Highly diastereoselective asymmetric Mannich reactions of 1,3-dicarbonyls with acyl imines

Article abstract of DOI:10.1021/ol060304b

The cinchona alkaloids catalyze direct asymmetric Mannich reactions of cyclic 1,3-dicarbonyl compounds with acyl imines to afford α-quaternary carbon-bearing reaction products in yields of up to 98%, a diastereomeric excess of 90% or greater, and enantios

Full text of DOI:10.1021/ol060304b

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2003-2006
Highly Diastereoselective Asymmetric
Mannich Reactions of 1,3-Dicarbonyls
with Acyl Imines
Amal Ting, Sha Lou, and Scott E. Schaus*
Department of Chemistry, Center for Chemical Methodology and Library DeVelopment
at Boston UniVersity, Life Science and Engineering Building, Boston UniVersity,
24 Cummington Street, Boston, Massachusetts 02215
seschaus@bu.edu
Received February 4, 2006
ABSTRACT
The cinchona alkaloids catalyze direct asymmetric Mannich reactions of cyclic 1,3-dicarbonyl compounds with acyl imines to afford
r-quaternary
carbon-bearing reaction products in yields of up to 98%, a diastereomeric excess of 90% or greater, and enantioselectivities up to 99% ee. A
model is proposed that accounts for both the observed diastereoselectivities and the enantioselectivities for the reactions.
Optically active amine-containing synthons bearing quater-
nary carbon centers are valuable building blocks for syn-
thesis.1 Such chiral amine synthons have been used for the
construction of pharmaceuticals and natural products.2 In
particular, cyclic derivatives of these chiral synthons have
been used in the construction of peptidomimetics.3 Incor-
poration of such cyclic amino acids into peptides induces
conformational constraints that are pertinent to the under-
standing of peptide structure and function.4 Hence, methods
for their construction in diastereo- and enantioenriched form
are highly desirable.5
The asymmetric direct Mannich reaction is an attractive
method for the construction of chiral amines.6 We recently
reported the asymmetric Mannich reaction of â-keto esters
(3) (a) Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc.
2005, 127, 11516. (b) Sadowsky, J. D.; Schmitt, M. A.; Lee, H.-S.;
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116, 6201. (b) Liu, M.; Sibi, M. P. Tetrahedron 2002 58, 7991. (c) Jang,
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44, 1525.
(4) (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2014. (b)
Avenoza, A.; Busto, J. H.; Corzana, F.; Jime`nez-Ose`s, G.; Peregrina, J. M.
Chem. Commun. 2004, 980. (c) Seebach, D.; Lelais, G. Biopolymers 2004,
76, 206. (d) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am.
Chem. Soc. 2005, 127, 5376. (e) Ooi, T.; Miki, T.; Maruoka, K. Org. Lett.
2005, 7, 191.
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I. L.; Kaul, R.; Rao, B. R.; Raghothama, S.; Balaram, P. J. Am. Chem. Soc.
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3885.
10.1021/ol060304b CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/15/2006

with aryl acyl imines catalyzed by the cinchona alkaloids
(Figure 1).7 The reaction generated products in high enantio-
effective at promoting the condensation but in lower enan-
tioselectivities (entries 3 and 5). The reactions using catalysts
3 and 5 did not remain homogeneous during the course of
the reaction, perhaps contributing to the observed low
enantioselectivities. In contrast, the reaction using dihydro-
quinidine 4 did remain homogeneous.
The asymmetric Mannich reaction catalyzed by cinchonine
was found to be equally effective with other nucleophiles
such as ethyl-2-oxocyclopentanecarboxylate 6b, â-diketone
6c, and â-keto lactone 6d (Table 2). We also investigated
Table 2. Asymmetric Mannich Reactions of â-Keto Esters and
â-Diketonesa
Figure 1. Cinchona alkaloids.
selectivity, and some acyl imines afforded Mannich products
in high diastereoselectivity. Recently, nucleophilic additions
to imines have been employed to produce quaternary carbon
stereocenters.5h-i,8 We have expanded the scope of the
reaction to include cyclic R-substituted â-keto esters and
â-diketones.2f The reaction provides a catalytic route toward
the construction of cyclic â-amino esters with R-quaternary
carbon centers in high diastereo- and enantiopurity.
yield
(%)b
de
ee
entry
Ar
nucleophile
(%)c (%)c
1d
2d
3
4
5
6
7
8
9
10e
11
12
13
14
15e
16e
17e
18f
19g
20e
Ph (7a)
Ph (7a)
Ph (7a)
Ph (8a)
Ph (8a)
Ph (8a)
6a
6b
6c
6a
6b
6c
6a
6b
6c
6d
6a
6b
6c
6d
6a
6b
6c
6a
6b
6c
10a (98)
10b (96)
10c (98)
11a (98)
11b (98)
11c (98)
12a (98)
12b (98)
12c (98)
12d (88)
13a (96)
13b (98)
13c (92)
13d (78)
14a (98)
14b (98)
14c (98)
15a (98)
15b (98)
15c (98)
98
96
98
98
99
99
93
98
94
38
97
98
92
38
99
99
99
99
99
99
90
93
93
90
90
91
96
92
94
91
92
99
98
99
99
99
99
90
92
93
Initially, we evaluated the reaction of methyl-2-oxocyclo-
pentanecarboxylate 6a with methyl benzylidene carbamate
7a (Table 1). The reaction, catalyzed by 5 mol % of
3-CH3-C6H4 (7b)
3-CH3-C6H4 (7b)
3-CH3-C6H4 (7b)
3-CH3-C6H4 (7b)
3-CH3-C6H4 (8b)
3-CH3-C6H4 (8b)
3-CH3-C6H4 (8b)
3-CH3-C6H4 (8b)
2-C4H3O (7c)
2-C4H3O (7c)
2-C4H3O (7c)
3-F-C6H4 (7d)
3-F-C6H4 (7d)
3-F-C6H4 (7d)
Table 1. Asymmetric Mannich Reaction of â-Keto Estersa
yield
(%)b
de
(%)c
ee
(%)c
entry
catalyst
1
2
3
4
5
cinchonine 1
cinchonidine 2
quinidine 3
dihydroquinidine 4
quinine 5
96
96
96
94
95
93
94
95
94
94
90
-88
18
88
-10
a Mannich reactions were carried out using 0.5 mmol of nucleophile 6a,b,
0.5 mmol of acyl imines 7a-d and 8a,b in CH2Cl2 (0.5 M) for 2-6 h, at
-55 °C under N2, followed by flash chromatography on silica gel. b Isolated
yield of the Mannich reaction product. c Determined by chiral HPLC
analysis: see Supporting Information for details. d Reactions were run at
-40 °C. e Reactions were run at -78 °C. f Reactions were run at -85 °C.
g Reactions were run at -90 °C.
a Mannich reactions were carried out using 1.0 mmol of nucleophile 6a
and 0.5 mmol of imine in CH2Cl2 (0.5 M) at -35 °C for 18 h under N2,
followed by flash chromatography on silica gel. b Isolated yield of the
Mannich reaction product. c Determined by chiral HPLC analysis.
other acyl imines in the reaction by varying the electronic
nature of the aryl substituent. Optimal conditions employed
cinchonine 1 in CH2Cl2 at -35 °C, afforded the correspond-
ing â-amino ester 9 in 96% isolated yield and in 90% ee
after 18 h (Table 1, entry 1). The use of cinchonidine 2 or
quinine 5 as the catalyst afforded the product in similar
diastereoselectivity but with the opposite sense of enantio-
selectivity (entries 2 and 5). Quinidine 3 and quinine 5 were
(6) (a) EnantioselectiVe Syntheses of â-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) List, B.; Pojarliev, P.; Biller, W. T.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (c) Co´rdova, A.; Notz,
W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
124, 1842. (d) Uraguchi, T.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(e) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 2896.
2004
Org. Lett., Vol. 8, No. 10, 2006

for 1,3-dicarbonyls 6a-d and methyl benzylidene carbamate
7a were applicable to a variety of acyl imines 7b-d (entries
7-10 and 15-20). The reactions of both electron-rich and
electron-poor aromatic acyl imines afforded products in high
diastereomeric excess (92-99%) and high enantiomeric
excess (90-99%). Lower temperatures were necessary to
achieve high enantioselectivity for highly electrophilic acyl
imines 7c and 7d (entries 15-20).
Table 4. Asymmetric Mannich Reactions of â-Keto Esters and
â-Diketonesa
A selection of 1,3-dicarbonyl compounds were evaluated
in the asymmetric Mannich reaction using the general
reaction conditions. A cyclic six-membered ring-containing
â-keto ester and R-alkyl-substituted methyl-2-methylaceto-
acetate were employed in the Mannich reaction with acyl
imine 7a. Although these nucleophiles reacted with high
levels of diastereoselectivity (>90% de), the reaction af-
forded the products in low isolated yields and in essentially
racemic form.
yield
(%)b
de
ee
entry
Ar
nucleophile
(%)c (%)c
1
2
3
4
5
6d
7
Ph (17a)
Ph (17a)
Ph (17a)
Ph (17a)
2-C4H3O (17b)
2-C4H3O (17b)
2-C4H3O (17b)
6a
6b
6c
6d
6a
6b
6c
20a (98)
20b (98)
20c (98)
20d (88)
21a (98)
21b (98)
21c (98)
90
94
95
38
99
98
94
99
98
99
98
99
93
98
The general reaction conditions also proved effective in
the asymmetric Mannich reactions of allyl benzylidene
carbamate 8a,b to afford the products in similar levels of
selectivities (Table 2, entries 4-6, 11-13). In all cases, the
reactions proceeded cleanly with nearly quantitative yields
in excellent enantioselectivity.
a Mannich reactions were carried out using 0.5 mmol of nucleophile 6a,b
and 0.5 mmol of acyl imines 17a,b in CH2Cl2 (0.5 M) for 2-3 h, at -78
°C under N2, followed by flash chromatography on silica gel. b Isolated
yield of the Mannich reaction product. c Determined by chiral HPLC
analysis: see Supporting Information for details. d Reaction was run at -85
°C.
We added a new class of electrophiles to our investigation
in the Mannich reaction: aryl-propenyl acyl imines 17a,b
(Tables 3 and 4). This substrate class was synthesized using
3) as nucleophiles. The optimal catalyst for these reactions
was determined to be dihydroquinidine 4. Reactions carried
out using 10 mol % of 4 at -78 °C for 3 h in CH2Cl2
afforded the Mannich products in high yields and enantio-
selectivities but with no diastereoselectivity.10 However,
cinchonine 1 was found to be the optimal catalyst for
Mannich reactions of 1,3-dicarbonyl compounds 6a-d with
this class of acyl imines. The reaction conditions required 5
mol % of 1 at -78 °C (Table 4). For the substrates we
examined, the Mannich products were obtained in excellent
diastereo- and enantioselectivities.
Table 3. Asymmetric Mannich Reactions of â-Keto Estersa
yield
(%)b
de
ee
entry
Ar
nucleophile
(%)c (%)d
The relative stereochemistry of the products obtained from
the cinchona alkaloid-catalyzed diastereoselective Mannich
reactions was established by comparison to known com-
pounds in the literature2f and confirmed by X-ray crystal-
lographic analysis. Crystallographic structural determination
of Mannich product 15a confirmed the syn diastereoselec-
tivity of the reaction. Absolute stereochemistry was assigned
as (2R,1S) by comparison of optical rotations of synthetic
derivatives described in the literature.2f,11
1
2
3
4
Ph (17a)
Ph (17a)
2-C4H3O (17b)
2-C4H3O (17b)
16a
16b
16a
16b
18a (98)
18b (97)
19a (98)
19b (98)
0
67
0
95
92
90
90
0
a Mannich reactions were carried out using 0.5 mmol of nucleophile 16a,b
and 0.5 mmol of acyl imines 17a,b in CH2Cl2 (0.5 M) for 2-3 h, at -78
°C under N2, followed by flash chromatography on silica gel. b Isolated
yield of the Mannich reaction product. c Determined by NMR analysis.
d Determined by chiral HPLC analysis: see Supporting Information for
details.
The high degree of selectivity observed in the reaction of
methyl 2-oxocyclopentanecarboxylate 6a with acyl imines
indicates a catalyst-associated complex with specific steric
requirements.12 On the basis of the results we obtained from
procedures similar to the preparation of simple benzylidene
carbamates.9 We first investigated â-keto esters 16a,b (Table
(7) Lou, S.; Taoka, B.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005,
127, 11256.
(8) (a) Marigo, M.; Kjaersgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem.-Eur. J. 2003, 9, 2359. (b) Saaby, S.; Nakama, K.; Liu, M.
A.; Hazell, R. G.; Jørgensen, K. A. Chem.-Eur. J. 2003, 9, 6145. (c)
Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507.
(d) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 11, 1191.
(9) For the preparation of 7a-d and 8a,b, see: Vidal, J.; Damestoy, S.;
Guy, L.; Hannachi, J.-C.; Aubry, A.; Collet, A. Chem.-Eur. J. 1997, 3,
1691. For the preparation of 17a,b, see Supporting Information.
(10) Products yielded from dihydroquinidine-catalyzed reactions have
the same stereochemistry to reactions catalyzed by cinchonine.
(11) Karlsson, S.; Ho¨gber, H.-E. Eur. J. Org. Chem. 2003, 2782. See
Supporting Information for the full analysis.
Org. Lett., Vol. 8, No. 10, 2006
2005

our experiments, we have developed a model that accounts
for the observed diastereo- and enantioselectivity (Figure 2).
use of the O-acetylated cinchonine catalyst in the reaction
affords the product in lower enantioselectivity (<40% ee).
Furthermore, approach of the acyl imine on the si-face of
the enol is partially blocked by the quinoline ring. This model
provides insight into the factors that result in a selective
reaction.17 Furthermore, we will use the model to design
catalysts for organocatalytic Mannich reactions that have
proven difficult to catalyze enantioselectively.
In summary, we have developed a highly diastereo- and
enantioselective direct Mannich reaction of â-keto esters to
acyl imines catalyzed by cinchonine and cinchonidine. A
model has been proposed for the reaction that accounts for
the observed selectivities. Continued investigations include
the expansion of the current methodology and synthetic utility
of the products.
Acknowledgment. Dr. Emil Lobkovsky (Cornell Uni-
versity) is gratefully acknowledged for X-ray crystallographic
analysis. The authors thank Mettler Toledo (Columbus, OH)
for assistance with instrumentation and Synthematix, Inc.
(Durham, NC) for assistance with chemical reaction planning
software. S.L. gratefully acknowledges a graduate research
fellowship from Merck Research LaboratoriessBoston. This
research was supported by a gift from Amgen, Inc., an NSF
CAREER grant (CHE-0349206), and the NIGMS CMLD
initiative (P50 GM067041).
Figure 2. Proposed catalytically active cinchonine/methyl 2-oxo-
cyclopentanecarboxylate enol tautomer complex (MMFF) ap-
proaching the re-face of methyl benzylidenecarbamate in the
formation of (R,S)-9.
Supporting Information Available: Experimental pro-
cedures, characterization data, chiral chromatographic analy-
sis, and crystal structure data for 15a, 15c, and 20c (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
We first considered the enol tautomer of methyl 2-oxo-
cyclopentanecarboxylate as the reactive intermediate in the
Mannich reaction. A MMFF conformation search13,14 identi-
fied the lowest-energy conformer of the enol form of 6a
complexed with cinchonine 1.
OL060304B
The ground-state conformation of methyl benzylidene
carbamate 7a was calculated and modeled in a reactive
conformation with the cinchonine/enol complex. The bi-
functional nature of the catalyst as a hydrogen bond donor
and acceptor is depicted by the coordination structure
illustrated in Figure 2.15,16 Consistent with this observation,
(15) (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV.
2003, 103, 2985. (b) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
Soc. 2004, 126, 9906. (c) Tian, S.-T.; Chen, Y.; Hang, J.; Tang, L.; McDaid,
P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (d) Liu, X.; Li, H.; Deng, L.
Org. Lett. 2005, 7, 167.
(16) Similar models have been proposed for diastereoselective â-keto
ester additions to nitroolefins: (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J.
Am. Chem. Soc. 2004, 126, 9906. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.;
Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005,
44, 105. (c) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005,
44, 6367.
(12) (a) Brown, H. C.; Brewster, J. H.; Shechter, H. J. Am. Chem. Soc.
1954, 76, 467. (b) Iglesias, E. New J. Chem. 2002, 26, 1352.
(13) Molecular Operating EnVironment, 2004.03; Chemical Computing
Group: Montreal, Quebec, Canada.
(17) For conformational studies of cinchona alkaloid-catalyzed reactions,
see: Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 1731. (b) Taggi,
A. E.; Hafez, A. M.; Dudding, T.; Lectka, T. Tetrahedron 2002, 58, 8351.
(14) Halgren, T. A. J. Comput. Chem. 1996, 17, 519.
2006
Org. Lett., Vol. 8, No. 10, 2006