Asymmetric aza-Michael reactions of α,β-unsaturated ketones with bifunctional organic catalysts

Article abstract of DOI:10.1002/anie.200802785

Synergy makes it possible: Bifunctional cinchona alkaloids are found to promote the first highly enantioselective organocatalytic aza-Michael reactions with α,β-unsaturated ketones. In addition to utilizing practical catalysts, readily accessible substrates, and commercially available reagents, this reaction affords a synthetically valuable scope that is complimentary to existing methods catalyzed by chiral metal complexes.

Full text of DOI:10.1002/anie.200802785

Communications
DOI: 10.1002/anie.200802785
Organocatalysis
Asymmetric Aza-Michael Reactions of a,b-Unsaturated Ketones with
Bifunctional Organic Catalysts**
Xiaojie Lu and Li Deng*
Chiral amine motifs are present in numerous biologically
active and therapeutically important molecules. Conse-
quently chiral amines constitute one of the most important
classes of chiral building blocks in organic synthesis. Accord-
ingly, significant efforts have been devoted to the develop-
ment of catalytic enantioselective transformations of inex-
pensive achiral precursors into optically active chiral amines.
Alongside enantioselective additions to achiral imines, cata-
lytic asymmetric conjugate additions with nitrogen nucleo-
philes (aza-Michael reactions) provide another fundamen-
tally important approach toward optically active chiral
amines.[1]
Although much progress has been made recently in the
development of asymmetric aza-Michael reactions with both
chiral metallic[2–4] and organic catalysts,[5–7] highly enantiose-
lective catalytic aza-Michael additions to simple a,b-unsatu-
rated ketones remain rare. To our knowledge, only three such
reactions have been reported, and all are catalyzed by chiral
Scheme 1. Proposed activation modes of aza-Michaeladdition of a,b-
unsaturated ketones 1 with 4.
metal complexes.[3] Inanaga and co-workers reported a chiral
scandium complex as a highly effective Lewis acid catalyst for
an asymmetric aza-Michael reactions of o-alkoxyhydroxyl-
amines to acyclic enones.[3a] Applying bifunctional catalysis
with a chiral lithium–yttrium heterobimetallic complex,
Shibasaki and co-workers established a highly efficient aza-
Michael reaction with a broader scope, affording high
enantioselectivity for a wide range of a,b-unsaturated ketones
1, (see Scheme 1) bearing either an aryl or alkyl b-substituent
(R1).[3b,c] However, the ketone substituent (R2) is limited to
aromatic rings for both of the aforementioned reactions.
More recently, Jacobsen and co-workers reported the con-
jugate addition of hydrazoic acid to enones catalyzed by a
salen–aluminum complex.[3d] Notably, this reaction afforded
good to excellent enantioselectivity for a,b-unsaturated
ketone 1, bearing various alkyl substituents as R1 and R2.
Herein, we report the first highly enantioselective aza-
Michael reaction with a,b-unsaturated ketones catalyzed by
a chiral organic catalyst. Significantly, this new catalytic
asymmetric aza-Michael reaction afforded consistently excel-
lent enantioselectivity for a wide variety of alkyl vinyl ketones
bearing either an alkyl or aryl group as R1, thereby providing
a synthetically valuable substrate scope that is complemen-
tary to those of existing chiral metal-based methods.
MacMillan and co-workers[6a] first reported the use of
chiral secondary amines, in this case chiral imidazolidinones,
to activate a,b-unsaturated aldehydes for highly enantiose-
lective aza-Michael reactions with N-siloxycarbamate using
iminium catalysis.[8] Presumably, the steric bulk of the chiral
secondary amines renders them highly chemoselective for
nucleophilic attack at the aldehyde group, while minimizing
catalyst decomposition through conjugate additions to enals.
On the other hand, a,b-unsaturated ketones 1 are sterically
more demanding and electronically less active toward imi-
nium formation with chiral amines. The activation of enones
for asymmetric aza-Michael reactions by chiral secondary
amines has not yet been reported.[9] Recently, 9-amino
cinchona alkaloid 4,[10] in combination with various acids,
has been shown to provide an effective catalyst system for the
activation of enones 1 for various asymmetric conjugate
addition reactions.[11] Presumably, compared to secondary
amines, the sterically less-hindered primary amine in 4 reacts
more readily with the ketone functionality in 1 to initiate the
iminium catalysis. Thus, we reasoned that, while the primary
amine activated the enone in the presence of acid by iminium
catalysis, the quinuclidine motif of cinchona alkaloid 4, in
either the free base (Scheme 1, mode a) or the protonated
form (mode b), could bind to nitrogen nucleophiles, such as
alkoxyamines, through hydrogen-bonding interactions,
thereby activating the nitrogen nucleophile for nucleophilic
[*] X. Lu, Prof. L. Deng
Department of Chemistry, Brandeis University
Waltham, MA, 02454-9110(USA)
Fax: (+1)781-736-2516
E-mail: deng@brandeis.edu
[**] We are gratefulfor financialsupport from theNationalInstitute of
Health (GM-61591).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802785.
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Chemie
attack by bringing it into the proximity of the activated enone.
We anticipated that this bifunctional catalysis by cinchona
alkaloid 4 could be applied to the development of an efficient
asymmetric aza-Michael reaction with a,b-unsaturated
ketones 1.
Accordingly, we investigated the aza-Michael reaction of
various nucleophiles to enone 1a catalyzed by the 9-amino
cinchona alkaloid 4 (Table 1). In the presence of 10 mol% of
over, catalyst 4 was found to also tolerate a significant range
of alkyl groups as the b-substituent (R1) in 1. Catalyst 4 was
also found to afford excellent enantioselectivity for alkyl vinyl
ketones bearing a b-aryl group, such as 1i, albeit with
drastically decreased activity (Table 2, entry 9 cf. entry 8).
Reaction optimization studies revealed that the cinchonidine-
derived catalyst 5 (see Scheme 1) afforded the optimal
enantioselectivity for enone 1i. Enantioselectivity remained
high when the reaction was carried
out in toluene at 408C, to provide
Table 1: Asymmetric aza-Michaelreaction of a,b-unsaturated ketones 1 with 4.
the corresponding adduct in syn-
thetically useful yield. Utilizing cat-
alyst 5’(see Scheme 1) derived from
cinchonine (in place of 4), the
Entry[a]
2
Cat.
t [h]
Conv. [%][b]
ee 3a [%][c]
corresponding antipodes of 3 were
generated in good to excellent opti-
cal purity (Table 2). Thus alkyl vinyl
ketones 1 bearing both b-aryl and
alkyl groups could be employed for
this cinchona alkaloid-catalyzed
aza-Michael reaction (Table 2). Sig-
nificantly, among existing highly
1
2
2a
2b
BnNH2
4
4
12
12
0
0
na
na
3
4
2c
2d
2e
2 f
4
4
4
4
4
5
4
4
12
48
12
12
12
12
12
72
64
52
38
88
87
79
48
99
75
67
83
77
84
82
93
93
5
enantioselective
catalytic
aza-
6
Michael reactions with enones, the
current reaction is unique in its
ability to afford high enantioselec-
tivity for alkyl vinyl ketones bearing
b-aryl groups (Table 2, entries 12–
16). As illustrated in Scheme 2, the
enantiomerically enriched Michael
adducts 3g and 3i, which bear
substituents of various steric and
electronic properties, could be read-
ily converted into the correspond-
7
2g
2g
2g
2g
8
9[d]
10[e]
[a] Unless noted, reactions were run with 0.1 mmol 1a, 0.15 mmol 2, see Supporting Information for
details. [b] Determined by 1H NMR analysis. [c] Determined by HPLC analysis. [d] Reaction was run with
20 mol% TFA. [e] Reaction was run with 0.2 mmol 1a, 0.30 mmol 2, 20 mol% 4, and 40 mol% TFA.
TFA=trifluoroacetic acid.
ing
N-Boc-protected
b-amino
4 and 40 mol% of trifluoroacetic acid (TFA), the conversion
and the enantioselectivity of the aza-Michael reaction was
found to be greatly influenced by the electronic as well as the
steric properties of the nitrogen nucleophiles. Various alkoxy-
amines bearing either an N-carbamate or N-sulfonamide
group were found to be active toward the 4-catalyzed aza-
Michael reaction. The reaction with Boc-protected N-benzy-
loxyamine 2g afforded the highest enantioselectivity, provid-
ing the desired adduct in 84% ee (Boc = tert-butoxycarbonyl,
Table 1, entry 7). Importantly, when the loading of TFA was
decreased from 40 mol% to 20 mol%, the reaction was found
to proceed in significantly improved enantioselectivity
(Table 1, entry 9). 99% conversion could be attained with
20 mol% of 4 and 40 mol% of TFA to afford the desired aza-
Michael adduct 3a in 93% ee (Table 1, entry 10).
Encouraged by this promising result, we investigated the
scope of the 9-amino cinchona alkaloid-catalyzed aza-
Michael reaction under the optimal conditions defined
through our model studies (as for Table 1, entry 10). As
illustrated in Table 2, the high enantioselectivity afforded by
catalyst 4 could be extended to a wide range of alkyl vinyl
ketones 1a–h. Significantly, alterations of the steric properties
of the aliphatic ketone substituent (R2) did not impact
negatively on the enantioselectivity of the reaction. More-
ketones 6 and 7 without significant deterioration in optical
purity.[12]
Scheme 2. Hydrogenation of 3.
In summary, we have developed the first highly enantio-
selective aza-Michael reaction of simple a,b-unsaturated
ketones with an organic catalyst. It is particularly noteworthy
that this new catalytic asymmetric aza-Michael reaction is
effective for a broad range of alkyl vinyl ketones bearing both
aryl and alkyl b-substituents. Utilizing commercially available
nitrogen nucleophiles and readily available chiral catalysts,
this asymmetric aza-Michael reaction provides a highly
promising method for the asymmetric synthesis of a wide
range of optically active chiral amines. Our current inves-
tigations are focused on the elucidation of the mechanism, as
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Communications
Table 2: Asymmetric aza-Michaeladdition of a,b-unsaturated ketones 1 with 4.
Keywords: alkaloids · amines ·
asymmetric catalysis · enones ·
Michaeladdition
.
Entry[a] Cat. Enone
R1
R2
Product
t [h][b]
yield 3 [%][b] ee 3 [%][b,c]
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lective aza-Michael reactions, see:
a) L.-W. Xu, C.-G. Xia, Eur. J. Org.
Chem. 2005, 633 – 639; b) M. Liu,
M. P. Sibi, Tetrahedron 2002, 58,
7991 – 8035.
1
4(5’) 1a
PhCH2CH2 Me
72(120) 80(80)
93(84)
94
2
4
4
1b
1c
nPen
Me
Me
Et
72
92
76
83
[2] For examples of highly enantiose-
lective aza-Michael additions to
carboxylic acid derivatives or sur-
rogates, catalyzed by metal-based
Lewis acids, see: a) M. P. Sibi, J. J.
Shay, M. Liu, C. P. Jasperse, J. Am.
Chem. Soc. 1998, 120, 6615 – 6616;
b) J. K. Myers, E. N. Jacobsen, J.
Am. Chem. Soc. 1999, 121, 8959 –
8960; c) W. Zhuang, R. G. Hazell,
K. A. Jørgensen, Chem. Commun.
2001, 1240 – 1241; d) M. P. Sibi, N.
Pradagaran, S. G. Ghorpade, C. P.
Jasperse, J. Am. Chem. Soc. 2003,
125, 11796 – 11797.
[3] For examples of highly enantiose-
lective aza-Michael reactions to b-
amino ketones, catalyzed by
metal-based Lewis acids, see:
a) X. L. Jin, H. Sugihara, K.
Daikai, H. Tateishi, Y. Z. Jin, H.
Furuno, J. Inanaga, Tetrahedron
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H. Qin, S. Matsunaga, M. Shiba-
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D. N. Zalatan, A. M. Lerchner,
E. N. Jacobsen, J. Am. Chem.
Soc. 2005, 127, 1313 – 1317.
[4] For an example of highly enantio-
selective aza-Michael reactions of
carbamates with a’-hydroxye-
nones, see: C. Palomo, M. Oiar-
bide, R. Halder, M. Kelso, E.
Gꢀmez-Bengon, J. M. Garcia, J.
Am. Chem. Soc. 2004, 126, 9188 –
9189.
[5] For examples of highly enantiose-
lective aza-Michael reactions to
carboxylic acid derivatives or sur-
rogates catalyzed by chiral organic
catalysts see: a) T. E. Horstmann,
D. J. Guerin, S. J. Miller, Angew.
Chem. 2000, 112, 3781 – 3784;
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3635 – 3638; b) D. J. Guerin, S. J.
3
90
4
4(5’) 1d
4(5’) 1e
nPen
nHex
nHep
Me
Et
162(170) 70(67)
120(168) 83(68)
93(90)
93(91)
96
5
Et
6
4
1 f
Et
96
70
7
4(5’) 1g
nBu
nBu
Me
Me
Me
Me
Me
192(196) 74(76)
91(86)
95
8
4
4
5
5
5
1h
1i
1i
1i
1i
nPr
96
24
24
24
84
70
9[d,e]
10[d,e]
11[d,g]
12[d,h,i]
13[d,h]
Ph
11[f]
13[f]
41[f]
67
94
Ph
96
Ph
93
Ph
90
5(5’) 1j
p-FC6H4
96(192) 61(60)
92(87)
14[d,h]
15[d,h]
16[d,h]
5
5
5
1k
1l
p-ClC6H4
p-BrC6H4
Me
Me
82
80
96
71
70
57
93
90
86
1m
p-MeC6H4 Me
[a] Unless noted, reactions were run with 0.2 mmol 1, 0.30 mmol 2g, see Supporting Information for
details. [b] Values in parentheses refer to 5’-catalyzed reactions, affording the opposite enantiomer of 3.
[c] Determined by HPLC analysis. [d] Reaction was run with 10 mol% catalyst and 20 mol% TFA. [e] The
reaction was checked after 24 h. [f] The conversion of the reaction was determined by 1H NMR analysis.
[g] Reaction was run at 408C and checked after 24 h. [h] Reaction was run with 0.2 mmol 1 and
0.60 mmol 2g at 408C in toluene. [i] Absolute configuration was assigned as S, see Supporting
Information for details.
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Received: June 12, 2008
Published online: August 29, 2008
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