% ee.
X-ray crystallographic analysis after transformation of the cyclopro-
pane carboxaldehyde to the corresponding p-bromobenzoyl ester.
Under the optimized conditions, cyclopropanation of 1-cyclohex-
enecarboxaldehyde afforded electrophilic bicyclic cyclopropane8c 2k
with high diastereoselectivity and excellent enantioselectivity,
although in moderate yield (entry 9).
The catalytic asymmetric cyclopropanation of α,β-disubstituted
acroleins was attempted in order to obtain highly functionalized
chiral cyclopropanes containing three stereogenic centers, including
two adjacent quaternary centers. Remarkably, good results were
obtained with α,β-dimethylacrolein (Table 2, entry 7). The stereo-
chemical relationship of 2i was unambiguously established by
20709
dx.doi.org/10.1021/ja209270e |J. Am. Chem. Soc. 2011, 133, 20708–20711

Journal of the American Chemical Society
COMMUNICATION
’ AUTHOR INFORMATION
Corresponding Author
dhryu@skku.edu; gshwang@kbsi.re.kr
’ ACKNOWLEDGMENT
This work was supported by grants NRF-20110031392
(Priority Research Centers Program), NRF-20110002654
(Basic Science Research Program), NRF-20110029186 (Mid-
career Researcher Program) and the Korea Basic Science Insti-
tute(T31409).
Figure 2. Transition state model for the asymmetric cyclopropanation
reaction between tert-butyl phenyldiazoacetate and α,β-disubstituted
acroleins.
Encouraged by the good results demonstrated in Table 2, we
applied this catalytic methodology to the cyclopropanation of
α-substituted acroleins using a range of diazoacetates. As summar-
ized in Table 3, although the electronic properties of the aryl-
diazoacetates15 varied vastly, the reactions produced the corre-
sponding cyclopropanes in high yields and diastereoselectivities
with excellent enantioselectivities (entries 1À9 and 11). It is notable
that the substituents at the α-position of the acrolein were also
electronically different (entries 1À6). The use of 4-methoxyphe-
nyldiazoacetate dramatically diminished the trans:cis ratio to
55:45,7c but high enantiocontrol was still achieved for each isomer
(95% ee for trans, 94% ee for cis; entry 10). Although the reaction
between tert-butyl diazoacetate and methacrolein afforded optically
active 2-pyrazoline10d in the presence of oxazaborolidinium catalyst
1a, the reactions of α-haloacroleins provided the corresponding
cyclopropanes 2w and 2x in high yields with excellent enantioselec-
tivities (entries 12 and 13).
The observed stereochemistry of the asymmetric cyclopropa-
nation using oxazaborolidinium ion catalyst 1b can be explained
by the transition state model shown in Figure 2. The mode of
coordination of the α,β-unsaturated aldehyde to 1b is the same as
that previously shown for enantioselective DielsÀAlder,10a
cyanosilylation,10b and 1,3-dipolar cycloaddition10d reactions.
In the pre-transition-state assembly (4 in Figure 2), the double
bond of the acrolein is situated above the 3,5-dimethylphenyl
group. This effectively shields the re face (back) of the acrolein
from attack by the diazoacetate. Because of the dipoleÀdipole
interaction between the two carbonyl groups, when the diazo-
acetate approaches the β-carbon of acrolein for the 1,4-addition,
the tert-butyl ester group is situated away from the aldehyde
group. Thus, the 1,4-addition of the diazoacetate from the si face
(front) of the acrolein is facilitated, leading to intermediate 5,
which can then cyclize with the loss of nitrogen to form
trans-(1R,2S,3S)-cyclopropane as the major enantiomer for 2i
and trans-(1S,2R)-cyclopropane for 2g.
’ REFERENCES
(1) (a) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (b) Wessjohann,
L. A.; Brandt, W.; Thiemann, T. Chem. Rev. 2003, 103, 1625.
(2) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b)
Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433.
(3) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
Rev. 2003, 103, 977. (b) Pellissier, H. Tetrahedron 2008, 64, 7041.
(4) (a) Caballero, A.; Prieto, A.; Díaz-Requejo, M. M.; Pꢀerez, P. J.
Eur. J. Inorg. Chem. 2009, 1137. (b) Goudreau, S. R.; Charette, A. B.
Angew. Chem., Int. Ed. 2010, 49, 486.
(5) For recent selected examples, see: (a) Zhu, S.; Xu, X.; Perman,
J. A.; Zhang, X. P. J. Am. Chem. Soc. 2010, 132, 12796. (b) Ito, J.-i.; Ujiie,
S.; Nishiyama, H. Chem.—Eur. J. 2010, 16, 4986. (c) Marcoux, D.;
Charette, A. B. Angew. Chem., Int. Ed. 2008, 47, 10155. (d) Zhu, S.;
Perman, J. A.; Zhang, X. P. Angew. Chem., Int. Ed. 2008, 47, 8460. (e)
Suematsu, H.; Kanchiku, S.; Uchida, T.; Katsuki, T. J. Am. Chem. Soc.
2008, 130, 10327. (f) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher,
L.; Fokin, V. V. J. Am. Chem. Soc. 2009, 131, 18034. (g) Marcoux, D.;
Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 6970. (h) Ichinose,
M.; Suematsu, H.; Katsuki, T. Angew. Chem., Int. Ed. 2009, 48, 3121.
(i) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1.
(6) For recent selected examples involved ylides, see: (a) Riches,
S. L.; Saha, C.; Filgueira, N. F.; Grange, E.; McGarrigle, E. M.; Aggarwal,
V. K. J. Am. Chem. Soc. 2010, 132, 7626. (b) Zhu, B.-H.; Zhou, R.; Zheng,
J.-C.; Deng, X.-M.; Sun, X.-L.; Shen, Q.; Tang, Y. J. Org. Chem. 2010,
75, 3454. (c) Appel, R.; Hartmann, N.; Mayr, H. J. Am. Chem. Soc. 2010,
132, 17894. (d) Ochiai, M.; Tada, N.; Okada, T.; Sota, A.; Miyamoto, K.
J. Am. Chem. Soc. 2008, 130, 2118. (e) Sun, X.-L.; Tang, Y. Acc. Chem.
Res. 2008, 41, 937. (f) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.;
Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433. For
recent selected examples involving an organocatalyst, see:(g) Russo, A.;
Meninno, S.; Tedesco, C.; Lattanzi, A. Eur. J. Org. Chem. 2011, 5096. (h)
Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni, G. Chem.—
Eur. J. 2011, 17, 2842. (i) Li, W.; Li, X.; Ye, T.; Wu, W.; Liang, X.; Ye, J.
Tetrahedron Lett. 2011, 52, 2715. (j) Kunz, R. K.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 3240. (k) In Asymmetric Organocatalysis;
List, B., Ed.; Springer: Berlin, 2010. (l) Papageorgiou, C. D.; Cubillo de
Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004,
43, 4641. For related research on Lewis acid catalysts, see:(m) Kakei, H.;
Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2007, 129, 13410.
In summary, the first case of highly enantiocontrolled catalytic
cyclopropanation using diazoacetate as an ylide has been developed.
This method gives highly functionalized tetrasubstituted cyclopro-
panes in high yields with excellent enantioselectivities. The absolute
configuration of the product is that predicted by the transition state
model in Figure 2. We believe that the resulting optically active
electrophilic cyclopropane derivatives with densely functionalized
groups could be highly valuable for further transformations.
(7) (a) Doyle, M. P.; Buhro, W. E.; Dellaria, J. F., Jr. Tetrahedron Lett.
1979, 20, 4429. (b) Branstetter, B.; Hossain, M. M. Tetrahedron Lett.
2006, 47, 221. (c) Hashimoto, T.; Naganawa, Y.; Kano, T.; Maruoka, K.
Chem. Commun. 2007, 5143.
(8) (a) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603. (b)
Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko,
J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
’ ASSOCIATED CONTENT
(9) (a) In Quaternary Stereocenters: Challenges and Solutions in
Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH, Weinheim,
Germany, 2006. (b) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005,
347, 1473. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (d) Cozzi,
S
Supporting Information. Experimental procedures, ana-
b
lytical data, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
20710
dx.doi.org/10.1021/ja209270e |J. Am. Chem. Soc. 2011, 133, 20708–20711

Journal of the American Chemical Society
COMMUNICATION
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969. (e)
Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363.
(10) (a) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100. (b) Ryu,
D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384. (c) Senapati, B. K.;
Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew. Chem., Int. Ed. 2009, 48, 4398.
(d) Gao, L.; Hwang, G.-S.; Lee, M. Y.; Ryu, D. H. Chem. Commun.
2009, 5460. (e) Senapati, B. K.; Gao, L.; Lee, S. I.; Hwang, G.-S; Ryu,
D. H. Org. Lett. 2010, 12, 5088.
(11) The trans geometry means the ester and aldehyde groups are
directed trans to each other in the cyclopropane.
(12) During this process, some 1-pyrazoline 3 was converted to 2c in
stereoselective manner. For decomposition of pyrazolines in a stereo-
selective manner, see: (a) García Ruano, J. L.; Peromingo, M. T.; Martín,
M. R.; Tito, A. Org. Lett. 2006, 8, 3295. (b) García Ruano, J. L.; Alonso de
Diego, S. A.; Martín, M. R.; Torrente, E.; Martín Castro, A. M. Org. Lett.
2004, 6, 4945. (c) Hamaguchi, M.; Nakaishi, M.; Nagai, T.; Tamura, H.
J. Org. Chem. 2003, 68, 9711. (d) Taber, D. F.; Guo, P.; Guo, N. J. Am.
Chem. Soc. 2010, 132, 11179.
(13) (a) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007,
129, 12074. (b) Miller, J. A.; Gross, B. A.; Zhuravel, M. A.; Jin, W.;
Nguyen, S. T. Angew. Chem., Int. Ed. 2005, 44, 3885. (c) Doyle, M. P.;
Forbes, D. C. Chem. Rev. 1998, 98, 911.
(14) For applications of halocyclopropanes, see: (a) Krief, A.;
Dumont, W.; Kremer, A. Tetrahedron Lett. 2009, 50, 2398. (b) Yoshida,
E.; Nagano, T.; Motoyoshiya, J.; Nishii, Y. Chem. Lett. 2009, 38, 1078.
(c) Nagano, T.; Motoyoshiya, J.; Kakehi, A.; Nishii, Y. Org. Lett. 2008,
10, 5453. (d) Carlier, P. R.; Zhang, Y. Org. Lett. 2007, 9, 1319. (e) Wu,
Y.; Vandewalle, M. Synlett 1996, 911. (f) Wichmann, J.; Adam, G. Eur.
J. Org. Chem. 1999, 3131.
(15) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc.
2000, 122, 3063.
20711
dx.doi.org/10.1021/ja209270e |J. Am. Chem. Soc. 2011, 133, 20708–20711