Resolution, absolute configuration and antifilarial activity of coumarinyl amino alcohols

Article abstract of DOI:10.1016/j.tetasy.2017.04.005

The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-L-proline (S)-11. Direct esterification of rac-5–10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10 and (R)-(?)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(?)-9 and (S)-(+)-10, (R)-(?)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action.

Full text of DOI:10.1016/j.tetasy.2017.04.005

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Resolution, absolute configuration and antifilarial activity
of coumarinyl amino alcohols
a
b
b
c
a,
⇑
Priyanka , Sweta Misra , Shailja Misra-Bhattacharya , Ray J. Butcher , Diksha Katiyar
a
Department of Chemistry, MMV, Banaras Hindu University, Varanasi 221005, India
Division of Parasitology, CSIR-Central Drug Research Institute, BS 10/1, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
Department of Chemistry, Howard University, 525 College Street NW, Washington DC 20059, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and
readily accessible chiral resolving agent N-carbethoxy- -proline (S)-11. Direct esterification of rac-5–10
Received 27 March 2017
Accepted 10 April 2017
Available online xxxx
L
with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography.
The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10
and (R)-(ꢀ)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configu-
rations were determined by X-ray crystal analysis and/or by comparison of the specific rotations.
Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(ꢀ)-
9
and (S)-(+)-10, (R)-(ꢀ)-10 were found to be less efficient in affecting the viability of macrofilariae of
Brugiamalayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enan-
tiomers in evoking antifilarial action.
Ó 2017 Elsevier Ltd. All rights reserved.
1
4,15
1
. Introduction
employed in the resolution of (±)-phenyl succinic acid,
2,3-
1
6
0
17
diphenylsuccinic acid, 1,1 -binaphthols,
C -symmetric acyclic
2
19
1
8
The wide use of enantiopure b-amino alcohols as chiral auxil-
1,3-diols and 2,3-diphenyl butane-1,4-diol and many others.
However, to the best of our knowledge, its use in the resolution
of vicinal amino alcohols has not been reported yet.
Herein we report our findings on the successful resolution of
racemic coumarinyl amino alcohols 5–10 using (S)-proline ethyl
ester (S)-11 as a resolving agent. Furthermore, in our previous
work we discovered that compounds 9 and 10 possess significant
antifilarial activity against the micro- and macrofilariae of human
iaries and organocatalysts2 in various synthetic transformations
as well as reaction intermediates in the synthesis of variety of nat-
ural and synthetic medicines,3 and unnatural amino acids has led
to an upsurge in their synthetic demand. As a result, a number of
synthetic methods have been developed for their synthesis includ-
ing asymmetric reduction of
1
4
a
-amino carbonyl compounds or
a
-
5
hydroxy carbonyl compounds, Sharpless asymmetric amino
6
20
hydroxylation of olefins, asymmetric hydroboration of enamines
filarial parasite, Brugia malayi. It is well known that enantiomers
and enantioselective ring opening of epoxides.7 The resolution of
b-amino alcohols via formation of diastereomers is also one of
the most efficient and widely used methods for the synthesis of
optically active b-amino alcohols especially because of practical
generally show different pharmacokinetic and pharmacodynamic
activities and sometimes it is seen that pharmaceutical activity
generally resides predominantly with one isomer whereas the
other enantiomer remains inactive or has some side effects.2
Thus we also found it interesting to assess the antifilarial activity
of individual enantiomers and report the results of in vitro antifi-
larial activities of these compounds. The in vitro antifilarial activi-
ties of rac-5–7 are also reported for the first time herein.
1,22
8
9
simplicity and low cost. Enantiomerically pure tartaric acid, O-
acyl tartaric acid, O-acyl mandelic acid, chiral 1,1 -bi-2-naph-
1
0
11
0
1
2
0
13
thylphosphoric acid, and boric acid and 1,1 -bi-2-naphthol are
some of the examples of resolving agents, which have been suc-
cessfully employed for the resolution of amino alcohols. Over the
past few decades, (S)-proline has also received considerable atten-
tion as a versatile resolving agent due to its low cost, low molecular
weight, easy handling and easy availability. It has been successfully
2. Results and discussion
2.1. Chemistry
⇑
Corresponding author. Tel.: +91 09415218260.
E-mail address: dikshakatiyar@gmail.com (D. Katiyar).
The racemic coumarinyl amino alcohols 5–10 were synthesized
via regioselective nucleophilic opening of oxirane rings by selected
http://dx.doi.org/10.1016/j.tetasy.2017.04.005
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
primary and secondary amines in the presence of
K
2
CO
3
Table 1
2
0,23
Crystallographic data collection and structural refinement information of rac-5 and
(R)-(ꢀ)-5
(Scheme 1).
The structures of all these compounds were estab-
1
13
lished on the basis of IR, H and C NMR and mass spectra data.
Out of these compounds, only 5 and 6 were obtained as solids
and only quality crystals of 5 could be obtained in acetone by slow
evaporation of solvent for X-ray diffraction study. The crystallo-
graphic data of compound 5 are summarized in Table 1 and its
X-ray structure is shown in Figure 1. The 2D packing structure of
rac-5, as shown in Figure 2, establishes the existence of four inter-
molecular H-bonding interactions: (i) C(10)-H(10A)---O(4) with
bond length of 2.31 Å (black), (ii) C(10)-H(10B)---O(2) with bond
length of 2.57 Å (green), (iii) C(11)-H(11)---O(1) with bond length
of 2.67 Å (red) and (iv) C(6)-H(6)---O(2) with bond length of 2.54 Å
rac-5
(R)-(ꢀ)-5
C17H21NO4
303.35
100(2)
1.54184
Orthorhombic
P212121
6.6770(2)
9.4799(2)
23.9593
Formula empirical
Fw
Temp [K]
k [Å]
Crystal system
Space group
a [Å]
C17H21NO4
303.35
120
1.54184
Monoclinic
P21/c
7.0002(3)
10.5240(4)
21.3883
b [Å]
c [Å]
(
10)
a
[°]
b [°]
[°]
90
99.401(4)
90
90
90
90
(
blue).
With racemic compounds 5–10 in hand, we focused our atten-
c
3
V [Å ]
1554.52
1516.56(7)
tion on their resolution into their two enantiomeric constituents
using commercially available (S)-proline as the resolving agent.
(
12)
Z
4
4
(S)-Proline is insoluble in dichloromethane therefore we used its
3
Density [mg/m ]
F(000)
Absolute structure parameter (Flack
parameter)
1.296
648
—
1.329
648
0.01(3)
ethyl ester (S)-11, which was synthesized according to the litera-
1
8,24
ture.
Firstly, we attempted the resolution of compound 5.
The reaction of rac-5 with (S)-11 (1.25 equiv) in the presence of
0
1
,3-dicyclohexylcarbodiimide (DCC, 1.25 equiv) and N,N -dimethy-
laminopyridine (DMAP, 10 mol%) in dry dichloromethane at room
temperature yielded a mixture of diastereomeric esters 12a and
2
5
rotations of (S)-(+)-5 and (R)-(ꢀ)-5 were calculated as ½
aꢁ
=
D
2
D
5
+10.6 (c 0.40, acetone) and ½
aꢁ
= ꢀ11.2 (c 0.40, acetone), respec-
1
2b. These diastereomers were easily separated by column chro-
matography using methanol-chloroform as eluent due to the
marked difference in their R values. The less polar diastereomer
2a (R 0.52; chloroform–methanol = 19:1), was eluted first fol-
lowed by the elution of the more polar diastereomer 12b (R
.41; chloroform–methanol = 19:1) in 42% and 44% yield, respec-
tively. Although we did not succeed in obtaining quality crystals
of (S)-(+)-5 for an X-ray diffraction study, crystals of (R)-(ꢀ)-5 were
obtained by recrystallization from acetone. The crystallographic
data of (R)-(ꢀ)-5 are summarized in Table 1 and its X-ray structure
is shown in Figure 3. The absolute configuration of (R)-(ꢀ)-5 was
unambiguously determined by X-ray analysis as (R) using Flack
f
1
f
f
0
tively. After the separation, diastereomeric esters 12a and 12b
were hydrolysed in the presence of methanolic KOH to afford
enantiopure coumarinyl amino alcohols (S)-(+)-5 and (R)-(ꢀ)-5,
respectively, as colorless solids. The structures of these compounds
2
5
parameter. The absolute configuration of (S)-(+)-5 was estab-
lished to be (S) by comparison of the sign of its specific rotation
to that of its opposite enantiomer (R)-(ꢀ)-5. The molecular packing
structure of R-(ꢀ)-5, as depicted in Figure 4, is stabilized by three
types of intermolecular H-bonding interactions: (i) C(10)-H
10A)---O(2) with bond length of 2.70 Å (green) and C(15)-H
15A)---O(2) with bond length of 2.71 Å (black), (ii) C(15)-H
15B)---O(1) with bond length of 2.64 Å (blue) and (iii) C(11)-H
1
13
were established on the basis of IR, H and C NMR, mass and 2D
COSY spectra. It is worth mentioning that the spectroscopic spectra
of both these enantiomers were found to be almost identical to
that of their racemic form 5. The enantiomeric excesses of the sep-
arated enantiomers (S)-(+)-5 and (R)-(ꢀ)-5 were determined to be
(
(
(
(
11)---p interaction with bond length of 3.38 Å (red centroid).
9
2% and 98.6% by HPLC with chiralpak AD-H column. The specific
R1
N
OH
2`
O
HO
O
R
O
O
O
R
O
O
1
O
R
O
NHR R2
1
R2
3
`
1`
epichlorohydrin
CO , 100 ºC
ethanol, rt
K
2
3
NR R2
N
R
1
a R = H
3
a R = H
1
b R = CH
3
3
b R = CH
3
5
6
H
H
CH (CH )11NH-
3
2
N
7
CH
3
O
O
O
O
O
O
O
O
NHR R2
1
epichlorohydrin
CO , 100 ºC
OH
R1
N
O
ethanol, rt
K
2
3
OH
R2
2
`
1
1
`
3`
2
4
NR R2
N
8
9
1
CH
3 2
(CH )11NH-
0 CH (CH ) CH =CH(CH ) NH-
3
2
7
2 8
Scheme 1. Synthesis of racemic coumarinyl amino alcohols.
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Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Figure 1. ORTEP plot of the X-ray structure of rac-5 with 30% probability.
Figure 2. 2D packing diagram of rac-5 viewed along b axis, showing Hydrogen-bonding interactions (dotted lines).
With the successful resolution of rac-5, we moved to the reso-
lution of racemic compounds 6–10. The esterification of com-
pounds 6–10 with (S)-11 as above in the presence of DCC and
DMAP in dichloromethane at room temperature gave almost 1:1
diastereomeric mixtures of 13a–17a and 13b–17b with marked
difference in their R values. These compounds were separated by
f
column chromatography using methanol/chloroform as eluents
as oils. Removal of the chiral auxiliary from diastereomers 13a–
Unfortunately, all of these enantiopure amino alcohols were
obtained as colorless oil or as semi solid and therefore crystals of
any of these compounds could not be obtained. The absolute con-
figurations of these compounds were deduced by analogy with
compounds (S)-(+)-5 and (R)-(ꢀ)-5. The absolute configurations
of coumarinyl amino alcohols (+)-6–10, which were obtained from
less polar diastereomers 13a–17a were assigned to be (S) while
those of compounds (ꢀ)-6–10 which were obtained from more
polar diastereomeric esters 13b–17b were assigned to be (R).
Next, in order to further corroborate the absolute configuration
of the obtained products, we decided to synthesize enantiomeri-
cally pure (S)-10 and (R)-10 by an alternative route using
1
7a and 13b–17b on treatment with methanolic KOH gave opti-
cally active (+)-6–10 and (ꢀ)-6–10 coumarinyl amino alcohols,
respectively, in good yields and with high enantiomeric purity
(Schemes 2 and 3). The results are summarized in Table 2.
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4
Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Figure 3. ORTEP plot of the X-ray structure of (R)-(ꢀ)-5 with 30% probability.
Figure 4. 2D packing diagram of (R)-(ꢀ)-5 viewed along c axis, showing Hydogen-bonding and CH-
p interactions (dotted lines).
enantiopure epichlorohydrin (Scheme 4). Thus, 4-hydroxy-
compounds of this series rac-9 and 10 demonstrated the best
potency in vitro against both macro- and microfilariae of B. malayi
in nanomolar range with high selectivity index. To examine the
coumarin 2 upon reaction with enantiomerically pure (R)-(ꢀ)-
2 3
epichlorohydrin in the presence of K CO produced epoxide 18
2
D
0
0
with an (S)-stereochemistry ½
a
ꢁ
= +6.6 (c 0.50, acetone) while
effect of stereogenic center at the 2 -position on the antifilarial
with enantiomerically pure (S)-(+)-epichlorohydrin gave epoxide
activity profile of these compounds, we evaluated the in vitro
antifilarial activity of (S)-(+)-9 and 10 and (R)-(ꢀ)-9 and 10 against
the adult female worms of B. malayi using the motility assay
20
1
8 with an (R)-stereochemistry ½
a
ꢁ
= ꢀ6.3 (c 0.50, acetone). The
D
absolute configurations of epoxides (S)-18 and (R)-18 were estab-
lished on the basis of literature reports, which describe that the ini-
tial nucleophilic attack on chiral epichlorohydrin followed by
2
8
according to the method of Nwaka et al. using ivermectin as a
standard antifilarial drug and diethylcarbamazine as a negative
control, since it does not show any in vitro activity. Surprisingly,
the results of the motility scores and the percent inhibition in
MTT reduction by adult worms indicated the reduced activity of
enantiopure compounds in comparison to their racemic forms
(Table 3). While rac-9 caused complete immobility of adult worms
(100%) at very low concentration (1.25 mM), its enantiomeric
components (S)-(+)-9 and (R)-(ꢀ)-9 showed only 75% and 70%
inhibition in motility of adult worms, respectively, at a signifi-
cantly higher concentration of 10 mM. Similarly, rac-10 killed the
adult worms at 0.312 mM while its enantiopure forms (S)-(+)-10
and (R)-(ꢀ)-10 required several times higher concentration
extrusion of the leaving group under basic condition leads to an
inversion of configuration of the product.2
6,27
Epoxides (S)-18
and (R)-18, when treated separately with oleyl amine produced
enantiomerically pure (S)-10 and (R)-10 enantiomers, respectively.
2
D
0
The specific rotations of these compounds, ½
a
ꢁ
= +5.3 (c 0.41, ace-
2
D
0
tone) for (S)-10 and ½
a
ꢁ
= ꢀ6.1 (c 0.42, acetone) for (R)-10, were
found to be in good agreement with those of resolved products
obtained earlier from rac-10 (Table 2), our prior stereochemical
assignments thus validating.
2
.2. Antifilarial activity
(
10 mM) to cause 80% and 75% inhibition in motility, respectively.
In our previous work, we have reported the antifilarial activity
The enantiomerically pure compounds also exerted lower
inhibition in the MTT reduction potential of adult parasites
of racemic 4-oxy coumarinyl amino alcohols.20 The two
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Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
N
EtOOC
higher R
f
R1
N
O
O
O
R1
N
H
OH
O
O
R2
O
O
R
O
R2
KOH/MeOH
reflux
R
1
2
R
NR R
1
2
R
NR R
N
1
1
2a
3a
H
H
N
(
S)-(+)-5
H
H
CH (CH )11NH-
3
2
R1
N
(S)-(+)-6
3 2
CH (CH )11NH-
N
OH
COOH
(S)-11
EtOOC
N
O
O
R
O
14a CH
3
N
R2
(S)-(+)-7 CH
3
DCC, DMAP
DCM, r.t., 3 h
5
-7
lower R
f
N
O
EtOOC
R1
H
OH
R1
N
N
O
O
R
O
O
O
R2
O
R
O
R2
KOH/MeOH
reflux
NR R2
1
1
2
R
H
R
NR R
N
N
(
R)-(-)-5
1
2b
3b
H
H
1
CH (CH )11NH-
3
2
(
R)-(-)-6
H
3 2
CH (CH )11NH-
N
14b CH3
(R)-(-)-7 CH
N
3
Scheme 2. Resolution of rac-5–7 coumarinyl amino alcohols using (S)-11.
O
O
higher R
f
O
O
O
O
R1
N
KOH/MeOH
reflux
R2
O
H
R1
N
O
1
2
R2
NR R
N
HO
NR R
COOEt
N
1
2
1
5a
N
O
O
COOH
11
N
EtOOC
(
S)-
16a
17a
CH (CH )11NH-
3
2
(S)-(+)-8
R1
N
CH (CH ) CH =CH(CH ) NH-
3
2
7
2
8
OH
DCC, DMAP
DCM, r.t., 3 h
(
S)-(+)-9
CH
3
(CH
(CH
2
)
11NH-
O
R2
(S)-(+)-10 CH
3
2
)
7
CH =CH(CH ) NH-
2 8
lower R
f
O
O
8
-10
O
O
O
O
R1
N
KOH/MeOH
reflux
O
H
R1
N
R2
1
2
O
NR R
R2
HO
N
N
COOEt
1
2
1
5b
NR R
1
1
6b
7b
CH
3
(CH
2
)
11NH-
N
(
R)-(-)-8
R)-(-)-9
R)-(-)-10 CH
CH (CH ) CH =CH(CH ) NH-
3
2
7
2 8
(
CH
3
(CH
(CH
2
)
11NH-
(
3
2
)
7
CH =CH(CH ) NH-
2 8
Scheme 3. Resolution of rac-8–10 coumarinyl amino alcohols using (S)-11.
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6
Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 2
Resolution of racemates 5–10
b
Racemic Compds
Enantiomers
(S)-(+)-5
R)-(ꢀ)-5
(S)-(+)-6
R)-(ꢀ)-6
(S)-(+)-7
R)-(ꢀ)-7
(S)-(+)-8
R)-(ꢀ)-8
(S)-(+)-9
R)-(ꢀ)-9
(S)-(+)-10
R)-(ꢀ)-10
Yield (%)
ee (%)a
[a]
D
5
41
42
35
41
41
40
43
44
45
43
44
42
92.0
98.6
n.d.
+10.6
ꢀ11.2
+8.7
(
6
7
8
9
(
n.d.
ꢀ9.4
93.4
92.6
96.4
95.2
n.d.
n.d.
92.4
91.8
+9.6
(
ꢀ8.9
+9.0
(
ꢀ8.6
+5.0
(
ꢀ4.7
+4.9
ꢀ5.6
1
0
(
n.d. = not determined due to lack of compounds.
a
Enantiomeric excesses were determined by HPCL with Chiralpak AD-H column.
All specific rotation were measured in acetone at room temperature.
b
O
O
H
O
Cl
(
R)-(-)-epichlorhydrin
oleyl amine
O
H
(S)-(+)-10
K
2
CO
3
, 100 oC, 2 h
ethanol, r.t., 6 h
O
O
O
(
S)-(+)-18
O
O
H
OH
O
Cl
2
(
S)-(+)-epichlorhydrin
oleyl amine
O
H
(R)-(-)-10
K
2
CO
3
, 100 oC, 2 h
ethanol, r.t., 6 h
O
(R)-(-)-18
Scheme 4. Synthesis of enantiomerically pure (S)-10 and (R)-10.
Table 3
In vitro motility scoring and MTT assay result of the compounds 5–7, 9 and 10 and reference drug against adult worms of B. malayi.
Compound
Conc. (mM)
% Inhibition in B. malayi female adult worm motility
Motility scorea
% Inhibition in MTT reduction
rac-5
20
95
90
90
85
75
70
100
100
80
75
90
80
85
70
85
75
100
—
1+
1+
1+
1+
1+
2+
D
47.2
49.7
46.8
43.8
38.9
45.3
99.5
90.4
38.9
45.3
42.4
38.2
46.2
42.3
47.6
37.8
61.2
—
10
rac-6
rac-7
20
10
20
10
rac-9b
1.25
0.312
20
rac-10b
D
(
(
(
(
S)-(+)-9
1+
1+
1+
1+
1+
2+
1+
1+
D
10
S)-(+)-10
R)-(ꢀ)-9
R)-(ꢀ)-10
20
10
20
10
20
10
Ivermectin
Control 1
8.9
—
4+
a
Motility scores: 4+ = 0%; 3+ = 1–49%; 2+ = 50–74%; 1+ = 75–99%; D = 100%.
Data from Ref. 20.
b
[
(S)-9,(R)-9:45.3%,42.3% and (S)-10,(R)-10:38.2%,37.8%] compared
to their respective racemic forms (rac-9: 99.5% and rac-10:
0.4%). Thus, the antifilarial action of rac-9 and 10 could be
inferior activity compared to the racemates. Racemic compounds
5–7, which were investigated for their antifilarial properties for
the first time, caused 90%, 85% and 70% motility inhibition,
respectively, leading to permanent paralysis in the adult para-
sites and inhibited MTT reduction potential of parasites in the
range of 38.9–49.7%.
9
attributed to the combined effect of both enantiomers and it
seems that on resolution the antifilarial properties are
distributed between the two enantiomers resulting into much
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Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
3
. Conclusion
4H), 2.25 (m, 2H), 2.0 (m, 2H), 1.53 (m, 4H), 1.41 (m, 2H), 1.26 (t,
J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ): d 172.2, 161.8, 160.1,
3
1
3
In conclusion, we have developed a practical and efficient
155.7, 154.6, 143.4, 128.9, 113.5, 113.3, 112.9, 101.7, 70.0, 69.7,
68.6, 61.4, 59.2, 55.2, 46.8, 31.0, 26.1, 24.3, 23.4, 14.8; FT-IR (KBr)
method for the resolution of rac-coumarinyl amino alcohols using
S)-proline ethyl ester as a chiral auxiliary. Enantiomers obtained
after the resolution of their respective rac-aminoalcohols were
ꢀ1
(
mmax, cm : 3417, 2931, 2874, 1729, 1690, 1614, 1508, 1232, 839.
+
ESI-MS (m/z): 473 (M+H) .
1
13
characterized by IR, H and C NMR spectroscopy. The X-ray struc-
ture of the resolved enantiomer (ꢀ)-5 confirmed the (R) stereo-
chemistry of the compound. The results of the antifilarial
motility assay indicate that the synergistic effects of both enan-
tiomers are required to produce significant antifilarial action. This
protocol could be extended to the resolution of other chemically
and medicinally important amino alcohol derivatives. The studies
related with the use of enantiopure coumarinyl amino alcohols
as chiral auxiliaries as well as ligands for certain enantioselective
reactions are currently under progress.
4.2.2. (S)-2-[(S)-1-(Dodecylamino-3-(2-oxo-2H-chromen-7-yl)
oxy-propan-2-yl]-1-ethyl pyrrolidine-1,2-dicarboxylate 13a
2
D
0
= ꢀ7.5 (c 0.56, acetone); 1H
Colorless oily liquid (41%); ½
a
ꢁ
NMR (500 MHz, CDCl ): d 7.62 (d, J = 9.5 Hz, 1H), 7.38 (d,
3
J = 8.5 Hz, 1H), 6.85 (m, 2H), 6.26 (d, J = 9.5 Hz, 1H), 4.6 (m, 1H),
4.13 (m, 5H), 3.51 (m, 6H), 2.16 (m, 2H), 1.91 (m, 2H), 1.66 (m,
1
3
2H), 1.27 (m, 13H), 0.87 (t, J = 6.5 Hz, 3H); C NMR (125 MHz,
CDCl ): d 172.6, 161.9, 161.1, 155.9, 154.5, 143.4, 129.0, 113.6,
113.4, 112.8, 101.9, 70.2, 69.8, 68.7, 61.5, 56.6, 52.0, 46.9, 31.9,
3
3
0.3, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 27.0, 26.9, 24.7, 22.7, 14.8,
ꢀ1
4
4
. Experimental
.1. General
14.2; FT-IR (KBr) mmax, cm :3429, 2925, 2855, 1728, 1712, 1614,
+
1
508, 1232, 1119, 835. ESI-MS (m/z): 573 (M+H) .
4
.2.3. (S)-1-Ethyl-2-[(S)-1-(4-methyl-2-oxo-2H-chromen-7-yl)
1H and 13C NMR spectra were recorded on JEOL 300 and at
00 MHz spectrometer with TMS as the internal standard. Chemi-
oxy-3-(piperidin-1-yl)propan-2-yl]pyrrolidine-1,2-
dicarboxylate 14a
5
2
D
0
= ꢀ11.9 (c 0.34, acetone); 1H
cal shifts are expressed in parts per million (ppm). The proton sig-
nals for residual non-deuterated solvents (d 7.26 for CDCl ) and
carbon signals (d 77.1 for CDCl ) were used as an internal reference
Colorless oily liquid (39%); ½
a
ꢁ
NMR (500 MHz, CDCl ): d 7.43 (d, J = 8.5 Hz, 1H), 6.78 (m, 2H),
6.07 (s, 1H), 4.45 (m, 1H), 4.06 (m, 5H), 3.65 (m, 2H), 3.44 (m,
2H), 2.55 (m, 4H), 2.38 (s, 3H), 2.05 (m, 2H), 1.92 (m, 2H), 1.63
(m, 4H), 1.35 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H); C NMR (125 MHz,
CDCl ): d 172.4, 161.7, 161.2, 155.7, 154.0, 152.5, 113.8, 112.5,
112.2, 111.9, 101.9, 70.2, 68.5, 68.4, 61.3, 58.3, 55.2, 47.2, 31.7,
3
3
3
1
13
for H and C NMR spectra, respectively. Coupling constants are
reported in Hertz. IR spectra were recorded on a JASCO FTIR 5300
in KBr from 400–4000 cm . Analytical thin layer chromatography
TLC) was performed on Silica gel 60 F254 aluminium sheets pre-
1
3
ꢀ1
3
(
ꢀ1
coated with a 0.25 mm thickness of silica gel. Melting points were
determined on Buchi 510 apparatus by an open capillary method
and are uncorrected. Enantiomeric excess (ee%) was determined
on chiral HPLC system using Daicel Chiralpak AD-H column (n-hex-
26.1, 25.3, 24.6, 18.7, 14.7; FT-IR (KBr) mmax, cm : 3425, 2926,
2854, 1730, 1704, 1625, 1567. ESI-MS (m/z): 487 (M+H) .
+
4.2.4. (S)-1-Ethyl-2-[(R)-1-(2-oxo-2H-chromen-7-yl-oxy)-3-(pip-
eridin-1-yl)propan-2-yl]pyrrolidine-1,2-dicarboxylate 12b
ꢀ1
ane/isopropanol = 9:1; flow rate 1.0 mL min ) and UV detector
working at 220 nm. Optical rotations were measured on Perkin–
Elmer 241 polarimeter at 25 °C using sodium D light. All the mate-
rials were obtained from commercial suppliers (SRL, and Spec-
trochem Pvt. Ltd) and were used without further purification.
Silica gel (60–120 mesh and 200–400 mesh) from commercial sup-
plier Spectrochem Pvt. Ltd was used for column chromatography.
ESI mass spectra were recorded using Quattro II (Micromass).
2
D
0
1
Colorless oily liquid (44%); ½
a
ꢁ
= +8.7 (c 0.48, acetone); H NMR
(500 MHz, CDCl ): d 7.63 (d, J = 9.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H),
3
6.85 (m, 2H), 6.26 (d, J = 9.5 Hz, 1H), 5.38 (m, 1H), 4.25 (m, 2H),
4.15 (m, 3H), 3.51 (m, 2H), 2.56 (m, 2H), 2.47 (m, 4H), 2.24 (m,
2H), 2.04 (m, 2H), 1.53 (m, 4H), 1.42 (m, 2H), 1.25 (t, J = 7.0 Hz,
1
3
3H); C NMR (125 MHz, CDCl
155.1, 143.3, 128.9, 113.5, 113.3, 112.9, 101.7, 70.0, 69.7, 68.6,
1.4, 59.2, 55.2, 55.1, 46.8, 31.0, 26.1, 24.3, 23.4, 14.8; FT-IR (KBr)
3
): d 172.3, 161.8, 161.1, 155.9,
6
ꢀ1
4
1
.2. Preparation of the diastereomeric esters 12a–17a and 12b–
7b
mmax, cm : 3417, 2931, 2874, 1729, 1690, 1614, 1508, 1232,
1124, 839. ESI-MS (m/z): 473 (M+H) .
+
N-Carbethoxy-
anhydrous dichloromethane (2 mL), then
1.25 mmol) in anhydrous dichloromethane (2 mL) was added
and the reaction mixture was stirred at room temperature for
h. To this reaction mixture, a solution of appropriate coumarinyl
L
-proline (S)-11 (1.25 mmol) was dissolved in
4.2.5. (S)-2-[(R)-1-Dodecylamino-3-(2-oxo-2H-chromen-7-yl-
a
solution of DCC
oxy)propan-2-yl]-1-ethyl pyrrolidine-1,2-dicarboxylate 13b
2
D
0
1
(
Colorless oily liquid (44%); ½
a
ꢁ
= +8.2 (c 0.52, acetone); H NMR
(500 MHz, CDCl ): d 7.63 (d, J = 9.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H),
3
1
6.86 (m, 2H), 6.26 (d, J = 9.5 Hz, 1H), 4.61 (m, 1H), 4.14 (m, 5H),
amino alcohol (1 mmol) in anhydrous dichloromethane (2 mL) and
DMAP (10 mol %) was added. The progress of the reaction was
monitored by TLC. After 2 h, the reaction mixture was diluted with
3.55 (m, 6H), 2.14 (m, 2H), 1.91 (m, 2H), 1.64 (m, 2H), 1.25 (m,
1
3
13H), 0.87 (t, J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl ): d 175.3,
3
161.7, 161.1, 155.3, 154.5, 143.3, 129.0, 113.6, 113.4, 112.9,
CH
was dried over anhydrous Na
pressure. The crude product was purified by silica gel (200–400
2
Cl
2
and the solid that formed was filtered. The organic layer
101.8, 70.0, 69.8, 68.7, 61.5, 56.6, 52.1, 46.8, 31.9, 30.4, 29.7,
29.6, 29.4, 29.3, 29.2, 26.9, 26.8, 24.8, 22.7, 22.7, 14.8, 14.2; FT-IR
2
SO and concentrated under reduced
4
ꢀ1
(KBr) mmax, cm : 3429, 2925, 2855, 1728, 1712, 1614, 1508,
+
mesh) column chromatography using 1% MeOH in CHCl
to yield two diastereomeric products as viscous liquid.
3
as eluent
1232, 1119, 835. ESI-MS (m/z): 573 (M+H) .
4
.2.6. (S)-1-Ethyl-2-[(R)-1-(4-methyl-2-oxo-2H-chromen-7-yl-
4
.2.1. (S)-1-Ethyl-2-[(S)-1-(2-oxo-2H-chromen-7-yl)oxy-3-(pip-
oxy)-3-(piperidin-1-yl)propan-2-yl]pyrrolidine-1,2-dicarboxy-
eridin-1-yl)propan-2-yl]pyrrolidine-1,2-dicarboxylate 12a
late 14b
20
= ꢀ9.3 (c 0.48, acetone); 1H
20
D
= +11.8 (c 0.34, acetone); 1
Colorless oily liquid (42%); ½
aꢁ
Colorless oily liquid (44%); ½
aꢁ
H
D
NMR (500 MHz, CDCl ):
3
d
7.63 (d, J = 9.5 Hz, 1H), 7.37 (d,
NMR (500 MHz, CDCl ): d 7.44 (d, J = 8.5 Hz, 1H), 6.76 (m, 2H),
3
J = 8.5 Hz, 1H), 6.86 (m, 2H), 6.26 (d, J = 9.5 Hz, 1H), 5.38 (m, 1H),
.25 (m, 2H), 4.15 (m, 3H), 3.49 (m, 2H), 2.55 (m, 2H), 2.44 (m,
6.07 (s, 1H), 4.45 (m, 1H), 4.06 (m, 5H), 3.65 (m, 2H), 3.44 (m,
2H), 2.55 (m, 4H), 2.38 (s, 3H), 2.07 (m, 2H), 1.90 (m, 2H), 1.63
4
Please cite this article in press as: Priyanka,; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.005

8
Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(
m, 4H), 1.35 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
155.2, 153.2, 132.5, 123.8, 122.8, 116.7, 115.4, 90.9, 70.7, 69.2,
68.1, 61.2, 56.4, 49.9, 46.7, 31.8, 30.2, 29.7, 29.6, 29.5, 29.4, 29.3,
3
CDCl ): d 172.3, 161.6, 161.3, 155.8, 154.1, 152.5, 113.9, 112.5,
ꢀ1
1
3
2
12.3, 111.9, 101.8, 70.3, 68.5, 68.3, 61.4, 58.2, 55.2, 55.1, 46.9,
29.2, 26.8, 26.6, 22.6, 22.6, 14.6, 14.0; FT-IR (KBr)
m
max, cm
:
ꢀ
+
1
+
1.1, 26.2, 25.3, 24.6, 18.7, 14.7; FT-IR (KBr)
mmax, cm : 3431,
3432, 2926, 1727, 1705, 1625, 1241; ESI MS (m/z): 573 (M+H) .
926, 2854, 1730, 1626, 1568. ESI-MS (m/z): 487 (M+H) .
4
.2.12. (S)-1-Ethyl-2-[(R)-1-(octadec-9-en-1-ylamino)-3-(2-oxo-
4
.2.7. (S)-1-Ethyl-2-[(S)-1-(2-oxo-2H-chromen-4-yl-oxy)-3-(pip-
2H-chromen-4-yl-oxy)propan-2-yl]pyrrolidine-1,2-dicarboxy-
eridin-1-yl)propan-2-yl]pyrrolidine-1,2-dicarboxylate 15a
late 17b
20
= ꢀ9.5 (c 0.48, acetone); 1H
20
D
1
Colorless oily liquid (40%); ½
aꢁ
Light yellow oily liquid (38%); ½
aꢁ
= +10.75 (c 0.4, acetone); H
D
3
NMR (500 MHz, CDCl ): d 7.77 (d, 1H, J = 7.5 Hz, 1H), 7.55 (m,
NMR (500 MHz, CDCl
3
): d 7.67 (d, J = 7.2 Hz, 1H), 7.52 (m, 1H), 7.25
1
H), 7.31 (m, 2H), 5.73 (s, 1H), 5.48 (m, 1H), 4.28 (m, 3H), 4.06
(m, 2H), 5.66 (s, 1H), 5.34 (m, 2H), 4.54 (m, 1H), 4.31 (m, 2H), 4.13
(
1
m, 1H), 3.50 (m, 2H), 2.58 (m, 6H), 1.92 (m, 2H), 1.56 (m, 2H),
(m, 3H), 3.53 (m, 6H), 2.14 (m, 2H), 1.94 (m, 6H), 1.61 (m, 2H), 1.28
(m, 27H), 0.87 (t, J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl ): d
3
.42 (m, 6H), 1.25 (m, 3H); 13C NMR (125 MHz, CDCl
13
3
): d 172.3,
1
6
65.2, 161.8, 155.0, 153.3, 132.5, 123.9, 122.9, 116.8, 115.0, 90.7,
9.6, 69.3, 68.4, 61.3, 58.8, 55.2, 46.7, 31.0, 26.0, 24.2, 23.3, 14.6;
172.3, 164.8, 161.1, 155.4, 153.4, 132.9, 130.0, 124.8, 122.9,
117.1, 116.6, 91.1, 71.4, 69.8, 68.9, 61.4, 56.4, 49.9, 46.8, 31.8,
ꢀ1
FT-IR (KBr)
m
max, cm : 3423, 2928, 1729, 1705, 1624, 1382,
32.7, 30.3, 29.9, 29.8, 29.7, 29.6, 29.4, 29.3, 27.2, 26.8, 24.4, 22.7,
+
ꢀ1
+
1
240. ESI-MS (m/z): 473 (M+H) .
14.7, 14.1; FT-IR (KBr)
1
m
max, cm : 3422, 2925, 1730, 1704, 1625,
241; ESI MS (m/z): 655 (M+H) .
4
.2.8. (S)-2-[(S)-1-Dodecylamino-3-(2-oxo-2H-chromen-4-yl-
oxy)propan-2-yl]-1-ethyl pyrrolidine-1,2-dicarboxylate 16a
4.3. General method for the hydrolysis of diastereomeric esters
20
= ꢀ9.0 (c 0.48, acetone); 1H
Colorless oily liquid (40%); ½
a
ꢁ
D
NMR (500 MHz, CDCl
3
): d 7.81 (d, J = 7.5 Hz, 1H), 7.54 (m, 1H),
The diastereomeric esters (0.5 mmol) were heated at reflux
with 1 M KOH in methanol (10 mL) for 1 h. Excess solvent was
removed under vacuum, after which water (10 mL) was added
and the reaction mixture was extracted with chloroform. The
7
3
(
.24 (m, 2H), 5.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 2H), 4.14 (m,
H), 3.50 (m, 6H), 2.19 (m, 2H), 1.89 (m, 2H), 1.61 (m, 2H), 1.25
): d
m, 21H), 0.88 (t, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl
3
1
1
3
72.4, 165.1, 161.4, 155.1, 153.3, 132.3, 123.9, 122.9, 116.8,
16.5, 90.9, 71.1, 70.4, 68.8, 61.4, 56.3, 48.9, 46.8, 31.9, 31.0,
0.3, 29.9, 29.7, 29.6, 29.4, 29.3, 26.8, 24.8, 22.7, 22.6, 14.7, 14.1;
extract was washed with brine, dried over anhydrous Na
concentrated under vacuum. The residue was purified by column
chromatography (SiO ) using 3% methanol in chloroform as eluent
to afford the desired enantiopure compounds.
2 4
SO and
2
ꢀ1
FT-IR (KBr) mmax, cm : 3432, 2926, 1727, 1705, 1625, 1241; ESI
MS (m/z): 573 (M+H) .
+
4
.3.1. (S)-7-[2-Hydroxy-3-(piperidin-1-yl)propoxy]-2H-chromen-
4
2
.2.9. (S)-1-Ethyl-2-[(S)-1-(octadec-9-en-1-ylamino)-3-(2-oxo-
H-chromen-4-yl-oxy)propan-2-yl] pyrrolidine-1,2-dicarboxy-
2-one (S)-(+)-5
(S)-(+)-5 was prepared according to the above procedure start-
2
D
5
late 17a
Light yellow oily liquid (39%); ½
NMR (500 MHz, CDCl
ing from 12a as off white solid. Mp.: 61–62 °C; ½
a
ꢁ
= +10.6 (c 0.40,
2
D
0
1
1
a
ꢁ
= ꢀ10.5 (c 0.4, acetone); H
3
acetone); H NMR (500 MHz, CDCl ): d 7.61 (d, J = 9.2 Hz, 1H), 7.35
3
): d 7.68 (d, J = 7.2 Hz, 1H), 7.51 (m, 1H),
(d, J = 8.6 Hz, 1H), 6.88 (dd, J = 8.6 and 2.3 Hz, 1H), 6.83 (s, 1H), 6.24
(d, J = 9.7 Hz, 1H), 4.10 (m, 1H), 4.01 (m, 2H), 2.64 (m, 2H), 2.49 (m,
7
2
.26 (m, 2H), 5.67 (s, 1H), 5.34 (m, 2H), 4.59 (m, 1H), 4.32 (m,
H), 4.12 (m, 3H), 3.53 (m, 6H), 2.12 (m, 2H), 1.94 (m, 6H), 1.62
1
3
2H), 2.40 (m, 2H), 1.60 (m, 4H), 1.47 (m, 2H); C NMR (125 MHz,
CDCl ): d 162.1, 161.2, 155.8, 143.4, 128.8, 113.3, 113.0, 112.8,
101.7, 71.0, 65.1, 60.9, 54.8, 26.0, 24.2; FT-IR (KBr)
3164, 2927, 1723, 1607, 1555, 1282. ESI-MS (m/z): 304 (M+H) .
13
(
(
1
6
2
3
m, 2H), 1.28 (m, 27H), 0.86 (t, J = 6.5 Hz, 3H);
125 MHz, CDCl ): d 172.4, 164.4, 161.2, 155.2, 153.4, 132.9,
30.0, 129.7, 124.7, 122.9, 117.5, 116.4, 91.1, 71.3, 70.1, 68.7,
1.3, 56.4, 49.9, 46.8, 31.9, 32.6, 30.3, 29.9, 29.8, 29.7, 29.6, 29.4,
9.3, 27.2, 26.9, 22.7, 22.7, 14.7, 14.1; FT-IR (KBr)
421, 2925, 2854, 1730, 1704, 1625, 1567, 1241, 1122, 770. ESI
C
NMR
3
ꢀ1
3
mmax, cm
:
+
ꢀ1
m
max, cm
:
4.3.2. (S)-7-(3-Dodecylamino-2-hydroxypropoxy)-2H-chromen-
2-one (S)-(+)-6
+
MS (m/z): 655 (M+H) .
(S)-(+)-6 was prepared according to the above procedure start-
2
D
0
ing from 13a as off white semi solid. ½
a
ꢁ
= +8.7 (c 0.30, acetone);
1
4
.2.10. (S)-1-Ethyl-2-[(R)-1-(2-oxo-2H-chromen-4-yl-oxy)-3-(pip-
3
H NMR (500 MHz, CDCl ): d 7.62 (d, J = 9.5 Hz, 1H), 7.36 (d,
eridin-1-yl)propan-2-yl]pyrrolidine-1,2-dicarboxylate 15b
J = 8.5 Hz, 1H), 6.86 (dd, J = 8.5 and 3.0 Hz, 1H), 6.82 (s, 1H), 6.24
(d, J = 9.5 Hz, 1H), 4.13 (m, 1H), 4.03 (m, 2H), 3.15 (br s, 1H), 2.86
(m, 2H), 2.70 (m, 2H), 1.53 (m, 2H), 1.27 (m, 18H), 0.87 (t,
20
1
Colorless oily liquid (40%); ½
a
ꢁ
= +8.8 (c 0.48, acetone); H NMR
D
1
(
500 MHz, CDCl
J = 7.5 Hz, 1H), 7.55 (m, 1H), 7.31 (m, 2H), 5.73 (s,1H), 5.50 (m,
H), 4.30 (m, 3H), 4.10 (m, 1H), 3.50 (m, 2H), 2.61 (m, 6H), 1.92
m, 4H), 1.56 (m, 2H), 1.42 (m, 4H), 1.23 (m, 3H); 13C NMR
125 MHz, CDCl ): d 172.4, 165.3, 162.0, 155.5, 153.4, 132.6,
24.0, 122.9, 116.8, 115.0, 90.8, 71.2, 69.6, 69.0, 61.4, 58.8, 55.3,
5.2, 46.7, 31.0, 26.0, 25.9, 24.3, 23.4, 14.7; FT-IR (KBr)
3 3
): d H NMR (500 MHz, CDCl ): d 7.78 (d, 1H,
1
3
3
J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl ) d: 161.8, 161.1, 155.7,
1
(
(
1
5
143.3, 128.7, 113.2, 112.8, 112.7, 101.6, 70.8, 67.4, 51.3, 49.6,
ꢀ1
31.8, 29.7, 29.6, 29.4, 29.3, 27.1, 22.6, 14.0. IR (cm , KBr)
m
max
:
+
3
3060, 2922, 1725, 1618, 1239; ESI-MS (m/z): 404 (M+H) .
m
max
,
4.3.3. (S)-7-[2-Hydroxy-3-(piperidin-1-yl)propoxy]-4-methyl-
2H-chromen-2-one (S)-(+)-7
ꢀ
1
cm : 3425, 2926, 1730, 1704, 1625, 1381, 1241. ESI-MS (m/z):
+
4
73 (M+H) .
(S)-(+)-7 was prepared according to the above procedure start-
2
D
5
ing from 14a as light yellow semi solid. ½
aꢁ
= +9.6 (c 0.28, ace-
1
4
.2.11. (S)-2-[(R)-1-Dodecylamino-3-(2-oxo-2H-chromen-4-yl-
3
tone); H NMR (500 MHz, CDCl ): d 7.47 (d, J = 8.6 Hz, 1H), 6.88
oxy)propan-2-yl]1-ethyl pyrrolidine-1,2-dicarboxylate 16b
(dd, J = 8.6 and 2.3 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.11 (s, 1H),
20
1
Colorless oily liquid (40%); ½
500 MHz, CDCl ): d 7.80 (d, J = 7.5 Hz, 1H), 7.54 (m, 1H), 7.27 (m,
H), 5.75 (s, 1H), 4.54 (m, 1H), 4.29 (m, 2H), 4.14 (m, 3H), 3.48 (m,
H), 2.17 (m, 2H), 1.93 (m, 2H), 1.54 (m, 2H), 1.25 (m, 13H), 0.87 (t,
a
ꢁ
= +8.2 (c 0.52, acetone); H NMR
4.11 (m, 1H), 4.01 (m, 2H), 2.63 (m, 2H), 2.90 (br s, 1H), 2.49 (m,
D
1
3
(
2
6
3
7H), 1.60 (m, 4H), 1.47 (m, 2H); C NMR (125 MHz, CDCl
3
): d
161.8, 161.3, 155.2, 152.6, 125.6, 113.8, 112.6, 112.1, 101.7, 70.9,
ꢀ
1
65.1, 60.9, 54.7, 25.9, 24.1, 18.7; FT-IR (KBr)
2933, 1723, 1614, 1266. ESI-MS (m/z): 318 (M+H) .
mmax, cm : 3424,
1
3
+
3
J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl ): d 172.5, 165.1, 162.6,
Please cite this article in press as: Priyanka,; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.005

Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
4
2
.3.4. (R)-7-[2-Hydroxy-3-(piperidin-1-yl)propoxy]-2H-chromen-
-one (R)-(ꢀ)-5
(m, 1H), 7.29 (m, 2H), 5.70 (s, 1H), 5.34 (m, 2H), 4.14 (m, 3H),
2.75 (m, 4H), 2.00 (m, 4H), 1.52 (m, 2H), 1.25 (m, 22H), 0.86 (m,
3H); C NMR (75 MHz, CDCl ): d 165.4, 162.8, 153.2, 132.4,
3
1
3
(
R)-(ꢀ)-5 was prepared according to the above procedure start-
2
D
5
ing from 12b as off white solid. Mp.: 62–63 °C; ½
a
ꢁ
= ꢀ11.2 (c 0.40,
129.8, 123.8, 122.9, 116.7, 115.5, 90.8, 90.6, 71.4, 67.1, 51.4, 49.7,
1
ꢀ1
acetone); H NMR (500 MHz, CDCl
3
): d 7.61 (d, J = 9.7 Hz, 1H), 7.35
31.8, 29.6, 27.1, 22.6, 14.1; FT-IR (KBr)
1735, 1627, 1247. ESI MS (m/z): 486 (M+H) .
m
max, cm : 3472, 2922,
+
(
d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.6 and 2.3 Hz, 1H), 6.81 (d, J = 2.3 Hz,
1
1
H), 6.24 (d, J = 9.2 Hz, 1H), 4.11 (m, 1H), 4.01 (m, 2H), 3.20 (br s,
H), 2.62 (m, 2H), 2.48 (m, 2H), 2.38 (m, 2H), 1.60 (m, 4H), 1.46
4.3.10. (R)-4-[2-Hydroxy-3-(piperidin-1-yl)propoxy]-2H-chromen-
2-one (R)-(ꢀ)-8
1
3
(
m, 2H); C NMR (125 MHz, CDCl
3
): d 162.1, 161.2, 155.8, 143.4,
1
28.8, 113.3, 113.0, 112.8, 101.7, 71.0, 65.1, 60.8, 54.7, 26.0, 24.2;
(R)-(ꢀ)-8 was prepared according to the above procedure start-
ꢀ1
25
FT-IR (KBr)
z): 304 (M+H) .
m
max, cm : 3166, 2928, 1726, 1608, 1230. ESI-MS (m/
ing from 15b as off white semi solid. ½
1
a
ꢁ
= ꢀ8.6 (c 0.20, acetone);
D
+
3
H NMR (300 MHz, CDCl ): d 7.79 (d, J = 7.8 Hz, 1H), 7.47 (m, 1H),
7
.22 (m, 2H), 5.64 (s, 1H), 4.64 (m, 1H), 4.11 (m, 2H), 3.08 (m,
1
3
4
2
.3.5. (R)-7-(3-Dodecylamino-2-hydroxypropoxy)-2H-chromen-
-one (R)-(ꢀ)-6
6H), 1.99 (m, 4H), 1.87 (m, 2H); C NMR (75 MHz, CDCl
3
): d
165.2, 162.8, 153.1, 132.5, 123.9, 123.0, 116.6, 115.3, 90.8, 70.8,
ꢀ1
(
R)-(ꢀ)-6 was prepared according to the above procedure start-
63.9, 60.3, 54.7, 25.7, 24.0; FT-IR (KBr) mmax, cm : 3456, 2946,
20
+
ing from 13b as off white semi solid. ½
a
ꢁ
= ꢀ9.4 (c 0.30, acetone);
1715, 1622, 1242; ESI MS (m/z): 304 (M+H) .
D
1
H NMR (500 MHz, CDCl
3
): d 7.62 (d, J = 9.5 Hz, 1H), 7.35 (d,
J = 8.5 Hz, 1H), 6.85 (dd, J = 8.5 and 2.0 Hz, 1H), 6.81 (s, 1H), 6.24
4.3.11. (R)-4-(3-Dodecylamino-2-hydroxypropoxy)-2H-chromen-
2-one (R)-(ꢀ)-9
(
d, J = 9.5 Hz, 1H), 4.13 (m, 1H), 4.02 (m, 2H), 3.15 (br s, 1H), 2.86
(
m, 2H), 2.69 (m, 2H), 1.53 (m, 2H), 1.26 (m, 18H), 0.87 (t,
(R)-(ꢀ)-9 was prepared according to the above procedure start-
1
3
20
D
J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl
3
) d: 161.9, 161.2, 155.8,
ing from 16b as off white semi solid. ½
aꢁ
= ꢀ4.7 (c 0.40, acetone);
1
1
3
3
43.4, 128.8, 113.3, 112.9, 112.8, 101.7, 71.0, 67.5, 51.4, 49.7,
3
H NMR (500 MHz, CDCl ): d 7.81 (d, J = 7.5 Hz, 1H), 7.51 (m, 1H),
ꢀ1
2.0, 29.8, 29.7, 29.5, 29.4, 27.2, 22.7, 14.2. IR (cm , KBr)
m
max
:
7.24 (m, 2H), 5.73 (s, 1H), 4.52 (m, 1H), 4.14 (m, 2H), 3.17 (m,
+
059, 2921, 1725, 1618, 1239; ESI-MS (m/z): 404 (M+H) .
2H), 2.96 (m, 2H), 1.72 (m, 2H), 1.28 (m, 18H), 0.87 (t, J = 7.5 Hz,
1
3
3
H); C NMR (125 MHz, CDCl
3
): d 165.4, 163.2, 153.1, 132.7,
4
2
.3.6. (R)-7-[2-hydroxy-3-(piperidin-1-yl)propoxy]-4-methyl-
H-chromen-2-one (R)-(ꢀ)-7
124.2, 123.1, 116.7, 115.3, 90.9, 70.7, 65.2, 50.7, 48.8, 31.9, 29.7,
29.6, 29.5, 29.4, 29.2, 26.8, 26.6, 22.7, 14.1; FT-IR (KBr)
cm : 3421, 2926, 1727, 1622, 1241; ESI-MS (m/z): 404 (M+H) .
m
max
+
,
ꢀ1
(
R)-(ꢀ)-7 was prepared according to the above procedure start-
2
D
5
ing from 14b as off light yellow semi solid. ½
a
ꢁ
= ꢀ8.9 (c 0.28, ace-
1
tone); H NMR (500 MHz, CDCl
3
): d 7.47 (d, J = 8.6 Hz, 1H), 6.86 (m,
H), 6.12 (s, 1H), 4.15 (m, 1H), 4.02 (m, 2H), 2.68 (m, 2H), 2.50 (m,
H), 2.38 (s, 3H), 1.63 (m, 4H), 1.48 (m, 2H); 13C NMR (125 MHz,
): d 161.8, 161.5, 155.2, 152.6, 125.6, 113.8, 112.6, 112.4,
4.3.12. (R)-4-[2-Hydroxy-3-(octadec-9-en-1-ylamino)propoxy]-
2H-chromen-2-one (R)-(ꢀ)-10
2
4
(R)-(ꢀ)-10 was prepared according to the above procedure
2
D
5
CDCl
01.7, 70.9, 65.0, 60.9, 54.8, 25.8, 24.0, 18.7; FT-IR (KBr)
3
starting from 17b as light yellow semi solid. ½
a
ꢁ
= ꢀ5.6 (c 0.40,
1
1
m
max
+
,
acetone); H NMR (300 MHz, CDCl
7.54 (m, 1H), 7.30 (m, 2H), 5.70 (s, 1H), 5.35 (m, 2H), 4.13 (m,
H), 2.66 (m, 4H), 2.00 (m, 4H), 1.51 (m, 2H), 1.25 (m, 22H), 0.86
3
): d 7.82 (d, J = 7.8 Hz, 1H),
ꢀ1
cm : 3418, 2925, 1715, 1614, 1281. ESI-MS (m/z): 318 (M+H) .
3
1
3
4
2
.3.7. (S)-4-[2-Hydroxy-3-(piperidin-1-yl)propoxy]-2H-chromen-
-one (S)-(+)-8
3
(t, J = 6.9 Hz, 3H); C NMR (75 MHz, CDCl ): d 165.4, 162.7,
153.2, 132.4, 129.9, 123.8, 122.9, 116.7, 115.5, 90.8, 71.4, 67.1,
(
S)-(+)-8 was prepared according to the above procedure start-
51.3, 49.7, 32.5, 31.8, 29.9, 29.6, 29.2, 27.1, 22.6, 14.0; FT-IR (KBr)
25
ꢀ1
ing from 15a as off white semi solid. ½
a
ꢁ
= +9.0 (c 0.20, acetone);
m
max, cm : 3345, 2921, 1735, 1626, 1249. ESI MS (m/z): 486 (M
D
1
+
H NMR (500 MHz, CDCl
3
): d 7.83 (d, J = 8.0 Hz, 1H), 7.53 (m, 1H),
+H) .
7
1
.27 (m, 2H), 5.68 (s, 1H), 4.22 (m, 1H), 4.10 (m, 2H), 3.01 (br s,
1
3
H), 2.69 (m, 2H), 2.51 (m, 4H), 1.64 (m, 4H), 1.48 (m, 2H);
): d 165.6, 162.9, 153.3, 132.5, 123.9, 123.1,
16.8, 115.6, 90.8, 71.5, 64.6, 60.7, 54.7, 26.0, 25.8, 24.0; FT-IR
C
4.4. Preparation of enantiopure coumarins (S)-10 and (R)-10
NMR (125 MHz, CDCl
1
3
(S)-18 was obtained from 4-hydroxycoumarin 2 (0.5 g,
ꢀ1
(
KBr)
m
max, cm : 3455, 1722, 1619, 1565, 1238. ESI-MS (m/z):
3.08 mmol) and (R)-(ꢀ)-epichlorohydrin (1.14 g, 12.34 mmol) by
+
20
3
04 (M+H) .
the applying the same procedure as for the racemic compound.
Epoxide (S)-18 (0.5 g 2.24 mmol) on reaction with oleyl amine
(0.52 g, 2.75 mmol) in ethanol at room temperature resulted in
the formation of enantiopure coumarinyl amino alcohol (S)-10,
which was purified by column chromatography on silica gel using
chloroform/methanol (97:3) as eluent. Off white semi solid; Yield:
71%.
An analogous method was applied for the synthesis of enantiop-
ure (R)-10 using and (S)-(+)-epichlorohydrin. Off white semi solid;
Yield: 68%.
4
2
.3.8. (S)-4-(3-Dodecylamino-2-hydroxypropoxy)-2H-chromen-
-one (S)-(+)-9
(
S)-(+)-9 was prepared according to the above procedure start-
20
1
ing from 16a as off white semi solid. ½
NMR (500 MHz, CDCl ): d 7.81 (d, J = 7.5, 1H), 7.51 (m, 1H), 7.24 (m,
H), 5.73 (s, 1H), 4.51 (m, 1H), 4.14 (m, 2H), 3.17 (m, 2H), 2.97 (m,
aꢁ
= +5.0 (c 0.4, acetone); H
D
3
2
2
1
3
H), 1.72 (m, 2H), 1.24 (m, 18H), 0.87 (t, J = 7.0 Hz, 3H); C NMR
): d 165.4, 163.1, 153.2, 132.7, 124.1, 123.1,
16.8, 115.3, 90.9, 70.6, 65.2, 50.7, 48.9, 31.9, 29.7, 29.6, 29.5,
9.4, 29.2, 26.8, 26.7, 22.7, 14.1; FT-IR (KBr)
926, 1727, 1623, 1240; ESI-MS (m/z): 404 (M+H) .
(
125 MHz, CDCl
3
1
2
2
ꢀ
1
m
max, cm : 3418,
4.4.1. (S)-4-(Oxiranylmethoxy)-2H-chromen-2-one (S)-18
+
20
D
Off white solid (80%); mp 80–81 °C; ½
a
ꢁ
= +6.6 (c 0.50, ace-
1
3
tone); H NMR (300 MHz, CDCl ): d 7.86 (d, J = 7.5 Hz, 1H), 7.56
4
2
.3.9. (S)-4-[2-Hydroxy-3-(octadec-9-en-1-ylamino)propoxy]-
H-chromen-2-one (S)-(+)-10
(m, 1H), 7.30 (m, 2H), 5.69 (s, 1H), 4.47 (d, J = 11.1 Hz, 1H), 4.02
(dd, J = 11.1 and 6.3 Hz, 1H), 3.46 (m, 1H), 2.99 (m, 1H), 2.82 (m,
1H); C NMR (75 MHz, CDCl ): d 165.0, 162.5, 153.2, 132.5,
3
1
3
(
S)-(+)-10 was prepared according to the above procedure start-
25
ing from 17a as light yellow semi solid. ½
a
ꢁ
= +4.9 (c 0.40, ace-
123.8, 123.1, 116.6, 115.3, 90.7, 69.7, 49.0, 44.3; FT-IR (KBr)
cm : 1721, 1622, 1249, 1108, 760. ESI-MS (m/z): 219 (M+H) .
m
max
,
D
1
ꢀ1
+
tone); H NMR (300 MHz, CDCl
3
): d 7.83 (d, J = 7.5 Hz, 1H), 7.54
Please cite this article in press as: Priyanka,; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.005

1
0
Priyanka et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4
.4.2. (R)-4-(Oxiranylmethoxy)-2H-chromen-2-one (R)-18
thankful to Council of Scientific and Industrial Research (CSIR),
20
Off white solid (81%); mp 80–81 °C; ½
a
ꢁ
= ꢀ6.3 (c 0.50, ace-
New Delhi, India for research fellowships to Priyanka and Sweta
Misra. We are grateful to Head, Department of Pharmaceutics, IIT
(BHU) for providing the facility of polarimeter.
D
1
tone); H NMR (300 MHz, CDCl
3
): d 7.85 (d, J = 8.1 Hz, 1H), 7.55
(
m, 1H), 7.30 (m, 2H), 5.69 (s, 1H), 4.47 (dd, J = 11.1 and 2.4 Hz,
1
2
1
H), 4.02 (dd, J = 11.1 and 6.3 Hz, 1H), 3.47 (m, 1H), 2.99 (m, 1H),
1
3
3
.82 (m, 1H); C NMR (75 MHz, CDCl ): d 165.1, 162.5, 153.2,
A. Supplementary data
32.5, 123.9, 123.0, 116.6, 115.2, 90.9, 69.8, 49.1, 44.3; FT-IR
ꢀ1
(
(
KBr) mmax, cm : 1723, 1621, 1239, 1108, 759. ESI-MS (m/z): 219
M+H) .
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.04.
+
0
05.
4
.5. X-ray crystallographic analysis
References
Crystallographic data for the structures reported herein have
been deposited with the Cambridge Crystallographic Data Centre
CCDC) as supplementary publications. CCDC 1402654 for rac-5
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tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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1
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1
1
0 mM concentration of each compound and the motility of para-
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We thank Banaras Hindu University (BHU), India for providing
the financial support for this work. The spectroscopic data pro-
vided by CISC staff, BHU is gratefully acknowledged. We are also
Please cite this article in press as: Priyanka,; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.04.005