Asymmetric Hydrolytic and Aminolytic Kinetic Resolution of Racemic Epoxides using Recyclable Macrocyclic Chiral Cobalt(III) Salen Complexes

Article abstract of DOI:10.1002/adsc.201700788

New chiral macrocyclic cobalt(III) salen complexes were synthesized and used as catalyst for the asymmetric kinetic resolution (AKR) of terminal epoxides and glycidyl ethers with aromatic/aliphatic amines and water as nucleophiles. This is the first occasion where a Co(III) salen complex demonstrated its ability to catalyze AKR as well as hydrolytic kinetic resolution (HKR) reactions. Excellent enantiomeric excesses of the epoxides, the corresponding amino alcohols and diols (upto 99%) with quantitative yields were achieved by using the chiral Co(III) salen complexes in dichloromethane at room temperature. This protocol was further extended for the synthesis of two important drug molecules, i.e., (S)-propranolol and (R)-naftopidil. The catalytic system was also explored for the synthesis of chirally pure diols and chiral cyclic carbonates using carbon dioxide as a greener renewable C₁ source. The catalyst was recycled for upto 5 catalytic cycles with retention of enantioselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201700788

Title: Asymmetric Hydrolytic and Aminolytic Kinetic Resolution of
Racemic Epoxides using Recyclable Macrocyclic Chiral Cobalt
(III) Salen Complexes
Authors: Rajkumar Tak, manish kumar, Tusharkumar Menapara,
Naveen Gupta, Rukhsana Kureshy, Noor-ul H. Khan, and
Eingathodi Suresh
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700788
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric Hydrolytic and Aminolytic Kinetic Resolution of
Racemic Epoxides using Recyclable Macrocyclic Chiral Cobalt
(III) Salen Complexes
Rajkumar Tak,a,b Manish Kumar,a Tusharkumar Menapara,a,b Naveen Gupta,a,b
Rukhsana I. Kureshy,a,b* Noor-ul H. Khan,a,b and E. Sureshb,c
aInorganic Materials and Catalysis Division, CSIR-Central Salt and Marine Chemicals Research Institute, G. B. Marg,
Bhavnagar 364002, Gujarat, India. E-mail: rukhsana93@yahoo.co.in
bAcademy of Scientific and Innovative Research, CSIR-Central Salt and Marine Chemicals Research Institute, Council of
Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar 364002, Gujarat, India.
cAnalytical Division and Centralized Instrument Facility, CSIR-Central Salt and Marine Chemicals Research Institute, G.
B. Marg, Bhavnagar-364002, Gujarat, India.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. New chiral macrocyclic Co(III) salen complexes This protocol was further extended for the synthesis of two
were synthesized and used as catalyst for asymmetric kinetic important drug molecules i.e., (S)-Propranolol and (R)-
resolution of terminal epoxides and glycidyl ethers with Naftopidil. The catalytic system was also explored for the
aromatic/aliphatic amines and water as nucleophiles. This is synthesis of chirally pure diol and chiral cyclic carbonate
the first occasion where a Co(III)-salen complex demonstrated using carbon dioxide as a greener renewable C1 source. The
its ability to catalyze AKR as well as HKR reactions. catalyst was recycled upto 5 catalytic cycles with retention of
Excellent enantiomeric excess of epoxides, corresponding enantioselectivity.
amino alcohols and diols (upto 99%) with quantitative yield
were achieved by using the chiral Co(III) salen complexes in
DCM at room temperature.
Keywords: Asymmetric synthesis; Cobalt; Kinetic
resolution; macrocyclic ligand; ring opening
Introduction
ligands) were required to catalyze hydrolytic kinetic
[4d,8-14]
resolution (HKR)
resolution (AKR)
and aminolytic kinetic
[15]
“High atom economy is one of the prime aspect of
green chemistry to be followed by synthetic
chemists.”[1] Asymmetric kinetic resolution of
racemic epoxides is an excellent example in this
category where two synthetically important products
can be produced in one go with 100% atom
efficiency.[2,3] The demands of chiral epoxides,[4]
amino alcohols,[5] diols[6] and cyclic carbonates[7]
have steadily increased over the years because of
their widespread consumption in pharmaceuticals,
agrochemicals and fine chemicals. With this
backdrop kinetic resolution of inexpensive and
readily available racemic epoxides with water and
amines to produce valuable diols and β-amino
alcohols respectively in their high enatio-purity
alongwith unreacted enantiomer of respective
epoxides is important. Ever since the landmark
findings of the kinetic resolution of epoxides by
Jacobsen et al.[4d,8] many groups have contributed in
this area of research.[9-14] But in most cases different
metal ions (may be with the same chiral salen
by using water or an amine as
nucleophiles respectively. Here, we are pleased to
report that our newly designed and synthesized
catalytic systems involving new chiral Co(III) salen
complexes of macrocyclic ligands 1a-8a work very
efficiently for AKR as well as HKR of a wide range
of inexpensive racemic epoxides like aryl epoxides,
terminal epoxides and functionalized epoxides. This
was in a way outcome of our continuous efforts
towards the asymmetric ring opening reactions.[16] As
a result we have achieved excellent enantioselectivity
of unreacted epoxides, β-amino alcohols and diols
(upto 99% ee) with high yields. Further, the chirally
pure epoxide i.e., naphthyl glycidyl ether 17a
obtained from the HKR or AKR reaction was used as
an intermediate for the synthesis of pharmaceutically
important drug (S)-Propranolol[17]- a β-adrenergic
blocking agent and (R)-Naftopidil[18] - a α1-
adrenoreceptor antagonist. Similarly, the enantiopure
diols, obtained from the HKR reaction were
1
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
converted to their corresponding chiral cyclic
(CO2) as a C1 source.[19] This protocol was carried out
at one gram scale for the synthesis of the above
described important molecules. The desired
configuration (R or S) of the chiral products i.e.,
unreacted epoxides, diols and β-amino alcohols can
carbonates by utilizing the carbon dioxide
be produced by just altering the configuration of the
catalyst. The chiral Co(III) salen complexes have an
added advantage of stability and recyclability.
Moreover, we have reused our catalyst several times
with the retention of enantioselectivity.
Scheme 1. Synthetic route for the macrocyclic Co(III) salen complexes 1-9. Conditions: a) 2,6-lutidine, SnCl4,
o
paraformaldehyde, dry toluene, reflux 8 h (yield: 93%); b) HCl, trioxane, 45-50 C, 48 h (yield: 90%); c) NaH, dry THF,
(R)/(S) Binol, 4-6 h, (yield: 92-95%); d) (1R,2R)/(1S,2S)-1,2 diphenylethylene diamine (yield: 84-88%) ; e)
(1R,2R)/(1S,2S)-1,2 cyclohexane diamine, (yield: 85-87%) dry methanol, 4-5 h; f) toluene, methanol, Co(OAc)2·4H2O,
(PNBA) (yield: 83-88%); g) NaH, dry THF, 1,3-dimethanol benzene, 5 h (yield: 90%).
2
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
To the best of our knowledge, the AKR reaction of
aryloxy epoxides with anilines by using chiral Co(III)
salen complexes to get the valuable chiral amino
alcohols and enantioenriched epoxides in a single
step is reported for the first time. In view of the fact
that the counter ion, mol% of catalyst, solvent and
reaction temperature are the most crucial parameters
of any asymmetric transformation, we have closely
monitored and optimized the reaction conditions for
the present protocol of kinetic resolution of the
racemic epoxides. By keeping these facts in mind and
based on our past knowledge and experience,[5e,f,15d]
here we chose catalyst 1 (1 mol%) with varoius
counter ion for the AKR of racemic phenyl glycidyl
ether 10 as a model substrate and aniline A as
representative nucleophile at room temperature (RT)
and the data are compiled in [Table 1, entries 1-4].
Among all the four tested counter ion, p-nitrobenzoic
acid (PNBA) has shown promising results in terms of
product yield and enantioselectivity for both the
products [Table 1, entries 4]. Our next target was to
optimize the amount of the catalyst used varied over
mol ratio from 1 mol% to 10 mol% [Table 1, entries
4-8] with respect to the racemic epoxides and found
that 5 mol% of the catalyst worked very efficiently
and yielded unreacted epoxides in excellent
enantioselectivity (ee, 93%) and corresponding amino
alcohol in 92% ee (both in quantitative yields). After
that we screened several solvents viz., Tol, ACN,
THF, DCE and CHCl3 [Table 1, entries 9-13] as
reaction media in our model AKR reaction, but
among all the above used solvents only DCM showed
the best result [Table 1, entry 6]. Likewise, the
reaction was subjected to temperature variation
[Table 1, entries 14-15], where we observed that, the
Results and Discussion
The chiral macrocyclic salen ligands 1a-8a were
synthesized starting from the readily available 2-(tert-
butyl)phenol for the synthesis of 3-(tert-butyl)-2-
hydroxybenzaldehyde followed by its conversion to
3-(tert-butyl)-5-(chloromethyl)-2-
hydroxybenzaldehyde, which was reacted with (R/S)-
1,1'-bi-2-naphthol
(BINOL)/racemic
1,1'-bi-2-
naphthol (BINOL)/ 1,3-phenylenedimethanol to
prepapre the corresponding dialdehyde.[5e,f,15d,16e] The
condensation of thus prepared dialdehydes with
(1R,2R)/(1S,2S)-1,2-diphenylethylene diamine and
(1R,2R)/(1S,2S)-1,2 cyclohexane diamine gave
macrocyclic chiral salen ligands 1a−8a [please see
the SI]. The newly synthesized and characterized
ligands were subjected to metallation with Cobalt(II)
acetate as a metal source under nitrogen atmosphere
in toluene. Subsequently, p-nitrobenzoic acid
(PNBA) was added to the reaction mixture while
exposing it to air to get macrocyclic Co(III) salen
complexes 1-8 [Scheme 3].[4i,7b,7g,15d]
The Jacobsen Co(III) salen complex 9 was prepared
by the reported procedure.[4d] All the chiral
macrocyclic salen ligands and complexes were
characterized by various physicochemical methods
viz. NMR, IR, MASS spectrometry, elemental
analysis and optical rotation [please see SI]. The
attempts to get the single crystal structure of the
complexes were failed however, X-ray structure of
the ligand 2a was successfully determined[20] [Figure
1] thereby confirming the macrocyclic nature of
ligands 1a-8a. After successful synthesis and
characterization, these complexes were used as
catalysts for kinetic resolution of terminal/aryloxy
epoxides.
room temperature (26-28 oC) is
the optimum
temperature [Table 1, entry 6] because on decreasing
o
the reaction temperature below RT, (10 and 0 C)
results were adversely affected [Table 1, entries 14-
15]. We have extended this protocol to a relatively
higher scale (5 mmol) and got similar performance
[Table 1, entry 16] for the AKR reaction. After
optimization of the reaction parameters, we
scrutinized all the above synthesized Co (III) salen
complexes 1-9 in our model AKR reaction.
Among these, the performance of catalysts 1-3
bearing chiral 1,2-diphenylethylene diamine as chiral
backbone was found to be better than the complexes
derived from chiral 1,2-cyclohexane diamine in terms
of yield and enantioselectivity of the epoxides as well
as of amino alcohols [Figure 2].
1
During the optimization study we have performed H
NMR experiments and observed that the ratio of
major 10A and minor enantiomer 10A' of amino
alcohol was in ratio of 98:2. The major enantiomer
formed because of the attack of aniline to phenyl
glycidyl ether 10 from its less hindered side. These
results supports that our catalytic system was highly
regioselective and gave high enantioselectivity in the
Figure 1. Thermal ellipsoid plot for the ligand 2a with
atom numbering scheme (45% probability factor for the
thermal ellipsoids; Lattice DCM is omitted for
clarity)[CCDC1556416]
desired
product.
3
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions for AKR reaction of phenyl glycidyl ether 10 with aniline A using the ligand
1a and Co(II) acetate.[a]
Entry Catalyst
[mol%]
Counter ion
Solvent
Temp.
[oC]
t
Epoxide 10a
Amino alcohol 10A
Yield[b]
ee[c]
%
Yield[b]
%
ee[d]
%
[h]
%
1
2
1.0
1.0
Acetic acid
Trichloroacetic
acid
DCM
DCM
RT
RT
24
24
20
20
68
b
19
21
38
36
3
1.0
Trifluoroacetic
acid
DCM
RT
24
21
78
24
45
4
5
6
7
8
9
10
11
12
13
14
15
16[e]
1.0
2.5
5
7.5
10
5
5
5
5
5
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
DCM
DCM
DCM
DCM
DCM
Tol
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
10
24
24
20
20
18
30
24
34
24
28
40
60
24
30
37
45
46
47
40
35
43
44
43
27
21
45
80
82
93
89
83
80
78
75
84
85
73
65
92
28
43
46
46
47
44
38
41
45
42
30
27
46
80
89
92
92
88
85
79
79
82
86
90
89
91
ACN
THF
DCE
CHCl3
DCM
DCM
DCM
5
5
5
0
RT
PNBA
[a]Conditions: Phenyl glycidyl ether 10 (0.2 mmol), aniline A (0.1 mmol). [b]Isolated yield of product after flash column
chromatography (out of 50% theoretical yield). [c]ee of 10a determined on Chiralcel OD column. [d]ee of 10A determined
on Chiralcel ADH column. [e]Reaction performed at 5 mmol scale keeping other conditions as per entry 6.
The Jacobsen Co(III) salen complex 9 gave the ring
opened product with the ratio of 55:45 of major and
minor products of amino alcohol. We have also
noticed that both the chiral moieties (diamine and
binol) were working synergistically to deliver the
products in high enantioselectivity, because when we
due to the presence of metal centre in close vicinity
of diamine molecules. Similar observations were also
made by several research groups[7b,21] and us.[5e,f,7g,15d,]
used
racemic
1,1'-bi-2-naphthol
and
1,3-
phenylenedimethanol (complex 7 & 8) instead of
chiral BINOL then we got inferior results [Figure 2].
Thus, Among all the Co(III) salen complexes,
complex 1 was found to be the best and was taken
forward for further studies on the AKR reaction as
preferred catalyst. Interestingly, the outcome of the
AKR reaction showed that the stereochemistry of
epoxides and amino alcohols was directly dependent
on the configuration of chiral diamine irrespective of
the configuration of BINOL. The probable reason of
this activity of the chiral Co(III) salen complex was
Figure 2. Screening of the catalyst.
4
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
Consequently, it is possible to get the desired
configuration of the product by selecting the suitable
configuration of the catalyst. In the present case, the
macrocyclic Co(III) salen complex 1 provided (R)-
configuration of amino alcohol and (S)-configuration
of chiral epoxides and on altering the macrocyclic
Co(III) salen complex 1 to complex 2 we got (S)-
configuration of amino alcohol and (R)-configuration
of chiral epoxides. Therefore, Co(III) salen complex
1 was used for the further studies of kinetic resolution
of aryloxy/terminal epoxides with anilines. During
the course of reaction we found that if AKR reaction
runs beyond the specified time, the NH group of
chirally pure aminoalcohol ((R)-1-phenoxy-3-
(phenylamino)propan-2-ol) 10A can act as
nucleophile and react with the enantiopure phenyl
out of 50% theoretical yield) and excellent
enantioselectivity (ee upto 92%) for the
corresponding amino alcohols.
Table 2. Product yield and ee values of AKR reaction of
phenyl glycidyl ether 10 with different amines A-N as
nucleophile catalyzed by macrocyclic Co(III) salen
complex 1.[a]
glycidyl ether 10a
to form 2-((2-hydroxy-3-
phenoxypropyl)(phenyl)amino)-3-phenoxypropan-1-
ol 10AB (isolated by flash column chromatography
and characterized by 1H NMR and HRMS- please see
SI).
After successful optimization of the catalyst and the
reaction conditions, we extended the scope of Co(III)
salen complex 1 for AKR of phenyl glycidyl ether 10
with a variety of amines A-N like 4-substituted
anilines viz., 4-Me, 4-OMe, 4-Cl, 4-Br, 4-CF3, 4-
NO2 aniline [Table 2, entries 2-7] and also with 2-
substituted anilines such as 2-Me, 2-OMe, 2-Cl
aniline [Table 2, entries 8-10]. In all these anilines we
got excellent enantioselectivity of the corresponding
amino alcohols (89-94%) and of phenyl glycidyl
ether (87-93%) with very good recovery of both
products by flash column chromatography. We have
also checked activity of the Co(III) salen complex 1
with some bulkier amines, like 1-naphthylamine K,
and achieved the product in a very high yield (47%)
with moderate enantioselectivity (ee, 78%) (Table 2,
entry 11).
AKR reaction with aliphatic amines are always a
challenging task for scientist around the world due to
their more basic nature, they generally deactivate the
metal catalyst,[5f-5h,16e] but we are very much pleased
that our catalytic system worked very efficiently with
aliphatic amines also. We have scrutinized some of
such amines namely, piperidine L, morpholine M and
thiomorpholine N as a nucleophile in the AKR
reaction with our model substrate i.e. phenyl glycidyl
ether 10 and found that they gave high yield (upto
46%) of the corresponding amino alcohols with very
good enantioselectivity (ee, 77-80%) [Table 2, entries
12-14]. In all these cases we were able to recover
unreacted enantioenriched epoxide 10a with good ee
(upto 80-95%) in quantitative yields.
After getting very exciting and encouraging results
we extended our study and explored the AKR activity
of our catalyst with other Ph-protected glycidols such
as glycidyl-2-methyl phenyl ether 11, 4-chloro phenyl
glycidyl ether 12, 4-methoxy phenyl glycidyl ether 13,
4-tert-butyl phenyl glycidyl ether 14, styrene oxide
[a]Conditions: Phenyl glycidyl ether 10 (0.2 mmol), amines
A-N (0.1 mmol), chiral Co(III) salen complex 1 (0.01
mmol). [b]Isolated yield of amino-alcohol 10A-N after flash
column chromatography (out of 50% theoretical yield).
[c]ee of epoxide 10a determined on Chiralcel OD column.
[d]ee of amino alcohols determined on Chiralcel ADH
column.
15,
2-((benzyloxy)methyl)oxirane
16
and
naphthylglycidyl ether 17 with aniline A [Scheme 2].
In all these cases we achieved high yield (upto 45%
5
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
Besides, Ph-protected glycidols, we have also
examined the catalytic efficiency of Co(III) salen
45%) and excellent enantioselectivity (ee upto 81-
87%). In all these AKR reactions the corresponding
unreacted chirally pure epoxides were isolated with
good yield and with excellent enantioselectivity (ee
upto 90%).
complex
1
with aliphatic epoxides like
epichlorohydrin 18, butyl glycidyl ether 19 and allyl
glycidyl ether 20 with aniline A as a nucleophile
which gave amino alcohols in good yield (upto 43-
Scheme 2. Variation of the substrate.[a]
[a]Conditions: Terminal epoxides 11-20 (0.2 mmol), aniline A (0.1 mmol), chiral Co(III) salen complex 1 (0.01 mmol).
[b]Isolated yield of amino alcohol after flash column chromatography (out of 50% theoretical yield). [c] ee of
enantioenriched epoxide. [d]ee of amino alcohol.
After successfully implementing our catalytic system enantioselectivity of HKR of racemic epoxides.
in the AKR reaction, we have explored its application Therefore, 0.025 mol % of complex 1 (Table 3, entry
in hydrolytic kinetic resolution (HKR) of epoxides by 4) at RT was used to screen various solvents viz.,
keeping all the other parameters same [as per Table 1, CH3CN, CHCl3, THF, DCE, Tol, Et2O [Table 3,
entry 6]. The literature says that the most important entries 6-11]. However, among all these solvents
parameters for HKR reactions are catalyst loading and screened, only DCM was found to be the solvent of
solvent of the reaction, so we have initiated our study choice [Table 3, entry 4]. Unfortunately with the
with phenyl glycidyl ether 10 as model substrate by above optimized conditions we were unable to
using Co(III) salen complex 1. First we varied produce highly optically pure epoxides and diols.
catalyst loading from 0.1 mol% to 0.01 mol% [Table Therefore, we decided to screen all the above
3, entries 1-5] and found that 0.025 mol% of catalyst synthesised Co(III) salen complexes 1-6 in HKR
loading was optimum to catalyze the reaction reaction of phenyl glycidyl ether 10 [Table 4]. It has
[4d,8b,22]
efficiently and gave the unreacted epoxides in 46% been established by many research group
that
yield (out of 50% theoretical yield) with 86% ee and chiral 1,2-cyclohexane diamine (in salen complexes)
45% yield and 86% ee for corresponding diol. The works better in comparsion to 1,2-diphenylethylene
nature of solvent is known to influence reactivity and diamine as a chiral backbone especially in HKR
6
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
reactions. Similarly, in the present system our Co(III)
salen complex 4 worked well to yield epoxides as
well as diols in high enantioselectivity.
Like AKR reaction, here also the configuration of the
product is dependent on the diamine part of the salen
irrespective of the configuration of BINOL in chiral
macrocyclic Cobalt (III) salen complex 4 (0.025
mol%) [Table 4]. The Co(III) salen complex 4
derived from (1S,2S)-(+)-1,2-diaminocyclohexane
gave the (R) form of diol and (S) form of the epoxides,
moreover, Co(III) salen complex 5 originating from
(1R,2R)-1,2-(-) diamine cyclohexane favored the
formation of (S) form of the diol and (R) form of the
epoxides.[4d,4i,7g,8a]
Figure 3. CD spectra of macrocyclic Co(III) salen
complexes 4 and 5 in DCM (1x10-3M).
Table 3. Optimization of reaction conditions for the
hydrolytic kinetic resolution of phenyl glycidyl ether 10
using the macrocyclic Co(III) salen complex 1.[a]
To strengthen the observed phenomenon we recorded
circular dichroism (CD) spectra of the Co(III) salen
complexes 4 and 5 in DCM and found two equally
opposites humps at 420 nm and 610 nm [Figure 3].
Complex 4 (Figure 3, blue color) favors (R) form of
diol and (S) form of the epoxides while complex 5
(Figure 3, red color) favors (S) form of diol and (R)
form of the epoxides.[23]
Table 4. Screening of chiral macrocyclic Co(III) salen
complexes 1−6 for the hydrolytic kinetic resolution of
Phenyl glycidyl ether 10.[a]
[a]Conditions: Phenyl glycidyl ether 10 (5 mmol), H2O (2.5
mmol). [b]Isolated yield after flash column chromatography
(out of 50% theoretical yield). [c]ee of 10a determined on
Chiralcel OD column. [d]ee of 10aa determined on
Chiralcel ADH column. [e]Epoxide configuration (S).
[f]Epoxide configuration (R).
[a]Conditions: Phenyl glycidyl ether 10 (5 mmol), H2O (2.5
mmol), chiral Co(III) salen complex 1. [b]Isolated yield after
flash column chromatography (out of 50% theoretical
yield). [c]ee of 10a determined on Chiralcel OD column.
[d]ee of 10aa determined on Chiralcel ADH column.
7
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
Table 5. Enantioselective hydrolytic kinetic resolution of
Ph-protected glycidols catalyzed by macrocyclic Co(III)
salen complex 4.[a]
styrene oxide 15 and 2-((benzyloxy)methyl)oxirane
16 where less amount of catalyst loading (0.01 mol%)
was sufficient for getting optimal results [Table 5
entries 6,7]. Furthermore, we have also checked the
activity of catalyst 4 for naphthylglycidyl ether 17,
which gave the best result with catalyst loading of
0.05 mol%.
The reactivity and selectivity of the Co(III) salen
complex 4 was further investigated with other
aliphatic terminal epoxides, viz., epichlorohydrin 18,
butyl glycidylether 19, allyl glycidylether 20, 1,2-
epoxyhexane 21, tert-butylglycidylether 22 with
catalyst loading (0.01 mol%). In all these reactions we
got excellent enantioselectivity (>99%) of the
epoxides with very good yield [Table 6].
Table 6. Enantioselective hydrolytic kinetic resolution of
aliphatic terminal epoxides catalyzed by macrocyclic
Co(III) salen complex 4.[a]
[a]Conditions: Epoxides 18-22 (5 mmol), H2O (2.5 mmol),
chiral Co(III) salen complex 4 (0.01 mol%), Time 12 h at
RT. [b]Isolated yield of enantioenriched epoxide (out of
50% theoretical yield). [c]ee of epoxide determined on
Chiraldex GTA column.
Encouraged by the overall results of AKR and HKR
reaction in terms of yield and enantioselectivity of
amino alcohols, diols and chiral epoxides, we have
evaluated the synthetic potential of this protocol for
the preparation of chiral drugs, viz., (S)-Propranolol
and (R)-Naftopidil by using chirally pure epoxides
obtained with our HKR protocol [Scheme 3].
In order to make a comparison of present catalytic
system using the catalyst 4 with our earlier reported
polymeric Co(III) salen complex[15d] we would like to
state that in polymeic system, one additional step was
needed to get the desired drug molecules, however in
this study the well-known β-adrenergic blocker, (S)-
propranolol,[17] was obtained directly in good yield
(95%) with excellent enantioselectivity (98%) by the
ring-opening reaction of chirally pure (S)-1-naphthyl
glycidyl ether with isopropylamine by using Na-
zeolite as a catalyst [Scheme 3]. Similarly when we
used catalyst 5 then from the same reaction we got the
enantiomerically pure (R)-1-napthyl glycidyl ether.
[a]Conditions: Epoxides 10-17 (5 mmol), H2O (2.5 mmol),
chiral Co(III) salen complex 4 at RT in DCM. [b]Isolated
yield after flash column chromatography (out of 50%
theoretical yield). [c]ee determined on Chiralcel OD, ADH,
ASH, ODH, IC HPLC column.
Having established the reaction parameters for use of
Co(III) salen complex 4, it was further explored in
HKR of variety of Ph-protected glycidols viz.,
glycidyl-2-methyl phenyl ether 11, 4-chloro phenyl
glycidyl ether 12, 4-methoxy phenyl glycidyl ether 13,
4-tert-butyl phenyl glycidyl ether 14. High yield as
well as excellent enantiomeric excess of epoxides and
diols (upto 99 %) [Table 5, entries 1-5] was obtained.
Next, the Co(III) salen complex 4 was screened for
8
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
The ring opening of this epoxide with 1-(2- The products diol 10aa and chirally enriched epoxide
methoxyphenyl)piperazine gave (R)-Naftopidil[18] in 10a were recovered from organic layer by column
very good yield (96%) with exceptional chromatography. The catalyst was successfully reused
enantioselectivity (98%) in DCM [Scheme 3].
five times with retention of enantioselectivity but in
slightly decreased yield of the diols possibly due to
the physical loss of the catalyst during the recovering
process [Figure 4]. Further, we have also checked
leaching experiment of the Co metal from complex 4
by ICP–AES (inductively coupled plasma atomic
emission spectroscopy) analysis and did not find any
trace of the metal in organic layer during the recovery
process.
Scheme 3. Synthesis of chiral drugs (S)-Propranolol and
(R)-Naftopidil.
Figure 4. Study of catalyst recyclability using Co(III) salen
complex 4. Reaction condition: Phenyl glycidyl ether 10
(10 mmol), catalyst (0.025 mol%), water (5 mmol), RT.
In a present scenario utilization of green-house gases
are one of the important part of research across the
globe, so keeping this in mind we used CO2 as
renewable C1 source for the synthesis of chirally pure
cyclic carbonate with recovered diols from the HKR
reaction. The coupling reaction of carbon dioxide
(CO2) and (R)-1-phenylethane-1,2-diol 15aa [Scheme
4] by using DBU, bmimPF6, and CH2Br2 under the
pressure of 10 bar of CO2 gave chirally pure cyclic
carbonate 15bb with very good enantiomeric excess
(ee, 96%) in quantitative yield.[19]
Conclusion:
In summary, we have designed and synthesized a
series of novel and very efficient macrocyclic Co(III)
salen complexes as AKR and HKR catalysts for the
ring opening reaction of a variety of terminal/aryloxy
epoxide. Enantiopure epoxides, diols and amino
alcohols with moderate to excellent yields (upto 96%)
with excellent enantioselectivities (upto 99%) were
obtained by using a variety of amines including
aromatic, aliphatic amines and water as nucleophile.
The reaction conditions were mild and having high
atom efficiency in both types of kinetic resolution
reactions. The enantiopure products obtained from
kinetic resolution of racemic epoxides with amines or
with water were efficiently converted into
pharmaceutically important β-adrenergic blocker
chiral drugs, viz., (S)-Propranolol and (R)-Naftopidil.
We have also transformed the chiral diol obtained
from HKR reaction into cyclic carbonate by using
CO2 as a C1 source. The representative Co(III) salen
complex 4 was successfully demonstrated for its re-
Scheme 4. Synthesis of cyclic carbonate.
Catalyst recycling:
The chiral macrocyclic Cobalt (III) salen catalyst 4 use (five times) in HKR with the retention of
was recovered quantitatively from the reaction enantioselectivity.
mixture by adding non-polar solvent like hexane after
the first catalytic run in HKR reaction. The
precipitated catalyst was dried in oven at 60 oC for 4 h
Experimental section:
and then it was directly used for next catalytic run
without further purification.
Synthesis of macrocyclic salen ligands:
9
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
The chiral macrocyclic salen ligands 1a-8a were
synthesized in stepwise manner starting from 3-(tert-
butyl)-2-hydroxybenzaldehyde followed by its conversion
to 3-(tert-butyl)-5-(chloromethyl)-2-hydroxybenzaldehyde,
which was reacted with (R/S)-1,1'-bi-2-naphthol
(BINOL)/racemic 1,1'-bi-2-naphthol (BINOL)/ 1,3-
phenylenedimethanol to prepare the corresponding
dialdehyde.[5e,f,15d,16e] The condensation of thus prepared
dialdehydes with (1R,2R)/(1S,2S)-1,2-diphenylethylene
diamine and (1R,2R)/(1S,2S)-1,2 cyclohexane diamine gave
macrocyclic chiral salen ligands 1a−8a (details of the
synthesis is given SI).
Acknowledgements:
(CSMCRI Communication No.087/2017)Rajkumar tak and RIK
are thankful to UGC and MLP 0028 for financial assistance.
Rajkumar Tak is thankful to AcSIR for Ph. D. Registration.
Authors are also thankful to Analytical Science and centralized
instrument facilities for providing instrumental facilities.
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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FULL PAPER
Asymmetric Hydrolytic and Aminolytic Kinetic
Resolution of Racemic Epoxides using Recyclable
Macrocyclic Chiral Cobalt (III) Salen Complexes
Adv. Synth. Catal. Year, Volume, Page – Page
Rajkumar Tak,a,b Manish Kumar,a Tusharkumar
Menapara,a,b Naveen Gupta,a,b Rukhsana I.
Kureshy,a,b* Noor-ul H. Khan,a,b and E. Sureshb,c
12
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10.1002/adsc.201700788
Advanced Synthesis & Catalysis
13
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