Asymmetric synthesis of 1,3-oxazolidines via intramolecular aza-michael addition by bifunctional organocatalysts

Article abstract of DOI:10.1246/cl.121245

A novel synthetic route to optically active 1,3-oxazolidines via formal [3 + 2] cycloaddition in the presence of cinchonaalkaloid- thiourea-based bifunctional organocatalysts is reported. This protocol gives easy access to a wide range of chiral 1,3- oxazolidines. In addition, the results show that bifunctional organocatalysts can effect the intramolecular aza-Michael addition, leading to the asymmetric synthesis of nitrogencontaining heterocycles.

Full text of DOI:10.1246/cl.121245

doi:10.1246/cl.121245
Published on the web March 19, 2013
355
Asymmetric Synthesis of 1,3-Oxazolidines via Intramolecular Aza-Michael Addition
by Bifunctional Organocatalysts
Yukihiro Fukata, Keisuke Asano,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyotodaigaku-katsura, Nishikyo-ku, Kyoto 615-8510
(Received December 14, 2012; CL-121245; E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp)
A novel synthetic route to optically active 1,3-oxazolidines
via formal [3 + 2] cycloaddition in the presence of cinchona-
alkaloid-thiourea-based bifunctional organocatalysts is reported.
This protocol gives easy access to a wide range of chiral 1,3-
oxazolidines. In addition, the results show that bifunctional
organocatalysts can effect the intramolecular aza-Michael
addition, leading to the asymmetric synthesis of nitrogen-
containing heterocycles.
solvents revealed that less polar solvents are more efficient for
the stereoselectivity (Table 1, Entries 8-10).8 When the reaction
was carried out in toluene at 0 °C, the enantioselectivity was
improved to 64% ee (Table 1, Entry 11). Notably, even when
the catalyst loading was reduced to 1 mol %, the stereoselectivity
Table 1. Optimization of conditionsa
Ph
Ts
O
N
O
Ph
Asymmetric 1,3-oxazolidine frameworks are found in
natural products and pharmaceutical compounds.1 They are also
utilized as versatile chiral intermediates leading to ¢-amino-
carbonyl compounds as well as synthetic reagents such as chiral
auxiliaries and ligands.2 Therefore, the development of an
efficient route to various asymmetric 1,3-oxazolidine derivatives
is highly desirable. Nevertheless, their synthesis is based mainly
on optically active starting materials, and there are very few
examples of catalytic enantioselective synthesis methods.3
Recently, we developed several asymmetric cycloetherifi-
cation reactions mediated by bifunctional organocatalysts, which
can facilitate multipoint recognition utilizing hydrogen bonding
in the intramolecular oxy-Michael addition step.4,5 This method-
ology could also be extended to the formal [3 + 2] cycloaddition
of £-hydroxy-¡,¢-unsaturated carbonyls with aldehydes via
hemiacetal intermediates.4b,4c Inspired by our previous results,
we attempted to use this formal cycloaddition approach for the
development of an efficient route to nitrogen-containing chiral
heterocycles through the intramolecular aza-Michael addition
(Scheme 1).6 Herein, we present a novel asymmetric catalytic
formal [3 + 2] cycloaddition method for the synthesis of 1,3-
oxazolidines using cinchona-alkaloid-thiourea-based bifunction-
al organocatalysts.7
major diastereomer
Ts
H
N
O
3aa
catalyst (10 mol%)
+
+
Ts
OH
Ph
Ph
Ph
solvent, 25 °C, 24 h
O
N
1a
2a
O
Ph
minor diastereomer
3aa'
Yield
drc
ee/%
Entry Catalyst Solvent
/%b (3aa:3aa¤) (3aa, 3aa¤)
1
2
3
4
5
6
7
8
9
10
11d
12d,e
13f
14d
15d
16d
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
CHCl3
Et2O
83
78
53
77
63
79
79
93
85
89
95
46
62
53
84
59
2.4:1
3.0:1
2.4:1
2.6:1
2.4:1
2.7:1
2.7:1
5.6:1
4.5:1
4.3:1
2.4:1
2.5:1
2.4:1
3.0:1
9.1:1
10:1
43, 30
59, 44
46, 46
51, 51
55, 48
54, 19
47, 22
54, 22
54, 32
56, 37
64, 59
64, 60
67, 62
53, 48
¹63, ¹40
¹62, ¹24
THF
CPMEg
DMEh
CH3CN
AcOEt
benzene
toluene
xylene
toluene
toluene
toluene
toluene
toluene
toluene
We initiated our investigations by carrying out the formal
cycloaddition of (E)-4-hydroxy-1-phenylbut-2-en-1-one (1a)
with (E)-N-benzylidene-4-methylbenzenesulfonamide (2a) in
the presence of the cinchonidine-derived bifunctional catalyst
4a (10 mol %) in CHCl3 at 25 °C. As expected, 1,3-oxazolidines
were formed as a diastereomer mixture with modest enantio-
selectivity in 83% yield (Table 1, Entry 1). Screening of various
aReactions were run using 1a (0.25 mmol), 2a (0.25 mmol),
and the catalyst (0.025 mmol) in the solvent (0.5 mL). bIsolated
yields. Diastereomeric ratios were determined by 1H NMR.
c
dReactions were run at 0 °C. Reaction was run using 1 mol %
e
f
g
of 4a (0.0025 mmol). Reaction was run at ¹20 °C. CPME:
h
cyclopentyl methyl ether. DME: 1,2-dimethoxyethane.
O
bifunctional
organocatalyst
R''
HN
OH
R'
O
R''
Ar
N
Ar
N
R
NH
NH
R'
O
N
+
O
O
N
NH
NH
H
H
S
S
R''
H
O
R
H
N
H
N
N
N
N
R
H
H
NH
alkoxyamine
intermediate
H
H
R'
NH
N
S
S
NH
Ar
NH
Ar
O
Scheme 1. Formal cycloaddition route to 1,3-oxazolidines
using bifunctional organocatalyst.
4a
4b
4c
4d
Ar = 3,5-(CF3)2C6H3
Chem. Lett. 2013, 42, 355-357
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

356
Table 2. Scope of substratesa
1-Naph
O
Ts
Ts
H
4a (10 mol %)
O
N
R2
O
N
Ts
O
Ts
4a (10 mol %)
toluene, 25 °C
108 h
O
O
N
PhO
+
N
+
OH
1-Naph
2f
PhO
OH
R1
R1
1i
77%
3if
37% ee
single diastereomer
toluene, 0 °C, 24 h
R2
H
1
2
3
O
Yield
ee
/%d
Entry R1
R2
3
drc
TiCl4
CH2Cl2
−78 °C to −40 °C, 4.5 h
O
/%b
TsHN
1
Ph
Ph
3aa
95 2.4:1 64
4-CH3OC6H4 3ab 75 3.7:1 65
5
53%
2e Ph
36% ee
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-CF3C6H4
4-BrC6H4
2-CH3C6H4 3ae
1-naphthyl
2-thienyl
cyclohexyl
t-Bu
3ac
70 4.3:1 66
Scheme 2. Formal [3 + 2] cycloaddition of £-hydroxy-¡,¢-
unsaturated ester 1i with 2f and further transformation to ¢-
amino-£-butyrolactone 5.
3ad 84 3.1:1 51
74 5.3:1 57
95 7.2:1 55
55 9.3:1 53
3af
3ag
1a
1.6 g
(10 mmol)
1) flash column
chromatography
2) recrystallization
8
9
3ah 99 1.9:1 74
3ai 62 2.6:1 87
3ba 58 2.2:1 63
3bf
3ca
3cf
Ph
O
Ts
4a (1 mol %)
O
N
+
3aa/3aa'
2.9 g
(6.8 mmol)
dr = 2.3:1
68% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
4-CH3OC6H4 Ph
4-CH3OC6H4 1-naphthyl
4-CF3C6H4
4-CF3C6H4
4-BrC6H4
4-BrC6H4
2-CH3C6H4 Ph
2-CH3C6H4 1-naphthyl
1-naphthyl
1-naphthyl
2-thienyl
2-thienyl
toluene, 0 °C
108 h
68% yield
2a
2.6 g
(10 mmol)
Ph
88 5.3:1 55
71 4.8:1 66
3aa
1.2 g
(2.8 mmol)
Ph
1-naphthyl
Ph
1-naphthyl
95
11:1 60
3da 84 4.0:1 68
(overall yield: 28%)
single diastereomer
98% ee
3df
3ea
3ef
3fa
3ff
87
55
90
93
87
11:1 60
11:1 23
11:1 19
11:1 24
11:1 20
Scheme 3. Asymmetric synthesis of 1,3-oxazolidine 3aa on a
gram scale.
Ph
1-naphthyl
Ph
1-naphthyl
3ga
3gf
74 2.6:1 61
91 7.2:1 49
to 87% ee was achieved when using imines with alkyl
substituents (Table 2, Entries 8 and 9). We next investigated
the reactions of various enones with imines 2a and 2f (Table 2,
Entries 10-23). In most cases, 2f gave the corresponding 1,3-
oxazolidines with high diastereoselectivity. Both electron-rich
and electron-deficient enones afforded the desired cycloaddition
products (Table 2, Entries 10-13). A substrate bearing a p-
bromophenyl group was tolerated, but o-tolyl- and 1-naphthyl-
substituted enones gave low enantioselectivities (Table 2,
Entries 14-19). Further, heterocycle- or alkyl-substituted enones
gave the corresponding 1,3-oxazolidines with acceptable stereo-
selectivities (Table 2, Entries 20-23). The absolute configuration
of 3af (the major diastereomer) was determined by X-ray
analysis (see Supporting Information for details16),12 and the
configurations of all other examples were assigned analogously.
The £-hydroxy-¡,¢-unsaturated ester 1i could also be used
with this protocol. The reaction of 1i with the imine 2f afforded
3if as a single diastereomer, albeit with low enantioselectivity
(Scheme 2). Subsequent treatment of 3if with titanium tetra-
chloride gave ¢-tosylamino-£-butyrolactone (5).13 The absolute
configuration of 5 was assigned as (R) by comparing the optical
rotation with the literature value13e (see Supporting Information
for details16).14
C6H5(CH2)2 Ph
3ha 45 3.3:1 65
3hf 54 6.3:1 65
23f C6H5(CH2)2 1-naphthyl
aReactions were run using 1 (0.25 mmol), 2 (0.25 mmol), and
4a (0.025 mmol) in toluene (0.5 mL). Isolated yields. Dias-
tereomeric ratios were determined by 1H NMR. dValues are for
the major diastereomers of 3. See Supporting Information for
minor diastereomers.16 eReaction was run at 25 °C. Reaction
b
c
f
was run for 48 h.
remained unchanged (Table 1, Entry 12). No dramatic improve-
ment in the stereoselectivity was observed when the reaction
temperature was decreased to ¹20 °C, and the yield decreased
considerably (Table 1, Entry 13). Catalyst screening identified
that 4c efficiently aided the formation of the opposite enantiomer
of 3aa in good yield and with high stereoselectivity (Table 1,
Entry 15).9
With the optimized conditions and 4a as the catalyst, we
explored the substrate scope (Table 2). £-Hydroxy-¡,¢-unsat-
urated ketones 1 could be prepared readily from commercially
available materials through our reported procedure.10 Using 1a
as the substrate, we examined the feasibility of extending the
reaction to various imines 2 (Table 2, Entries 1-9).11 The
corresponding products were obtained with similar stereoselec-
tivities regardless of the electronic nature of the imine (Table 2,
Entries 2 and 3). An imine bearing a p-bromophenyl group also
afforded the corresponding product (Table 2, Entry 4). In
addition, imines with o-tolyl, 1-naphthyl, and 2-thienyl sub-
stituents gave the cycloadducts with high diastereoselectivity
(Table 2, Entries 5-7). Notably, a high enantioselectivity of up
Although a major limitation of this reaction is its moderate
stereoselectivity, we were able to establish the catalytic synthesis
of enantioenriched 3aa on a gram scale (Scheme 3). Formal
[3 + 2] cycloaddition of 1a (1.6 g, 10 mmol) with 2a (2.6 g,
10 mmol) in the presence of 1 mol % 4a afforded 3aa/3aa¤
(2.9 g, 6.8 mmol, 68% yield) in a 2.3:1 diastereomeric ratio, with
68% ee for the major diastereomer 3aa. Separation of the major
diastereomer by flash silica gel column chromatography using
toluene/EtOAc/hexane (v/v/v = 30/1/10) as an eluent and
Chem. Lett. 2013, 42, 355-357
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

357
1) Zn(BH4)2, Et2O
0 °C, 2.5 h
9783527627844. b) A. G. Doyle, E. N. Jacobsen, Chem. Rev.
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Chem., Int. Ed. 2006, 45, 1520.
Ph
O
Ph
O
Ts
92%, dr = 1:1
O
N
OH HN
2) Na/naphthalene
THF, −78 °C, 1 h
85%
Ph
Ph
6
7
For examples of aminocyclizations utilizing the interaction
between a quinuclidine moiety in an organocatalyst and an
acidic N-H group, see: a) L. Zhou, J. Chen, C. K. Tan, Y.-Y.
Yeung, J. Am. Chem. Soc. 2011, 133, 9164. b) J. Chen, L.
Zhou, Y.-Y. Yeung, Org. Biomol. Chem. 2012, 10, 3808.
a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2003, 125, 12672. b) T. Okino, Y. Hoashi, T. Furukawa, X.
Xu, Y. Takemoto, J. Am. Chem. Soc. 2005, 127, 119. c) B.
Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7,
1967. d) A. Hamza, G. Schubert, T. Soós, I. Pápai, J. Am.
Chem. Soc. 2006, 128, 13151. e) S. J. Connon, Chem.®Eur.
J. 2006, 12, 5418. f) J.-L. Zhu, Y. Zhang, C. Liu, A.-M.
Zheng, W. Wang, J. Org. Chem. 2012, 77, 9813.
3aa
98% ee
6
98% ee
Scheme 4. Deprotection of 3aa.15
subsequent one-time recrystallization with 2-propanol gave 1.2 g
of 3aa (2.8 mmol, overall yield: 28%) with 98% ee. Besides, the
tosyl group could be removed after reduction of the carbonyl
group by treatment with sodium naphthalenide to afford 6 in
high yield without any deterioration of the optical purity
(Scheme 4).
In summary, we have developed a novel, efficient route to
a wide range of optically active 1,3-oxazolidines via organo-
catalytic formal [3 + 2] cycloaddition. Despite its moderate
stereoselectivity, this protocol is expected to contribute signifi-
cantly to the construction of a 1,3-oxazolidine library. In
addition, we have demonstrated that bifunctional organocatalysts
can aid the asymmetric synthesis of nitrogen-containing hetero-
cycles via the intramolecular aza-Michael addition. Further
studies toward stereoselectivity improvement and the application
of this methodology to the synthesis of other heterocycles are
currently underway in our laboratory. The results of these studies
will be reported in due course.
8
9
With an increase in the reaction time when using toluene as a
solvent at 25 °C, the diastereomeric ratio improved, but the
ee decreased slightly. See Supporting Information for more
details, Table S1.16
Results of further catalyst screening were listed in Support-
ing Information (Table S2).16
10 M. Sada, S. Ueno, K. Asano, K. Nomura, S. Matsubara,
Synlett 2009, 724.
11 Reactions of imines with other protecting groups on the
nitrogen atom were also investigated; sterically hindered
imines such as N-mesitylsulfonylimine and N-(2-nosyl)-
imine dramatically improved the diastereoselectivity but
caused a slight decrease in the ee. See Supporting Informa-
tion for more details, Table S3.16
12 The absolute configuration of 3aa¤ (the minor diastereomer)
was determined by X-ray analysis to be as follows (see
Supporting Information for details).16
We thank Professor Takuya Kurahashi (Kyoto University)
for X-ray crystallographic analysis. This work was supported
financially by the Japanese Ministry of Education, Culture,
Sports, Science and Technology.
Ph
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Ts
O
N
1
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Ph
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14 The relative configuration of 3if was determined by X-ray
analysis. See Supporting Information for details.16
4
5
15 The reduction of 3aa with Zn(BH4)2 gave a diastereomer
mixture (1/1). One of the isolated diastereomers of the
alcohol obtained by reduction was used for subsequent
deprotection. See Supporting Information for more details.16
16 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
For reviews on asymmetric catalysis based on hydrogen
bonding, see: a) Hydrogen Bonding in Organic Synthesis, ed.
by P. M. Pihko, Wiley-VCH, Weinheim, 2009. doi:10.1002/
Chem. Lett. 2013, 42, 355-357
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/