Improvement of TADDOLate-TiCl2-Catalyzed 1,3-Dipolar Nitrone Cycloaddition by Substitution of the Oxazolidinone Auxiliary of the Alkene with Succinimide

Article abstract of DOI:10.1021/jo962214y

A significant improvement of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of acyclic nitrones with α,β-unsaturated carbonyl compounds is described using succinimide as a new auxiliary for the α,β-unsaturated carbonyl moiety. In the absence of a catalyst, N-crotonoylsuccinimide reacts with C,N-diphenylnitrone to give the endo-isoxazolidine, whereas in the presence of 10 mol % TiCl₂(i-PrO)₂ the exo-product is obtained. Four different TiCl₂-TADDOLate complexes have been tested as catalysts for the 1,3-dipolar cycloaddition reactions, and the most successful catalyst was applied (5 mol %) in a series of reactions between two different alkenoylsuccinimides and three different nitrones. The crude products containing an N-acylsuccinimide moiety were converted directly into the corresponding carboxamides upon treatment with hydrazine. The 1,3-dipolar cycloaddition reactions proceed with a high degree of exo-selectivity, often >90% de, which is an improvement compared with previous experiments performed using the oxazolidinone auxiliary for the alkenoyl moiety. Furthermore, the enantioselectivities are also improved compared with previous work, and ee up to 73% is obtained, which is the highest ee found for these metal-catalyzed exo-selective 1,3-dipolar cycloaddition reactions. The ee can be improved to >90% by recrystallization. The absolute structure of the 1,3-dipolar cycloaddition adduct is determined on the basis of the X-ray crystal structure of a compound with a known configuration. On the basis of this knowledge of the absolute structure of the product the mechanism of the reaction is briefly discussed.

Full text of DOI:10.1021/jo962214y

J . Org. Chem. 1997, 62, 2471-2477
2471
Im p r ovem en t of TADDOLa te-TiCl
2
-Ca ta lyzed 1,3-Dip ola r Nitr on e
Cycloa d d ition Rea ction s by Su bstitu tion of th e Oxa zolid in on e
Au xilia r y of th e Alk en e w ith Su ccin im id e
Kim B. J ensen, Kurt V. Gothelf, Rita G. Hazell, and Karl Anker J ørgensen*
Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
Received November 26, 1996X
A significant improvement of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of
acyclic nitrones with R,â-unsaturated carbonyl compounds is described using succinimide as a new
auxiliary for the R,â-unsaturated carbonyl moiety. In the absence of a catalyst, N-crotonoylsuc-
cinimide reacts with C,N-diphenylnitrone to give the endo-isoxazolidine, whereas in the presence
2 2 2
of 10 mol % TiCl (i-PrO) the exo-product is obtained. Four different TiCl -TADDOLate complexes
have been tested as catalysts for the 1,3-dipolar cycloaddition reactions, and the most successful
catalyst was applied (5 mol %) in a series of reactions between two different alkenoylsuccinimides
and three different nitrones. The crude products containing an N-acylsuccinimide moiety were
converted directly into the corresponding carboxamides upon treatment with hydrazine. The 1,3-
dipolar cycloaddition reactions proceed with a high degree of exo-selectivity, often >90% de, which
is an improvement compared with previous experiments performed using the oxazolidinone auxiliary
for the alkenoyl moiety. Furthermore, the enantioselectivities are also improved compared with
previous work, and ee up to 73% is obtained, which is the highest ee found for these metal-catalyzed
exo-selective 1,3-dipolar cycloaddition reactions. The ee can be improved to >90% by recrystalli-
zation. The absolute structure of the 1,3-dipolar cycloaddition adduct is determined on the basis
of the X-ray crystal structure of a compound with a known configuration. On the basis of this
knowledge of the absolute structure of the product the mechanism of the reaction is briefly discussed.
In tr od u ction
the rate of the reaction with the nitrone.7a,c The reaction
between N-crotonoyloxazolidinone and C,N-diphenyl-
nitrone does not proceed at room temperature (rt) in the
One of the most important reactions for the construc-
tion of 5-membered hetereocyclic rings is the 1,3-dipolar
cycloaddition reaction between an alkene and a nitrone.
1
(3) (a) Olsson, T.; Stern, K.; Westman, G.; Sundell, S. Tetrahedron
990, 46, 2473. (b) Ito, M.; Kibayashi, C. Tetrahedron 1991, 47, 9329.
1
In this reaction, up to three new chiral centers can be
formed in the isoxazolidine adduct, and several papers
(
c) Carruthers, W.; Coggins, P.; Weston, J . B. J . Chem. Soc., Chem.
Commun. 1991, 117. (d) Takahashi, T.; Fujii, A.; Sugita, J .; Hagi, T.;
Kitano, K.; Arai, Y.; Koizumi, T.; Shiro, M. Tetrahedron: Asymmetry
2
3
describe the use of chiral nitrones or chiral alkenes for
the purpose of controlling the stereoselectivity of this 1,3-
dipolar cycloaddition reaction. The application of achiral
metal complexes as catalysts for the reaction has also
been studied.4 Recently, the use of chiral metal com-
1
991, 2, 1379. (e) Panfil, I.; Belzecki, C.; Urbanczyk-Lipkowska, Z.;
Chmielewski, M. Tetrahedron 1991, 47, 10087. (f) Krol, W. J .; Mao,
S.; Steele, D. L.; Townsend, C. A. J . Org. Chem. 1991, 56, 728. (g)
Brandi, A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M.; Zablocka, M.;
Wisniewski, W J . Org. Chem. 1991, 56, 4382. (h) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Giaroni, P.; Raimondi, L. Tetrahedron Lett.
1991, 32, 1659. (i) Ito, M.; Maeda, M.; Kibayashi, C. Tetrahedron Lett.
1992, 33, 3765. (j) Bravo, P.; Bruch e´ , L.; Farina, A.; Fronza, G.; Meille,
S. V.; Merli, A. Tetrahedron: Asymmetry 1993, 4, 2131. (k) Saito, S.;
Ishikawa, T.; Moriwake, T. Synlett 1994, 279. (l) Rispens, M. T.; Keller,
E.; Lange, B.; Zijlstra, R. W. J .; Feringa, B. L. Tetrahedron: Asymmetry
plexes as catalysts for the 1,3-dipolar cycloaddition
reaction has been studied by others.5
In previous papers we have described the development
of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition
reaction between nitrones and alkenes.
plication of various metal catalysts, especially titanium-
IV) and magnesium(II) complexes, N-alk-2′-enoyl-1,3-
oxazolidin-2-ones were activated for 1,3-dipolar
cycloaddition reaction by coordination of the two carbonyl
oxygen atoms of the alkenoyloxazolidinone to the metal
catalyst. By this coordination the LUMO-energy of the
alkene is significantly lowered compared with the free
alkene, and this change of the LUMO-energy increases
1
994, 5, 607. (m) Ina, H.; Ito, M.; Kibayashi, C. J . Chem. Soc., Chem.
6
,7
By the ap-
Commun. 1995, 1015. (n) Langlois, N.; Bac, N. V.; Dahuron, N.;
Delcroix, J .-M.; Deyine, A.; Griffart-Brunet, D.; Chiaroni, A.; Riche,
C. Tetrahedron 1995, 51, 3571. (o) Galley, G.; J ones, P. G.; P a¨ tzel, M.
Tetrahedron: Asymmetry 1996, 7, 2073. (p) Tamura, O.; Gotanda, K.;
Terashima, R.; Kikuchi, M.; Miyawaki, T.; Sakamoto, M. J . Chem. Soc.,
Chem. Commun. 1996, 1861. (q) Ishikawa, T.; Tajima, Y.; Fukui, M.;
Saito, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1863. (r) Bravo, P.;
Bruc e´ , L.; Crucianelli, M.; Farina, A.; Meille, S. V.; Marli, A.; Seresini,
P. J . Chem. Res., Synop. 1996, 348.
(
a
(
4) (a) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992,
3
3, 7889. (b) Kanemasa, S.; Tsuruoka, T.; Wada, E. Tetrahedron Lett.
1993, 34, 87. (c) Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K.
J . Am. Chem. Soc. 1994, 116, 2324. (d) Kanemasa, S.; Tsuruoka, T.
Chem. Lett. 1995, 49. (e) Murahashi, S.-I.; Imada, Y.; Kohno, M.;
Kawakami, T. Synlett 1993, 395. (f) Tamura, O.; Yamaguchi, T.; Noe,
K.; Sakamoto, M. Tetrahedron Lett. 1993, 34, 4009. (g) Tamura, O.;
Yamaguchi, T.; Okabe, T.; Sakamoto, M. Synlett 1994, 620. (h)
Gilbertson, S. R.; Dawson, D. P.; Lopez, O. D.; Marshall, K. L. J . Am.
Chem. Soc. 1995, 117, 4431. (i) Tokunaga, Y.; Ihara, M.; Fukumoto,
K. Tetrahedron Lett. 1996, 37, 6157. (j) Shimizu, M.; Ukaji, Y.; Inomata,
K. Chem. Lett. 1996, 455. (k) Naito, T.; Shirikawa, M.; Ikai, M.;
Ninomiya, I.; Kiguchi, T. Recl. Trav. Chim. Pays-Bas 1996, 115, 13.
(5) (a) Seerden, J .-P. G.; Scholte op Reimer, A. W. A.; Scheeren, H.
W. Tetrahedron Lett. 1994, 35, 4419. (b) Seerden, J .-P.; Kuypers, M.
M. M.; Scheeren, H. W. Tetrahedron Asymmetry 1995, 6, 1441. (c)
Seebach, D.; Marti, R. E.; Hintermann, T. Helv. Chim. Acta 1996, 79,
710. (d) Hori, K.; Kodama, H.; Otha, T.; Furukawa, I. Tetrahedron Lett.
1996, 37, 5947.
X
Abstract published in Advance ACS Abstracts, March 15, 1997.
1) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis; VCH: New York, 1988. (b) Tufariello, J . J . In 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
984; Vol. 2, pp 83-168. (c) Mulzer, J . In Organic Synthesis Highlights;
Mulzer, J ., Altenbach, H.-J ., Braun, M., Krohn, K., Reissig, H.-U., Eds.;
VCH: New York, 1991; p 77.
(
1
(
2) (a) Kiers, D.; Moffat, D.; Overton, K.; Tomanek, R. J . Chem. Soc.,
Perkin Trans. 1 1991, 1041. (b) Brandi, A.; Cicchi, S.; Goti, A.;
Pietrusiewicz, K. M. Tetrahedron: Asymmetry 1991, 2, 1063. (c) Goti,
A.; Cicchi, S.; Brandi, A.; Pitrusiewicz, K. M. Tetrahedron: Asymmetry
991, 2, 1371. (d) McCraig, A. E.; Wightman, R. H. Tetrahedron Lett.
993, 34, 3939. (e) Saito, S.; Ishikawa, T.; Kishimoto, N.; Kohara, T.;
Moriwake, T. Synlett 1994, 282. (f) Oppolzer, W.; Deerberg, J .; Tamura,
O. Helv. Chim. Acta 1994, 77, 554.
1
1
(6) Gothelf, K. V.; J ørgensen, K. A. J . Org. Chem. 1994, 59, 5687.
S0022-3263(96)02214-1 CCC: $14.00 © 1997 American Chemical Society

2
472 J . Org. Chem., Vol. 62, No. 8, 1997
J ensen et al.
absence of a catalyst, and only a slow conversion is
observed at 50 °C. However, by the use of titanium(IV)
or magnesium(II) catalysts (5-50 mol %) the reaction
proceeds at rt.
9,12 have also been described. But to the best of our
knowledge the application of succinimide 10 as an
auxiliary for alkenoyl compounds has not been reported.
In the previously reported reactions the diastereo-
selectivity could be controlled, especially in favor of the
endo-diastereomer.7 By using semiempirical calculations
it was found that the exo-transition state of the reaction
between 1 and 2 is preferred if no steric hindrance is
present (eq 1).7 However, in the metal-catalyzed reac-
a
In the present work we will describe the improvement
of both the exo-selectivity and the enantioselectivity of
the TiCl -TADDOLate-catalyzed 1,3-dipolar cycloaddi-
2
tion reaction by the introduction of succinimide as
auxiliary on the alkenoyl moiety instead of the oxazoli-
dinone.
Resu lts a n d Discu ssion
1
. Syn th etic Develop m en t. The synthesis of N-alk-
2
′-enoylsuccinimide has not been described previously;
however, there are a few reports on the synthesis of
N-acylsuccinimides or N-acylphthalimides.13 These com-
pounds are most commonly synthesized from succinimide
or phthalimide, which is deprotonated with a base and
reacted with an activated carbonyl compound such as an
acid chloride. In the present case we found that the best
method was by deprotonation of succinimide with n-BuLi
and subsequent treatment with the alk-2-enoyl chloride
(
eq 2).10 The products are relatively unstable, and a
tions, the presence of steric interference between the
C-aryl group of the nitrone and a bulky ligand on the
metal, located orthogonal to the plane consisting of the
partial decomposition takes place during work up. The
N-crotonoyl- and N-hex-2′-enoylsuccinimides, 11a and
1
tively. We have also synthesized the analogous phthal-
imide derivatives by a similar procedure; however, these
products were too unstable to be used for the 1,3-dipolar
cycloaddition reaction.
1b, are obtained in 50% and 61% isolated yield, respec-
metal and the two carbonyl oxygen atoms of 1, favors the
formation of the endo-diastereomer.7
a,b
Use of 10 mol %
of TiCl -TADDOLate, 4a , as a catalyst for the reaction
2
gave an excess of the exo-diastereomer, and in one case
an exo:endo ratio of 90:10 could be achieved with this
catalyst, whereas for other substrates the exo-selectivity
was lower.6 The highest enantioselectivity obtained for
the exo-isomer so far is 60% ee. Both titanium catalyst
5
and magnesium catalyst 6 induce a high degree of endo-
selectivity for all substrate combinations tested, and
application of the Ti(OTos) -TADDOLate catalyst led to
induction of enantioselectivities >90% in several cases.
When the MgI -bisoxazoline catalyst 6 was used the
2
7
b
2
The reaction between the C,N-diphenylnitrone (2a ) and
N-crotonoylsuccinimide (11a ) has been compared with
7
a
maximum ee obtained was 82%. The mechanism of the
titanium-catalyzed reactions and the structure of the
intermediate between 1 and 4a have been discussed by
6
the reaction of N-crotonoyloxazolidinone (1a ) (eq 3).
The reaction between 1a and 2a needs elevated temper-
atures to proceed, whereas 11a reacts with 2a at rt to
give 94% conversion after 71 h (Table 1, entries 1-4).
The succinimide derivative 11a thus seems to be more
reactive toward a 1,3-dipolar cycloaddition reaction with
7
,8
5c,9
us and others.
In order to obtain a strong bidentate coordination of
the alkene moiety to the metal catalyst we have applied
1
,3-oxazolidin-2-one as an auxiliary for the alkenoyl
moiety. This auxiliary and 4,5-substituted chiral analogs
that were introduced by Evans et al. are now very
2
a than the corresponding oxazolidinone derivative 1a .
7
To our great surprise the uncatalyzed reactions of 11a
and 1a with 2a proceeded with opposite diastereoselec-
1
0
commonly used in Lewis acid-catalyzed reactions. Aux-
iliaries in which the ring oxygen is substituted with
14
tivity. In the reaction of 1a with 2a the expected exo-
nitrogen 8,1
0,11
or the oxygen atoms with sulfur atoms
(
11) Amaroso, R.; Cardillo, G.; Sabatino, P.; Tomasini, C.; Trer e´ , A.
(7) (a) Gothelf, K. V.; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem.
J . Org. Chem. 1993, 58, 5615.
1
996, 61, 346. (b) Gothelf, K. V.; Thomsen, I.; J ørgensen, K. A. J . Am.
(12) (a) Evans, D. A.; Lectka, T.; Miller, S. J . Tetrahedron 1993, 34,
7027. (b) Evans, D. A.; Miller, S. J .; Lectka, T. J . Am. Chem. Soc. 1993,
115, 6460.
Chem. Soc. 1996, 118, 59. (c) Gothelf, K. V.; J ørgensen, K. A. Acta
Chem. Scand. 1996, 50, 652.
(
8) (a) Gothelf, K. V.; Hazell, R. G.; J ørgensen, K. A. J . Am. Chem.
Soc. 1995, 117, 4435. (b) Gothelf, K. V.; J ørgensen, K. A. J . Org. Chem.
995, 60, 6847. (c) Gothelf, K. V.; J ørgensen, K. A. J . Chem. Soc., Perkin
Trans. 2 1997, 111.
9) (a) Haase, C.; Sarko, C. R.; DiMare, M. J . Org. Chem. 1995, 60,
777. (b) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner,
D. A.; K u¨ hnle, F. N. M. J . Org. Chem. 1995, 60, 1788.
10) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
988, 110, 1238.
(13) (a) Heller, G.; J acobsen, P. Ber. 1921, 54, 1112. (b) Dunbar, R.
E.; Swenson, W. M. J . Org. Chem. 1958, 23, 1793. (c) Rothman, E. S.;
Serota, S.; Swern, D. J . Org. Chem. 1964, 29, 646.
(14) In an attempt to account for the endo-selectivity in the 1,3-
dipolar cycloaddition reaction of nitrone 2a with N-crotonoylsuccin-
imide (11a ) a series of ab initio calculations have been performed using
a 3-21G* basis set. The geometry of both 11a -s-cis (total energy )
-583.970 au) and 11a -s-trans have been optimized, and it has been
found that the former is 5 kcal/mol more stable than the latter. The
1
(
1
(
1

TADDOLate-TiCl
2
-Catalyzed Cycloaddition Reactions
J . Org. Chem., Vol. 62, No. 8, 1997 2473
Ta ble 1. Com p a r ison of th e 1,3-Dip ola r Cycloa d d ition Rea ction of Alk en es 11a a n d 1a w ith Nitr on e 2a in th e Absen ce
a n d P r esen ce of TiCl2(i-P r O)2 a s th e Ca ta lyst
alkenea
solvent
catalyst (amount)
reaction time (h)
T (°C)
product
convn (%)
b
endo:exob
entry
1
2
3
4
5
6
1a
1a
11a
11a
1a
CHCl3
-
-20
-20
-20
-71
20
50
50
rt
rt
rt
0 to rt
3a
3a
12a
12a
3a
39
36
68
94
61
9:91
29:71
86:14
95:5
14:86
6:94
Toluene
CH2Cl2
Toluene
Toluene
Toluene
-
-
-
TiCl2(i-PrO)2 (10%)
TiCl2(i-PrO)2 (5%)
11a
20
12a
100
a
The reactions were performed on a 0.1 mmol scale. b Conversions and endo:exo ratios were determined by 1H NMR spectroscopy.
of 2 or 5 mol % of various TiCl
-TADDOLates 4a -d .17
2
The products 12 were converted directly into the crude
amide derivatives 13, similar to the reaction outlined in
eq 4. The results are presented in Table 2.
2 2
In the presence of 5 mol % of catalyst 4a in CH Cl as
the solvent a quantitative conversion is obtained after
20 h (Table 2, entry 1). The exo-selectivity is high;
however, the enantioselectivity of the reaction is lower
than the analogous reaction of the oxazolidinone deriva-
tive.6 The reaction was also performed in a mixture of
toluene/petroleum ether, a solvent mixture that has been
used successfully in similiar reactions,6 and in the
present reaction the enantioselectivity was improved
(Table 2, entry 2). If the reaction is performed in toluene
with 5 mol % of 4a as the catalyst, an enantioselectivity
of 73% is obtained, the highest observed for the exo-
selective reaction so far (Table 2, entry 3). Application
of catalysts 4b,c leads to high exo-selectivities, but the
enantioselectivities are poorer (Table 2, entries 4 and 5).
Surprisingly, the reaction catalyzed by 4b leads to an
excess of the opposite enantiomer. The catalytic proper-
ties of 4d are comparable to those of catalyst 4a (Table
2, entry 6). It appears from the results listed in Table 2
that catalyst 4a is most suitable for the reaction and that
toluene should be used as the solvent. The exo-selectivity
is much better than for the analogous reactions with the
oxazolidinone derivative 1a .6
3
a was primarily obtained, especially when the reaction
is performed in CHCl (Table 1, entries 1 and 2).
3
Surprisingly, the reaction of 11a with 2a gave endo-12a ,
and when the reaction was performed in toluene a high
preference for endo-12a was obtained (Table 1, entries
,18
3
2 2
,4). In the presence of 10 mol % of TiCl (i-OPr) as the
catalyst the reaction of 1a proceeds at rt to give primarily
exo-12a with 61% conversion (Table 1, entry 5), whereas
the reaction of 11a takes place at 0 °C to rt in the
presence of 5 mol % of the catalyst to give complete
conversion after 20 h (Table 1, entry 6). The reaction of
1
1a in the presence of TiCl
2 2
(i-OPr) as the catalyst gives
1
5
the exo-isomer with a high degree of selectivity.
In the reactions presented in Table 1 the conversions
and diastereoselectivities have been determined from the
1
H NMR spectra of the crude products. However, in
attempts to isolate the product it was observed that 12a ,
as well as derivatives of 12a , decompose during various
chromatography procedures. This problem was avoided
by converting 12a directly into the stable amide deriva-
tive 13a , by addition of a 4-fold excess of aqueous
hydrazine to the crude reaction product 12a (eq 4).16
The more general application of this new exo-selective
catalytic approach to the 1,3-dipolar cycloaddition reac-
tion is demonstrated by performing the reaction with
other derivatives of the starting materials. We have
chosen the N-alk-2′-enoylsuccinimides 11a and 11b and
the three different nitrones 2a -c. The most successful
TiCl -TADDOLate catalyst 4a was applied (5 mol %) in
2
these reactions (eq 5). The intermediate products 12 are
directly transformed to the amides 13. The reactions are
1
allowed to continue until H NMR spectra of the reaction
The reaction of N-crotonoylsuccinimide (11a ) with C,N-
diphenylnitrone (2a ) has been performed in the presence
mixtures reveal that >95% conversion has taken place.
The reactions are performed at a temperature starting
at -20 to -13 °C, and the temperature is then allowed
to raise slowly to rt. The results are presented in Table
dihedral angle of the alkene plane relative to the succinimide plane of
1
1a -s-trans is 24°. A comparison of the approach of 2a to 11a -s-cis
3
.
leading to endo-12a and exo-12a reveals that for the latter a steric
repulsion between the C-phenyl substituent of the nitrone and one of
the carbonyls of the succinimide group may account for the former
reaction path.
(17) (a) Seebach, D.; Weidmann, B.; Wilder, L. In Modern Synthetic
Methods; Scheffold, R., Ed.; Salle + Sauerl a¨ ender, Wiley: New York:
1983; Vol. 3, p 217. (b) Ito, Y. N.; Ariza, X.; Beck, A. K.; Boh a´ c, A.;
Ganter, C.; Gawley, R. E.; K u¨ hnle, F. N. M.; Tuleja, J .; Wang, Y. M.;
Seebach, D. Helv. Chim. Acta 1994, 77, 2071.
(18) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima,
M.; Sugimori, J . J . Am. Chem. Soc. 1989, 111, 5340.
(15) We have also tried to use N-crotonoylsuccinimide (11a ) as the
substrate in Ti-TADDOLate catalyzed Diels-Alder reactions with
cyclopentadiene as the reagent, but the Diels-Alder product was
formed with low diastereoselectivity.
(16) Ing, H. R.; Manske, R. H. F. J . Chem. Soc. 1926, 2348.

2
474 J . Org. Chem., Vol. 62, No. 8, 1997
J ensen et al.
Ta ble 2. Effects of Ca ta lysts 4a -d in th e 1,3-Dip ola r Cycloa d d ition Rea ction betw een 11a a n d 2a
catalyst
(mol %)
reaction
time (h)
a
b
entry
solvent
T (°C)
convn (%)
endo-13a :exo-13a
ee exo-13a
1
2
3
4
5
6
4a (5)
4a (5)
4a (5)
4b (5)
4c (5)
4d (2)
CH2Cl2
tolene/petroleum ether
toluene
toluene
toluene
20
5 d
19
48
7 d
40
-18 to rt
-15 to rt
-18 to -10
-13 to rt
-12 to rt
-20 to -10
>95
>95
>95
>95
>95
>95
<5:>95
<5:>95
<5:>95
<5:>95
<5:>95
<5:>95
52
68
73
44
42
71
c
toluene
a
Determined by 1H NMR spectroscopy of the crude product. b The ee was determined by HPLC (Daicel Chiralcel OD using hexane:
c
i-PrOH) after conversion of the crude product into 13a and purification. Opposite enantiomer.
Ta ble 3. Asym m etr ic 1,3-Dip ola r Cycloa d d ition Rea ction s betw een 11a ,b a n d 2a -c Ca ta lyzed by 5 Mol % of
TiCl2-TADDOLa te Ca ta lyst 4a
a
b
endo-13:exo-13c
entry
alkene
nitrone
ratio 11/2
product
reaction time
yield (%)
ee exo
d
1
2
3
4
5
6
11a
11a
11a
11b
11b
11b
2a
2b
2c
2a
2b
2c
1/1.1
1/1.1
1/1.1
1.4/1
1.4/1
1.4/1
13a
13b
13c
13d
13e
13f
24 d
48
44
24
44
76
38
64
70
38
63
<5:>95
36:64
<5:>95
7:93
<5:>95
11:89
72
55
65
59
14
52
d
d
e
e
e
24
a
The reactions were performed on a 1.0 mmol scale. For details see the Experimental Section. Isolated yields. c The endo:exo ratio
b
1
d
e
was determined by H NMR spectroscopy. The ee was determined by HPLC (Daicel Chiralcel OD using hexane:i-PrOH). The ee was
determined by H NMR spectroscopy using Eu(hfc)3 as a chiral shift reagent.
1
For the aim of determining the absolute configuration
of the product exo-13a , obtained from the asymmetric 1,3-
dipolar cycloaddition reaction catalyzed by 4a , it was
a
necessary to determine the absolute configuration of exo -
3
b, which contains a stereocenter with a known config-
a
uration. After purification by PTLC, exo -3b was recrys-
tallized from MeOH to give crystals suitable for an X-ray
The exo-selectivity of the reactions involving these new
succinimide auxiliaries is very high for almost all entries
and indeed better than those obtained for the corre-
sponding oxazolidinone derivatives (Table 3).6 The iso-
lated yields of the exo-diastereomers are satisfying for
most entries; however, for the reactions involving the
N-benzyl nitrone, yields tend to be lower (Table 3, entries
crystallographic investigation. The structure of exo -3b
a
is presented in Figure 1.
The X-ray structure of exo -3b shows that it has two
a
molecules in the unit cell of space group P2 . Inspection
1
of the X-ray structure in Figure 1 reveals that the
substituents at C3 and C4 are cis to each other in the
isoxazolidine ring, in agreement with the NMR experi-
ments. The isoxazolidine ring adopts an envelope con-
formation, with a dihedral angle C3-C4-C5-O1 of
30.4(2)°. The structural data for the isoxazolidine ring
turn out to be very similar to other isoxazolidines
characterized19 and will not be considered further.
2
and 5). With one exception, the ee’s obtained in these
exo-selective reactions are also higher than those ob-
tained in the similar reactions involving the oxazolidi-
none auxiliary.6 The product exo-13a is crystalline, and
by recrystallization from a mixture of EtOAc and petro-
leum ether the optical purity could be increased to 94%
ee.
From the structure of exo -3b, the configuration of the
a
2
. X-r a y Str u ctu r e Deter m in a tion a n d Absolu te
three stereocenters in the isoxazolidine ring can be
Assign m en t of th e Ster eoch em istr y. The reaction
between 2a and the chiral valine-derived oxazolidinone
assigned to be 3S,4S,5R. For the determination of the
absolute structure of exo-13a , this compound and exoa-
3b should be transformed into the same derivative.
Several methods have been tested for the conversion of
1
b was performed in order to obtain an exo-product with
7
a
a known configuration of one of the stereocenters (eq 6).
The reaction between 1b and 2a is catalyzed by TiCl
2
-
(
i-PrO)
2
and gives one of the four possible diastereoiso-
-3b, with a high degree of selectivity since only
(19) (a) Reference 7a and references therein. (b) The authors have
deposited atomic coordinates for the structure with the Cambridge
Crystallographic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK.
mers, exo
a
minor amounts (<5%) of other isomers could be detected
by H NMR spectroscopy.
1

TADDOLate-TiCl
2
-Catalyzed Cycloaddition Reactions
J . Org. Chem., Vol. 62, No. 8, 1997 2475
a
F igu r e 1. X-ray structure of exo -3b showing the absolute
stereochemistry of the isoxazolidine ring.
F igu r e 2. Approach of the nitrone 2a in an exo-fashion to
the N-crotonoylsuccinimide (11a ) coordinated to the Ti-
TADDOLate 4a , in which the two chloride ligands are facing
trans to the plane consisting of titanium and the four oxygen
atoms.
Sch em e 1
the oxazolidinone derivative into the corresponding iso-
propyl ester without success, such as treatment with
Ti(i-PrO)
4
and i-PrOH in toluene, as described in previous
work.7 However, upon treatment with LiOH and H
O
2
a
2
a
in refluxing THF, exo -3b could be transformed into the
carboxylic acid derivative 15 (Scheme 1).20 This proce-
dure failed for the final product of the asymmetric 1,3-
dipolar cycloaddition reaction, exo-13a ; however, using
the same procedure as described for exo
a
-3b, performed
F igu r e 3. Approach of the nitrone 2a in an exo-fashion to
the N-crotonoylsuccinimide (11a ) coordinated to the Ti-
TADDOLate 4a , in which the two chloride ligands are facing
cis to each other.
at 0 °C, the crude product of the reaction, exo-12a , was
converted to the acid derivative 15′ (Scheme 1). By
HPLC analysis using a Chiralcel OD column the two
enantiomers in 15′ (72% ee) were separated. The minor
enantiomer in 15′ and the only enantiomer in 15 have
identical retention times, whereas the major enantiomer
in 15′ and the only enantiomer in 15 have different
retention times. On the basis of this information the
absolute configuration of the major enantiomer in 15′,
and therefore also in exo-12a and exo-13a , can be as-
signed to be 3R,4R,5S.
tigations. Several intermediates consisting of the Ti-
TADDOLate catalyst 4a and the N-crotonoylsuccinimide
(11a ) can be considered, depending on the arrangement
of the chloride ligands and 11a at the titanium atom. If
the chloride ligands are located trans relative to the plane
of the titanium atom and the four oxygen atoms of the
TADDOLate and the N-crotonoylsuccinimide ligands
coordinated to the titanium atom, the intermediate is
very similar to a complex that has been isolated and
characterized.8 The approach of the nitrone 2a in an
exo-fashion to the R-Re face of the alkene in this inter-
mediate is outlined in Figure 2.
3
. Mech a n istic Acp ects of th e 1,3-Dip ola r Cy-
cloa d d ition Rea ction . On the basis of the assignment
of the absolute configuration of exo-12a (3R,4R,5S) the
nitrone has to approach the R-Re face of the alkene 11a
in the 1,3-dipolar cycloaddition reaction with 2a catalyzed
by 4a .
a
The absolute configuration of the isoxazolidine ring
obtained by the approach of the nitrone to the intermedi-
ate as outlined in Figure 2 is in accordance with the
experimental results. Due to the chloride ligands at the
titanium atom, the nitrone reacts with the alkene to give
the exo-diastereomer, since no steric repulsion between
the chloride ligand and the C-phenyl substituent at the
nitrone is present.7b The mechanism of the 1,3-dipolar
cycloaddition presented in Figure 2 is similar to the
The intermediate in the Ti-TADDOLate-catalyzed
reactions involving alkenes such as N-crotonoyloxazoli-
dinone (1a ) has received considerable interest,5
c,8,9
and
we will apply these observations for the present inves-
(
20) (a) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1
1
987, 28, 6141. (b) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev.
996, 96, 835.

2
476 J . Org. Chem., Vol. 62, No. 8, 1997
J ensen et al.
butanetetraols17 were synthesized according to the literature.
mechanism of the 1,3-dipolar cycloaddition and Diels-
Alder reactions catalyzed by the Ti-TADDOLate com-
TiCl
stirring Ti(i-OPr)
(39.19 mL) at rt under N
under N at rt. (+)-(S)-3-Crotonoyl-4-isopropyl-2-oxazolidinone
1b), Eu(hfc) , (E)-crotonyl chloride, (E)-2-hexenoyl chloride,
and 4 Å molecular sieves were received from Aldrich.
-N-((E)-2′-Bu t en oyl)su ccin im id e (11a ). Succinimide
2
(i-PrO)
2
as a 0.1 M toluene solution was synthesized by
(2 mmol) and TiCl (2 mmol) in dry toluene
for 1 h. The solution was stored
4
4
plexes using N-crotonoyloxazolidinone (1a ), as the alkene
suggested earlier by us.6-8
2
2
Another intermediate in the Ti-TADDOLate-catalyzed
addition reactions that is based on a cis arrangement of
the chloride ligands at the titanium intermediate has
(
3
1
been suggested to be the most active intermediate.9
A
(2.99 g, 30.0 mmol) was dissolved in dry THF (105 mL). The
similar intermediate containing the N-crotonoylsuccin-
imide (11a ) is outlined in Figure 3.
In Figure 3 the nitrone also approaches the R-Re face
of the alkene leading to the same absolute configuration
of the isoxazolidine ring as the approach presented in
Figure 2.
On the basis on the present results we cannot distin-
guish if the reaction proceeds via the intermediates
presented in Figures 2 or 3, but only conclude that both
reaction paths can account for the observed diastereo-
and enantioselectivity.
mixture was stirred at -78 °C, and BuLi (1.6 M in hexane,
2
0.6 mL, 33.0 mmol) was added. After 1 h, (E)-crotonyl
chloride (3.45 g, 33 mmol) was added, and the mixture was
stirred overnight while the temperature increased to rt. The
mixture was quenched with excess aqueous NH
4
Cl and
extracted two times with Et O. Then the organic layer was
2
washed with brine. The organic phases were collected and
dried, and the solvent was evaporated. The crude product was
refluxed in (i-Pr)
hot. The precipitate was crystallized by dissolving with the
smallest quantity of CHCl and then adding (i-Pr) O while
refluxing until the solution started to precipitate, and CHCl
2
O and filtered while the solution was still
3
2
3
was added until the solution was clear again. The solution
stood overnight and the product precipitated. Yield: 50%.
It should also be noted that very recently Seebach et
al. have suggested that the reaction proceeds via a
cationic intermediate.5
1
Mp: 103-5 °C. Yellow powder. H NMR (CDCl ): δ 1.99 (dd,
3
c
J ) 7.2, 1.7 Hz, 3H), 2.82 (s, 4H), 6.42 (dq, J ) 15.4, 1.7 Hz,
1
2
H), 7.26 (dq, J ) 14.9, 7.1 Hz, 1H). 13C NMR (CDCl
3
): δ 19.3,
+
9.2, 125.2, 150.7, 164.6, 175.2. MS: m/z 167 (M ).
Con clu sion
1
-N-((E)-2′-Hexen oyl)su ccin im id e (11b) was synthesized
according to the above procedure on a 17.0 mmol scale. Before
addition of (E)-2-hexenoyl chloride (2.43 g, 18.31 mmol), the
temperature was raised to -10 °C and then decreased to -78
The diastereo- and enantioselectivity of the 1,3-dipolar
cycloaddition reaction of nitrones with alkenes using Ti-
TADDOLates as the catalyst has been significantly
improved by exchanging the oxazolidinone auxiliary with
succinimide. The reaction gives exo-isoxazolidines with
generally >90% diastereoselectivity and in some cases
ee’s >70%, the highest obtained for the exo-diastereomer
in metal-catalyzed 1,3-dipolar cycloaddition reactions.
The ee can be improved to >90% by recrystallization. The
absolute configuration of the exo-diastereomer is deter-
mined to be 3R,4R,5S on the basis of the X-ray structure
of an exo-isoxazolidine with known absolute configura-
tion. Two intermediates can account for the absolute
configuration of the exo-isoxazolidine, one in which the
two chloride ligands at the titanium atom are located
trans to the plane of the titanium atom and the four
oxygens of the TADDOLate- and the N-alk-2′-enoyl-
succinimide ligands, while the other has the two chloride
ligands located cis. With these intermediates the nitrone
can approach the R-Re face of the alkene leading to the
exo-isoxazolidine with the same absolute configuration
as observed experimentally.
°
C again to assure that BuLi had reacted completely. After
extraction and washing, the crude material was purified by
flash chromatography on silica gel (Et O). Yield: 61%.
2
1
Orange oil. R ) 0.27 (Et O). H NMR (CDCl ): δ 0.94 (t, J
f
2
3
) 7.5 Hz, 3H), 1.52 (sextet, J ) 7.5 Hz, 2H), 2.26 (dq, J ) 6.2,
1.6 Hz, 2H), 2.80 (s, 4H), 6.37 (dt, J ) 15.4, 1.1 Hz, 1H), 7.21
1
3
(
2
1
dt, J ) 15.9, 7.1 Hz, 1H). C NMR (CDCl ): δ 14.2, 21.6,
3
+
9.2, 35.3, 123.8, 155.4, 164.7, 175.2. MS: m/z ) 196 (M
).
Asym m etr ic 1,3-Dipolar Cycloaddition Reaction s. Gen -
er a l P r oced u r e for th e Rea ction Usin g 5 Mol % of th e
TiCl
+
2
-TADDOLa te Ca ta lyst. To a 0.1 M dry toluene
solution of Ti(i-OPr) Cl2 (1 mL, 0.1 mmol) was added the
2
appropriate TADDOL ligand (0.11 mmol). The solution was
stirred for 30 min. In another flask 1-N-alk-2′-enoylsuccin-
imide 11 (1.0-1.4 mmol, see Table 3) was dissolved in dry
toluene (8 mL), and 4 Å molecular sieves were added (200-
3
N
00 mg). This mixture was stirred for 10-15 h at rt under
2
, and then the catalyst solution (0.5 mL, 0.05 mmol) was
added. The temperature of the mixture was then decreased
to -18 °C, and the nitrone 2 (1.0-1.1 mmol, see Table 3) was
added. Toluene (2 mL) was used to wash the inner glass side
from the nitrone deposited. After the mixture was stirred for
4
2 4
8 h, 4 equiv of N H (aq) (194 µL, 4 mmol) was added, and
Exp er im en ta l Section
the mixture was stirred for 1-2 h. The mixture was acidified
with 4 M HCl and stirred for another 30 min. The mixture
Gen er a l Met h od s. The 1H NMR and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively. Chemical
was filtered and washed with toluene. Aqueous NaHCO
M (60 mL) was added to the filtrate, and the solution was
extracted three times with Et
layer was dried and the solvent evaporated. The crude product
was purified by PTLC (silica gel, EtOAc: petroleum ether, 50:
3
1
1
13
shifts for H NMR and C NMR are reported in ppm downfield
from tetramethylsilane (TMS). HPLC was performed using
a 4.6 mm × 25 cm Daicel Chiracel OD column. Mass spectra
were recorded at 70 eV with a direct inlet. Preparative thin-
layer chromatography (PTLC) was performed on 200 × 200 ×
2
O (80-100 mL). The organic
5
0, and a few drops of Et
in the region R ) 0.26-0.51. The band was extracted with
% MeOH in CH Cl
(+)-(3R,4R,5S)-5-Meth yl-2-N,3-d ip h en ylisoxa zolid in e-
4-ca r boxa m id e (exo-13a ). Yield: 76%. [R] ) +132° (c )
1.0, CHCl ). R ) 0.26 (EtOAc:petroleum ether 60:40). HPLC
(Daicel Chiralcel OD, hexane:i-PrOH ) 89:11, flow rate ) 1.0
mL/min): t ) 11.4 min (major), t ) 16.7 min (minor). Ee )
72%. H NMR (CDCl ): δ 1.37 (d, J ) 7.1 Hz, 3H), 3.35 (dd,
3
N). The band from exo-13 appeared
1
.8 mm silica gel (60 HP254+366, Merck) on glass plates.
f
5
2
2
.
Solvents were dried using standard procedures. The 4 Å
molecular sieves were activated by heating to 250 °C overnight
in high vacuum. All glass equipment were dried in an oven
at 160 °C before use.
D
3
f
Ma ter ia ls. The starting materials 3-((E)-2′-butenoyl)-1,3-
1
0,20
oxazolidin-2-one (1a ),
benzylidenephenylamine N-oxide
R
R
2
1
21
1
(
2a ), benzylbenzylideneamine N-oxide (2b), (4-methyl-
3
2
1
benzylidene)phenylamine N-oxide (2c), and the four chiral
2R,3R)-2,3-O-(2-propylidene)-1,1,4,4-tetraphenyl-1,2,3,4-
J ) 7.9, 5.2 Hz, 1H), 4.79 (dq, J ) 6.0, 5.5 Hz, 1H), 4.93 (d, J
) 8.8 Hz, 1H), 5.08 (s, br, 1H), 5.85 (s, br, 1H), 6.95 (m, 3H),
(
(
21) (a) Kamm, O. Organic Synthesis; Wiley: New York, 1932;
(22) (a) Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 1992,
70, 265. (b) Beckett, A. H.; Coutts, R. T.; Ogunbona, F. A. Tetrahedron
1973, 29, 4189.
Collect. Vol. I, p 435. (b) Wheeler, O. H.; Gore, P. H. J . Am. Chem.
Soc. 1956, 78, 3363.

TADDOLate-TiCl
2
-Catalyzed Cycloaddition Reactions
J . Org. Chem., Vol. 62, No. 8, 1997 2477
7
.21 (m, 2H), 7.34 (m, 3H), 7.48 (m, 2H). 13C NMR (CDCl
3
):
P r oced u r e for th e Con ver sion of Isoxa zolid in e exo-
12a in to (+)-(3R,4R,5S)-5-Meth yl-2-N,3-d ip h en ylisoxa zo-
lid in e-4-ca r boxylic Acid (15′). To the crude product 12a
(about 0.125 mmol) from the asymmetric 1,3-dipolar cyclo-
δ 19.4, 62.2, 71.8, 77.5, 115.8, 122.6, 128.0, 128.7, 129.2, 129.3,
+
1
37.8, 151.8, 171.9. MS: m/z ) 282 (M ).
+)-(3R,4R,5S)-2-N-Ben zyl-5-m eth yl-3-p h en ylisoxa zo-
lid in e-4-ca r boxa m id e (exo-13b). Yield: 38%. [R] ) +68°
c ) 1.0, CHCl ). R ) 0.28 (EtOAc:petroleum ether 60:40).
HPLC (Daicel Chiralcel OD, hexane:i-PrOH ) 90:10, flow rate
1.0 mL/min): t ) 12.7 min (major) and 16.5 min (minor).
): δ 1.36 (d, J ) 6.1 Hz, 3H), 3.04
(
D
addition reaction between 2a and 11a , dissolved in THF/H
2
O
(
3
f
(3:1, 1.5 mL) at 0 °C, was added 6 equiv of H (35%, 0.1
2 2
O
mL, 0.75 mmol) followed by addition of 2.0 equiv of LiOH (7.4
mg, 0.25 mmol). The mixture was stirred at 0-25 °C for 7 h.
The excess of H O was quenched with sodium hydrogensulfite
)
R
1
Ee ) 55%. H NMR (CDCl
3
2
2
(
)
dd, J ) 8.8, 5.5 Hz, 1H), 3.74 (d, J ) 14.3 Hz, 1H), 4.14 (d, J
at 0 °C. THF was removed by evaporation, and the water layer
14.8 Hz, 1H), 4.15 (d, J ) 8.2 Hz, 1H), 4.58 (dq, J ) 6.1, 5.5
was extracted two times with Et O. The organic layer was
2
Hz, 1H), 5.35 (s, br, 1H), 5.83 (s, br, 1H), 7.27-7.43 (m, 10H).
washed with brine, dried over MgSO , filtered by suction, and
4
1
3
C NMR (CDCl
3
): δ 20.9, 60.7, 63.0, 72.5, 76.9, 127.9, 128.7,
evaporated in vacuo. The crude material was purified twice
1
28.7, 128.8, 129.1, 129.4, 136.0, 137.7, 173.4. MS: m/z ) 296
by PTLC (silica gel, MeOH:CH
Et N). Two bands appeared in the region R
lower band was the acid 15′. R ) 0.26-0.34 (MeOH:CH Cl ,
2
Cl
2
, 5:95 and a few drops of
+
(
M ).
+)-(3R ,4R ,5S )-5-Me t h y l-3-(4′-m e t h y lp h e n y l)-2-N -
ph en ylisoxazolidin e-4-car boxam ide (exo-13c). Yield: 62%.
R] ) +183° (c ) 1.0, CHCl ). R ) 0.38, (EtOAc:petroleum
3
f
) 0.20-0.50. The
(
f
2
2
5:95). HPLC (Daicel Chiralcel OD, hexane:i-PrOH:formic acid
[
D
3
f
23
)
)
)
97:3:0.2, flow rate ) 1.0 mL/min):
t
R
) 5.6 min (minor), t
6.8 min (major). Ee ) 72%. H NMR (CDCl ): δ 1.47 (d, J
6.1 Hz, 3H), 3.37 (dd, J ) 9.7, 9.7 Hz, 1H), 4.76 (dq, J )
R
ether 60:40). HPLC (Daicel Chiralcel OD, hexane:i-PrOH )
1
3
9
0:10, flow rate ) 1.0 mL/min): t
R
) 12.6 min (major), t
7.3 min (minor). Ee ) 66%. H NMR (CDCl ): δ 1.36 (d, J
6.0 Hz, 3H), 2.34 (s, 3H), 3.27 (dd, J ) 8.8, 5.5 Hz, 1H), 4.75
dq, J ) 6.05, 6.05 Hz, 1H), 4.86 (d, J ) 8.8 Hz, 1H), 5.31 (s,
br, 1H), 5.91 (s, br, 1H), 6.95 (m, 3H), 7.19 (m, 4H), 7.35 (d, J
R
)
1
1
)
(
3
6
.0, 9.8 Hz, 1H), 4.89 (d, J ) 9.4 Hz, 1H), 6.97 (m, 3H), 7.21
m, 2H), 7.31 (m, 3H), 7.49 (m, 2H). MS: m/z ) 283 (M ).
+
(
P r oced u r e for th e Con ver sion of Isoxa zolid in e exo
a
-
3
b in to (-)-(3S,4S,5R)-5-Meth yl-2-N,3-d ip h en ylisoxa zo-
1
3
)
1
8.2 Hz, 2H). C NMR (CDCl
3
): δ 19.5, 21.8, 62.4, 71.6, 77.5,
lid in -4-ca r boxylic Acid (15). exo -3b (10.5 mg, 26.6 µmol)
a
15.8, 122.5, 127.9, 129.2, 129.9, 134.7, 138.3, 151.9, 172.0.
was treated similar to the above procedure, but the mixture
was refluxed for 3 days. The excess of H was quenched at
rt with sodium hydrogensulfite. The mixture was acidified
with 4 M HCl and extracted with Et O. The organic layer was
dried over MgSO . Work up procedures followed the above
procedure, but the chromatographic purification was only
performed once. R ) 0.26-0.34, (MeOH:CH Cl , 5:95). HPLC
Daicel Chiralcel OD, hexane:i-PrOH:formic acid ) 97:3:0.2,
+
MS: m/z ) 296 (M ).
+)-(3R,4R,5S)-2-N,3-Dip h en yl-5-p r op ylisoxa zolid in e-
-ca r boxa m id e (exo-13d ). Yield: 70%. [R] ) +87° (c ) 1.0,
CHCl ). R ) 0.42 (EtOAc:petroleum ether 50:50). Ee deter-
mined by H NMR spectroscopy using Eu(hfc)
NMR (CDCl
2
O
2
(
4
D
2
3
f
1
1
4
3
: ee ) 59%. H
): δ 0.95 (t, J ) 7.2 Hz, 3H), 1.45-1.66 (m, 4H),
.33 (dd, J ) 8.5, 5.2 Hz, 1H), 4.60 (dt, J ) 7.7, 5.0 Hz, 1H),
.86 (d, J ) 8.8 Hz, 1H), 5.46 (s, br, 1H), 5.97 (s, br, 1H), 6.94
3
f
2
2
3
4
(
2
3
1
3
flow rate ) 1.0 mL/min):
t
R
) 5.6 min (major). Ee ) >99%.
(
m, 3H), 7.18-7.36 (m, 5H), 7.45 (m, 2H). C NMR (CDCl
3
):
1
H NMR (CDCl
3
): δ 1.46 (d, J ) 6.0 Hz, 3H), 3.35 (dd, J )
δ 14.6, 20.1, 36.1, 61.2, 71.6, 81.4, 115.9, 122.6, 128.0, 128.6,
+
9.9, 9.9 Hz, 1H), 4.74 (dq, J ) 6.1, 9.9 Hz, 1H), 4.88 (d, J )
9
2
1
29.1, 129.2, 137.7, 151.6, 172.2. MS: m/z ) 310 (M ).
+)-(3R,4R,5S)-2-N-Ben zyl-3-p h en yl-5-p r op ylisoxa zoli-
d in e-4-ca r boxa m id e (exo-13e). Yield: 38%. [R] ) +50°
c ) 1.0, CHCl ). R ) 0.37, (EtOAc:petroleum ether 50:50).
Ee determined by H NMR spectroscopy using Eu(hfc) : ee )
): δ 0.94 (t, J ) 7.2 Hz, 3H), 1.37-1.70
m, 4H), 3.10 (dd, J ) 8.2, 5.0 Hz, 1H), 3.73 (d, J ) 14.3 Hz,
H), 4.11 (d, J ) 7.7 Hz, 1H), 4.15 (d, J ) 14.3 Hz), 4.43 (dt,
J ) 6.6, 4.3 Hz, 1H), 5.30 (s, br, 1H), 5.98 (s, br, 1H), 7.28-
.9 Hz, 1H), 6.97 (m, 3H), 7.21 (m, 2H), 7.32 (m, 3H), 7.49 (m,
(
+
H). MS: m/z ) 283 (M ).
D
X-r a y An a lysis of exo
a
-3b. X-ray diffraction analysis of
(
3
f
1
exo -3b was carried out on a HUBER 4-circle diffractometer
a
3
1
a 23 26 2
at 298 K. The structure of exo -3b C H N O4 (Mw 394.48
amu) was determined from a monoclinic crystal of dimensions
1
(
1
4%. H NMR (CDCl
3
3
0.8 × 0.5 × 0.5 mm (space group P2
1
) with unit cell a ) 9.572-
(1) Å, b ) 8.541(1) Å, c ) 13.778(2) Å, â ) 109.119(9)°, V )
1064.2(2) Å . It has two molecules per cell, D ) 1.2 g‚cm ,
x
1
3
3
-3
7
7
1
.42 (m, 10H). C NMR (CDCl
3
): δ 14.0, 19.0, 37.4, 60.0, 61.4,
-
1
1.5, 80.2, 127.3, 128.0, 128.1, 128.2, 128.6, 129.0, 135.1, 137.0,
73.1. MS: m/z ) 324 (M ).
µ ) 0.079 mm . The cell dimensions were determined from
the setting angles of 29 reflections with 20 < 2θ < 28° using
Mo KR radiation (λ ) 0.710 73 Å). A total of 4655 reflections
were measured (2θ < 60°) using the ω-2θ step scan technique.
Data reduction included corrections for background, deadtime,
and Lorentz polarization, and absorption effects were consid-
ered insignificant. Crystal deterioration was found to be
negligible. The structure was solved using SIR92 and refined
by full-matrix least-squares methods including positional and
anisotropic displacement parameters for non-hydrogen atoms.
Hydrogen atoms were refined isotropically. The final R values
were 0.043 for 3195 reflections (I > 2σ(I)) and 366 variables.
+
(
+)-(3R ,4R ,5S )-3-(4′-Me t h y lp h e n y l)-2-N -p h e n y l-5-
pr opylisoxazolidin e-4-car boxam ide (exo-13f). Yield: 63%.
R] ) +77° (c ) 1.0, CHCl ). R ) 0.51 (EtOAc:petroleum
ether 50:50). Ee determined by H NMR spectroscopy using
[
D
3
f
1
1
Eu(hfc)
3
1
3
: ee ) 52%. H NMR (CDCl
H), 1.42-1.65 (m, 4H), 2.33 (s, 3H), 3.37 (dd, J ) 8.3, 4.4 Hz,
H), 4.60 (dt, J ) 7.7, 4.3 Hz, 1H), 4.85 (d, J ) 8.8 Hz), 5.11
3
): δ 0.93 (t, J ) 6.9 Hz,
2
4
(s, br, 1H), 5.93 (s, br, 1H), 6.94 (m, 3H), 7.14-7.23 (m, 4H),
13
7
3
1
.35 (d, J ) 8.2 Hz, 2H). C NMR (CDCl ): δ 14.5, 20.0, 21.8,
3
6.2, 61.7, 71.2, 81.6, 115.8, 122.5, 127.8, 129.2, 130.0, 134.5,
38.3, 151.7, 172.2. MS: m/z ) 324 (M ).
+
(
-)-(3S′,4S,4′S,5′R)-4-Isop r op yl-3-[(5′-m et h yl-2′-N,3′-
d ip h en ylisoxa zolid in -4′-yl)ca r b on yl]-1,3-oxa zolid in -2-
on e (exo -3b). Synthesized according to the general proce-
dure on a 0.253 mmol scale using the catalyst TiCl (i-PrO)
10 mol %) in CH Cl at rt for 5 days. The mixture was filtered
through a 20-30 mm layer of silica gel, and the silica gel layer
was washed with 2% MeOH in CH Cl (3 mL). After evapora-
tion of the solvent, the crude material was purified by PTLC
silica gel, MeOH:CH Cl , 1:99). The crude product was
recrystallized in MeOH. Yield: 53%. De was determined by
Ack n ow led gm en t. We are indebted to Statens
Teknisk Videnskabelige Forskningsråd for financial
support.
a
2
2
(
2
2
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra and HPLC data (22 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
2
2
(
2
2
1
H NMR spectroscopy: de >95%. R
f
) 0.4-0.54 (MeOH:CH
2
-
1
Cl , 1:99). H NMR (CDCl ): δ 0.22 (d, J ) 6.6 Hz, 3H), 0.66
2
3
(
7
6
d, J ) 7.2 Hz, 3H), 1.44 (d, J ) 6.1 Hz, 3H), 1.55 (d-sep J )
J O962214Y
.2, 2.1 Hz, 1H), 4.04-4.20 (m, 4H), 5.10 (dq J ) 10.9 Hz, 1H),
.92 (m, 3H), 7.16 (m, 2H), 7.23- 7.34 (m, 3H), 7.52 (m, 2H).
(
23) Omamoto, Y.; Aburatani, R.; Kaida, Y.; Hatada, K. Chem. Lett.
1
3
C NMR (CDCl ): δ 15.0, 17.7, 18.7, 29.0, 59.2, 60.7, 64.2,
3.1, 75.9, 116.6, 122.9, 128.9, 129.1, 129.3, 129.7, 138.8, 150.5,
54.2, 169.1.
3
1
988, 1125.
7
1
(24) Altomare, A.; Cascarano, G.; Guaglinard, A.; Burla, M. C.;
Polidori, G.; Camalli, M. J . Appl. Crystallogr. 1994, 27, 435.