Formal [3+2]-cycloaddition of ketenes and oxaziridines catalyzed by chiral lewis bases: Enantioselective synthesis of oxazolin-4-ones

Article abstract of DOI:10.1002/anie.201003532

Choose the right cat.: A highly enantioselective synthesis of oxazolin-4-ones by the formal [3+2]-cycloaddition of ketenes and a racemic oxaziridines has been developed (see scheme; cat.=N-heterocyclic carbenes for disubstituted ketenes or cinchona alkaloids for monosubstituted ketenes, Ts=4-toluenesulfonyl).

Full text of DOI:10.1002/anie.201003532

Communications
DOI: 10.1002/anie.201003532
Asymmetric Catalysis
Formal [3+2] Cycloaddition of Ketenes and Oxaziridines Catalyzed by
Chiral Lewis Bases: Enantioselective Synthesis of Oxazolin-4-ones**
Pan-Lin Shao, Xiang-Yu Chen, and Song Ye*
The oxidation of enolates with oxaziridine derivatives has
been widely utilized for the synthesis of a-hydroxy carbonyl
compounds since Davis et al. reported their pioneering work
in 1980s.[1,2] Asymmetric Davisꢀ oxaziridine oxidation reac-
tions generally require a stoichiometric amount of chiral
oxaziridine or auxiliary. It is therefore highly desirable to
develop a catalytic, enantioselective version of Davisꢀ oxida-
tion and related reactions.[3]
During the past decades, great success has been achieved
through enantioselective [2+2] and [4+2] cycloaddition
reactions of ketenes[4] catalyzed by chiral Lewis bases such
as cinchona alkaloids,[5] planar-chiral DMAP derivatives,[6]
and N-heterocyclic carbenes (NHCs)[7,8] (Scheme 1a;
DMAP = 4-dimethylaminopyridine).[9] The key intermediate
produce a new intermediate II, and thus open new possibil-
ities for catalytic ketene reactions (Scheme 1b).
Based on the above analysis, herein we report a novel
enantioselective formal [3+2] cycloaddition of ketenes and
oxaziridines for the synthesis of oxazolin-4-ones,[10] which are
not only biologically interesting intermediates[11] but are also
masked a-hydroxy carbonyl compounds.[12]
Initially, we observed that the NHC 1a’, which was
generated in situ from the triazolium salt 1a in the presence of
Cs2CO3, catalyzed the cycloaddition reaction of ketene 2a
and racemic oxaziridine 3a and furnished the desired
oxazolin-4-one 4 in 47% yield with 1:1 diastereoselectivity
and promising enantioselectivity (Scheme 2). When oxazir-
idine rac-3b bearing a 2-chlorophenyl group was used, the
corresponding cycloadduct 5a was obtained in better yield
with 3:1 diastereoselectivity and decreasing enantioselectiv-
ity.
Scheme 1. a) LB-catalyzed cycloaddition reactions of ketene deriva-
tives; b) Possible oxidation of generated zwitterionic enolate II with
oxaziridine compounds. Ts=4-toluenesulfonyl.
Scheme 2. Cycloaddition reaction of ketene 2a and racemic oxaziri-
dines 3a and 3b catalyzed by NHC 1a’. TBS=tert-butyldimethylsilyl,
THF=tetrahydrofuran.
of these catalytic reactions involves the zwitterionic enolate
intermediate I generated by the addition of a Lewis base to
ketene compounds. We envision that this zwitterionic enolate
I could be subject to oxidation with oxaziridine derivatives to
A series of NHCs,[7a,13] derived from l-pyroglutamic acid,
were then screened for the model reaction of phenyl-
(ethyl)ketene 2a and racemic oxaziridine 3b (Table 1). It
was found that both NHC 1c’ and 1d’ could afford the desired
cycloadduct 5a in good yield with high diastereoselectivities
and enantioselectivities (Table 1, entries 3 and 4). More
interestingly, we noticed that the opposite enantioselectivity
could be induced by appropriate NHC catalysts, although
they all bear the same chiral center (Table 1, entries 1–3 vs.
entries 4–7). Not only NHCs 1e’,f’ bearing a proximal free
hydroxy group (Table 1, entries 5 and 6), but also NHC 1g’
bearing a bulky N-aryl group (Table 1, entry 7) showed some
sort of reversed enantioselectivity. N-heterocyclic carbene
1d’, which has both of the above features, afforded the best
result (Table 1, entry 4). In other words, both the free hydroxy
group and the bulky N-substituent are believed to contribute
to the reverse of enantioselectivity.[14]
[*] P.-L. Shao, X.-Y. Chen, Prof. Dr. S. Ye
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
Fax: (+86)10-6255-4449
E-mail: songye@iccas.ac.cn
[**] Financial support from the National Natural Science Foundation of
China (nos. 20872143, 20932008), the Ministry of Science and
Technology of China (no. 2009ZX-5909501-018), and the Chinese
Academy of Sciences is gratefully acknowledged.
Supporting information (including experimental procedures,
characterization data, and NMR spectra) for this article is available
on the WWW under http://dx.doi.org/10.1002/anie.201003532.
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Chemie
Table 1: Screening of NHC catalysts and optimization of reaction
conditions.
diastereo- and enantioselectivities (Table 2, entries 1–5).
However, only a trace amount of cycloadduct was observed
for the reaction of 2-chlorophenyl(ethyl)ketene (2 f; Table 2,
entry 6). Moreover, 2-naphthyl(ethyl)ketene (2g) worked
well, while 1-naphthyl(ethyl)ketene (2h) did not (Table 2,
entries 7 and 8). In addition, when aryl(alkyl)ketene with a
methyl, nPr, or nBu group was employed, good yield, high
diastereo-, and enantioselectivities were observed (Table 2,
entries 9–12).
Consistent with the model reaction in Table 1, cyclo-
addition reactions catalyzed by NHC 1c’ furnished the
desired products with opposite enantioselectivities but in
somewhat lower yields compared with those catalyzed by
NHC 1d’ (Table 2, entries 1’, 2’, and 9’–12’).
The kinetic resolution of racemic oxaziridine 3b was also
observed for the NHC-catalyzed reaction. Optically active
(À)-3b was recovered in 15–26% yield with 76–99% ee for
the reactions catalyzed by NHC 1d’ (Table 2, entries 1–12).
Meanwhile, (+)-3b was recovered in 28–36% yield with
10–67% ee for the reactions catalyzed by NHC 1c’ (Table 2,
entries 1’, 2’, and 9’–12’).
In contrast to stable disubstituted ketenes, unstable
monosubstituted ketenes, which were generated in situ from
the acyl chlorides, did not react with oxaziridine 3b in the
presence of NHCs. However, cinchona alkaloids 8a and 8b
were found to be suitable catalysts for the reaction of
monosubstituted ketenes and the oxaziridine 3b (Table 3).
Both phenylketene and ethylketene worked well and gave the
cycloadducts in moderate to good yields with high enantio-
selectivities (Table 3, entries 1 and 3). The pseudoenantiom-
ers, TMS-quinidine (8a) and TMS-quinine (8b), led to the
cycloadducts in high but opposite enantioselectivities
(Table 3, entries 2 and 4). It should be noted that while
cinchona alkaloids 8a,b worked well as the catalysts for the
reaction of monosubstituted ketenes, they did not work for
the reaction of disubstituted ketenes 2.[16]
Entry
1
2a/3b
5a
Yield [%][a]
cis/trans[b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1d
1d
1d
1d
1:1.2
1:1.2
1:1.2[d]
1:1.2[e]
1:1.2
1:1.2
1:1.2
1:2
(À)-5a
(À)-5a
(À)-5a
(+)-5a
(+)-5a
(+)-5a
(+)-5a
(+)-5a
(+)-5a
(+)-5a
(+)-5a
64
50
65
71
62
42
38
68
80
91
24
3:1
7:1
9:1
14:1
8:1
7:1
52
74
90
91
32
10
55
92
82
95
12
5:1
14:1
10:1
15:1
4:1
9
10
11
2:1
1:1.2[f]
1:1.2[g]
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy
(300 mhz) of the reaction mixture. [c] Determined by HPLC on a chiral
stationary phase. [d] (+)-3b was recovered in 28% yield with 67% ee.
[e] (À)-3b was recovered in 21% yield with 98% ee. [f] (+)-3b (with
55% ee) was used instead of rac-3b. [g] (À)-3b (with 88% ee) was used
instead of rac-3b. Bn=benzyl, PMP=para-methoxyphenyl, TMS=tri-
methylsilyl.
Increasing the loading of the oxaziridine benefited the
enantioselectivity, while the reaction with excess ketene
provided the cycloadduct in better yield but with compro-
mised enantioselectivity (Table 1, entries 8 and 9).
Notably, when 1.2 equivalents of racemic oxaziridine
rac-3b was used, the optically active oxaziridine (À)- or
(+)-3b could be recovered in reasonable yield with good
enantiopurity (67% ee or 98% ee) for the reactions catalyzed
by NHC 1c’ or 1d’, respectively (Table 1, entries 3 and 4). On
the other hand, employing optically active oxaziridines as the
reagents had a great effect on the yield and enantioselectivity
of the cycloaddition reaction. For example, better yield (91%
vs. 71%) and enantioselectivity (95% ee vs. 91% ee) were
observed when (+)-3b (with 55% ee) was used instead of
rac-3b for the reaction catalyzed by 1d’ (Table 1, entry 10 vs.
4). On the contrary, utilizing (À)-3b (with 88% ee) dramat-
ically diminished the yield and enantioselectivity (Table 1,
entry 11 vs. 4). Notably, both reactions, no matter which
oxaziridine (+)-3b or (À)-3b was used,[15] afforded (+)-5a as
the major enantiomer when NHC 1d’ was chosen as the
catalyst (Table 1, entries 10 and 11).
The resulting oxazolin-4-one products present opportuni-
ties for further chemical transformations. For example, the a-
hydroxy acid 9a and the 1, 2-diols 10a, 11a and 11b could be
readily synthesized by saponification and reduction of the
corresponding cycloadducts, respectively, without erosion of
enantiopurity (Scheme 3).
A number of aryl(alkyl)ketenes were then examined for
the cycloaddition catalyzed by NHC 1c’ or 1d’ (Table 2).
Ketenes with a para-substituted aryl group (with both
electron-withdrawing 4-Cl and 4-Br, and electron-donating
4-Me) and a meta-substituted aryl group (3-Cl), provided the
corresponding oxazolin-4-ones 5 in good yields with high
Scheme 3. Synthesis of optically active hydroxy acid and diols derived
from oxazolin-4-one derivatives.
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Table 2: Formal [3+2] cycloaddition reaction of disubstituted ketenes and oxaziridine 3b catalyzed by NHC 1d’ or 1c’.
Entry
2
Ar, R
Cat.
5
Yield [%][a]
cis/trans[b]
ee [%][c]
3b
Yield [%][a]
ee [%][c]
1
1’
2a
2a
Ph, Et
1d
1c
(+)-5a
(À)-5a
71
65
14:1
9:1
91
90
(À)-3b
(+)-3b
21
28
98
67
2
2’
2b
2b
4-ClC6H4, Et
1d
1c
(+)-5b
(À)-5b
71
38
8:1
8:1
89
87
(À)-3b
(+)-3b
19
36
98
27
3
4
2c
2d
4-BrC6H4, Et
4-MeC6H4, Et
1d
1d
(+)-5c
(+)-5d
78
57
14:1
16:1
91
92
(À)-3b
(À)-3b
15
26
99
76
5
6
7
2e
2 f
2g
3-ClC6H4, Et
2-ClC6H4, Et
2-naphthyl, Et
1d
1d
1d
(+)-5e
5 f
68
10:1
–
91
–
(À)-3b
–
25
–
87
–
–
–
trace
61
(À)-5g
10:1
94
(À)-3b
21
77
8
9
9’
2h
2i
2i
1-naphthyl, Et
Ph, Me
1d
1d
1c
5h
(+)-5i
(À)-5i
trace
52
42
–
15:1
6:1
–
85
86
–
–
25
35
–
92
36
(À)-3b
(+)-3b
10
10’
2j
2j
4-ClC6H4, Me
1d
1c
(+)-5j
(À)-5j
72
37
10:1
8:1
91
79
(À)-3b
(+)-3b
17
36
92
42
11
11’
2k
2k
Ph, nPr
Ph, nBu
1d
1c
(+)-5k
(À)-5k
60
43
14:1
10:1
92
90
(À)-3b
(+)-3b
21
32
76
21
12
12’
2l
2l
1d
1c
(+)-5l
(À)-5l
61
41
14:1
14:1
95
91
(À)-3b
(+)-3b
18
36
94
10
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy (300 mhz) of the reaction mixture. [c] Determined by HPLC on a chiral
stationary phase.
The structure of oxazolinone cis-4 (see Scheme 2) was
established by X-ray crystal structure analysis.[17] The absolute
configuration of oxazolin-4-one 5a and 7a,b were assigned
after their chemical transformations into hydroxy acid and/or
intermediate II as well as the imine III. Further addition of
the intermediate II with the imine III gives a zwitterionic
complex IV, which collapses to furnish the final cycloadduct
and regenerate the Lewis base catalyst (Scheme 4).
In summary, an unprecedented catalytic formal
[3+2] cycloaddition of ketenes and oxaziridines was reported.
N-heterocyclic carbenes and cinchona alkaloids were found to
be the catalysts of choice for the reaction of disubstituted and
monosubstituted ketenes, respectively. Both enantiomers of
oxazolin-4-one derivatives were obtained in moderate to
good yields with good diastereo- and enantioselectivities by
diols.[18] The cis/trans isomers of oxazolin-4-one
7
was
assigned by the NOE interactions of the two isomers.[19]
The formal cycloaddition reaction described here is
believed to be initialized by the addition of a Lewis base to
a ketene substrate, which results in the formation of a
zwitterionic enolate intermediate I. The subsequent oxidation
of enolate I with an oxaziridine compound affords the
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2005, 44, 4292; c) N. Momiyama, H. Yamamoto, J. Am. Chem.
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Table 3: Formal [3+2] cycloaddition of monosubstituted ketenes and
oxaziridine 3b catalyzed by cinchona alkaloids.
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Entry
6
Cat.
7
Yield [%][a]
cis/trans[b]
ee [%][c]
1
2
3
4
6a
6a
6b
6b
8a
8b
8a
8b
(À)-7a
(+)-7a
(À)-7b
(+)-7b
62
44
47
42
5:1
8:1
6:1
5:1
99, 99
99, 20
99, 99
99, 70
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[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy
(300 mhz) of the reaction mixture. [c] Determined by HPLC on a chiral
stationary phase; ee value of the cis isomer, ee value of the trans isomer.
DIPEA=N,N-diisopropylethylamine.
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Fu, Angew. Chem. 2008, 120, 7156; Angew. Chem. Int. Ed. 2008,
47, 7048.
Scheme 4. Possible catalytic cycle.
choosing the appropriate NHCs with suitable substituents or
the appropriate pseudoenantiomers of the cinchona alkaloids.
The resulting oxazolin-4-one derivatives are successfully
converted into the corresponding a-hydroxy acids or
1,2-diols in one step. In addition, the kinetic resolution of
racemic oxaziridine compounds was also observed in some
cases. Further studies of this intriguing kinetic resolution are
underway.
[7] a) Y.-R. Zhang, L. He, X. Wu, P.-L. Shao, S. Ye, Org. Lett. 2008,
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Angew. Chem. 2005, 117, 7674; Angew. Chem. Int. Ed. 2005, 44,
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[9] For the asymmetric reactions of ketenes catalyzed by Lewis acids
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Received: June 10, 2010
Revised: August 3, 2010
Published online: September 28, 2010
Keywords: asymmetric catalysis · cycloaddition · ketenes ·
.
oxaziridines · oxazolidin-4-ones
[1] For the synthesis and application of a-hydroxy acids, see:
a) G. M. Coppola, H. F. Schuster, a-Hydroxy Acids in Enantio-
selective Synthesis, VCH, Weinheim, Germany, 1997; b) J. M.
Janey, Angew. Chem. 2005, 117, 4364; Angew. Chem. Int. Ed.
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Angew. Chem. 2007, 119, 5419; Angew. Chem. Int. Ed. 2007, 46,
5325.
[14] The switch of enantioselectivity was previously observed by our
research group: X.-L. Huang, L. He, P.-L. Shao, S. Ye, Angew.
Chem. 2009, 121, 198; Angew. Chem. Int. Ed. 2009, 48, 192.
[15] (+)-3b and (À)-3b were prepared from the resolution of rac-3b
by the cycloaddition reaction of ketenes catalyzed by NHC 1c’
and 1d’, respectively.
[16] As reported (Refs. [4–7]), NHCs are efficient catalysts for
reactions of disubstituted ketenes but not for monosubstituted
ones, while cinchona alkaloids are good for monosubstituted
ketenes but not for disubstituted ones.
[17] CCDC 787203 (cis-4) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[18] The absolute configuration of other oxazolinone derivatives
5b–l was assigned by the comparison of their optical rotation
and/or CD spectra with compound 5a.
[10] The synthesis of oxazolin-4-ones from ketenes and sulfilimines:
a) D. M. Ketcha, M. Abou-Gharbia, F. X. Smith, D. Swern,
Tetrahedron Lett. 1983, 24, 2811; b) M. Abou-Gharbia, D. M.
Ketcha, D. E. Zacharias, D. Swern, J. Org. Chem. 1985, 50, 2224.
[11] For bioactive oxazolin-4-ones, see: V. R. Macherla, J. Liu, M.
Sunga, D. J. White, J. Grodberg, S. Teisan, K. S. Lam, B. C. M.
Potts, J. Nat. Prod. 2007, 70, 1454.
[12] The asymmetric synthesis of a-hydroxy acids through the
[2+2] cycloaddition of ketenes and nitroso compounds: a) M.
Dochnahl, G. C. Fu, Angew. Chem. 2009, 121, 2427; Angew.
Chem. Int. Ed. 2009, 48, 2391; b) I. Chatterjee, C. K. Jana, M.
Steinmetz, S. Grimme, A. Studer, Adv. Synth. Catal. 2010, 352,
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[13] a) D. Enders, J. Han, Tetrahedron Lett. 2008, 49, 1367; b) D.
Enders, J. Han, A. Henseler, Chem. Commun. 2008, 3989; c) D.
Enders, J. Han, Synthesis 2008, 3864.
[19] See the Supporting Information for details.
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Angew. Chem. Int. Ed. 2010, 49, 8412 –8416