A switch of enantiofacial selectivities using designed similar chiral ligands in zirconium-catalyzed asymmetric aza Diels-Alder reactions

Full text of DOI:10.1021/jo9902300

4220
J . Org. Chem. 1999, 64, 4220-4221
Ta ble 1. Effect of Solven ts, Tem p er a tu r e, a n d Molecu la r
Sieves
A Sw itch of En a n tiofa cia l Selectivities Usin g
Design ed Sim ila r Ch ir a l Liga n d s in
Zir con iu m -Ca ta lyzed Asym m etr ic Aza
Diels-Ald er Rea ction s
Shuj Kobayashi,*,† Ken-ichi Kusakabe,
Susumu Komiyama, and Haruro Ishitani
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, CREST, J apan Science and Technology Corporation
(J ST), Hongo, Bunkyo-ku, Tokyo, 113-0033, J apan, and
Department of Applied Chemistry, Faculty of Science, Science
University of Tokyo (SUT), Kagurazaka, Shinjuku-ku, Tokyo
162-0825, J apan
entry
solvent
T/°C
MS
yield/%
ee/%
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
-45
-45
0
none
none
none
MS 3A
MS 4A
MS 5A
MS 3A
MS 3A
MS 3A
66
83
45
80
76
77
54
96
93
84
82 (S)a
57
0
0
0
90
89
89
77
88
91
Received February 8, 1999
-45
23
23
Synthesis of both enantiomers is a very important task
not only in organic chemistry but also in medicinal and
bioorganic chemistry.1 In chemical transformations, synthe-
ses of both enantiomers are generally carried out using both
enantiomers of chiral sources. While there are many chiral
sources in nature, it is sometimes difficult to obtain both
enantiomers, for instance, those of amino acids, monosac-
charides, alkaloids, etc. When such chiral sources are
employed in asymmetric syntheses, preparation of both
enantiomers is difficult. On the other hand, from a mecha-
nistic point of view, both enantiomers can be produced by
controlling the enantiofaces of prochiral compounds. There-
fore, it would be possible to control them by designing
ligands that even have the same chirality.2,3 In this paper,
we report an example of this; a switch of enantiofacial
selectivities using similar types of ligands in chiral zirconium-
catalyzed aza Diels-Alder reactions.
a
Catalyst 1 was used.
substrate interaction including the reaction course and to
improve selectivities, it was indicated from both experiments
and modeling studies that the substituents on the 3,3′-
positions of the BINOL ligand influenced the enantioselec-
tivities strongly.8 We prepared 3,3′-substituted BINOL (3
and 4).9 In the presence of Zr(OtBu)4 (20 mol %), (R)-6,6′-
Recently, we reported the first enantioselective aza Diels-
Alder reactions of imino dienophiles using a chiral zirconium
catalyst (1) prepared from Zr(O-t-Bu)4, (R)-6,6′-dibromo-1,1′-
binaphthol ((R)-Br-BINOL), and N-methylimidazole (NMI).4-6
According to these reactions, optically active piperidine
derivatives having an S-configuration were prepared from
achiral imines and 1-methoxy-3-trimethylsiloxy-1,3-butadi-
ene (Danishefsky’s diene,7 2) in high enantioselectivities. In
the course of our investigations to examine the catalyst-
† Present address: Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033.
(1) (a) Ojima, I., Ed. Catalytic Asymmetric Syntesis; VCH: New York,
1993. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn Wiley
& Sons: New York, 1994. (c) No´gra´d´ı, M. Stereoselective Synthesis, 2nd ed.;
VCH: New York, 1995.
(2) Syntheses of both enantiomers using the same chiral source: (a)
Kobayashi, S.; Ishitani, H. J . Am. Chem. Soc. 1994, 116, 4083. (b) Yamada,
T.; Imagawa, K.; Nagata, T. Mukaiyama, T. Chem. Lett. 1992, 2231. (c)
Desimori, G.; Faita, G.; Invernizzi, A.; Righetti, P. P. Tetrahedron 1997,
53, 7671. (d) Gothef, K. V.; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem.
1998, 63, 5483.
(3) Syntheses of both enantiomers using similar ligands that have the
same chirality: (a) Kobayashi, S.; Horibe, M. J . Am. Chem. Soc. 1994, 116,
9805. (b) Kobayashi, S.; Horibe, M. Chem. Eur. J . 1997, 3, 1472.
(4) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed.
Engl. 1998, 37, 979. (b) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996,
37, 7357.
(5) For asymmetric aza Diels-Alder reactions: (a) Waldmann, H.
Synthesis 1994, 535. (b) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49,
1749. (c) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J .
Am. Chem. Soc. 1994, 116, 10520. (d) Ku¨ndig, E. P.; Xu, L. H.; Romanens,
P.; Bernardinelli, G. Synlett 1996, 270. (e) Ishihara, K.; Kurihara, H.;
Matsumoto, M.; Yamamoto, H. J . Am. Chem. Soc. 1998, 120, 6920. (f)
Kirschbaum, S.; Waldmann, H. J . Org. Chem. 1998, 63, 4926 and references
therein.
dibromo-3,3′-diphenyl-1,1′-binaphthol (3, 40 mol %), and
NMI (60 mol %), aldimine 5, which was prepared from
o-tolualdehyde and 2-aminophenol, reacted with 2 in toluene
at -45 °C to afford the corresponding piperidine derivative
in 84% ee (Table 1, entry 1). The absolute configuration was
proved to be R, which was the reverse of that using (R)-Br-
BINOL instead of 3 under the same reaction conditions
(entry 2). Several reaction conditions were examined, and
interesting effects of molecular sieves were found. When the
reaction was carried out at 0 °C without molecular sieves,
the enantioselectivity decreased to 57% ee. On the other
(8) Yamamoto et al. demonstrated the effect of 3,3′-silyl-substituted
BINOL. (a) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.; Yamamoto, H.
Bull. Chem. Soc. J pn. 1988, 61, 2975. (b) Maruoka, K.; Itoh, T.; Shirasaka,
T.; Yamamoto, H. J . Am. Chem. Soc. 1988, 110, 310. (c) Maruoka, K.;
Concepcion, A. B.; Yamamoto, H. Bull. Chem. Soc. J pn. 1992, 65, 3501. (d)
Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H. Tetrahedron Lett.
1988, 29, 3967.
(9) (a) Cox, P. J .; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253. (b)
Morgan, J .; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1990, 715. (c) Alo,
B. I.; Kandil, A.; Pantil, P. A.; Sharp, M. J .; Siddiqui, M. A.; Snieckus, V. J .
Org. Chem. 1991, 56, 3763. (d) Sogah, G. D. Y.; Cram, D. J . J . Am. Chem.
Soc. 1979, 101, 3035.
(6) For asymmetric Mannich-type reactions using the similar zirconium
catalyst: (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J . Am. Chem. Soc. 1997,
119, 7153. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J . Am. Chem. Soc. 1998,
120, 431.
(7) (a) Danishefsky, S. J .; Kitahara, T. J . Am. Chem. Soc. 1974, 96, 7807.
(b) Krewin, J . F., J r.; Danishefsky, S. J . Tetrahedron Lett. 1982, 23, 3739.
10.1021/jo9902300 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

Communications
J . Org. Chem., Vol. 64, No. 12, 1999 4221
Ta ble 2. Ca ta lytic Asym m etr ic Aza Diels-Ald er
Sch em e 1. Wor k in g Mod el
Rea ction s
Our working model to obtain such interesting selectivities
is shown in Scheme 1. The two bulky tert-butoxy groups are
expected to locate at the two apical positions. One of the 3,3′-
phenyl groups would effectively shield one face of an imine,
and consequently, a diene attacks from the opposite side.14
J udging from this model, similar selectivities were expected
in the Mannich-type reactions of imines with silyl enolates.
Actually, when ligand 4 was used in the reaction of imine 8
with S-ethylthio-1-trimethylsiloxyethene, the corresponding
â-amino thioester was obtained in an 84% ee (Scheme 2).
As expected, the sense of the chiral induction in this case
was the reverse of that observed when using catalyst 1.6a,15
a
b
4 was used instead of 3. The imine was prepared from
cyclohexanecarboxyaldehyde and 2-amino-3-methylphenol.
hand, 90% ee of the product was obtained when MS 3A was
added to the reaction pot. While MS 4A and 5A were also
effective, the enantioselectivity decreased when the reaction
was carried out at -45 °C with MS 3A. Furthermore, the
best result was obtained when the reaction was performed
at 23 °C in benzene. It is noted that the chemical yield was
also improved more than 25% and that 91% ee of the product
was obtained even at 23 °C.10
Sch em e 2. Ma n n ich -Typ e Rea ction
Other examples were tested, and the results are sum-
marized in Table 2.11 In all cases, the reactions proceeded
smoothly to afford the corresponding piperidine derivatives
in high yields with high ee’s. In addition, reverse enantio-
selectivities were observed in these reactions compared to
those obtained using 1 as a catalyst. It is noteworthy that
chemical yields and enantiomeric excesses were improved
in most cases using the new catalyst system.
In summary, a switch of enantiofacial selectivities using
a 3,3′-disubstituted BINOL (3 or 4) has been achieved in
chiral zirconium-catalyzed asymmetric aza Diels-Alder
reactions. While piperidine derivatives with S configurations
were prepared using 1 (reported previously), the same
piperidine derivatives having R configurations were pro-
duced using a similar ligand 3 or 4. In addition to the
synthetic utility preparing both enantiomers of the piperi-
dine derivatives, this report has demonstrated the possibility
of changing reaction courses (enantiofacial selectivities) by
designing chiral sources even with the same chiralities.
We then examined the precise structure of the zirconium
catalyst by NMR analysis. When Zr(O-t-Bu)4 (1 equiv), 6 (2
equiv),12 and NMI (3 equiv) were combined in benzene-d6
at 23 °C, two independent species that were assigned to a
new zirconium catalyst and free 6 were observed. While the
signals of free 6 were still observed when Zr(O-t-Bu)4 (1
equiv), 6 (1 equiv), and NMI (3 equiv) were stirred at 23 °C,
only the signals assigned to the new zirconium catalyst were
detected when the mixture was stirred at 80 °C for 2.5 h.
These results indicated the formation of 7b as the new
zirconium catalyst. The structure was also supported by the
following experiment: Zr(O-t-Bu)4 (0.2 equiv), 3 (0.2 equiv),
NMI (0.6 equiv), and MS 3A were combined in benzene, and
the mixture was stirred for 2.5 h at 80 °C (formation of 7a ).
Imine 5 (1 equiv) and 2 (1.2 equiv) were then added to the
catalyst solution, and the mixture was stirred for 48 h at
23 °C. After the same workup procedures described above,
the desired piperidine derivative was obtained in a >98%
yield with an 89% ee, values comparable to those obtained
when the catalyst was prepared by combining Zr(O-t-Bu)4
(1 equiv), 3 (2 equiv), and NMI (3 equiv) at 23 °C (Table 1,
entry 9).13
Ack n ow led gm en t. This work was partially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, J apan, and a
SUT Special Grant for Research Promotion.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and physical data of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9902300
(13) It was assumed that formation of 7 was slow and incomplete at 23
°C due to the bulky 3,3′-phenyl groups of 3.
(14) One of the reviewers pointed out that the tert-butoxy group of the
catalyst would play a major role in shielding one or the other side of the
imino moiety. Actually, we performed the reaction using a catalyst having
an n-propoxy group instead of a tert-butoxy group and found that the
selectivity was slightly decreased. Further investigations are needed to
clarify the precise transition states. We that the reviewer for the fruitful
suggestions.
(10) When 10 mol % of the catalyst was used, chemical yield and
enantioselectivity decreased (81%, 77% ee).
(11) Experimental details are shown in the Supporting Information.
(12) Prepared from (R)-(+)-1,1′-bi-2-naphthol and bromobenzene-d5. See
the Supporting Information.
(15) For the assumed transition states of the reactions using 1, see refs
4a and 6. See also: Ishitani, H.; Kitazawa, T.; Kobayashi, S. Tetrahedron
Lett. 1999, 40, 2161.