Asymmetric Mannich reactions of β-keto esters with acyl imines catalyzed by cinchona alkaloids

Article abstract of DOI:10.1021/ja0537373

Cinchona alkaloids catalyze the enantioselective Mannich reaction of β-keto esters with acyl aryl imines. The reaction requires 10 mol % of cinchonine or cinchonidine. The reaction products are obtained in good yields (81-99%), high enantioselectivities (

Full text of DOI:10.1021/ja0537373

Published on Web 07/26/2005
Asymmetric Mannich Reactions of â-Keto Esters with Acyl Imines Catalyzed
by Cinchona Alkaloids
Sha Lou, Brandon M. Taoka, Amal Ting, and Scott E. Schaus*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Life Science and
Engineering Building, Boston UniVersity, 24 Cummington Street, Boston, Massachusetts 02215
Received June 7, 2005; E-mail: seschaus@bu.edu
Table 1. Asymmetric Mannich Reactions of â-Keto Estersa
Highly functionalized amine-containing building blocks in enan-
tioenriched form are valuable starting materials for asymmetric
synthesis.1 The asymmetric direct Mannich reaction2 is an attractive
approach toward the construction of these building blocks.3 In
particular, the direct addition of â-keto esters to imines affords
multifunctional secondary amines.4 We proposed a chiral base-
mediated direct addition of â-keto esters to acyl imines.5 The
cinchona alkaloids are effective organic chiral bases capable of
promoting a range of nucleophilic reactions in an asymmetric
manner,6 including alcoholysis of anhydrides,7 cyanation of car-
bonyl-containing compounds,8 aza-Henry reactions,9 conjugate
additions to ynones,10 chalcones,11 nitroolefins,12 and vinyl sul-
fones.13 Herein, we report the enantioselective addition of â-keto
esters to acyl aryl imines catalyzed by the cinchona alkaloids
cinchonine and cinchonidine.
entry
catalyst
ester
imine
yield (%)b
drc
% eed
1
2
1
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
4a
4a
4b
4c
4c
4c
4c
4c
4c
4c
4c
4d
5a (85)
5a (86)
5b (91)
5c (99)
5c (96)
5c (90)
5c (95)
5d (99)
5d (95)
5d (97)
5d (98)
5e (91)
3:1
1:1
80
60
86
92
90
60
65
94
90
60
65
90
quinine
3
1
2:1
4
1
3:1
5
2
2:1
6
quinine
quinidine
1:1
7
1:1
8
1
2
20:1e
20:1
4:1
9
10
11
12
quinine
quinidine
1
5:1
2:1
a Reactions were carried out using 0.5 mmol ester 3, 0.5 mmol imine 4,
and 0.05 mmol catalyst in CH2Cl2 (0.5 M) at -35 °C for 16 h under Ar,
followed by flash chromatography on silica gel. b Isolated yield. c Deter-
mined by 1H NMR analysis. d Enantiomeric excess of diastereomeric
mixture determined by chiral HPLC analysis; see Supporting Information.
e The major isomer is (1R,2S).
We initially evaluated the use of cinchona alkaloids as the catalyst
in the asymmetric Mannich reaction of allyl acetoacetate 3a with
acyl imines (Table 1). The reaction of 3a with tert-butyl benzylidene
carbamate 4a catalyzed by cinchonine 1 in CH2Cl2 at -35 °C
afforded the corresponding â-amino ester 5a in 85% isolated yield
of a 3:1 mixture of diastereomers (entry 1, Table 1). For purposes
of analysis, the mixture of diastereomers was subjected to decar-
boxylation using Pd(II) and methyl acetoacetate to yield the
corresponding ketone in 87 and 80% ee. In comparison, the quinine-
catalyzed reaction of 3a with 4a afforded the product in 1:1 dr and
60% ee. Higher enantioselectivities were obtained in the reactions
of 3a with ethyl benzylidine carbamate 4b and 3a with methyl
benzylidine carbamate 4c (86 and 92% ee, respectively, entries 3
and 4) although in low diastereomeric ratios. The reaction of 3a
with 4c using cinchonidine as the catalyst afforded the product in
similar diastereomeric ratio and enantiomeric excess but with the
opposite sense of enantioselectivity (entry 5). Other cinchona
alkaloids, such as quinine and quinidine, were not as effective at
promoting the reaction enantioselectively (entries 6 and 7).
The cinchonine- and cinchonidine-promoted asymmetric Mannich
reaction of â-keto esters with acyl imines was also found to be
equally effective with methyl acetoacetate 3b as the nucleophile.
However, the reaction was highly diastereoselective; the addition
of 3b to 4c afforded the product 5d in 20:1 dr and in 94% ee (entry
8). The enantiomeric excess of product derived from 3b was deter-
mined by selective conversion to the Z-enamine with benzylamine
using HC(OCH3)3 and cat. Yb(OTf)3. The asymmetric Mannich
reaction was similarly diastereo- and enantioselective using cin-
chonine as the catalyst (entry 9), and quinine and quinidine were
not as effective at promoting the reaction (entries 10 and 11). Last,
the reaction of 3b with allyl benzylidene carbamate 4d was not
diastereoselective, but afforded the product in 90% ee.
The reaction conditions that proved optimal for â-keto ester 3a,
benzylidene carbamate 4c, and cinchonine as the catalyst (Table
1, entry 4) were found to be general for a variety of aryl methyl
carbamate imines (Table 2).14 While most aryl imines readily
formed the Mannich products with 3a in good isolated yields (81-
99%) and good enantioselectivities (80-96% ee, Table 2), the
products were isolated as a mixture of diastereomers. In contrast,
the direct Mannich products from the reaction of methyl acetoacetate
3b with aryl imines were isolated in 10-20:1 diastereomeric ratios
(entries 1-3 and 8, Table 3) and good enantioselectivities (81-
94% ee). Neither the diastereomeric ratio nor the percent enantio-
meric excess eroded when the isolated Mannich products were
exposed to the reaction conditions, indicating that the observed
results reflect the imine addition selectivity. However, not all
electrophiles afforded the corresponding Mannich products with
3b in diastereomeric ratios greater than 1:1, but in these cases, the
mixture of diastereomers was obtained in g90% ee (Table 2, entries
4-7).
The asymmetric Mannich reaction provided ready access to
highly functionalized building blocks, the synthetic utility of which
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J. AM. CHEM. SOC. 2005, 127, 11256-11257
10.1021/ja0537373 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of â-Amino Alcohols
Table 2. Asymmetric Mannich Reactions of â-Keto Ester 3aa
entry
Ar
% yieldb
drc
yield (%)d
% eee
1
2
Ph
99
93
98
98
96
99
95
81
84
96
3:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
5:1
7a (80)
7b (80)
7c (97)
7d (84)
7e (81)
7f (83)
7g (81)
7h (96)
7i (82)
7j (83)
92
83
93
91
96
90
80
93
92
95
TMSI in CH3CN followed by treatment with MeOH to yield amino
alcohol 10 (86% over three steps).
4-Cl-C6H4
3
4-F-C6H4
4
3-F-C6H4
In summary, we have developed a diastereo- and enantioselective
direct Mannich reaction of â-keto esters to acyl aryl imines
catalyzed by cinchonine and cinchonidine. We have used the
products from the reaction in the synthesis of enantioenriched
dihydropyrimidones and â-amino alcohols. Ongoing investigations
include the expansion of the current methodology and synthetic
utility of the products.
5
3-CH3-C6H4
3-CF3-C6H4
3,4-(OCH2O)C6H3
2-C4H3O
6
7
8
9
2-C4H3S
2-naphthyl
10
a Mannich reactions were carried out using 0.5 mmol ester 3, 0.5 mmol
imine 6, and 0.05 mmol cinchonine 1 in CH2Cl2 (0.5 M) at -35 °C for 16
h under Ar, followed by flash chromatography on silica gel. b Isolated yield
of Mannich reaction product. c Determined by 1H NMR analysis. d Isolated
yield of 7. e Enantiomeric excess of 7 determined by chiral HPLC analysis.
Acknowledgment. The authors thank Mettler Toledo (Colum-
bus, OH) for assistance with instrumentation, and Synthematix, Inc.
(Durham, NC) for assistance with chemical reaction planning
software. This research was supported by an award from Amgen,
Inc., an NSF CAREER grant (CHE-0349206), and the NIGMS
CMLD initiative (P50 GM067041).
Table 3. Asymmetric Mannich Reactions of â-Keto Ester 3ba
Supporting Information Available: Experimental procedures,
characterization data, and chiral chromatographic analysis. This material
is available free of charge via the Internet at http://pubs.acs.org.
% yieldb
drc
yield (%)d
% eee
References
entry
Ar
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1
2
3
4
5
6
7
8
Ph
99
81
87
99
88
83
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20:1f
10:1
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1:1
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94
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4-Cl-C6H4
4-F-C6H4
3-F-C6H4
3-CH3-C6H4
2-C4H3O
1:1
1:1
1:1
20:1
2-C4H3S
2-naphthyl
a Mannich reactions were carried out using 0.5 mmol ester 3, 0.5 mmol
imine 6, and 0.05 mmol cinchonine 1 in CH2Cl2 (0.5 M) at -35 °C for 16
h under Ar, followed by flash chromatography on silica gel. b Isolated yield
of Mannich reaction product. c Determined by 1H NMR analysis. d Isolated
yield of 8. e Enantiomeric excess of 8 determined by chiral HPLC analysis.
f The major isomer is (1R,2S).
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The diastereomerically enriched Mannich product 5d was easily
converted to the corresponding â-amino alcohol using a reduction/
deprotection sequence (Scheme 2). Reduction of 5d using Zn(BH4)2
at -78 °C afforded the amino alcohol in 95% yield and >20:1 dr.
The methyl carbamate was deprotected via a two-step process using
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