Chiral catalyst optimization using both solid-phase and liquid-phase methods in asymmetric aza Diels-Alder reactions

Article abstract of DOI:10.1021/ol005656b

(Equation presented) In the presence of 1-5 mol % of a chiral zirconium catalyst, aza Diels-Alder reactions of aldimines with Danishefsky's dienes proceeded smoothly to afford the corresponding piperidine derivatives in high yields with high enantioselect

Full text of DOI:10.1021/ol005656b

ORGANIC
LETTERS
2
000
Vol. 2, No. 9
225-1227
Chiral Catalyst Optimization Using Both
Solid-Phase and Liquid-Phase Methods
in Asymmetric Aza Diels−Alder
Reactions
1
Sh u¯ Kobayashi,* Ken-ichi Kusakabe, and Haruro Ishitani
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
CREST, Japan Science and Technology Corporation (JST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received February 12, 2000
ABSTRACT
In the presence of 1−5 mol % of a chiral zirconium catalyst, aza Diels−Alder reactions of aldimines with Danishefsky’s dienes proceeded
smoothly to afford the corresponding piperidine derivatives in high yields with high enantioselectivities. For the catalyst optimization, solid-
phase and liquid-phase methods were successfully used. In the solid-phase approach, polymer-supported (R)-1,1′-binaphthols (BINOLs) have
been synthesized and rapid optimization using the solid-phase reactions has been achieved. On the other hand, novel chiral zirconium cyanides
were developed as excellent catalysts using the liquid-phase approach.
Asymmetric reactions using chiral catalysts provide one of
the most promising and powerful methods for construction
of chiral molecules. In these reactions, development of chiral
examples of catalytic asymmetric aza Diels-Alder reactions
using a chiral ytterbium catalyst. This report showed
4
1
examples of asymmetric reactions using azadienes (imino-
dienes). After that, we also disclosed reactions of azadieno-
philes (imino dienophiles) with Danishefsky’s diene using
catalysts is crucial, and in particular, development of efficient
methods for catalyst optimization is strongly desired. In this
paper, we disclose a truly efficient new method for chiral
catalyst optimization using both solid-phase and liquid-phase
approaches in asymmetric aza Diels-Alder reactions.
Catalytic aza Diels-Alder reactions provide one of the
most powerful methods for the synthesis of chiral nitrogen-
5,6
chiral zirconium-binaphthol complexes. While high yields
and selectivities were attained in these reactions in several
cases, further optimization of the catalyst structure was
desired. In addition, another problem was the rather high
2
containing heterocycles. While rather fruitful results have
(4) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357.
3
been reported in catalytic asymmetric Diels-Alder reactions,
(5) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int.
Ed. 1998, 37, 979. (b) Kobayashi, S.; Kusakabe, K.; Komiyama, S.; Ishitani,
H. J. Org. Chem. 1999, 64, 4220. Cf. (c) Ishitani, H.; Ueno, M.; Kobayashi,
S. J. Am. Chem. Soc. 1997, 119, 7153. (d) Hattori, K.; Yamamoto, H.
Tetrahedron 1993, 49, 1749.
successful results are limited in catalytic asymmetric aza
Diels-Alder reactions. In 1996, we reported the first
(
1) (a) Ojima, I., Ed. Catalytic Asymmetric Syntesis; VCH: New York,
993. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis, John Wiley
Sons: New York, 1994.
(6) Other examples of catalytic asymmetric aza-Diels-Alder reactions:
(a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617. (b) Yao, S.;
Johannsen, M.; Hazell, R. G.; Jφrgensen, K. A. Angew. Chem., Int. Ed.
1998, 37, 3121. (c) Bromidge, S.; Wilson, P. C.; Whiting, A. Tetrahedron
Lett. 1998, 39, 8905.
1
&
(
2) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(
3) For example, Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007.
1
0.1021/ol005656b CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/04/2000

loading of the catalyst (10-20 mol %). To address these
issues, we planned to optimize the catalyst structure using
both solid-phase and liquid-phase methods.7
4
lithium aluminum hydride (LiAlH ) to give 4, whose
hydroxyl group was protected by its tert-butyldimethylsilyl
(TBS) ether (5). The 3,3′-positions of 5 were then brominated
via an aromatic lithium intermediate to afford 6, and after
deprotection of the TBS ether (7), 1% divinylbenzene-cross
linked chloromethylated polystyrene (Merrifield resin) was
used as a polymer support to form 8. A key step to introduce
aryl substituents at the 3,3′-positions of 8 was carried out
using the Suzuki reaction with boronic acids under the
We divided the catalyst into three parts (X, Y, Z in Scheme
1). First, to optimize Y, polymer-supported (R)-1,1′-binaph-
Scheme 1
10
influence of a palladium catalyst. After deprotection of the
MOM groups, the desired polymer-supported BINOL deriva-
tives (10) were obtained successfully. All the solid-phase
1
13
reactions were monitored by H and C swollen-resin magic
1
1
angle spinning (SR-MAS) NMR.
Polymer-supported BINOLs thus prepared were treated
t
4
with Zr(O Bu) to form polymer-supported zirconium 11. In
the presence of 20 mol % of various zirconium 11, the model
aza Diels-Alder reactions of aldimine 12 with Danishefsky’s
1
2
diene (13) were performed, and the results of selected
examples are shown in Table 1. While the 4-tert-butylphenyl
group gave lower enantiomeric excess (ee), higher ees were
obtained when 3,5-xylyl, 4-biphenyl, 4-fluorophenyl, and
8
thol (BINOL) derivatives were prepared. The synthetic route
is shown in Scheme 2. 6-Tethered (R)-BINOL derivative 2
was prepared according to the literature.9 After MOM
protection (3), the ester moiety of 3 was reduced using
3
-trifluoromethylphenyl groups were introduced at the 3,3′-
positions of the BINOLs. Among them, the 4-fluorophenyl
Table 1. Catalyst Optimization Using 11 in the Reaction of 12
with 13
Scheme 2. Synthesis of Polymer-Supported BINOLsa
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Org. Lett., Vol. 2, No. 9, 2000

2
3
and 3-trifluoromethylphenyl groups were the most promising
in both yields and selectivities. One advantage using
polymer-supported BINOLs is that the ligand can be easily
recovered by simple filtration and reused. For example, in
the reaction of 12 with 1-methoxy-2-methyl-3-(trimethyl-
siloxy)-1,3-butadiene in the presence of 20 mol % of 11a
the R and R positions. In addition, it was revealed that a
slow addition of the substrates to the catalyst was effective.
Finally, 94% ee of the aza Diels-Alder adduct was obtained
when only 2 mol % of the catalyst (1f) was employed.
Several examples of the catalytic asymmetric aza Diels-
1
3
Alder reactions are shown in Table 3. In all cases, the
(
Ar ) 3-trifluoromethylphenyl); first run, >99% yield, 91%
ee; second run, 97% yield, 90% ee; third run, 97% yield,
0% ee. It is also noted that many chiral ligands were
9
Table 3. Catalytic Asymmetric Aza Diels-Alder Reactions
synthesized and optimized rapidly using the solid-phase
methods.
We next optimized the X and Z parts using liquid-phase
methods. We prepared several zirconium catalysts, which
were tested in the model reaction of 12 with 13, and the
results are summarized in Table 2. It was found that higher
Table 2. Catalyst Optimization Using 1 in the Reaction of 12
with 13
reaction proceeded smoothly to afford the corresponding
piperidine derivatives in good to high yields with high
enantiomeric excesses using 1-5 mol % of the chiral
zirconium catalyst.
In summary, a novel chiral zirconium complex for
asymmetric aza Diels-Alder reactions has been developed
by efficient catalyst optimization using both solid-phase and
liquid-phase approaches. High yields, high selectivities, and
low loading of the catalyst have been achieved, and the
effectiveness of chiral catalyst optimization using a combina-
tion of solid-phase and liquid-phase methods has been
demonstrated.
selectivities were obtained when electron-withdrawing cyano
groups were introduced at the R positions. Higher selectivi-
ties were also observed when electron-withdrawing groups
such as fluoro and trifluoromethyl groups were employed at
4
(7) Solid-phase and liquid-phase methods have advantages and disad-
vantages, and we believe that combining the advantages of these methods
leads to the most efficient catalyst optimization.
(8) For chiral catalyst optimization using solid-phase methods, see (a)
Francis, M. B.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 937. (b)
Porte, A. M.; Reibenspies, J.; Burgess, K. J. Am. Chem. Soc. 1998, 120,
9
180. (c) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 37, 6475.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan.
(
d) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1703, and
references cited therein.
(
9) Bayston, D. J.; Fraser, J. L.; Ashton, M. R. Baxter, A. D.; Polywka,
M. E. C.; Moses, E. J. Org. Chem. 1998, 63, 3137.
10) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (b) Cox, P. J.; Snieckus, V.
Tetrahedron Lett. 1992, 33, 2253. (c) Frenette, R.; Friesen, R. W.
Tetrahedron Lett. 1994, 35, 9177.
Supporting Information Available: Experimental details
and physical data of the catalysts and the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
(
11) Kobayashi, S.; Akiyama, R.; Furuta, T.; Moriwaki, M. Molecules
998, 2, 35. Conversions from 9 to 10 are >95%.
12) (a) Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc. 1974, 96,
1
OL005656B
(
7
3
807. (b) Krewin, Jr., J. F.; Danishefsky, S. J. Tetrahedron Lett. 1982, 23,
739.
(13) Details are shown in Supporting Information.
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