Design and synthesis of a s-triazene based asymmetric organocatalyst and its application in enantioselective alkylation

Article abstract of DOI:10.1039/c5ra11209e

A very efficient chiral organocatalyst was prepared from the readily available cyanuric chloride. The asymmetric catalyst exhibited a highly enantioselective catalytic performance for the alkylation of a glycinate Schiff base, which provides a useful procedure for the enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids.

Full text of DOI:10.1039/c5ra11209e

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Cite this: DOI: 10.1039/x0xx00000x
Design and Synthesis of s-Triazene based Asymmetric
Organocatalysis and its Application in
Enantioselective Alkylation
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
Shrawan K. Mangawa, Ashawani K. Singh and Satish K. Awasthi*
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scientists because of easy accessibility from sufficiently available chiral
starting materials. Literature survey reveals that guanidines and
amidines as asymmetric organocatalysts have shown several synthetic
applications in organic synthesis.12ꢀ14 Indeed, guanidine group
containing molecules more often form stabilized complex salts via
parallel interactions including hydrogen bonding with anionic
compounds.15
A very efficient chiral organocatalyst was prepared from
the easily available cyanuric chloride. The asymmetric
catalyst exhibited the high enantioselective catalytic
performance in the alkylation of glycinate Schiff base,
which allows useful procedure for enantioselective synthesis
of structurally diverse natural and unnatural
amino acids.
α-alkyl-α-
Our research group is highly active within the field of catalyticꢀorganicꢀ
transformations and designing
systems for the synthesis of biologically active molecules.16 We
diversified our idea by targeting the use of ꢀtriazene as starting
materials for the synthesis of a new class of quaternary ammonium
salts. It is well documented that ꢀtriazene show excellent catalytic
sꢀtriazene based effective catalytic
s
The development of enantioselective CꢀC bond formation is a topic of
great interest in organic synthesis.1 Recent advances highlights the
benefits/significance of environmental friendly and efficient catalyst for
such enantioselective transformations. Among others, phase transfer
catalysts (PTCs) are known to play a pivotal role in enantioselective
modifications in organic synthesis. Within PTCs, usage of several
nitrogen and phosphorous containing quaternary centres is much
frequent as chiral PTCs.2 Such chiral PTCs have broad spectrum of
applications owing to their diverse catalytically active structural motifs
and high catalytic potential.3 It is well acknowledged that chiral PTCs
are nonꢀmetal containing environmental friendly organocatalysts.4
Additionally, chiral PTCs have many advantages over homogenous
reactions, due to their high catalytic potential and broad spectrum of
applications.5 Use of Cinchona alkaloid salts have been reported as
catalysts under biphasic conditions initially for the enantioselective
alkylation of glycinate Schiff base by O’Donell et al. in 1989.6
s
property for organic transformation reactions such as CꢀC and CꢀN
bond formations.17 Literature survey revealed that the nature of the
guanidine and thiourea containing groups of the catalyst have a strong
influence on the catalytic performance for the alkylation of αꢀamino
acids.18 In view of various studies, we designed three different chiral
PTCs based on sꢀtriazine for alkylation of prochiral substrate 3 to
produce optically active αꢀamino acids in good yields. The overall
synthesis of three different chiral PTCs are mentioned in scheme 1. In
the first step, chloro group of sꢀtriazene was substituted by chiral amine
(s)ꢀphenylethylamine to give compound 1, containing guanidine type
moiety. Then compound 1 was reacted with propargyl bromide to
produce compound 2, which on further reaction with benzyl bromide in
toluene yielded chiral quaternary ammonium salt sT1. After successful
synthesis of chiral PTC sT1, we further investigated the chemistry and
designed two new catalyst based on pyrrolidine and piperidine
containing quaternary salts sT2 and sT3 shown in scheme 1. For the
synthesis of chiral quaternary salts sT2 and sT3, compound 1 was
reacted with 1,5ꢀdibromopentane and 1,4ꢀdibromobutane, respectively.
Subsequently,
o
ꢀalkylation of the Cinchona alkaloids resulted high
enantiomeric excess.7 Later,
a
chiral C2ꢀsymmetric quaternary
ammonium salts, a new PTC class was introduced by Maruoka et al. in
1999 with a binaphthyl structure for alkylation of glycinate derivative.8
Shortly, the Maruoka catalysts were found to be very efficient for
variety of asymmetric transformations even at very low catalyst
loadings (<1 mol%). In addition, Shibasaki’s tartaric acidꢀderived
bidentate PTCs,9 Lygo’s spirocyclic catalysts10 and guanidine type
catalysts11 were found to be highly efficient in asymmetric synthesis.
The novel chiral quaternary catalysts have drawn attention of many
1
The structures of the chiral quaternary salts were confirmed by H, 13C
NMR and mass spectrometry (see the supporting information).
Herein, we show the enantioselective alkylation of glycinate Schiff base
using newly developed chiral catalysts sT1, sT2 and sT3 to produce
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optically active αꢀamino acids, which are frequently used in peptide and
peptidomimetics synthesis.
Table 1. Screening of chiral catalysts for enantioselectivity
Entry
Temp
(°C)
50%
Basea in
water
Catalyst
Mol % of
Catalyst
Yieldb
(%)
eec
(%)
(w/v)
1
2
3
4
5
6
7
8
9
10
11
12
13
rt
rt
rt
10
10
10
0
0
0
ꢀ10
ꢀ10
-10
ꢀ10
0.5 ml
sT1
sT1
sT1
sT1
sT1
sT1
sT1
sT1
sT1
sT1
sT1
sT1
sT1
2
5
10
2
5
10
2
5
10
2
5
10
10
74
76
76
72
68
58
74
60
85
53
58
90
40
22
28
46
48
52
60
48
60
70
72
76
82
50
,,
,,
,,
,,
,,
,,
,,
,,
,,
,,
,,
0.24 gm
pallates
,,
14
15
16
17
18
19
20
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
sT2
sT2
sT2
sT3
sT3
sT3
ꢀꢀꢀꢀꢀꢀ
2
5
10
2
5
10
ꢀꢀꢀꢀꢀꢀ
59
70
65
58
68
68
52
26
38
39
28
50
,,
,,
,,
,,
,,
,,
Scheme 1. Synthesis of chiral PTCs sT1, sT2 and sT3.
Based on this, we began with the synthesis of prochiral substrate
benzophenone imine glycinate 3
for the asymmetric alkylation study.19
38
race
To optimize the enantioselective potential of synthesized quaternary
salts in the asymmetric alkylations, we performed alkylation with
a
50% KOH aqueous solution ( 5 gm dissolved in water and make up 10 ml
KOH solution) bExperimental yield, cDetermined by HPLC using
CHIRALCEL ODꢀH column. eRacemic Mixture chromatogram shown in
supporting information S26
excess of benzyl bromide as shown in scheme 2. All reactions were
carried out under biphasic conditions to get maximum yield and high
enantioselectivity, using different mol % of catalyst and varying
temperature ranges for the scope of CꢀC bond forming practice.
Then, we investigated the affect of other two chiral ammonium
quaternary salts sT2 and sT3 (Table 1, Entries 14-19) under the
It is observed that at room temperature with 2 mol % catalyst loading,
the alkylated product showed lower enantioselectivity (Table 1, Entry
similar reaction conditions. It is noticed that piperidine and pyrrolidine
derived catalysts sT2 and sT3 using 10 mol % at ꢀ10 °C gave a reduced
1
). Subsequently, increase of catalyst loading from 2 mol % to 5 and 10
mol catalyst at room temperature resulted in increase in
enantioselectivity (Table 1, Entries 2, 3). Further, lowering of
temperature from room temperature to ꢀ10 increased the
enantiomeric excess (ee) in comparison to
Nꢀalkyne and
Nꢀbenzyl
%
derived catalyst sT1. It is obvious from the analysis of table
1
that the
chiral ammonium salt sT1 was found most promising PTC among all.
°
C
In conclusion, the reaction performed with an excess of electrophile in
enantioselectivities of the compounds as shown in Table 1. The
alkylated product showed better enantioselectivity at 10 mol % of
catalyst loading (Table 1, Entries 3, 6, 9, 12). The reaction was also
performed in liquidꢀsolid state (Table 1, Entry 13) and showed poor
enantioselectivity, therefore remaining two catalyst sT2 & sT3 were not
evaluted in liquidꢀsolid phase.
the presence of 10 mol % of sT1 at ꢀ10
condition for asymmetric alkylation of glycinate Schiff base (Table 1
Entry 12). This optimized reaction condition were used (Table 1,
Entry 12) for the alkylation of glycinate Schiff base with different
electrophiles and hydrolyzed alkylated product 4 to get corresponding
products (5-14) in better enantioselectivity given in table
°C was found to be the suitable
,
3
2.
Scheme 2. Optimization of catalysts.
2 | J. Name., 2012, 00, 1-3
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Table 2. Scope of the αꢀalkylation of benzophenone glycinate Schiff base
using different electrophiles
Conclusions
In conclusion, we designed and synthesized new efficient sꢀtriazene
based Nꢀquaternary ammonium salts sT1, sT2 and sT3 as phase transfer
catalysts (PTCs) and used efficiently to alkylate glycinate Schiff base to
produce natural and unnatural αꢀamino acids. The asymmetric catalytic
potential of these compounds in the asymmetric αꢀalkylation of
glycinate Schiff base depends on their substituent’s and reaction
conditions. Under optimized conditions, the αꢀalkylated products could
be obtained in excellent yields and up to 95% ee. More enantioselective
applications of catalysts are under progress.
Entry
1
Electrophile
(RBr)
Product Time (h) Yieldb (%) eec (%)
5
3.5
75
95
2
3
6
7
3.5
4.5
85
90
89
82
4
8
6.0
67
81
Acknowledgement
5
6
9
4.5
5.5
55
85
75
85
SKM and AKS are thankful to CSIR, India for providing fellowship.
SKA acknowledges the University of Delhi for financial support.
Authors are thankful to Dr. Nisha Saxena for manuscript preparations.
10
7
8
9
11
12
13
5.5
4.5
4.5
80
76
90
77
68
83
Notes and references
aChemical Biology Laboratory, Department of Chemistry, University of
Delhi, India.
Emailꢀ satishpna@gmail.com; skawasthi@chemistry.du.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
10
14
4.5
85
90
1
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(glycinate Schiff base). ꢀTriazene form guanidine type moiety with
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