Anti-selective direct asymmetric Mannich reactions catalyzed by axially chiral amino sulfonamide as an organocatalyst

Article abstract of DOI:10.1021/ja056008w

A direct asymmetric Mannich reaction using a novel axially chiral amino trifluoromethanesulfonamide (S)-3 has been developed in highly anti-selective and enantioselective manners. Thus, in the presence of a catalytic amount of (S)-3, the reactions between

Full text of DOI:10.1021/ja056008w

Published on Web 11/02/2005
anti-Selective Direct Asymmetric Mannich Reactions Catalyzed by Axially
Chiral Amino Sulfonamide as an Organocatalyst
Taichi Kano, Yukako Yamaguchi, Osamu Tokuda, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received September 1, 2005; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1
Asymmetric Mannich reactions provide a powerful method for
synthesizing optically active â-amino carbonyl units, which are
useful chiral building blocks for a number of biologically active
and pharmaceutically important compounds.1 In particular, direct
asymmetric Mannich reactions between carbonyl compounds and
certain imines would be most desirable for this purpose.2-4
Accordingly, small organic molecules, such as L-proline and its
derivatives, were recently found to catalyze the reaction between
aldehydes and imines to furnish syn- or anti-â-amino aldehydes as
a major product, depending on the choice of catalyst.3c,d While a
proline-catalyzed direct asymmetric Mannich reaction of imine 4
gives the syn-â-amino aldehyde, syn-5, preferentially with excellent
enantioselectivity through the anti-enamine intermediate A (Scheme
1),3c a general and selective method for obtaining the opposite anti-
â-amino aldehyde, anti-5, remains unattainable.3d In this context,
we are interested in the possibility of obtaining anti-5 via the syn-
enamine intermediate B by using a certain amino acid which has a
longer spatial distance between the amino and carboxyl groups than
L-proline catalyst. Our recently designed axially chiral amino acid
(S)-1,5 which catalyzes the direct asymmetric aldol reaction between
acetone and aldehydes, seems to be an appropriate candidate to
achieve the hitherto difficult syn-enamine intermediate B resulting
from a decrease of the steric repulsion between the enamine and
acid moieties. In addition, the imine activated by the remote acidic
Table 1. anti-Selective Mannich Reactions between
proton is expected to react preferentially with the syn-enamine
intermediate B to give a desired anti-isomer, anti-5. Our hypothesis
has been verified by designing an axially chiral organocatalyst of
type 3 that allows a highly anti-selective direct asymmetric Mannich
reaction between aldehyde and imine 4 with excellent enantio-
selectivity.
Isovaleraldehyde and R-Imino Ester 4 Catalyzed by (S)-1-3a
mol
(%)
time
(h)
First, we examined the direct Mannich reaction between iso-
valeraldehyde and R-imino ester 4 derived from p-anisidine and
ethyl glyoxylate. Thus, in the presence of 5 mol % of (S)-1, the
reaction between isovaleraldehyde (3 equiv) and R-imino ester 4
in dioxane at room temperature afforded the corresponding â-amino
aldehyde 5 in 60% yield with the anti/syn ratio of 1:1.1 and
enantiomeric excess of 86% for the anti-isomer (Table 1, entry 1).
This low anti/syn selectivity prompted us to modify (S)-1 and
develop new axially chiral amino sulfonamides of type (S)-2 and
(S)-3 with a more remote acidic proton from the secondary amino
group than the carboxyl group in (S)-1.
The efficiency of these new catalysts (S)-2 and (S)-3 was
evaluated under the identical conditions, except for the use of lower
catalyst loadings (2 mol %). Unfortunately, attempted use of (S)-2
resulted in a significant loss of reactivity and enantioselectivity,
although moderate anti-selectivity was observed (Table 1, entry
2). In marked contrast, however, switching the catalysts from (S)-2
to (S)-3, which contains a more acidic trifluoromethanesulfonamide
group, dramatically enhanced both reactivity and stereoselectivities
in this system (93% yield; anti/syn ) >20:1; >99% ee for the
major anti-isomer) (entry 3). We then examined the solvent effect
entry
catalyst
solvent
% yieldb
anti/sync
% eed
1
2
3
4
5
6
7
8
(S)-1
(S)-2
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
5
2
2
2
2
2
2
2
20
24
0.5
6
6
6
dioxane
dioxane
dioxane
THF
EtOAc
DMSO
CHCl3
toluene
60
11
93
38
72
20
70
98
1/1.1
3.8/1
>20/1
>20/1
8.3/1
6.3/1
9.1/1
9.1/1
86
72
>99
99
90
97
98
>99
6
0.5
a The reaction of isovaleraldehyde (3 equiv) and R-imino ester 4 was
carried out in a solvent in the presence of catalyst (S)-1-3 at room
temperature. b Isolated yield. c Determined by 1H NMR. d The enantiomeric
excess of the anti-isomer was determined by HPLC analysis using chiral
column (Chiralpak AS-H, Daicel Chemical Industries, Ltd.).
by using (S)-3 in the direct asymmetric Mannich reaction. Other
solvents, such as THF, EtOAc, DMSO, or CHCl3, were found to
be less satisfactory in terms of the chemical yield and stereoselec-
tivities (entries 4-7). Whereas the reaction in toluene solvent
proceeded smoothly with excellent enantioselectivity, a slight
decrease in anti-selectivity was observed (entry 8). Accordingly,
dioxane was determined to be the solvent of choice.
9
16408
J. AM. CHEM. SOC. 2005, 127, 16408-16409
10.1021/ja056008w CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. anti-Selective Mannich Reactions between Various
Aldehydes and R-Imino Ester 4 Catalyzed by (S)-3a
(S)-1, the C-C bond forming reaction catalyzed by (S)-1 takes place
not only on the Si face of the syn-enamine but also on the Re face
of the anti-enamine in the reaction catalyzed by (S)-1 (Figure 1,
right). As a result, both anti- and syn-isomers are obtained.
In summary, we have developed a highly anti-selective direct
asymmetric Mannich reaction between aldehydes and the R-imino
ester catalyzed by the novel axially chiral amino sulfonamide (S)-
3. The procedure converts the R-imino ester to functional â-amino
aldehydes with significantly higher anti/syn ratio and enantio-
selectivity than previously possible. We are currently working to
expand the scope of this methodology and to apply the novel
sulfonamide catalyst for other organocatalytic asymmetric reactions.
catalyst
(mol %)
time
(h)
entry
R1
R2
% yieldb
anti/sync
% eed
1
2
3
4
5
6
7
8
9
Me
Me
Bu
Bu
Bn
i-Pr
t-Bu
i-Pr
i-Pr
Et
Et
Et
Et
Et
Et
Et
allyl
t-Bu
1
0.2
1
0.5
1
2
5
2
2
0.5
22
4
8
4
0.5
16
0.5
0.5
93
82
93
92
92
93
42
99
99
13/1
11/1
>99
97
99
>20/1
>20/1
11/1
>20/1
>20/1
16/1
97
>99
>99
>99
>99
>99
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
16/1
a The reaction between aldehydes (3 equiv) and R-imino esters was
carried out in dioxane in the presence of (S)-3 at room temperature. b Isolated
yield. c Determined by 1H NMR. d The enantiomeric excess of the anti-
isomer was determined by HPLC analysis using chiral column. Details are
given in Supporting Information.
Supporting Information Available: Experimental details and
characterization data for new compounds including the preparation of
catalysts (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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Figure 1. Possible transition states for the direct asymmetric Mannich
reaction catalyzed by (S)-3 (left) and (S)-1 (right).
The reaction between other aldehydes and R-imino esters in the
presence of a catalytic amount of (S)-3 was carried out in dioxane
at room temperature, and the selected data are summarized in Table
2. In the case of primary alkyl aldehydes, 1 mol % of (S)-3 is
sufficient to produce the corresponding â-amino aldehydes in high
yields (>92%) with virtually complete enantioselectivities (99%
ee) and excellent anti-selectivities (>11/1) (entries 1, 3, and 5).
The catalyst loading can be reduced to less than 1 mol % of (S)-3
with slightly decreased yield and stereoselectivities (entries 2 and
4). Although the reaction of a sterically hindered aldehyde required
a higher catalyst loading and proceeded in moderate yield, optimal
anti-selectivity and enantioselectivity were observed (entry 7).
Moreover, this reaction system was also applicable to other R-imino
esters (entries 8 and 9). It should be noted that self-aldol products
were not detected even in the presence of excess aldehyde (3 equiv).
The observed stereochemistry in the reaction using (S)-3 could
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rigid and distant trifluoromethanesulfonamide group (Figure 1, left).
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