Anionic Inverse Electron-Demand 1,3-Dipolar Cycloaddition of Nitrones with Ynolates. Facile Stereoselective Synthesis of 5-Isoxazolidinones Leading to β-Amino Acids

Article abstract of DOI:10.1021/ol0264455

(Equation Presented) The inverse electron-demand 1,3-dipolar cycloaddition of nitrones with ynolates, followed by quenching with t-BuOH, produced substituted 5-isoxazolidinones with good trans-selectivity. These products were easily converted into β-amino

Full text of DOI:10.1021/ol0264455

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3119-3121
Anionic Inverse Electron-Demand
1,3-Dipolar Cycloaddition of Nitrones
with Ynolates. Facile Stereoselective
Synthesis of 5-Isoxazolidinones Leading
to â-Amino Acids
Mitsuru Shindo,*,†,‡ Kotaro Itoh,† Chinatsu Tsuchiya,‡ and Kozo Shishido‡
Institute for Medicinal Resources, UniVersity of Tokushima,
Sho-machi 1, Tokushima 770-8505, Japan, and PRESTO,
Japan Science and Technology Corporation
shindo@ph2.tokushima-u.ac.jp
Received July 1, 2002
ABSTRACT
The inverse electron-demand 1,3-dipolar cycloaddition of nitrones with ynolates, followed by quenching with t-BuOH, produced substituted
5-isoxazolidinones with good trans-selectivity. These products were easily converted into â-amino acids.
The 1,3-dipolar cycloaddition of nitrones with alkenes1 is
an important method for preparing isoxazolidines, which can
be converted into numerous building blocks for organic
synthesis. Commonly, these cycloadditions involve the
reaction of an electron-deficient alkene dipolarphile (LUMO)
with a nitrone (HOMO). In inverse electron-demand 1,3-
dipolar cycloadditions, alkenyl ethers or ketene acetals are
used as electron-rich dipolarphiles (HOMO); nitrone (LUMO)
activation by Lewis acids and/or with electron-withdrawing
substituents or high reaction temperature are required.2
However, uncatalyzed anionic 1,3-dipolar cycloadditions of
nonactivated nitrones have not yet been reported, as far as
we know.
Since developing a new synthetic method for ynolates,3
we have continued our investigation of ynolate chemistry,4
including [2 + 2] cycloadditions.3,5 Although ynolates can
be potentially dipolarophilic, there have been no reports on
1,3-dipolar [3 + 2] cycloadditions of ynolates. Herein, we
describe the first anionic inverse electron-demand 1,3-dipolar
cycloaddition of ynolates with nitrones to provide syntheti-
cally useful 5-isoxazolidinones6 leading to â-amino acids
(Scheme 1).
(2) For recent examples, see: (a) Kanemasa, S.; Tsuruoka, T.; Wada, E
Tetrahedron Lett. 1993, 34, 87-90. (b) Seerden, J.-P. G.; Scholte op Reimer,
A. W. A.; Scheeren, H. W. Tetrahedron Lett. 1994, 35, 4419-4422. (c)
Simonsen, K. B.; Bayon, P.; Hazell, R. G.; Gothelf, K. V.; Jorgensen, K.
A. J. Am. Chem. Soc. 1999, 121, 3845-3853. (d) Tamura, O.; Gotanda,
K.; Yoshino, J.; Morita, Y.; Terashima, R.; Kikuchi, M.; Miyawaki, T.;
Mita, N.; Yamashita, M.; Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000,
65, 8544-8551.
† PRESTO, Japan Science and Technology Corporation.
‡ University of Tokushima.
(1) For reviews, see: (a) Padwa, A. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p
1069. (b) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990. (c) Kobayashi, S., Jorgensen, K. A., Eds.
Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Oxford,
2002. (d) Frederickson, M. Tetrahedron 1997, 53, 403-425. (e) Gothelf,
K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909. (f) Gothelf, K.
V.; Jorgensen, K. A. Chem. Commun. 2000, 1449-1458. (g) Padwa, A.,
Pearson, W. H., Eds.; Chemistry of Heterocyclic Compounds; Wiley: New
York, 2002; Vol. 58.
(3) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433-4436. (b) Shindo,
M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411-2422. (c) Shindo,
M.; Koretsune, R.; Yokota, W.; Itoh, K.; Shishido, K. Tetrahedron Lett.
2001, 42, 8357-8360.
(4) For reviews, see: (a) Shindo, M. Chem. Soc. ReV. 1998, 27, 367-
374. (b) Shindo, M. J. Synth. Org. Chem. Jpn. 2000, 58, 1155-1166. (c)
Shindo, M. Yakugaku Zasshi 2000, 120, 1233-1246. See, also: (d) Shindo,
M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000, 65, 5443-5445. (e) Shindo,
M.; Matsumoto, K. Mori, S.; Shishido, K. J. Am. Chem. Soc. 2002, 124,
6840-6841.
10.1021/ol0264455 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/08/2002

by using several proton sources and quenching conditions,
as shown in Table 1. When the reaction was protonated with
Scheme 1
Table 1. Protonation of the 5-Isoxazolidinone Enolates
entry
HX
conditions
yield (%) trans:cis
1
2
3
4
5
6
7
aq NaHCO3
phenol
2,6-dimethylphenol -78 °C
AcOH
TFA
-78 °C
-78 °C
70
70
79
70
58
57
77
93:7
79:21
58:42
68:32
60:40
>99:1
>99:1
First, we examined the reaction of the ynolate (1a) with
the nitrone (2a) bearing a N-phenyl substituent (Scheme 2).
-78 °C
-78 °C
-78 °C; 0 °C
-78 °C; 0 °C
EtOH
t-BuOH
Scheme 2
an aqueous NaHCO3 solution at -78 °C, 4b was obtained
in the trans/cis ratio of 93:7 (entry 1). The trans product
was formed predominantly under the kinetic conditions
presumably as a result of the steric interaction between the
methyl and phenyl substituents in the late transition state of
the protonation.7 Quenching with more sterically hindered
(entries 2 and 3) and more acidic (entries 4 and 5) proton
sources gave poorer ratios. However, when the reaction was
quenched with ethanol at -78 °C and warmed to 0 °C to
effect isomerization to the thermodynamically stable prod-
ucts, complete trans selectivity was achieved (entry 6).
To a -78 °C THF solution of the ynolate (1a), generated
from the R,R-dibromoester (3a) with t-BuLi, was added
N-phenyl nitrone (2a). After 1 h, no starting nitrone remained
and the reaction was quenched with saturated aqueous
NaHCO3. After workup and purification, we isolated the
desired 5-isoxazolidinone (4a) in 74% yield. Since no
4-oxazolidinone was detected, the regioselectivity was excel-
lent, probably as a result of the FMO interaction. Next, the
cycloaddition with the N-benzyl nitrone (2b) was carried out
at -78 °C but did not take place. The reaction proceeded at
0 °C to afford the desired 5-isoxazolidinone (4b) in 70%
yield. Despite the lower reactivity of the N-benzyl nitrones,
we used them in further reactions because of the facile
removal of the N-substituent from the products.
Table 2. 1,3-Dipolar Cycloaddition of Ynolates with Nitrones
To Afford 5-Isoxazolidinones
entry
R1
R2
Me
Me
Et
quencha
4
yield (%)
trans:cis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15b
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
iPr
Me
A
B
A
B
A
B
A
B
A
B
A
A
B
A
A
4c
4c
4d
4d
4e
4e
4f
4f
4g
4g
4h
4i
42
53
85
85
77
35
17
56
37
59
80
72
67
75
76
83:12
>99:1
86:14
89:11
9:91
>99:1
10:90
>99:1
78:22
>99:1
86:14
18:82
91:9
The ratio of the cis and trans diastereomers of the
5-isoxazolidinones should be dependent on the method used
to quench the reaction. We then attempted to control the ratio
Et
iPr
iPr
tBu
tBu
Me
Me
Et
iPr
iPr
Ph
(5) For pioneering work on cycloaddition of aldehydes and ketones,
see: (a) Scho¨llkopf, U.; Hoppe, I. Angew. Chem., Int. Ed. Engl. 1975, 14,
765. (b) Hoppe, I.; Scho¨llkopf, U. Liebigs Ann. Chem. 1979, 219-226. (c)
Kowalski C. J.; Fields, K. W. J. Am. Chem. Soc. 1982, 104, 321-323.
Cycloaddition of aldimines: (d) Shindo, M.; Oya, S.; Sato, Y.; Shishido,
K. Heterocycles 1998, 49, 113-116. (e) Shindo, M.; Oya, S, Murakami,
R. Sato, Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 5943-5946. (f)
Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.; Shishido, K. Tetrahedron
Lett. 2000, 41, 5947-5950.
(6) For examples of syntheses of 5-isoxazolidinones, see: (a) Sibi, M.
P.; Liu, M. Org. Lett. 2001, 3, 4181-4184. (b) Ishikawa, T.; Nagai, K.;
Senzaki, M.; Tatsukawa, A. Saito, S. Tetrahedron 1998, 54, 2433-2448.
(c) Panfil, I.; Maciejewski, S.; Belzecki, C.; Chielewski, M. Tetrahedron
Lett. 1989, 30, 1527-1528. (d) Baldwin, J. E.; Harwood: L. M.; Lombard,
M. J. Tetrahedron 1984, 40, 4363-4370.
4i
4j
4k
96:4
70:30
CO2Et
a Method A: quenching with aqueous NaHCO3 at -78 °C. Method B:
quenching with t-BuOH at -78 °C, then warming to 0 °C. b The cyclo-
addition was carried out at -78 °C.
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Org. Lett., Vol. 4, No. 18, 2002

Finally, quenching with tert-butyl alcohol afforded the best
result (entry 7). Thus, the trans-5-isoxazolidinones (4) were
produced in good yield with excellent stereoselectivity via
the thermodynamically controlled protonation method.
To test the generality of this cycloaddition, we examined
reactions using several kinds of nitrones and ynolates. As
shown in Table 2, the 5-isoxazolidinones were obtained
regiospecifically in good to moderate yields. In the reactions
of sterically hindered nitrones, the cis-products were pre-
dominantly produced via kinetic protonation (quenching
method A), probably as a result of the steric interaction
between R1 and the proton source in the early transition states
(entries 5 and 7). The thermodynamically controlled pro-
tonation (quenching method B) provided the desired 5-isox-
azolidinones with high trans-selectivity (entries 2, 4, 6, 8,
10, and 13). The nitrone bearing an ester (R2 ) CO2Et)
showed higher reactivity and gave the product (4k) at -78
°C (entry 15).
Scheme 4
In conclusion, we have developed a 1,3-dipolar cyclo-
addition of ynolates with nitrones to afford 5-isoxazolidi-
nones having good trans-selectivity and excellent regio-
selectivity. This is the first example of a [3 + 2] cyclo-
addition of an anionic dipolarophile with nonactivated
nitrones not using Lewis acids. Since the cycloadducts are
enolates, this reaction can be used in tandem reactions. This
is a short, stereoselective access to â-amino acids, since the
resulting 5-isoxazolidinones can be easily reduced in high
yield.
The 3,4-dihydroisoquinoline N-oxides (5, 7) also afforded
the desired cycloadducts (6, 8) (Scheme 3).
Scheme 3
Scheme 5
Acknowledgment. This research was partially supported
by a Grant in Aid for Scientific Research on Priority Areas
(A) “Exploitation of Multi-Element Cyclic Molecules” from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
The cycloadducts, nucleophilic 5-isoxazolidinone enolates,
can react with electrophiles. As shown in Scheme 4, one-
pot alkylation reactions provided the 3,4,4-trisubstituted
isoxazolidinones (9, 10) in good yields, and 10 was obtained
as a single isomer.
Supporting Information Available: Experimental pro-
cedure and spectral data of selected compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
The 5-isoxazolidinones (4) thus prepared can be converted
into 2,3-disubstitutred â-amino acids (11) via hydrogenation6d
in excellent yields without isomerization (Scheme 5).
OL0264455
(7) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185.
Org. Lett., Vol. 4, No. 18, 2002
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