Catalytic enantioseleetive Mannich-type reactions using a novel chiral zirconium catalyst [3]

Full text of DOI:10.1021/ja970498d

J. Am. Chem. Soc. 1997, 119, 7153-7154
Scheme 1. Preparation of the Catalyst
7153
Catalytic Enantioselective Mannich-Type Reactions
Using a Novel Chiral Zirconium Catalyst
Haruro Ishitani, Masaharu Ueno, and Shuj Kobayashi*
Department of Applied Chemistry, Faculty of Science
Science UniVersity of Tokyo (SUT)
CREST, Japan Science and Technology Corporation (JST)
Kagurazaka, Shinjuku-ku, Tokyo 162, Japan
ReceiVed February 17, 1997
Asymmetric Mannich-type reactions provide useful routes for
the synthesis of optically active â-amino ketones or esters, which
are versatile chiral building blocks in the preparation of many
nitrogen-containing biologically important compounds.1 While
several diastereoselective Mannich-type reactions have already
been reported,2 very little is known about the enantioselective
versions. In 1991, Corey et al. reported the first example of
the enantioselective synthesis of â-amino acid esters using chiral
boron enolates.3 Yamamoto et al. showed enantioselective
reactions of aldimines with a ketene silyl acetal using a
stoichiometric amount of a Brønsted acid-assisted chiral Lewis
acid.4 Quite recently, Enders et al. reported efficient enantio-
selective Mannich-type reactions based on the chiral hydrazone
method;5 however, a stoichiometric amount of a chiral source
was needed. Asymmetric Mannich-type reactions using small
amounts of chiral sources have not been reported to the best of
our knowledge. In this paper, we disclose the first truly catalytic
enantioselective Mannich-type reactions of aldimines with silyl
enolates using a novel zirconium catalyst.
Our approach is based on chiral Lewis acid-catalyzed
reactions. Asymmetric reactions using chiral Lewis acids are
of great current interest as one of the most efficient methods
for the preparation of chiral compounds.6 While rather rapid
progress has been made on the enantioselective reactions of
carbonyl compounds using chiral Lewis acids (aldol reactions,
allylation reactions, Diels-Alder reactions, etc.),7 very few
examples have been reported for their aza analogues.8 We
thought that this was due to two main difficulties. First, many
Lewis acids are deactivated or sometimes decomposed by the
nitrogen atoms of starting materials or products, and even when
the desired reactions proceed, more than stoichiometric amounts
of the Lewis acids are needed because the acids are trapped by
the nitrogen atoms. Second, aldimine-chiral Lewis acid
complexes are rather flexible and often have several stable
conformers (including E/Z isomers of aldimines), while alde-
hyde-chiral Lewis acid complexes are believed to be rigid.
Therefore, in the additions to aldimines activated by chiral Lewis
acids, plural transition states would exist to decrease selectivities.
To solve these problems, we first screened various metal salts
in the achiral reactions of aldimines with silylated nucleophiles.
After careful investigation of the catalytic ability of the salts,
we found unique characteristics in zirconium(IV) (Zr(IV)) and
decided to design a chiral Lewis acid based on Zr(IV) as a center
metal.9,10 On the other hand, as for the problem of the
conformation of the aldimine-Lewis acid complex, we planned
to utilize a bidentate chelation (see below).11 A necessary
condition is easy removal of the chelation part of the substrates
after the reactions.
A chiral zirconium catalyst was prepared in situ according
to Scheme 1.12 In the presence of 20 mol % catalyst 1, aldimine
3 prepared from 1-naphthaldehyde and 2-aminophenol was
treated with the ketene silyl acetal derived from methyl
isobutylate (4) in dichloromethane at -15 °C. The reaction
proceeded smoothly to afford the corresponding adduct in a
quantitative yield, and the enantiomeric excess of the product
was 34% (Table 1). The ee was improved to 70% when
N-methylimidazole (NMI) was used as an additive. Moreover,
the ee was further improved when catalyst 2 was used,13 and
the desired adduct was obtained in a 95% ee when the reaction
was carried out at -45 °C.14 It should be noted that the same
high level of ee was obtained when 2 mol % catalyst was
employed. We then tested other aldimines and silyl enolates,
and the results are summarized in Table 2. Not only aldimines
derived from aromatic aldehydes but also aldimines from
heterocyclic and aliphatic aldehydes15 worked well in this
reaction, and good to high yields and enantiomeric excesses
(1) Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Chapter 2.3, Vol. 2, p 893.
(2) For example, (a) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetra-
hedron Lett. 1996, 37, 3881. (b) Arend, M. Risch, N. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2861. (c) Matsumura, Y. Tomita, T. Tetrahedron Lett.
1994, 35, 3737. (d) Page, P. C. B.; Allin, S. M.; Collington, E. W.; Carr,
R. A. E. J. Org. Chem. 1993, 58, 6902. (e) Frauenrath, H.; Arenz, T.; Raabe,
G.; Zorn, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 83. (f) Nolen, E. G.;
Aliocco, A.; Broody, M.; Zuppa, A. Tetrahedron Lett. 1991, 32, 73. (g)
Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am.
Chem. Soc. 1990, 112, 8215. (h) Katritzky, A. R.; Harris, P. A. Tetrahedron
1990, 46, 987. (i) Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl.
1989, 28, 1067. (j) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 5603. (k) Gennari, C.; Venturini, I.; Gislon, G.; Schimperna, G.
Tetrahedron Lett. 1987, 28, 227. (l) Broadley, K.; Davies, S. G. Tetrahedron
Lett. 1984, 25, 1743. (m) Seebach, D.; Betschart, C.; Schiess, M. HelV.
Chim. Acta 1984, 67, 1593.
(3) Corey, E. J.; Decicco, C. P.; Newbold, R. C. Tetrahedron Lett. 1991,
39, 5287.
(4) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J.
Am. Chem. Soc. 1994, 116, 10520.
(5) Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 981. See also, Risch, N.; Esser, A. Liebigs Ann. Chem.
1992, 233.
(9) Different types of chiral zirconium catalysts, which are effective in
ring opening reactions of epoxides, Diels-Alder reactions, and polymer-
ization, etc.: (a) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768. (b)
Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini, E.; Umani-Ronchi, A.
Tetrahedron Lett. 1995, 36, 7897. (c) Hoveyda, A. H.; Morken, J. P. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1262, and references cited therein.
(10) Rare earths (Sc, Y, Ln) are also promising candidates for the catalytic
activations of aldimines: (a) Kobayashi, S.; Araki, M.; Ishitani, H.;
Nagayama, S.; Hachiya, I. Synlett 1995, 233. (b) Kobayashi, S.; Araki, M.;
Yasuda, M. Tetrahedron Lett. 1995, 36, 5773. See also ref 11.
(11) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357.
(12) Titanium(IV)-1,1′-bi-2-naphthol complexes were used in some
asymmetric reactions: (a) Reetz, M. T.; Kyung, S.-H.; Bolm, C.; Zierke,
T. Chem. Ind. 1986, 824. (b) Aoki, S.; Mikami, K.; Terada, M.; Nakai, T.
Tetrahedron 1993, 49, 1783. (c) Costa, A. L.; Piazza, M. G.; Tagliavini,
E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001.
(d) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115,
8467. (e) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993,
58, 6543. (f) Matsukawa, S.; Mikami, K. Tetrahedron: Asymmetry 1995,
6, 2571. (g) Ganthier, Jr, D. R.; Carreira, E. M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2363. (h) Yu, C.-M.; Choi, H.-S.; Jung, W.-H.; Lee, S.-S.
Tetrahedron Lett. 1996, 37, 7095.
(6) (a) Narasaka, K. Synthesis 1991, 1. (b) Santelli, M.; Pons, J.-M. Lewis
Acids and SelectiVity in Organic Synthesis; CRC Press: Boca Raton, FL,
1995.
(7) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,
1993.
(13) For the use of 6,6′-dibromo-1,1′-bi-2-naphthol, see: (a) Terada, M.;
Motoyama, Y.; Mikami, K. Tetrahedron Lett. 1994, 35, 6693. (b) Sasai,
H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388.
(8) (a) Denmark, S. E.; Nicaise, O. J.-C. J. Chem. Soc., Chem. Commun.
1996, 999. (b) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata,
K. Chem. Lett. 1997, 59.
(14) When the aldimine prepared from aniline or 2-methoxyaniline was
used under the same reaction conditions, the corresponding â-amino esters
were obtained in good yields but with less than 5% ee’s.
S0002-7863(97)00498-8 CCC: $14.00 © 1997 American Chemical Society

7154 J. Am. Chem. Soc., Vol. 119, No. 30, 1997
Table 1. Examination of Reaction Conditionsa
Communications to the Editor
Scheme 3. Assumed Catalytic Cycle
catalyst (mol %) additive (mol %) temp, °C yield, % ee, %
1 (20)
1 (20)
2 (20)
2 (20)
2 (10)
2 (5)
-15
-15
-15
-45
-45
-45
-15
-45
quant
80
73
83
quant
69
34
70
90
95
92
95
91
86
NMI (20)
NMI (20)
NMI (20)
NMI (10)
NMI (5)
DMI (5)
NMI (2)
2 (5)
2 (2)
quant
75
a NMI ) N-methylimidazole; DMI ) 1,2-dimethylimidazole.
Table 2. Catalytic Enantioelective Mannich-Type Reactions
R1
silyl enolate
yield, %a
ee, %b
the same temperature and cooled to -45 °C. Dichloromethane
solutions (0.75 mL) of 3 (0.8 mmol) and 4 (0.96 mmol) were
successively added. The mixture was stirred for 10 h, and
saturated NaHCO3 was added to quench the reaction. The
aqueous layer was extracted with dichloromethane, and the crude
adduct was treated with THF-1N HCl (10:1) at 0 °C for 30
min. After a usual workup, the crude product was chromato-
graphed on silica gel to give the desired adduct. The optical
purity was determined by HPLC analysis using a chiral
column.18
The assumed catalytic cycle of this enantioselective reaction
is shown in Scheme 3. Catalyst 219 is postulated to coordinate
aldimine 8 to form zirconium complex 9. A silyl enolate attacks
the aldimine to produce 10, whose trimethylsilylated oxygen
atom attacks the zirconium center to afford the product along
with the regeneration of catalyst 2. The product was obtained
as a trimethylsilylated form (11) without the acidic workup (see
a typical experimental procedure).
Ph
4
4
4
70
86
quant
78
88
quant
89
56
87
83
92
88
86
>98
89
80
p-ClPh
1-naphthyl
Ph
p-ClPh
1-naphthyl
2-furyl
H2CdC(OSiMe3)SEt (5)
5
5
5
5
c
c-C6H11
a Isolated yields after acidic workup (see a typical experimental
procedure). b Determined by HPLC analyses (see the Supporting
Information). c The aldimine prepared from cyclohexanecarboxaldehyde
and 2-amino-3-methylphenol was used. When the reaction was carried
out at -23 °C, 71% yield and 71% ee were obtained. See ref 15.
Scheme 2. Conversion to â-Amino Ester
In summary, the first catalytic enantioselective Mannich-type
reactions of aldimines with silyl enolates have been achieved
by using a novel chiral zirconium catalyst. High levels of
enantioselectivities in the synthesis of chiral â-amino ester
derivatives have been obtained according to these reactions. The
novel zirconium catalyst has been shown to be effective for
the catalytic activation of aldimines. Further investigations to
clarify the precise structure of the catalyst and mechanism of
these reactions as well as to develop other enantioselective
reactions using this catalyst are now in progress.
were obtained. Similar high levels of ee’s were also obtained
when the silyl enol ether derived from S-ethyl thioacetate (5)
was used. The N-substituent of the product was easily removed
according to Scheme 2. Thus, methylation of the phenolic OH
of 6 using methyl iodide and potassium bicarbonate and
deprotection using cerium ammonium nitrate (CAN)16 gave
â-amino ester 7. The absolute configuration assignment was
made by comparison of the optical rotation of 7 with that in
the literature.17
Acknowledgment. H.I. thanks the JSPS fellowship for Japanese
Junior Scientists. This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science, Sports,
and Culture, Japan.
A typical experimental procedure is described for the reaction
of aldimine 3 with ketene silyl acetal 4. To Zr(OtBu)4 (0.04
mmol) in dichloromethane (0.25 mL) were added 6,6′-dibromo-
1,1′-bi-2-naphthol (0.088 mmol) in dichloromethane (0.5 mL)
and N-methylimidazole (0.048 mmol) in dichloromethane (0.25
mL) at room temperature. The mixture was stirred for 1 h at
Supporting Information Available: Text describing the experi-
mental procedure and NMR and HPLC data (5 pages). See any current
masthead page for ordering and Internet access instructions.
JA970498D
(18) Details are shown in the Supporting Information.
(19) The role of NMI or DMI is not clear at this stage. White precipitates
were observed after combining Zr(OtBu)4 and 6,6′-dibromo-1,1′-bi-2-
naphthol in dichloromethane, and the precipitates dissolved completely when
NMI or DMI was added. From this observation, although the precise
structure of the catalyst has not yet been clarified, it is assumed that a
monomeric catalyst may be produced by adding NMI or DMI, while an
oligomeric structure may be formed without the ligand. We also found that
the catalyst was obtained as a white powder after removal of the solvent.
The powder did not contain t-BuOH and was effective in the present
asymmetric Mannich-type reactions.
(15) It was found that the aldimine prepared from cyclohexanecarbox-
aldehyde and 2-aminophenol was unstable and was difficult to supply the
reaction. On the other hand, high ee shown in Table 2 was obtained by
using the aldimine prepared from cyclohexanecarboxaldehyde and 2-amino-
3-methylphenol.
(16) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765.
(17) Kunz, H.; Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1989,
28, 1068.