Catalytic enantioselective 1,3-dipolar cycloadditions between nitrones and alkenes using a novel heterochiral ytterbium(III) catalyst [18]

Full text of DOI:10.1021/ja980702c

5840
J. Am. Chem. Soc. 1998, 120, 5840-5841
N-benzylidenebenzylamine N-oxide (1) and 3-(2-butenoyl)-1,3-
oxazolidin-2-one (2) as models, and the 1,3-dipolar cycloaddition
reaction was performed in the presence of a chiral Yb(III) catalyst
(20 mol %) prepared from Yb(OTf)3, (S)-1,1′-binaphthol ((S)-
BINOL), and triethylamine (Et3N). The reaction proceeded
smoothly at room temperature to afford the corresponding
isoxazolidine derivative in a 65% yield with high endo/exo
selectivity (99/1), and a moderate enantiomeric excess (ee) of
the endo adduct was observed (Table 1). The enantiomeric excess
was improved to 78% when cis-1,2,6-trimethylpiperidine (TMP)
was used instead of Et3N. Furthermore, it was found that use of
chiral amines influenced the selectiVity dramatically and that
combination of the chirality of BINOL and the amine was crucial
for the selectiVity. Namely, 71% ee of the endo adduct was
obtained in the model reaction using a catalyst prepared by the
combination of (S)-BINOL and N-methyl-bis[(R)-1-phenylethyl]-
amine ((R)-MPEA), while only 35% ee was observed by the
combination of (S)-BINOL and (S)-MPEA. Moreover, it was
exciting to find that 96% ee of the endo adduct was obtained
with an excellent yield (92%) and diastereoselectivity (endo/exo
) 99/1) by the combination of (S)-BINOL and a newly prepared
chiral amine, N-methyl-bis[(R)-1-(1-naphthyl)ethyl]amine ((R)-
MNEA).10 The chiral Yb(III) catalyst thus prepared has two
independent chiralities (heterochiral Yb(III) catalyst, Vide infra),
and it was found that the sense of the chiral induction in these
reactions was mainly determined by BINOL and that the chiral
amine increased or decreased the induction relatively.
Catalytic Enantioselective 1,3-Dipolar Cycloadditions
between Nitrones and Alkenes Using a Novel
Heterochiral Ytterbium(III) Catalyst
Shuj Kobayashi*,† and Mikako Kawamura
Department of Applied Chemistry, Faculty of Science
Science UniVersity of Tokyo (SUT), CREST
Japan Science and Technology Corporation (JST)
Kagurazaka, Shinjuku-ku, Tokyo 162
ReceiVed March 3, 1998
Asymmetric cycloadditions provide powerful methods for the
synthesis of chiral complex molecules because multiple asym-
metric centers can be constructed in one-step transformations.
Among them, reactions using chiral catalysts are the most efficient
and promising, and fruitful results have recently been reported
in asymmetric Diels-Alder reactions.1 On the other hand, 1,3-
dipolar cycloadditions between nitrones and alkenes are most
useful and convenient for the preparation of isoxazolidine
derivatives, which are readily converted to 1,3-amino alcohol
equivalents under mild reducing conditions.2 Despite the impor-
tance of chiral amino alcohol units for the synthesis of biologically
important alkaloids, amino acids, â-lactams, and amino sugars,
etc.,3 catalytic enantioselective 1,3-dipolar cycloadditions remain
relatively unexplored.3,4 In this paper, we describe highly
diastereo- and enantioselective 1,3-dipolar cycloadditions using
a novel heterochiral ytterbium(III) (Yb(III)) catalyst.
Several examples of the 1,3-dipolar cycloadditions between
nitrones and 3-(2-alkenoyl)-1,3-oxazolidin-2-ones using the novel
heterochiral Yb(III) catalyst are shown in Table 2. In most cases,
the desired isoxazolidine derivatives were obtained in excellent
yields with excellent diastereo- and enantioselectivities.11 It is
noted that high levels of selectivities were attained at room
temperature. Nitrones derived from aromatic and heterocyclic
aldehydes gave satisfactory results, and even in the reaction using
the nitrone derived from an aliphatic aldehyde, the cycloaddition
proceeded smoothly to give the endo adduct in an excellent
enantiomeric excess, although low endo/exo selectivity was
observed. Moreover, it was found that alkenes which could be
employed in the present 1,3-dipolar cycloaddition were not limited
to 3-(2-alkenoyl)-1,3-oxazolidin-2-one derivatives. When N-
phenylmaleimide was used as a dipolarophile, the desired
isoxazolidine derivative was obtained in a 70% yield with endo/
We have recently reported the unique characteristics of
lanthanide triflates as Lewis acid catalysts5 and have developed
efficient chiral lanthanide catalysts in Diels-Alder reactions6 and
aza Diels-Alder reactions.7 One of the features of the lanthanide
catalysts is that catalytic processes are successfully completed
even in reactions using nitrogen-containing compounds, while
most Lewis acids are decomposed or deactivated in the presence
of basic nitrogen atoms. In the course of our investigations to
explore truly efficient asymmetric processes, we have focused
on catalytic enantioselective 1,3-dipolar cycloadditions of nitrones
with alkenes using a chiral lanthanide catalyst.8,9 First, we chose
† Present address: Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033.
(1) For example, see: (a) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92,
1007. (b) Santelli, M.; Pons, J.-M. Lewis Acids and SelectiVity in Organic
Synthesis; CRC Press: Boca Raton, FL, 1995; p 267. (c) Ager, D. J.; East,
M. B. Asymmetric Synthetic Methodology CRC Press: Boca Raton, FL, 1996;
p 309.
(2) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; John Wiley & Sons: Chichester, 1984; Vol. 2, p 83. (b) Torssell, K.
B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH:
Weinheim, 1988.
(3) For a review, see: Frederickson, M. Tetrahedron 1997, 53, 403.
(4) For pioneering works in this field, see: (a) Seerden, J.-P. G.; Scholte
op Reimer, A. W. A.; Scheeren, H. W. Tetrahedron Lett. 1994, 35, 4419. (b)
Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1994, 59, 5687. (c) Seerden,
J.-P. G.; Kuypers, M. M. M.; Scheeren, H. W. Tetrahedron: Asymmetry 1995,
6, 1441. (d) Gothelf, K. V.; Thomsen, I.; Jørgensen, K. A. J. Am. Chem. Soc.
1996, 118, 59. (e) Seebach, D.; Marti, R. E.; Hintermann, T. HelV. Chim.
Acta 1996, 79, 1710. (f) Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I.
Tetrahedron Lett. 1996, 37, 5947. (g) Ukaji, Y.; Taniguchi, K.; Sada, K.;
Inomata, K. Chem. Lett. 1997, 547. (h) Jensen, K. B.; Gothelf, K. V.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 1997, 62, 2471 and references therein.
(5) For example, see: (a) Kobayashi, S.; Busujima, T.; Nagayama, S. J.
Chem. Soc., Chem. Commun. 1998, 19. (b) Kobayashi, S.; Nagayama, S. J.
Am. Chem. Soc. 1997, 119, 10049. (c) Kobayashi, S.; Akiyama, R.; Kawamura,
M.; Ishitani, H. Chem. Lett. 1997, 1039. (d) Kobayashi, S.; Ishitani, H.; Ueno,
M. Synlett 1997, 115. (e) Kobayashi, S. Synlett 1994, 689 and references
therein.
(8) We have recently found that lanthanide triflates are excellent catalysts
in achiral 1,3-dipolar cycloadditions between nitrones and alkenes and also
in three-component coupling reactions of aldehydes, hydroxylamines, and
alkenes. Kobayashi, S.; Akiyama, R.; Kawamura, M.; Ishitani, H. Chem. Lett.
1997, 1039. Cf. Minakata, S.; Ezoe, T.; Ilhyong, R.; Komatsu, M.; Ohshiro,
Y. The 72nd Annual Meeting of the Chemical Society of Japan, Tokyo, 1997,
2F3 37. See also ref 9.
(9) Quite recently, Jørgensen et al. reported similar asymmetric 1,3-dipolar
cycloadditions using Yb(OTf)3-PyBOX; however, enantiomeric excesses
obtained were up to 73%. Sanchez-Blanco, A. I.; Gothelf, K. V.; Jøgensen,
K. A. Tetrahedron Lett. 1997, 38, 7923.
(10) (R)-MNEA was prepared from (R)-1-(1-naphthyl)ethylamine. Details
are described in the Supporting Information.
(11) A typical experimental procedure is described for the reaction of
N-benzylidenebenzylamine N-oxide (1) with 3-(2-butenoyl)-1,3-oxazolidin-
2-one (2): To a mixture of Yb(OTf)3 (0.10 mmol), (S)-BINOL (0.10 mmol),
and MS 4A (125 mg) was added (R)-MNEA (0.20 mmol) in dichloromethane
(1 mL) at 0 °C, and the mixture was stirred for 30 min at the same temperature.
Compounds 1 (0.50 mmol) in dichloromethane (0.25 mL) and 2 (0.50 mmol)
in dichloromethane (0.25 mL) were successively added, and the mixture was
stirred for 20 h at room temperature. Saturated sodium hydrogen carbonate
was then added to quench the reaction, and the insoluble materials were filtered.
After a usual work up, the crude product was purified by column chroma-
tography on silica gel to afford the desired isoxazolidine derivative (92% yield,
endo/exo ) 99/1). The diastereomeric ratio was determined by 1H NMR
analysis, and the enantiomeric excess of the endo adduct was determined to
be 96% ee by HPLC analysis (Daicel Chiralpak OD). The absolute config-
uration was assigned to be 3′R, 4′S, 5′R by comparison of the optical rotation
with that of the literature.4b.
(6) (a) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett.
1993, 34, 4535. (b) Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994, 116,
4083. (c) Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59, 3758.
(d) Kobayashi, S.; Ishitani, H.; Araki, M.; Hachiya, I. Tetrahedron Lett. 1994,
35, 6325. (e) Kobayashi, S.; Ishitani, H.; Hachiya, I.; Araki, M. Tetrahedron
1994, 50, 11623.
(7) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357.
S0002-7863(98)00702-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/30/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 23, 1998 5841
Scheme 1. A Novel Heterochiral Yb(III) Catalyst
Table 1. Effect of Amines
1
2
Scheme 2. Conversion to â-Lactam
amine
yield (%)
endo/exo
ee (%)b
Et3N
65
73
73
92
80
92
87
99/1
>99/1
99/1
>99/1
97/3
99/1
99/1
63
62
78
71
35
96
62
iPr2NEt
cis-1,2,6-TMPc
(R)-MPEAd
(S)-MPEA
(R)-MNEAe
(S)-MNEA
a Chiral Yb(III) ) Yb(OTf)3 + (S)-BINOL + amine. b ee of the endo
adducts. c cis-1,2,6-Trimethylpiperidine.
(Scheme 2). Isoxazolidine derivative 3 (96% ee), prepared via
the catalytic enantioselective 1,3-dipolar cycloaddition, was treated
with methoxymagnesium iodide16 to give methy ester 4. Reduc-
tive N-O bond cleavage and deprotection of the N-benzyl part
of 4 was performed in the same pot using Pd/C under hydrogen
atmosphere (10 kg/cm2)17 to afford amino ester 5. After the
resulting alcohol moiety was protected as its tert-butyldimethyl-
silyl (TBS) ether, cyclization of 6 proceeded smoothly using
lithium diisopropylamide (LDA)18 to afford the corresponding
â-lactam (7)19,20 in a good yield. The enantiomeric excess of 7
was 96% (determined by HPLC analysis), which means no
racemization occurred during the transformation.
Table 2. Catalytic Enantioselective 1,3-Dipolar Cycloadditions
In summary, catalytic enantioselective 1,3-dipolar cycloaddi-
tions using a novel heterochiral Yb(III) catalyst have been
developed. Wide substrate generality and high levels of stereo-
selectivities have been achieved in these reactions. Further
investigations into the synthesis of biologically important natural
products using these asymmetric cycloadditions are now in
progress.
R1
R2
yield (%)
endo/exo
ee (%)b
Ph
CH3
CH3
CH3
CH3
CH3
H
92
93
82
89
88
91
89
88
99/1
99/1
95/5
95/5
98/2
>99/1
98/2
53/47
96
92
90
89
85
79
93
96
p-Cl-Ph
p-MeO-Ph
2-furyl
1-naphthyl
Ph
Acknowledgment. This work was partially supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan, and a SUT Special Grant for Research
Promotion.
Ph
C3H7
CH3
C2H5
Supporting Information Available: Experimental procedures and
physical data of the products (6 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
a Chiral Yb(III) ) Yb(OTf)3 + (S)-BINOL + (R)-MNEA. b ee of
the endo adducts.
JA980702C
exo ) >99/1, and the enantiomeric excess of the endo adduct
was 70% ee under the standard reaction conditions.12,13
(14) A bond pair (953 and 987 cm-1), which indicated hydrogen bonds
(the OH‚‚‚N and O-‚‚‚H+N equilibrium), was observed in the area from 930
to 1000 cm-1 in the IR spectra of the heterochiral Yb(III) catalyst.15 Direct
coordination of the amine to Yb(III) is doubtful in light of the fact that the
1,3-dipolar cycloaddition proceeded very slowly when Yb(OTf)3 and (R)-
MNEA were first combined and then (S)-BINOL was added.
(15) Fritsch, J.; Zundel, G. J. Phys. Chem. 1981, 85, 556.
(16) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc.
1985, 107, 4346.
As for the structure of the heterochiral Yb(III) catalyst, the
following structure was supported from our previous work
(Scheme 1).6c-e Actually, the existence of hydrogen bonds
between the phenolic hydrogens of (S)-BINOL and the nitrogens
of (R)-MNEA was confirmed by the IR spectra of the catalyst.14,15
Finally, to demonstrate the synthetic utility of the present
reactions, we synthesized a 6-hydroxyethyl â-lactam derivative
(17) Kametani, T.; Huang, S. P.; Nakayama, A.; Honda, T. J. Org. Chem.
1982, 47, 2328.
(12) It is believed that bidentate coordination (for example, Yb(III)-3-(2-
alkenoyl)-1,3-oxazolidin-2-one) is necessary to obtain high selectivities in
many chiral lanthanide-catalyzed reactions.13 These results are very interesting
and promising because it has been shown that even monodentate coordination
can achieve good selectivities by using the heterochiral Yb(III) catalyst.
(13) See refs 6 and 7. See also: (a) Marko, I. E.; Evans, G. R. Tetrahedron
Lett. 1994, 35, 2771. (b) Burgess, K.; Lim, H.-J.; Porte, A. M.; Sulikowski,
G. A. Angew. Chem., Int. Ed. Engl. 1996, 35, 220. Quite recently, asymmetric
hetero Diels-Alder reactions of aldehydes with Danishefsky’s diene using a
chiral Yb(III) phosphate were reported. (c) Hanamoto, T.; Sugimoto, Y.;
Inanaga, J. Synlett 1997, 79.
(18) Sekiya, M.; Ikeda, K.; Terao, Y. Chem. Pharm. Bull. 1981, 29, 1747.
1
(19) For 7: H NMR (CDCl3) δ 0.35 (s, 6H), 0.97 (s, 9H), 1.17 (d, 3H, J
) 6.2 Hz), 2.69 (d, 1H, d, J ) 9.4, 10.5 Hz), 3.85 (d, 1H, J ) 10.5 Hz), 4.25
(dq, 1H, J ) 9.4, 6.2 Hz), 7.19-7.36 (m, 6H); 13C NMR (CDCl3) δ -1.6,
19.1, 21.9, 25.3, 58.8, 68.0, 70.9, 127.2, 128.1, 128.7, 151.5, 171.8; HRMS
calcd for C17H27NO2Si (M+) 305.1811, found 305.1764.
(20) For carbapenems and penems, see: (a) Palomo, C. In Recent Progress
in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-
Verlag: Heidelberg, 1990; p 565. (b) Perrone, E.; Franceschi, G. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.;
Springer-Verlag: Heidelberg, 1990; p 613.