Enantioselective preparation of cis -β-azidocyclopropane esters by cyclopropanation of azido alkenes using a chiral dirhodium catalyst

Article abstract of DOI:10.1021/ol3006437

A diastereo- and enantiocontrolled preparation of the conformationally restricted cis-β-azidocyclopropane esters have been developed. The Rh ₂(S-DOSP)₄ was found to be an efficient catalyst in hexane for the cyclopropanation of azido

Full text of DOI:10.1021/ol3006437

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2246–2249
Enantioselective Preparation of
cis-β-Azidocyclopropane Esters by
Cyclopropanation of Azido Alkenes
Using a Chiral Dirhodium Catalyst
Peiming Gu,*,†,‡ Yan Su,†,‡ Xiu-Ping Wu,† Jian Sun,† Wanyi Liu,† Ping Xue,† and
Rui Li*,†
Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation
Base of Natural Gas Conversion and Department of Chemistry, Ningxia University,
Yinchuan 750021, China, and State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China
gupm@nxu.edu.cn; ruili@nxu.edu.cn
Received March 13, 2012
ABSTRACT
A diastereo- and enantiocontrolled preparation of the conformationally restricted cis-β-azidocyclopropane esters have been developed.
The Rh2(S-DOSP)4 was found to be an efficient catalyst in hexane for the cyclopropanation of azido alkenes with diazo esters, and 19
cis-β-azidocyclopropane esters were prepared in excellent yields. The value of the diastereomer ratio was up to 99:1, and the enantiomeric excess
was up to 95%. Furthermore, the relative and absolute configuration was confirmed by X-ray analysis.
Cyclopropanation of olefins with diazoalkanes in the
presence of metal catalysts has been extensively explored.1
Among the cyclopropanes, the β-N-functionalized cyclo-
propane esters have attracted particular interest from
bio-organic chemists in peptide syntheses.2,3 However,
the most sensitive approach to enantioenriched β-N-
functionalizedcyclopropaneestersbycatalytic asymmetric
cyclopropanation of enamine derivatives with a chiral
dirhodium catalyst could only give poor control of the
relative and absolute configuration.4 In this paper, we
report the first efficient diastereo- and enantioselective
preparation of cis-β-azidocyclopropane esters5 by cyclo-
propanation of azido alkenes with diazo esters using a
chiral dirhodium catalyst (Scheme 1).
Scheme 1. Asymmetric Cyclopropanation of Azido Alkenes
with Diazo Esters
† Ningxia University.
‡ Lanzhou University.
(1) For selected reviews on cyclopropanation of olefins, see: (a)
Pellissier, H. Tetrahedron 2008, 64, 7041–7095. (b) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–1050.
(c) Davies, H. M. L.; Antoulinakis, E. Org. React. 2001, 57, 1–326.
(d) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911–936.
(2) For a review, see: Gnad, F.; Reiser, O. Chem. Rev. 2003, 103,
1603–1623.
(3) For selected recent examples, see: (a) Koglin, N.; Zorn, C.;
Beumer, R.; Cabrele, C.; Bubert, C.; Sewald, N.; Reiser, O.; Beck-
Sickinger, A. G. Angew. Chem., Int. Ed. 2003, 42, 202–205. (b) De Pol, S.;
Zorn, C.; Zerbe, O.; Reiser, O. Angew. Chem., Int. Ed. 2004, 43, 511–514.
(c) Urman, S.; Gaus, K.; Yang, Y.; Strijowski, U.; Sewald, N.; De Pol, S.;
Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 3976–3978.
The β-azidocyclopropane esters incorporating two
stereogenic centers on the ring possess a restricted
(4) (a) Miller, J. A.; Hennessy, E. J.; Marshall, W. J.; Scialdone,
M. A.; Nguyen, S. T. J. Org. Chem. 2003, 68, 7884–7886. (b) Melby, T.;
Hughes, R. A.; Hansen, T. Synlett 2007, 2277–2279. (c) Paulini, K.;
Reissig, H.-U. Liebigs Ann. Chem. 1991, 455–461.
r
10.1021/ol3006437
Published on Web 04/25/2012
2012 American Chemical Society

conformation, and two types of diastereomers (cis and
trans) are derived from the orientations of the azido and
carboxyl groups. The synthesis of β-azidocyclopropane
esters must address diastereoselectivity as well as enantios-
electivity. We are more interested in the cis-β-azidocyclo-
propane esters as they could be regarded as precursors of
cis-β-aminocyclopropane carboxylic acids (cis-β-ACCs),
which were widely used in peptide syntheses.3 Further-
more, the β-azidocyclopropane esters have two potential
chelating groups oriented in the same direction, offering
the possibility of chiral ligand design.
enantioselectivities were observed when R-substituted styr-
enes were used for the cyclopropanation.8
To test our proposal, the first attempt to attain the cis-
β-azidocyclopropane ester employed the cyclopropana-
tion of the benzyl diazophenylacetate (BnDPA) 1a and
R-azido-styrene 2a (Table 1). Several commercially avail-
able chiral dirhodium catalysts were screened (Table 1,
entries 1À4). Among them, Rh2(S-DOSP)4 and Rh2
(S-PTAD)4 gave positive results in hexane. The Rh2
(S-DOSP)4-catalyzed (0.2 mol %) cyclopropanation
of diazo ester 1a in the presence of azido alkene 2a
(5 equiv) at room temperature afforded the cis-β-azidocy-
clopropane ester 3aa in 79% yield (entry 3), and the dia-
stereoselectivity (96:4 dr) as well as the enantioselectivity
(85% ee) were controlled. The product from the Rh2(S-
PTAD)4-catalyzed reaction was obtained in an even higher
yield (89%) and enantioselectivity (89% ee); however,
the diastereoselectivity (83:17 dr) was imperfect (entry 4).
It should be noted that opposite enantioselectivity
was observed in this case, and a similar situation was
reported by Davies’s group with the cyclopropanation of
4-chlorostyrene withR-aryl-R-diazoketone.9 Further experi-
ments using Rh2(S-DOSP)4 and Rh2(S-PTAD)4 in hexane
at À5 °C revealed that Rh2(S-DOSP)4 was better than Rh2
(S-PTAD)4 (entry 5 vs 6). The yield of 3aa was improved to
95%, and the diastereoselectivity (98:2 dr) and enantio-
selectivity (89% ee) were slightly increased. If the tem-
perature was lowered (À10 °C), insolubility of diazo
ester 1a took place. After the catalyst was identified as
Rh2(S-DOSP)4, various solvents including diethyl ether,
toluene, DCM, and THF were investigated at À5 °C
(entries 7À10); however, no better results could be obtained
than that in hexane.
The asymmetric cyclopropanation of N-protected
enamines gave trans-β-aminocyclopropane esters in poor
diastereo- and enantioselectivities using chiral dirhodium
catalysts.4 Moreover, the attempted cyclopropanation of a
Boc-protected enamine by Doyle’s catalyst led to no
conversion.4a As prior solvents for many cyclopropana-
tions with rhodium catalysts were hydrocarbons, we con-
sidered that the low yields and diastereoselectivities as well
as enantioselectivities for the cyclopropanation of the
N-protected enamines with the diazo esters by chiral
dirhodium catalysts might be due to the following situa-
tions: the steric hindrance from the protection group, the
nucleophilicity of the protected-enamine nitrogen, and
poor solubility of the protected enamine in hydrocarbons.
The azido group was smaller than the protected-amino
group, and it generally showed weak nucleophilicity when
it existed in organic azide under neutral conditions.6 More-
over the alkyl azide was revealed to be better incorporated
with hydrocarbon solvents than protected enamine. With
this in mind, we envisioned that the azido alkenes would be
more suitable substrates than the protected-enamine ana-
logues for stereocontrolled cyclopropanation, which
would generate high enantioenriched β-N-functionalized
cyclopropane esters. In order to attain the more confor-
mationally restricted β-azidocyclopropane esters, we decided
to install two quaternary carbons on the cyclopropane ring.
One of the quaternary carbons was designed to attach to the
carbonyl group, and the other one was bound to the azido
nitrogen. The cis-β-azidocyclopropane esters would be
obtainedwhenR-azido-styrene analogueswereused, asthe
ester was the directing group in the cyclopropanation. For
the preparation of the enantioenriched β-azidocyclopropane
esters to be successful, there were two central issues to be
addressed: (1) could the azido alkenes be suitable for
cyclopropanation as no such alkenes were employed
previously;7 (2) would the cyclopropanation proceed in
a good stereocontrolled manner in the presence of a
chiral dirhodium catalyst, as poor diastereo- and
Table 1. Optimization of the Cyclopropanationa of 1a and 2a
t
yieldb
(%)
drc
eed
(%)
entry
Rh
solvent
(°C)
(c:t)
1
A
B
C
D
C
D
C
C
C
C
hexane
hexane
hexane
hexane
hexane
hexane
Et2O
rt
61
96:4
67:33
96:4
83:17
98:2
83:17
99:1
95:5
87:13
À
83
82
85
89
89
85e
78
81
52
À
2
rt
83
3
rt
79
4
rt
89
5
6
À5
À5
À5
À5
À5
À5
95
32
7
63
8
toluene
DCM
THFf
87
9
80
10
trace
(5) For the preparation of racemic β-azidocyclopropane esters in
moderate yield by the Michael initiated ring closure reaction, see: (a)
Mangelinckx, S.; Kimpe, N. D. Synlett 2006, 369–374. (b) Su, J.; Qiu, G.;
Liang, S.; Hu, X. Synth. Commun. 2005, 35, 1427–1433.
(6) The azido group shows nucleophilicity under acidic conditions;
ꢀ
for a selected example, see: Aube, J.; Milligan, G. L. J. Am. Chem. Soc.
a Cyclopropanation of diazo ester 1a (0.2 mmol) and azido alkene
2a (1.0 mmol) in the presence of chiral dirhodium catalyst (0.0004
mmol) for 3 h under the conditions mentioned in the table. b Isolated
yield after purification. c Determined from the crude reaction mixture
by 1H NMR. d Determined by chiral HPLC. e Enantioselectivity of
the product was observed to be opposite to that of other catalysts.
f Trace product was obtained after 24 h.
1991, 113, 8965–8966.
(7) We had examined the cyclopropanation of 2-nitroethenylbenzene
with various diazo esters using many dirhodium catalysts but failed to
obtain any desired β-nitrocyclopropane ester.
Org. Lett., Vol. 14, No. 9, 2012
2247

With the optimal conditions established above (in bold,
Table 1), the scope of diazo esters was explored (Table 2).
The cyclopropanations of the azido alkene 2a with the
analogues of the diazophenylacetate (1bÀ1i) were investi-
gated. In all cases, the diastereoselectivities of the reaction
were well controlled (>90:10 dr). First, three diazophenyl-
acetates 1bÀ1d were examined (entries 1À3). Ethyl diazo-
phenylacetate 1b gave better control in enantioselectivity
than diazo ester 1a (91% vs 89% ee), but the yield (82% vs
95%) and diastereoselectivity (90:10 vs 98:2 dr) decreased.
Introduction of para-substituents on the benzyl group
effected little change in the diastereoselectivity (entries 2
and 3), and 4-bromobenzyl diazophenylacetate 1c could
maintain the yield (92%) and improve the enantioselectivity
(95% ee), while methoxybenzyl diazophenylacetate 1d
caused a drop in yield (84%) and maintained the enantio-
selectivity (90% ee). The relative and absolute configura-
tion10 of 3ca was assigned to be (1R,2S) by X-ray crystal-
lographic analysis (Figure 1). Further experiments focused
on modification of the aromatic ring neighboring a diazo
unit (entries 4 and 5).
Reaction of diazo 4-bromophenyl acetate 1e resulted in
comparable diastereoselectivity (99:1 dr) and enantioselec-
tivity (91% ee) but gave cyclopropane in a slightly lower
yield (86%, entry 4). Cyclopropanation of diazo 4-meth-
oxyphenyl acetate 1f delivered cyclopropane 3fa in 99%
yield (entry 5) with good diastereoselectivity (95:5 dr), but
the enantioselectivity (75% ee) was affected. Because the
4-bromobenzyl diazo ester resulted in good enantioselec-
tivity for cyclopropanation compared to that of benzyl
diazo ester(entry 2 vs3), diazoester1gwas expected to give
a better enantiocontrolled cyclopropane than that of 1f,
which did occur (92% vs 75% ee, entry 6 vs 5). An even
higher enantioselectivity was expected by employing diazo
ester 1h, and a comparable stereocontrolled cyclopropana-
tion (99:1 dr, 93% ee) was obtained (entry 7). The naph-
thalene analogue 1i was also examined but did not give a
better result (entry 8).
Table 2. Scope of Diazo Esters in the Cyclopropanationa
yield
(%)b
ee
entry
1
diazo ester
1b Ar = Ph;
product
drc
(%)d
3ba
82
90:10
91
95
90
91
75
92
93
85
R = Et
2
3
4
5
6
7
8
1c Ar = Ph;
3ca
3da
3ea
3fa
92
84
86
99
70
97
91
99:1
99:1
99:1
95:5
99:1
99:1
94:6
R = 4-Br-Bn
1d Ar = Ph;
R = 4-OMe-Bn
1e Ar = 4-Br-C6H4;
R = Bn
1f Ar = 4-OMe-C6H4;
R = Bn
1g Ar = 4-Br-C6H4;
R = 4-OMe-Bn
1h Ar = 4-Br-C6H4;
R = 4-Br-Bn
1i Ar = Naphth;
R = Bn
3ga
3ha
3ia
a Cyclopropanation of azido alkene 2a (1.0 mmol) with diazo ester 1x
(0.2 mmol) in the presence of Rh2(S-DOSP)4 (0.7 mg, 0.0004 mmol) for
3 h in hexane at À5 °C. b Isolated yield after purification. c Determined
from the crude reaction mixture by 1H NMR. d Determined by chiral
HPLC.
A series of azido alkenes 2bÀ2f were investigated for
asymmetric cyclopropanation with diazo ester 1a and 1h
(Table 3). In all cases, the azido alkenes underwent asym-
metric cyclopropanation with high diastereoselectivities.
Generally, the cyclopropanesfrom theazido alkenesand
diazo ester 1a were obtained in better yields than that of
diazo ester 1h. The enantioselectivities were also well
controlled for different kinds of alkenes besides the 4-cya-
nophenyl alkene 2e (entries 7 and 8). The poor enantio-
selectivities for the reactions of alkene 2e partly resulted
from the poor solubility in hexane at À5 °C, which agreed
with our assumption on the poor enantioselectivity in the
Figure 1. X-ray crystal structure of 3ca.
cyclopropanation of protected enamines above. Finally,
the reactions were conducted at room temperature, which
might affect the selectivities.
The gram-scale cyclopropanation of alkene 2d with
diazo ester 1a at rt for 17 h gave cyclopropane 3ad in the
same yield and with similar diastereoselectivity when com-
pared withthat of the general scale reaction atÀ5 °C, while
the enantioselectivity was slightly lower (86% vs 92%).
The gram-scale reaction required a longer reaction time
(8) (a) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007,
72, 5931–5934. (b) Shltama, H.; Katsuki, T. Chem.;Eur. J. 2007, 13,
4849–4858. (c) Uchida, T.; Katsuki, T. Synthesis 2006, 1715–1723. (d)
Huber, D.; Mezzetti, A. Tetrahedron: Asymmetry 2004, 15, 2193–2197.
(e) Berkessel, A.; Kaiser, P.; Lex, J. Chem.;Eur. J. 2003, 9, 4746–4756.
(f) Davies, H. M. L.; Nagashima, T.; Klino, J. L., III. Org. Lett. 2000, 2,
823–826.
(9) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787–790.
(10) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897–6907.
2248
Org. Lett., Vol. 14, No. 9, 2012

In conclusion, we have designed and realized a practical
diastereo- and enantiocontrolled preparation of confor-
mationally restricted cis-β-azidocyclopropane esters. The
reaction conditions were investigated, and Rh2(S-DOSP)4
was proven to be an efficient promoter in hexane at À5 °C.
The scopes of the diazo esters and azido alkenes were
explored, and 19 cis-β-azidocyclopropane esters were pre-
pared in excellent yields. The stereoselectivities were well
controlled, the value of the diastereomer ratio was up to
99:1, and the enantiomeric excess was up to 95%. Cur-
rently, extensive conversion of the β-azidocyclopropane
esters and application of the cyclopropanes in synthesis of
constrained peptides and natural products are underwayin
our laboratory.
Table 3. Scope of Azido Alkenes in the Cyclopropanationa
entry
azido alkene
prod
yieldb
drc
eed
91
1
2
3
4
5
2b Ar = 4-Br-C6H4
3ab
3hb
3ace
3hce
3ad
99
68
90
99
92
(92)f
76
97
80
99
99
99:1
94:6
99:1
96:4
96:4
(96:4)f
97:3
93:7
95:5
95:5
95:5
2b
88
91
90
92
(86)f
90
85
73
90
93
2c Ar = 4-OMe-C6H4
2c
2d Ar = 4-F-C6H4
Acknowledgment. This work was supported by the Key
Project of Chinese Ministry of Education (211193), the 100
Talents Program of Ningxia, the Natural Science Founda-
tion of Ningxia (NZ1043 and NZ1165), the National Basic
Research Program 973 of China (No. 2010CB534916), and
the “211” Project in Ningxia University (ndzr09-1).
6
2d
3hd
3aeg
3heg
3af
7
2e Ar = 4-CN-C6H4
8
2e
9
2f Ar = Naphth
10
2f
3hf
a Cyclopropanation of azido alkene 2y (1.0 mmol) with diazo ester 1a
or 1h (0.2 mmol) in the presence of Rh2(S-DOSP)4 (0.7 mg, 0.0004 mmol)
for 3 h in hexane at À5 °C. b Isolated yield after purification. c Determined
from the crude reaction mixture by 1H NMR. d Determined by chiral
HPLC. e Cyclopropanation of azido alkene 2c completed in 12 h. f Gram-
scale cyclopropanation at rt. g Cyclopropanation at rt.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for the reaction products
and X-ray crystallographic data for compound 3ca. This
material is available free of charge via the Internet at
http://pubs.acs.org.
and high temperature to complete, which might slightly
decrease the enantioselectivity.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
2249