Norepinephrine alkaloids as antiplasmodial agents: Synthesis of syncarpamide and insight into the structure-activity relationships of its analogues as antiplasmodial agents

Article abstract of DOI:10.1016/j.ejmech.2017.07.052

Syncarpamide 1, a norepinephrine alkaloid isolated from the leaves of Zanthoxylum syncarpum (Rutaceae) exhibited promising antiplasmodial activities against Plasmodium falciparum with reported IC₅₀ values of 2.04 μM (D6 clone), 3.06 μM (W2 clone) and observed by us 3.90 μM (3D7 clone) and 2.56 μM (K1 clone). In continuation of our work on naturally occurring antimalarial compounds, synthesis of syncarpamide 1 and its enantiomer, (R)-2 using Sharpless asymmetric dihydroxylation as a key step has been accomplished. In order to study structure-activity-relationship (SAR) in detail, a library of 55 compounds (3–57), which are analogues/homologues of syncarpamide 1 were synthesized by varying the substituents on the aromatic ring, by changing the stereocentre at the C-7 and/or by varying the acid groups in the ester and/or amide side chain based on the natural product lead molecule and further assayed in vitro against 3D7 and K1 strains of P. falciparum to evaluate their antiplasmodial activities. In order to study the effect of position of functional groups on antiplasmodial activity profile, a regioisomer (S)-58 of syncarpamide 1 was synthesized however, it turned out to be inactive against both the strains. Two compounds, (S)-41 and its enantiomer, (R)-42 having 3,4,5-trimethoxy cinnamoyl groups as side chains showed better antiplasmodial activity with IC₅₀ values of 3.16, 2.28 μM (3D7) and 1.78, 2.07 μM (K1), respectively than the natural product, syncarpamide 1. Three compounds (S)-13, (S)-17, (S)-21 exhibited antiplasmodial activities with IC₅₀ values of 6.39, 6.82, 6.41 μM against 3D7 strain, 4.27, 7.26, 2.71 μM against K1 strain and with CC₅₀ values of 147.72, 153.0, >200 μM respectively. The in vitro antiplasmodial activity data of synthesized library suggests that the electron density and possibility of resonance in both the ester and amide side chains increases the antiplasmodial activity as compared to the parent natural product 1. The natural product syncarpamide 1 and four analogues/homologues out of the synthesized library of 55, (S)-41, (R)-42, (S)-55 and (S)-57 were assayed in vivo assay against chloroquine-resistant P. yoelii (N-67) strain of Plasmodium. However, none of the five molecules, 1, (S)-41, (R)-42, (S)-55 and (S)-57 exhibited any promising in vivo antimalarial activity against P. yoelii (N-67) strain. Compounds 4, 6, 7 and 11 showed high cytotoxicities with CC₅₀ values of 5.87, 5.08, 6.44 and 14.04 μM, respectively. Compound 6 was found to be the most cytotoxic as compared to the standard drug, podophyllotoxin whereas compounds 4 and 7 showed comparable cytotoxicities to podophyllotoxin.

Full text of DOI:10.1016/j.ejmech.2017.07.052

Accepted Manuscript
Norepinephrine alkaloids as antiplasmodial agents: Synthesis of syncarpamide and
insight into the structure-activity relationships of its analogues as antiplasmodial
agents
Eswar K. Aratikatla, Tushar R. Valkute, Sunil K. Puri, Kumkum Srivastava, Asish K.
Bhattacharya
PII:
S0223-5234(17)30574-3
10.1016/j.ejmech.2017.07.052
EJMECH 9615
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 6 February 2017
Revised Date: 21 July 2017
Accepted Date: 22 July 2017
Please cite this article as: E.K. Aratikatla, T.R. Valkute, S.K. Puri, K. Srivastava, A.K. Bhattacharya,
Norepinephrine alkaloids as antiplasmodial agents: Synthesis of syncarpamide and insight into the
structure-activity relationships of its analogues as antiplasmodial agents, European Journal of Medicinal
Chemistry (2017), doi: 10.1016/j.ejmech.2017.07.052.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Norepinephrine alkaloids as antiplasmodial agents: Synthesis of syncarpamide and
insight into the structure-activity relationships of its analogues as antiplasmodial agents
Eswar K. Aratikatla, Tushar R. Valkute, Sunil K. Puri, Kumkum Srivastava, and Asish K. Bhattacharya*
O
O
O
R1
O
H
O
R1
O
MeO
MeO
Oxy
Analogues
O
O
HN
O
HN
O
H
Analogues
Syncarpamide
Antiplasmodial activity against
P. falciparum 3D7 clone IC50 = 3.9 µM
P. falciparum K1 clone IC50 = 2.56 µM

ACCEPTED MANUSCRIPT
Norepinephrine alkaloids as antiplasmodial agents: Synthesis of
syncarpamide and insight into the structure-activity relationships of its
analogues as antiplasmodial agents
a,b
a
c
c
Eswar K. Aratikatla, Tushar R. Valkute, Sunil K. Puri, Kumkum Srivastava,
a,b
and Asish K. Bhattacharya *
a
Division of Organic Chemistry, CSIR-National Chemical Laboratory (CSIR-NCL),
Dr. Homi Bhabha Road, Pune-411 008, India
Phone: +91 20 25902309. Fax: +91 20 25902629. E-mail: ak.bhattacharya@ncl.res.in
Academy of Scientific and Innovative Research (AcSIR), CSIR-NCL, Pune-411 008, India
b
c
Parasitology Division, CSIR-Central Drug Research Institute,
Sector-10, Janakipuram Extension, Sitapur Road, Lucknow 226 031, India
Abstract: Syncarpamide 1, a norepinephrine alkaloid isolated from the leaves of Zanthoxylum
syncarpum (Rutaceae) exhibited promising antiplasmodial activities against Plasmodium
falciparum with reported IC50 values of 2.04 µM (D6 clone), 3.06 µM (W2 clone) and
observed by us 3.90 µM (3D7 clone) and 2.56 µM (K1 clone). In continuation of our work on
naturally occurring antimalarial compounds, synthesis of syncarpamide 1 and its enantiomer,
(R)-2 using Sharpless asymmetric dihydroxylation as a key step has been accomplished. In
order to study structure-activity-relationship (SAR) in detail, a library of 55 compounds (3-57),
which are analogues/homologues of syncarpamide 1 were synthesized by varying the
substituents on the aromatic ring, by changing the stereocentre at the C-7 and/or by varying the
acid groups in the ester and/or amide side chain based on the natural product lead molecule and
further assayed in vitro against 3D7 and K1 strains of P. falciparum to evaluate their
1

ACCEPTED MANUSCRIPT
antiplasmodial activities. In order to study the effect of position of functional groups on
antiplasmodial activity profile, a regioisomer (S)-58 of syncarpamide 1 was synthesized
however, it turned out to be inactive against both the strains. Two compounds, (S)-41 and its
enantiomer, (R)-42 having 3,4,5-trimethoxy cinnamoyl groups as side chains showed better
antiplasmodial activity with IC50 values of 3.16, 2.28 µM (3D7) and 1.78, 2.07 µM (K1),
respectively than the natural product, syncarpamide 1. Three compounds (S)-13, (S)-17, (S)-21
exhibited antiplasmodial activities with IC values of 6.39, 6.82, 6.41 µM against 3D7 strain,
5
0
4
.27, 7.26, 2.71 µM against K1 strain and with CC50 values of 147.72, 153.0, >200 µM
respectively. The in vitro antiplasmodial activity data of synthesized library suggests that the
electron density and possibility of resonance in both the ester and amide side chains increases
the antiplasmodial activity as compared to the parent natural product 1. The natural product
syncarpamide 1 and four analogues/homologues out of the synthesized library of 55, (S)-41,
(
R)-42, (S)-55 and (S)-57 were assayed in vivo assay against chloroquine-resistant P. yoelii (N-
7) strain of Plasmodium. However, none of the five molecules, 1, (S)-41, (R)-42, (S)-55 and
S)-57 exhibited any promising in vivo antimalarial activity against P. yoelii (N-67) strain.
Compounds 4, 6, 7 and 11 showed high cytotoxicities with CC values of 5.87, 5.08, 6.44 and
6
(
5
0
1
4.04 µM, respectively. Compound 6 was found to be the most cytotoxic as compared to the
standard drug, podophyllotoxin whereas compounds 4 and 7 showed comparable cytotoxicities
to podophyllotoxin.
Keywords: norepinephrine alkaloids; syncarpamide; synthesis; antiplasmodial activity;
cytotoxicity; in vitro activity; in vivo activity; natural products
2

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1
.
Introduction
The protozoan parasites of the genus Plasmodium cause malaria, which affects more than
0% of the world’s population living in tropical and subtropical regions of America, Asia, and
5
Africa. The WHO reported that more than 212 million people were diagnosed with malaria
leading to approximately 429,000 deaths worldwide in the year 2015 [1,2]. Deaths due to
malaria and confirmed cases (by microscopy) of malaria in India in the year 2015 were
reported to be approximately 440 and 1169,261, respectively [2]. Development of resistance by
the parasites against generally used antimalarial drugs e.g. quinine, chloroquine etc. further
complicates its treatment. The situation was improved with the isolation of artemisinin, a
natural sesquiterpene lactone endoperoxide from the Chinese plant Artemisia annua and
development of its oil-soluble (artemether and arteether) and water-soluble (artelinate and
artesunate) derivatives renewed the hope in efficient treatment of malaria and cerebral malaria
[
3-7]. Isolation of artemisinin from A. annua rekindled interest of several research groups
worldwide to look for new naturally occurring antimalarials from terrestrial plants. In 2004,
Ross et al [8] reported isolation and antiplasmodial activity of norepinephrine alkaloid,
syncarpamide 1 from the leaves of Zanthoxylum syncarpum (Rutaceae) (Figure 1).
Syncarpamide 1 exhibited antiplasmodial activities against P. falciparum with reported [8,9]
IC values of 2.04 µM (D6 clone), 3.06 µM (W2 clone) and 3.90 µM (3D7 clone) and 2.56
5
0
µM (K1 clone) [present work], respectively.
<
<Please insert Figure 1 >>
Interesting antiplasmodial activities of syncarpamide 1 prompted us to synthesize
analogues/homologues of syncarpamide by varying substituents on the aromatic ring, by
changing the stereocentre of the C-7 and/or by varying the acid groups in the ester and/or
3

ACCEPTED MANUSCRIPT
amide side chain in order to develop novel antimalarial agents and to study structure-activity
relationship of the molecule, syncarpamide 1. Further, synthesis of regioisomer of
syncarpamide i.e. to interchange the position of oxygen and nitrogen at C-7 and C-8,
respectively in the syncarpamide 1 to study the role of position of heteroatoms on
antiplasmodial activities was carried out.
2
2
.
Results and discussion
.1. Chemistry
The retrosynthetic analysis of syncarpamide 1 is shown in Scheme 1. It was opined that
syncarpamide 1 could be synthesized by one-pot esterification and amide formation of the
amino alcohol 1a, which in turn can be obtained by the application of Sharpless asymmetric
dihydroxylation (SAD) of 1,2-dimethoxy-4-vinyl benzene 1e followed by functional group
manipulations.
<
<Please insert Scheme 1 >>
2
.1.1. Synthesis of analogues and oxy-analogues of syncarpamide using various substituted
aromatic aldehydes (1-38)
Synthesis of syncarpamide 1, its enantiomer and their oxy-analogues (i.e. the NH at C-8 is
replaced by oxygen) was carried out by varying the substituents on the aromatic aldehyde ring
(Table 1). It was envisaged that straightforward synthesis of oxy-analogues could be achieved
by the Steglich esterification of 1,2-diol with cinnamic acid (Scheme 2). Different substituted
aromatic aldehydes f with one carbon Wittig salt, methyltriphenylphosphonium bromide under
n
strong basic conditions ( BuLi or NaH or NaNH ) furnished corresponding styrenes e [10-14].
2
Styrenes e on Sharpless asymmetric hydroxylation [15] with AD-mix-α or AD-mix-β afforded
the S- or R-diols d [16-25], respectively with high enantiomeric excess (ee). Different
4

ACCEPTED MANUSCRIPT
substituted chiral diols d were reacted with cinnamic acid under DCC, DMAP conditions to
furnish the desired oxy-analogues of syncarpamide (Scheme 2) with high enantiomeric excess
(ee) determined by HPLC analysis [see SI].
<
<Please insert Scheme 2>>
In order to synthesize analogues of syncarpamide 1, different substituted 1,2-amino alcohols
were coupled with cinnamic acid as depicted in Scheme 2. Monotosylation [26-28] of
corresponding diols d with tosyl chloride furnished compounds c, which furnished azido
alcohols b [29-33] when treated with NaN . Subsequent reduction of azido alcohols b with
3
1
0% Pd/C furnished the desired amino alcohols a [34-38]. Amino alcohols a when treated with
cinnamic acid under DCC, DMAP conditions furnished the desired analogues of syncarpamide
(Scheme 3) with high enantiomeric excess (ee) confirmed by HPLC analysis [see SI].
<
<
<Please insert Scheme 3>>
<Please insert Table 1>>
2
.1.2. Synthesis of analogues of syncarpamide using various carboxylic acids (39-52)
A second variation in the analogue synthesis of syncarpamide 1 was thought for varying both
the cinnamoyl groups with various aliphatic and/or aromatic carboxylic acids. When the amino
alcohol 1a was coupled with two equivalents of the aromatic or aliphatic acid furnished the
analogues of syncarpamide (39-48, Table 2) having same groups in the ester as well as amide
side chains (Scheme 4). Similarly, analogues of syncarpamide bearing different side chains (-
OX and -NHY) were synthesized as depicted in Scheme 5. Azido alcohol 1b was coupled with
aliphatic or aromatic acid to furnish 1g, which on reduction with either 10% Pd/C or PPh3
5

ACCEPTED MANUSCRIPT
afforded compound 1h. Compound 1h was again coupled with various aliphatic or aromatic
acids to furnish the desired analogues (49-52, Table 3, entries 1-4).
<
<
<
<
<Please insert Scheme 4>>
<Please insert Table 2>>
<Please insert Scheme 5>>
<Please insert Table 3>>
2
.1.3. Synthesis of other analogues (53-58)
Following the above-mentioned strategy, further interesting analogues/homologues of
syncarpamide 1 were synthesized (Figure 2).
<
<Please insert Figure 2>>
Further, from the structure-activity relationship point of view, it was felt necessary to
synthesize a compound having functional groups interchanged with reference to the parent
molecule i.e. regioisomer 58 to verify its activity profile vis-a-vis syncarpamide 1. Dimethoxy
styrene 1e on Sharpless amino hydroxylation [39] furnished compound 1i that on Cbz
deprotection with Pd/C (10%) furnished the desired amino alcohol 1j, which was coupled with
cinnamic acid to furnish the regioisomer 58 of syncarpamide 1 (Scheme 6).
<
<Please insert Scheme 6>>
Biological Studies
3
.
3
.1. In vitro antiplasmodial activity
6

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In the present study, in vitro antiplasmodial activity of syncarpamide 1 and its
analogues/homologues synthesized by varying substituents on the aromatic ring, by changing
the stereocentre of the C-7 and/or by varying the acid groups in the ester and/or amide side
chain were evaluated against P. falciparum chloroquine-sensitive (CQ) strain 3D7 and
chloroquine-resistant strain K1 with chloroquine (CQ) as a reference drug [40-41]. Also, the
impact of regioisomer (S)-58 of syncarpamide 1 on antiplasmodial activity was studied.
Cytotoxicity of all the synthesized molecules was carried out using Vero cell line (C1008;
Monkey kidney fibroblast) [42].
3
.1.1. In vitro antiplasmodial activity of analogues and oxy-analogues 1-38
Syncarpamide 1 showed in vitro activities against 3D7 and K1 strains of P. falciparum with
IC values of 3.90 and 2.56 µM, respectively and CC value of 80.66 µM against Vero cell
5
0
50
line (C1008; Monkey kidney fibroblast). Initially, the role of substituents on the aromatic ring
of the syncarpamide 1 and also its enantiomer on the antiplasmodial activity (Table 4) was
studied. The enantiomer of syncarpamide 1 i.e. (R)-2 was found to be less active against both
strains. The oxy-analogues of syncarpamide 1 i.e. (S)-3 and (R)-4 also showed less
antiplasmodial activities. (R)-4 showed cytotoxic activity with CC value of 5.84 µM against
50
Vero cell line. Addition of one more methoxy group on the aromatic ring of syncarpamide
showed antiplasmodial activity in the case of (S)-5 with IC values of 6.69 and 3.64 µM,
5
0
respectively against 3D7 and K1 strains of P. falciparum with CC50 value of 66.74 µM
whereas (R)-6 was less active and also cytotoxic with CC value of 5.08 µM. Similar results
5
0
were observed with oxy-analogues (S)-7 and (R)-8. Compound (S)-7 exhibited IC values of
5
0
3
.37 and 3.47 µM against 3D7 and K1 strains, respectively and CC50 value of 6.44 µM
indicating its cytotoxicity. Compound (S)-9 exhibited IC value of 7.69 µM against 3D7 strain
5
0
and CC value of 77.81 µM. The oxy-analogue (S)-11 bearing methoxy group at o-position
50
7

ACCEPTED MANUSCRIPT
showed antiplasmodial activity against both the strains with IC values of 3.80 (3D7) and 3.23
5
0
µM (K1) having cytotoxicity with CC value of 14.04 µM. Compound (S)-13 exhibited IC
50
50
values of 6.39 and 4.27 µM against 3D7 and K1 strains, respectively and CC value of 147.72
50
µM. Compound (S)-17 exhibited IC values of 6.82 (3D7) and 7.26 µM (K1) with CC value
5
0
50
of 153.0 µM. Compounds 10, 12, 14, 15, 16, 18, 19 and 20 showed less antiplasmodial
activities. Compound (S)-21 exhibited IC values of 6.41 (3D7) and 2.71 µM (K1) with CC
5
0
50
value of >200 µM. Compounds (S)-23, (S)-25, (R)-26, (S)-29, (R)-30, (S)-35 and (R)-38 were
found to be selective against 3D7 strain only and showed activities with IC values of 5.79,
5
0
3
3
.85, 4.72, 6.77, 6.97, 5.95 and 7.42 µM, respectively with cytotoxicity (CC ) values of 28.43,
50
1.69, 63.88, 140.67, 49.36, 31.79, >200 µM, respectively. It is pertinent to mention here that
compounds 4, 6, 7 and 11 showed high cytotoxicities with CC values of 5.87, 5.08, 6.44 and
5
0
1
4.04 µM, respectively (Table 4). Compound 6 was found to be more cytotoxic than the
standard drug, podophyllotoxin whereas compounds 4 and 7 showed comparable cytotoxicities
to podophyllotoxin.
<
<Please insert Table 4>>
3
.1.2. In vitro antiplasmodial activity of analogues 39-52
Next, attention was focused on the variation of side chain of syncarpamide moiety and its
enantiomer (Table 5). Efforts in this direction resulted in the synthesis of two compounds, (S)-
1 and its enantiomer, (R)-42, which showed better activity than the parent compound,
4
syncarpamide 1. When the side chain was changed from cinnamoyl to 3,4,5-trimethoxy
cinnamoyl groups, an increase in antiplasmodial activities was observed against both the
strains of P. falciparum. Compound (S)-41 was found to possess IC values of 3.16 and 1.78
5
0
µM against 3D7 and K1 strain, respectively but was less cytotoxic with CC value of 87.98
50
8

ACCEPTED MANUSCRIPT
µM. Its enantiomer, (R)-42 showed IC values of 2.28 and 2.07 µM against 3D7 and K1 strain,
5
0
respectively [CC value of 88.94 µM]. The better activity could be attributed to the increase in
50
electron-density in the side chain of both the ester as well as amide groups. Both the
compounds (S)-46 and (S)-48 showed IC values of 8.49 and 7.92 µM (3D7) and 4.56 and
5
0
3
.37 µM (K1), respectively. Compounds (S)-46 and (S)-48 showed CC values of 58.91 and
50
4
0.79 µM, respectively. The activities observed in (S)-46 and (S)-48 may be attributed to the
possibility of resonance in the side chains. However, compound (S)-47 lacked activity due to
the presence of OTBS group at the m-position on the aromatic ring of the side chains.
<
<Please insert Table 5>>
Compound (S)-39 and (R)-40 bearing benzoyl groups in the ester as well as amide
functionalities instead of cinnamoyl group were found to be selectively active against 3D7
strain having IC values of 6.67, 3.66 µM with CC values of 38.94, 103.76 µM, respectively.
5
0
50
Compounds (S)-43 and its enantiomer, (R)-44 with dihydro cinnamoyl groups as side chain
was also selective in exhibiting their antiplasmodial activity against 3D7 strain with IC values
5
0
of 2.86, 5.86 µM with CC50 values of 39.34, 73.19 µM, respectively. The remaining
compounds (S)-45, (S)-49, (S)-50, (S)-51 and (S)-52 did not show any activities against any of
the strains. This could be explained due to the complete lack of aromaticity in the side chains
of (S)-45 and partial lack of aromaticity in the side chains of (S)-51 and (S)-52. Effect of partial
resonance on the antiplasmodial activity could be seen in the compounds (S)-49 and (S)-50 as
these two compounds possessed dihydro cinnamoyl group in the ester and amide side chain,
respectively.
3
.1.3. In vitro antiplasmodial activity of other analogues (53-58)
9

ACCEPTED MANUSCRIPT
Next, efforts were directed towards molecules having polycyclic aromatic ring in place of
the syncarpamide core structure (S)-53 and (R)-54 (Table 6). Only (R)-54 exhibited
antiplasmodial activity against K1 strain with an IC value of 2.15 µM [CC : 180.94 µM].
5
0
50
The two oxy-analogues (S)-55 and (S)-56 showed good activity against both the strains.
Compound (S)-55 was found to be the most active with IC value of 2.34 (3D7) and 2.62 µM
5
0
(
K1) [CC : 55.70 µM] whereas compound (S)-56 possessed IC value of 6.29 (3D7) and 2.23
50 50
µM (K1) [CC : 47.38 µM]. The most active compound amongst all the synthesized
50
compounds was found to be compound (S)-57 having IC value of 1.89 and 1.93 µM against
5
0
3
D7 and K1 strains of P. falciparum, respectively [CC value of 42.68 µM]. Compound (S)-
50
5
7 is highly electron-rich due to the presence of three methoxy groups each on the core
structure (aromatic ring) and also on the aromatic rings of the side chains of the ester and
amide functionalities. The role of three methoxy groups each on the aromatic rings of the ester
and amide groups on the antiplasmodial activity can be easily gauged by comparing compound
(S)-57 with that of (S)-5.
<
<Please insert Table 6>>
Interestingly, compound (S)-58 which is a regioisomer of syncarpamide 1 was found to be
totally inactive against both the strains (3D7 and K1) of P. falciparum (Table 6). This
underlines the positional effect of oxygen and nitrogen at C-7 and C-8, respectively in the
syncarpamide 1 to exert antiplasmodial activity.
3
.2. In vivo antimalarial assay
Five compounds, syncarpamide 1, (S)-41, (R)-42, (S)-55 and (S)-57 which showed high in
vitro antiplasmodial activities against both the strains (3D7 and K1) of P. falciparum were
1
0

ACCEPTED MANUSCRIPT
further taken up for their in vivo antimalarial assay against chloroquine-resistant P. yoelii (N-
6
7) strain of Plasmodium [43]. The results are shown in Table 7. Unfortunately, none of the
five molecules, 1, (S)-41, (R)-42, (S)-55 and (S)-57 exhibited any promising in vivo
antimalarial activity against P. yoelii (N-67) strain. There was no significant difference in
percent parasite survival on day 4 in respect to untreated mice, however in mice treated with
arteether no parasite survived on day 4.
<
<Please insert Table 7>>
Conclusions
4
.
In summary, we have accomplished the synthesis of the antiplasmodial compound,
syncarpamide 1 and its enantiomer, (R)-2 using Sharpless asymmetric dihydroxylation as a key
step. We have also synthesized a library of 55 compounds (3-57), which are
analogues/homologues of syncarpamide 1 by varying the substituents on the aromatic ring, by
changing the stereocentre at the C-7 and/or by varying the acid groups in the ester and/or
amide side chain based on the natural product lead molecule. Further, we have successfully
synthesized a regioisomer (S)-58 of syncarpamide 1. Two compounds, (S)-41 and its
enantiomer, (R)-42 having 3,4,5-trimethoxy cinnamoyl groups as side chains showed better
antiplasmodial activity against both the strains (3D7 and K1) than the natural product,
syncarpamide 1. The increase in electron-density in the side chain of both the ester as well as
amide groups results in the better activities. Three compounds (S)-13, (S)-17, (S)-21 exhibited
comparable antiplasmodial activities with syncarpamide 1. Compound (S)-47 lacked activity
due to the presence of OTBS at the m-position on the aromatic ring of the side chains whereas
compounds (S)-46 and (S)-48 showed some degree of activities which may be attributed to the
possibility of resonance in the side chains. The electron density and possibility of resonance in
the both ester and amide side chains increases the in vitro antiplasmodial activity as compared
1
1

ACCEPTED MANUSCRIPT
to the parent natural product 1. The role of stereochemistry at C-7 towards antiplasmodial
activities is not a major contributing factor as could be made out by looking at the in vitro
antiplasmodial activities of molecules (S)-41 and (R)-42. However, four synthesized
compounds (4, 6, 7 and 11) showed high cytotoxicities with CC values of 5.87, 5.08, 6.44
5
0
and 14.04 µM, respectively.
Five compounds, syncarpamide 1, (S)-41, (R)-42, (S)-55 and (S)-57 were assayed in
vivo assay against chloroquine-resistant P. yoelii (N-67) strain of Plasmodium. However, none
of the five molecules, 1, (S)-41, (R)-42, (S)-55 and (S)-57 exhibited any promising in vivo
antimalarial activity against P. yoelii (N-67) strain. The high order of in vitro antiplasmodial
activities exhibited by compounds (S)-41, (R)-42, (S)-55, (S)-56 and (S)-57 qualifies these
compounds as candidates for further development as new antimalarial agents
.
5
.
Experimental section
5
.1.
General
All melting points were recorded on a Büchi melting point apparatus in open capillaries
and are uncorrected. Commercially available reagents and solvents were used as such received.
Dry THF, MeOH and DCM were prepared following the standard procedures. All dry
reactions were carried out under argon atmosphere and flash chromatography was performed
®
with CombiFlash R 200i with UV/VIS and ELSD, Isco Teledyne Inc., USA using RediSep
f
1
column (SiO ). H NMR spectra were recorded on 500 or 400 or 200 MHz spectrometer and
2
1
3
C NMR spectra were recorded at 125 or 100 or 50 MHz. Chemical shifts are reported as δ
values (ppm) relative to internal standard tetramethylsilane in CDCl . HRMS (ESI) were
3
recorded on an Orbitrap (quadrupole plus ion trap) and TOF mass analyser. FT-IR spectra were
recorded on an FT-IR-8300 Shimadzu spectrometer. Optical rotations were recorded on a
1
2

ACCEPTED MANUSCRIPT
JASCO P-1020 polarimeter. HPLC was performed with Shimadzu CLASS-VP or Agilent
HPLC system (UV detection at 254 or 215 nm, Column: Chiralpak-IA or IB (0.46 mm φ X 250
n
mmL), Mobile phase: EtOH in hexane, flow rate 1 mL/min. Racemic samples of final
compounds were prepared by manual mixing of equal quantities of R- and S-isomers.
5
.2. General procedures
5
.2.1. General procedure for the synthesis of substituted styrenes:
To a stirred suspension of methyltriphenylphosphonium bromide in THF, base
(
inorganic base like NaH, NaNH or organic base like n-BuLi) was added under argon at 0 ºC
2
and stirred for 30 min. After the mixture was cooled again to 0 ºC, aromatic aldehyde in THF
was added drop wise and stirred for 12 h. The mixture was concentrated in vacuo and residue
was dissolved in water and the aqueous layer was extracted with DCM (3x35 mL). The
combined organic extracts were dried over anhydrous Na SO , concentrated and purified by
2
4
silica gel (100-200 mesh) column chromatography in petroleum ether: ethyl acetate (95:5) to
afford pure styrene (85-99% yield).
5
.2.2. General procedure for dihydroxylation of styrenes:
A round-bottomed flask, equipped with a magnetic stirrer, was charged with 5 mL of
tert-butyl alcohol, 5 mL of water, and 1.4 g of AD-mix-α or AD-mix-β. Stirring at rt produced
two clear phases; the lower aqueous phase appears bright yellow. The mixture was cooled to 0
ºC whereupon some of the dissolved salts precipitated. One mmol of olefin was added at once,
and the heterogeneous slurry was stirred vigorously at 0 ºC for 6-24 h (progress was monitored
by TLC). While the mixture was stirred at 0 ºC, anhydrous sodium sulfite (1.5 g) was added
and the mixture was allowed to warm to rt and further stirred for 30-60 min. EtOAc (10 mL)
was added to the reaction mixture and after separation of the layers, the aqueous phase was
further extracted with EtOAc (3x5 mL). The combined organic extracts were dried over
anhydrous Na SO and concentrated to afford the diol and the ligand. This crude reaction
2
4
1
3

ACCEPTED MANUSCRIPT
mixture was purified by silica gel column chromatography (100-200 mesh) eluting with
EtOAc/petroleum ether (1:1) to afford the pure1,2-diol in 80-98% yield.
5
.2.3. General procedure for monotosylation of 1,2-diol:
To a stirred solution of diol (1.0 eq) in DCM (10 mL) was added pyridine (10.0 eq) at 0
ºC followed by p-toluenesulfonyl chloride (2.0 eq) and the reaction mixture was stirred for 3-4
h at 0 ºC. After completion of the reaction (TLC), reaction mixture was treated with 10% HCl
at 0 ºC, and extracted with EtOAc (3x20 mL) The combined organic layers were pooled and
washed with water (2x20 mL) and brine (1x20 mL), dried over anhydrous Na SO , filtered,
2
4
and concentrated. The concentrate was purified by silica gel chromatography (100-200 mesh)
using EtOAc/petroleum ether (2:3) to furnish the desired monotosylated product (75-90%
yield).
5
.2.4. General procedure for preparation of 1,2-azido alcohols:
A solution of monotosylate (1.0 eq), tetrabutylammonium iodide (0.05 eq) and sodium
azide (3.0 eq) in DMF was heated at 80-90 ºC for 3-4 h. After completion of the reaction
TLC), reaction mixture was cooled to 0 ºC and water (5 mL) was added. The aqueous layer
(
was extracted with ethyl acetate (3x35 mL). The combined organic layers were washed with
brine (2x20 mL), dried over anhydrous Na SO , filtered, and concentrated. The concentrate
2
4
was purified by silica gel column chromatography (100-200 mesh) using EtOAc/petroleum
ether (3:7) to afford the desired product in 80-95% yield.
5
.2.5. General procedure for the preparation of 1,2-aminoalcohols:
,2-Azido alcohol was dissolved in anhydrous MeOH and 10% palladium on carbon
10% w/w) was added. The reaction mixture was stirred under hydrogen atmosphere until
1
(
completion as determined by TLC and disappearance of azide spot. The reaction mixture was
filtered through Celite (pre-washed with MeOH) and the solvent was removed in vacuo, which
gave the crude compound that was used in the next step without further purification.
5
.2.6. General procedure for coupling with DCC/DMAP:
1
4

ACCEPTED MANUSCRIPT
To a stirred solution of 1,2-diol/1,2-amino alcohol (1 mmol) in dry DCM (5 mL),
corresponding acid (2.5 mmol), DCC (2.5 mmol) and DMAP (4.0 mmol) were added and
stirred at rt for 12 h. After completion of the reaction (TLC), reaction mixture was filtered to
remove insoluble DCU and the filtrate was washed with water (10 mL), brine (10 mL), dried
over anhydrous Na SO and concentrated to furnish a crude residue, which was purified by
2
4
silica gel column chromatography (100-200 mesh) using EtOAc/petroleum ether (1:1) to
afford the final compound in 75-80% yield.
5
.3.1. (S)-2-Cinnamamido-1-(3,4-dimethoxyphenyl)ethyl cinnamate (1):
26
D
Colorless solid; mp 132-135 °C; R = 0.34 (EtOAc-petroleum ether, 2:3); [α]
+41.5 (c 1,
f
CHCl ); IR (CHCl ): 3364, 3301, 3068, 3017, 2932, 2846, 1710, 1664, 1627, 1516, 1455,
3
3
-1 1
1
336, 1258, 1217, 1163, 1030, 984, 861, 758, 672 cm ; H NMR (400 MHz, CDCl ): δ 7.72
3
(d, J = 16.1 Hz, 1H), 7.63 (d, J = 15.7 Hz, 1H), 7.55-7.43 (m, 4H), 7.42-7.29 (m, 6H), 7.03-
6
7
.85 (m, 3H), 6.49 (d, J = 16.1 Hz, 1H), 6.39 (d, J = 15.7 Hz, 1H), 6.07 (brs, 1H), 6.01 (dd, J =
1
3
.7, 5.0 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.92-3.83 (m, 2H, overlapped); C NMR (100
MHz, CDCl ): δ 166.5, 165.9, 149.2, 149.1, 145.8, 141.5, 134.7, 134.1, 130.5, 130.2, 129.7,
3
1
28.9, 128.7, 128.1, 127.8, 120.3,119.0, 117.6, 111.2, 109.8, 74.7, 55.9, 55.9, 44.6; ESI-
+
+
LCMS: m/z 479.95 (M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd 480.1781, found
28
27
5
4
80.1772; HPLC: ee 99.2 % [Chiralpak-IA (0.46 mm φ X 250 mmL), 30% EtOH in hexane,
-1
flow rate 1.0 mL min , UV detection at 254 nm, t = 17.0 min].
R
5
.3.2. (R)-2-Cinnamamido-1-(3,4-dimethoxyphenyl)ethyl cinnamate (2):
23
D
Colorless solid; mp 123-125 °C; R = 0.34 (EtOAc-petroleum ether, 2:3); [α]
-42.0 (c 1,
f
CHCl ); IR (CHCl ): 3364, 3301, 3068, 3017, 2932, 2846, 1710, 1664, 1627, 1516, 1455,
3
3
-
1 1
1
7
3
336, 1258, 1217, 1163, 1030, 984, 861, 758, 672 cm ; H NMR (200 MHz, CDCl ) δ 7.80-
3
.57 (m, 2H, two doublets overlapped), 7.57-7.44 (m, 4H), 7.43-7.29 (m, 6H), 7.06-6.82 (m,
H), 6.50 (d, J = 15.9 Hz, 1H), 6.40 (d, J = 15.7 Hz, 1H), 6.15-5.94 (m, 2H), 3.90 (s, 3H), 3.87
1
5

ACCEPTED MANUSCRIPT
1
3
(
s, 3H), 3.97-3.80 (m, 2H, overlapped); C NMR (100 MHz, CDCl ) δ 166.5, 165.9, 149.2,
3
1
1
49.1, 145.8, 141.5, 134.7, 134.1, 130.5, 130.2, 129.7, 128.9, 128.7, 128.1, 127.8, 120.3,119.0,
+
17.6, 111.2, 109.8, 74.7, 55.9, 55.9, 44.6; ESI-LCMS: m/z 480.25 (M+Na) ; HRMS: m/z for
+
C H NO Na (M+Na) : calcd 480.1781, found 480.1770; HPLC: ee 96.2 % [Chiralpak-IA
28
27
5
-1
(
0.46 mm φ X 250 mmL), 30% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 21.0 min].
R
5
.3.3. (S)-1-(3,4-Dimethoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (3):
24
D
Colorless viscous liquid; R = 0.48 (EtOAc-petroleum ether, 3:7); [α] +29.4 (c 0.5, CHCl3);
f
IR (CHCl ): 3021, 2961, 2938, 1713, 1637, 1579, 1519, 1451, 1422, 1330, 1310, 1256, 1216,
3
-1 1
1
161, 1071, 1028, 863, 756, 711, 684 cm ; H NMR (200 MHz, CDCl ) δ 7.82-7.65 (m, 2H,
3
two doublets overlapped), 7.59-7.44 (m, 4H), 7.44-7.31 (m, 6H), 7.09-6.84 (m, 3H), 6.59-6.39
(m, 2H, two doublets overlapped), 6.19 (dd, J = 8.2, 4.0 Hz, 1H), 4.67-4.42 (m, 2H), 3.91 (s,
1
3
3
1
4
H), 3.88 (s, 3H); C NMR (50 MHz, CDCl ) δ 166.6, 166.1, 149.3, 149.1, 145.5, 145.5,
3
34.2, 130.4, 129.1, 128.9, 128.1, 119.4, 117.7, 117.5, 73.4, 66.1, 56.0, 55.9; ESI-LCMS: m/z
+
+
81.02 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd 481.1622, found 481.1626;
2
8
26
6
HPLC: ee 97.4 % [Chiralpak-IA (0.46 mm φ X 250 mmL), 30% EtOH in hexane, flow rate 1.0
-1
mL min , UV detection at 254 nm, t = 14.0 min].
R
5
.3.4. (R)-1-(3,4-Dimethoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (4):
2
D
5
Colorless viscous liquid; R = 0.48 (EtOAc-petroleum ether, 3:7); [α] -26.9 (c 0.5, CHCl3);
f
IR (CHCl ): 3364, 3020, 1712, 1664, 1637, 1518, 1464, 1450, 1421, 1388, 1329, 1310, 1216,
3
-1 1
1
161, 1027, 988, 928, 864, 771, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.82-7.64 (m, 2H,
3
two doublets overlapped), 7.60-7.44 (m, 4H), 7.44-7.31 (m, 6H), 7.09-6.83 (m, 3H), 6.59-6.37
(m, 2H, two doublets overlapped), 6.18 (dd, J = 8.2, 3.9 Hz, 1H), 4.67-4.42 (m, 2H), 3.91 (s,
1
3
3
1
H), 3.88 (s, 3H); C NMR (50 MHz, CDCl ) δ 166.6, 166.1, 149.3, 149.1, 145.6, 145.6,
3
34.3, 134.3, 130.5, 128.9, 128.2, 119.4, 117.8, 117.5, 111.2, 73.5, 66.2, 56.0, 56.0; ESI-
1
6

ACCEPTED MANUSCRIPT
+
+
LCMS: m/z 481.02 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd 481.1622, found
2
8
26
6
4
81.1626; HPLC: ee 97.9 % [Chiralpak-IA (0.46 mm φ X 250 mmL), 30% EtOH in hexane,
-1
flow rate 1.0 mL min , UV detection at 254 nm, t = 22.5 min].
R
5
.3.5. (S)-2-Cinnamamido-1-(3,4,5-trimethoxyphenyl)ethyl cinnamate (5):
26
D
Colorless solid; mp 126-128 °C; R = 0.37 (EtOAc-petroleum ether, 2:3); [α]
+39.0 (c 1,
f
CHCl ); IR (CHCl ): 3361, 3165, 3018, 1711, 1664, 1633, 1594, 1509, 1463, 1422, 1330,
3
3
-1 1
1
216, 1164, 1130, 770, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.75 (d, J = 16.0 Hz, 1H),
3
7
.65 (d, J = 15.5 Hz, 1H), 7.57-7.44 (m, 4H), 7.44-7.30 (m, 6H), 6.65 (s, 2H), 6.52 (d, J = 16.0
Hz, 1H), 6.40 (d, J = 15.5 Hz, 1H), 6.10-5.92 (m, 2H), 3.95-3.78 (m, 11H) or {3.87 (s, 6H),
1
3
3
1
1
5
.84 (s, 3H), 3.90-3.78 (m, 2H, overlapped)}; C NMR (100 MHz, CDCl ) δ 166.6, 166.0,
3
53.4, 149.2, 149.1, 145.8, 141.5, 134.7, 134.1, 130.5, 130.2, 129.7, 128.9, 128.8, 128.2,
27.8, 120.3, 119.0, 117.5, 111.1,109.8, 103.5, 74.7, 60.8, 55.9, 55.9, 44.6; ESI-LCMS: m/z
+
+
10.26 (M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd 510.1887, found 510.1876;
2
9
29
6
HPLC: ee 100% [Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0
-1
mL min , UV detection at 220 nm, t = 10.0 min].
R
5
.3.6. (R)-2-Cinnamamido-1-(3,4,5-trimethoxyphenyl)ethyl cinnamate (6):
26
D
Colorless solid; mp 126-127 °C; R = 0.37 (EtOAc-petroleum ether, 2:3); [α]
-39.0 (c 1,
CHCl ); IR (CHCl ): 3361, 3165, 3018, 1711, 1664, 1633, 1594, 1509, 1463, 1422, 1330,
f
3
3
-1 1
1
216, 1164, 1130, 770, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.75 (d, J = 16.0 Hz, 1H),
3
7
.65 (d, J = 15.5 Hz, 1H), 7.57-7.44 (m, 4H), 7.44-7.30 (m, 6H), 6.65 (s, 2H), 6.52 (d, J = 16.0
Hz, 1H), 6.40 (d, J = 15.5 Hz, 1H), 6.10-5.92 (m, 2H), 3.95-3.78 (m, 11H) or {3.87 (s, 6H),
1
3
3
1
1
5
.84 (s, 3H), 3.90-3.78 (m, 2H, overlapped)}; C NMR (100 MHz, CDCl ) δ 166.6, 166.0,
3
53.4, 149.2, 149.1, 145.8, 141.5, 134.7, 134.1, 130.5, 130.2, 129.7, 128.9, 128.8, 128.2,
27.8, 120.3, 119.0, 117.5, 111.1,109.8, 103.5, 74.7, 60.8, 55.9, 55.9, 44.6; ESI-LCMS: m/z
+
+
10.08 (M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd 510.1887, found 510.1873;
2
9
29
6
1
7

ACCEPTED MANUSCRIPT
HPLC: ee 98.3% [Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0
-1
mL min , UV detection at 220 nm, t = 21.6 min].
R
5
.3.7. (S)-1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (7):
28
D
Colorless viscous liquid; R = 0.45 (EtOAc-petroleum ether, 3:7); [α] +23.0 (c 1, CHCl ); IR
f
3
(
CHCl ): 3019, 2956, 2921, 1713, 1636, 1593, 1503, 1458, 1377, 1311, 1213, 1158, 1129, 982,
3
-1 1
7
51, 669 cm ; H NMR (400 MHz, CDCl ) δ 7.79-7.67 (m, 2H, two doublets overlapped),
3
7
.57-7.48 (m, 4H), 7.44-7.34 (m, 6H), 6.68 (s, 2H), 6.55 (d, J = 15.9 Hz, 1 H), 6.46 (d, J = 15.9
1
3
Hz, 1 H), 6.16 (dd, J = 8.3, 3.4 Hz, 1H), 4.62-4.46 (m, 2H), 3.89 (s, 6H), 3.84 (s, 3H); C
NMR (100 MHz, CDCl ) δ 166.6, 160.0, 153.4, 145.8, 145.6, 138.1, 134.2, 132.2, 130.5,
3
1
30.5, 128.9, 128.1, 117.5, 117.4, 103.8, 73.7, 66.2, 60.8, 56.2; ESI-LCMS: m/z 511.04
+
+
(
M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd 511.1727, found 511.1736; HPLC: ee
29 28 7
-1
9
8.6 % [Chiralpak-IA (0.46 mm φ X 250 mmL), 30% EtOH in hexane, flow rate 1.0 mL min ,
UV detection at 254 nm, t = 12.7 min].
R
5
.3.8. (R)-1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (8):
2
D
5
Colorless viscous liquid; R = 0.45 (EtOAc-petroleum ether, 3:7); [α] -22.4 (c 0.5, CHCl3);
f
IR (CHCl ): 3360, 3164, 3020, 2935, 2848, 1713, 1635, 1603, 1509, 1458, 1419, 1319, 1216,
3
-1
1
1
164, 866, 762, 669 cm ; H NMR (500 MHz, CDCl ) δ 7.78-7.68 (m, 2H, two doublets
3
overlapped), 7.57-7.48 (m, 4H), 7.42-7.35 (m, 6H), 6.68 (s, 2H), 6.54 (d, J = 15.9 Hz, 1H),
.45 (d, J = 15.9 Hz, 1H), 6.16 (dd, J = 8.6, 3.4 Hz, 1H), 4.57 (dd, J = 11.9, 8.6 Hz, 1H), 4.49
6
1
3
(
dd, J = 11.9, 3.4 Hz, 1H), 3.89 (s, 6H), 3.84 (s, 3H); C NMR (125 MHz, CDCl ) δ 166.6,
3
1
1
66.0, 153.4, 145.8, 145.6, 138.2, 134.2, 132.2, 130.5, 130.5, 128.9, 128.2, 128.1, 117.5,
+
17.4, 103.8, 73.7, 66.2, 60.8, 56.2; ESI-LCMS: m/z 511.06 (M+Na) ; HRMS: m/z for
+
C H O Na (M+Na) : calcd 511.1727, found 511.1733; HPLC: ee 97.9 % [Chiralpak-IA (0.46
29
28
7
-1
mm φ X 250 mmL), 30% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254 nm, t
R
=
28.0 min].
1
8

ACCEPTED MANUSCRIPT
5
.3.9. (S)-2-Cinnamamido-1-(2-methoxyphenyl)ethyl cinnamate (9):
27
D
Colorless solid; mp 112-114 °C; R = 0.45 (EtOAc-petroleum ether, 2:3); [α] +31.5 (c 0.5,
f
CHCl ); IR (CHCl ): 3369, 3016, 2925, 2856, 2404, 1710, 1666, 1629, 1526, 1455, 1323,
3
3
-1 1
1
215, 1170, 1040, 982, 859, 764, 673 cm ; H NMR (400 MHz, CDCl ) δ 7.74 (d, J = 16.1
3
Hz, 1H), 7.59 (d, J = 15.7 Hz, 1H), 7.55-7.26 (m, 12H), 7.02-6.88 (m, 2H), 6.55 (d, J = 16.1
Hz, 1H ), 6.47 (dd, J = 7.8, 3.4 Hz, 1H), 6.40 (d, J = 15.7, 1H), 6.15 (brs, 1H), 3.88 (s, 3H),
1
3
3
1
1
.97-3.77 (m, 2H, overlapped); C NMR(100 MHz, CDCl ) δ 166.5, 165.9, 156.2, 145.7,
3
41.0, 134.8, 134.2, 130.4, 129.6, 129.4, 128.9, 128.7, 128.2, 127.8, 126.4, 126.1, 120.7,
+
20.6, 117.7, 110.7, 69.9, 55.5, 43.9; ESI-LCMS: m/z 450.13(M+Na) ; HRMS: m/z for
+
C H NO Na (M+Na) : calcd 450.1676, found 450.1668; HPLC: ee 94.4 % [Chiralpak-IB
27
25
4
-1
(
0.46 mm φ X 250 mmL), 20% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 10.0 min].
R
5
.3.10. (R)-2-Cinnamamido-1-(2-methoxyphenyl)ethyl cinnamate (10):
2
D
7
Colorless solid; mp 112-114 °C; R = 0.45 (EtOAc-petroleum ether, 2:3); [α] -28.7 (c 0.5,
f
CHCl ); IR (CHCl ): 3369, 3016, 2925, 2856, 2404, 1710, 1666, 1629, 1526, 1455, 1323,
3
3
-1 1
1
215, 1170, 1040, 982, 859, 764, 673 cm ; H NMR (400 MHz, CDCl ) δ 7.74 (d, J = 16.1
3
Hz, 1H), 7.59 (d, J = 15.7 Hz, 1H), 7.55-7.25 (m, 12H), 7.03-6.87 (m, 2H), 6.52 (d, J = 16.1
Hz, 1H ), 6.45 (dd, J = 8.1, 3.7 Hz, 1H), 6.38 (d, J = 15.7, 1H), 6.17 (brs, 1H), 3.88 (s, 3H),
1
3
3
1
1
.98-3.77 (m, 2H, overlapped); C NMR (100 MHz, CDCl ,) δ 166.5, 165.9, 156.2, 145.7,
3
41.0, 134.8, 134.2, 130.4, 129.6, 129.4, 128.9, 128.7, 128.2, 127.8, 126.4, 126.1, 120.7,
+
20.6, 117.7, 110.7, 69.9, 55.5, 43.9; ESI-LCMS: m/z 450.12 (M+Na) ; HRMS: m/z for
+
C H NO Na (M+Na) : calcd 450.1676, found 450.1673; HPLC: ee 96.9 % [Chiralpak-IB
27
25
4
-1
(
0.46 mm φ X 250 mmL), 20% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 7.9 min].
R
5
.3.11. (S)-1-(2-Methoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (11):
1
9

ACCEPTED MANUSCRIPT
28
D
Colorless viscous liquid; R = 0.44 (EtOAc-petroleum ether, 1:4); [α] +0.8 (c 1, CHCl ); IR
f
3
(
CHCl ): 2956, 2919, 1713, 1635, 1600, 1493, 1455, 1355, 1308, 1278, 1245, 1157, 1048,
3
-1
1
1
024, 981, 863, 758, 709, 683 cm ; H NMR (200 MHz, CDCl ) δ 7.83-7.61 (m, 2H, two
3
doublets overlapped), 7.60-7.29 (m, 12H), 7.04-6.87 (m, 2H), 6.67-6.38 (m, 3H), 4.58-4.47 (m,
1
3
2
1
5
4
H), 3.89 (s, 3H); C NMR (50 MHz, CDCl ) δ 166.6, 165.9, 156.3, 145.4, 145.2, 134.4,
3
30.3, 130.3, 129.4, 128.8, 128.1, 128.1, 126.9, 125.0, 120.6, 118.0, 117.8, 110.6, 68.9, 65.4,
+
+
5.5; ESI-LCMS: m/z 451.04 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd
2
7
24
5
51.1516, found 451.1507; HPLC: ee 97.2% [Chiralpak-IB (0.46 mm ꢀ X 250 mmL), 40%
-1
EtOH in hexane, flow rate 1.0 mL min , UV detection at 220 nm, t = 6.4 min].
R
5
.3.12. (R)-1-(2-Methoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (12):
28
D
Colorless viscous liquid; R = 0.44 (EtOAc-petroleum ether, 1:4); [α] -0.8 (c 1, CHCl ); IR
f
3
(
CHCl ): 3019, 2360, 2341, 1713, 1663, 1579, 1495, 1439, 1329, 1310, 1283, 1248, 1216,
3
-1 1
1
162, 1050, 980, 770, 711, 684 cm ; H NMR (200 MHz, CDCl ) δ 7.83-7.62 (m, 2H, two
3
doublets overlapped), 7.60-7.29 (m, 12H), 7.05-6.87 (m, 2H), 6.66-6.38 (m, 3H), 4.57-4.48 (m,
1
3
2
1
6
4
H), 3.89 (s, 3H); C NMR (100 MHz, CDCl ) δ 166.7, 166.0, 156.3, 145.4, 145.2, 134.4,
3
30.4, 130.4, 129.5, 128.9, 128.9, 128.2, 128.2, 127.0, 125.0, 120.7, 118.0, 117.8, 110.6, 69.0,
+
+
5.4, 55.6; ESI-LCMS: m/z 451.10 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd
27
24
5
51.1516, found 451.1514; HPLC: ee 96.7% [Chiralpak-IB (0.46 mm ꢀ X 250 mmL), 40%
-1
EtOH in hexane, flow rate 1.0 mL min , UV detection at 220 nm, t = 9.5 min].
R
5
.3.13. (S)-2-Cinnamamido-1-(3-methoxyphenyl)ethyl cinnamate (13):
23
D
Colorless solid; mp 139-141 °C; R = 0.39 (EtOAc-petroleum ether, 2:3); [α] +42.5 (c 0.5,
f
CHCl ); IR (CHCl ): 3361, 3164, 3019, 2400, 1710, 1664, 1634, 1514, 1450, 1411, 1389,
3
3
-1 1
1
330, 1311, 1215, 1165, 1129, 1043, 978, 769, 668 cm ; H NMR (500 MHz, CDCl ) δ 7.73
3
(
d, J = 15.9 Hz, 1H), 7.63 (d, J = 15.6 Hz, 1H), 7.55-7.42 (m, 4H), 7.41-7.26 (m, 7H), 7.03 (d,
J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.50 (d, J = 16.2 Hz, 1H), 6.39 (d, J =
5.6 Hz, 1H), 6.14 (brs, 1H), 6.03 (dd, J = 7.9, 3.4 Hz, 1H), 3.80 (s, 3H), 3.94-3.78 (m, 2H,
1
2
0

ACCEPTED MANUSCRIPT
1
3
overlapped); C NMR (125 MHz, CDCl ) δ 166.4, 166.0, 159.8, 145.9, 141.5, 139.3, 134.7,
3
1
5
4
34.1, 130.5, 129.8, 129.7, 128.9, 128.8, 128.2, 127.8, 120.3,118.6, 117.5, 113.9, 112.1, 74.7,
+
+
5.3, 44.8; ESI-LCMS: m/z 450.02 (M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd
27
25
4
50.1676, found 450.1673; HPLC: ee 96.9% [Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40%
-1
EtOH in hexane, flow rate 1.0 mL min , UV detection at 254 nm, t =13.7 min].
R
5
.3.14. (R)-2-Cinnamamido-1-(3-methoxyphenyl)ethyl cinnamate (14):
2
D
3
Colorless solid; mp 138-140 °C; R = 0.39 (EtOAc-petroleum ether, 2:3); [α] -47.8 (c 0.5,
f
CHCl ); IR (CHCl ): 3361, 3164, 3019, 2400, 1710, 1664, 1634, 1514, 1450, 1411, 1389,
3
3
-1 1
1
330, 1311, 1215, 1165, 1129, 1043, 978, 769, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.74
3
(d, J = 16.0 Hz, 1H ), 7.64 (d, J = 15.7 Hz, 1 H), 7.55-7.43 (m, 4H), 7.42-7.28 (m, 7H), 7.05-
6
.95 (m, 2H), 6.86 (ddd, J = 8.2, 2.7, 0.9 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1 H), 6.39 (d, J = 15.7
1
3
Hz, 1 H), 6.13-5.98 (m, 2H), 3.81 (s, 3H), 3.99-3.73 (m, 2H, overlapped); C NMR (50 MHz,
CDCl ) δ 166.3, 165.9,159.8, 145.9, 141.5, 139.4, 134.7, 134.2, 130.5, 129.8, 129.7, 128.9,
3
1
28.8, 128.2, 127.8, 120.3,118.7, 117.5, 113.9, 112.2, 74.7, 55.3, 44.8; ESI-LCMS: m/z 450.04
+
+
(
M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd 450.1676, found 450.1671; HPLC:
27 25 4
ee 96.6% [Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL
-1
min , UV detection at 254 nm, t =17.8 min].
R
5
.3.15. (S)-1-(3-Methoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (15):
2
D
3
Colorless solid; mp 67-69 °C; R = 0.45 (EtOAc-petroleum ether, 1:4); [α]
+22.7 (c 0.5,
f
CHCl ); IR (CHCl ): 3365, 3169, 3021, 2931, 1713, 1633, 1451, 1316, 1268, 1216, 1165,
3
3
-1 1
1
042, 986, 865, 765, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.83-7.64 (m, 2H, two doublets
3
overlapped), 7.58-7.45 (m, 4H), 7.44-7.26 (m, 7H), 7.09-6.98 (m, 2H), 6.88 (ddd, J = 8.2, 2.5,
0
4
1
.9 Hz, 1H), 6.59-6.38 (m, 2H, two doublets overlapped), 6.22 (dd, J = 7.2, 4.7 Hz, 1H), 4.63-
1
3
.46 (m, 2H), 3.82 (s, 3H); C NMR (50 MHz, CDCl ) δ 166.5, 165.9, 159.8, 145.6, 145.5,
3
38.2, 134.3, 130.4, 129.8, 128.9, 128.2, 119.0, 117.7, 117.5, 114.0, 112.5, 73.5, 66.2, 55.3;
+
+
ESI-LCMS: m/z 451.00 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd 451.1516,
27
24
5
2
1

ACCEPTED MANUSCRIPT
found 451.1513; HPLC: ee 100 % [Chiralpak-IB (0.46 mm φ X 250 mmL), 30% EtOH in
-1
hexane, flow rate 1.0 mL min , UV detection at 254 nm, t = 17.0 min].
R
5
.3.16. (R)-1-(3-Methoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (16):
2
D
3
Colorless solid; mp 67-69 °C; R = 0.45 (EtOAc-petroleum ether, 1:4); [α]
-25.6 (c 0.5,
f
CHCl ); IR (CHCl ): 3365, 3169, 3021, 2931, 1713, 1633, 1451, 1316, 1268, 1216, 1165,
3
3
-1 1
1
042, 986, 865, 765, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.81-7.63 (m, 2H, two doublets
3
overlapped), 7.58-7.46 (m, 4H), 7.43-7.26 (m, 7H), 7.09-6.97 (m, 2H), 6.88 (ddd, J = 8.2, 2.5,
0
4
1
.9 Hz, 1H), 6.59-6.38 (m, 2H, two doublets overlapped), 6.21 (dd, J = 7.2, 4.6 Hz, 1H), 4.63-
1
3
.47 (m, 2H), 3.82 (s, 3H); C NMR (50 MHz, CDCl ) δ 166.5, 165.9, 159.8, 145.6, 145.5,
3
38.2, 134.3, 130.4, 129.8, 128.9, 128.2, 119.0, 117.7, 117.5, 114.0, 112.5, 73.5, 66.2, 55.3;
+
+
ESI-LCMS: m/z 451.01 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd 451.1516,
27
24
5
found 451.1513; HPLC: ee 98.4 % [Chiralpak-IB (0.46 mm φ X 250 mmL), 30% EtOH in
-1
hexane, flow rate 1.0 mL min , UV detection at 254 nm, t = 45.4 min].
R
5
.3.17. (S)-2-Cinnamamido-1-(4-methoxyphenyl)ethyl cinnamate (17):
26
D
Colorless solid; mp 137-139 °C; R = 0.38 (EtOAc-petroleum ether, 2:3); [α] +51.5 (c 0.6,
f
CHCl ); IR (CHCl ): 3361, 3165, 3019, 1688, 1620, 1525, 1411, 1390, 1216, 1043, 771, 669
3
3
-1 1
cm ; H NMR (200 MHz, CDCl ) δ 7.77-7.57 (m, 2H, two doublets overlapped), 7.54-7.42
3
(m, 4H), 7.41-7.28 (m, 8H), 6.91 (d, 2H, p-disubstituted), 6.54-6.32 (m, 2H, two doublets
overlapped), 6.16-6.06 (m, 1H), 6.01 (dd, J = 7.3, 5.6 Hz, 1H), 3.92-3.81 (m, 2H), 3.79 (s, 3H);
1
3
C NMR (50 MHz, CDCl ) δ 166.5, 165.9, 159.7, 145.7, 141.4, 134.7, 134.2, 130.4, 129.8,
3
1
4
29.7, 128.9, 128.7, 128.1, 128.0, 127.8, 120.4, 117.5, 114.1, 74.7, 55.3, 44.6; ESI-LCMS: m/z
+
+
49.96 (M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd 450.1676, found 450.1673;
2
7
25
4
HPLC: ee 96.8% [Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0
-1
mL min , UV detection at 254 nm, t =15.0 min].
R
5
.3.18. (R)-2-Cinnamamido-1-(4-methoxyphenyl)ethyl cinnamate (18):
2
2

ACCEPTED MANUSCRIPT
2
D
6
Colorless solid; mp 138-140 °C; R = 0.38 (EtOAc-petroleum ether, 2:3); [α] -59.5 (c 0.58,
f
CHCl ); IR (CHCl ): 3361, 3165, 3019, 1688, 1620, 1525, 1411, 1390, 1216, 1043, 771, 669
3
3
-1 1
cm ; H NMR (200 MHz, CDCl ) δ 7.78-7.57 (m, 2H, two doublets overlapped), 7.54-7.42
3
(m, 4H), 7.42-7.28 (m, 8H), 6.91 (d, 2H, p-disubstituted), 6.55-6.32 (m, 2H, two doublets
overlapped), 6.13 (t, J = 5.5 Hz, 1H), 6.01 (dd, J = 7.6, 5.3 Hz, 1H), 3.93-3.81 (m, 2H), 3.79 (s,
1
3
3
1
H); C NMR (50 MHz, CDCl ) δ 166.5, 165.9, 159.7, 145.7, 141.4, 134.7, 134.2, 130.4,
3
29.8, 129.7, 128.9, 128.7, 128.1, 128.0, 127.8, 120.4, 117.5, 114.1, 74.7, 55.3, 44.6; ESI-
+
+
LCMS: m/z 450.31 (M+Na) ; HRMS: m/z for C H NO Na (M+Na) : calcd 450.1676, found
2
7
25
4
4
50.1671; HPLC: ee 99.4% [Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane,
-1
flow rate 1.0 mL min , UV detection at 254 nm, t = 26.0 min].
R
5
.3.19. (S)-1-(4-Methoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (19):
2
D
6
Colorless solid; mp 93-96 °C; R = 0.43 (EtOAc-petroleum ether, 1:4); [α]
+32.5 (c 0.5,
f
CHCl ); IR (CHCl ): 3022, 2964, 2358, 1713, 1633, 1513, 1452, 1251, 1215, 1167, 1036, 986,
3
3
-1
1
9
30, 896, 832, 762, 672, 607 cm ; H NMR (500 MHz, CDCl ) δ 7.76-7.66 (m, 2H, two
3
doublets overlapped), 7.56-7.47 (m, 4H), 7.43-7.33 (m, 8H), 6.93 (d, 2H, p-disubstituted), 6.52
(d, J = 16.2 Hz, 1 H), 6.46 (d, J = 15.9 Hz, 1 H), 6.19 (dd, J = 8.6, 3.7 Hz, 1H), 4.57 (dd, J =
1
3
1
1
1.9, 8.5 Hz, 1H), 4.48 (dd, J = 11.9, 3.7 Hz, 1H), 3.80 (s, 3H); C NMR (125 MHz, CDCl ) δ
3
66.6, 166.1,159.8, 145.5, 134.3, 130.4, 128.9, 128.2, 117.8, 117.5, 114.1, 73.2, 66.1, 55.3;
+
+
ESI-LCMS: m/z 451.07 (M+Na) ; HRMS: m/z for C H O Na (M+Na) : calcd 451.1516,
2
7
24
5
found 451.1514; HPLC: ee 98.3 % [Chiralpak-IB (0.46 mm φ X 250 mmL), 40% EtOH in
-1
hexane, flow rate 1.0 mL min , UV detection at 254 nm, t = 17.7 min].
R
5
.3.20. (R)-1-(4-Methoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (20):
2
D
6
Colorless solid; mp 76-79 °C; R = 0.43 (EtOAc-petroleum ether, 1:4); [α]
-31.3 (c 0.5,
f
CHCl ); IR (CHCl ): 3022, 2964, 2358, 1713, 1633, 1513, 1452, 1251, 1215, 1167, 1036, 986,
3
3
-1
1
9
30, 896, 832, 762, 672, 607 cm ; H NMR (400 MHz, CDCl ) δ 7.77-7.65 (m, 2H, two
3
2
3

ACCEPTED MANUSCRIPT
doublets overlapped), 7.57-7.46 (m, 4H), 7.44-7.33 (m, 8H), 6.94 (d, 2H, p-disubstituted), 6.52
(d, J = 16.1 Hz, 1H), 6.46 (d, J = 16.1 Hz, 1H), 6.19 (dd, J = 8.6, 3.9 Hz, 1H), 4.59 (dd, J =
1
3
1
1
1
1.7, 8.3 Hz, 1H), 4.49 (dd, J = 12.0, 3.9 Hz, 1H), 3.80 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
66.6, 166.0, 159.8, 145.4, 134.3, 134.2, 130.4, 128.9, 128.7, 128.2, 128.1, 117.8, 117.5,
+
14.1, 73.2, 66.1, 55.3; ESI-LCMS: m/z 451.09 (M+Na) ; HRMS: m/z for C H O Na
27
24
5
+
(
M+Na) : calcd 451.1516, found 451.1514; HPLC: ee 98.7 % [Chiralpak-IB (0.46 mm φ X
-1
2
50 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254 nm, t = 31.5
R
min].
.3.21. (S)-2-Cinnamamido-1-(2,3-dimethoxyphenyl)ethyl cinnamate (21):
Colorless solid; mp 105-108 °C; R = 0.38 (EtOAc-petroleum ether, 2:3); [α]
5
26
D
-7.9 (c 0.5,
f
CHCl ); IR (CHCl ): 3366, 3170, 3020, 2358, 1706, 1666, 1627, 1520, 1419, 1216, 1168,
3
3
-
1 1
1
1
1
040, 927, 763, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.73 (d, J = 15.9 Hz, 1H), 7.61 (d, J =
3
5.7 Hz, 1H), 7.56-7.43 (m, 4H), 7.42-7.29 (m, 6H), 7.15-6.99 (m, 2H), 6.90 (dd, J = 7.6, 2.2,
H), 6.51 (d, J = 16.0 Hz, 1H), 6.44-6.32 (m, 2H), 6.14 (t, J = 5.4 Hz, 1H), 3.98 (s, 3H), 3.87
1
3
(
s, 3H), 3.90-3.84 (m, 2H, overlapped); C NMR (50 MHz, CDCl ) δ 166.5, 166.0, 152.6,
3
1
1
46.2, 145.8, 141.3, 134.8, 134.2, 131.9, 130.5, 129.7, 128.9, 128.8, 128.2, 127.9, 124.6,
+
20.5, 118.4, 117.6, 112.4, 69.9, 60.9, 55.8, 44.3; ESI-LCMS: m/z 480.22 (M+Na) ; HRMS:
+
m/z for C H NO Na (M+Na) : calcd 480.1781, found 480.1777; HPLC: ee 96.5%
2
8
27
5
-1
[
Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 15% EtOH in hexane, flow rate 1.0 mL min , UV
detection at 254 nm, t = 32.8 min].
R
5
.3.22. (R)-2-Cinnamamido-1-(2,3-dimethoxyphenyl)ethyl cinnamate (22):
26
D
Colorless solid; mp 105-107 °C; R = 0.38 (EtOAc-petroleum ether, 2:3); [α] +8.0 (c 0.58,
f
CHCl ); IR (CHCl ): 3366, 3170, 3020, 2358, 1706, 1666, 1627, 1520, 1419, 1216, 1168,
3
3
-1 1
1
040, 927, 763, 668 cm ; H NMR (200 MHz, CDCl ) δ 7.75 (d, J = 16.0 Hz, 1H), 7.62 (d, J =
3
1
5.7 Hz, 1H), 7.56-7.45 (m, 4H), 7.43-7.30 (m, 6H), 7.15-6.99 (m, 2H), 6.90 (dd, J = 7.6, 2.2
2
4

ACCEPTED MANUSCRIPT
Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.45-6.32 (m, 2H), 6.16 (t, J = 4.9 Hz, 1H), 3.99 (s, 3H),
1
3
3
1
1
.88 (s, 3H), 3.95-3.81 (m, 2H, overlapped); C NMR (50 MHz, CDCl ) δ 166.5, 166.0,
3
52.6, 146.2, 145.8, 141.3, 134.8, 134.2, 131.9, 130.5, 129.7, 128.9, 128.8, 128.2, 127.9,
+
24.6, 120.5, 118.4, 117.6, 112.4, 69.9, 60.9, 55.8, 44.3; ESI-LCMS: m/z 480.23 (M+Na) ;
+
HRMS: m/z for C H NO Na (M+Na) : calcd 480.1781, found 480.1780; HPLC: ee 93.8%
28
27
5
-1
[
Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 15% EtOH in hexane, flow rate 1.0 mL min , UV
detection at 254 nm, t = 29.1 min].
R
5
.3.23. (S)-1-(2,3-Dimethoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (23):
23
D
Colorless viscous liquid; R = 0.4 (EtOAc-petroleum ether, 1:4); [α] -17.0 (c 0.5, CHCl ); IR
f
3
(
CHCl ): 3021, 2943, 2843, 2358, 1713, 1637, 1482, 1448, 1298, 1272, 1215, 1168, 1084,
3
-1 1
1
042, 993, 929, 868, 760, 672, 611 cm ; H NMR (500 MHz, CDCl ) δ 7.78-7.65 (m, 2H, two
3
doublets overlapped), 7.52 (m, 4H), 7.42-7.32 (m, 6H), 7.12-7.01 (m, 2H), 6.92 (d, J = 7.6 Hz,
1
H), 6.60-6.49 (m, 2H), 6.47 (d, J = 16.2 Hz, 1H), 4.61 (dd, J = 11.9, 8.6 Hz, 1H), 4.46 (dd, J
13
=
11.6, 3.1 Hz, 1H), 4.01 (s, 3H), 3.89 (s, 3H); C NMR (125 MHz, CDCl ) δ 166.6, 166.0,
3
1
1
52.6, 146.4, 145.4, 145.3, 134.3, 134.3, 130.5, 130.4, 130.3, 128.9, 128.8, 128.1, 124.2,
+
18.8, 117.8, 117.7, 112.6, 69.1, 65.6, 60.8, 55.8; ESI-LCMS: m/z 481.04 (M+Na) ; HRMS:
+
m/z for C H O Na (M+Na) : calcd 481.1622, found 481.1616; HPLC: ee 97.3% [Chiralpak-
28
26
6
-1
IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at
2
54 nm, t = 7.4 min].
R
5
.3.24. (R)-1-(2,3-Dimethoxyphenyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (24):
2
D
3
Colorless viscous liquid; R = 0.4 (EtOAc-petroleum ether, 1:4); [α] +18.0 (c 0.5, CHCl3);
f
IR (CHCl ): 3021, 2943, 2843, 2358, 1713, 1637, 1482, 1448, 1298, 1272, 1215, 1168, 1084,
3
-1 1
1
042, 993, 929, 868, 760, 672, 611 cm ; H NMR (500 MHz, CDCl ) δ 7.80-7.67 (m, 2H, two
3
doublets overlapped), 7.58-7.48 (m, 4H), 7.44-7.33 (m, 6H), 7.13-7.02 (m, 2H), 6.92 (d, J =
.6 Hz, 1H), 6.61-6.51 (m, 2H), 6.47 (d, J = 16.2 Hz, 1H), 4.61 (dd, J = 11.9, 8.2 Hz, 1H), 4.48
7
1
3
(
dd, J = 11.9, 3.1 Hz, 1H), 4.01 (s, 3H), 3.89 (s, 3H); C NMR (125 MHz, CDCl ) δ 166.6,
3
2
5

ACCEPTED MANUSCRIPT
1
1
66.0, 152.6, 146.4, 145.5, 145.3, 134.3, 134.3, 130.5, 130.4, 130.3, 128.9, 128.8, 128.2,
+
24.2, 118.8, 117.8, 117.7, 112.5, 69.1, 65.6, 60.8, 55.8; ESI-LCMS: m/z 481.09 (M+Na) ;
+
HRMS: m/z for C H O Na (M+Na) : calcd 481.1622, found 481.1619; HPLC: ee 98.2%
2
8
26
6
-1
[
Chiralpak-IA (0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV
detection at 254 nm, t = 8.5 min].
R
5
.3.25. (S)-2-Cinnamamido-1-phenylethyl cinnamate (25):
2
D
8
Colorless solid; mp 181-183°C; R = 0.52 (EtOAc-petroleum ether, 2:3); [α]
+59.8 (c 0.5,
f
CHCl ); IR (CHCl ): 3292, 3022, 2927, 2864, 2404, 2358, 1711, 1667, 1630, 1516, 1419,
3
3
-1 1
1
327, 1216, 1167, 1095, 1030, 929, 764, 670 cm ; H NMR (200 MHz, CDCl ) δ 7.26-7.82
3
1
3
(
m, 17H), 6.30 - 6.60 (m, 2H), 6.06 (m, 2H), 3.69 - 4.06 (m, 2H); C NMR (100 MHz, CDCl )
3
δ 166.5, 166.1, 146.0, 141.6, 137.9, 134.8, 134.2, 130.6, 129.8, 129.0, 128.9, 128.6, 128.3,
+
1
27.9, 126.6, 120.4, 117.6, 74.9, 44.9; ESI-LCMS: m/z420.11 (M+Na) ; HRMS: m/z for
+
C H NO Na (M+Na) : calcd 420.1570, found 420.1566; HPLC: ee 97.1% [Chiralpak-IA
26
23
3
-1
(
0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 12.8 min].
R
5
.3.26. (R)-2-Cinnamamido-1-phenylethyl cinnamate (26):
2
D
8
Colorless solid; mp 183-185°C; R = 0.52 (EtOAc-petroleum ether, 2:3); [α]
-57.3 (c 0.5,
f
CHCl ); IR (CHCl ): 3292, 3022, 2927, 2864, 2404, 2358, 1711, 1667, 1630, 1516, 1419,
3
3
-1 1
1
327, 1216, 1167, 1095, 1030, 929, 764, 670 cm ; H NMR (200 MHz, CDCl ) δ 7.81-7.26
3
1
3
(
m, 17H), 6.59-6.30 (m, 2H), 6.17-5.99 (m, 2H), 4.07-3.71 (m, 2H); C NMR (100 MHz,
CDCl ) δ 166.5, 166.1, 146.0, 141.6, 137.9, 134.8, 134.3, 130.6, 129.8, 129.0, 128.9, 128.6,
3
+
1
28.3, 127.9, 126.6, 120.4, 117.6, 74.9, 44.9; ESI-LCMS: m/z 420.15 (M+Na) ; HRMS: m/z
+
for C H NO Na (M+Na) : calcd 420.1570, found 420.1562; HPLC: ee 94.8% [Chiralpak-IA
2
6
23
3
-1
(
0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 20.4 min].
R
2
6

ACCEPTED MANUSCRIPT
5
.3.27. (S)-1-Phenylethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (27):
26
D
Colorless solid; mp 131-133 °C; R = 0.26 (EtOAc-petroleum ether, 1:9); [α] +42.7 (c 0.5,
f
-1 1
CHCl ); IR (CHCl ): 3022, 1714, 1638, 1436, 1320, 1216, 1166, 767, 671 cm ; H NMR (200
3
3
MHz, CDCl ) δ 7.84-7.65 (m, 2H, two doublets overlapped), 7.60-7.28 (m, 15H), 6.60-6.37
3
1
3
(
m, 2H, two doublets overlapped), 6.24 (dd, J = 7.5, 4.6 Hz, 1H), 4.65-4.44 (m, 2H); C NMR
(
50 MHz, CDCl ) δ 166.6, 166.0, 145.6, 145.5, 136.7, 134.2, 130.4, 128.9, 128.7, 128.2, 126.8,
3
+
1
17.7, 117.5, 73.6, 66.2; ESI-LCMS: m/z 421.24 (M+Na) ; HRMS: m/z for C H O Na
2
6
22
4
+
(
M+Na) : calcd 421.1410, found 421.1411; HPLC: ee 96.5% [Chiralpak-IA (0.46 mm ꢀ X
-1
2
50 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254 nm, t = 8.8
R
min].
.3.28. (R)-1-Phenylethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (28):
5
2
D
6
Colorless solid; mp 132-134 °C; R = 0.26 (EtOAc-petroleum ether, 1:9); [α] -42.0 (c 0.5,
f
-1
1
CHCl ); IR (CHCl ): 3022, 1714, 1638, 1436, 1320, 1216, 1166, 767, 671 cm ; H NMR (200
3
3
MHz, CDCl ) δ 7.84-7.65 (m, 2H, two doublets overlapped), 7.60-7.28 (m, 15H), 6.61-6.37
3
1
3
(
m, 2H, two doublets overlapped), 6.24 (dd, J = 7.5, 4.4 Hz, 1H), 4.66-4.45 (m, 2H); C NMR
(
50 MHz, CDCl ) δ 166.6, 166.0, 145.6, 145.5, 136.7, 134.2, 130.4, 128.9, 128.7, 128.2, 126.8,
3
+
1
17.7, 117.5, 73.6, 66.2; ESI-LCMS: m/z 421.17 (M+Na) ; HRMS: m/z for C H O Na
2
6
22
4
+
(
M+Na) : calcd 421.1410, found 421.1404; HPLC: ee 92.6% [Chiralpak-IA (0.46 mm ꢀ X
-1
2
50 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254 nm, t = 16.6
R
min].
.3.29. (S)-2-Cinnamamido-1-(p-tolyl)ethyl cinnamate (29):
Colorless solid; mp 139-140 °C; R = 0.5 (EtOAc-petroleum ether, 2:3); [α]
5
2
D
8
+55.4 (c 0.5,
f
CHCl ); IR (CHCl ): 3441, 3021, 2926, 2403, 1711, 1669, 1630, 1515, 1438, 1326, 1216,
3
3
-1 1
1
168, 1036, 928, 858, 768, 671 cm ; H NMR (200 MHz, CDCl ) δ 7.79-7.56 (m, 2H, two
3
doublets overlapped), 7.55-7.13 (m, 14H), 6.51 (d, J = 15.9 Hz, 1H), 6.39 (d, J = 15.5 Hz, 1H),
1
3
6
.16-5.96 (m, 2H), 4.00-3.73 (m, 2H), 2.35 (s, 3H); C NMR (100 MHz, CDCl ) δ 166.6,
3
2
7

ACCEPTED MANUSCRIPT
1
1
66.1, 145.8, 141.5, 138.5, 134.9, 134.8, 134.3, 130.6, 129.8, 129.5, 129.0, 128.9, 128.3,
+
27.9, 126.6, 120.5, 117.7, 74.9, 44.8, 21.3; ESI-LCMS: m/z 434.07 (M+Na) ; HRMS: m/z for
+
C H NO Na (M+Na) : calcd 434.1727, found 434.1725; HPLC: ee 95.2% [Chiralpak-IA
27
25
3
-1
(
0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 12.2 min].
R
5
.3.30. (R)-2-Cinnamamido-1-(p-tolyl)ethyl cinnamate (30):
2
D
8
Colorless solid; mp 139-141°C; R = 0.5 (EtOAc-petroleum ether, 2:3); [α]
-59.6 (c 0.5,
f
CHCl ); IR (CHCl ): 3441, 3021, 2926, 2403, 1711, 1669, 1630, 1515, 1438, 1326, 1216,
3
3
-1 1
1
168, 1036, 928, 858, 768, 671 cm ; H NMR (200 MHz, CDCl ) δ 7.79-7.56 (m, 2H, two
3
doublets overlapped), 7.55-7.13 (m, 14H), 6.51 (d, J = 15.9 Hz, 1H), 6.39 (d, J = 15.5 Hz, 1H),
1
3
6
1
1
.16-5.96 (m, 2H), 4.00-3.73 (m, 2H), 2.34 (s, 3H); C NMR (100 MHz,CDCl ) δ 166.6,
3
66.0, 145.8, 141.6, 138.5, 134.9, 134.8, 134.3, 130.6, 129.8, 129.5, 129.0, 128.9, 128.3,
+
27.9, 126.6, 120.4, 117.7, 74.9, 44.8, 21.3; ESI-LCMS: m/z 434.07 (M+Na) ; HRMS: m/z for
+
C H NO Na (M+Na) : calcd 434.1727, found 434.1721; HPLC: ee 95.3% [Chiralpak-IA
27
25
3
-1
(
0.46 mm ꢀ X 250 mmL), 40% EtOH in hexane, flow rate 1.0 mL min , UV detection at 254
nm, t = 20.4 min].
R
5
.3.31. (S)-1-(p-Tolyl)ethane-1,2-diyl (2E,2'E)-bis(3-phenylacrylate) (31):
27
D
Colorless solid; mp 103-105 °C; R = 0.26 (EtOAc-petroleum ether, 1:9); [α] +40.1 (c 0.5,
f
CHCl ); IR (CHCl ): 3361, 3164, 3022, 1712, 1634, 1523, 1445, 1401, 1316, 1268, 1215,
3
3
-1
1
1
165, 1036, 762, 670 cm ; H NMR (400 MHz, CDCl ) δ 7.81-7.66 (m, 2H, two doublets
3
overlapped), 7.59-7.48 (m, 4H), 7.45-7.33 (m, 8H), 7.22 (d, 2H, p-disubstituted), 6.54 (d, 1H, J
=
16.0), 6.46 (d, 1H, J = 16.0), 6.23 (dd, J = 8.2, 3.7 Hz, 1H), 4.61-4.45 (m, 2H), 2.37 (s, 3H);
1
3
C NMR (50 MHz, CDCl ) δ 166.6, 166.0, 145.5, 138.5, 134.3, 133.7, 130.4, 129.4, 128.9,
3
+
1
28.2, 126.8, 117.8, 117.5, 73.5, 66.2, 21.2; ESI-LCMS: m/z 435.16 (M+Na) ; HRMS: m/z for
+
C H O Na (M+Na) : calcd 435.1567, found 435.1559; HPLC: ee 98.3% [Chiralpak-IA (0.46
27
24
4
2
8