First example of an organocatalytic asymmetric Mannich reaction between aldimines of glycinates and sulphonyl imines

Article abstract of DOI:10.1139/cjc-2016-0089

The catalytic enantioselective Mannich-type reaction between glycinate Schiff base and imines has been one of the most efficient routes for accessing α,β-diamino acids. However, the glycinate Schiff bases used in the references were almost ketimines. Only

Full text of DOI:10.1139/cjc-2016-0089

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First Example of Organocatalytic Asymmetric Mannich
Reaction between Aldimines of Glycinates and Sulphonyl
Imines
Lei Wu1,2, Guangxun Li2, Migu He2, Yingwei Wang1, Gang Zhao1* & Zhuo Tang2*
1 College of Chemical Engineering, Sichuan University, Chengdu, 610064, (China)
2Natural Products Research Center, Chengdu Institute of Biology Chinese Academy of Sciences Chengdu
Sichuan 610041 (China)
1Corresponding author, (E mail addresses: gzhao@scu.edu.cn )
2Corresponding author, (E mail addresses: tangzhuo@cib.ac.cn )
1

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Abstract: The catalytic enantioselective Mannichꢀtype reaction between glycinates schiff
base and imines have being one of the most efficient routes for accessing α, βꢀdiamino acids.
However, the Glycinates Schiff bases used in the references were almost ketimines. Only
several examples of aldimines were used in the presence of metal catalyst. We developed the
first example of asymmetric direct Mannich reaction using aldimines of glycinates instead of
ketimines of glycinates. The reaction was well catalyzed by chiral guanidine with high yield
(up to 92%) and moderate stereoselectivity (up to 65%).
Keywords: Organocatalyst, Aldimine, Glycinates, Sulphonyl imine, Chiral guanidine
2

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Graphical Abstract
First Example of Organocatalytic Asymmetric Mannich
Reaction between Aldimines of Glycinates and Sulphonyl
Imines
Lei Wu1,2, Guangxun Li2, Migu He2, Yingwei Wang1, Gang Zhao1* & Zhuo Tang2*
3

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Introduction
The Optically active α,βꢀdiamino acids and their derivatives[1] have attracted tremendous attention among
organic chemists and biochemists through the years because of their wideꢀranging significant bioactivity，
as well as valuable synthetic applications.[2,3] As we know, catalytic asymmetric direct Mannichꢀtype
reaction of glycinates Schiff bases was one of the most efficient routes to optically active α, βꢀdiamino
acids (Scheme 1a).[4ꢀ9] However, to our knowledge, the glycinate Schiff bases used for Mannichꢀtype
reactions were synthesized from glycinates and special ketones [10ꢀ12] (Scheme 1b). Although the ketimines
of glycinates Schiff base were efficiently applied in the literatures, [13ꢀ20] the corresponding Aldimines of
glycinates Schiff base were difficult to be used in the Mannich reactions due to the following reasons: 1)
the lower Pka of the α proton; 2) the competition of the two different types of imines as electrophiles may
cause the reaction dirty. However, aldimines of glycinates were better choice considering the convenient
transformation of the resulting products as well as atom economy, Scheme 1c. In fact,
aldimines of glycinates were precursors of azomethine ylide, widely used in the asymmetric 1,3ꢀdipolar
cycloaddition with various dipoalrophiles.[21ꢀ25]
Scheme 1
More recently, Carretero and coꢀworks have described the FesulphosꢀCuI catalysed asymmetric direct
[26]
Mannich reaction with aldimines of glycinates.
The obtained unstable Mannich products need in situ
selective reduction of imines to amino group. However, to the best of our knowledge, metal free
asymmetric direct Mannichꢀtype reaction using aldimines of glycinates have never been reported. This
might be ascribed to the unstable property of α anions of these aldimines donor compared with fluorenone
or benzophenone imines which could be stabilized by resonance involving 1, 4 πꢀelectrons of the aromatic
ketone moiety.[10ꢀ12] Herein we report the first chiral guanidine catalyzed Mannich reaction using aldimine
of glycinates.
4

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Results and discussion
As we know, in the biological system, conversion of αꢀketo acid to αꢀamino acid in the presence of
pyridoxal is a very important process.[27ꢀ29] The hydroxyl group of the aldimine is vital for the high
reactivity and enantioselectivity.[30,31] Moreover, studies show that hydroxyl group could stabilize α anions
in the presence of base (scheme 1). [32,33] Therefore, we initiated our studies with salicylic aldimine (4a) and
pꢀMethyl arylsulfonyl imine (5a) in the presence of different catalysts in toluene at room temperature,
Figure 1. As shown in (Table 1, entries 1ꢀ3), catalysts with tertiary amine, such as cinchonine, quinine or
DABCO, couldn’t catalyse this reaction smoothly. However, 1,1,3,3ꢀtetramethylguanidine (TMG) (Table 1,
entry 4) could efficiently catalyze the reaction with high yield.[34] Meanwhile, as we expected, the ordinary
aldimine could not react under the same reaction conditions, (Table 1, entry 5).
Figure 1
Table 1
Chiral guanidines have been shown to be efficient catalysts for asymmetric reaction due to the high
pKa values [35ꢀ39] and hydrogenꢀbonding activity.[40,41] Therefore, chiral guanidine (6a) was synthesized and
used as catalyst for this mannich type reaction. The result revealed that this catalyst could catalyze the
reaction with high yield and poor stereoselectivity (Table 1, entry 6). Moreover, oꢀmethyl arylsulfonyl
imine (5b) instead of pꢀmethyl arylsulfonyl imine (5a) led cleanly to a mixture of (7b) with improving
diastereoselectivity (Table 1, entry 7).
Scheme 2
Further experiment for increasing the stereoselectivity, we screened the reaction conditions such as
reaction temperature and solvent (Table S1, See supporting information). Under the optimal conditions, the
yield as well as the stereoselectivity were slightly improved (Table 2, entry 1). Then we turned our
attention to examine different salicylic aldimines. As a result, aldimines with electron donating group (4b,
4e), electron withdrawn group (4c) as well as bulkier group (4d) were investigated. We found that sterically
hindered aldimine (4d) offer higher enantioselectivity (Table 2, entry 2ꢀ5). Meanwhile, salicylic aldimine
5

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(4f) bearing diꢀhydroxyl groups were synthesised and used as substrate. However, no product was obtained
in our reaction (Table 2, entry 6).
Table 2
Next, we examined more chiral guanidines. As a result, a variety of chiral guanidines derived from
Lꢀproline, which was previously used as proper catalyst for Michael reaction of acylsilane and nitro olefin
were prepared (Scheme 2). The results suggested that catalysts containing various electronic properties on
the aromatic ring of the amide moiety appeared to have a very limited effect on the stereoselectivity (Table
3, entries 1ꢀ2). It was noteworthy that the bulkier group on the amide posed positive impact to
enantioselectivity. Catalyst (6d) with diphenylmethylamine gave slightly higher ee value and similar dr
value (Table 3, entry 3). However, the other guanidine catalyst bearing larger amide failed to afford good
results (Table 3, entries 4ꢀ5). We also tried to promote the catalytic result through introducing more
hydrogen bond donors into chiral guanidine catalyst (6h). Unfortunately, the desired result was not found
(Table 3, entry 6).
Table 3
Next, we examined different sulfonyl imine and iminoester in the presence of 6d under optimized
condition. Fortunately, sterically hindered Nꢀ(8ꢀquinolyl)sulfonyl aldimines 5d afford higher
enanotioselectivity (Table 4, entry 2). Meanwhile, ethyl esters moiety was suitable for higher
enantioselectivity under identical conditions (Table 4, entries 2ꢀ4).
Table 4
After that, we examined the catalysts again with 4d and 5d as substrate. The results were summarized in
Table 5. It was interesting that guanidine 6g with bulky 2, 6ꢀdiisopropyl substituent achieved the best
enantioselectivity (Table 5, entry 4).
Table 5
Finally, various sulfonyl imines were used to afford the corresponding products 7 with high yield (87%)
and moderate enantioselectivity (Table 6). Moreover, substituents on the phenyl ring of the imine,
6

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including electronꢀwithdrawing (Table 6, entry 3), electronꢀdonating (Table 6, entry 2), neutral (Table 7,
entry 1, 4) or imine with condensedꢀring (Table 6, entry 6) and hetero aromatic (Table 6, entry 5) furnished
the desired products maintaining high yield and moderate stereoselectivity. The absolute configuration of 7
was determined by comparing NMR and chiral HPLC spectra of the derivative of 7 with literature, (see
supporting information).[ 20]
Table 6
In summary, we have developed an organocatalytic asymmetric Mannichꢀtype reaction of aldimines of
glycine esters by screening a number of organocatalyst and substrate, thus creating the first example of
organocatalytic Mannich reaction of aldimines of glycine esters with sulphonyl imine with excellent yields
and middle stereoselectivity. Further investigations to understand the exact role of the salicylic aldimine are
underway.
Experimental
All reactions that required anhydrous conditions were carried by standard procedures under nitrogen
atmosphere. Commercially available reagents from Alfa Aesar and Aldrich were used as received. The
1
solvents were dried by distillation over the appropriate drying reagents. H NMR spectra were
recorded on commercial instruments (400 MHz). Chemical shifts were reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard (CDCl3, δ = 7.26). Spectra were
reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t =triplet, q = quartet,
m = multiplet), coupling constants (Hz), integration and assignment. 13C NMR spectra were collected
on commercial instruments (101 MHz) with complete proton decoupling. Chemical shifts are reported
in ppm from the tetramethylsilane with the solvent resonance as internal standard (CDCl3, δ = 77.0).
Mass spectra were recorded on ThermoQuest Finnigan LCQDECA system equipped with an ESI source.
Typical procedural for preparation of 7
To a 10 mL tube with a magnetic stirring bar were sequentially added the aldimines of glycine imine
schiff base 4 (0.06 mmol, 1.0 equiv), sulfonyl imine 5 ( 0.066 mmol , 1.1 equiv), 40 mg 4A molecular
sieve and 15 mol% of catalyst 6g in 1.5 mL ice EA under dry nitrogen at 0°C for 12 h.. When the
7

Page 8 of 19
reaction completed (monitored by TLC), the obtained mixture was purified directly by flash
chromatography on silica gel to afford 7 for HꢀNMR (confirmed the dr). The ee of the major isomer
was determined by chiral HPLC analysis. (Note: The dr of some 7 was determined by HPLC
analysis.), characterizations and analysis of product could be found in the supporting information.
Acknowledgements
This work was supported by the National Sciences Foundation of China (Grant No. 21402188).
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10

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Scheme 1 strategy used for the preparation of α, βꢀdiamino acid
a) strategy used for the preparation of
-diamino acid
R3
*
R3
*
NH2
*
R2
N
R1
R2
*
R1
N
CO Et
+
2
H2N
N
N
R3
H
CO2Et
CO2Et
b)
Ketoimines used in the literature
N
CO2R
N
O
CO2R
N
P(OR)2
1
2
3
Aldimine used in this work
c)
N
CO2R
Ar
N
CO2R
Base
Ar
OH
H
4
O

Page 12 of 19
Scheme 2 Chiral guanidines used in this study.

Page 13 of 19
Figure 1 Substrates and products structures

Page 14 of 19
Table 1 Initial screening of Mannich reaction[a].
Entry
Substrate
Cat.
Yield[%][b]
Anti/syn[c]
ee[%][d]
4a,5a
1
2
3
4
5
6
7
DABCO
Quinine
Cinchonine
TMG
7a: 30
7a: 24
7a: 17
7a: 91
n.d
-
-
4a,5a
13:1
11:1
-
15/4
26/6
-
4a,5a
4a,5a
4a’,5b
4a,5a
TMG
-
-
6a
7a: 85
7b: 84
1.2:1
1.8:1
3/0
5/7
4a,5b
6a
[a] Unless otherwise noted, the reaction was carried out with 0.06 mmol 1a or 4a, 0.066 mmol 5a or 5b，
Molecular sieves 4 Å (40 mg) and 20 mol% catalyst in toluene (1.0 mL) at 25 ℃ for 20 h. [b] Yield of
isolated product. [c] Determined by chiral HPLC. [d] Corresponding ee of anti/syn.

Page 15 of 19
Table 2 Catalytic Mannich-type reactions of 5b[a]
[a]
Unles
s
Entry
Substrate
4a,5b
4b,5b
4c,5b
Cat.
Yield[%][b]
Anti/syn[c]
ee[%][d]
1
2
3
4
5
6
6a
6a
6a
6a
6a
6a
7a: 87
7c: 90
7d: 78
7e: 87
n.d
1.7:1
5.5:1
5:1
11/5
7/2
other
wise
noted,
the
8/0
4d,5b
4e,5b
2.6:1
16/4
reacti
on
4f,5b
n.d
was
carried out with 0.06 mmol 4, 0.066 mmol 5b，molecular sieves 4 Å (40 mg) and 15 mol% catalyst in EA (1.0
mL) at 0℃ for 20 h. [b] Yield of isolated product. [c] Determined by chiral HPLC. [d] Corresponding ee of
anti/syn.

Page 16 of 19
Table 3 Catalytic Mannich-type template reactions [a]
Entry
Substrate
4d,5b
4d,5b
4d,5b
4d,5b
4d,5b
4d,5b
Cat.
Yield[%][b]
Anti/syn[c]
ee[%][d]
1
2
3
4
5
6
6b
6c
6d
6e
6f
7e: 82
7e: 50
7e: 79
7e: 76
7e: 76
7e: 81
1.8:1
1.3:1
1.2:1
5:1
10/12
14/16
22/14
0/0
2.6:1
2.8:1
16/10
13/17
6h
[a] Unless otherwise noted, the reaction was carried out with 0.06 mmol 4d, 0.066 mmol 5b，molecular
sieves 4 Å (40 mg) and 15 mol% catalyst in EA (1.0 mL) at 0℃ for 20 h. [b] Yield of isolated product. [c]
Determined by chiral HPLC. [d] Corresponding ee of anti/syn.

Page 17 of 19
Table 4 Influence of imine protecting group and imine ester[a]
Entry
Substrate
4d,5c
Cat.
6d
Yield[%][b]
Anti/syn[c]
ee[%][d]
14/20
51/47
46/44
42/26
1
2
3
4
7f: 90
2:1
4d,5d
4g,5d
6d
7g: 78
1.6:1
6d
7h: 87
1.5:1
4h,5b
6d
7i: 76
1.5:1
[a] Unless otherwise noted, the reaction was carried out with 0.06 mmol 4, 0.066 mmol 5，molecular sieves
4 Å (40 mg) and 15 mol% 6d in EA (1.0 mL) at 0 ℃ for 20 h. [b] Yield of isolated product. [c] Determined
by chiral HPLC. [d] Corresponding ee of anti/syn.

Page 18 of 19
Table 5 Optimization of the reaction catalyst [a]
Entry
Substrate
4d,5d
4d,5d
4d,5d
4d,5d
4d,5d
4d,5d
4d,5d
4d,5d
Cat.
6b
6d
6e
6g
6i
Yield[%][b]
7g: 92
7g: 84
7g: 82
7g: 88
7g: 50
7g: 52
7g: 45
7g: 71
Anti/syn[c]
1.8:1
1.7:1
1.2:1
1.8:1
1.9:1
1.1:1
1.3:1
3:1
ee[%][d]
44/28
51/47
37/46
54/47
9/0
1
2
3
4
5
6
7
8
6j
-6/4
6k
6l
5/2
10/0
[a] Unless otherwise noted, the reaction was carried out with 0.06 mmol 4d, 0.066 mmol 5d，molecular
sieves 4 Å (40 mg) and 15 mol% catalyst in EA (1.0 mL) at 25 ℃ for 20 h. [b] Yield of isolated product. [c]
Determined by chiral HPLC. [d] Corresponding ee of anti/syn.

Page 19 of 19
Table 6 Generality of the reaction with various sulfonyl imines[a]
Entry
Substrate
4d,5e
4d,5f
Cat.
6d
6d
6d
6d
6d
6d
Yield[%][b]
7j: 88
Anti/syn[c]
1.8:1
ee[%][d]
55/39
55/44
46/47
65/60
61/24
58/44
1
2
3
4
5
6
7k: 83
7l: 91
1.9:1
4d,5g
4d,5h
4d,5i
1.7:1
7m: 87
7n: 90
7o: 82
2.1:1
1.7:1
4d,5j
2.0:1
[a] Unless otherwise noted, the reaction was carried out with 0.06 mmol 4d, 0.066 mmol 5，molecular sieves 4 Å (40
mg) and 15 mol% 6d in EA (1.0 mL) at 0℃ for 20 h. [b] Yield of isolated product. [c] Determined by chiral HPLC. [d]
Corresponding ee of anti/syn.
1