S. Kanemasa et al. / Tetrahedron Letters 43 (2002) 657–660
659
4-methine protons in higher fields and formyl proton in
a lower field than those of the minor exo-cycloadduct of
3a whose formyl group is magnetically shielded by the
adjacent cis-phenyl group. The regiochemistry of 3a was
easily characterized by lower chemical shifts of the
5-methylene protons than those of 4a.
(4) the electronically controlled regioisomers are pro-
duced as the major regioisomers in the ATPH-catalyzed
nitrone cycloadditions.
The above effective catalytic cycle of ATPH should be
noteworthy. Participation of betaine intermediates is
likely to effect the catalytic cycle: 1,3-dipolar cycloaddi-
tions possibly proceed stepwise when catalyzed by a
strong Lewis acid catalyst.6 Especially in the catalyzed
reactions via the ATPH/dipolarophile complex, the a-
position of dipolarophiles is sterically so hindered that
the concerted bond formation in the 1,3-dipolar cycload-
ditions becomes rather difficult since it contains bond a
formation at the congested a-position. The betaine
intermediate formed through the stepwise reaction is
followed by cyclization which results in serious steric
hindrance. Then, the free cycloadducts are liberated from
the ATPH/cycloadduct complexes. If this is the case,
ATPH would work as effective catalyst in 1,3-dipolar
cycloaddition reactions using other 1,3-dipoles and a,b-
unsaturated aldehydes. Research along this line is now
under way.
The reaction of nitrone 1 with 3-buten-2-one (2b) shows
a more dramatic change of regioselectivity between the
catalyzed and uncatalyzed reactions. Without catalyst,
the sterically controlled cycloadduct 4b is produced as the
by far major regioisomer after 24 h at room temperature,
albeit only in a poor yield (7%, 3b:4b=92:8). However,
under catalyzed conditions, by use of a catalytic amount
of ATPH, the isoxazolidine-4-carbaldehyde derivative 3b
is produced as a single regioisomer and diastereomer.
Thus, not only the formyl group but also the rather
bulkier methyl keto-group can coordinate to the alu-
minum ion of the ATPH catalyst and can be activated.
Methacrolein (2c) is a 1,1-disubstituted alkene and its
uncatalyzed reaction with nitrone 1 gives 5,5-disubsti-
tuted isoxazolidine 4c as the exclusive and sterically
controlled regioisomer (5% yield). Under ATPH-cataly-
sis, however, this reaction is accelerated at 0°C to give
a 91:9 mixture of regioisomeric cycloadducts 3c and 4c.
In this case, an exclusive reversal of regioselectivity in
favor of the electronically controlled regioisomer 3c can
not be achieved. On the other hand, crotonaldehyde as
a 1,2-disubstituted alkene reacts with nitrone 1 in an
exclusively regioselective manner under both noncata-
lyzed and ATPH-catalyzed conditions to give the isoxa-
zolidine-4-carbaldehyde 3d as the electronically
controlled product. Methyl acrylate is not reactive both
under non-catalyzed and ATPH-catalyzed conditions.
Although the coordination of methyl esters to ATPH is
known,7h a sufficient activation for nitrone cycloaddi-
tions was not observed.
Acknowledgements
This work was partly supported by the Grant-in-Aid for
Scientific Research on Priority Areas (A) (No. 13029087)
from the Ministry of Education, Science, Sports and
Culture, of Japanese Government.
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