Air-stable, storable, and highly selective chiral Lewis acid catalyst

Article abstract of DOI:10.1021/ol026452t

(matrix presented) An air-stable storable, and highly selective chiral Lewis acid catalyst for asymmetric Mannich-type reactions has been developed. The catalyst can be stored for more than three months in air at room temperature without loss of activity.

Full text of DOI:10.1021/ol026452t

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3395-3397
Air-Stable, Storable, and Highly
Selective Chiral Lewis Acid Catalyst
Masaharu Ueno, Haruro Ishitani, and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received July 1, 2002
ABSTRACT
An air-stable, storable, and highly selective chiral Lewis acid catalyst for asymmetric Mannich-type reactions has been developed. The catalyst
can be stored for more than three months in air at room temperature without loss of activity. Moreover, it has also been demonstrated that
the catalyst can be recovered and reused.
Asymmetric synthesis with chiral catalysts has attracted much
attention because large quantities of chiral molecules can
be prepared from a small amount of a chiral source.1 While
several excellent chiral catalysts have been developed in
oxidation and reduction, carbon-carbon bond-forming reac-
tions, and other transformations, they are often unstable in
air and/or in the presence of water. This is especially the
case in chiral Lewis acid catalysis because most Lewis acids
are air- and moisture-sensitive.2 Therefore, many catalysts
are prepared in situ in an appropriate solvent just before use,
and they cannot be preserved for extended periods. In this
paper, we describe an air-stable, storable, and highly selective
chiral Lewis acid catalyst for asymmetric Mannich-type
reactions.3 The catalyst can be stored for more than three
months in air at room temperature without loss of activity.4
The catalyst was prepared from Zr(OtBu)4 (1 mmol), (R)-
6,6′-bis(pentafluoroethyl)-1,1′-bi-2-naphthol5 ((R)-6,6′-C2F5-
BINOL, 2.0 mmol), N-methylimidazole (NMI, 4.0 mmol),
and powdered MS 5A (6.0 g/mmol) in benzene at 80 °C for
2 h. After removal of the solvent under reduced pressure at
50 °C for 1 h, a chiral zirconium catalyst with powdered
molecular sieVes (ZrMS) was formed. ZrMS thus prepared
was first tested in a model Mannich-type reaction of imine
1a with ketene silyl acetal 2a. While ZrMS was not effective
in the absence of NMI, high yields and selectivities were
obtained after adding NMI. The best result was obtained
when 10 mol % of ZrMS was combined with 20 mol % of
1999, 121, 5450. (i) Martin, S. F.; Lopez, O. D. Tetrahedron Lett. 1999,
40, 8949. (j) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.,
III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124,
67. (k) Yamada, K-i.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 3504. (l) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (m) Co´rdova, A.; Notz,
W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002,
124, 1842. (n) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int.
Ed. 2001, 40, 2271. (o) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (p) Knudsen, K.
R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am.
Chem. Soc. 2001, 123, 5843. (q) Kobayashi, S.; Matsubara, R.; Kitagawa,
H. Org. Lett. 2002, 4, 143. (r) Kobayashi, S.; Hamada, T.; Manabe, K. J.
Am. Chem. Soc. 2002, 124, 5640.
(4) Shibasaki et al. reported a stable chiral La catalyst: Kim, Y. S.;
Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 6506.
(5) (a) Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 3292. (b) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobatyashi, S. Org. Lett. 2002, 4, 1221. See also ref 3f.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfalts,
A., Yamamoto, Y., Eds.; Springer: Berlin, Germany, 1999; Vol. 1-3. (b)
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed; Wiley-VCH: New
York, 2000.
(2) Lewis Acid in Organic Synthesis; Yamamoto, Y., Ed.; Wiley-VCH:
Weinheim, Germany, 2000; Vol. 1, p 2.
(3) Recent examples of catalytic enantioselective Mannich-type reac-
tions: (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. (c) Kobayashi, S.; Hasegawa, Y.; Ishitani, H. Chem. Lett.
1998, 1131. (d) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
2000, 122, 8180. (e) Kobayashi, S.; Ishitani, H.; Yamashita, Y.; Ueno, M.;
Shimizu, H. Tetrahedron 2001, 57, 861. (f) Kobayashi, S.; Kobayashi, J.;
Ishitani, H.; Ueno, M. Chem. Eur. J. Submitted for publication. (g) Fujieda,
H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997,
119, 2060. (h) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc.
10.1021/ol026452t CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/31/2002

Table 1. Effect of NMI
Table 3. Catalytic Enantioselective Mannich-Type Reactions
with ZrMS
entry
NMI/mol %
yield/%
ee/%
1
2
3
4
0
12
20
30
quant.
94
quant.
89
5a
87
90
89
a Absolute configulation was S.
NMI (Table 1, entry 3). In addition, ZrMS was found to be
remarkably stable to air and moisture: it was stable at least
13 weeks in air at room temperature (Table 2). It should be
Table 2. ZrMS as a Storable Chiral Lewis Acida
storage time/week
yield/%
0
quant.
90
2
quant.
90
5
98
90
13
99
90
ee/%
a The Mannich-type reaction of 1a with 2a was performed.
noted that a significant decrease of the yield and selectivity
was observed when a similar zirconium catalyst, which was
prepared from Zr(OtBu)4, (R)-6,6′-C2F5BINOL, and NMI,
was used after 1-day storage in air at room temperature,
presumably due to decomposition of the catalyst.
a The imine was prepared from isovaleraldehyde and 2-amino-m-cresol.
b 1,2-Dimethylimidazole was used instead of NMI, and toluene was used
as a solvent at -78 °C. c E/Z ) >99/<1. d E/Z ) <1/>99. e Yields and ee
values of the Mannich reactions using the chiral zirconium catalyst prepared
from Zr(OtBu)4, (R)-6,6′-C2F5BINOL, and NMI in dichloromethane are
shown in parentheses. Cf. ref 3d.
ZrMS was successfully applied to other Mannich-type
reactions by using various substrates (Table 3). Imines
derived from not only aromatic and heterocyclic but also
aliphatic aldehydes reacted smoothly in the presence of a
catalytic amount of ZrMS to afford the desired Mannich-
type adducts in high yields with high enantiomeric excess.
While the syn-adduct was obtained in the reaction of R-TBSO
enolate 2c, the anti-adduct was produced by using R-BnO
enolate 2d, both in high diastereo- and enantioselectivities.
These yields and selectivities were almost comparable to
those obtained with use of the chiral zirconium catalyst
prepared in situ in dichloromethane under Ar atmosphere
(Table 3, in parentheses).
selectivity in the Mannich-type reaction. On the other hand,
rather simple spectra were recorded when ZrMS was
combined with NMI in CD2Cl2 at room temperature for 30
min (Figure 1c; after filtration). It should be noted that the
spectra were similar to those of the chiral zirconium catalyst
prepared from Zr(OtBu)4, (R)-6,6′-C2F5BINOL, and NMI,
which was an efficient catalyst for the Mannich-type reac-
tions of imines with silicon enolates.3a,c
Other molecular sieves than MS 5A in ZrMS were also
examined.6 When powdered MS 3A was used in the reaction
of 1a with 2a, high yield and enantiomeric excess (94% yield,
It is remarkable that easy treatment with powdered
molecular sieves has enhanced the stability of the chiral
Lewis acid significantly without loss of activity. We then
performed NMR experiments to clarify the structure of
ZrMS. First, ZrMS was treated with CD2Cl2 at room
temperature for 30 min, and after filtration, 1H and 13C NMR
spectra were measured (Figure 1a). The spectra were
complicated, and an oligomeric structure of Zr was assumed,
because a similar oligomeric structure was formed by the
combination of Zr(OtBu)4 and (R)-6,6′-C2F5BINOL (Figure
1b). This oligomeric catalyst was known to give low
(6) Effects of molecular sieves on reactivity and/or selectivity were
reported. For example: (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S.
Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(b) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949.
(c) Mikami, K.; Terada, M.; Matsumoto, Y.; Tanaka, M.; Nakamura, Y.
Microporous Mesoporous Mater. 1998, 21, 461. (d) Iwasawa, N.; Hayashi,
Y.; Sakurai, H.; Narasaka, K. Chem. Lett. 1989, 1581. (e) Motoyama, Y.;
Okano, M.; Narusawa, H.; Mikihara, N.; Aoki, K.; Nishiyama, H.
Organometallics 2001, 20, 1580. (f) Moharram, S. M.; Hirai, G.; Koyama,
K.; Oguri, H.; Hirama, M. Tetrahedron Lett. 2000, 41, 6669. (g) Gothelf,
K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1998, 63, 5483. (h)
Desimoni, G.; Faita, G.; Mortoni, A.; Righetti, P.-P. Tetrahedron Lett. 1999,
40, 2001. (i) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40,
3213.
3396
Org. Lett., Vol. 4, No. 20, 2002

Finally, recovery and reuse of ZrMS were investigated.
In the presence of ZrMS (10 mol %), imine 1a was treated
with ketene silyl acetal 2a in dichloromethane at -45 °C.
After 18 h, the reaction vessel was warmed to room
temperature, and MS 5A was added. After all volatile
solvents and materials were removed under reduced pressure
(3 h), hexane was added and decantation was conducted three
times. While the desired product was isolated from the
hexane solution (89% yield, 92% ee), the residue was
pumped up under reduced pressure for 3 h and was used for
the 2nd run. Almost the same levels of yields and selectivities
were obtained (2nd run: 94% yield, 91% ee; 3rd run: 99%
yield, 90% ee), although a small amount of the Zr (ca. 5%)
was leached for each run according to this procedure.8
In summary, we have developed an air-stable, storable,
and highly selective chiral Lewis acid catalyst, which was
successfully used in asymmetric Mannich-type reactions.
Despite many trials to obtain air-stable and storable catalysts,
the solution is so simple. It has been revealed that the easy
treatment with powdered molecular sieves is the key to create
this remarkable Lewis acid. To the best of our knowledge,
this is the first example of the use of molecular sieves to
stabilize an air- and moisture-sensitive catalyst.9 The catalyst
was stable for more than three months in air at room
temperature without loss of activity. Furthermore, the catalyst
was recovered and reused. It is noted that other Lewis acids
may also be stabilized against air and moisture by using the
same concept. Further investigations along this line are now
in progress.
Acknowledgment. This work was partially supported by
CREST and SORST, Japan Science and Technology Cor-
poration (JST), and a Grant-in-Aid for Scientific Research
from Japan Society of the Promotion of Science. M.U. thanks
the JSPS Research Fellowship for Japanese Young Scientists.
Figure 1. NMR experiments: (a) ZrMS in CD2Cl2, (b) Zr(OtBu)4
and 2.0 equiv of 6,6′-(C2F5)2-BINOL in CD2Cl2, (c) ZrMS and 2.0
equiv of NMI in CD2Cl2, and (d) chiral zirconium catalyst in CD2-
Cl2. See text.
Supporting Information Available: Experimental details
and spectra data. This material is available free of charge
via the Internet at http://pubs.acs.org.
88% ee) were obtained even in the absence of NMI. After
53 days, however, the selectivity decreased (96% yield, 67%
ee). Although the selectivity was maintained after 53 days
with powdered MS 4A (95% yield, 80% ee), the initial ee
was lower (89% yield, 82% ee). On the other hand, when
another ZrMS was prepared from Zr(OtBu)4, (R)-3,3′-
BrBINOL, and powdered MS 3A (without NMI) and was
used in the reaction of 1a with 2a, the desired Mannich-
type adduct was obtained in 80% yield with 97% ee. The
yield and selectivity were maintained after 12 days (79%
yield, 96% ee). It is noted that the idea of ZrMS was applied
to other chiral zirconium catalyst systems.7
OL026452T
(7) In our preliminary experiments, a similar chiral zirconium catalyst
with powdered molecular sieves, which was stored for more than three
months, efficiently catalyzed asymmetric aza Diels-Alder reactions without
loss of activity. (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.
(8) Determined by fluorescence X-ray analysis. All details are shown in
the Supporting Information.
(9) It was reported that AlCl3 was protected with cross-linked polysty-
rene: Neckers, D. C.; Kooistra, D. A.; Green, G. W. J. Am. Chem. Soc.
1972, 94, 9284. We tested cross-linked polystyrene instead of molecular
sieves, but successful results were not obtained.
Org. Lett., Vol. 4, No. 20, 2002
3397