Asymmetric 1,3-dipolar cycloaddition reaction of nitrones and acrolein with a bis-titanium catalyst as chiral Lewis acid

Article abstract of DOI:10.1021/ja0523284

A μ-oxo-type chiral bis-Ti(IV) oxide (S,S)-1 can be successfully utilized in the asymmetric 1,3-dipolar cycloaddition reactions between various nitrones 2 and acrolein to give the corresponding isoxazolidines with high to excellent enantioselectivities. F

Full text of DOI:10.1021/ja0523284

Published on Web 08/04/2005
Asymmetric 1,3-Dipolar Cycloaddition Reaction of Nitrones and Acrolein with
a Bis-Titanium Catalyst as Chiral Lewis Acid
Taichi Kano, Takuya Hashimoto, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received April 11, 2005; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Table 1. Asymmetric 1,3-Dipolar Cycloaddition between Nitrone 2
The asymmetric 1,3-dipolar cycloaddition reaction between
nitrones and alkenes is still of great interest in organic synthesis
since the resulting optically active isoxazolidines can easily be
converted into biologically active â-amino acids and â-lactams, as
well as important chiral building blocks, such as γ-amino alcohols.1
In this area, Lewis acid-catalyzed asymmetric 1,3-dipolar cycload-
dition reactions between nitrones and electron-deficient alkenes
(normal electron demand reaction) have been investigated intensely.2-4
In most cases, bidentate dipolarophiles, such as 3-(2-alkenoyl)-2-
oxazolidinones, can be utilized to facilitate the effective coordination
to Lewis acid catalysts in the presence of nitrones having strong
coordination ability.2,4d In addition, N-benzylideneaniline-N-oxide
is employed as a typical acyclic nitrone to achieve high levels of
enantioselectivity; however, such cycloaddition products are not
suitable for further transformations due to the functionally stable
phenyl group on the nitrogen atom.3 Although there have been
several examples of the catalytic asymmetric 1,3-dipolar cycload-
dition with R,â-unsaturated aldehydes as monodentate dipolaro-
philes, the scope and generality of the nitrones remain insufficient.4,5
In this context, we are interested in the possibility of using chiral
bis-metal Lewis acids6-9 that often exhibit unique reactivity and
selectivity in several asymmetric reactions. Here, we wish to report
that bis-Ti(IV) catalyst of type 1 can be successfully utilized to
realize the asymmetric 1,3-dipolar cycloaddition reactions between
various nitrones and acrolein.
and Acroleina
entry
catalyst
(mol %)
conditions
C, h)
yield
(%)b,c
ee (%)d
[config]e
(
°
1
2
(S,S)-1
10
20
0, 2
0, 2
78
40
89 [S]
60 [S]
Ti(Oi-Pr)4
(S)-BINOL
ClTi(Oi-Pr)3
(S)-BINOL
(S,S)-1
3
20
0, 2
36
60 [S]
4
5
10
10
-20, 17
-40, 24
90
94
91 [S]
93 [S]
(S,S)-1
a The reaction of nitrone 2 and acrolein (1.5 equiv) was carried out in
the presence of chiral bis-Ti(IV) oxide (S,S)-1 or chiral mono-Ti(IV) in
CH2Cl2. b Isolated yield. c Only the endo isomer was detected by 1H NMR
spectroscopy. d Determined by HPLC analysis using chiral column (Chiral-
pak OD-H, Daicel Chemical Industries, Ltd.). e Determined by comparison
of the sign of optical rotation with the reported value.5a
Table 2. Asymmetric 1,3-Dipolar Cycloadditions between Nitrones
and Acroleina
The requisite µ-oxo-type bis-Ti(IV) oxide (S,S)-1 was prepared
as described previously by treatment of triisopropoxytitanium
chloride (2 equiv) with Ag2O and subsequent addition of (S)-BINOL
(2 equiv).6 We first investigated the asymmetric 1,3-dipolar
cycloaddition between acrolein and nitrone 2 bearing an easily
removable N-benzyl group, as shown in Table 1. Thus, in the
presence of 10 mol % of bis-Ti(IV) oxide (S,S)-1, nitrone 2 was
treated with acrolein (1.5 equiv) at 0 °C for 2 h to afford the desired
endo-isoxazolidine in 78% yield and 89% ee (entry 1). In contrast,
the reaction catalyzed by 20 mol % of (S)-BINOL/Ti(IV) complexes
prepared from (S)-BINOL/Ti(Oi-Pr)4 or (S)-BINOL/ClTi(Oi-Pr)3
(1:1 molar ratio) gave the cycloadduct in low yields with moderate
enantioselectivities under the same conditions (entries 2 and 3).
Upon further investigation, it was found that by using the lower
temperature (-20 and -40 °C), the isoxazolidine was obtained in
good yields with high enantioselectivities at the expense of the
reaction rate (entries 4 and 5).
a The reaction of nitrones and acrolein (1.5 equiv) was carried out in
the presence of chiral bis-Ti(IV) oxide (S,S)-1 in CH2Cl2 at -40 °C.
b Isolated yield. c Only the endo isomer was detected by 1H NMR
spectroscopy. d Determined by HPLC analysis using chiral column (Chiral-
pak OD-H, Daicel Chemical Industries, Ltd.).
We next examined the scope of asymmetric 1,3-dipolar cycload-
dition between various nitrones and acrolein catalyzed by bis-
Ti(IV) oxide (S,S)-1 under the optimized conditions (Table 2). The
reactions with various aryl-substituted nitrones provided the cor-
responding isoxazolidines with rigorous endoselectivity in high to
9
11926
J. AM. CHEM. SOC. 2005, 127, 11926-11927
10.1021/ja0523284 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Culture, Sports, Science and Technology, Japan. T.H. thanks the
Japan Society for the Promotion of Science for Young Scientists
for Research Fellowships.
Supporting Information Available: Experimental details and
characterization data for new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
excellent enantiomeric excesses (88-94% ee) (entries 1-5). The
sterically hindered tert-butyl-substituted nitrone also showed excel-
lent enantioselectivity (entry 6), while the use of the cyclohexyl
analogue lowered the enantioselectivity (entry 7). Furthermore, the
synthetically useful nitrone with a 1,3-dithianyl group10 could be
successfully utilized in the 1,3-dipolar cycloaddition (entry 8).
Indeed, hydrolysis of the resulting isoxazolidine 3 with mercuric
salts produced the corresponding acetyl isoxazolidine 4 in good
yield (Scheme 1). Meanwhile, TBDPS protection of 3, followed
by reductive desulfurization with Raney-nickel, provided amino
alcohol 5 in moderate yield. In both cases, the transformations
proceeded without any loss of enantiomeric purity.
Plausible reaction pathways have been proposed to account for
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compared to that of other mono-Ti(IV)/BINOL complexes. First,
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may react with the free nitrone, as indicated in [D], to give the
corresponding cycloadduct. The direct attack of acrolein to [A] is
also conceivable.
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the same conditions.
In summary, we have developed an asymmetric 1,3-dipolar
cycloaddition reaction between various nitrones and acrolein
catalyzed by the µ-oxo-type chiral bis-Ti(IV) oxide (S,S)-1, which
gave rise to the corresponding isoxazolidines with high to excellent
enantioselectivities. Further study is underway to expand the scope
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Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
JA0523284
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