Development of recyclable chiral macrocyclic metal complexes for asymmetric aminolysis of epoxides: Application for the synthesis of an enantiopure oxazolidine ring

Article abstract of DOI:10.1039/c8nj02960a

New recyclable chiral salen complexes Cr(iii)1-7 were synthesized from various macrocyclic chiral ligands having multistereogenic chiral centers which work synergistically to give the best results in terms of the enantioselectivity and yield of the products. Among the synthesized complexes, the Cr(iii)-4 salen complex efficiently catalyzed the ring opening reaction of various aromatic ester epoxides, trans-epoxides and meso-epoxides with anilines to furnish the corresponding β-amino-α-hydroxyl esters and β-amino alcohols with an excellent ee of up to 99% and a high yield of up to 95%. Furthermore, the chirally pure β-amino-α-hydroxyl esters were converted into pharmaceutically important oxazolidine ring systems. Moreover, the chromium catalyst was recycled up to 5 cycles with the retention of its activity.

Full text of DOI:10.1039/c8nj02960a

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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PleNaeswe dJoounrnoatlaodfjCuhsetmmiastrrgyins
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DOI: 10.1039/C8NJ02960A
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ARTICLE
Development of recyclable chiral macrocyclic metal complexes for
asymmetric aminolysis of epoxides: application for the synthesis
of enantiopure oxazolidine ring
Received 00th January 20xx,
Accepted 00th January 20xx
Raj Kumar Tak,a,b Manish Kumar,a Mohd Nazish,a,b Tushar Kumar Menapara,a,b Rukhsana I.
Kureshy*a,b and Noor-ul H. Khan,a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
New recyclable chiral salen complexes Cr(III) 1-7 were synthesized from various macrocyclic chiral ligands having multi
stereogenic chiral centers which works synergistically to give the best results in terms of enantioselectivity and yield of the
products. Among the synthesized complexes, Cr(III)-4 salen complex efficiently catalyzed the ring opening reaction of various
aromatic ester epoxides, trans-epoxide and meso-epoxide with anilines to furnish the corresponding β-amino-α-hydroxyl
esters and β-amino alcohols with excellent ee upto 99% and high yield upto 95%. Further the chirally pure β-amino-α-
hydroxyl esters were converted into pharmaceutically important oxazolidine ring systems. Moreover, the chromium catalyst
was recycled upto 5 cycles with retention of its activity.
tested in ring opening reaction of ester epoxides with anilines
and we found that among all the metal complexes, only Cr(III)
complex gave the best results of our desired product i.e β-
Introduction
The epoxides are very imperative molecules in the modern era
of synthetic chemistry because of two adjacent stereocenters
can be generated from the epoxides by the addition of achiral
nucleophiles. Therefore, epoxides are used as a crucial
intermediate for the preparation of fine chemicals, specialty
chemicals, agrochemicals, natural products and biologically
active molecules.1 In this procession asymmetric ring-opening
(ARO) reaction of epoxides with amines is one of the best and
an efficient way for the synthesis of important chiral β-amino
alcohols and β-amino-α-hydroxyl esters, which are important
motif found in many bioactive and natural products and have
high demand in pharmaceutical industries.2-6
amino-α-hydroxyl esters.
In recent times the development of unique chiral metal
complexes for multi-organic transformation becomes a prime
interest across the world.7 So, in the continuation of our
ongoing research work8,9 here we prepared the multicentered
stereogenic macrocyclic chiral salen ligands which were used to
synthesize new metal complexes with various transition metals
like Ti, Cr, Cu and Ni. Further the formed metal complexes were
Figure 1. Bioactive molecules contain the β-amino-α-hydroxyl ester and
oxazolidine core structure.
Then we synthesised a number of Cr(III) complexes 1-7 and
optimised that Cr(III)-4 complex having (1S,2S)-1,2-
diaminocyclohexane diamine as chiral backbone works very
efficiently with wide range of ester epoxides and gave excellent
results in terms of enantioselectivity up to 99% and yield up to
95%. Besides ester epoxides, we also checked the catalytic
activity of Cr(III)-4 complex in ring opening reaction of trans-
epoxides and meso-epoxide with aniline as nucleophile and in
these cases also we got excellent results in terms of yield and
enantioselectivity of the products. Moreover the reaction
protocol was extended for the preparation of pharmaceutically
important oxazolidine ring system which is the core structure of
a.Inorganic Materials and Catalysis Division.
b.Academy of Scientific and Innovative Research, Central Salt and Marine Chemicals
Research Institute (CSMCRI), Council of Scientific & Industrial Research (CSIR), G.
B. Marg, Bhavnagar- 364 002, Gujarat, India.
E-mail: rukhsana93@yahoo.co.in*.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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many bioactive compounds such as anticancer prodrugs: achieve the high enantioselectivity and yield of the
doxazolidine and its derivatives.10 In addition, the catalyst was corresponding enantiopure products.8a
recycled up to five catalytic cycles with retention of its activity. The initial experiments, showed that only chromium metal
complex Cr(III)-1, synthesized from ligand 1a gave good
enantioselectivity 78% and good yield 70% of corresponding β-
amino-α-hydroxyl esters 10a in comparison to other metal
Result and discussion
complexes [Table 1, entry 2]. After getting these encouraging
results with complex Cr(III)-1, [Table 1, entry 2 ] we varied other
reaction parameters for attaining the best result.
The chiral macrocyclic salen ligands 1a-7a were synthesized in
two easy steps. In the first step 3-(tert-butyl)-5-(chloromethyl)-
2-hydroxybenzaldehyde was reacted with (R/S)-1,1'-bi-2-
In this direction, first we tested the catalyst loading from 1 mol%
to 10 mol% [Table 2, entries 1-4] and found that the catalyst
loading 2.5 mol% is sufficient to achieve the very good result of
β-amino-α-hydroxyl esters in 78% enantioselectivity and 70%
yield [Table 2, entry 2].
naphthol
(BINOL)
to
prepare
the
corresponding
dialdehydes.[8a,9] And in the second step condensation reaction
of dialdehydes were done with (1R,2R)/(1S,2S)-1,2-
diphenylethylene diamine and (1R,2R)/(1S,2S)-1,2 cyclohexane
diamine which gave the macrocyclic chiral salen ligands 1a−7a9
[Figure 2].
Table 2. Optimization of reaction conditions for the ring opening reaction of trans-methyl
3 phenyloxirane-2-carboxylate 10 with aniline a by using complex Cr(III)-1.[a]
Entry
Catalyst
[mol%]
1.0
Solvent
T[oC]
t[h]
Yield
[%][b]
60
ee
[%][c]
69
1
2
DCM
DCM
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
30
20
20
18
36
25
20
16
20
20
2.5
5
70
72
78
60
78
76
95
79
85
78
77
75
60
70
70
65
74
78
3
DCM
4
10
DCM
5
2.5
2.5
2.5
2.5
2.5
2.5
Toluene
ACN
Figure 2. Structure of chiral salen ligands.
6
Table 1. Optimization of metals for the ring opening reaction of trans-methyl 3-
phenyloxirane-2-carboxylate 10 with aniline a.[a]
7
THF
8
MeOH
CHCl3
9
10
DCM:MeOH
(9:1)
11
2.5
DCM:MeOH
(1:1)
RT
20
90
70
Entry
Metals
Ti(OiPr)4
CrCl2
t [h]
20
Yield [%][b]
ee [%][c]
12
13
2.5
2.5
DCM
10
0
40
50
65
55
76
75
1
2
3
4
10
70
40
30
nd
78
5
20
DCM
Cu(OTf)2
NiCl2
20
[a]Conditions: Trans-methyl 3-phenyloxirane-2-carboxylate 10 (0.2 mmol), aniline a
(0.12 mmol), Cr(III)-1 (0.001-0.02mmol). [b]Isolated yield after flash chromatograph
with respect to aniline. [c]ee determined on Chiralcel ADH column.
20
0
[a]Conditions: Trans-methyl 3-phenyloxirane-2-carboxylate 10 (0.2 mmol), aniline a
(0.12 mmol), ligand 1a (0.005 mmol), metal salt (0.005 mmol).[b]Isolated yield after
flash chromatography with respect to aniline. [c]ee determined on Chiralcel ADH
column.
Since the solvent is well known to affect the enantioselectivity
and yield of the product, so we varied the different solvents like
Toluene, ACN, THF, MeOH and CHCl3 [Table 2, entries 5-9]. We
got very good enantioselectivity, when we used DCM as a
solvent but the better yield was isolated when we used
methanol as reaction media. Therefore, we decided to screen
After successful characterization of the synthesized macrocyclic
chiral ligands by various spectroscopic methods such as NMR,
IR and HRMS We chose ligand 1a as representing ligand on the
basis of our previous experiences and reports where we
established that two chiral moieties works synergistically to
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the mixture of DCM and MeOH in the ratio of [9:1] and [1:1] Binol and CHDA worked synergistically to gave very good yield
[Table 2, entries 10-11]. and enantioselectivity of the product.
Out of which we found that the mixture of DCM and MeOH [9:1] During the catalyst optimization, we found that the
gave the improved results in terms of yield of the product 85%. stereochemistry of amino alcohols was directly dependent on
The reaction was further subjected to lowering of the the configuration of chiral diamine moiety irrespective of the
temperature to see the effect of temperature on the configuration of Binol, although the presence of chiral Binol in
enantioselectivity and yield of the product [Table 2, entries 12- ligands are equally important as CHDA moiety. Most probably,
13]. However, room temperature was found to be optimum it is due to the close vicinity of the chiral diamine with the metal
[Table 2, entry 10] to get the good outcome from the center.[5b,9,11] To understand the observed phenomenon, we
asymmetric ring opening reaction.
recorded electronic and Circular Dichroism (CD) spectra of the
macrocyclic Cr(III)-4 and Cr(III)-5 salen complexes in DCM and
Interestingly, the complex Cr(III)-4 show positive Cotton effects
at 429 nm, favoured the product with (2S,3S) configuration
[Table 3, entry 3], whereas salen complex Cr(III)-5 shows equally
opposite hump at 429 nm, favoured the product with opposite
configuration i.e., (2R,3R) [Table 3, entry 4]. Accordingly, we
were able to furnish the desired configuration of the product by
selecting a suitable configuration of the catalyst [Figure 3].
Table 3. Variation of Cr(III) metal complexes.[a]
Entry
Catalyst
Cr(III)-2
Cr(III)-3
Cr(III)-4
Cr(III)-5
Cr(III)-6
Cr(III)-7
Cr(III)-8
Cr(III)-9
Time [h]
20
20
20
20
20
20
20
20
Yield %[b]
ee %[c]
78[e]
79[d]
99[d]
98[e]
97[d]
79[d]
75[d]
60[d]
1
2
3
4
5
6
7
8
86
85
95
94
95
85
80
65
[a]Conditions: Trans-methyl 3-phenyloxirane-2-carboxylate 10 (0.2 mmol), aniline a
(0.12 mmol), Complex Cr(III) 2-9 (0.005 mmol). [b]Isolated yield after flash
chromatograph with respect to aniline. [c]ee determined on Chiralcel ADH column.
[d]Product with (2S,3S) configuration. [e]Product with (2R,3R) configuration.
Figure 3
. A) Electronic spectra of Cr(III)-4 and Cr(III)-5 in DCM. B) CD spectra of
Cr(III)-4 and Cr(III)-5 in DCM (1 x 10-3M).
After established the optimum reaction parameters with
complex Cr(III)-1 for the enantioselective ring opening of trans-
Further we characterized the Cr(III)-4 complex by different
spectroscopic techniques such as IR, ESI-MS and MALDI-TOF. A
distinct peak at m/z 826.72 attributed to [M-Cl+MeOH] in (ESI-
MS) confirm the formation of Cr(III)-4 complex and Matrix-
assisted Laser deposition/ionization (MALDI)- m/z 818.36 [M-
Cl+Na+H] and 852.36 [M+Na] spectra verify the formation of
Cr(III)-4 complex. Here we also confirm the formation of Cr(III)-
methyl 3-phenyloxirane-2-carboxylate 10 with aniline
a as a
nucleophile (Table 2, entry 10), we synthesized the chromium
metal complexes Cr(III)-2 – Cr(III)-7 of all the ligands 2a-7a
respectively by the reported procedure.5b,8b The optimized
protocol was extended to other Cr(III) complexes 2-6 and found
that the complex Cr(III)-4 having (1S,2S)-1,2 cyclohexane
diamine as chiral linker give β-amino-α-hydroxyl esters 10a with
excellent enantioselectivity 99% and high yield 95% [Table 3,
entry 3]. Here we also checked the significance of Binol as linker,
so that we prepared Cr(III) complex of ligand 7a which was
synthesized by using racemic Binol with CHDA but we got
inferior results in terms of enantioselectivity and we got only
79% of ee in β-amino-α-hydroxyl esters 10a [Table 3, entry 6].
To strengthen our findings, here we have also checked our
model reaction with chromium complex of Jacobsen ligands 8a
and 9a, and in these cases, we got moderate results in terms of
enantioselectivity 75% and 60% and yield 80% and 65% of β-
amino-α-hydroxyl esters 10a respectively [Table 3, entry 6, 7].
Thus from Table 3 it was confirmed that two chiral moieties
4
complex by FT-IR spectra, which gave the characteristic OH,
aliphatic C–H and C=N stretching frequencies at, 3422, 2943 and
1595 cm-1 respectively (data is given in supporting information).
Our repeated attempts to get the single crystal structure of
complex, suitable for the X-ray analysis failed.
Having established very good results with the complex Cr(III)-4
under the optimized reaction conditions, the scope of the active
catalyst was explored for the asymmetric ring opening reaction
of trans-methyl 3-phenyloxirane-2-carboxylate 10 with a variety
of amines a–h. A vast range of anilines were tested in the
reaction and irrespective of the substitution position at aniline,
we got excellent results in terms of enantioselectivity [93–99%]
and yield [up to 90–95%] of the respective products i.e., chiral
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β-amino-α-hydroxyl esters except in the case of 4-NO2-aniline aromatic ester epoxides such as trans-ethyl 3-phenyloxirane-2-
because of its very low reactivity, we did not get the ring opened carboxylate 11
,
,
trans-methyl 3-(2-fluorophenyl)oxirane-2-
trans-methyl 3-(3-fluorophenyl)oxirane-2-
trans-methyl 3-(3-nitrophenyl) oxirane-2-
product [Table 4].
carboxylate 12
carboxylate 13
,
Table 4. Product yield and ee values for the aminolysis of aromatic epoxide 10-15 with
different amines a–m as a nucleophile catalyzed by Cr(III)-4 under optimized reaction
conditions.[a]
carboxylate 14 and trans-methyl 3-(4-nitrophenyl) oxirane-2-
carboxylate 15 with aniline as nucleophile under optimized
a
reaction condition. We got good to excellent enantioselectivity
[79–94%] with high to very high yield [80–83%] of the
corresponding chiral β-amino-α-hydroxyl ester with these
substrates [Table 4].
After successfully establishment of reaction protocol for
aromatic ester epoxides, we have also checked the catalytic
activity of Cr(III)-4 for ring opening reaction of trans epoxides
such as trans-stilbene oxide 16, trans-β-methyl styrene oxide 17
and trans-butene oxide 18 with a variety of anilines having
electron donating/withdrawing groups at different positions,
gave excellent ee upto 92% and high yield upto 92% of the chiral
β-amino-alcohols.
Table 5. Product yield and ee values for ARO of trans and meso epoxide 16-19 with
different anilines as nucleophile catalyzed by complex Cr(III)-4 under the optimized
reaction conditions.[a]
[a]Conditions: Aromatic epoxides 10-15 (0.2 mmol), aniline a-m (0.12 mmol), Cr(III)-
4 (0.005 mmol). [b]Isolated yield after flash chromatography with respect to aniline.
[c]ee determined on Chiralcel ADH column.
We also checked the activity of Cr(III)-4 with bulkier amine (1-
naphthylamine) i, for which we obtained a very good yield of
[a]Conditions: Trans and meso-epoxides 16-19 (0.2 mmol), anilines (0.12 mmol),
Cr(III)-4 (0.005 mmol). [b]Isolated yield after flash chromatography with respect to
aniline. [c]ee determined on Chiralcel ADH column.
92% with high enantioselectivity 96% of the product. Besides
aromatic amines, we have also examined the scope of aliphatic
amines j-m such as cyclohexane amine, piperidine, morpholine
and thiomorpholine with the present protocol. Unfortunately,
we did not afford the ring-opened product under our optimized
condition, probably because of high basicity of these amines
blocking the acidic sites of the catalyst leaving the epoxides un-
activated [Table 4].5b,6g,8d
We explored the same protocol for ARO reaction of meso-
stilbene oxide 19 with aniline a and got very good yield 85% with
moderate enantioselectivity 68% of the corresponding chiral β-
amino-alcohol [Table 5].
Although enantiopure β-amino-α-hydroxyl esters have wide
applications in various types of fields but during the literature
The scope of Cr(III)-4 was extended with other aromatic esters
epoxides having different substitutions at different position in
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survey10 we found that our ARO reaction products i.e., β-amino-
α-hydroxyl esters can be transformed into another very
important pharmaceutically molecules i.e oxazolidine ring. So,
after successful optimization and implementation of reaction
protocol for ARO reaction of epoxides with aniline, we extended
the synthetic utility and in this process the β-amino-α-hydroxyl
esters were treated with DMSO/P2O5 to produce the chirally
pure oxazolidine ring system.10a We executed the reaction
protocol with different variety of β-amino-α-hydroxyl esters
having electron withdrawing or electron donating groups in
various positions at aromatic rings. The substituted oxazolidine
ring were recovered with very good yield up to 93% and with
excellent enantioselectivity up to 95% [Table 6]. Likewise, we
also transformed chirally pure ethyl (2S,3S)-2-hydroxy-3-
phenyl-3-(phenylamino)propanoate 11a to enantiopure
oxazolidine ring 11a’ with very good yield of 85% and with good
enantioselectivity of 70%. We got similar type of results in terms
of yield [88%, 78%] and enantioselectivity [72%, 77%], when we
used chirally pure methyl (2S,3S)-2-hydroxy-3-(3-nitrophenyl)-
3-(phenylamino)propanoate 14a and (2S,3S)-2-hydroxy-3-(4-
nitrophenyl)-3-(phenylamino)propanoate 15a for the synthesis
of corresponding oxazolidine ring [14a’, 15a’] [Table 6].
Scheme 1. Plausible mechanism for the ring opening of trans-methyl 3-
phenyloxirane-2-carboxylate 10 with aniline a.
Recyclability
The recyclability and reusability of the catalyst was a prime
aspect in the current era of catalysis. Our catalytic system was
precipitate out in a non-polar solvent like hexane due to its
higher molecular weight and lower solubility in these solvents.
Hence, we recovered the Cr(III)-4 catalyst from the reaction
mixture by adding hexane, after completion of the reaction. The
catalyst was recycled and reused for five cycles with retention
of configuration [Figure 4]. Further, we took the IR spectra of
fresh and reused catalyst which shows no major structural
changes during the catalytic run which confirms the stability of
the catalyst.
Table 6. Product yield and ee values for oxazolidine synthesis.[a]
[a]Conditions: β-amino-α-hydroxyl ester (0.2 mmol), DMSO/P2O5. [b]Isolated yield
after flash chromatography. [c]ee determined on Chiralcel ADH column.
Figure 4. Recyclability study of Cr(III)-4 complex.
Here we also proposed the plausible mechanism for the ring
opening of trans-methyl 3-phenyloxirane-2-carboxylate 10 with
aniline a, [Scheme 1]. The Cr(III) catalyst coordinates with the
Experimental
epoxide oxygen to activate the epoxide ring, followed by an
attack of aniline and generate an active intermediate. The
resulting ring opened intermediate would then undergo a rapid
proton transfer to assist the regeneration of Cr(III) catalyst and
the desired amino alcohol.12
Anhydrous chromium (II) chloride, aniline, substituted anilines,
aliphatic amines and trans-epoxides were purchased from
Aldrich Chemicals and were used as received. All the solvents
used in the present study were dried by known purification
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technique. NMR spectra were obtained with 600 MHz, 500 dark brown color which was stirred for 4 h under a blanket of
MHz, 200 MHz and are referenced internally with TMS. nitrogen and then exposed to air for a further 3 h. The dark
Enantiomeric excess (ee) were determined by HPLC using Daicel brown solution was diluted with TBME (t-butyl methyl ether)
Chiralpak ADH, OD, IA, and AD chiral columns with 2- resulting in the precipitation of the complexes Cr(III) 1-7. The
propanol/hexane as eluent. FT-IR spectra were carried out by complexes were filtered and washed with saturated NH4Cl
using KBr. Optical rotations were determined by automatic solution and brine to remove the excess of chromium chloride,
polarimeter (Digipol 781). Circular Dichroism (CD) spectra were the complexes were dried overnight under vacuum.
obtained by using a JASCO J-815 CD spectrophotometer (Japan).
High-resolution mass spectra were obtained with Agilent
Technologies (6545 Q-TOF LC-MS). For the product purification
General procedure of ring opening reaction of trans-epoxide with
aniline
flash chromatography was performed using silica gel 100-200
To a 5 mL vial equipped with a magnetic stirring bar, the
mesh. The following abbreviations were used to designate
macrocyclic Cr(III) salen complexes (0.005 mmol) was taken in
chemical shift multiplicities: s = singlet, d = doublet, t = triplet,
dichloromethane (0.8 mL) and the resulting solution was stirred
q = quartet, m = multiplet, br = broad coupling constants are
for 5 minute followed by the addition of an appropriate epoxide
given in Hertz (Hz).
(0.2 mmol). The resulting mass was stirred for 10 minutes
followed by the addition of the desired aniline as a nucleophile
Synthetic procedure for ligand 1a-3a
(0.12 mmol) at room temperature (27±2 °C). The reaction
A solution of dialdehyde (500 mg, 0.75 mmol) in dry DCM (1.2
mixture was allowed to stir for the specified time. The progress
mL) was added to
a solution of (1S,2S)/ (1R,2R)-1,2-
of the reaction was checked on TLC using hexane/ethyl acetate
(8/2) as the mobile phase. After the completion of the reaction,
solvent was removed under vacuum and the product was
purified by column chromatography using silica gel 100-200
mesh as stationary phase and n-hexane: ethyl acetate (8:2) as
mobile phase. The recovered catalyst was dried under vacuum
and stored in a desiccator for its use in subsequent catalytic
runs.
diphenylethylenediamine (191.06 mg, 0.90 mmol) in dry MeOH
(0.68 mL) at ambient temperature (25-30 oC). The stirring of the
solution was continued at room temperature for 5 h. The
completion of the reaction was checked on TLC. After
completion of the reaction the solvent was removed under
reduced pressure. The bright yellow solid product thus obtained
was taken in dichloromethane (40 mL) and the organic layer was
washed with water (2 x 40 mL), brine (40 mL) and was dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure to get bright yellow solid product.9
Synthetic procedure for enantiopure oxazolidine ring
In a small vial equipped with a magnetic stirring bar, Phosphorus
pentoxide was taken in dry DMSO (1 mL) and the resulting
solution was ultrasonicated for 10 min. After that chirally pure
β-amino-α- hydroxyl esters were taken in DMSO (1 mL) and
added in resulting solution. The reaction mixture was allowed
to stir for the specified time. The progress of the reaction was
checked on TLC using n-hexane/ethyl acetate (9/1) as mobile
phase. After the completion of reaction, it was quenched with
cooled saturated sodium bicarbonate solution (10 mL) followed
by a small amount of water. The mixture was extracted with
ethyl acetate (3 x 10 mL). The combined organic layers were
washed with water (3 x 10 mL) to remove unreacted DMSO,
then washed with brine, dried over sodium sulfate and the
product was purified by column chromatography using silica gel
100-200 mesh as stationary phase and n-hexane: ethyl acetate
(9:1) as mobile phase.10a
Synthetic procedure for ligand 4a-6a
A solution of dialdehyde
mL) was added to
c
a
(500 mg, 0.75 mmol) in dry DCM (1.2
solution of (1S,2S)/ (1R,2R)-1,2-
diaminocyclohexane (108.12 mg, 0.90 mmol; in 0.6 mL dry
MeOH) at room temperature (25-30 oC) and the resulting
reaction mixture was stirred for 2 h and monitored on TLC.
(Caution: this time should not be extended lest insoluble
polymeric material would form). After completion of the
reaction the solvent was removed under reduced pressure. The
bright yellow solid product thus obtained was taken in
dichloromethane (40 mL) and the organic layer was washed
with water (2 x 40 mL), brine (40 mL) and was dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure to get bright yellow solid product.9
Conclusions
Synthetic procedure of chiral macrocyclic Cr(III) salen complexes
In the present work, we have designed, synthesized and
characterized the efficient chiral macrocyclic Cr(III) salen
complexes having multi stereogenic chiral centers. The Cr(III)
complexes have been used for the ARO of aromatic ester
A 100-mL, 2-necked, round-bottom flask with a nitrogen inlet
and outlet was charged with a yellow solution of ligand in dry
degassed THF (25 mL). To the yellow solution, anhydrous
chromium(II) chloride was added and the solution turned into a
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8NJ02960A
T. Ohshima and M. Shibasaki, Tetrahedron 2002, 58, 75; e) B.
Plancq and T. Ollevier, Chem. Commun., 2012, 48, 3806 ; f) H.
Bao, J. Wu, H. Li, Z. Wang, T. You and K. Ding, Eur. J. Org. Chem.
2010, 2010, 6722.
epoxides, trans-epoxide and meso-epoxide with anilines to
synthesize the pharmaceutically important β-amino-α-hydroxyl
ester and β-amino-alcohols derivatives (yield up to 95%, with
excellent enantioselectivity upto 99%). This reaction protocol
was extended for the synthesis of pharmaceutically active
oxazolidine ring system. The catalyst was also recycled and
successfully reused five times with retention of configuration.
7
8
a) X. H. Liu, L. L. Lin and X. M. Feng, Acc. Chem. Res., 2011, 44
574; b) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103
2921; c) H. Pellissier and H. Clavier, Chem. Rev., 2014, 114
,
,
,
2775; d) V. Bhat, E. R. Welin, X. Guo, and B. M. Stoltz, Chem.
Rev., 2017, 117, 4528.
a) M. Kumar, R. I. Kureshy, D. Ghosh, N. H. Khan, S. H. R. Abdi,
H. C. Bajaj, ChemCatChem, 2013, 5, 2336; b) R. I. Kureshy, K. J.
Prathap, M. Kumar, P. K. Bera, N. H. Khan, S. H. R. Abdi and H.
C. Bajaj, Tetrahedron, 2011, 67, 8300; c) M. K. Choudhary, R.
Tak, R. I. Kureshy, A. Ansari, N. H. Khan, S. H.R. Abdi and H. C.
Bajaj, J. Mol. Catal. A: Chem, 2015, 409, 85; d) R. Tak, M.
Kumar, R. I. Kureshy, M. K. Choudhary, N. H. Khan, S. H. R. Abdi
and H. C. Bajaj, RSC Adv. 2016, 6, 7693; e) M. Kumar, R.
I.Kureshy, A. K. Shah, A. Das, N. H. Khan, S. H. R. Abdi, H. C.
Bajaj, J. Org. Chem., 2013, 78, 9076.
Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
(CSMCRI Communication No. 076 /2018). Rajkumar Tak and RIK
are thankful to UGC and HCP-0009 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 instruments facilities.
9
R. Tak, M. Kumar, T. Menapara, N. Gupta, R. I. Kureshy, N. H.
Khan and E. Suresh, Adv. Synth. Catal., 2017, 359, 3990.
10 a) J. Wang, F. D. Rochon, Y. Yang, L. Hua, M. M. Kaysera,
Tetrahedron: Asymmetry, 2007, 18, 1115; b) D. J. Burkhart, B.
L. Barthel, G. C. Post, B. T. Kalet, J. W. Nafie, R. K. Shoemaker,
T. H. Koch, J. Med. Chem. 2006, 49, 7002; c) G. C. Post, B. L.
Barthel, D. J. Burkhart, J. R. Hagadorn and T. H. Koch, J. Med.
Chem. 2005, 48, 7648.
Notes and references
11 a) P. Yana and H. Jinga, Adv. Synth. Catal. 2009, 351, 1325; b)
L. Jin, Y. Huang, H. Jing, T. Chang, P. Yan, Tetrahedron:
Asymmetry, 2008, 19, 1947; c) S. I. Murahashi, S. Noji, N.
Komiya, Adv. Synth. Catal. 2004, 346, 195.
12 a) E. N. Jacobsen, Acc. Chem. Res., 2000, 33, 421; b) B. Gao,
M. Xie, A. Sun, X. Hu, X. Ding, X. Liu, L. Lin and X. Feng, Adv.
Synth. Catal.,2012, 354, 1509; c) M. Meguro, N. Asaob and Y.
Yamamoto, J. Chem. Soc., Perkin Trans. 1, 1994, 0, 2597; d)
Karl B. Hansen, James L. Leighton and Eric N. Jacobsen, J. Am.
Chem. Soc., 1996, 118 ,10924; e) J. Auge and F. Leroy,
Tetrahedron Lett.,1996, 37, 7715; f) A. T. Placzek, J. L.
Donelson, R. Trivedi, R. A. Gibbs and S. K. De, Tetrahedron
Lett.,2005, 46, 9029.
1
a) E. M. McGarrigle and D. G. Gilheany, Chem. Rev., 2005, 105,
1563; b) Q.-H. Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu and K.-X. Su,
Chem. Rev., 2005, 105, 1603; c) O. A. Wong and Y. Shi, Chem.
Rev., 2008, 108, 3958; d) E. N. Jacobsen, Acc. Chem. Res.,
2000, 33, 421.
2
a) D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96
835; b) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561; c) M.
Yamashita, K. Yamada and K. Tomioka, Org. Lett., 2005,
2369; d) S. Hashiguchi, A. Kawada and H. Natsugari, J. Chem.
,
7
,
Soc. Perkin Trans.,1991,
1995, 95, 1859.
1, 2435; e) S. Knapp, Chem. Rev.,
3
4
a) Q. Wang, W. Huang, H. Yuan, Q. Cai, L. Chen, H. Lv and X.
Zhang, J. Am. Chem. Soc., 2014, 136, 16120; b) C. G. Goodman,
D. T. Do and J. S. Johnson, Org. Lett., 2013, 15, 2446; d) K. C.
Nicolaou, W. M. Dai and R. K. Guy, Angew. Chem. Int. Ed. Engl.,
1994, 33, 15; Angew. Chem. 1994, 106, 38; e) H. Suda, T.
Takita, T. Aoyagi and H. Umezawa, J. Antibiot., 1976, 29, 100;
f) I. Saiki, J. Murata, K. Watanabe, H. Fujii, F. Abe and I. Azuma,
Jpn. J. Cancer Res., 1989, 80, 873.
a) M. D. Gill, A. N. Pegg and C. M. Rayner, Tetrahedron Lett.
1995, 36, 8327; b) M. C. Wani, H. L. Taylor, M. E. Wall, P.
Coggon and A. T. McPhail, J. Am. Chem. Soc. 1971, 93, 2325;
c) H. Suda, T. Takita, T. Aoyagi, H. Umezawa, J. Antibiot. 1976,
29, 600; d) H. J. Ha, G. S. Park, Y. G. Ahn, G. S. Lee, Bioorg. Med.
Chem. Lett., 1998,
8, 1619; e) D. G. I. Kingston, Chem.
Commun., 2001,2001, 867; f) S. B. Horwitz, J. Nat. Prod., 2004,
67, 136.
5
6
a) G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, M.
Massaccesi, P. Melchiorre and L. Sambri, Org. Lett. 2004, 6,
2173; b) R. Tak, M. Kumar, T. Menapara, M. K. Choudhary, R.
I. Kureshy and N. H. Khan, ChemCatChem, 2016, , 1.
8
a) R. I. Kureshy, M. Kumar, S. Agrawal, N. H. Khan, B. Dangi, S.
H. R. Abdi and H. C. Bajaj, Chirality 2011, 23, 76; b) K. Arai, M.
M. Salter, Y. Yamashita and S. Kobayashi, Angew. Chem. 2007,
119, 973; Angew. Chem. Int. Ed. 2007, 46, 955; c) K. Tanaka, S.
Oda and M. Shiro, Chem. Commun., 2008, 0, 820; d) A. Sekine,
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C8NJ02960A
Development of recyclable chiral macrocyclic metal complexes for asymmetric aminolysis
of epoxides: application for the synthesis of enantiopure oxazolidine ring
Raj Kumar Tak, Manish Kumar, Mohd Nazish, Tushar Kumar Menapara, Rukhsana I. Kureshy* and Noor-ul H.
Khan.
An efficient macrocyclic Cr(III)-salen complexes were synthesized for the ring opening
reaction of various epoxides, with anilines to furnish the corresponding β-amino-α-hydroxyl
esters and β-amino alcohols with excellent ee upto 99% and high yield upto 95%.