Enantioselective nitrone cycloadditions of α,β-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine-cerium(IV) triflate complexes

Article abstract of DOI:10.1021/ol061223i

Enantioselective nitrone cycloadditions with β-substituted α,β-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl) pyridine-cerium(IV) triflate complexes 1 have been reported. The isoxazolidine products were efficiently transformed into densely functionalized β′-hydroxy-β-amino acid derivatives.

Full text of DOI:10.1021/ol061223i

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3351-3354
Enantioselective Nitrone Cycloadditions
of -Unsaturated 2-Acyl Imidazoles
Catalyzed by
r,â
Bis(oxazolinyl)pyridine−Cerium(IV)
Triflate Complexes
David A. Evans,* Hyun-Ji Song, and Keith R. Fandrick
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received May 18, 2006
ABSTRACT
Enantioselective nitrone cycloadditions with
â-substituted r,â-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine−cerium(IV)
triflate complexes 1 have been reported. The isoxazolidine products were efficiently transformed into densely functionalized â′-hydroxy-â-
amino acid derivatives.
In this study, we report the utility of R,â-unsaturated 2-acyl
imidazoles as effective dipolarophiles in the catalyzed
enantioselective nitrone cycloaddition with the chiral cerium-
(IV) complex 1. The isoxazolidine cycloaddition products
are valuable precursors to biologically active â-amino acids,
â-lactams, amino sugars, and alkaloids.1 A range of chiral
Lewis acid and organocatalysts have been reported for this
useful transformation, and each system has its assets and
liabilities.2 Ideal attributes of this reaction might include high
enantio- and diastereoselectivities, a broad reaction scope,
and convenient reaction temperatures. The goal in this study
has been to attempt to improve on the practicality of these
enantioselective processes.
We recently reported the enantioselective Friedel-Crafts
alkylation of R,â-unsaturated 2-acyl imidazoles catalyzed by
the illustrated chiral Sc(III) complex (eq 1).3 The preparation
of the requisite R,â-unsaturated 2-acyl imidazoles3 and the
conversion of 2-acyl imidazoles to useful carbonyl deriva-
tives have been previously described.3,4
The present study began with a survey of chiral lan-
thanide-pybox5,6 complexes in the prototypical cycloaddition
(1) For recent reviews, see: (a) Martin, J. N.; Jones, R. C. F. Synthetic
Application of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley and Sons:
Hoboken, NJ, 2003; Chapter 1, p 1. (b) Gothelf, K. V.; Jørgensen, K. A.
Chem. ReV. 1998, 98, 863-910.
10.1021/ol061223i CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/20/2006

both overall yields and enantioselectivities as compared to
their late lanthanide counterparts.10,11 Upon further examina-
tion, we found that both Ce(III)‚6 triflate and Ce(IV)‚6 triflate
(1) displayed excellent enantiofacial selectivities and yields
for the illustrated reaction with crotyl 2-acyl imidazole. The
Ce(IV)‚6 triflate complex (1)12 was found to be a more gener-
al catalyst, as Ce(III)‚6 triflate performed sluggishly with
more challenging substrates such as cinnamyl 2-acyl imi-
dazole.
We next turned our attention to the effects of solvent, lig-
and substitution, and temperature on the cycloaddition (Table
1). It was found that the cis- and trans-bisphenyl-pybox
Table 1. Optimization of the Catalyst and Reaction Parameters
of the Nitrone Cycloadditiona,b
temp
(°C)
t
(h)
entry ligand
solvent
mol %
% yield % eec
Figure 1. Lanthanide survey for the nitrone cycloaddition reaction
1
2
2
3
4
5
6
7
8
6
6
6
6
6
6
6
6
6
6
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CF3C6H5
EtOAc
Et2O
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
0
0
19
26
42
18
28
68
82
84
3
86
87
96
68
91
72
74
97
98
90
85
96
99
78
78
99
99
96
86
87
98
91
94
64
80
99
97
97
73
with crotyl 2-acyl imidazole.
3
0
100
100
40
4
0
illustrated in eq 2 (Figure 1). Although the illustrated Sc-
(III)-pybox complex was an efficient catalyst for the Frie-
del-Crafts reactions (eq 1),3 it was found to display poor
enantiofacial control for the corresponding nitrone cycload-
ditions. Other proven Lewis acid catalysts from our group,
such as the Cu(II)-pybox, Cu(II)-box,7 and Ni(II)-box8
complexes, also performed poorly for the illustrated trans-
formation.9
5
0
6
0
40
24
7
0
8
0
110
17
9
0
10
11
12
13
14
15
16
17
18
0
11
0
110
17
THF
0
CH3CN
i-PrOH
EtOAc
EtOAc
EtOAc
EtOAc
0
110
110
17
0
0
2
0
72
5
5
+20
+60
11
From the lanthanide screen, it was concluded that the early
lanthanide-pybox complexes were superior with respect to
8
a All reactions performed at 0.1 M in substrate with 25 mg 4 Å MS/mL
of solvent. b For all reactions, the endo:exo ratio was >99:1. c Enantiomeric
excess determined by chiral HPLC.
(2) For Lewis acid catalyst examples, see: (a) Kano, T.; Hashimoto, T.;
Maruoka, K. J. Am. Chem. Soc. 2005, 127, 11926-11927. (b) Suga, H.;
Nakajima, T.; Itho, K.; Kakehi, A. Org. Lett. 2005, 7, 1431-1434. (c)
Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem. Soc.
1998, 120, 12355-12356. (d) Palomo, C.; Oiarbide, M.; Arceo, E.; Garc´ıa,
J. M.; Lo´pez, R.; Gonza´lez, A.; Linden, A. Angew. Chem., Int. Ed. 2005,
44, 6187-6190. (e) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc.
2004, 126, 718-719. (f) Kobayashi, S.; Kawamura, M. J. Am. Chem. Soc.
1998, 120, 5840-5841. For organocatalyst examples, see: (g) Jen, W. S.;
Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-
9875. (h) Karlsson, S.; Hogberg, H.-E. Eur. J. Org. Chem. 2003, 2782-
2791.
(3) For indole Friedel-Crafts reactions with R,â-unsaturated 2-acyl
imidazoles, see: (a) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem.
Soc. 2005, 127, 8942-8943. For pyrrole Friedel-Crafts reactions, see: (b)
Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249-2252.
(4) For the transformation of 2-acyl-benzimidazoles to esters, amides,
â-diketones, and â-ketoesters, see: (a) Miyashita, A.; Suzuki, Y.; Nagasaki,
I.; Ishiguro, C.; Iwamoto, K.-I.; Higashino, T. Chem. Pharm. Bull. 1997,
45, 5, 1254-1258. For the transformation of 2-acyl-imidazoles to ketones,
â-diketones, â-ketoesters, and aldehydes, see: (b) Ohta, S.; Hayakawa, S.;
Nishimura, K.; Okamoto, M. Chem. Pharm. Bull. 1987, 35, 1058-1069.
(5) For a good review of metal-pybox complexes as chiral catalysts,
see: Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119-
3154.
(6) For the reviews of asymmetric catalysis by lanthanide complexes,
see: (a) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727-2751. (b)
Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int. Ed. 2002, 41,
3554-3571. (c) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102,
2187-2209. (d) Inanaga, J.; Furuno, H.; Hayano, T. Chem. ReV. 2002, 102,
2211-2225. (e) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-
L. Chem. ReV. 2002, 102, 2227-2302.
ligands 6 and 7 afforded the best enantioselectivities and
yields of the ligands explored (Table 1, entries 1-7). Ethyl
acetate proved to be the solvent of choice (entries 8-14),
and the reaction could be performed at ambient temperatures
while maintaining excellent enantiofacial selectivities (entries
17 and 18). Trace amounts of moisture were found to be
(7) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335.
(8) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706-8707.
(9) For Sc(III) and Ni(II), excellent endoselectivity (>99:1) with poor
enantioselectivity (max 6% ee) was observed. For Cu(II), a high dr (>99:
1) with low ee (23%) and a low dr (3.5:1) with moderate ee (46% and
58%) were observed.
(10) For the ionic radii of lanthanide cations, see: Shannon, R. D. Acta
Crystallogr. 1976, A32, 751-767.
3352
Org. Lett., Vol. 8, No. 15, 2006

deleterious to the diastereo- and enantioselectivity of the
cycloaddition.13
The scope of the reaction is provided in Table 2. The
Scheme 1. Conversion of Isoxazolidine 9a to
â′-Hydroxy-â-amino Acid Derivatives 11a-d
Table 2. Substrate Survey of the Nitrone Cycloaddition with
R,â-Unsaturated 2-Acyl Imidazoles Catalyzed by 1a
t
endo:
exo
entry R1
R2
R3
Me
Me
Me
Me
Me
(h)
% eeb % yield
1
2
Bn Ph
17 >99:1 97
48 >99:1 92
36
99 (9a)
92 (9b)
Me Ph
Ph Ph
3
6:1 80(90)c 98 (9c)
4
Bn 4-MeO-C6H4
Bn 4-Cl-C6H5
Bn 4-MeO2C-C6H5 Me
20 >99:1 96
20 >99:1 95
36 >99:1 99
24 >99:1 90
24 >99:1 96
88 (9d)
90 (9e)
95 (9f)
92 (9g)
97 (9h)
5
6
cleavage procedure (MeOTf in CH3CN),3b we could obtain
the corresponding methyl ester (80% yield) or carboxylic
acid (73% yield) without protecting the base-labile â-hy-
droxyl group of the 2-acyl imidazole 10a (Scheme 1).
Improved yields of the corresponding ester and carboxylic
acid were realized if the sensitive â-hydroxyl group of the
2-acyl imidazole 10a was protected as the TBS ether. We
also found that the addition of 4 Å MS during the methylation
of 10a,b was advantageous.
7
Bn 1-naphthyl
Bn 2-naphthyl
Bn Et
Me
8
Me
9
Me
20 2.4:1 87(76)c 97 (9i)
10
11
12d
13d
Bn c-Hx
Bn Ph
Me
24 1.5:1 85(66)c 76 (9j)
Et
36
50:1 92
80 (9k)
92 (9l)
72 (9m)
Bn Ph
i-Pr
n-Bu
Ph
36 >99:1 91
36 >99:1 87
Bn Ph
14d,e Bn Ph
120
72
3:1 95(93)c 80 (9n)
60:1 83
15d
Bn Ph
CO2Et
80 (9o)
a All reactions performed at 0.1 M in substrate with 25 mg 4 Å MS/mL
of solvent. b Enantiomeric excess was determined by chiral HPLC. c Num-
bers in parentheses are for minor diastereomers. d 10 mol % of 1 was needed.
e 3 days at 0 °C, then 2 days at room temperature.
illustrated reaction is well tolerant of N-aryl and N-alkyl
nitrone substitution (entries 1-3). The more versatile N-
benzyl nitrones provided the best diastereo- and enantiose-
lectivities among the three substituents explored. C-Aryl
nitrone substitution was also well tolerated in the cycload-
dition (entries 4-8). However, reactions with the corre-
sponding C-alkyl-substituted nitrones, while maintaining
good enantioselectivities (entries 9 and 10), afforded disap-
pointing diastereoselectivities. A range of alkyl, aryl, and
carboxyl â-substituents on the R,â-unsaturated 2-acyl imi-
dazole reaction component is well tolerated in the illustrated
reaction (entries 11-15).
To elaborate the cycloaddition products, we turned our
attention to the conversion of isoxazolidine 9a to the syn-
thetically useful â′-hydroxy-â-amino acid derivatives 11a-d
(Scheme 1).2f Hydrogenation of the N-O bond catalyzed
by Pd(OH)2/C with concurrent N-Boc protection proceeded
well (80% yield, Scheme 1). Utilizing our previously reported
(11) For the size effect of rare earth metals on ee, see: (a) Evans, D. A.;
Nelson, S. G.; Gagne, R.; Muci, A. R. J. Am. Chem. Soc. 1993, 115, 9800-
9801. (b) Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M. Tetrahedron
Lett. 1993, 34, 2657-2660. (c) Kobayashi, S.; Ishitani, H. J. Am. Chem.
Soc. 1994, 116, 4083-4084. (d) Schaus, S. E.; Jacobsen, E. N. Org. Lett.
2000, 2, 1001-1004. (e) Kobayashi, S.; Hamada, T.; Nagayama, S.;
Manabe, K. Org. Lett. 2001, 3, 165-167.
(12) Ce(IV) triflate was prepared from CAN and dispensed from a
glovebox. For the preparation of Ce(IV) triflate, see: Imamoto, T.; Koide,
Y.; Hiyama, S. Chem. Lett. 1990, 1445-1446.
(13) The addition of 4 Å MS to the reaction mixture of catalyst 1, 2-acyl
imidazole, and (Z)-N-benzylidene(phenyl)methanamine oxide in ethyl acetate
(Table 2, entry I) raised the endo:exo diastereoselectivity from 22:1 to >99:
1, the enantioselectivity from 71% ee to 98% ee, and the yield from 86%
to 97%.
Figure 2. Determination of the absolute stereoconfiguration of 14.
Org. Lett., Vol. 8, No. 15, 2006
3353

Employing the reaction sequence illustrated in Figure 2
followed by coupling of the carboxylic acid with (S)-(-)-
R-methylbenzylamine and subsequent Boc and TES depro-
tections, we were able to obtain the crystalline amide 14 in
62% overall yield. The absolute stereochemistry of 14, and
thus the parent isoxazolidine 9a, was determined by an X-ray
structure of 14.14
Nonlinear effects can act as a probe for the reaction
mechanism.15 The enantiomeric excess of nitrone cycload-
dition product 9a was monitored as a function of enantio-
meric composition of the chiral ligand 6 (Figure 3).
Significant (+)-nonlinear effects were observed in this
analysis, which might suggest the possible formation of a
reservoir of nonreactive aggregates.15 We were able to obtain
9a with the selectivity of 90% enantiomeric excess while
only employing the ligand that had an enantiomeric excess
of 60%.
In summary, we have developed a Ce(IV)-cis-bis-Ph-
pybox complex (1) catalyzed asymmetric endoselective
nitrone cycloaddition with an excellent substrate scope under
mild reaction conditions employing R,â-unsaturated 2-acyl
imidazoles. This chemistry was found to be amenable for
the efficient asymmetric synthesis of densely functionalized
â′-hydroxy-â-amino acid derivatives.
Figure 3. (+)-Nonlinear effects of the nitrone cycloaddition with
crotonyl 2-acyl imidazole catalyzed by 1.
20), and Merck research laboratories. H.-J.S. gratefully
acknowledges a Novartis Graduate Fellowship.
Supporting Information Available: Experimental pro-
cedures, proton and carbon NMR spectra for all new
compounds, and stereochemical determination with X-ray
crystallographic data are available. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by grants
from the National Science Foundation, NIH (GM-33328-
(14) This absolute stereoconfiguration was consolidated via Mosher’s
ester analysis and optical rotation comparison with a known compound.
Details are provided in the Supporting Information. The stereochemistry
of all the other isoxazolidines was assigned by analogy.
(15) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922-
2959.
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Org. Lett., Vol. 8, No. 15, 2006