Synthesis of cyclopropane-containing building blocks via Ir-catalyzed enantioselective allylic substitution reaction

Article abstract of DOI:10.1002/cjoc.201090259

Chiral cyclopropane-containing building blocks, which are very important synthetic intermediates for natural products or pharmaceuticals, were easily synthesized via Ir-catalyzed enantioselective allylic substitution reaction.

Full text of DOI:10.1002/cjoc.201090259

COUMMUNICATION
Synthesis of Cyclopropane-containing Building Blocks via
†
Ir-Catalyzed Enantioselective Allylic Substitution Reaction
Xia, Jibao(夏纪宝)
Zhuo, Chunxiang(卓春祥)
You, Shuli(游书力)
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
Chiral cyclopropane-containing building blocks, which are very important synthetic intermediates for natural
products or pharmaceuticals, were easily synthesized via Ir-catalyzed enantioselective allylic substitution reaction.
Keywords iridium, asymmetric catalysis, allylic alkylation, allylic amination, regioselectivity
Introduction
Scheme
1
Synthesis of cyclopropane-containing II via
Ir-catalyzed asymmetric allylic substitution reaction
Cyclopropane subunit occurs in many pharmaceuti-
cals and natural products that show bioactivities. For
1
example, chromene-typed compound A, which bears a
cycolpropyl group, has been reported to have submi-
cromolar activities against pathogenic microorganisms
such as Staphylococcus aureus and Pseudomonas
demonstrated the cyclometallated iridium as the active
catalytic species. With this catalytic system, we envis-
2
carinii (Figure 1). Recently, a series of cyclopropane-
8
containing corticotropin-releasing factor-1 (CRF1) re-
ceptor antagonists, which showed important biological
aged that the use of (E)-3-cyclopropylallyl methyl car-
bonate 1 as substrate could afford the enantioenriched
cyclopropane-containing compounds II with XH as
versatile nucleophiles (Scheme 1). Herein, we report our
studies on the Ir-catalyzed enantioselective synthesis of
cyclopropane-containing compounds II, which are very
useful building blocks for construction of complicated
molecules.
The Ir-catalyzed enantioselective allylic alkylation
of sodium dimethyl malonate to methyl carbonate 1 was
first investigated. Excellent regioselectivity (91/9) and
enantioselectivity (95% ee) were obtained using ligand
L1 (Table 1, Entry 1). Superior results were obtained
when ligand L2 was used. The branched alkylation
product 2a was obtained in 90% isolated yield with im-
proved regioselectivity (96/4) and excellent enantiose-
lectivity (99% ee) (Table 1, Entry 2). Under the modi-
fied conditions, sodium diethyl malonate and sodium
diisopropyl malonate were also investigated and good
results were obtained (Table 1, Entries 3 and 4). In the
case of product 2c, the ee value was underestimated due
to the difficulty in chiral HPLC separation.
3
activities, were synthesized by Bristol-Myers Squibb.
Consequently, the synthesis of enantiopure cyclopro-
pane-containing compounds I is highly desirable
(
Scheme 1). The enantiopure I (X＝NH
2
or NHBn)
4
could be obtained by resolution. Alternatively, there
were reports on the synthesis of enantiopure I (X＝NH
2
)
5
employing chiral auxiliary. To our knowledge, the
catalytic asymmetric methods for the synthesis of enan-
tiopure cyclopropane-containing compounds I are rare.
Figure
1
Cylcopropane-containing biologically important
compounds.
Results and discussion
Next, the Ir-catalyzed enantioselective allylic amina-
9
tion of phthalimide was investigated. Several bases
Ir-catalyzed asymmetric allylic substitution reactions
6
,7
were investigated based on previous optimal conditions
have been studied extensively in the past decade. Re-
(
Table 2, Entries 1—3). The highest ee of 95% was ob-
cently, studies by Hartwig et al. and Helmchen et al.
*
E-mail: slyou@mail.sioc.ac.cn
Received August 12, 2010; revised and accepted August 23, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20872159, 20821002, 20923005) and National Basic Research Pro-
gram (973) of China (No. 2010CB833302).
†
Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
Chin. J. Chem. 2010, 28, 1525— 1528
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1525

Xia, Zhuo & You
COMMUNICATION
1
0
Table 1 Ir-catalyzed asymmetric allylic alkylation
Employing Han’s reaction conditions, allylic amina-
tion product 6 was obtained in 67% yield with good
regioselectivity (83/17) and enantioselectivity (97% ee)
(
Table 3, Entry 5).
Table 3
di-tert-butyl iminodicarbonate
Ir-catalyzed asymmetric allylic amination with
a
c
b
c
d
Entry
R
L t/h Conv. /%
2
Yield /% 2/3 ee /%
1
2
3
Me L1 48
Me L2 48
88
＞99
＞99
96
2a
2a
2b
2c
86
90
92
86
91/9 95
96/4 98
97/3 98
95/5 ＞86
c
d
c
e
Entry L DBU/equiv. T/℃ t/h Conv. /% Yield /% 6/7 ee /%
Et
L2 12
b
1
2
3
4
5
L1
L2
L2
L2
L2
1
1
1
1
r.t. 72 ＜5
—
37
—
40
—
—
—
—
—
4
i-Pr L2 24
b
r.t. 48
50 48
r.t. 48
52
73
67
92/8
a
－
1
1
(0.2 mol•L ) in THF with the following molar ratio: n(1)∶
b
88/12
87/13
n(NaCH(CO R) )∶n([Ir(cod)Cl] )∶n(L)＝1∶1.5∶0.02∶0.04.
2
2
2
b
c
1
Isolated yield of 2. Determined by H NMR of the crude reac-
d
tion mixture. Determined by chiral HPLC analysis.
0.2
50
5
＞99 67 (10) 83/17 98
a
－
1
1
(0.2 mol•L ) in THF with the following molar ratio: n(1) ∶
tained using DBU as base, although the reaction was
sluggish at room temperature (Table 2, Entry 3). This
issue was successfully addressed when the reaction was
carried out at 50 ℃ (Table 2, Entry 5). The allylic
amination product 4 was obtained in 77% yield with
good regioselectivity (85/15) and excellent enantiose-
lectivity (97% ee).
b
n(NuH)∶n([Ir(cod)Cl] )∶n(L)＝1∶1.2∶0.02∶0.04. The
2
c
1
precatalyst was activated with n-PrNH . Determined by
H
2
d
NMR of the crude reaction mixture. Isolated yield of 6, the
number in the parenthesis indicates the yield of linear product 7.
e
Determined by chiral HPLC analysis after transformed into 8.
Selective deprotection of one Boc group of 6 was
2 2
accomplished upon the treatment with TFA in CH Cl
(Scheme 2). The N-Boc protected product 8 was ob-
tained in 99% yield with 98% ee. Compound 8 was then
Table 2
phthalimide
Ir-catalyzed asymmetric allylic amination with
a
2
readily hydrogenated with TsNHNH in refluxed DME
to afford compound 9 in good yield without notable loss
of optical purity.
Scheme 2
b
c
b
d
Entry Base
T/℃ t/h Conv. /% Yield /% 4/5 ee /%
1
2
3
4
5
Et
3
N
r.t. 74
79
43
5
84/16 93
DABCO r.t. 48
DBU r.t. 48
DABCO 50
DBU 50 12
＜10
14
—
—
90
95
5
2
＞99
79
84/16 84
＞99
77 (11) 85/15 97
a
－
1
1
(0.2 mol•L ) in THF with the following molar ratio: n(1)∶
n(NuH)∶n([Ir(cod)Cl] )∶n(L2)∶n(base)＝1∶1.2∶0.02∶
To explore the synthetic utility, the enantiopure
N-Boc protected 8 was converted to its corresponding
2
b
1
0
.04∶1. Determined by H NMR of the crude reaction mixture.
c
Isolated yield of 4, the number in the parenthesis indicates the
α-amino acid through oxidative cleavage by RuCl
3
and
d
yield of linear product 5. Determined by chiral HPLC analysis.
NaIO . The crude α-amino acid was then directly trans-
4
formed into the corresponding ester 10 using
Ir-catalyzed enantioselective allylic amination of
TMSCHN in mixed solvent of benzene and methanol
2
di-tert-butyl iminodicarbonate was also investigated.
(Scheme 3).
1
526
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Chin. J. Chem. 2010, 28, 1525— 1528

Synthesis of Cyclopropane-containing Building Blocks
Scheme 3
and (E)-3-cyclopropylallyl methyl carbonate 1 (78.1 mg,
.50 mmol) were added. Then, the freshly prepared so-
0
dium dimethyl malonate (0.75 mmol in 2 mL THF) was
added. The reaction was stirred at room temperature
until the carbonate was fully consumed, monitored by
1
TLC or H NMR. Then the crude reaction mixture was
2 2
filtrated through a pad of celite and washed with CH Cl ,
the solvent was removed under reduced pressure. The
ratio of regioisomers (branched to linear) was deter-
1
mined by H NMR of the crude reaction mixture. The
crude residue was purified by flash column chromatog-
raphy (ethyl acetate/petroleum ether) to afford the de-
sired branched allylic product 2.
Conclusions
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In conclusion, cyclopropane-containing enantiopure
compounds were easily synthesized via Ir-catalyzed
asymmetric allylic substitution reaction. These allylic
substitution products have been demonstrated important
synthetic intermediates.
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