Organocatalytic highly enantio- and diastereoselective Mannich reaction of β-ketoesters with N-boc-aldimines

Article abstract of DOI:10.1021/jo900880t

(Figure Presented) The catalytic enantioselective Mannich reaction promoted by chiral bifunctional organocatalysts is described. The treatment of β-ketoesters with N-Boc-aldimines under mild reaction conditions afforded the corresponding β-amino β-ketoest

Full text of DOI:10.1021/jo900880t

pubs.acs.org/joc
containing natural products such as those belonging to the
Organocatalytic Highly Enantio- and
Diastereoselective Mannich Reaction of β-Ketoesters
with N-Boc-aldimines
alkaloid family.1,2 Enantioselective Mannich reactions are
efficient and powerful methods to prepare chiral β-amino
carbonyl derivatives.3 Tremendous efforts have been made
in the development of efficient chiral catalysts for enantio-
selective Mannich reactions with preformed enolates4 and
enolizable β-dicarbonyl and related compounds.5 Highly
enantioselective direct Mannich reactions with aldehydes
and ketones have also been accomplished with chiral metal
complexes and organocatalysts.6,7
Young Ku Kang and Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan,
Chungnam 336-745, Korea
dyoung@sch.ac.kr
Recently, several groups presented catalytic asymmetric
Mannich reactions of β-ketoesters using organocatalysts to
circumvent the problems commonly associated with conven-
tional metal catalysis. For example, Terada et al. have
developed a new chiral phosphorodiamidic acid to catalyze
the addition of acetylacetates to imines in a highly enantio-
selective fashion.8 The Jørgensen and Ricci groups have
reported a highly enantio- and diastereoselective Mannich
reaction using β-ketoesters catalyzed by cinchona alkaloid-
derived catalysts.9 Also, Schaus et al. have used cinchonine
itself to catalyze the highly enantioselective addition of β-
ketoesters to imines.10 More recently, the Dixon, Takemoto,
and Deng groups have reported highly enantioselective
Mannich reactions of β-ketoesters, catalyzed by bifunctional
organocatalysts containing thiourea functionality.11 Bifunc-
tional organocatalysts possessing a combination of hydro-
gen-bonding donors and chiral tertiary amines have been
developed for activation of both electrophilic and nucleo-
philic components. They have emerged as powerful tools for
Received April 29, 2009
The catalytic enantioselective Mannich reaction pro-
moted by chiral bifunctional organocatalysts is described.
The treatment of β-ketoesters with N-Boc-aldimines
under mild reaction conditions afforded the correspond-
ing β-amino β-ketoesters with excellent diastereoselec-
tivities (up to 100:0 dr) and excellent enantioselectivities
(up to 99% ee).
(5) (a) Hamashima, Y.; Sasamoto, N.; Umebayashi, N.; Sodeoka, M.
Chem. Asian J. 2008, 3, 1443. (b) Chen, Z.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (c) Kobayashi, S.;
Gustafsson, T.; Shimizu, Y.; Kiyohara, H.; Matsubara, R. Org. Lett. 2006,
8, 4923. (d) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebaya-
shi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525.
(6) Selected examples of metal-catalyzed Mannich-type reactions of
aldehydes and ketones, see: (a) Cutting, G. A.; Stainforth, N. E.; John, M.
P.; Kociok-Kohn, G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10632.
(b) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2007, 129, 9588. (c) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778. (b) Harada, S.; Handa, S.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365.
(c) Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.;
Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4564.
Optically active β-amino acids are fundamental building
blocks for the preparation of pharmaceutical and agrochemi-
cal target molecules. In addition, these compounds are useful
chiral starting materials in the synthesis of bioactive amine
(1) For reviews on the synthesis of β-amino acids: (a) Juaristi, E.
Soloshonok, V. A. Enantioselective Synthesis of β-Amino Acids; Wiley:
New York, 2005. (b) Ma, J. Angew. Chem., Int. Ed. 2003, 42, 4290. (c) Liu,
M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (d) Magriotis, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 4377.
(2) For recent syntheses of β-amino acids, see: (a) Berkessel, A.;
Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed. 2005, 44, 2. (b) Hsiao,
Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.;
Armstrong, J. D.; Grabowski, E. J.; Tillyer, R. D.; Spindler, F.; Malan, C.
J. Am. Chem. Soc. 2004, 126, 9918. (c) Zhou, Y.; Tang, W.; Wang, W.; Li, W.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952. (d) Sibi, M. P.; Asano, Y.
J. Am. Chem. Soc. 2001, 123, 9708. (e) Myers, J.; Jacobsen, E. N. J. Am.
Chem. Soc. 1999, 121, 8959.
(3) For selected recent reviews, see: (a) Verkade, J. M. M.; van Hemert,
L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37,
29. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (c) Marques, M.
M. B. Angew. Chem., Int. Ed. 2006, 45, 348. (d) Cordova, A. Acc. Chem. Res.
2004, 37, 102.
(4) For selected examples of Mannich-type reactions of enolates, see: (a)
Sikert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631. (b) Itoh, J.;
Fuchibe, K.; Akiyama, T. Synthesis 2008, 1319. (c) Kobayashi, S.; Yazaki,
R.; Seki, K.; Ueno, M. Tetrahedron 2007, 63, 8425. (d) Saruhashi, K.;
Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 11232. (e) Kobayashi, S.; Ueno,
M.; Saito, S.; Mizuki, Y.; Ishitani, H.; Yamashita, Y. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5476. (f) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K.
Angew. Chem., Int. Ed. 2004, 43, 1566. (g) Wenzel, A. G.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 12964.
(7) For selected examples of direct organocatalytic Mannich-type reac-
tions, see: (a) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B.
Nature 2008, 452, 453. (b) Zhang, H.; Mitsumori, S.; Utsumi, N.; Imai, M.;
Garcia-Delgado, N.; Mifsud, M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk,
K. N.; Tanaka, F.; Barbas, C. F. III. J. Am. Chem. Soc. 2008, 130, 875.
(c) Vesely, J.; Rios, R.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2007, 48,
421. (d) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054.
(e) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc.
2005, 127, 16408. (f) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
Chem., Int. Ed. 2005, 44, 4079.
(8) Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006, 133.
(9) (a) Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini, F.; Fochi, M.;
Pettersen, D.; Sgarzani, V.; Ricci, A. Chem.;Eur. J. 2007, 13, 8338.
(b) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 2896.
(10) (a) Goss, J. M.; Schaus, S. E. J. Org. Chem. 2008, 73, 7651. (b) Lou,
S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998. (c) Ting, A.; Lou, S.;
Schaus, S. E. Org. Lett. 2006, 8, 2003. (d) Lou, S.; Taoka, B. M.; Ting, A.;
Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
(11) (a) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191.
(b) Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto, Y. Synthesis 2007, 2571.
(c) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
5734 J. Org. Chem. 2009, 74, 5734–5737
Published on Web 06/25/2009
DOI: 10.1021/jo900880t
r
2009 American Chemical Society

Kang and Kim
JOCNote
TABLE 1. Optimization of the Reaction Conditions
entry
cat.
T (°C)
time (h)
yielda (%)
drb
eec (%)
1
2
3
4
5
6
I
I
I
II
III
IV
rt
-40
-78
-78
-78
-78
4
10
90
86
43
43
90
94
95
97
90
86
90:10
85:15
97:3
97:3
76:24
77:23
81
89
97
99
54
55
aRefers to the isolated mixture of diastereomers. bDetermined by 1H
NMR of the crude reaction mixture. cEnantiomeric excess of the major
diastereomer, determined by chiral HPLC analysis with chiral column
(Chiralpak AD-H).
TABLE 2. Variation of the N-Boc-imines
FIGURE 1. Structures of bifunctional organocatalysts.
the enantioselective formation of carbon-carbon bonds and
carbon-heteroatom bonds.12
entry
2, R
2a, Ph
2b, 2-furanyl
2c, 2-naphthyl
2d, p-OMe-Ph
2e, p-Me-Ph
2f, p-Cl-Ph
time (h)
yielda (%)
drb
eec (%)
As part of a research program related to the development
of synthetic methods for the enantioselective construction of
stereogenic carbon centers,13 we recently reported chiral
amine-thiourea bifunctional organocatalyst I (Figure 1) to
be a highly selective catalyst for the enantioselective amina-
tion of active methines.14 We envisioned that the assembly of
a structurally well-defined chiral 1,2-diamine and binaphthyl
scaffold with a thiourea motif could constitute a new class of
bifunctional organocatalyst. The rigid binaphthyl structure
can serve as an efficient stereocontrolling axial chiral ele-
ment. Herein, we wish to describe the direct enantioselective
Mannich reaction of β-ketoesters with simple N-Boc-imines
catalyzed by bifunctional organocatalysts bearing both cen-
tral and axial chiral elements.
1
2
3
4
5
6
7
86
96
96
80
80
90
100
3a, 97
3b, 96
3c, 90
3d, 72
3e, 96
3f, 89
3g, 61
97:3
100:0
98:2
96:4
99:1
99
99
99
99
97
99
98
100:0
96:4
2g, -CH2CH2Ph
aRefers to the isolated mixture of diastereomers. bDetermined by 1H
NMR of the crude reaction mixture. cEnantiomeric excess of the major
diastereomer, determined by chiral HPLC analysis with chiral column
(Chiralpak AD-H).
Mannich reaction of methyl cyclopentanone 2-carboxylate
(1a) with N-Boc-benzaldimine (2a). When the reaction was
performed in toluene at room temperature in the presence of
10 mol % of catalyst I, product 3a was isolated in high yield
with 81% ee (Table 1, entry 1). Further tuning of the
conditions found the reaction to be optimal when performed
in toluene at -78 °C for 90 h, producing 3a with a high level
of diastereocontrol (97:3) and excellent enantioselectivity
(97%) (entry 3). We examined the impact of the structure
of catalysts I-IV on the selectivity (Table 1, entries 3-6).
Excellent results have been obtained with catalyst II (entry 4,
97% yield, 97:3 dr, 99% ee).
We then explored the possibility of using wide range of
N-Boc-protected para-substituted aromatic and heteroaro-
matic aldimines 2 with β-ketoester 1a under the optimized
reaction conditions. As shown in Table 2, the products 3a-f
were formed in high yields (72-97%), excellent diastereos-
electivities (96:4-100:0), and excellent enantioselectivities
(97-99%). Furthermore, aliphatic N-Boc-aldimine (2g)
was also an effective substrate for this process (entry 7).
The absolute configuration of 3a was determined by com-
paring the chiral HPLC data and specific rotation with an
authentic sample.5,9-11
A survey of some reaction parameters was performed, and
some representative results are presented in Table 1. Our
investigation began with the catalytic enantioselective
(12) For selected recent reviews for bifunctional organocatalysts, see:
(a) Connon, S. J. Synlett 2009, 354. (b) Yu, X.; Wang, W. Chem. Asian J.
2008, 3, 516. (c) Tylor, M. S.; Jacobson, E. N. Angew. Chem., Int. Ed. 2006,
45, 1520. (d) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (e) Connon,
S. J. Chem.;Eur. J. 2006, 12, 5418. (f) Akiyama, T.; Itoh, J.; Fuchibe, K.
Adv. Synth. Catal. 2006, 348, 999. (g) Takemoto, Y. Org. Biomol. Chem.
2005, 3, 4299. (h) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138.
(13) (a) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. J. Fluorine Chem. 2009,
130, 259. (b) Lee, J. H.; Bang, H. T.; Kim, D. Y. Synlett 2008, 1821. (c) Kang,
Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y. Synlett 2007, 1135. (d) Kang, Y.
K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4265. (e) Kim, H. R.; Kim, D. Y.
Tetrahedron Lett. 2005, 46, 3115. (f) Kim, S. M.; Kim, H. R.; Kim, D. Y. Org.
Lett. 2005, 7, 2309. (g) Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem.
2004, 69, 6897. (h) Kim, D. Y.; Choi, Y. J.; Park, H. Y.; Joung, C. U.; Koh, K.
O.; Mang, J. Y.; Jung, K.-Y. Synth. Commun. 2003, 33, 435. (i) Kim, D. Y.;
Park, E. J. Org. Lett. 2002, 4, 545. (j) Kim, D. Y.; Huh, S. C.; Kim, S. M.
Tetrahedron Lett. 2001, 42, 6299. (k) Kim, D. Y.; Huh, S. C. Tetrahedron
2001, 57, 8933.
(14) (a) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659. (b) Jung, S.
H.; Kim, D. Y. Tetrahedron Lett. 2008, 49, 5527. Recently, Shao et al.
reported the asymmetric Michael reaction of 2,4-pentanedione to nitrostyr-
enes promoted by catalyst I; see: (c) Peng, G.-Z.; Shao, Z.-H.; Fan, B.-M.;
Song, H.; Li, G.-P.; Zhang, H.-B. J. Org. Chem. 2008, 73, 5202.
J. Org. Chem. Vol. 74, No. 15, 2009 5735

Kang and Kim
JOCNote
TABLE 3. Variation of the β-Ketoesters
entry
1
cat.
time (h)
yielda (%)
drb
eec (%)
1d
2e
3f
4
1a
1b
1c
1d
1e
II
II
II
I
86
78
29
7
3a, 97
3h, 68
3i, 93
3j, 88
3k, 83
97:3
94:6
80:20
99:1
63:37
99
95
93
96
71
FIGURE 2. Proposed stereochemical model.
In conclusion, we have developed a highly efficient cata-
lytic enantioselective Mannich reaction of β-ketoesters using
bifunctional organocatalysts I and II. The desired β-amino
carbonyl compounds were obtained in good to high yields,
and excellent diastereoselectivities (up to 100:0) and excellent
enantioselectivities (up to 99% ee) were observed. We believe
that this method provides an efficient route for the prepara-
tion of chiral β-amino acid derivatives, and the availability
of these compounds should facilitate medicinal chemical
studies in various fields. Further study of these bifunctional
organocatalysts in asymmetric reactions is under current
investigation.
5
I
110
aRefers to the isolated mixture of diastereomers. bDetermined by 1H
NMR of the crude reaction mixture. cEnantiomeric excess of the major
diastereomer, determined by chiral HPLC analysis with chiral column
(Chiralpak AD-H for 3a, 3j, and 3k, OD-H for 3i, and Chiralcel
OJ for 3h). dReaction was carried out at -78 °C. eReaction was carried
out in Et2O. fReaction was carried out at -40 °C.
SCHEME 1. Enantioselective Mannich Reaction of Diethyl
Malonate with N-Boc-aldimine
Experimental Section
General Procedure for the Mannich Reaction of β-Ketoesters.
To a stirred solution of β-ketoester (0.3 mmol) and catalyst I or
II (0.03 mmol) in toluene (1.5 mL) was added N-Boc-aldimine
(72 mg, 0.36 mmol) at the temperature in Table 3. The reaction
mixture was stirred for 7-110 h at the indicated temperature.
The mixture was diluted with saturated NH4Cl solution (30 mL)
and extracted with ethyl acetate (2 ꢀ 30 mL). The combined
organic layers were dried over MgSO4, filtered, concentrated,
and purified by flash chromatography to afford the β-amino
β-ketoester.
To examine the generality of the catalytic enantioselective
Mannich reaction of β-ketoesters 1 by using new bifunc-
tional organocatalysts I and II, we studied the addition of
various β-ketoesters 1 to N-Boc-benzaldimine (2a). As can be
seen by the results summarized in Table 3, the corresponding
products 3h-j were obtained in high to excellent yields,
excellent diastereoselectivities, and excellent enantioselectiv-
ities. The cyclic β-ketoester 1b and cyclic aromatic β-ketoe-
sters 1c,d reacted with N-Boc-benzaldimine (2a) to give the
corresponding Mannich products 3h-j in 68-93% yields
and 93-96% ee. In contrast to the cyclic β-ketoesters,
unfortunately, the reaction of acyclic β-ketoester 1e pro-
ceeded slowly even to give the Mannich product 3k in
moderate enantioselectivity (entry 5).
We examined the direct enantioselective Mannich reaction
of diethylmalonate (4) with N-Boc-benzaldimine (2a) using
bifunctional organocatalyst I in toluene at room tempera-
ture. In the presence of 10 mol % of catalyst I, the reaction
proceeded to afford the β-aminated product 5 after 96 h with
81% yield and 93% ee (Scheme 1).
Methyl (1R)-1-[(S)-1-tert-Butoxycarbonylaminophenylme-
thyl]-2-oxocyclopentanecarboxylate (3a). To a stirred solution
of β-ketoester 1a (42 mg, 0.3 mmol) and catalyst II (19 mg, 0.03
mmol) in toluene (1.5 mL) was added N-Boc-aldimine 2a (72
mg, 0.36 mmol) at -78 °C. The reaction mixture was stirred for
86 h at -78 °C. The mixture was diluted with saturated NH4Cl
solution (30 mL) and extracted with ethyl acetate (2 ꢀ 30 mL).
The combined organic layers were dried over MgSO4, filtered,
concentrated, and purified by flash chromatography to give
compound 3a (101 mg, 97%). Major diastereoisomer: [R]27
=
D
-56.2 (c=0.4, CHCl3, 99% ee); 1H NMR (200 MHz, CDCl3) δ=
7.30-7.23 (m, 5H), 5.87 (brs, 1H), 5.16 (d, J=9.4 Hz, 1H), 3.67
(s, 3H), 2.54-2.42 (m, 1H), 2.42-2.30 (m, 2H), 2.04-1.80 (m,
3H), 1.38 (s, 9H); 13C NMR (50 MHz; CDCl3) δ=210.8, 169.8,
155.1, 138.2, 128.3, 128.0, 127.4, 79.7, 64.8, 55.6, 52.6, 37.5, 30.5,
28.1, 18.9; MS (ESI) m/z=348.0 [M þ H]þ 120.9, 123.0, 149.9,
206.6; ESI-HRMS m/z calcd for C19H26NO5 [MþH]þ 348.1811,
found 348.1818; tR HPLC (95:5 n-hexane/i-PrOH, 220 nm,
1.0 mL/min) Chiralpak AD-H column, tR=13.7 min (major),
tR=38.3 (minor).
Although the reason for the observed enantioselectivity is
still unclear, we believe that a carbonyl group of the N-Boc-
benzaldimine (2a) is activated by the urea or thiourea moiety
through hydrogen bonding, and the β-ketoester moiety is
activated by the basic nitrogen atom in tertiary amine
(Figure 2). These interactions control the stereochemical
outcome of the reaction and increase the reaction rate.
Methyl (2R)-2-[(S)-1-tert-Butoxycarbonylaminophenylme-
thyl]-1-tetralone-2-carboxylate (3j). To a stirred solution of
β-ketoester 1d (61 mg, 0.3 mmol) and catalyst I (20 mg, 0.03
mmol) in toluene (1.5 mL) was added N-Boc-aldimine 2a
5736 J. Org. Chem. Vol. 74, No. 15, 2009

Kang and Kim
JOCNote
(72 mg, 0.36 mmol) at room temperature. The reaction mixture
was stirred for 7 h at room temperature. The mixture was diluted
with a saturated NH4Cl solution (30 mL) and extracted with ethyl
acetate (2 ꢀ 30 mL). The combined organic layers were dried over
MgSO4, filtered, concentrated, and purified by flash chromatog-
raphy to give compound 3j (108 mg, 88%). Major diastereoi-
m/z calcd for C24H27F6NO5 [M]þ 409.1889, found 409.1886; tR
HPLC (90:10, n-hexane/i-PrOH, 254 nm, 1.0 mL/min) Chiralpak
AD-H column, tR=12.2 min (major), tR=20.6 (minor).
Acknowledgment. This research was supported by Korea
Research Foundation Grant founded by the Korean
Government (MEST, Basic Research Promotion Fund)
(KRF-2009-0071799).
somer: [R]26D =26.2 (c=0.8, CHCl3, 96% ee); H NMR (200
1
MHz, CDCl3) δ=7.75 (d, J=7.7 Hz, 1H), 7.44-7.51 (m, 3H),
7.19-7.39 (m, 5H), 5.99 (d, J=11.4 Hz, 1H), 5.33 (d, J=11.4 Hz,
1H), 3.48 (s, 3H), 3.08 (d, J=6.23 Hz, 2H), 2.68-2.75 (m, 1H),
2.22-2.36 (m, 1H), 1.35 (s, 9H); 13C NMR (50 MHz, CDCl3)
δ =194.4, 170.1, 154.9, 142.2, 138.7, 133.6, 132.2, 128.6, 128.2,
128.0, 127.5, 126.6, 125.6, 79.4, 63.0, 57.6, 52.2, 30.2, 28.0, 25.7;
MS (ESI): m/z=409.8 [M þ H]þ 121.0, 149.9, 206.0; EI-HRMS
Supporting Information Available: General experimental
procedures, H and 13C NMR spectra, characterization data,
1
and HPLC assays. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 15, 2009 5737