Chiral zirconium complex as bronsted base catalyst in asymmetric directtype mannich reactions

Article abstract of DOI:10.1002/asia.200900524

Asymmetric direct-type Mannich reaction using a chiral zirconium complex as Bronsted base is demonstrated. Zirconium complexes prepared from Zr(OtBu) and 3, 3′-disubstituted BINOL are found to be good catalysts in the reactions of an iminoester with malonates, and high enantioselectivities are obtained. (Chemical equation presented).

Full text of DOI:10.1002/asia.200900524

DOI: 10.1002/asia.200900524
Chiral Zirconium Complex as Brønsted Base Catalyst in Asymmetric Direct-
type Mannich Reactions
Shu Kobayashi,* Matthew M. Salter, Yumi Yamazaki, and Yasuhiro Yamashita[a]
¯
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
Development of efficient methods for preparation of opti-
cally active amino acids is one of the most important topics
in synthetic organic chemistry. Asymmetric Mannich-type
reactions have been recognized as one of the most efficient
methods to provide optically active b-amino esters, because
new carbon–carbon bond formation and chiral induction are
achieved at the same time in a single reaction step. Recent-
ly, several types of catalytic asymmetric Mannich-type reac-
tions have been reported;[1] among them, direct-type Man-
nich reactions are the most attractive from an atom econom-
ical point of view, because no stoichiometric amounts of
bases or metals for pre-activation of carbonyl donors are re-
quired.[2]
scribe a successful example of catalytic asymmetric, direct-
type Mannich reactions using a chiral zirconium catalyst as
Brønsted base.
We selected the Mannich-type reaction of malonate with
a-iminoester as a model, providing an efficient method for
preparation of optically active a-amino acid derivatives
(Scheme 1).[6] While asymmetric variants of this reaction
In previous papers, our group has reported asymmetric
Mannich-type reactions using chiral zirconium Lewis acid
catalysts prepared from zirconium alkoxides and BINOL de-
rivatives.[3,4] The zirconium catalysts could interact with
imines and their equivalents to create excellent asymmetric
environments, realizing high enantioselection. On the other
hand, some zirconium catalysts possess alkoxide parts on
their structure, suggesting that such catalysts could poten-
tially work as Brønsted bases. While it was already disclosed
that zirconium alkoxides worked as Brønsted bases in
direct-type aldol reactions, few successful examples of cata-
lytic asymmetric direct-type reactions using chiral zirconium
catalysts as Brønsted bases were reported.[5] Herein, we de-
Scheme 1. Asymmetric Direct-type Mannich Reaction Using a Chiral Zir-
conium Catalyst.
were reported using chiral Cu[6a], Pd[6b], Ni[6c] catalysts or or-
ganocatalysts[6d–n] and high enantioselectivities were ob-
served, scope of substrates is still limited in some cases. We
decided to employ a zirconium complex prepared from zir-
conium tert-butoxide and 3,3’-disubstituted BINOL deriva-
tive, which could form a 1:1 complex with the remaining
two alkoxide parts in their structure. In this complex, we ex-
pected that the BINOL part could increase the Lewis acidity
of the zirconium metal (compared with the alkoxide parts)
to assist activation of electrophiles, and at the same time
that the tert-butoxide group could work as a Brønsted base
to activate carbonyl compounds effectively.
[a] Prof. Dr. S. Kobayashi, Dr. M. M. Salter, Y. Yamazaki,
Dr. Y. Yamashita
Department of Chemistry
School of Science and Graduate School of Pharmaceutical Sciences
The University of Tokyo
The HFRE Division, ERATO, Japan Science and Technology
Agency (JST)
7-3-1 Hongo, Bunkyo-ku, Tokyo (Japan), 113-0033 (Japan)
Fax : (+81)3-5684-0634
In the reaction of ethyl 2-(4-methoxyphenylimino)acetate
(1) with diethyl methyl malonate (2a, R1 =Me), the catalyst
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
prepared from ZrACHTUNGTERNU(NG OtBu)4 and 3,3’-Ph2BINOL (3a) worked
Chem. Asian J. 2010, 5, 493 – 495
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
493

COMMUNICATION
well in toluene at À458C to afford the Mannich-type adduct
in good yield with moderate enantioselectivity (Table 1,
entry 1). It was found that the 3,5-disubstituted benzenes at
Substrate scope of b-dicarbonyl compounds was then ex-
amined. The malonates with primary alkyl chains, Er, Pr,
and Bu, worked well, and high enantioselectivities (95–
98% ee) were obtained (Table 2, entries 1–3). The allyl sub-
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope of b-dicarbonyl compounds.[a]
Entry
3
x
Solvent
Additive
Yield [%][b]
ee [%]
Entry
2 (R1)
x
3
Solvent
Yield[b] [%]
ee [%]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3 f
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
3g
20
20
20
20
20
20
20
20
20
20
20
10
10
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
THF
THF
THF
THF
THF
THF
THF
THF
–
–
–
–
–
–
–
–
76
89
83
78
78
89
62
trace
41
66
86
47
78
53
63
86
60
61
52
37
60
90
90
92
-
91
97
96
91
96
87
87
98
95
1
2
3
4
2b (Et)
2c (Pr)
2d (Bu)
2e (Allyl)
2 f (Bn)
2g (iPr)
2h (Ph)
2i (Cl)
5
5
5
5
5
10
10
10
10
20
3g
3g
3g
3g
3g
3h
3h
3e
3h
THF
THF
THF
THF
80
72
78
60
25
47
40
72
50[f]
96
95
98
95
87
89
10
22
79[g]
5
THF
6[c]
7[c]
8[c,d]
9[e]
toluene
toluene
toluene
toluene
7
8c
9
10
–
–
11[d]
12[d]
13[d,f]
14[d,g]
15[d,g,h]
16[d,g,h,i]
17[e,g,h,j]
MS 3ꢁ
MS 3ꢁ
MS 3ꢁ
MS 3ꢁ
MS 3ꢁ
MS 3ꢁ
MS 3ꢁ
[a] The reaction of 1 (0.600 mmol) with 2 (0.720 mol) was conducted by
using chiral Zr complex prepared from Zr(OtBu) (x mol%) and
a
ACHTUNGTRENNUNG
BINOL derivative 3 (1.1x mol%) at À208C for 18 h in 0.25m in the pres-
ence of MS 3ꢁ unless otherwise noted. 1 was slowly added during the re-
action time (18 h). [b] Yield of isolated product. [c] Without MS 3 ꢁ.
[d] Dimethyl ester was used. [e] Benzyl 2-oxocyclohexanecarboxylate (5)
was used as a substrate. The reaction was conducted at 08C for 24 h with-
out slow addition using a zirconium catalyst (20 mol%). [f] As a diaster-
eomixture. Diastereomer ratio was 3:1. [g] ee of major diastereomer.
5
5
2
[a] The reaction of 1 (0.600 mmol) with 2a (R1 =Me, 0.600 mmol) was
conducted by using chiral Zr complex prepared from Zr(OtBu)4
a
ACHTUNGTRENNUNG
(x mol%) and BINOL derivative 3 (1.1x mol%) at À458C for 24 h in
0.25m unless otherwise noted. The concentration was based on 1.
[b] Yield of isolated product. [c] Zr
ACHTUNGERTN(NUNG OiPr)4·iPrOH complex was used in-
stead of Zr(OtBu)4. [d] 18 h. [e] 46 h. [f] 0.4m. [g] 0.8m. [h] 1.2 equivalents
of 2a were added. [i] 1 was slowly added over 10 h. [j] 1 was slowly added
over 20 h.
ACHTUNGTRENNUNG
stituent also worked well (entry 4). On the other hand, the
benzyl substituent decreased the reactivity, although good
enantioselectivity was maintained (entry 5). When the malo-
nate bearing the iPr group was examined, good results were
obtained by using BINOL 3h (entry 6). The substrate con-
taining aromatic or halogen substituent did not work well
(entries 7, 8). The reaction of b-ketoester 5 was also investi-
gated, however selectivities were not sufficient (entry 9).
Next, deprotection of the obtained product was investigat-
ed. Oxidative cleavage of the PMP group using celium am-
monium nitrate (CAN) proceeded smoothly to afford the
desired primary amine in high yield under standard condi-
tions (in a water–acetonitrile mixture at room temperature)
(Scheme 2).[7,8]
the R2 parts did not increase the enantioselectivity signifi-
cantly (entries 2–4). On the other hand, it was revealed that
Br, CF3, and Me groups at the R2 parts were effective, and
high enantioselectivities were obtained (entries 5–7). Inter-
estingly, no reaction occurred when Zr
ACHTUNGTERN(NGNU OiPr)4 was used in-
stead of Zr(OtBu)4, suggesting that Brønsted basicity of the
ACHTUNGTRENNUNG
tert-butoxy group was very important in this catalyst system
(entry 8). When the catalyst prepared from 3g was used, ex-
cellent enantioselectivity (97% ee) was obtained when THF
was used as a solvent (entry 10). For improvement of the
yield, addition of MS 3 ꢁ was effective to afford the desired
Mannich-type product in 86% yield with 96% ee (entry 11).
We then investigated the reduction of the catalyst loading.
In the reaction using 10 mol% of the catalyst, significant de-
crease of the yield was observed; however, the reactivity
was improved by conducting the reaction in higher concen-
tration (entries 12, 13). While 5 mol% of the catalyst also
worked at higher concentration, both yield and selectivity
decreased (entry 14). Use of a slight excess amount of malo-
nate improved the yield (entry 15). Finally, it was found that
slow addition of the iminoester was very effective to im-
prove the enantioselectivity dramatically, and that the high-
est enantioselectivity (98% ee) was obtained (entry 16).
Under the reaction conditions, even 2 mol% of the catalyst
also worked well to give the product in moderate yield
while keeping a high enantioselectivity (entry 17).
Scheme 2. Deprotection of p-methoxyphenyl group.
A proposed catalytic cycle was shown in Scheme 3. First
the malonate interacts with the zirconium catalyst in a bi-
dentate fashion to form the active zirconium enolate (A) se-
lectively. The iminoester then coordinates to the zirconium
and is activated. Finally, the zirconium enolate attacks the
imine part of the iminoester to afford the desired product.
Formation of the zirconium enolate was confirmed by 1H
494
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 493 – 495

Chiral Zirconium Complex as Brønsted Base Catalyst
[1] General reviews of asymmetric Mannich reactions see: a) S. Kobaya-
shi, H. Ishitani, Chem. Rev. 1999, 99, 1069; b) M. Liu, M. P. Sibi, Tet-
rahedron 2002, 58, 7991; c) J.-A. Ma, Angew. Chem. 2003, 115, 4426;
Angew. Chem. Int. Ed. 2003, 42, 4290; d) S. Kobayashi, M. Ueno in
Comprehensive Asymmetric Catalysis, Supplement 1 (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 2004, Chap. 29.5,
pp. 143; e) M. Ueno, S. Kobayashi in Enantioselective Synthesis of b-
Amino Acids, 2nd ed. (Eds.: E. Juaristi, V. A. Soloshonok), Wiley,
New York, 2005, pp. 139; f) G. K. Friestad, A. K. Mathies, Tetrahe-
dron 2007, 63, 2541.
[2] Recent reviews of direct-type asymmetric Mannich reactions, see:
a) M. M. B. Marques, Angew. Chem. 2006, 118, 356; Angew. Chem.
Int. Ed. 2006, 45, 348; b) A. Ting, S. E. Shaus, Eur. J. Org. Chem.
2007, 5797; c) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M.
Quaedflieg, F. P. J. T. Rutjes, Chem. Soc. Rev. 2008, 37, 29.
Scheme 3. Proposed catalytic cycle.
[3] Reviews of zirconium alkoxide in catalysis see: a) S. Yamasaki, M.
Kanai, M. Shibasaki, Chem. Eur. J. 2001, 7, 4066; b) K. Krohn, Syn-
thesis 1997, 1115.
and 13C NMR analysis of a mixture of the malonate and the
zirconium complex.
In conclusion, we have demonstrated that the zirconium
[4] a) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
7153; b) S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc. 1998,
120, 431; c) S. Kobayashi, Y. Hasegawa, H. Ishitani, Chem. Lett. 1998,
1131; d) H. Ishitani, T. Kitazawa, S. Kobayashi, Tetrahedron Lett.
1999, 40, 2161; e) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem.
Soc. 2000, 122, 8180; f) S. Kobayashi, H. Ishitani, Y. Yamashita, M.
Ueno, H. Shimizu, Tetrahedron 2001, 57, 861–866; g) M. Ueno, H.
Ishitani, S. Kobayashi, Org. Lett. 2002, 4, 3395–3397; h) S. Kobayashi,
M. Ueno, S. Saito, Y. Mizuki, H. Ishitani, Y. Yamashita, Proc. Natl.
Acad. Sci. USA 2004, 101, 5476; i) Y. Ihori, Y. Yamashita, H. Ishitani,
S. Kobayashi, J. Am. Chem. Soc. 2005, 127, 15528.
[5] Pioneering works using zirconium alkoxides as a Brønsted base: a) G.
Stork, C. S. Shiner, J. D. Winkler, J. Am. Chem. Soc. 1982, 104, 310;
b) G. Stork, J. D. Winkler, C. S. Shiner, J. Am. Chem. Soc. 1982, 104,
3767; c) H. Sasai, Y. Kirio, M. Shibasaki, J. Org. Chem. 1990, 55,
5306; Examples using zirconium complexes for Brønsted base cataly-
sis, see: d) C. M. Mascarenhas, M. O. Duffey, S.-Y. Liu, J. P. Morken,
Org. Lett. 1999, 1, 1427; e) C. Schneider, M. Hansch, Chem.
Commun. 2001, 1218; f) C. Schneider, M. Hansch, Synlett 2003, 837;
g) W. Yao, J. Wang, Org. Lett. 2003, 5, 1527.
[6] Examples of direct-type asymmetric Mannich reactions of b-dicar-
bonyl compounds, see: a) M. Marigo, A. Kjærsgaard, K. Juhl, N.
Gathergood, K. A. Jørgensen, Chem. Eur. J. 2003, 9, 2359; b) Y. Ha-
mashima, N. Sasamoto, D. Hotta, H. Somei, N. Umebayashi, M. So-
deoka, Angew. Chem. 2005, 117, 1549; Angew. Chem. Int. Ed. 2005,
44, 1525; c) Z. Chen, H. Morimoto, S. Matsunaga, M. Shibasaki, J.
Am. Chem. Soc. 2008, 130, 2170; d) D. Uraguchi, M. Terada, J. Am.
Chem. Soc. 2004, 126, 5356; e) T. B. Poulsen, C. Alemparte, S. Saaby,
M. Bella, K. A. Jørgensen, Angew. Chem. 2005, 117, 2956; Angew.
Chem. Int. Ed. 2005, 44, 2896; f) S. Lou, B. M. Taoka, A. Ting, S. E.
Schaus, J. Am. Chem. Soc. 2005, 127, 11256; g) M. Terada, K. Sorima-
chi, D. Uraguchi, Synlett 2006, 133; h) A. Ting, S. Lou, S. E. Schaus,
Org. Lett. 2006, 8, 2003; i) C. M. Bode, A. Ting, S. E. Shaus, Tetrahe-
dron 2006, 62, 11499; j) A. L. Tillman, J. Ye, D. J. Dixon, Chem.
Commun. 2006, 1191; k) J. Song, Y. Wang, L. Deng, J. Am. Chem.
Soc. 2006, 128, 6048; l) F. Fini, L. Bernardi, R. P. Herrera, D. Peters-
en, A. Ricci, V. Sgarzani, Adv. Synth. Catal. 2006, 348, 2043; m) O.
Marianacci, G. Micheletti, L. Bernardi, F. Fini, M. Fochi, D. Petters-
en, V. Sgarzani, A. Ricci, Chem. Eur. J. 2007, 13, 8338; n) S. Lou, P.
Dai, S. E. Schaus, J. Org. Chem. 2007, 72, 9998.
complex prepared from ZrACTHNUTRGNE(NUG OtBu)4 and 3,3’-disubstituted
BINOL was a good chiral Brønsted base catalyst and that
the asymmetric direct-type Mannich reactions of malonates
with an iminoester proceeded in high yields with high enan-
tioselectivities. To the best of our knowledge, this is the first
example of successful catalytic direct activation of carbonyl
compounds using chiral zirconium Brønsted base catalysts.
Further investigation using zirconium alkoxides in asymmet-
ric catalysis is now in progress.
Experimental Section
Typical experimental procedure is described for the reaction shown in
Table 1, entry 16. Under argon atmosphere, to a well-dried flask were
added ligand 3g (0.0330 mmol), MS 3 ꢁ (50 mg), and THF (0.5 mL), and
the mixture was stirred at room temperature. ZrACTHNURTGNENG(U OtBu)4 (0.0300 mmol)
was added, and the catalyst solution was stirred for 1 h at the same tem-
perature. After adding 2a (0.720 mmol) to this solution, the whole was
cooled at À458C. A solution of 1 (0.600 mmol) in THF (0.5 mL) was
slowly added to the mixture over 18 h. The reaction was stopped by addi-
tion of water, and the mixture was separated after addition of dichloro-
methane. The aqueous phase was extracted with dichloromethane, then
the organic phases were combined and dried over anhydrous sodium sul-
fate. After filtration and concentration in vacuo, the crude mixture was
purified by silica gel column chromatography to afford the corresponding
product. The optical purity was determined by HPLC analysis using a
chiral column.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Science Re-
search from the Japan Society for the Promotion of Science (JSPS) and
Global COE Program (Chemistry Innovation through Cooperation of
Science and Engineering), The University of Tokyo, MEXT, Japan.
[7] a) T. Fukuyama, R. K. Frank, C. F. Jewell, J. Am. Chem. Soc. 1980,
102, 2122; b) D. R. Kronenthal, C. Y. Han, M. K. Taylor, J. Org.
Chem. 1982, 47, 2765.
[8] Deacarboxylation of related disubstituted malonate, see: a) K. F.
McClure, M. Z. Axt, Bioorg. Med. Chem. Lett. 1998, 8, 143; b) H.
Hilpert, Tetrahedron 2001, 57, 7675.
Keywords: asymmetric catalysis · Brønsted base · mannich
reaction · zirconium
Received: October 5, 2009
Published online: January 22, 2010
Chem. Asian J. 2010, 5, 493 – 495
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
495