Chiral DBFOX/Ph Complex catalyzed enantioselective nitrone cycloadditions to α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol0361148

1,3-Dipolar cycloadditions of nitrones with α-alkyl- and α-arylacroleins are catalyzed with the DBFOX/Ph complexes of nickel(II) and magnesium-(II) salts to produce the sterically controlled isoxazolidine-5-carbaldehydes, while the reactions with α-bromoa

Full text of DOI:10.1021/ol0361148

ORGANIC
LETTERS
2004
Vol. 6, No. 5
675-678
Chiral DBFOX/Ph Complex Catalyzed
Enantioselective Nitrone Cycloadditions
to r,â-Unsaturated Aldehydes
Moto Shirahase,† Shuji Kanemasa,* and Yoji Oderaotoshi‡
Institute for Materials Chemistry and Engineering, CREST of JST (Japan Science and
Technology Agency), Kyushu UniVersity, 6-1 Kasugakoen, Kasuga 816-8580, Japan,
Department of Molecular and Material Sciences, Graduate School of Engineering
Sciences, Kyushu UniVersity, 6-1 Kasugakoen, Kasuga 816-8580, Japan, and
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Suita 565-0871, Japan
kanemasa@cm.kyushu-u.ac.jp
Received October 29, 2003
ABSTRACT
1,3-Dipolar cycloadditions of nitrones with r-alkyl- and r-arylacroleins are catalyzed with the DBFOX/Ph complexes of nickel(II) and magnesium-
(II) salts to produce the sterically controlled isoxazolidine-5-carbaldehydes, while the reactions with r-bromoacrolein are effectively catalyzed
with the zinc(II) complexes to produce the electronically controlled isoxazolidine-4-carbaldehydes. Enantioselectivities up to 99.5% ee have
been observed in the reactions performed at room temperature.
Catalyzed enantioselective 1,3-dipolar cycloadditions of
nitrones provide a direct synthetic access to enantiomers of
isoxazolidines whose high synthetic potential is based on
their transformations to γ-amino alcohols through reductive
cleavage of the nitrogen-oxygen bond.1 Although various
chiral Lewis acids have been successfully applied to make
isoxazolidines through nitrone cycloadditions,2,3 the nickel-
(II) or iron(II) chiral complexes derived from DBFOX/Ph
ligand3 and the nickel(II) complexes derived from Pybox2i
are among those that thus far provide the best results. Strong
binding of nitrones to the catalyst is a serious problem in
the Lewis acid catalyzed nitrone cycloadditions, and there-
fore, bidentate dipolarophiles such as 3-(2-alkenoyl)-2-
oxazolidinones have been mostly used to secure the tight
coordination of acceptors to the catalyst.2,3 Successful use
of monodentate dipolarophiles in the metal complex cata-
lyzed nitrone cycloadditions has remained relatively un-
explored,4-6 while a few examples of the chiral amine
(2) Reactions with two-point binding dipolarophiles: (a) Gothelf, K. V.;
Jørgensen, K. A. J. Org. Chem. 1994, 59, 5687-5691. (b) Seebach, D.;
Marti, R. E.; Hintermann, T. HelV. Chim. Acta 1996, 79, 1710-1740. (c)
Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. Tetrahedron Lett. 1996, 37,
5947-5950. (d) Jensen, K.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K.
A. J. Org. Chem. 1997, 62, 2471-2477. (e) Kobayashi, S.; Kawamura, M.
J. Am. Chem. Soc. 1998, 120, 5840-5841. (f) Hori, K.; Kodama, H.; Ohta,
T.; Furukawa, I. J. Org. Chem. 1999, 64, 5017-5023. (g) Desimoni, G.;
Faita, G.; Mortoni, A.; Righetti, P. Tetrahedron Lett. 1999, 40, 2001-2004.
(h) Kodama, H.; Ito, J.; Hori, K.; Ohta, T.; Furukawa, I. J. Organomet.
Chem. 2000, 603, 6-12. (i) Iwasa, S.; Tsushima, S.; Shimada, T.;
Nishiyama, H. Tetrahedron Lett. 2001, 42, 6715-6717.
† Graduate School of Engineering Sciences, Kyushu University.
‡ Graduate School of Engineering, Osaka University.
(3) Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem.
Soc. 1998, 120, 12355-12356.
(1) For recent reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Chem.
ReV. 1998, 98, 863-909. (b) Gothelf, K. V.; Jørgensen, K. A. Chem.
Commun. 2000, 1449-1458. (c) Gothelf, K. V.; Jørgensen, K. A. Asym-
metric Reactions. In Synthetic Application of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson,
W., Eds.; John Wiley & Sons: New York, 2002; Chapter 12, pp 817-
899.
(4) Kanemasa, S.; Ueno, N.; Shirahase, M. Tetrahedron Lett. 2002, 43,
657-660.
(5) Viton, F.; Bernardinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc. 2002,
124, 4968-4969.
(6) (a) Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4,
2457-2460. (b) Ohtsuki, N.; Kezuka, S.; Kogami, Y.; Mita, T.; Ashizawa,
T.; Ikeno, T.; Yamada, T. Synthesis 2003, 9, 1462-1466.
10.1021/ol0361148 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/29/2004

catalyzed nitrone cycloadditions have been reported.7,8
Therefore, catalyzed enantioselective nitrone cycloadditions
to R,â-unsaturated aldehydes are still a challenging research
subject.
We have recently reported that a pinhole catalyst ef-
fectively activates nitrone cycloadditions to R,â-unsaturated
aldehydes and ketones.4 Nitrones should coordinate pre-
dominantly to the catalyst in Lewis acid-catalyzed nitrone
cycloadditions.9 However, if the resulting Lewis acid/nitrone
complexes still have a catalytic capability, the complexes
would work as chiral pinhole catalysts (Scheme 1, A and B,
5-carbaldehyde 3 as a sterically controlled regioisomer as
shown in Scheme 1.10 Reduction of 3 with NaBH4 produced
isoxazolidine-5-methanol 4 (73% based on 1a) whose
enantiopurity was determined to be 96% ee.11,12 Although
the zinc(II) complex catalyst B (X ) ClO4) was more active
than the nickel(II) complex A, the product obtained after
the reduction of 3 with NaBH4 was a 55:45 regioisomeric
mixture of 4 (95% ee) and 4′ (83% ee) as shown in Table 1.
Table 1. Enantioselective Nitrone Cycloadditions to
R,â-Unsaturated Aldehydesa
Scheme 1
Ln ) nitrone(s) and/or anionic counterion(s)) and effective
activation of R,â-unsaturated aldehydes can be expected. This
expectation has actually been realized.
In this paper, we describe the DBFOX/Ph complex
catalyzed enantioselective nitrone reactions to R,â-unsatur-
ated aldehydes. The sterically controlled isoxazolidine-5-
carbaldehydes are produced in the reactions of R-alkyl- and
R-arylacroleins in the presence of either nickel(II) or
magnesium complexes, while the electronically controlled
isoxazolidine-4-carbaldehydes are given in the zinc(II)
complex-catalyzed reactions with R-bromoacrolein. The
reactions with other aldehydes such as acrolein, crotone-
aldehyde, and 1-cyclopentenecarbaldehyde have been ex-
amined under the catalysis of nickel(II), zinc(II), and cobalt-
(II) complexes. It has been found that a variety of DBFOX/
Ph complexes of zinc(II) salts are isolable and storable in
open air without loss of catalytic activity, and replacement
of one iodide anion of the ZnI2 complex with a noncoordi-
nating anion leads to the most powerful catalysts. Enanti-
oselectivities up to 99.5% ee have been observed in the
reactions performed at room temperature.
a In room temperature in dichloromethane in the presence of 10 mol %
of the DBFOXPh complex catalyst and MS 4A. b rs: regioselectivity. ds:
diastereoselectivity. c Products were obtained by reduction of the cycload-
ducts with sodium borohydride in ethanol.
Thus, the zinc complex B tends to activate the formation of
electronically controlled cycloadduct 4′. In our previous
theoretical work on Lewis acid catalyzed nitrone cyclo-
additions,9 a stronger Lewis acid favors the preferred
formation of electronically controlled cycloadducts.
Reaction of N-benzylideneaniline N-oxide (1a) with meth-
acrolein (2) in dichloromethane at room temperature (48 h)
in the presence of MS 4A (500 mg/mmol) and 10 mol % of
the nickel(II) complex A, prepared by stirring equivalents
of R,R-DBFOX/Ph and Ni(ClO4)2‚6H2O in the same solvent
for a few hours, gave a single diastereomer of isoxazolidine-
(10) General experimental procedures have been described in the
Supporting Information for the reactions between nitrone 1a and meth-
acrolein (2) as well as between 1a and R-bromoacrolein (5).
(11) In the reactions of 1a to 2 and 5, chemical yields and regio- and
diastereoselectivities are given for isoxazolidinecarbaldehydes 3 and 6, while
enantioselectivities are given for isoxazolidinemethanols 4 and 7.
(12) Enantioselectivities have been determined on the basis of the chiral
hplc analysis (Daicel Chiral Cell OD-H) for isoxazolidine methanols 4 and
7.
(7) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 9874-9875.
(8) Karlsson, S.; Hoegberg, H.-E. Eur. J. Org. Chem. 2003, 15, 2782-
2791.
(9) Tanaka, J.; Kanemasa, S. Tetrahedron 2001, 57, 899-905.
676
Org. Lett., Vol. 6, No. 5, 2004

1,3-Dipolar cycloadditions of nitrone 1a with a variety of
R,â-unsaturated aldehydes were examined, and the results
are listed in Table 1. In all cases of nitrone cycloadditions
to R,â-unsaturated aldehydes, the use of MS 4A was essential
in order to attain high reactivity and selectivities. For
example, reaction of 1a with 5 catalyzed by the zinc(II)
complex B (X ) OTf) at -40 °C in the absence of MS 4A
resulted in much lower chemical yields and selectivities (46
h, 36%, endo/exo ) 87:13 for 6a, 86% ee for 7a).
Accordingly, all the reactions shown in Table 1 have been
performed in the presence of MS 4A (500 mg/mmol).
The nitrone cycloaddition of 1a with R-bromoacrolein (5),
which is more electrophilic than 2, is sluggish under
uncatalyzed conditions, and the electronically controlled
isoxazolidine-4-carbaldehyde regioisomer 6a was given as
a 51:49 diastereoisomeric mixture only in a poor yield (41
h, 23%). Switch of the regioselectivity observed is di-
polarophile-controlled due to the strongly electron-withdraw-
ing nature of R-bromide moiety of 5. The nickel(II) complex
catalyst A (X ) ClO4) was not effective to activate this
reaction showing poor catalytic activation and enantioselec-
tivity (31% after 41 h at room temperature, endo/exo )
90:10, 42% ee for the major endo-6a). However, we have
found that the zinc(II) complex B is the most effective
catalyst. Thus, the catalyzed reaction was completed in 1 h
at room temperature in the presence of the zinc(II) complex
B (X ) OTf, 10 mol %)13 and MS 4A, producing a 95:5
diastereomeric mixture of 6a in 85% yield (Scheme 2).10-12
nickel(II) complex A (X ) ClO4), but enantioselectivities
were excellent both for regioisomers 13 and 13′. Reactions
to R-ethylacrolein (9) and R-phenylacrolein (10), having an
R-substituent bulkier than that of 2, were exclusively
regioselective in favor of the sterically controlled isoxazo-
lidine-5-methanols 14 and 15, respectively, under the ca-
talysis of the nickel(II) and magnesium(II) complexes,
followed by the sodium borohydride reduction. However,
enantioselectivities in these cases were moderate. Croton-
aldehyde (11) as 1,2-disubstituted alkene was successfully
activated with the zinc(II) complex B (X2 ) IOTf) to show
the exclusive regioselectivity, but both diastereoselectivity
and enantioselectivity were low. Although other catalysts
failed to activate cyclopentene-1-carbaldehyde (12), high
enantioselectivity was attained only by catalysis of the cobalt-
(II) perchlorate complex.
A dramatic difference of catalytic effectiveness was
observed depending upon the halide counteranions of the
zinc complex catalysts (Scheme 2). Thus, the zinc(II) iodide
complex B (X ) I) effectively activated the reaction of
nitrone 1a with R-bromoacrolein 5 showing excellent
selectivities (3 h at room temperature, 72%, endo/exo ) 94:6
for 6a, 95% ee for 7a). However, to our surprise, the zinc-
(II) bromide complex B (X ) Br) gave much lower
selectivities (10 h, 65%, endo/exo ) 81:19 for 6a, 16% ee
for 7a). Based on the difference of bond energies between
the Zn-I and Zn-Br bonds,14 we believe that at least one
of the iodide anions of complex B (X ) I) is dissociated
from the metal center of the complex under the reaction
conditions, while both bromide ions of complex B (X ) Br)
stay on the zinc metal.
Scheme 2
When one of the bromide ions of B (X ) Br) was replaced
with a less coordinating perchlorate anion by treatment with
1 equiv of AgClO4, a great improvement of both reactivity
and selectivities resulted as shown in Scheme 2 (3 h, 90%,
endo/exo ) 95:5 for 6a, 94% ee for 7a). This indicates that
the zinc(II) bromide complex B (X ) Br), which has only
one vacant position on the metal center, shows insufficient
catalytic activity in the nitrone cycloadditions with R-bro-
moacrolein; two vacant positions are essential for both high
catalytic activity and selectivity. These observations provide
us important information for the consideration of reaction
mechanism.
It should be noted that the zinc(II) halide complexes B
(X ) I and Br) were isolable and storable in open air without
loss of catalytic activity.15 Exchange of either one or both
of the iodide ions of complex B (X ) I) with noncoordinating
counteranions such as perchlorate, tetrafluoroborate, and
triflate ions leads to the corresponding zinc(II) complexes
which are more reactive catalysts. All of the resulting
complexes were again stable enough to be isolated and
stored.15 Thus, when the catalysts either in situ-prepared or
isolated were employed in the reactions of 1a with 5 and
Enantioselectivity of the major endo cycloadduct 6a was
determined to be 98% ee after its NaBH4 reduction to
isoxazolidine-4-methanol 7a. Thus, the electronically con-
trolled regioisomer 6a was the sole product in the reaction
of 1a with 5, regardless of the presence or absence of catalyst
The reaction of nitrone 1a with acrolein (8) showed a low
regioselectivity (rs ) 74:26) even under the catalysis of the
(14) The bond energy for the first ionization of ZnBr2 is much higher
than that of ZnI2 (Liao, M.-S.; Zhang, Q.; Schwarz, W. H. E. Inorg. Chem.
1995, 34, 5597-5605).
(13) The DBFOX/Ph complex of zinc(II) triflate was prepared by stirring
equimolr amounts of the ligand and Zn(OTf)2 in dichloromethane for a
few hours at room temperature. The resulting heterogeneous mixture was
used for the subsequent reactions with nitrones.
(15) 1H NMR Spectra of the derivative of DBFOX/Ph‚ZnX2 complexes
will be reported elsewhere in near future. Shirahase, M.; Kanemasa, S.;
Hasegawa, M. Manuscript in preparation.
Org. Lett., Vol. 6, No. 5, 2004
677

the catalytic activity was compared, comparable results were
observed to confirm the high stability of all these complex
catalysts. Especially active were the R,R-DBFOX/Ph com-
plexes of zinc salts having the formula of ZnIClO4 and
ZnIBF4, which can be derived by treatment of the diiodide
complex B (X ) I) with one equivalent amount of silver
ions bearing a less coordinating anion. When the reaction
temperature was lowered to -40 °C (40 h) either in the
reaction catalyzed by the complex derived from B (X ) I)
and AgClO4 (1 equiv, 10 mol %) or that catalyzed by the
complex B (X ) OTf), endo cycloadduct 6a was produced
in 83 or 94% with an enantioselectivity of 99.5 or 99.7% ee
for 7a, respectively.
assigned as shown in Table 1 on the basis of the expected
structural similarity of 9 and 10 to the starting material 2.
Absolute configuration of the cycloadduct 17 to cyclopen-
tene-1-carbaldehyde (12) was detremined to be 3R,3aS,6aS-
enantiomer by comparison of its optical rotation of the
authentic sample.5b Other cycloadducts 13 and 16 derived
from 8 and 11, respectively, remained uncharacterized.
After optimization, the reactions of nitrones 1a-g having
a variety of C-substituents with R-bromoacrolein 5 were
examined in the presence of a catalytic amount (10 mol %)
of the zinc(II) complex B (X2 ) IClO4) at room temperature
(Scheme 3). In almost all the cases, excellent endo selectivi-
Scheme 3
Figure 1. Absolute configurations of derivatives of isoxazolidine-
5-methanol 18 and -4-methanol 19.
In conclusion, nitrone cycloadditions to a variety of R,â-
unsaturated aldehydes were effectively catalyzed by the
nickel(II), zinc(II), magnesium(II), and cobalt(II) complexes
derived from the R,R-DBFOX/Ph ligand. Highly useful were
the nickel(II) and magnesium(II) complexes for the reactions
of methacrolein, and the zinc(II) complexes for the reactions
of R-bromoacrolein. Especially active are the catalysts
derived from the ZnI2 complex by replacement of an iodide
anion with a noncoordinating anionic ligand. The highest
enantioselectivity up to 99.5% ee was observed in the
reaction with R-bromoacrolein performed at room temper-
ature. Other R-substituted acrolein derivatives as well as
1-cyclopentenecarbaldehyde were also effectively catalyzed.
Thus, the reactions of acyclic nitrones with R,â-unsaturated
aldehydes, catalyzed by DBFOX/Ph complexes, provided
much higher enantioselectivities than the reported examples.
ties and enantioselectivities were obtained for isoxazolidine-
4-carbaldehydes 6a-g and isoxazolidine-4-methanols 7a-
g. In particular, N-(2-naphthylmethylene)aniline N-oxide (1g)
produced the isoxazolidine-4-methanol derivative 7g in an
absolutely high enantioselectivity of 99.5% ee in the reaction
performed at room temperature. Such high generality of
C-substituents of nitrones 1 in the reactions to 5 is also a
synthetic advantage of our enantioselective nitrone cyclo-
additions.
The absolute configurations of 3 and 6a were determined
to be the 3R,5R- and 3R,4R-enantiomers on the basis of X-ray
crystal structures of the p-bromobenzoate derivatives 18 and
19 of isoxazolidine methanols 4 and 7a, respectively.16 This
indicates that the preferred attack of nitrones to the Re(R)-
faces of R,â-unsaturated aldehydes 2 and 5 took place in
the transition structure of these nitrone cycloadditions. The
absolute configurations of 14 and 15 were temporarily
Acknowledgment. Financial support from the Grant-in-
Aid for Scientific Research on Priority Areas (A) (No.
13029087) from the Ministry of Education, Culture, Sports,
Science and Technology of Japanese Government is ac-
knowledged.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds as well as
X-ray crystallographic data of p-bromobenzoates of 4 and
7a. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) X-ray analysis data for 18 and 19 are given in the Supporting
Information.
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