Highly diastereo- and enantioselective Mannich reactions of synthetically flexible ketimines with secondary amine organocatalysts

Article abstract of DOI:10.1002/anie.201107375

High selectivity: A highly diastereo- and enantioselective Mannich reaction between a synthetically flexible ketimine and aldehydes has been developed. The syn- or anti-Mannich products contain tetrasubstituted chiral carbon centers and were obtained with almost complete stereoselectivity by using either L-proline or an axially chiral aminosulfonamide, respectively, as the catalyst (see scheme, Tf=trifluoromethanesulfonyl). Copyright

Full text of DOI:10.1002/anie.201107375

Angewandte
Chemie
DOI: 10.1002/anie.201107375
Organocatalysis
Highly Diastereo- and Enantioselective Mannich Reactions of
Synthetically Flexible Ketimines with Secondary Amine
Organocatalysts**
Taichi Kano, Sunhwa Song, Yasushi Kubota, and Keiji Maruoka*
Asymmetric Mannich reactions provide a powerful method
for synthesizing optically active b-aminocarbonyl units, which
are useful chiral building blocks for a number of biologically
active and pharmaceutically important compounds.[1] Among
these reactions, catalytic asymmetric Mannich reactions of
ketimines that afford tetrasubstituted chiral carbon centers
are rare,[2,3] and, with few exceptions, only aromatic ketimines
are used as acceptors.[2c–e] The use of non-aromatic ket-
imines[4] has distinct advantages in terms of broadening the
range of substrates that can be used and their high synthetic
utility for asymmetric Mannich reactions. As the catalytic
asymmetric synthesis of tetrasubstituted carbon atoms
remains a significant challenge in organic synthesis[5] and
examples of asymmetric Mannich reactions with non-aro-
matic ketimines are scarce, we are interested in the develop-
ment of organocatalytic Mannich reactions between non-
aromatic ketimines and aldehydes.[6] To overcome the low
reactivity of ketimines, we chose ketimine 1 (Scheme 1),[7]
enantioselective Mannich reaction of 1 with aldehydes
catalyzed by either proline or an axially chiral aminosulfon-
amide of type (S)-3 (Scheme 2).
Scheme 2. Structures of catalysts (S)-2 and (S)-3. Tf=trifluorometha-
nesulfonyl.
We examined the reaction between 3-phenylpropanal and
1 in the presence of 20 mol% of l-proline in various solvents
at room temperature (Table 1). Although the desired Man-
nich product 4 was formed in moderate to good yield in all of
the solvents that were tested (Table 1, entries 1–5), only a
trace amount of 4 was isolated after chromatography on a
silica gel column as a result of the low stability of 4. Therefore,
4 was treated with NaBH4 in situ and converted into the
corresponding g-lactone 5. Among the solvents examined,
Scheme 1. Synthesis of ketimine 1. MS=molecular sieves.
Table 1: syn-Selective Mannich reactions between ketimine 1 and 3-
phenylpropanal catalyzed by l-proline.[a]
which is sterically less congested and strongly activated by
two different ester groups, as an ideal electrophile. Ketimine 1
is readily prepared from commercially available 2-amino-
phenol and diethyl ketomalonate. As 1 is substituted with
versatile ester functional groups and a removable N-protect-
ing group, the Mannich reaction with this ketimine would be
synthetically useful. Herein, we report a highly diastereo- and
Entry Solvent Temp [8C] Time [h] Yield [%][b] syn/anti[c] ee [%][d]
1
THF
RT
1
1
1
1
1
6
5
53 (31)
83 (53)
83 (56)
70 (51)
83 (63)
87 (64)
90 (72)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
99
99
99
99
98
99
99
2
3
toluene RT
CH2Cl2 RT
[*] Dr. T. Kano, S. Song, Prof. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
4
DMF
RT
5
MeCN RT
6
MeCN
MeCN
0
0
7[e]
Dr. Y. Kubota
Nippon Soda Co., Ltd.
345, Takada, Odawara, Kanagawa 250-0280 (Japan)
[a] The reaction of 1 (0.1 mmol) with 3-phenylpropanal (0.5 mmol) was
performed in the presence of l-proline (0.02 mmol) in a solvent (50 mL).
[b] Determined by 1H NMR spectroscopy by using an internal standard
technique. The numbers in parentheses are isolated yield of 5.
[**] This work was supported by a Grant-in-Aid for Scientific Research
from MEXT (Japan).
1
[c] Determined by H NMR spectroscopy. [d] The ee value of syn-5 was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107375.
determined by HPLC on a chiral stationary phase. [e] Benzoic acid
(0.01 mmol) was used as an additive. Bn=benzyl.
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Table 3: Mannich reactions between ketimine 1 and various aldehydes
catalyzed by l-proline or (S)-3.[a]
acetonitrile was found to be the best in terms of yield (Table 1,
entry 5). When the reaction was performed in acetonitrile at
08C in the presence of benzoic acid as co-catalyst, g-lactone 5
was obtained in good yield with virtually complete syn
selectivity and enantioselectivity (Table 1, entry 7).
We have previously developed the axially chiral amino-
sulfonamide catalyst (S)-2 (Scheme 2).[8] The direct asym-
metric Mannich reaction of aldimines catalyzed by (S)-2 give
mainly anti products,[9] whereas proline and the related
catalysts have the opposite syn selectivity.[1i] We anticipated
that the development of an anti-selective Mannich reaction
with the sterically more hindered ketimine would be more
difficult because of the moderate nucleophilicity of (S)-2.
Fortunately, (S)-2 promotes the reaction of 1 with 3-phenyl-
propanal in THF at room temperature to give optically pure
anti-5 exclusively, albeit in low yield (Table 2, entry 1). At
Entry
R
Conditions[a]
Yield [%][b]
syn/anti[c]
ee [%][d]
1[e]
2[e]
3
4
5
6
7
8
9
Et
Bu
Hex
Bn
CH2Cy
Et
Bu
Hex
Bn
A
A
A
A
A
B
B
B
B
B
62
72
62
72
71
60
60
79
59
60
>20:1
>20:1
>20:1
>20:1
>20:1
1:>20
1:>20
1:>20
1:>20
1: >20
99
99
99
99
99
99
99
99
99
99
10
CH2Cy
Table 2: anti-Selective Mannich reactions between ketimine 1 and 3-
phenylpropanal catalyzed by (S)-2 or (S)-3.[a]
[a] Conditions A: The reaction of the aldehyde (0.5 mmol) with 1
(0.1 mmol) was performed in the presence of l-proline (0.02 mmol) and
benzoic acid (0.01 mmol) in MeCN (50 mL) for 5 h at 08C; Conditions B:
The reaction of the aldehyde (0.3 mmol) with 1 (0.1 mmol) was
performed in the presence of (S)-3 (0.005 mmol) in DMAc (50 mL) for 5 h
1
at 458C. [b] Yield of isolated product. [c] Determined by H NMR
spectroscopy. [d] The ee value of the major isomer was determined by
HPLC on a chiral stationary phase. [e] The reaction was performed for
12 h.
Entry Solvent Temp [8C] Time [h] Yield [%][b] syn/anti[c] ee [%][d]
1[e]
2[e]
3
4
5
6
7
8
THF
THF
THF
toluene 45
MeCN 45
DMF
DMAc 45
DMAc 45
RT
45
45
4
4
4
4
4
4
4
12
25 (22)
35 (32)
40 (34)
27 (27)
42 (36)
47 (39)
55 (51)
70 (59)
1:>20
1:>20
1:>20
1:>20
1:>20
1:>20
1:>20
1:>20
99
99
99
99
95
99
99
99
Analysis of the structure of syn-6 by X-ray crystallography
provided clear proof that the Mannich reactions of 1
catalyzed by l-proline gave syn-g-lactones with 3S,4S config-
uration (Scheme 3). On the other hand, the absolute config-
uration of anti-6, which was obtained in the reaction catalyzed
by (S)-3, was determined to be 3S,4R by treating anti-6 with
NaOEt to convert it into syn-6, and by comparison of the
HPLC retention times.
45
[a] Unless otherwise noted, the reaction of 1 (0.1 mmol) with 3-
phenylpropanal (0.3 mmol) was performed in the presence of (S)-3
(0.005 mmol) in a solvent (50 mL). [b] Determined by 1H NMR spec-
troscopy by using an internal standard technique. The numbers in
parentheses are yield of isolated 5. [c] Determined by 1H NMR
spectroscopy. [d] The ee value of anti-5 was determined by HPLC on a
chiral stationary phase. [e] (S)-2 (0.005 mmol) was used instead of (S)-3.
Bn=benzyl.
Based on the stereochemistry of the products, the
transition-state models shown in Scheme 4 account for the
458C, the yield of the reaction improved without the loss of
stereoselectivity (Table 2, entry 2). The reaction with the
more nucleophilic (S)-3 gave
a better yield (Table 2,
entry 3),[10,11] and the best solvent for the reaction was
dimethylacetamide (DMAc, Table 2, entry 7). A longer
reaction time resulted in a slight increase in the yield of the
reaction (Table 2, entry 8).
The diastereo- and enantioselective direct Mannich
reaction of 1 with several other donor aldehydes was
examined under the optimal reaction conditions (Table 3).
All of the reactions with sterically less congested aldehydes
proceeded to give either syn- or anti-g-lactones with almost
perfect diastereo- and enantioselectivity, respectively. How-
ever, the reactions with bulky aldehydes, such as 3-methyl-
butanal, gave only a trace amount of the desired products.
Scheme 3. Synthesis of syn-6 (top) and the X-ray crystal structure of
syn-6 with ellipsoids set at 50% probability (bottom). Ar=4-Br-C6H4.
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Scheme 7. Deprotection of syn-5. Bn=benzyl.
Scheme 4. Transition-state models for the asymmetric Mannich reac-
tion catalyzed by l-proline (left) and (S)-3 (right). Tf=trifluorometha-
nesulfonyl.
rare example of a Mannich reaction of a non-aromatic
ketimine. Further application of the present Mannich reaction
and Mannich reactions with other ketimines are under
investigation.
selectivity of the reaction. In the case of the reaction catalyzed
by l-proline, the Re face of 1 approaches the Re face of the
dominant s-trans-enamine (TS1, Scheme 4). Whereas both
the s-trans-enamine and the s-cis-enamine may be formed in
the reaction catalyzed by (S)-3, only the s-cis-enamine can
react with activated 1, which gives the 3S,4R isomer predom-
inantly (TS2, Scheme 4).
The Mannich product 4 and g-lactones 5 are versatile
intermediates in organic synthesis and can be readily con-
verted into important chiral building blocks. For example,
treatment of syn-4 with benzylamine in situ and subsequent
reduction with Et3SiH in the presence of BF3·OEt2 gave g-
lactam syn-7 without the loss of optical purity (Scheme 5).[12]
g-Lactone syn-5 was converted into the corresponding amide
Received: October 19, 2011
Revised: November 21, 2011
Published online: December 15, 2011
Keywords: aldehydes · asymmetric catalysis · ketimines ·
.
Mannich reaction · organocatalysis
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