Catalytic asymmetric 1,3-dipolar cycloaddition of nitrones to alkylidene malonates: Highly enantioselective synthesis of multisubstituted isoxazolidines

Article abstract of DOI:10.1002/chem.201100053

All under control! A catalytic asymmetric 1,3-dipolar cycloaddition reaction of nitrones to alkylidene malonates, catalyzed by chiral N,N'-dioxide-Ni(ClO₄)₂.6 H₂O complexes, has been developed with excellent yields, diaste

Full text of DOI:10.1002/chem.201100053

DOI: 10.1002/chem.201100053
Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Nitrones to Alkylidene
Malonates: Highly Enantioselective Synthesis of Multisubstituted
Isoxazolidines
Donghui Chen, Zhen Wang, Jiangting Li, Zhigang Yang, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*[a]
The asymmetric 1,3-dipolar cycloaddition reaction is one
of the most powerful methods for the synthesis of enantio-
merically enriched five-membered heterocyclic com-
pounds.[1] In particular, the catalytic asymmetric nitrone–
alkene cycloaddition reaction has received a great deal of
attention because most nitrones are stable compounds that
do not require an in situ formation compared with many
other 1,3-dipoles. Furthermore, the corresponding isoxazoli-
dines are particularly useful synthetic intermediates for vari-
ous natural products,[2] in which they are the framework of
many biologically active compounds, such as antifungal,[3]
anti-tuberculosis,[4] and antiviral agents .[5] Since the pioneer-
and challenging to expand the scope and usage of the reac-
tion. Herein, we report a highly enantioselective [3+2] cy-
cloaddition of nitrones to alkylidene malonates catalyzed by
a chiral N,N’-dioxide–NiACHTUNGRTNEUNG(ClO4)2·6H2O complex in good
yield with excellent diastereo- and enantioselectivity
(Scheme 1).
Scheme 1. Chiral N,N’-dioxides used in the cycloaddition reaction.
Initially, the asymmetric 1,3-dipolar cycloaddition of di-
ethyl 2-benzylidenemalonate (1a) and C,N-diphenylnitrone
(2a) was catalyzed by N,N’-dioxide–metal complexes, which
have shown high levels of enantiocontrol in many reac-
tions.[15] The primary metal-screening was performed with
L1 and the results are listed in Table 1. The L1–MgACHTUNGTRENNUNG(ClO4)2
complex offered high activity and good diastereoselectivity
but unsatisfactory enantioselectivity (Table 1, entry 1). Co-
AHCTUNGTREN(GNUN ClO4)2·6H2O provided considerable enantioselectivity when
it coordinated with L1, whereas the yield and diastereoselec-
tivity were very low (Table 1, entry 2). However, the combi-
ing works of Scheeren[6] and Jørgensen in 1994,[7] chiral
metal complexes[8–12] as well as organic catalysts[13] have
been successfully developed for the catalytic asymmetric
1,3-dipolar cylcloaddition of nitrones to alkenes. Neverthe-
less, the alkene part was always limited to N-alkenoyl
amides and generally a high catalyst loading was necessary.
On the other hand, alkylidene malonate, which easily under-
goes activation by bidentate coordination to various metal
ions,[14] was rarely utilized as a dipolarphile in the catalytic
asymmetric 1,3-dipolar cycloaddition.[12g] Therefore, the
search for more efficient catalyst systems is still desirable
nation of N,N’-dioxide L1 with NiACTHUNGTRNEG(UN ClO4)2·6H2O provided an
efficient catalyst system to afford the desired product in
91% yield with 93:7 diastereomeric ratio (d.r.) and 92%
enantiomeric excess (ee) (Table 1, entry 3). Encouraged by
these results, we modified the complex with different nickel
salts and found that the activity of the reaction was heavily
dependent on the counterion. For example, Ni
NiCl2 did not promote the reaction at all (Table 1, entries 4
and 5), therefore, Ni(ClO4)2·6H2O was chosen as the pre-
ACHTUNGTNER(NUNG acac)2 or
AHCTUNGTRENNUNG
[a] D. Chen, Z. Wang, J. Li, Z. Yang, Dr. L. Lin, Dr. X. Liu,
Prof. Dr. X. Feng
catalyst. Next, our attention was turned to the structure of
the chiral N,N’-dioxide ligands (Scheme 1). Disappointingly,
when bulky ligands L2 (with a 2,6-diisopropylphenyl group)
or L3 (with a tert-butyl group) were utilized instead of the
phenyl group on the amide moiety, the diastereoselectivity
decreased drastically, whereas L3 gave a good ee value but
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100053.
L2 gave
a low value and reversed enantioselectivity
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Chem. Eur. J. 2011, 17, 5226 – 5229

COMMUNICATION
Table 1. Screening of metals and ligands for the catalytic asymmetric 1,3-
Table 2. Scope of alkylidene malonates in the catalytic asymmetric 1,3-
dipolar cycloaddition of 2a to 1a.[a]
dipolar cycloaddition with 2a.[a]
Entry R1
R2 Product t [h] Yield [%][b] d.r.[c] ee [%][c]
Entry Ligand Metal
Yield
[%][b]
d.r.[c] (exo/
endo)
ee [%][c,d]
(exo)
1
2
3
4
Ph
Ph
Ph
Ph
Ph
Et
3aa
45 94
64 89
70 86
94 72
20 83
24 99
24 91
45 86
48 94
80 86
45 80
102 86
96 46
40 84
93:7
96:4
97:3
99:1
99:1
99:1
98:2
95:5
97:3
96:4
99
97
99
99
95
96
97
99
98
97
Me 3ba
iPr 3ca
tBu 3da
Bn 3ea
1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L6
Mg
Co
Ni
[Ni
NiCl2
(ClO4)2
98
94:6
58:42
93:7
–
58
81
92
–
–
À29
93
2
N
3
N
4
N
n.r.[e]
n.r.[e]
5
6
pNO2C6H4 Et
3 fa
3ga
3ha
3ia
5
–
7
8
9
pBrC6H4
mClC6H4
pClC6H4
Et
Et
Et
6
7
8
9
10
11
12
13[f]
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
N
44:56
58:42
96:4
48:52
94:6
91:9
77:23
93:7
60
10
11
12
13
14
pMeOC6H4 Et
pMeC6H4 Et
2-naphthyl Et
2-thienyl Et
cyclohexyl Et
3ja
3ka
3la
3ma
3na
À37
90:10 99
99
94:6
92:8
97
97
99
98
87:13 83
99 (3S,5S)
[a] Reaction conditions: nitrone 2a (0.15 mmol), N,N’-dioxide L6
(2.4 mg, 0.0055 mmol), and Ni(ClO4)2·6H2O (1.8 mg, 0.005 mmol) in
CH2Cl2 (0.5 mL) were placed in a dry tube and stirred at 308C for 1.0 h,
then alkyl benzylidenemalonate 1 (0.1 mmol) was added. [b] Yield of iso-
lated product. [c] Determined by HPLC analysis.
[a] Reaction conditions: nitrone 2a (29.6 mg, 0.15 mmol), N,N’-dioxide L
(0.012 mmol), and metal (0.01 mmol) in CH2Cl2 (0.5 mL) were placed in
a dry tube and stirred at 308C for 1.0 h, then dialkyl benzylidenemalo-
nate 1a (24.8 mg, 0.1 mmol) was added. [b] Yield of isolated product.
[c] Determined by HPLC analysis; the absolute configuration was deter-
mined to be (3S, 5S) by comparison with the optical rotation values in
the literature.[12g] [d] The ee value of exo-3aa. [e] No reaction. [f] Ni-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(ClO4)2·6H2O (5 mol%) and L6 (5.5 mol%) were used and the reaction
was stirred for 45 h.
hexylmethylene malonate is also a suitable substrate for the
cycloaddition reaction with high yield and enantioselectivity
(Table 2, entry 14).
Next, the scope of the nitrones was investigated (Table 3).
When the substituent R2 on the nitrogen atom was changed
from a phenyl group to a methyl or a benzyl group, high
enantio- and diastereocontrol were observed, but the yields
decreased dramatically, even when the reaction time was
prolonged to more than four days (Table 3, entries 1 and 2).
However, the electronic character and the position of the
(Table 1, entries 6 and 7). However, the following ligand
screening indicated that (S)-pipecolic acid was a superior
skeleton than l-proline and L6 was found to be the best
chiral ligand for the cycloaddition reaction, which gave the
product in 98% yield, with 94:6 d.r. and 99% ee (Table 1,
entries 8–12). Notably, the amount of the L6–nickel(II) com-
plex could be reduced to 5 mol% without any significant
change in results (Table 1, entry 13). Therefore, the best re-
Table 3. Scope of nitrones in the catalytic asymmetric 1,3-dipolar cyclo-
sults were achieved by using the L6–Ni
ACHTUGNTRNE(UNNG ClO4)2·6H2O com-
addition with 1a.[a]
plex (5 mol%; molar ratio L6/Ni(ClO4)2·6H2O (1.1:1.0)), ni-
AHCTUNGTRENNUNG
trone (0.15 mmol), and alkylidiene malonate (0.1 mmol) in
CH2Cl2 (0.5 mL) at 308C.
Under the optimal reaction conditions, the scope of the
dipolarophiles was first examined for the catalytic asymmet-
ric 1,3-dipolar cycloaddition reaction (Table 2). The ester
group of the alkylidene malonates had a slight effect on the
diastereo- and enantioselectivities (Table 2, entries 1–5).
Even when R2 was a bulky tBu group, up to 99:1 d.r. and
99% ee could still be obtained, despite the decreased cata-
lytic activity (Table 2, entry 4). Additionally, alkylidene mal-
onates with either an electron-withdrawing or electron-do-
nating substituent on the aromatic ring in the R1 group
could be converted to the corresponding isoxazolidine deriv-
atives in good yields with up to 99:1 d.r. and up to 99% ee
(Table 2, entries 6–11). It was notable that the system dem-
onstrated good tolerance to fused-ring and heteroaromatic
substrates (Table 2, entries 12 and 13). Additionally, cyclo-
Entry R1
R2 Product t [h] Yield [%][b] d.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Me 3ab
Bn 3ac
104 54
104 71
48 80
48 83
48 96
40 80
48 86
40 85
>99:1 94
>99:1 97
99:1 99
95:5 98
97:3 98
99:1 97
97:3 97
97:3 99
oNO2C6H4 Ph 3ad
pBrC6H4
pFC6H4
pMeOC6H4 Ph 3ag
pMeC6H4 Ph 3ah
2-naphthyl Ph 3ai
Ph 3ae
Ph 3af
[a] Reaction conditions: nitrone 2 (0.15 mmol), N,N’-dioxide L6 (2.4 mg,
0.0055 mmol), and Ni(ClO4)2·6H2O (1.8 mg, 0.005 mmol) in CH2Cl2
(0.5 mL) were placed in a dry tube and stirred at 308C for 1.0 h, then di-
ethyl benzylidenemalonate 1a (0.1 mmol) was added. [b] Yield of isolat-
ed product. [c] Determined by HPLC analysis.
AHCTUNGTRENNUNG
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X. Feng et al.
substituent on the phenyl group in R1 had no obvious effects
on the activity, diastereo- and enantioselectivity, and various
optically pure isoxazolidines could be achieved in good
yields (Table 3, entries 3–7). Moreover, a fused-aromatic-
ring-containing nitrone also exhibited excellent diastereo-
and enantioselectivity in good yield (Table 3, entry 8).[16]
Acknowledgements
We acknowledge the National Natural Science Foundation of China
(Nos. 20732003 and 21021001), and the National Basic Research Program
of China (973 Program: No 2011CB808600) for financial support. We
also thank the Sichuan University Analytical & Testing Center for NMR
analyses and the State Key Laboratory of Biotherapy for HRMS analy-
ses.
Based on the experiments and previous reports,[14c,15i]
a
possible transition state was proposed to elucidate the origin
of the asymmetric stereoselectivity. As shown in Scheme 2,
Keywords: asymmetric
catalysis
·
cycloaddition
·
diastereoselectivity · enantioselectivity · nickel
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Experimental Section
Typical experimental procedure: Nitrone 2a (29.6 mg, 0.15 mmol), N,N’-
dioxide L6 (2.4 mg, 0.0055 mmol), and NiACTHUNTGRNEG(UN ClO4)2·6H2O (1.8 mg,
0.005 mmol) in CH2Cl2 (0.5 mL) were placed in a dry tube and stirred at
308C for 1h. Next, diethyl benzylidenemalonate 1a (24.8 mg, 0.1 mmol)
was added and the process was monitored by TLC. After 1a had disap-
peared, the reaction mixture was purified by flash chromatography (pe-
troleum ether/ethyl acetate=25:1) on silica gel to afford the desired
product as a white solid in 94% yield, 93:7 d.r., and 99% ee.
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Highly Enantioselective Synthesis of Multisubstituted Isoxazolidines
COMMUNICATION
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[16] C-Cyclohexyl-N-phenylnitrone was also examined (the product was
obtained in 24% yield, with 86:14 d.r. and 77% ee).
Received: January 6, 2011
Revised: February 26, 2011
Published online: April 5, 2011
Chem. Eur. J. 2011, 17, 5226 – 5229
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5229