tions. One prominent nitrone auxiliary is N-hydroxy-R-
methylbenzylamine, which can be easily cleaved by
hydrogenation.5 However, N-hydroxy-R-methylbenzyl-
amine nitrones 1 (Figure 1) behave poorly with unsub-
stituted alkenes, and moderate diastereoselectivities are
quite common in such 1,3-DC reactions.6
Syn th esis of Cyclic a n d Acyclic â-Am in o
Acid s via Ch ela tion -Con tr olled 1,3-Dip ola r
Cycloa d d ition
Roger Hanselmann,*,† J iacheng Zhou,‡ Philip Ma,§ and
Pat N. Confalone
Bristol-Myers Squibb Pharma Company,
Experimental Station, E 336/ 36, P.O. Box 80336,
Wilmington, Delaware 19880-0336
Hanselmann@Rib-X.com
Received J uly 1, 2003
Abstr a ct: Isoxazolidines have been synthesized in diaster-
eomeric excess up to 94% via a MgBr2-induced chelation-
controlled 1,3-dipolar cycloaddition reaction with N-hydrox-
yphenylglycinol as a chiral auxiliary. The diastereomerically
pure isoxazolidines were further transformed into cyclic and
acyclic â-amino acid derivatives.
F IGURE 1. Intermediate chiral nitrone.
The poor selectivity is likely due to the conformational
flexibility of the intermediate chiral nitrone 1. We became
interested in the possibility of increasing the diastereo-
selectivity of such 1,3-DC reactions by conformationally
constraining the intermediate chiral nitrone, while an
easily cleavable auxiliary was maintained. The N-hy-
droxyphenylglycinol nitrone 2 (Figure 1) fulfills this
requirement nicely.7 The primary hydroxyl group and the
polarized oxygen in 2 are ideally placed for a tight
chelation with an appropriate metal, and the required
N-hydroxyphenylglycinol 4 can be easily synthesized in
both enantiomeric forms from commercially available
phenylglycinol.8 To test this hypothesis, we synthesized
aldehyde 3 and the N-hydroxyphenylglycinol 4 according
to literature procedures.9 When 3 was reacted with
N-hydroxyphenylglycinol 4 in CH2Cl2 in the absence of
any chelating metals, isoxazolidines 5 and 6 were isolated
in a ratio of 63:37. The observed lack of selectivity is
consistent with similar ratios observed with nitrone 1.
However, we were quite pleased to observe dramatic
improvements in the selectivity upon the addition of
MgBr2 (Table 1).10 When the same reaction was per-
formed in the presence of anhydrous MgBr2, the ratio
drastically improved to 93:7 (5:6).
The 1,3-dipolar cycloaddition (1,3-DC) reaction has
emerged as a powerful tool in organic synthesis. The
isoxazolidines formed through 1,3-DC reactions are im-
portant intermediates in the preparation of natural
products, such as alkaloids and â-amino acids. Up to
three continuous stereocenters can be formed through
1,3-DC reactions and the challenge of controlling the
absolute and relative stereochemistry has attracted much
attention in recent years.1
Although some powerful enantioselective synthetic
methodologies have been reported,2 diastereoselective
approaches have proven to be reliable competitive syn-
thetic strategies.1 The diastereoselective 1,3-DC approach
relies on the effective chirality transfer induced by the
chiral auxiliary, which can be located at the nitrone3 or
alkene.4 Of the two options, the chiral nitrone strategy
has proven to be more flexible for further transforma-
† Current address: Rib-X Pharmaceuticals, Department of Chem-
istry, 300 George Street, New Haven, CT, 06511. The research
described was carried out at the former DuPont Pharmaceuticals Co.
‡ Current address: Rib-X Pharmaceuticals, Department of Chem-
istry, 300 George Street, New Haven, CT, 06511. E-mail: Zhou@Rib-
X.com.
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§ Current address: Synica USA Inc., 102 Puckering Way, Suite 200,
Exton, PA. 19341. E-mail: Ma1synicausa@aol.com.
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10.1021/jo034940o CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/10/2003
J . Org. Chem. 2003, 68, 8739-8741
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