Synthesis of novel chiral bis(2-oxazolinyl)xanthene (xabox) ligands and their evaluation in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone

Article abstract of DOI:10.1016/j.tetlet.2004.01.043

Chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) were synthesized and the chiral environments were evaluated in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones resulting in good to excellent enantioselectivities. 1,3-Dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone in the presence of a bis(2-oxazolinyl)xanthene (4c; xabox-Bn) and Mn(II) or Mg(II) complex as a chiral Lewis acid catalyst proceeded smoothly to give the corresponding cycloadducts ranging from 96:4 to >99:1 of endo:exo ratio and ranging from 91% to 98% ee for the endo adduct.

Full text of DOI:10.1016/j.tetlet.2004.01.043

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2121–2124
Synthesis of novel chiral bis(2-oxazolinyl)xanthene (xabox) ligands
and their evaluation in catalytic asymmetric 1,3-dipolar
cycloaddition reactions of nitrones with 3-crotonoyl-2-
oxazolidinone
Seiji Iwasa,a,* Yosuke Ishima,a Herman Setyo Widagdo,a Katsuyuki Aokia and
Hisao Nishiyamab,*
aSchool of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
bGraduate School of Engineering, Department of Applied Chemistry, Nagoya University, Chikusa, Nagoya, Aichi 464-8603, Japan
Received 18 December 2002; revised 6 January 2004; accepted 13 January 2004
Abstract—Chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) were synthesized and the chiral envi-
ronments were evaluated in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones resulting in good to excellent
enantioselectivities. 1,3-Dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone in the presence of a bis(2-
oxazolinyl)xanthene (4c; xabox-Bn) and Mn(II) or Mg(II) complex as a chiral Lewis acid catalyst proceeded smoothly to give the
corresponding cycloadducts ranging from 96:4 to >99:1of endo:exo ratio and ranging from 91% to 98% ee for the endo adduct.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In order to develop a powerful synthetic alternative
methodology to enzymatic synthesis, much attention has
been paid to the design and synthesis of chiral ligands of
optically active organic molecules.1 Bis- and tridentate
oxazoline-derived C2-symmetry chiral ligands have
played an important role in the field of asymmetric
induction since these are easily accessible from amino
alcohols and carboxylic acids.2;3 During the course of
our studies on the design of oxazoline-derived chiral
ligands, we became interested in a C2-symmetric helical
chiral ligand based on the C2-symmetry to increase the
rigidity of the chiral environment.4 Here, a series of new
tridentate oxazoline-derived chiral ligands having a
xanthene backbone was synthesized, and the chiral
environment after the complexation with metals may be
constructed as a helical structure. These new ligands
were investigated and evaluated in catalytic asymmetric
1,3-dipolar cycloaddition (D.C.) reactions of nitrones
with 3-crotonoyl-2-oxazolidinone.5;6
The oxazoline-derived xanthene ligands were synthe-
sized from the corresponding carboxylic acid in four
steps to give 70–80% yields (Scheme 1). The reaction of
xanthene-2,6-dicarboxylic acid chloride with amino
alcohols 2 under basic conditions afforded the corre-
sponding dihydroxyl amides 3a–c in 71–85% yields. The
crude reaction products 3 can be used for the next step
without any purification. The dihydroxyl amides 3 were
easily converted to chiral bis(2-oxazolinyl)xanthenes
(xabox) via mesylation of 3 followed by oxazoline ring
formation reactions in a one-pot procedure in high
yields.
The chiral environment of these new xabox ligands was
evaluated in nitrone 1,3-D.C. reaction by comparing
with our previous reaction in which pybox/Ni(II) com-
plexes were employed.7 Initially, we have chosen Ni(II)
as a central metal and briefly examined the chiral
shielding substituent effect on the oxazoline rings. It was
found that xabox-Bn 4c was the best ligand for the
nitrone 1,3-D.C. reaction (Scheme 2). Therefore, we
used xabox-Bn 4c for further optimization and the
results are summarized in Table 1. The metal profile
showed that the combination of xabox-Bn 4c and
Mn(II) and Mg(II) gave the highest enantioselectivities
(entries 1–3 and 6).8 These results indicate that the
Keywords: 1,3-Dipolar cycloaddition; Nitrone; Molecular catalyst;
Xanthene backbone; Nitrogen ligand.
* Corresponding authors. Tel.: +81-532446817; fax: +81-532485833
(S.I.); e-mail: iwasa@tutms.tut.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.043

2122
S. Iwasa et al. / Tetrahedron Letters 45 (2004) 2121–2124
Scheme 1. Synthesis of chiral 4,6-bis(2-oxazolinyl)xanthene (xabox) ligands.
Scheme 2. Catalytic asymmetric 1,3-D.C. reaction of nitrones 5 and 6 with (S,S)-xabox-Bn/metal catalysts.
Table 1. (S,S)-xabox-Bn and Mn(II) and Mg(II) catalyzed 1,3-D.C. reaction of nitrones 5 and crotonoyl-oxazolidinone 6a
Entry
Metal
Nitrone
Product
Temp. (ꢁC)
Time (h)
Yieldb (%)
endo:exoc
endo eed (%)
1Cu(OTf)
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
25
25
25
10
0
24
55
86:14
77
2
2
Ni(ClO4)2Æ(H2O)6
Mn(ClO4)2Æ(H2O)6
Mn(ClO4)2Æ(H2O)6
Mn(ClO4)2Æ(H2O)6
Mg(ClO4)2Æ(H2O)6
Mg(ClO4)2Æ(H2O)6
Mg(ClO4)2Æ(H2O)6
Mn(ClO4)2Æ(H2O)6
Mn(ClO4)2Æ(H2O)6
Mn(ClO4)2Æ(H2O)6
2187
2185
48
5
850:1
92:8
85
3
93
96:4
4
95
93
85
92
5
72
12
78
96
96:4
>99:1
99:1
6
25
10
0
7
24
48
88
85
8
>99:192
96:4
97:3
9
25
25
25
12
12
90
95
94
95
10
11
24
8198:2
91
a 5a (0.25 mmol), 6 (0.25 mmol), (S,S)-xabox-Bn 4c (0.025 mmol), metal-perchlorate (0.025 mmol), MS 4A (250 mg), dichloromethane (1.5 mL). The
catalyst was prepared under MS 4A at 40 ꢁC for 4 h.
b Isolated yield.
c The ratios were determined by 1H NMR (300 MHz).
d The ees were determined by chiral HPLC analysis (Daicel Chiralpak AD).
xabox ligand system seems to need a smaller ionic
diameter for the central metals to coordinate in the
cavity of the chiral environment compared to the pybox
system. Temperature effects were also examined for both
metals (entries 4, 6, 7, and 8). The nitrone 1,3-D.C.
reactions proceeded smoothly at 0–25 ꢁC in the presence
of 10 mol % of 4c and metals to afford the cycloadducts
in high yields as well as high stereoselectivities, though
the reaction time was prolonged. Encouraged by the
marked results for both the diastereo- and enantio-

S. Iwasa et al. / Tetrahedron Letters 45 (2004) 2121–2124
2123
Scheme 3. Complexation of xabox-i-Pr 3a and RhCl3(H2O)3.
catalytic asymmetric reactions as a new chiral inducer.
X-ray analysis of the complex shows a facial coordina-
tion of the xabox ligand to the metal, which may give
information on the mechanism of the 1,3-D.C. reaction
for the transition state.
Acknowledgements
S.I. and H.N. thank Prof. Shuji Kanemasa (Kyushu
University) for providing DBFOX and helpful discus-
sions and also the Ministry of Education, Culture,
Sports, Science and Technology for partial financial
support.
References and notes
Figure 1. Crystal structure of complex 8.
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Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
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selectivities, we then examined the optimized catalytic
conditions for catalytic asymmetric 1,3-D.C. reaction of
various nitrones with 3-alkenoyl oxazolidinones (entries
9–11). The cycloadducts were obtained with excellent
stereoselectivities for all of the nitrones.9
Furthermore, we examined the complexation of various
xabox ligands with several transition metals to investi-
gate the coordination type of the complexes and the
mechanism. Among them, RhCl3 and xabox-i-Pr 4a
underwent smooth complexation whose structures were
determined by X-ray analysis as a facial type complex-
ation (Scheme 3 and Fig. 1).10 However, it was sur-
prising that the complexation of Kanemasaꢀs DBFOX
and RhCl3 or Ru[(p-cymene)Cl2]2 failed to give complex
mixtures. The different topology of the ligand may have
given different stability to both ligands. We now believe
that the interaction between the xabox/metal complex
and the substrates might include a facial coordination
intermediate in the nitrone 1,3-D.C. reactions with
3-alkenoyl-2-oxazolidinone even though different metals
are used.
2. (a) Ghosh, K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1; (b) Fache, F.; Schulz, E.; Tomma-
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Tetrahedron Lett. 1997, 38, 3211; (c) Reetz, M. T.;
Sostmann, S. J. Organomet. Chem. 2000, 603, 105; (d)
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J.-A.; Tang, F.-Y.; Kang, L.; Zhou, Q.-L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2002, 13, 161.
5. For reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Acta
Chem. Scand. 1996, 50, 652; (b) Gothelf, K. V.; Jørgensen,
K. A. Chem. Rev. 1998, 98, 863; (c) Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998; Vols. 1, 2; (d) Kanemasa, S. Synlett 2002,
1371; (e) Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, 2002; p 274.
6. (a) Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1994,
59, 5687; (b) Seerden, J.-P. G.; Scholte op Reimer, A. W.
A.; Scheeren, H. W. Tetrahedron Lett. 1994, 35, 4419; (c)
Gothelf, K. V.; Thomsen, I.; Jørgensen, K. A. J. Am.
In conclusion, various xabox ligands having a xanthene
backbone were synthesized and were applied to catalytic
asymmetric 1,3-D.C. reactions of nitrones with 3-alke-
noyl oxazolidinone resulting in good to excellent stereo-
selectivities. Chiral xabox ligands can be used for other

2124
S. Iwasa et al. / Tetrahedron Letters 45 (2004) 2121–2124
Chem. Soc. 1996, 118, 59; (d) Jensen, K. B.; Gothelf, K.
presence of MS 4A. After the complexation, the MS was
filtered off to give a pale blue solution which was again
filtered via membrane filter. The catalyst solution was
added to pre-activated MS 4A at room temperature
followed by addition of 3-crotonoyl-2-oxazolidinone 6
and nitrone. The resulting suspension was stirred at 25 ꢁC
and the reaction was monitored by TLC. At the end of the
reaction, the reaction product was directly purified by
flash column chromatography on silica gel to give the
desired 1,3-D.C. product.
V.; Jørgensen, K. A. Helv. Chem. Acta 1997, 80, 2039; (e)
Sanchez-Blanco, A. I.; Gothelf, K. V.; Jørgensen, K. A.
Tetrahedron Lett. 1997, 38, 7923; (f) Kanemasa, S.;
Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem.
Soc. 1998, 120, 12355; (g) Kobayashi, S.; Kawamura, M.
J. Am. Chem. Soc. 1998, 120, 5840; (h) Ellis, W. W.;
Gavrilova, A.; Sands, L.; Rheingold, A. L.; Bosnich, B.
Organometallics 1999, 18, 332; (i) Desimoni, G.; Faita, G.;
Mortoni, A.; Righetti, P. Tetrahedron Lett. 1999, 40, 2001;
(j) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999,
10. X-ray analysis: a single crystal (0.15 · 0.2 · 0.6 mm) was
obtained by recrystallization from CHCl3–ether–hexane.
ꢁ ꢁ
Selected bond lengths and angle: 2.129 A, Rh–O; 2.05 A,
ꢀ
40, 3213; (k) Simonsen, K. B.; Bayon, P.; Hazell, R. G.;
Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 1999,
121, 3845; (l) Hori, K.; Komada, H.; Ohta, T.; Furukawa,
I. J. Org. Chem. 1999, 63, 5017; (m) Seebach, D.; Heckel,
A. Angew. Chem. Int. Ed. 2000, 39, 163; (n) Jen, W. S.;
Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 9874; (o) Mita, T.; Ohtsuki, N.; Ikeno, T.;
Yamada, T. Org. Lett. 2002, 4, 2457; (p) Kanemasa, S.;
Ueno, N.; Shirahase, M. Tetrahedron Lett. 2002, 43, 657;
ꢁ
ꢁ
ꢁ
Rh–N1; 2.07 A, Rh–N2; 2.330 A, Rh–Cl1; 2.331 A, Rh–
ꢁ
Cl2; 2.270 A, Rh–Cl3; 93.8ꢁ, N1–Rh–N2; 86.9ꢁ, N1–Rh–
O; 83.7ꢁ, N2–Rh–O; 89.1ꢁ, N1–Rh–Cl1; 178.2ꢁ, N1–Rh–
Cl2; 91.6ꢁ, N1–Rh–Cl3; 173.7ꢁ, N2–Rh–Cl1; 86.8ꢁ, N2–
Rh–Cl2; 92.1ꢁ, N2–Rh–Cl3; 90.8ꢁ, O–Rh–Cl1; 91.5ꢁ, O–
Rh–Cl2; 175.5ꢁ, O–Rh–Cl3.
Crystal data: C39H48N2O3Cl6Rh, orthorhombic, space
ꢁ
€
(q) Viton, F.; Bernardinelli, G.; Kundig, E. P. J. Am.
Chem. Soc. 2002, 124, 4968.
group P212121 (No. 19), a ¼ 16:735ð2Þ A, b ¼
3
ꢁ
ꢁ
ꢁ
27:482ð6Þ A, c ¼ 9:067ð2Þ A, V ¼ 4169ð1Þ A , qcalcd
¼
7. (a) Iwasa, S.; Nakamura, H.; Nishiyama, H. Heterocycles
2000, 52, 939; (b) Iwasa, S.; Tsushima, S.; Shimada, T.;
Nishiyama, H. Tetrahedron Lett. 2001, 42, 6715; (c) Iwasa,
S.; Tsushima, S.; Shimada, T.; Nishiyama, H. Tetrahedron
2002, 58, 227; (d) Iwasa, S.; Maeda, H.; Nishiyama, K.;
Tsushima, S.; Tsukamoto, Y.; Nishiyama, H. Tetrahedron
2002, 58, 8281.
8. (a) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 1996, 61, 346; (b) Crosignani, S.; Desimoni, G. G.;
Faita, G.; Fillippone, S.; Mortoni, A.; Righetti, P.; Zema,
M. Tetrahedron Lett. 1999, 40, 7007; (c) Faita, G.; Paio,
A.; Quadrelli, P.; Rancati, F.; Seneci, P. Tetrahedron 2001,
57, 8313.
1:447 g cmꢀ1, Z ¼ 4, l ¼ 8:31cm ꢀ1. The crystal contains
a 1:1 mole ratio of 8 and CHCl3: the solvent molecules in
the crystal were omitted in Figure 1. The intensity data
(28:99 < # < 29:88ꢁ) were collected on a Rigaku AFC-7R
diffractometer with graphite-monochromated Mo Ka
ꢁ
radiation (k ¼ 0:71069 A), and the structure was solved
by Patterson methods (DIRDIF92, PATTY). The final
cycle of refinement was based on 2686 observed reflections
(I > 3:00rðIÞ) and 433 variable parameters and converged
with R ¼ 5:6% and Rw ¼ 6:1%. Crystallographic data for 8
have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication number
CCDC-199961. Copies of the data can be obtained, on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0)-1223336033 or e-mail: deposit@
ccdc.cam.ac.uk].
9. General procedure is as follows: catalysts were prepared
by heating xabox-Bn 3c with Mn(II)(ClO4)2Æ(H2O)6 or
Mg(II)(ClO4)2Æ(H2O)6 at 40 ꢁC for 4 h in CH2Cl2 in the