Catalytic asymmetric 1, 3-dipolar cycloaddition reaction of nitrones with α′-phosphoric enones by a chiral ligand-copper(II) triflate complex

Article abstract of DOI:10.1002/adsc.200700377

Using the C₂-symmetric bis-oxazoline copper(II) catalyst 6f as a chiral Lewis acid, α′-phosphoric enones 2 undergo 1,3-dipolar cycloaddition with nitrones 3 to provide isoxazolidines 4 with very high enantioselectivity and endo/exo selectivity.

Full text of DOI:10.1002/adsc.200700377

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DOI: 10.1002/adsc.200700377
Catalytic Asymmetric 1, 3-Dipolar Cycloaddition Reaction of
Nitrones with a’-Phosphoric Enones by a Chiral Ligand-
Copper(II) Triflate Complex
Kyoung-Chan Lim,a Young-Taek Hong,a and Sunggak Kima,*
a
Center for Molecular Design & Synthesis and Department of Chemistry, School of Molecular Science (BK-21), Korea
Advanced Institute of Science and Technology, Daejeon 305-701, Korea
Fax : (+82)-42-869-8370; e-mail: skim@kaist.ac.kr
Received: July 30, 2007; Revised: November 13, 2007; Published online: February 6, 2008
Abstract: Using the C2-symmetric bis-oxazoline
copper(II) catalyst 6f as a chiral Lewis acid, a’-
phosphoric enones 2 undergo 1,3-dipolar cycloaddi-
tion with nitrones 3 to provide isoxazolidines 4 with
very high enantioselectivity and endo/exo selectivi-
ty.
Figure 1. 1,5-Chelation of oxazolidinone 1 and a’-phosphoric
enone 2.
Keywords: asymmetric catalysis; copper salts; cyclo-
addition; Lewis acids; synthetic methods
Recently, we have reported catalytic enantioselec-
tive Friedel–Crafts alkylations of indoles using a’-
phosphoric enones in which the enantioselectivities of
upto 98% ee were obtained.[12] In our continued
1,3-Dipolar cycloaddition reactions of nitrones with al- effort to examine the synthetic efficiency of a’-phos-
kenes have proved to be synthetically very useful, pro- phoric enone templates in enantioselective organic re-
viding important isoxazolidine adducts used for prepar- actions, we have studied the Lewis acid-catalyzed
ing 3-amino alcohols and alkaloids.[1] During the past asymmetric 1,3-dipolar cycloaddition reaction of ni-
two decades various enantioselective total syntheses trones.
have been achieved using chiral isoxazolidines derived
We initially screened several Lewis acids for 1,3-di-
from asymmetric 1,3-dipolar cycloaddition reactions.[2] polar cycloaddition of phosphoric enone 2a with ni-
However, the asymmetric 1,3-dipolar cycloaddition re- trone 3a. The similar reaction was reported previous-
action was mainly achieved by incorporating chiral ly, where an 83:17 endo/exo selectivity using dichloro-
centers in the nitrone and/or the alkene.
diisopropoxytitanium was obtained.[13] Among the
The chiral Lewis acid-catalyzed asymmetric 1,3-di- Lewis acids tested, cupric triflate gave the best result
polar cycloaddition reactions have mainly utilized the in terms of the highest endo/exo selectivity and the re-
metal-assisted activation of electron-deficient alkenes action rate. Magnesium triflate was also somewhat ef-
through formation of 1,4- or 1,5-metal-chelated spe- fective but slowed down the reaction as shown in
cies.[3] Contrary to the Lewis acid-catalyzed asymmet- Table 1.
ric Diels–Alder reactions,[4] the application of Lewis
Our next attention was given to the nitrone addi-
acids in asymmetric 1,3-dipolar cycloaddition reac- tions to substrate 2a using a catalytic amount (20
tions is relatively unexplored. Previously reported mol%) of chiral Lewis acids derived from cupric tri-
alkene templates include N-enoyl derivatives of oxa- flate and bis-oxazoline (Box) derivatives (Figure 2) in
zolidinones 1,[5] pyrrolidinone,[6] and pyrazolidinone,[7] dichloromethane.[14] As shown in Table 2, several fea-
as well as the recently reported a’-hydroxy enones.[8] tures are noteworthy. First, among the chiral ligands
We have been interested in using a’-phosphoric tested in this study, (4R,5S)-diPh-Box 6f was most at-
enones 2 in asymmetric reactions based on two fac- tractive, giving the highest enantioselectivity along
tors. First, a’-phosphoric enone templates can form with very high endo/exo selectivity (entries 3 and 4).
1,5-metal-chelated species (Figure 1).[9] Second, they Second, the chemical yields of the present reaction
can be readily converted into enones by the Horner– were not high, ranging from 40% to 63% (entries 1–
Wadsworth–Emmons (HWE) reaction[10] and also can 4). The addition of 4 Š molecular sieves improved the
be removed to provide ketones.[11]
chemical yield significantly but lowered the enantiose-
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Catalytic Asymmetric 1, 3-Dipolar Cycloaddition Reaction of Nitrones
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Table 1. Screening of Lewis acids.
Table 2. Screening of chiral ligands in the Cu(II)-catalyzed
1,3-dipolar cycloaddition.
Entry L* T [oC] t [h] Yield [%][a] endo/exo[b] ee [%][c]
Lewis Acid
Cu(OTf)2
Time [h]
Yield [%][a]
endo/exo[b]
1
6a
6b
6f
0
0
0
12
12
12
4
41
63
57
40
46
80
61
74
77
48
0
97:3
94:6
96:4
96:4
96:4
98:2
98:2
98:2
88:12
91:9
79
G
3
3
3
20
57
69
37
76
97:3
2
61
Zn(OTf)2
G
86:14
75:25
91:9
3
90
Sc(OTf)3
E
4
5
6
7
8
9
10
11
6f r.t.
6a r.t.
6f r.t.
6a À40
6f À40
6c À40
84
65[d]
82[d]
65[d]
89[d]
83[d]
0
Mg
A
4
4
[a]
[b]
Isolated yield.
Determined by H NMR.
1
60
60
60
24
24
6d
6e
0
0
[a]
[b]
Isolated yield.
1
The endo/exo ratio was determined by H NMR spectros-
copy.
The ee was determined by chiral HPLC.
In the presence of 4 Š molecular sieves.
[c]
[d]
furan was also very effective and comparable to tolu-
ene (entry 3). Since nitrone 3b was slightly soluble in
toluene, two mixed solvent systems were examined
and similar results were obtained without any prob-
lems (entries 4 and 5). To test the catalytic ability of
cupric triflate, we reduced the amount of the catalyst
to 10 mol%. The reaction of 2b with 3b in the pres-
ence of 10 mol% cupric triflate and 6f in tetrahydro-
Figure 2. Chiral bis-oxazoline (Box) ligands.
lectivity to some extent (entries 5–9). The effect of furan at 08C gave the same enantioselectivity, endo/
molecular sieves in the asymmetric reactions has been exo selectivity, and chemical yield but was slowed
noted previously.[15] Finally, the chiral ligands bearing down slightly (26 h vs. 20 h for 20 mol% catalyst).
alkyl substituents were totally unsuccessful (entries 10 Thus, the remaining reactions were normally carried
and 11). The reaction using 6d gave a mixture of race- out using 10 mol% cupric triflate and 12 mol% 6f in
mic products, whereas the reaction using 6e did not tetrahydrofuran at 08C.
occur.
The experimental results obtained in this study are
To optimize the reaction conditions, we briefly ex- summarized in Table 4. Several noteworthy features
amined the solvent effect using (4R,5S)-diPh-Box 6f are apparent. First, the present 1,3-dipolar cycloaddi-
and the result was very promising as shown in tion reactions proceeded smoothly, yielding the isoxa-
Table 3. When the same reaction was repeated in tol- zolidine adducts in high yields with almost complete
uene at 08C, the reaction was faster and the yield im- endo selectivities (>99:1) for the nitrones 3a and 3b.
proved significantly (entry 2). Even more gratifyingly, Second, N-benzyl nitrone 3b exhibited higher enantio-
a high enantioselectivity (99% ee) was achieved along selectivities than N-phenyl nitrone 3a. For instance,
with a better endo/exo selectivity (99:1). Tetrahydro- the reaction of a’-phosphoric enone 2a (R1 =Me)
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381

Kyoung-Chan Lim et al.
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Table 3. Effect of solvent in the 1,3-dipolar cycloadditions.
Table 4. Cu(II)-catalyzed 1,3-dipolar cycloaddition of nitro-
nes 3 with a’-phosphoric enones 2.
try R1
R2 R3
t
Yield endo/ ee
Entry Solvent
T
t
Yield
ee
En
[oC]
[h] [%][a]
[%][b]
[h] [%][a] exo[b] [%][c]
1
2
3
4
5
CH2Cl2
toluene
THF
toluene+CH2Cl2
toluene+THF
r.t.
0
0
0
0
48
20
20
20
20
43
97
82
92
95
85
99
1
2
3
4
5
6
7
8
N
26 82
>99:1 99
>99:1 86
>99:1 91
>99:1 85
>99:1 93
>99:1 84
>99:1 93
>99:1 99
8
8
6
92
90
92
99
Bn Ph
Ph Ph
Bn Ph
Ph Ph
Bn Ph
Ph Ph
Bn Ph
Bn Ph
Bn Ph
Bn Et
99[c]
99[c]
10 89
48 81
48 87
48 92
[a]
[b]
[c]
Isolated yield.
The ee was determined by chiral HPLC.
A 1:1 ratio of the two solvents.
9
7 d 79[d] >99:1 99
10
11
12
4
12
6
75
0
76
>99:1 90
with 3b under the same conditions gave 91% ee
(entry 3), whereas the reaction with 3a gave 85% ee
(entry 4). Similar phenomena have been observed
consistently throughout the experiments. Third, as the
substituent R1 was changed from primary alkyl to ter-
tiary alkyl, the reaction was slowed down but the
enantioselectivity was increased to some extent, even
though the enantioselectivity was not proportional to
the steric bulkiness of the substituent. Finally, the re-
action of a’-phosphoric cinnamyl enone (R1 =Ph) did
not proceed and the starting material was recovered
unchanged (entry 11).
6:5
73
(75)[e]
83
13
14
15
Bn
(CH2)2Ph 4
94
6:5
(80)[e]
87
Bn i-Pr
24 91
65
10:1
(47)[e]
Bn c-Hex
4
>99:1 84
[a]
[b]
[c]
[d]
[e]
According to our brief studies with the nitrones de-
rived from aliphatic aldehydes, they exhibited inferior
results, depending on the structure of the nitrones to
some extent (entries 12–15). The nitrones derived
from primary aliphatic aldehydes did not show appre- acid 8 using osmium tetroxide with sodium periodate.
ciable endo/exo selectivities, while giving good enan- On comparison of the optical rotation value and spec-
tioselectities (entries 12 and 13). However, the nitro- tral data of 8 with those of the previously known com-
nes derived from secondary aliphatic aldehydes pound,[8] the absolute configuration could be assigned
showed higher endo/exo selectivities than the former as (3S,4R) in isoxazolidine ring. For further compari-
(entries 14 and 15). Similar low endo/exo selectivities son, two additional isoxazoline adducts 4a and 4d
with the aliphatic alkyl nitrones were observed previ- were also converted into the previously known com-
ously.[16]
pounds 13[5c] and 14,[16] respectively (Scheme 2). Ini-
To determine the absolute configuration of isoxazo- tially, 11 and 12 were obtained from 4a and 4d by the
line adduct 4, 4c was converted into the previously same routine operations. The previously known com-
known compound 8 as shown Scheme 1. Treatment of pound 14 was obtained from 12 by esterification, hy-
4c with benzaldehyde and potassium carbonate in eth- drogenolysis, and the subsequent protection of the
anol at room temperature for 2 h afforded enone 7 in amino groupby the Boc group. The optical rotation
89% yield.[17] Enone 7 was converted to carboxylic value and the spectral data clearly indicate that 14
382
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Catalytic Asymmetric 1, 3-Dipolar Cycloaddition Reaction of Nitrones
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Scheme 1. Conversion of isoxazolidine adduct 4c into 8.
Figure 3. Stereochemical model for the catalyst-substrate
complex.
catalytic asymmetric 1,3-dipolar cycloaddition of ni-
trones. Using the chiral Lewis acid, Cu
A
AHCTREUNG
ducts were obtained in high yields with high exo/endo
selectivities and high enanitioselectivities.
Experimental Section
Scheme 2. Conversion of 4a and 4d into 13 and 14.
Typical Procedure
Copper(II) trifluoromethanesulfonate (7 mg, 0.02 mmol)
and (4R,5S)-diPh-Box 6f (11 mg, 0.022 mmol) dissolved in
THF (2 mL) were stirred for 4 h at room temperature.
Then, (E)-dimethyl 2-oxopent-3-enylphosphonate (2a,
38 mg, 0.2 mmol) dissolved in THF (1 mL) was added to the
reaction mixture. After being stirred for additional 30 min
at 08C, a solution of N-benzylidenebenzeneamine oxide (3a,
59 mg, 0.3 mmol) in THF (1 mL) was added to the reaction
mixture. The reaction mixture was stirred for 6 h at 08C,
then concentrated under reduced pressure. The residue was
should be (2R,3S)-methyl 2-[(S)-(tert-butoxycarbonyl-
A
N
thermore, 11 was also converted into oxazolidinone
13 by routine operations[18] and the same conclusion
was also obtained by comparison of the optical rota-
tion value of 13 and that of the known compound.[5c]
The copper(II)-bis(oxazoline)-catalyzed enantiose-
lective reactions have been relatively well studied and
it is understood that the Cu(II)-bis(oxazoline) enone purified by a silica gel column chromatography using ethyl
acetate and n-hexane (2:1) as eluant to give dimethyl 2-
[(3R,4S,5R)-5-methyl-2,3-diphenylisoxazolidin-4-yl]-2-oxo-
complexes might exist as square planar intermedi-
ates.[19] Based on the observed enantioselectivity in
this study, the s-trans enone template in the distorted
square planar geometry would be possible (Figure 3).
Although a clear answer for the control of the confor-
mation of enone templates awaits further studies, it
could result from a p–p stabilization of the transition
state.[20]
A
4.13, CH2Cl2); H NMR (400 MHz, CDCl3): d=1.49 (d, 3H,
J=5.99 Hz), 2.94 (m, 2H), 3.57, (m, 1H), 3.60 (dd, 6H, J1 =
11.28, J2 =24.72 Hz), 4.43 (m, 1H), 4.94 (d, 1H, J=7.27 Hz),
6.91 (m, 3H), 7.19 (m, 2H), 7.28 (m, 1H), 7.36 (m, 2H),
7.48 (d, 2H, J=9.41 Hz); 13C NMR (100 MHz, CDCl3): d=
17.5, 40.9 (42.2), 52.7 (52.8, 52.9, 53.0), 73.4, 73.7, 77.2, 114.2,
121.7, 126.5, 127.9, 128.8, 129.0, 141.3, 151.3, 198.4 (198.4);
In conclusion, we have found that the a’-phosphoric
enone bidentate template is highly efficient for the IR (NaCl): n=1712, 1597, 1488, 1453, 1259, 1181, 1031, 880,
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Kyoung-Chan Lim et al.
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804, 757, 699 cmÀ1; HR-MS (ESI): m/z=390.1465, calcd. for
C20H25NO5P [M+H]+: 390.1469. The product ratio was de-
termined by HPLC analysis (Chiral AS-H, i-PrOH/hexane=
30/70, 0.5 mLminÀ1, 220 nm); tr =25.69 min (major), tr =
30.52 min (minor).
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Acknowledgements
We thank the Center for Molecular Design and Synthesis
(CMDS), KEPCO, and BK21 programfor financial support.
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