A highly diastereoselective and enantioselective Ti(OTos)2-TADDOLate-catalyzed 1,3-dipolar cycloaddition reaction of alkenes with nitrones

Article abstract of DOI:10.1021/ja952726e

A highly diastereo- and enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of 3-((E)-2′-alkenoyl)-1,3-oxazolidin-2-ones with nitrones has been developed. A series of TiX₂-TADDOLate catalysts are investigated for their effects o

Full text of DOI:10.1021/ja952726e

J. Am. Chem. Soc. 1996, 118, 59-64
59
A Highly Diastereoselective and Enantioselective
Ti(OTos)2-TADDOLate-Catalyzed 1,3-Dipolar Cycloaddition
Reaction of Alkenes with Nitrones
Kurt V. Gothelf, Ib Thomsen, and Karl Anker Jørgensen*
Contribution from the Department of Chemistry, Aarhus UniVersity,
DK-8000 Aarhus C, Denmark
ReceiVed August 10, 1995X
Abstract: A highly diastereo- and enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of 3-((E)-2′-
alkenoyl)-1,3-oxazolidin-2-ones with nitrones has been developed. A series of TiX2-TADDOLate catalysts are
investigated for their effects on the rate and diastereo- and enantioselectivities in the 1,3-dipolar cycloaddition reaction
of alkenes with nitrones. The TiCl2-TADDOLate catalysts are known to catalyze the 1,3-dipolar cycloaddition
reaction of alkenes with nitrones, giving primarily the exo-isomer of the isoxazolidines with an optical purity of up
to 60% ee. If the chloride atoms of the catalyst are substituted with more bulky ligands, such as the tosylato ligand,
the endo-isomer is obtained with a diastereoselectivity of >90%. The synthetic aspects of this new method are
presented by a series of reactions in which diastereoselectivities of >90% are generally obtained and, most remarkably,
enantioselectivities of >90% are frequently obtained. The diastereo- and enantioselectivities of the reaction of the
alkenes with nitrones can be accounted for by a transition state model directly derived from a TiCl2-TADDOLate-
3-cinnamoyloxazolidinone intermediate which has recently been isolated and characterized.
Introduction
In a previous paper we described the application of 10 mol%
TiCl2-TADDOLate catalyst, which strongly activates alkenes,
such as 1a, for a 1,3-dipolar cycloaddition reaction with a
nitrone, such as 2a, giving primarily the exo-isoxazolidine 3a
with an ee of 60% (eq 2).8a More recently it has been shown
Since the important contribution to the field of 1,3-dipolar
cycloaddition reactions by Huisgen et al. in the 1960s,1 the
application of 1,3-dipoles has developed to be a cornerstone in
organic synthesis.2 One of today’s challenges in this field is to
control the regio-, diastereo- and enantioselectivities of these
reactions. The 1,3-dipolar cycloaddition reaction of alkenes with
nitrones is one of the fundamental reactions in this field, since
the isoxazolidines formed are very usefull “building block” in
organic synthesis.2 The 1,3-dipolar cycloaddition reaction of
alkenes 1 with nitrones 2 proceeds to give a pair of diastereo-
mers of the isoxazolidine, exo and endo, respectively, each
consisting of a pair of enantiomers which can contain up to
three contiguous asymmetric centers (eq 1).
(3) For recent 1,3-dipolar cycloaddition reactions with chiral nitrones,
see: (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 1991,
2, 1371. (d) McCraig, A. E.; Wightman, R. H. Tetrahedron Lett. 1993, 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.
(4) For recent 1,3-dipolar cycloaddition reactions with chiral alkenes,
see: (a) Olsson, T.; Stern, K.; Westman, G.; Sundell, S. Tetrahedron 1990,
46, 2473. (b) Ito, M.; Kibayashi, C. Tetrahedron 1991, 47, 9329. (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 1991, 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.; Bruche´, 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 1994, 5, 607. (m) Ina, H.; Ito, M.; Kibayashi, C.
J. Chem. Soc., Chem. 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.
(5) (a) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992,
33, 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.
(6) (a) Murahashi, S.-I.; Imada, Y.; Kohno, M.; Kawakami, T. Synlett
1993, 395. (b) Tamura, O.; Yamaguchi, T.; Noe, K.; Sakamoto, M.
Tetrahedron Lett. 1993, 34, 4009. (c) Tamura, O.; Yamaguchi, T.; Okabe,
T.; Sakamoto, M. Synlett 1994, 620. (d) Gilbertson, S. R.; Dawson, D. P.;
Lopez, O. D.; Marshall, K. L. J. Am. Chem. Soc. 1995, 117, 4431.
(7) (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.
The diastereoselective synthesis of isoxazolidines by the
application of optically active starting material is described in
numerous reports.3,4 Kanemasa et al.5 and others6 have
described the application of metal complexes to control the
diastereoselectivity of the reaction. However, only a few reports
from outside this laboratory describe the use of a chiral metal
catalyst to induce both diastereo- and enantioselectivities in the
1,3-dipolar cycloaddition reactions of alkenes with nitrones.7
X Abstract published in AdVance ACS Abstracts, December 15, 1995.
(1) Huisgen, R. Angew. Chem. 1963, 75, 604.
(2) For general reviews see: (a) Padwa, A., Ed. 1,3-Dipolar Cyclo-
addition Chemistry; Wiley: New York, 1984. (b) Torssell, K. B. G. Nitrile
Oxides, Nitrones and Nitronates in Organic Synthesis; VCH: New York,
1988.
0002-7863/96/1518-0059$12.00/0 © 1996 American Chemical Society

60 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Gothelf et al.
that Mg(II)-bisoxazoline complexes can selectively catalyze
the formation of endo-3a with an optical purity of 79% ee for
a similar type of substrate (eq 2).8b
the improvement of the diastereo- and enantioselectivities. On
the basis of the structural assignment of 4, we have developed
a new TiX2-TADDOLate complex to be the first highly
diastereo- and enantioselective catalyst for the 1,3-dipolar
cycloaddition reaction of alkenes with nitrones.
Results and Discussion
The reaction of alkene 1a with nitrone 2a (eq 3) in the
presence of different TiX2-TADDOLate catalysts 5a-g has
been performed in order to investigate the impact on the 1,3-
dipolar cycloaddition reaction of changing the two chloride
ligands of the TiCl2-TADDOLate catalyst with other ligands.
In a recent paper we described the isolation and characteriza-
tion of complex 4 consisting of 3-cinnamoyloxazolidinone
chelated to the asymmetric TiCl2-TADDOLate catalyst.9
Complex 4 is proposed to be an intermediate, not only in the
1,3-dipolar cycloaddition reaction of alkenes with nitrones but
probably also in the asymmetric TiCl2-TADDOLate-catalyzed
Diels-Alder reaction.10 The structure of the reactive intermedi-
ate responsible for the stereochemical outcome of the TiCl2-
TADDOLate-catalyzed Diels-Alder reaction has recently been
subject to some discussion.10,11 DiMare et al. suggests, on the
basis of NMR experiments, a structure with the four oxygen
atoms attached to the titanium atom in the same plane, very
similar to the isolated structure 4, to be most abundant at -70
°C.11 However, they and others propose a different structure,
in which the two chloride atoms attached to the titanium atom
are facing cis to each other, to be more reactive, and to be
responsible for the reaction course.10c-e,11 In a recent paper
we suggested, on the basis of reactions of 4 with cyclopenta-
diene, and several other Diels-Alder reactions catalyzed by the
TiCl2-TADDOLate complex 4 and related complexes, that 4
can account for the diastereo- and enantioselectivities in the
TiCl2-TADDOLate-catalyzed Diels-Alder reaction.12
Catalysts 5a-d are synthesized according to the literature,10a,d
whereas the new Ti(pseudo-halide)2-TADDOLate catalysts
5e-g have been synthesized as outlined for catalyst 5f in eq 4.
The most efficient method for the synthesis of 5e-g is by
treatment of Ti(O-i-Pr)2Cl2 with silver tosylate (eq 4) or silver
triflate, respectively, followed by filtration and addition of the
TADDOL ligand.13
The structural assignment of the possible intermediate 4 in
the TiCl2-TADDOLate-catalyzed addition reactions is impor-
tant, not only for an understanding of the mechanism of these
reaction, but also for the development of new catalysts and for
(8) (a) Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1994, 59, 5687.
(b) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem., in press.
(9) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Am. Chem. Soc.
1995, 117, 4435.
(10) (a) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima,
M.; Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340. (b) Narasaka, K.;
Tanaka, H.; Kanai, F. Bull. Chem. Soc. Jpn. 1991, 62, 387. (c) Corey, E.
J.; Matsumura, Y. Tetrahedron Lett. 1991, 32, 6289. (d) Ito, Y. N.; Ariza,
X.; Beck, A. K.; Boha´c, A.; Ganter, C.; Gawley, R. E.; Ku¨hnle, F. N. M.;
Tuleja, J.; Wang, Y. M.; Seebach, D. HelV. Chim. Acta 1994, 77, 2071. (e)
Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.;
Ku¨hnle, F. N. M. J. Org. Chem. 1995, 60, 1788. (f) Cativiela, C.; Lopz, P.;
Mayoral, J. A. Tetrahedron: Asymmetry 1991, 2, 1295.
(11) Haase, C.; Sarko, C. R.; DiMare, M. J. Org. Chem. 1995, 60, 1777.
(12) Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 6847.

Cycloaddition Reaction of Alkenes with Nitrones
J. Am. Chem. Soc., Vol. 118, No. 1, 1996 61
Table 1. Catalytic Effects of TiX2-TADDOLate Complexes on
Table 2. Ti(OTos)2-TADDOLate-Catalyzed Asymmetric
1,3-Dipolar Cycloaddition Reactions of Alkenes 1a,b with Nitrones
2a-d in the Presence of 50 mol % Catalyst
the 1,3-Dipolar Cycloaddition Reaction of Alkene 1a with Nitrone
2a
amount
(%)
conva
ee (%), endob
(exo)c
ee (%),
entry catalyst
(time (h)) endo:exoa
entrya alkene nitrone product yieldb (%) endo:exoc endod
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5f
5f
5g
10
100
100
10
10
10
25
50
50
98 (48)
93 (20)
0
98 (20)
73 (20)
<10 (20)
55 (48)
99 (48)
86 (48)
10:90
12:88
-
64:36
79:21
-
82:18
>95:<5
85:15
62 (60)
- (22)
-
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
2a
2b
2c
2d
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
61
56
54
71
63
66
58
55
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
93
40
51
91
93
53
56
92
76 (64)
0
-
90
93
85
3g
3h
aThe reactions were performed on a 0.5 mmol scale in toluene at 0
°C, employing 50 mol% catalyst. For further details see the Experi-
mental Section. Isolated yields. The endo:exo ratio was determined
by 1H NMR spectroscopy. d The ee of the endo-isomer was determined
by HPLC using a Daicel Chiralcel OD column.
a Conversions and endo:exo ratios were determined by 1H NMR
spectroscopy of the crude product. b The enantiomeric excess of endo-
3a was determined by HPLC (Daicel Chiralcel OD using hexane/i-
PrOH, 90:10). c The ee was determined by 1H NMR spectroscopy using
Eu(hfc)3 as the chiral shift reagent.
b
c
lower selectivities are observed in the reactions of this catalyst,
compared with the use of 5f (entry 9).
The results obtained in the reaction of 1a with 2a in the
presence of the catalysts 5a-g are presented in Table 1. The
TiCl2-TADDOLate catalyst 5a has proved to be the most
effective chloride-containing catalyst for the asymmetric 1,3-
dipolar cycloaddition reaction of alkenes with nitrones. In the
reaction of 1a with 2a an endo:exo ratio of 10:90 with an ee of
60% exo-3a is obtained, while endo-3a is formed in 62% ee
(Table 1, entry 1).8a The TiCl2-TADDOLate complex 5b
which has been applied with success in Diels-Alder reactions10a,e
gives poor results in the 1,3-dipolar cycloaddition reaction (entry
2).8a The complex 5c does not accelerate the reaction rate
sufficiently, since no conversion is observed after 24 h (entry
3). This lack of catalytic effects of 5c is probably caused by
the increased electron donation of the alkoxide ligands attached
to the titanium atom compared with chloride ligands, but steric
effects might also affect the reaction rate. When catalyst 5d,
the bromide analog to 5a, is applied as the catalyst at 10 mol
% in the reaction of 1a with 2a, a faster reaction rate is observed.
The diastereoselectivity now changes to give a slight excess of
the endo-isomer, and the enantioselectivity is improved to 76%
ee of endo-3a, while exo-3a is formed in 64% ee (entry 4). In
order to increase the steric bulk at the titanium atom and still
obtain a fair conversion, we focused on the application of
pseudo-halides as ligands at the titanium atom. By the
application of catalyst 5e in the reaction, a slightly lower
conversion is observed compared with the respective chloride
catalysts (entry 5). The reaction now proceeds in an endo-
selective manner, but the product is unfortunately racemic. Using
10 mol % tosylato derivative 5f as catalyst for the 1,3-dipolar
cycloaddition reaction of 1a with 2a leads to a low conversion
(<10%) after 20 h (entry 6). By the application of 25 mol%
catalyst 5f, the reaction rate is still low; however, a conversion
of 55% is observed after 2 days with the endo-isomer as the
predominant product (entry 7). Most remarkably, the isolated
endo-isomer proved to have an optical purity of 90% ee (entry
7). Enhancing the catalyst amount to 50 mol % gives a
satisfactory conversion after 48 h, and the reaction proceeds
now with an excellent endo-selectivity as the endo-3a:exo-3a
ratio is >95:<5 (entry 8). The optical purity of the endo-
isoxazolidine obtained in this reaction is 93% ee, and this is
the highest observed so far for catalytic 1,3-dipolar cycloaddition
reactions of alkenes with nitrones. This level of asymmetric
induction is comparable to the best results obtained in the
asymmetric TiCl2-TADDOLate-catalyzed Diels-Alder reac-
tions.10 The catalyst 5g is also promising; however, slightly
The present results encouraged us to test catalyst 5f in a series
of reactions with other substrates on a 0.5 mmol scale. In the
reaction of 1a with 2a identical diastereo- and enantio-
selectivities are observed as in the 0.1 mmol scale reaction
(Table 2, entry 1), and it should also be noted that the
enantioselectivity is not improved when the reaction is per-
formed at -20 °C. In reactions of N-alkyl and N-benzyl
nitrones 2b and 2c with 1a, satisfying conversions and excellent
diastereoselectivities are obtained (entries 2 and 3). However,
for these substrates the enantioselectivities are only moderate
(entries 2 and 3). In the reaction of 1a with nitrone 2d in which
the R-C-substituent has been altered compared with 2a, high
diastereo- and enantioselectivities are observed in the presence
of 5f as the catalyst (entry 4). The same series of nitrones 2a-d
have also been employed in the reactions with 3-N-(2′-hexenoyl)-
oxazolidinone (1b). In the four entries 5-8 a similar trend is
observed as for the reactions with 1a. In all entries fair yields
and excellent diastereoselectivities (endo:exo ) >95:<5) are
obtained. The N-phenyl nitrones 2a and 2d react with the alkene
1b in the presence of 5f as the catalyst to give the isoxazolidines
3e and 3h with ee’s of >90% (entries 5 and 8), whereas the
less rigid nitrones 2b and 2c also give lower enantioselectivities
in the reactions with 1b (entries 6 and 7). The general features
observed for these new Ti(OTos)2-TADDOLate-catalyzed 1,3-
dipolar cycloaddition reactions are thus (i) the reactions proceed
generally with a diastereoelectivity of >90% to give the endo-
isomer of the products 3a-h and (ii) the enantioselectivity is
not affected significantly by the substituent on the alkene,
whereas it seems to be controlled by the substituent on the
nitrone nitrogen atom, as the N-alkyl or N-benzyl nitrones give
an ee of 40-56% and the more rigid N-phenyl nitrones give
>90% ee.
The 1,3-dipolar cycloaddition reactions of 1a,b with 2a-c
leading to the products 3a-c,e-g have also been performed
with 5a as the catalyst, and the endo-isoxazolidines have the
same absolute configurations as observed for the above
reactions.8a,14 In a recent work we have indirectly determined
the absolute configuration of endo-3a.8b This was based on the
structure of the (S)-valin-derived endo-isoxazolidine 6, which
has been determined by X-ray crystallography.8b In the present
(14) The signs of the optical rotations in ref 8a in this work are the
same; however, the relative optical rotations and ee’s reported are in some
entries not in full agreement. This is due to experimential error and the
fact that the ee’s reported in ref 8a are measured by 1H NMR with Eu(hfc)3
as the chiral shift reagent. We have observed deviations of up to 15% by
this method.21 The optical purities reported in this work are determined by
HPLC with <2% deviations of the ee’s.
(13) (a) Hollis, T. K.; Robinson, N. P.; Bosnich, B. Organometallics
1992, 11, 2745. (b) Jaquith, J. B.; Guan, J.; Wang, S.; Collins, S.
Organometallics 1995, 14, 1079.

62 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Gothelf et al.
Scheme 1
Figure 1. Proposed approach of nitrone 2a to alkene 1a coordinated
to the TiCl2-TADDOLate catalyst 5a, leading to exo-3a. The arrow
shows the axial chloride ligand which is exchanged with bulkier ligands.
work we can directly determinate the absolute configuration of
endo-3c. Upon treatment of isoxazolidine endoa-6 with Ti(O-
i-Pr)4 and i-PrOH, the isopropyl ester (+)-7 is obtained with
an optical rotation of +77°. The same procedure is performed
with (-)-endo-3c (51% ee) to give (-)-7 with an optical rotation
of -28°. The reaction sequences are outlined in Scheme 1.
The two isopropyl esters (+)-7 and (-)-7 are identical in all
respects (NMR, MS, and TLC) except for their optical rotation.
On the basis of the X-ray structure of 6, we can now assign the
three chiral centers in the isoxazolidine ring of endo-3c to be
(3S,4R,5S).
On the basis of the experimental results presented in this paper
and the X-ray structure of the intermediate 4, a transtion state
(TS) model for the reaction of alkenes with nitrones in the
presence of the new Ti(OTos)2-TADDOLate catalyst leading
to the highly diastereo- and enantioselective reactions will now
be proposed. For the reaction of 1a with 2a in the absence of
a catalyst, the exo-TS energy is calculated to be 25 kcal‚mol-1
lower in energy than the endo-TS, showing that the uncatalyzed
reaction will lead to exo-3a in agreement with the experimental
results.8a,b If one assumes that the intermediate in the Ti(OTos)2-
TADDOLate-catalyzed reaction, in which 1a is coordinated to
5f, has a geometry similar to 4, we can now begin to understand
the mechanism of the approach of the nitrone to the alkene
coordinated to the catalyst.
For the TiCl2-TADDOLate-catalyzed reaction no significant
steric repulsion between the nitrone R-C-substituent and the axial
chloride ligand for the exo-approach of the nitrone to the alkene
coordinated to the TiCl2-TADDOLate catalyst is apparent and
the exo-product is primarily obtained in agreement with the
experimental results. We have used the Z-geometry of the
nitrone 2a as this is the most stable isomer at room tempera-
ture.15 The approach of the nitrone 2a to 1a coordinated to the
TiCl2-TADDOLate catalyst 5a leading to exo-3a is outlined
in Figure 1.
Figure 2. Proposed approach of nitrone 2a to alkene 1a coordinated
to the Ti(OTos)2-TADDOLate catalyst 5f, leading to endo-3a.
the much more bulky ligands such as triflato and tosylato are
introduced, the exo-approach (Figure 1; the arrow shows the
axial chloride ligand which is exchanged with the bulky ligand)
will indeed be unfavorable due to the repulsion between the
axial ligand on the titanium atom and the nitrone R-C-
substituent. However, no increased sterical hindrance is present
for the endo-TS, which explains the high endo-selectivities
observed for these catalysts. The proposed approach of nitrone
2a to the alkene 1a coordinated to the Ti(OTos)2-TADDOLate
catalyst 5f leading to endo-3a is outlined in Figure 2.
On the basis of the approach of the nitrone to the alkene
coordinated to Ti(OTos)2-TADDOLate catalyst 5f, it is thus
obvious that the R-C-substituent of the nitrone is responsible
for the endo/exo-selectivity obtained in reactions catalyzed by
TiX2-TADDOLate complexes. The absolute configurations of
endo-3a and endo-3c are known, and both of the products arise
from the endo-R-Re16 approach of the nitrone to the alkene 2a
coordinated to the catalyst. We propose that this approach is
similar for the reaction paths leading to the other endo-products
3b,d-h obtained in these 1,3-dipolar cycloaddition reactions.
It should be mentioned that for the TiCl2-TADDOLate-
When the chloride ligands are substituted with bromides, the
Ti-X bond length increases, as well as the atomic radius of
the ligand, and the increased sterical hindrance leads to an
increased appearance of the endo-isomer (Table 1, entry 4). As
(15) It is generally accepted that acyclic nitrones obtain a stable
Z-geometry at rt. (See, e.g.: DeShong, P.; Lander, S. W.; Leginus, J. M.;
Dicken, M. C. In AdVances in Cycloaddition; Curran, D. P., Ed.; Jai Press:
London, 1988; Vol. 1, pp 87-128). In a recent publication (Bravo, P.;
Bruche´, L.; Farina, A.; Fronza, G.; Meille, S. V.; Merli, A. Tetrahedron:
Asymmetry 1993, 4, 2131) it was claimed that the R-C,N-diphenyl nitrone
2a exhibits a stable E-configuration at rt with reference to Torssell, K. B.
G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH:
New York, 1988 (ref 2b in this paper, pp 85); however, this postulate is
not to be found there. Recently, Seerden et al.7b have described nitrone 2a
with an E-geometry referring to Bravo et al. Tetrahedron: Asymmetry 1993,
4, 2131. Thus, we assume that the proposed stable E-geometry of 2a might
be based on a misunderstanding.
(16) The approach of the (Z)-nitrone 2a to the 3-(2′-(E)-alkenoyl)-1,3-
oxazolidin-2-one 1a is described by endo-R-Re, which means that the nitrone
approaches the R,â-unsaturated carbonyl moiety of 1a in the endo-fashion.2a
The face of 1a to which the nitrone approaches is the Re-face of the R-C
atom in the R,â-unsaturated carbonyl moiety.

Cycloaddition Reaction of Alkenes with Nitrones
J. Am. Chem. Soc., Vol. 118, No. 1, 1996 63
those used in Figures 2 and 3. If the less rigid N-alkyl and
N-benzyl nitrones were going to approach the alkene coordinated
to the Ti(OTos)2-TADDOLate catalyst having the tosylato
ligands in a cis-orientation at the titanium atom, the same high
ee as for the N-phenyl nitrones should be observed, since the
phenyl group shields the upper R-Si-side of the alkene and the
approach of the nitrone should exclusively be expected to take
place at the R-Re-face of the alkene. But the present results
show a relatively large decrease in ee when the less rigid N-alkyl
and N-benzyl nitrones are applied, which also seems to disfavor
an intermediate with the two halogen/pseudo-halolgen ligands
attached to the titanium atom in a cis-fashion.
We thus propose that the reaction path for the 1,3-dipolar
cycloaddition reaction of nitrones with alkenes catalyzed by
these new Ti(OTos)2-TADDOLate complexes takes place via
an intermediate where the two tosylato ligands at the titanium
atom of Ti(OTos)2-TADDOLate catalyst are placed trans at
the titanium atom as proposed in Figure 2.
Figure 3. Approach of the nitrone 2a to the alkene 1a coordinated to
the Ti(OTos)2-TADDOLate catalyst having the two tosylato ligands
placed in a cis-orientation at the titanium center. The steric repulsion
between the N-phenyl substituent and the phenyl substituent of the
TADDOL ligand is indicated by the arrow.
Conclusion
A highly diastereo- and enantioselective Ti(OTos)2-
TADDOLate-catalyzed 1,3-dipolar cycloaddition reaction of
alkenes with nitrones is developed. It is shown that the tosylato
ligand at the titanium atom is of utmost importance for both
the diastereo- and enantioselectivities. The Ti(OTos)2-
TADDOLate-catalyzed reaction of N-phenyl nitrones with
alkenes proceeds to give the endo-isoxazolidines with a dia-
stereoselectivity of >90% and very high enantioselectivities in
the range of 91-93%. Reactions of N-alkyl and N-benzyl
nitrones with different alkenes give the endo-isoxazolidines with
the same high diastereoselectivity (>90%), but the ee is in the
range of 40-56%. On the basis of the absolute configuration
of the product an endo-R-Re-attack of the nitrone on the alkene
coordinated to the Ti(OTos)2-TADDOLate catalyst, in which
the tosylato ligands are placed trans at the titanium atom, is
proposed.
catalyzed Diels-Alder reaction the endo-R-Re-attack on 2a
chelated to the catalyst is also favored.9,10,12 The endo-R-Re-
attack outlined in Figure 2 can be accounted for by the following
three points: (i) the axial phenyl group of the TADDOL ligand
is shielding the upper side (R-Si) of the alkene. (ii) The alkene
part is probably slightly tilted out of the plane, consisting of
the four oxygen atoms attached to the titanium atom, leading
to increased shielding of the R-Si-face of the alkene. (iii) The
two tosylato ligands on the titanium atom facing trans to each
other might be tilted toward the alkene, the upper ligand group
more than the lower. Arguments i and ii are based on the X-ray
structure of 4.9 For the large tosyl ligand the upper might be
pushed further toward the alkene caused by steric repulsion with
the axial phenyl substituent of the TADDOL ligand, giving rise
to the excellent ee’s observed with the present catalyst.
The N-substituent of the nitrone proved to be of major
importance for the enantioselectivity of the reaction. Inspection
of the model in Figure 2 reveals that an R-Si-approach of the
rigid N-phenyl nitrone gives rise to major steric repulsion with
the TADDOL-phenyl substituent, whereas reduced steric repul-
sion is present for the less rigid N-alkyl and N-benzyl nitrones
in the R-Si-attack. This explains why much higher enantio-
selectivities are obtained with nitrones 2a and 2d, compared
with 2b and 2c. By the present model for the TS of this new
metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction,
one can account both for the endo-R-Re-approach of the nitrone
to the alkene and for the deviations in enantioselectivity.
DiMare et al. has proposed another structure with the two
halides facing cis to each other to be the most reactive
intermediate in the TiCl2-TADDOLate-catalyzed Diels-Alder
reaction.11 Application of their alternative model for the present
1,3-dipolar cycloaddition reaction reveals that for this structure
the R-Re-attack of the nitrone on the alkene will also be favored.
In their model the phenyl group shielding the upper R-Si-side
of the alkene is centered just above the double bond.
Experimental Section
General Methods. The 1H NMR and 13C NMR spectra were
recorded at 300 and 50 MHz, respectively. Chemical shifts for H
1
NMR and 13C NMR are reported in parts per million downfield from
tetramethylsilane (TMS). HPLC analysis was performed using a 4.6
mm × 25 cm Daicel Chiralcel OD column. Mass spectra were recorded
at 70 eV with a direct inlet. Optical rotations were measured on a
Perkin-Elmer 241 polarimeter. Preparative thin layer chromatography
(TLC) was performed on 200 × 200 × 0.8 mm silica gel (PF254+366
Art. 7748, Merck) on glass plates. Solvents were dried using standard
procedures. The 4 Å powdered molecular sieves were activated by
heating to 250 °C for 3 h in high vacuum. All glass equipment and
syringes were dried in an oven at 130 °C prior to use.
Materials. The starting materials 3-((E)-2′-butenoyl)-1,3-oxazolidin-
2-one (1a),17 3-((E)-2′-hexenoyl)-1,3-oxazolidin-2-one (1b),17 ben-
zylidenephenylamine N-oxide (2a),18 benzylidenepropylamine N-oxide
(2b),19 benzylbenzylideneamine N-oxide (2c),20 (4-methylbenzylidene)-
phenylamine N-oxide (2d),18 and (2R,3R)-2,3-O-(2-propylidene)-1,1,4,4-
tetraphenyl-1,2,3,4-butanetetrols10d were synthesized according to the
literature. Silver p-toluenesulfonate was received from Fluka. Pow-
The approach of the nitrone 2a to the alkene 1a coordinated
to the Ti(OTos)2-TADDOLate catalyst having the tosylato
ligands in a cis-orientation at the titanium atom is presented in
Figure 3. By this approach of the nitrone, a significant steric
repulsion of the N-phenyl substituent of the nitrone and the
phenyl substituent at the TADDOL ligand is observed as
indicated by the arrow in Figure 3. It should be noted that the
bond lengths between the reacting atoms (2.5 Å) are similar to
(17) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238.
(18) Wheeler, O. H.; Gore, P. H. J. Am. Chem. Soc. 1956, 78, 3363.
(19) Christensen, D.; Jørgensen, K. A.; Hazell, R. G. J. Chem. Soc.,
Perkin Trans. 1 1990, 2391.
(20) Beckett, A. H.; Coutts, R. T.; Ogunbona, F. A. Tetrahedron 1973,
29, 4189.
(21) Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994,
35, 8595.

64 J. Am. Chem. Soc., Vol. 118, No. 1, 1996
Gothelf et al.
dered molecular sieves (4 Å) were received from Aldrich. Millex filter
units, 45 µm pore size, were received from Millipore.
) 55 min (major). Ee: 91%. 1H NMR (CDCl3): δ 1.56 (d, J ) 6.0
Hz, 3H), 2.35 (s, 3H), 3.94 (m, 2H), 4.28 (m, 2H), 4.46 (m, 1H), 4.81
(dd, J ) 6.7, 7.7 Hz, 1H), 5.16 (d, J ) 7.2 Hz, 1H), 6.96 (m, 3H), 7.22
(m, 4H), 7.37 (d, J ) 7.1 Hz, 2H). 13C NMR (CDCl3): δ 17.6, 21.0,
42.8, 61.7, 62.3, 74.2, 79.3, 114.5, 121.5, 126.4, 128.6, 129.4, 137.4,
137.6, 151.3, 152.7, 170.6. MS: m/z ) 366 (M+).
(-)-(3′S,4′R,5′S)-3-[(2′-N,3′-Diphenyl-5′-propylisoxazolidin-4′-yl)-
carbonyl]-1,3-oxazolidin-2-one (endo-3e). Yield: 63%. [R]D ) -31°
(c ) 1.0, CHCl3). HPLC (Daicel Chiralcel OD, hexane:i-PrOH ) 9:1,
flow rate ) 1.0 mL min): tR) 21 min. (minor), tR ) 27 min. (major).
Ee ) 93%.
Preparation of the Ti(OTos)2-(R,R)-TADDOLate catalyst 5f.
Silver p-toluene sulfonate (0.837 g, 3 mmol) is placed in a 25 mL flask
with a magnetic stirring bar under N2. A solution of Ti(O-i-Pr)2Cl2
(0.1 M, 1mmol) in toluene (10 mL) is added, and the suspension is
stirred for 24 h at room temperature (rt). The suspension is transferred
to a syringe and filtered through a Millex filter unit into a 25 mL flask
containing the appropriate TADDOL ligand (0.513 g, 1.1 mmol), a
magnetic stirring bar, and N2. The 0.1 M catalyst solution is stirred
0.5 h prior to use.
General procedure for the Asymmetric Ti(OTos)2-TADDOLate-
Catalyzed 1,3-Dipolar Cycloaddition Reaction. To a 10 mL reaction
flask containing a magnetic stirring bar, toluene (5 mL), and 4 Å
powdered molecular sieves (250 mg) are added the alkene 1a (0.5
mmol) and the nitrone 2a (0.6 mmol). The flask is closed with a septum
and cooled to 0 °C on an ice bath (occasionally to -20 °C on an ice/
NaCl bath). After stirring for 15 min the above described catalyst
solution of 5f (2.5 mL, 0.25 mmol) is added through the septum via
syringe. The reaction mixture is allowed to warm to rt over 24 h, and
after a total reaction time of 48 h, 10 mL of 5% MeOH in CH2Cl2 is
added to the reaction mixture. After stirring for 10 min, the mixture
is filtered through a 20 mm layer of silica gel. The silica gel layer is
washed with another 10 mL of 5% MeOH in CH2Cl2 and the solvent
evaporated in Vacuo. The crude product is purified by preparative TLC
(silica gel, Et2O/petroleum ether, 2:1, or MeOH/CH2Cl2, 1:99).
The 1H NMR, 13C NMR, and mass spectra of compounds 3a-c and
3e-g have been reported previously.8a,b
(-)-(3′S,4′R,5′S)-3-[(2′-N,5′-Dipropyl-3′-phenylisoxazolidin-4′-yl)-
carbonyl]-1,3-oxazolidin-2-one (endo-3f). Yield: 66%. [R]D: -22.3°
(c ) 1.0, CHCl3). HPLC (Daicel Chiralcel OD, hexane:i-PrOH ) 9:1,
flow rate 1.0 mL/min): tR ) 10 min (major), tR ) 15 min (minor). Ee:
53%.
(-)-(3′S,4′R,5′S)-3-[(2′-N-Benzyl-3′-phenyl-5′-propylisoxazolidin-
4′-yl)carbonyl]-1,3-oxazolidin-2-one (endo-3g). Yield: 58%. [R]D:
-7.8° (c ) 1.0, CHCl3). HPLC (Daicel Chiralcel OD, hexane:i-PrOH
) 9:1, flow rate 1.0 mL/min): tR ) 18 min (major), tR ) 36 min
(minor). Ee: 56%.
(-)-(3′S,4′R,5′S)-3-[(3′-(4′′-Methylphenyl)-2′-N-phenyl-5′-propyl-
isoxazolidin-4′-yl]carbonyl]-1,3-oxazolidin-2-one (endo-3h). Yield:
55%. [R]D: ) -34.1° (c ) 1.0, CHCl3). HPLC (Daicel Chiralcel OD,
hexane:i-PrOH ) 9:1, flow rate 1.0 mL/min): tR ) 19 min (minor), tR
) 27 min (major). Ee: 92%. 1H NMR (CDCl3): δ 1.01 (t, J ) 7.1
Hz, 3H), 1.50 (m, 1H), 1.72 (m, 2H), 1.99 (m, 1H), 2.35 (s, 3H), 3.93
(m, 2H), 4.25-4.39 (m, 3H), 4.87 (t, J ) 7.1 Hz, 1H), 5.11 (d, J ) 7.2
Hz, 1H), 6.96 (m, 3H), 7.22 (m, 4H), 7.37 (d, J ) 7.2 Hz, 2H). 13C
NMR (CDCl3): δ 13.8, 19.6, 20.9, 34.1, 42.8, 61.1, 61.6, 74.3, 83.2,
114.4, 121.4, 126.3, 128.6, 129.4, 137.4, 137.5, 151.4, 152.6, 170.9.
MS: m/z ) 394 (M+).
(-)-(3′S,4′R,5′S)-3-[(5′-Methyl-2′-N,3′-diphenylisoxazolidin-4′-yl)-
carbonyl]-1,3-oxazolidin-2-one (endo-3a). Yield: 61%. [R]D: -15.5°
(c )1.0, CHCl3). HPLC (Daicel Chiralcel OD, hexane:i-PrOH ) 9:1,
flow rate 1.0 mL/min.): tR ) 42 min (minor), tR ) 60 min (major).
Ee: 93%.
(-)-(3′S,4′R,5′S)-3-[(5′-Methyl-3′-phenyl-2′-N-propylisoxazolidin-
4′-yl)carbonyl]-1,3-oxazolidin-2-one (endo-3b). Yield: 56%. [R]D:
-0.8° (c )1.0, CHCl3). HPLC (Daicel Chiralcel OD, hexane:i-PrOH
) 9:1, flow rate 1.0 mL/min): tR ) 15 min (major), tR ) 22 min
(minor). Ee: 40%.
(+)-(3′S,4′R,5′S)-3-[(2′-N-Benzyl-5′-methyl-3′-phenylisoxazolidin-
4′-yl)carbonyl]-1,3-oxazolidin-2-one (endo-3c). Yield: 54%. [R]D:
+5.5° (c ) 1.0, CHCl3). HPLC (Daicel Chiralcel OD, hexane:i-PrOH
) 9:1, flow rate 1.0 mL/min): tR ) 28 min (major), tR ) 47 min
(minor). Ee: 51%.
(-)-(3′S,4′R,5′S)-3-[(5′-Methyl-3′-(4′′-methylphenyl)-2′-N-phenyl-
isoxazolidin-4′-yl]carbonyl]-1,3-oxazolidin-2-one (endo-3d). Yield:
71%. [R]D: ) -21.7° (c )1.0, CHCl3). HPLC (Daicel Chiralcel OD,
hexane:i-PrOH ) 9:1, flow rate 1.0 mL/min): tR) 33 min (minor), tR
Acknowledgment. Thanks are expressed to Statens Teknisk-
Videnskabelige Forskningsråd for financial support.
Supporting Information Available: 1H NMR and 13C NMR
spectra of (-)-endo-3d, (-)-endo-3h, (+)-7, and (-)-7 (4
pages). Spectra not found in the present supporting information
are found in ref 8. This material is contained in many libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, can be ordered from the ACS, and can
be downloaded from the Internet; see any current masthead page
for ordering information and Internet access instructions.
JA952726E