Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering potent and selective PTP1B inhibitors

Article abstract of DOI:10.1016/j.ejmech.2018.12.032

Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key regulating effects in insulin signaling and leptin receptor pathways. In this work, a series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared and their PTP1B inhibitory potency, selectivity and membrane permeability were evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited remarkable inhibitory activity, significant selectivity as well as good membrane permeability (e.g. compound 28a, IC₅₀ = 120, 1940 and 2670 nM against PTP1B, TCPTP and SHP2 respectively, and P_app = 1.74 × 10^?6 cm/s). Molecular simulations indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger binding affinity than their cis-isomers by constructing more interactions with non-catalytic sites of PTP1B. Further biological activity studies revealed that compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated insulin receptor β (IRβ) phosphorylation with no significant cytotoxicity.

Full text of DOI:10.1016/j.ejmech.2018.12.032

Accepted Manuscript
Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering
potent and selective PTP1B inhibitors
Fangzhou Xie, Fengzhi Yang, Yaoyao Liang, Liang Li, Yu Xia, Faqin Jiang, Wenlu
Liu, Yunyue Qi, Sharmin Reza Chowdhury, Dongsheng Xie, Lei Fu
PII:
S0223-5234(18)31069-9
DOI:
https://doi.org/10.1016/j.ejmech.2018.12.032
EJMECH 10965
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 30 October 2018
Revised Date: 11 December 2018
Accepted Date: 14 December 2018
Please cite this article as: F. Xie, F. Yang, Y. Liang, L. Li, Y. Xia, F. Jiang, W. Liu, Y. Qi, S.R.
Chowdhury, D. Xie, L. Fu, Investigation of stereoisomeric bisarylethenesulfonic acid esters for
discovering potent and selective PTP1B inhibitors, European Journal of Medicinal Chemistry (2019), doi:
https://doi.org/10.1016/j.ejmech.2018.12.032.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Investigation of Stereoisomeric Bisarylethenesulfonic Acid Esters for Discovering
Potent and Selective PTP1B Inhibitors
a,1
b,1
a
a
a,c
a
Fangzhou Xie , Fengzhi Yang , Yaoyao Liang , Liang Li , Yu Xia , Faqin Jiang ,
d
a
a
e,
a,
Wenlu Liu , Yunyue Qi , Sharmin Reza Chowdhury , Dongsheng Xie *, Lei Fu *
a
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Pharmacy, Shanghai Jiao Tong University (SJTU), 800 Dongchuan Road, Shanghai
2
00240, China
b
Shanghai Ambiopharm, Inc., 388 Chugong Rd., Shanghai Chemical Industry Park,
Shanghai 201424, China.
c
Viva Biotech (Shanghai) Limited, Shanghai 201203, China
d
School of Materials Science and Engineering, Shanghai Jiao Tong University, 800
Dongchuan Rd., Shanghai 200240, China.
e
ChemPartner Co., Ltd., 998 Halei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203,
China.
1
Both authors contributed equally to this work
*
Corresponding authors.
E-mail addresses: dshxie@chempartner.com (D.S. Xie), leifu@sjtu.edu.cn (L. Fu)
Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising
therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key
regulating effects in insulin signaling and leptin receptor pathways. In this work, a
series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared
and their PTP1B inhibitory potency, selectivity and membrane permeability were
evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited
remarkable inhibitory activity, significant selectivity as well as good membrane
permeability (e.g. compound 28a, IC = 120, 1940 and 2670 nM against PTP1B,
5
0
-6
TCPTP and SHP2 respectively, and Papp = 1.74 × 10 cm/s). Molecular simulations

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indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger
binding affinity than their cis-isomers by constructing more interactions with
non-catalytic sites of PTP1B. Further biological activity studies revealed that
compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated
insulin receptor β (IRβ) phosphorylation with no significant cytotoxicity.
Key words: PTP1B Inhibitors, Selectivity, Pyrrolidine bisarylethenesulfonic acid
esters, Type 2 diabetes
1
. Introduction
Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), which
together maintain proper levels of tyrosine phosphorylation, are crucial for cellular
processes including growth, differentiation, metabolism, migration, and survival [1].
PTKs and PTPs provide potential molecular targets for the therapeutic interventions
of associated diseases such as autoimmune disorders, diabetes, obesity and cancers
[
2-5]. So far, more than dozens of PTKs inhibitors have been already approved for
clinical use, but only a few of PTPs inhibitors went through deep investigations and
came into clinical trials. There is a huge space for PTPs to develop novel
chemotherapeutic agents for the associated diseases [6,7].
Protein tyrosine phosphatase 1B (PTP1B), the first isolated enzyme of PTPs family,
is a key negative regulator of insulin signaling and leptin receptor pathways [8-10].
PTP1B deficient rodents were viable and healthy, and displayed improved insulin
sensitivity and resistance to diet-induced obesity [11], which had provided a strong
evidence of PTP1B to be a promising drug target for the treatment of type 2 diabetes
and obesity [12].
Various PTP1B inhibitors have been developed in the past decades for further
pharmacological research [13,14]. However, the most typically potent PTP1B
inhibitors with anionic pharmacophores [15-17] suffered a drawback of poor
membrane permeability. High ionization of these inhibitors in physiological situation
prevent them from penetrating cellular membranes, although the anionic

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pharmacophores could bind specifically to the catalytic site of PTP1B and offer potent
inhibitory activity in vitro. Another knotty problem is the poor selectivity of existing
inhibitors for PTP1B over other members of PTPs family, particularly T-cell PTP
(TCPTP) which is vital for rodent survival [18,19].
In view of these, some of recent researches on PTP1B inhibitors are focusing on the
improvement of molecular selectivity and membrane permeability [20-22]. We
previously reported a number of linear arylethenesulfonic acid ester compounds
(Fig.1, compounds I and II) as nonionic PTP1B inhibitors, revealing that sulfonic
acid ester was an effective bioisostere of phosphoric acid and carboxylic acid moiety
in inhibition of PTP1B [23,24]. Some of Y-shaped bisarylethenesulfonic acid esters
(e.g. compound III), which probably interact with multiple secondary binding sites (B,
C, D or E site) in addition to the catalytic site (A site) of PTP1B [25], showed high
potency, good membrane permeability, and PTP1B selectivity in some degree. Hence,
compared with linear structures, more complex stereo-chemical structure resulting
from extra branching could contribute to increasing binding affinity and improving
bisarylethenesulfonic acid esters’ selectivity in inhibition of PTP1B.
Fig. 1
To further explore the SARs of bisarylethenesulfonic acid esters and search for
potent, selective and membrane permeable PTP1B inhibitors, we designed,
synthesized and biologically evaluated a series of stereoisomeric pyrrolidine
bisarylethenesulfonic acid esters (cis- and trans-isomers here). With amyloxalyl as the
preferred linker, some of derivatives, particularly the trans-isomers, exhibited potent
PTP1B inhibitory activity and significant selectivity. Furthermore, the differences in
PTP1B activity and selectivity between the two kinds of stereoisomers were analyzed
and explained by docking simulations. As the most potent and selective PTP1B
inhibitor in this presentation, compound 28a could enhance insulin-stimulated glucose
uptake and insulin-mediated insulin receptor β (IRβ) phosphorylation without
significant cytotoxicity. This research gives us valuable insights on discovering novel
PTP1B inhibitors with higher potency and better selectivity.

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2
. Chemistry
The key intermediates (7a and 7b) of stereoisomeric pyrrolidine
bisarylethenesulfonic acid ester derivatives were synthesized according to the method
outlined in Schemes 1 and 2, respectively. Compound 7a was prepared from
L(+)-tartaric acid (1a) via 7 steps (Scheme 1). Firstly, a ring-closing reaction was
conducted by heating 1a with benzylamine, and then the cyclization product (2a) was
reduced to the diol (3a) by LiAlH . Intermediate 3a reacted with methanesulfonic
4
anhydride to afford the dimethanesulfonate (4a) [26], which underwent a nucleophilic
substitution to give the dialdehyde (5a). In the presence of NaH, 5a was converted to
6
a through Wittig-Horner reaction by treatment with ethyl (diethoxyphosphoryl)
methanesulfonate [24]. Finally, 6a was debenzylated via two steps to afford 7a as the
key intermediate of trans-derivatives [27].
Scheme 1
Compound 7b, the common intermediate of cis-derivatives, was prepared from
cis-butenedioic anhydride (1b) via 9 steps (Scheme 2). Compound 1b was treated
with benzylamine and then experienced a cis-dihydroxylation by hydrogen peroxide
to give 2b [28]. Intermediate 2b underwent the same procedure to intermediate 2a in
Scheme 1 to provide 3b and 4b. Via two separated steps of nucleophilic substitution
at different temperatures, 4b was converted to 5b. Also following the same procedure
in Scheme 1, 5b was converted to 6b and finally 7b.
Scheme 2
Strategies for synthesis of stereoisomeric pyrrolidine bisarylethenesulfonic acid
ester derivatives (8a-28a and 16b–28b) from intermediate 7a or 7b are depicted in
Schemes 3. Compound 8a and 9a were synthesized from 7a by reductive amination
with corresponding aldehydes. Intermediate 7a condensed with various arylformic
acids using HBTU to yield compounds 10a-12a. Intermediate 7a also reacted with
triphosgene and various arylamines to give 13a-15a [29]. Compounds 16a-28a and

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1
6b-28b were prepared from intermediate 7a or 7b by acylation with ethyl oxalyl
monochloride, hydrolysis with aqueous LiOH [30,31] and condensation with
arylamines in sequence.
Scheme 3
3
. Result and discussion
3
.1. PTP1B enzyme inhibitory activities and structure activity relationships
We have already realized that branching especially with big and long chains could
change the stereochemistry environment of linear bisarylethenesulfonic acid esters,
and construct richer and differentiated interactions with PTP1B, endowing these
molecules with potent and to some extent selective PTP1B inhibition. In fact, a more
effective strategy to change stereochemistry environment of molecules is to design
stereoisomers. For the convenience of chemical synthesis, we took
pyrrolidine-3,4-bisarylethenesulfonic acid esters as the core scaffold for discovering
potent and selective PTP1B inhibitors. Pyrrolidine-3,4-bisarylethenesulfonic acid
esters including cis- and trans-stereoisomers are easily branched by alkylation and
acylation at the 1-amino. Four kinds of linkers, which are methylene, carbonyl,
amylacyl, and amyloxalyl, were investigated in this presentation. As shown in the
Table 1, all pyrrolidine bisarylethenesulfonic acid esters, whichever the linker is,
were more potent than their parent molecule (i.e. compound 7a, IC = 16.8 µM),
5
0
indicating that branched chains of bisarylethenesulfonic acid esters can provide
additional interactions with PTP1B. Consistent with our previous research, bigger or
longer hydrophobic chains contributed to more significant inhibitory activity (e.g.
compound group 6a/8a/9a, 13a/14a/15a, and 16a/17a/18a). In addition, compound 6a,
1
0a, 13a, and 16a showed gradual increasing PTP1B inhibitory activity (IC = 9.34,
50
7
.81, 3.51 and 2.52 µM respectively), and similar phenomena were also observed in
compound group 8a/11a/14a/17a and 9a/12a/15a/18a, suggesting that amyloxalyl is
an active linker for high PTP1B inhibitory activity. Therefore, both linker’s structure
and hydrophobic surface area of branched chains influenced the PTP1B inhibitory
activity of bisarylethenesulfonic acid esters.

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Table 1
With amyloxalyl as the optimized linker, more pyrrolidine bisarylethenesulfonic
acid esters were subsequently designed, and their cis- and trans-isomers were
investigated by pairwise comparison. As shown in Table 2, both for trans- and
cis-derivatives, those with bigger or longer hydrophobic chains exhibited more potent
PTP1B inhibitory activity, e.g., the IC s of compound pair 16a/16b, 17a/17b and
5
0
1
8a/18b followed the sequences of 16a > 17a > 18a and 16b > 17b > 18b. Also, the
activity of compound pair 26a/26b, 27a/27b and 28a/28b increased in sequence with
the increase of hydrophobic groups. With the biggest hydrophobic chains in this
research, biphenylyloxyphenyl derivatives (24a/24b) and dodecylphenyl derivatives
(28a/28b) provided the most potent PTP1B inhibition. Nevertheless, more importantly,
all of the trans- derivatives showed folds higher PTP1B inhibitory activity than their
cis-isomers without any exception. In the cases of compound pair 26a/26b, 27a/27b
and 28a/28b, their differences in activity between two stereoisomers became more
and more significant with the increase of hydrophobic groups (the ratio of IC s are
5
0
2
.5, 4.3 and 6.9, respectively). These clearly indicated that trans-pyrrolidine
bisarylethenesulfonic acid esters have more potent binding affinity with PTP1B than
the cis-isomers, and branching plus stereoisomerisation of bisarylethenesulfonic acid
esters is an effective way to discover potent PTP1B inhibitors.
Table 2
3
.2. Selectivity over TCPTP, SHP2 and membrane permeability
Another question we were eager to know was that if stereoisomeric pyrrolidine
bisarylethenesulfonic acid esters particularly those trans-isomers could interact
differentially with PTPs, and show PTP1B selectivity. For those compound pairs in
which trans-isomers’ IC s were below 300 nM against PTP1B (i.e. 19a/19b, 24a/24b,
5
0
2
7a/27b & 28a/28b) and some individual compound pairs (7a/7b & 16a/16b), we
further evaluated their inhibitory activity against TCPTP and SHP2. As shown in
Table 3, these stereoisomeric molecules showed different inhibitory activity against

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the three PTPs, but more significant selectivity for PTP1B over TCPTP and SHP2
was observed in the trans-derivatives.
Similar to the compound II (Fig. 1), nearly no PTP1B selectivity was observed in
compound pair 7a/7b. Compound 16a, in comparison to its cis-derivative (16b), just
demonstrated very week PTP1B selectivity. Nevertheless, the situation changed
quickly with the increase of hydrophobic groups’ size. Compound 19a, 24a and 27a
showed 8.5-12.7 folds selectivity for PTP1B over TCPTP and SHP2, and their
cis-isomers (19b, 24b & 27b) showed 2.8-6.5 folds PTP1B selectivity. Compound
2
8a showed 16.2 and 22.2 folds selectivity for PTP1B over TCPTP and SHP2
respectively, while its cis-derivative (28b) showed 3.5-5.5 folds PTP1B selectivity
over other 2 PTPs. Compared with the precursors without stereoisomerism
(compound I & II, Fig. 1), trans-pyrrolidine bisarylethenesulfonic acid esters could
provide PTP1B selectivity more effectively. Therefore, branching plus
stereoisomerisation of bisarylethenesulfonic acid esters is a more effective strategy to
discover selective PTP1B inhibitors as well as potent ones.
In addition, these compounds were evaluated in a parallel artificial membrane
permeability assay (PAMPA) which could predict the membrane permeability of small
molecules [32,33]. Atenolol and propranolol, representing medium and high
membrane permeability respectively, were used as validity controls to monitor the
consistency of the assay. The permeability rates (P ) of these tested compounds were
app
listed in Table 3. All tested compounds showed sufficient membrane permeability
−
6
(
Papp = 0.87 to 2.26 ×10 cm/s, superior to atenolol), indicating that these
stereoisomeric pyrrolidine bisarylethenesulfonic acid esters have great potential in
penetrating cellular membrane.
Table 3
3
.3. Molecular docking
To understand the binding mode of stereoisomeric pyrrolidine bisarylethenesulfonic
acid esters and explain the difference of PTP1B activity between cis- and
trans-stereoisomers, we performed the molecular docking for compound 28a and 28b.

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As illustrated in Fig. 2, one arylethenesulfonic acid ester chain of both stereoisomers
stretches deep into A site (the catalytic binding site of PTP1B), constructing multiple
interactions including hydrogen bonds and π-π stacking reactions (with Y47).
Specifically, eight hydrogen bonds with S217, G219, I220, G221 and R222 are
formed by 28a, while five hydrogen bonds with S217, G221 and R222 are formed in
the case of 28b. The second sulfonic acid ester chain of 28a stretches into B site and
forms two hydrogen bonds with R25. By contrast, the second sulfonic acid ester chain
of 28b cannot stretch into B site due to the configuration limitation. Instead, it
expands to the E site without definite interactions. In addition, both in 28a and 28b,
the hydrophobic chain introduced by means of a linker (amyloxalyl) stretches into C
site, forming multiple hydrophobic interactions (with R48 and K42 for 28a, and with
K37 and L38 for 28b respectively). The linker in the case of 28b also forms hydrogen
bonds with R48.
From above analysis, newly introduced hydrophobic branches did bring additional
interactions with PTP1B compared with the non-substituted molecules (7a & 7b).
That is why they can greatly enhance the PTP1B activity of pyrrolidine
bisarylethenesulfonic acid esters. On the other hand, the configurations of
cis-pyrrolidine bisarylethenesulfonic acid esters limit their interactions with the target
protein, particularly the second sulfonic acid ester chain. As the result, cis-isomers of
pyrrolidine bisarylethenesulfonic acid esters are less potent than their trans-isomers.
As a class of potential ABC type PTP1B inhibitors, trans-pyrrolidine
bisarylethenesulfonic acid ester derivatives may interact with multiple secondary
binding sites in addition to the catalytic binding site of PTP1B, which can also explain
why they have better PTP1B selectivity than their cis-isomers and precursors without
stereoisomerism.
Fig. 2
3
.4. Effects of selected PTP1B inhibitors on cell viability
To determine the non-toxic concentrations of stereoisomeric bisarylethenesulfonic
acid esters, we selected four compounds (24a, 24b, 28a and 28b) and evaluated their

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effects on HepG2 and A549 cell viability by means of CCK8 assay. As shown in Fig.
3
, all of the tested compounds showed no inhibitory effect on HepG2 and A549 cells
at 1.56 µM. From 6.25 µM to 100 µM, inhibitory effects on HepG2 were observed in
a dose dependent manner, but the HepG2 cell viability was still over 75% even at 100
µM of tested drugs. Three of the four tested compounds (24a, 24b & 28b) can hardly
inhibit the viability of A549 cell at 100 µM, and only less than 10% cell viability was
inhibited by compound 28a at 100 µM which is over 800 folds of the IC value.
5
0
These results indicated that the newly found PTP1B inhibitors have no significant
cytotoxicity.
Fig. 3
3
.5. Effects of selected PTP1B inhibitors on insulin-stimulated glucose uptake
It has been proved that PTP1B inhibition results in an improvement in insulin
sensitivity and glucose metabolism by inhibiting insulin signaling pathways [34]. To
test this effect with newly obtained PTP1B inhibitors, we evaluated compounds 24a
and 28a on 2-NBDG uptake in HepG2 cell. As shown in Fig. 4, insulin-stimulated
glucose uptake in HepG2 cells was increased by Pioglitazone which was used as the
positive control, and the increased percentages were 51.1%, 70.2%, and 78.9% at the
concentrations of 5, 10 and 20 µM respectively. The glucose uptake in HepG2 cells
was also significantly increased by treatment with tested compounds (24a and 28a).
The increased percentages were 49.1%, 60.5% and 65.1% for 24a, and 59.1%, 83.4%
and 81.1% for 28a at 5, 10 and 20 µM respectively. The latter was better than the
former, and even slightly better than the positive control. The better effect of
compound 28a on 2-NBDG uptake was possibly related to its stronger PTP1B
inhibitory activity (two folds potent than compound 24a).
Fig. 4
3
.6. Effect of compound 28a on phosphorylation of insulin receptor β (IRβ)
Previous researches have suggested a critical role of the insulin receptor β (IRβ) in
insulin-mediated signaling pathways. PTP1B directly inactivates IRβ by

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dephosphorylating tyrosine residues, and attenuate insulin signaling. Inhibition of
PTP1B by inhibitors can improve the phosphorylation level of IRβ [35]. Thus we
further evaluated the effect of compound 28a on the phosphorylation level of IRβ in
HepG2 cell. As shown in Fig. 5, compound 28a dose-dependently increased the
expression of phosphorylated IRβ (p-IRβ) of HepG2 cells at concentrations of 1 µM,
2
µM and 5 µM, and the relative density of p-IRβ to β-actin which was used as
internal control was increased by 15%, 73% and 308% respectively. These results
demonstrated that 28a, as a new PTP1B inhibitor, could induce insulin signaling on
the cellular level.
Fig. 5
4
. Conclusions
In this study, a series of novel stereoisomeric pyrrolidine bisarylethenesulfonic acid
ester derivatives were systematically investigated as potential highly potent and
selective PTP1B inhibitors. Some of trans-pyrrolidine bisarylethenesulfonic acid
esters demonstrated potent and selective PTP1B inhibitory activity over TCPTP and
SHP2 as well as good membrane permeability. Trans-derivative 28a with the most
potent PTP1B activity (IC50 = 120 nM) provided significantly improved PTP1B
selectivity (16 and 22 folds over TCPTP and SHP2 respectively) compared with the
precursors without stereoisomerism. Molecular docking calculated the binding mode
and explained the reasons for better inhibitory activity and selectivity of
trans-pyrrolidine bis-arylethenesulfonic acid esters. We also tested and verified the
effects of compound 28a on insulin-stimulated glucose uptake and insulin-mediated
insulin receptor β (IRβ) phosphorylation. This study indicated that branching and
stereoisomerisation of bisarylethenesulfonic acid esters is a more effective strategy to
discover potent, selective and membrane permeable PTP1B inhibitors.
5
5
5
. Experimental section
.1. Chemistry
.1.1 General synthetic methods

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All chemicals and solvents were obtained from commercial sources and purified
using standard methods according to the need. And the solvents used were redistilled
and dried by standard procedures whenever required.
Melting points were recorded on RY-1Gmeltingpoint apparatus and are uncorrected.
All reactions were monitored by thin-layer chromatography (TLC) on silica gel plates.
1
Column chromatography was performed on silica gel 200-300 mesh. HNMR (400
1
3
MHz) and C NMR (100 MHz) was recorded on a Brucker 400 MHz. The spin
multiplicities are indicated by the symbols, s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet) and brs (broad singlet). The chemical shifts were given in δ
1
13
(
ppm) refer to the signal of CDCl (δ 7.26, H NMR and δ 77.00, C NMR) and the
3
1
13
signal of (CD ) SO (δ 2.54, H NMR and δ 39.52, C NMR). Chemical shift values
3
2
are given in parts per million and coupling constants ( J ) in Hertz. High resolution
mass spectroscopy was conducted using Agilent 6230 LC-MS. Optical rotations were
measured with a SPSI SGW-1 polarimeter.
5
.1.2 (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (2a)
To a suspension of L(+)-tartaric acid (1a) (20 g, 134 mmol) in 200 mL oxylene was
added benzylamine (14.4 g, 134 mmol). The reaction was then heated to reflux for 5 h.
The reaction mixture was cooled to room temperature, evaporated in vacuum and then
washed with DCM to afford 2a as light yellow solid (24.2 g, 85%). M.p.: 197-200 °C.
1
H NMR (400 MHz, DMSO-d ) δ 4.43 (d, J = 5.2 Hz, 2H), 4.60 (dd, J = 8.0 Hz, 14.4
6
13
Hz, 2H), 6.35 (d, J = 5.2 Hz, 2H), 7.28-7.37 (m, 5H); C NMR (100 MHz, DMSO-d )
6
δ 41.2, 74.5, 127.5, 127.5, 128.6, 136.0, 174.6; HRMS (ESI) m/z calcd for C H NO
4
11
11
+
D
[
M+Na] 244.0580, found 244.0582. [α]23 = +144.2 (c = 0.86, MeOH).
5
.1.3 (3S,4S)-1-benzylpyrrolidine-3,4-diol (3a)
To a suspension of LiAlH (5.1 g, 135 mmol) in 200 mL dry THF was added
4
dropwise a solution of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (2a) (10
g, 45 mmol) in 300 mL dry THF at 0 °C. The reaction was then heated to reflux for
another 24 h. The reaction mixture was cooled to 0 °C and quenched with H O (5.1
2

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mL) / 15% NaOH (5.1 mL) / H O (15.3 mL) in turn, followed by the addition of 300
2
mL EtOAc. After stirring at R.T. for 15 min, the obtained suspension was filtered on a
pad of celite (washing with EtOAc) and the filtrate was evaporated in vacuum,
purified by flash chromatography (DCM:MeOH = 30:1) to afford 3a as light brown
1
solid (6.2 g, 73%). M.p.: 94-96 °C. H NMR (400 MHz, DMSO-d ) δ 2.34 (dd, J =
6
4
4
1
.4 Hz, 9.6 Hz, 2H), 2.77-2.81 (m, 2H), 3.49-3.63 (m, 2H), 3.89 (t, J = 4.0 Hz, 2H),
1
3
.89 (brs, 2H), 7.25-7.36 (m, 5H); C NMR (100 MHz, DMSO-d ) δ 60.0, 60.8, 77.6,
6
+
26.8, 128.1, 128.6, 139.0; HRMS (ESI) m/z calcd for C H NO [M+H] 194.1176,
11
15
2
D
found 194.1178. [α]20 = +7.2 (c = 0.56, CHCl3).
5
.1.4 (3S,4S)-1-benzylpyrrolidine-3,4-diyl dimethanesulfonate (4a)
To a solution of (3S,4S)-1-benzylpyrrolidine-3,4-diol (3a) (6 g, 31 mmol) and Et N
3
(12.8 mL, 93 mmol) in 200 mL dry DCM was added dropwise a solution of
methanesulfonic anhydride (12.9 g, 74 mmol) in 100 mL dry DCM at 0 °C. The
reaction was allowed to warm at R.T. for 6 h. The reaction mixture was washed with
saturated aqueous NaHCO , 5% HCl and brine in sequence, dried over anhydrous
3
Na SO , evaporated in vacuum, and purified by flash chromatography (petroleum
2
4
1
ether:EtOAc = 3:1) to afford 4a as light yellow oil (8.5 g, 78%). H NMR (400 MHz,
CDCl ) δ 2.75 (dd, J = 4.0 Hz, 11.2 Hz, 2H), 3.05 (s, 6H), 3.07-3.11 (m, 2H),
3
13
3
.60-3.67 (m, 2H), 5.12 (t, J = 4.0 Hz, 2H), 7.26-7.34 (m, 5H); C NMR (100 MHz,
CDCl ) δ 38.3, 57.8, 59.1, 82.4, 127.5, 128.5, 128.7, 136.7; HRMS (ESI) m/z calcd
3
+
D
for C H NO S [M+H] 350.0727, found 350.0732. [α]20 = +24.6 (c = 0.56, CHCl3).
1
3
19
6 2
5
.1.5 4,4'-(((3R,4R)-1-benzylpyrrolidine-3,4-diyl)bis(oxy))dibenzaldehyde (5a)
A mixture of (3S,4S)-1-benzylpyrrolidine-3,4-diyl dimethanesulfonate (4a) (7 g, 20
mmol), p-hydroxybenzaldehyde (5.4 g, 44 mmol), KI (0.3 g, 2 mmol) and K CO (8.6
2
3
g, 60 mmol) in 20 mL DMF was heated to 100 °C for 8 h. The reaction mixture was
cooled to room temperature, diluted with H O and then extracted with EtOAc. The
2
combined organic layers were washed with brine and dry over anhydrous Na SO .
2
4
The solvent was removed to afford the crude product. It was purified by flash

ACCEPTED MANUSCRIPT
chromatography (petroleum ether:EtOAc = 6:1) to afford 5a as light yellow oil (4.0 g,
1
4
6
4
4%). H NMR (400 MHz, CDCl ) δ 2.81 (dd, J = 4.0 Hz, 10.4 Hz, 2H), 3.24 (dd, J =
3
.0 Hz, 10.4 Hz, 2H), 3.67-3.75 (m, 2H), 4.97 (t, J = 4.0 Hz, 2H), 7.01 (d, J = 8.4 Hz,
13
H), 7.26-7.33 (m, 5H), 7.81 (d, J = 8.4 Hz, 4H), 9.87 (s, 2H); C NMR (100 MHz,
CDCl ) δ 58.1, 59.7, 81.9, 115.5, 127.4, 128.4, 128.8, 130.4, 132.1, 137.2, 162.1,
3
+
1
90.6; HRMS (ESI) m/z calcd for C H NO [M+H] 402.1700, found 402.1710.
2
5
23
4
D
[
α]21 = -45.1 (c = 0.11, CHCl3).
5
.1.6
diethyl
2
,2'-((((3R,4R)-1-benzylpyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(
ethene-1-sulfonate) (6a)
To
a
solution
of
4
,4'-(((3R,4R)-1-benzylpyrrolidine-3,4-diyl)bis(oxy))dibenzaldehyde (5a) (3.6 g, 8.2
mmol) and ethyl (diethoxyphosphoryl) methanesulfonate (4.5 g, 19.3 mmol) in 100
mL dry THF, NaH (60% in mineral oil) (1.3 g, 33 mmol) was added in small portions
at 0 °C. Then the reaction was stirred at room temperature for 6 h. TLC showed the
reaction was completed. The reaction mixture was quenched with saturated aqueous
NH Cl, and extracted with EtOAc. The combined organic layers were washed with
4
brine, dried over anhydrous Na SO , concentrated under vacuum, and purified by
2
4
flash chromatography (petroleum ether:EtOAc = 4:1) to afford 6a as white solid (4.5
1
g, 92%). M.p.: 108-110 °C. H NMR (400 MHz, CDCl ) δ 1.35 (t, J = 7.2 Hz, 6H),
3
2
.76 (dd, J = 2.8 Hz, 10.4 Hz, 2H), 3.18 (dd, J = 5.6 Hz, 10.4 Hz, 2H), 3.63-3.72 (m,
H), 4.17 (q, J = 7.2 Hz, 4H), 4.87-4.89 (m, 2H), 6.56 (d, J = 15.6 Hz, 2H), 6.91 (d, J
2
=
8.4 Hz, 4H), 7.23-7.30 (m, 5H), 7.40 (d, J = 8.4 Hz, 4H), 7.48 (d, J = 15.6 Hz, 2H);
1
3
C NMR (100 MHz, CDCl ) δ 14.8, 58.1, 59.6, 66.6, 81.7, 115.8, 118.7, 125.1, 127.3,
3
1
28.4, 128.8, 130.4, 137.2, 144.0, 159.7; HRMS (ESI) m/z calcd for C H NO S
8 2
3
1
35
+
D
[
M+H] 614.1877, found 614.1888. [α]21 = -19.3 (c = 0.25, CHCl3).
5
.1.7
diethyl

ACCEPTED MANUSCRIPT
2
,2'-((((3R,4R)-pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethane-1
-sulfonate) (7a)
To
a
solution
of
diethyl
2
,2'-((((3R,4R)-1-benzylpyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis
(ethene-1-sulfonate) (6a) (4.0 g, 6.5 mmol) in 100 mL DCM was added 1-chloroethyl
chloroformate (1.4 g, 9.75 mmol). The mixture was heated to reflux for 4 h before
concentration to move the solvent under vacuum. The residue was dissolved in 100
mL MeOH, and allowed to heat to reflux for 1 h. The reaction mixture was cooled to
room temperature, and concentrated to afford the crude product 7a as brown
1
semi-solid (3.3 g, 95%) which was used for next step without further purification. H
NMR (400 MHz, DMSO-d ) δ 1.33 (t, J= 7.2 Hz, 6H), 3.55-3.58 (m, 2H), 3.77-3.79
6
(m, 2H), 4.21 (q, J = 7.2 Hz, 4H), 5.36 (d, J = 3.2 Hz, 2H), 7.15 (d, J = 8.4 Hz, 4H),
7
.37 (d, J = 15.6 Hz, 2H), 7.61 (d, J = 15.6 Hz, 2H), 7.83 (d, J = 8.4 Hz, 4H), 9.72 (s,
1
3
2
H); C NMR (100 MHz, DMSO-d ) δ 14.7, 48.7, 66.9, 78.3, 116.2, 120.3, 126.2,
6
+
1
31.0, 143.4, 158.1; HRMS (ESI) m/z calcd for C H NO S [M+H] 524.1407,
24
29
8 2
found 524.1404.
5
.1.8 (3R,4S)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (2b)
To a suspension of cis-butenedioic anhydride (1b) (49 g, 0.5 mol) in 600 mL AcOH
was added benzylamine (54 g, 0.5 mmol). The reaction was then heated to reflux for 5
h. The reaction mixture was concentrated and the residue was dissolved in 300 mL
EtOAc. The EtOAc layer was washed with saturated aqueous NaHCO and brine. The
3
organic layer was dried over anhydrous Na SO , concentrated in vacuum, purified by
2
4
flash
chromatography
(petroleum
ether:EtOAc
=
8:1)
to
afford
1
1
-benzyl-1H-pyrrole-2,5-dione as a white solid (26.9g, 29%). M.p.: 58-60 °C. H
13
NMR (400 MHz, CDCl ) δ 4.65 (s, 2H), 6.68 (s, 2H), 7.24-7.30 (m, 5H); C NMR
3
(
100 MHz, CDCl ) δ 41.4, 127.8, 128.3, 128.7, 134.2, 136.1, 170.4; HRMS (ESI) m/z
3
+
calcd for C H NO [M+H] 188.0706, found 188.0709.
11
9
2
A stock solution containing Mn(ClO ) ·6H O (220 mg, 0.6 mmol) and
4
2
2
pyridine-2-carboxylic acid (450 mg, 3.6 mmol) in 200 mL acetone was prepared. 120

ACCEPTED MANUSCRIPT
mL this stock solution (360 µmol Mn(ClO ) ·6H O, 0.3 mol%, and 2.2 mmol
4
2
2
pyridine-2-carboxylic acid, 1.8 mol%) was added to the solution of
-benzyl-pyrrole-2,5-dione (22.6 g, 120 mmol) in 240 mL acetone while stirring the
1
mixture at room temperature. After addition of 6 mL of a 0.6 M aqueous NaOAc (3.6
mmol, 3.0 mol%), the mixture was cooled to 0 °C, and to it H O (30 wt% in water,
2
2
2
2.7 mL, 240 mmol, 2.0equiv.) was added dropwise. After stirring for 16 h at 0 °C,
the mixture was allowed to warm to room temperature, and excess solid NaHSO was
3
added to remove residual peroxides (verified by peroxide test strips). The mixture was
filtered, and the filtrate was concentrated to give 2b as a white solid (26.5 g, 99%).
1
M.p.: 122-124 °C. H NMR (400 MHz, DMSO-d ) δ 4.48 (s, 2H), 4.60 (s, 2H), 6.10
6
1
3
(
brs, 2H), 7.28-7.36 (m, 5H); C NMR (100 MHz, DMSO-d ) δ 41.0, 68.1, 127.5,
6
+
1
27.5, 128.5, 136.0, 176.4; HRMS (ESI) m/z calcd for C H NO [M+Na] 244.0580,
11
11
4
found 244.0583.
5
.1.9 (3S,4R)-1-benzylpyrrolidine-3,4-diol (3b)
According to the procedure described for 3a, 2b (25 g, 113 mmol) was treated with
1
LiAlH (12.5 g, 330 mmol) to afford 3b (7.2 g, 33%) as brown oil. H NMR (400
4
MHz, DMSO-d ) δ 3.07 (d, J = 8.4 Hz, 2H), 3.39 (d, J = 8.4 Hz, 2H), 4.19 (s, 2H),
6
13
4
.38 (s, 2H), 5.56 (s, 2H), 7.45(s, 3H), 7.65-7.66 (m, 2H); C NMR (100 MHz,
DMSO-d ) δ 56.2, 59.2, 69.4, 128.8, 129.3, 130.7, 131.3; HRMS (ESI) m/z calcd for
6
+
C H NO [M+H] 194.1176, found 194.1178.
11
15
2
5
.1.10 (3S,4R)-1-benzylpyrrolidine-3,4-diyl dimethanesulfonate (4b)
According to the procedure described for 4a, 3b (7 g, 36 mmol) was treated with
Et N (14.9 mL, 108 mmol) and methanesulfonic anhydride (15 g, 86 mmol) to afford
3
1
4
b (9.2 g, 72%) as brown oil. H NMR (400 MHz, CDCl ) δ 2.78-2.81 (m, 2H), 3.06
3
1
3
(
s, 6H), 3.16-3.20 (m, 2H), 3.68 (s, 2H), 5.07 (s, 2H), 7.24-7.31 (m, 5H); C NMR
(
100 MHz, CDCl ) δ 38.4, 56.6, 59.6, 75.7, 127.5, 128.5, 128.6, 137.3; HRMS (ESI)
3
+
m/zcalcd for C H NO S [M+H] 350.0727, found 350.0729.
1
3
19
6 2

ACCEPTED MANUSCRIPT
5
.1.11 4,4'-(((3S,4R)-1-benzylpyrrolidine-3,4-diyl)bis(oxy))dibenzaldehyde (5b)
A mixture of (3S,4R)-1-benzylpyrrolidine-3,4-diyl dimethanesulfonate (4b) (8 g,
3 mmol), p-hydroxybenzaldehyde (5.6 g, 46 mmol), KI (0.3 g, 2 mmol) and K CO
2
2
3
(5.7 g, 40 mmol) in 25 mL DMF was heated to 100 °C for 4 h. The reaction mixture
was cooled to room temperature, diluted with H O and then extracted with EtOAc.
2
The combined organic layers were washed with brine, dried over anhydrous Na SO ,
2
4
and concentrated to afford the crude product which was purified by flash
chromatography (petroleum ether:EtOAc 5:1) to afford
3S,4S)-1-benzyl-4-(4-formylphenoxy)pyrrolidin-3-yl methanesulfonate as light
=
(
1
yellow oil (5.3 g, 62%). H NMR (400 MHz, CDCl ) δ 2.66-2.69 (m, 1H), 2.83-2.86
3
(m, 1H), 2.97 (s, 3H), 3.06-3.19 (m, 2H), 3.51-3.73 (m, 2H), 4.93 (s, 1H), 5.11 (s, 1H),
6
.95 (d, J = 8.4 Hz, 2H), 7.24-7.27 (m, 5H), 7.77 (d, J = 8.4 Hz, 2H), 9.81 (s, 1H);
1
3
C NMR (100 MHz, CDCl ) δ 38.1, 57.2, 57.5, 59.2, 81.0, 83.0, 115.3, 127.2, 128.2,
3
1
28.5, 130.3, 131.8, 137.0, 161.6, 190.4; HRMS (ESI) m/z calcd for C H NO S
19
21
5
+
[
M+H] 376.1213, found 376.1220.
A
mixture of (3S,4S)-1-benzyl-4-(4-formylphenoxy)pyrrolidin-3-yl
methanesulfonate (5 g, 13 mmol), p-hydroxybenzaldehyde (3.2 g, 26 mmol), KI (0.45
g, 3 mmol) and Cs CO (6.5 g, 20 mmol) in 20 mL DMF was heated to 120 °C for 24
2
3
h. The reaction mixture was cooled to room temperature, diluted with H O and then
2
extracted with EtOAc. The combined organic layers were washed with brine, dried
over anhydrous Na SO and concentrated to afford the crude product. It was purified
2
4
by flash chromatography (petroleum ether:EtOAc = 3:1) to afford 5b as light yellow
1
oil (1.6 g, 30%). H NMR (400 MHz, CDCl ) δ 2.82-2.84 (m, 2H), 3.36-3.38 (m, 2H),
3
3
8
1
.75 (s, 2H), 5.02 (s, 2H), 6.88 (d, J = 8.4 Hz, 4H), 7.26-7.33 (m, 5H), 7.74 (d, J =
1
3
.4 Hz, 4H), 9.84 (s, 2H); C NMR (100 MHz, CDCl ) δ 57.7, 59.9, 75.1, 115.4,
3
27.4, 128.4, 128.8, 130.2, 131.8, 137.5, 162.8, 190.6; HRMS (ESI) m/z calcd for
+
C H NO [M+H] 402.1700, found 402.1707.
25
23
4
5
.1.12
diethyl
2
,2'-((((3S,4R)-1-benzylpyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(

ACCEPTED MANUSCRIPT
ethene-1-sulfonate) (6b)
According to the procedure described for 6a, 6b (2.1 g, 93%) was prepared from 5b
(1.5 g, 3.8 mmol) as brown semi-solid. The crude product was used for the next step
without further purification.
5
.1.13
diethyl
2
,2'-((((3S,4R)-pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethane-1
-sulfonate) (7b)
According to the procedure described for 7a, 7b (1.3 g, 61%) was prepared from 6b
1
(
2.0 g, 3.5 mmol) as brown semi-solid via 2 steps. H NMR (400 MHz, DMSO-d ) δ
6
1
4
1
.32 (t, J = 7.2 Hz, 6H), 3.51-3.53 (m, 2H), 3.74-3.76 (m, 2H), 4.19 (q, J = 7.2 Hz,
H), 5.46 (s, 2H), 7.08 (d, J = 8.4 Hz, 4H), 7.35 (d, J = 15.6 Hz, 2H), 7.56 (d, J =
1
3
5.6 Hz, 2H), 7.78 (d, J = 8.4 Hz, 4H), 9.46 (s, 1H), 9.71 (s, 1H); C NMR (100
MHz, DMSO-d ) δ 14.7, 66.9, 96.6, 109.6, 115.9, 120.0, 125.8, 128.3, 130.9, 143.5;
6
+
HRMS (ESI) m/z calcd for C H NO S [M+H] 524.1407, found 524.1403.
2
4
29
8 2
5
.1.14 General procedure for 8a and 9a:
To stirred
a
solution
of
diethyl
2
1
,2'-((((3R,4R)-pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethane-
-sulfonate) (7a) (1.0 equiv.), substituted phenylaldehyde (1.2 equiv.) and
NaBH(OAc) (3 equiv.) in DCM under argon at room temperature was added catalytic
3
amount of acetic acid. The reaction mixture was stirred at room temperature for 12 h
before concentration. The residue was dissolved in EtOAc and washed with saturated
aqueous NaHCO and brine, dried over anhydrous Na SO , concentrated, and purified
3
2
4
by flash chromatography (petroleum ether: EtOAc = 3:1) to afford the target product.
5
2
1
.1.14.1
diethyl
,2'-((((3R,4R)-1-(4-phenoxybenzyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(
E,1'E)-bis(ethene-1-sulfonate) (8a)
1
White semi-solid (74%). H NMR (400 MHz, CDCl ) δ 1.37 (t, J = 7.2 Hz, 6H),
3

ACCEPTED MANUSCRIPT
2
7
1
5
1
7
.76 (dd, J = 2.8 Hz, 10.4 Hz, 2H), 3.18-3.22 (m, 2H), 3.62-3.70 (m, 2H), 4.18 (q, J =
.2 Hz, 4H), 4.90 (s, 2H), 6.59 (d, J = 15.6 Hz, 2H), 6.93-6.99 (m, 8H), 7.08-7.10 (m,
1
3
H), 7.25 -7.34 (m, 4H), 7.41-7.52 (m, 6H); C NMR (100 MHz, CDCl ) δ 14.8, 58.0,
3
9.0, 66.6, 81.7, 115.8, 118.6, 118.8, 118.9, 123.3, 125.2, 129.7, 130.1, 130.4, 132.1,
+
43.9, 156.5, 157.0, 159.8; HRMS (ESI) m/z calcd for C H NO S [M+H]
37
39
9 2
D
06.2139, found 706.2146. [α]21 = -18.1 (c = 0.36, CHCl3).
5
.1.14.2
diethyl
2
,2'-((((3R,4R)-1-(4-(4-isopropylphenoxy)benzyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-
phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (9a)
1
White semi-solid (78%). H NMR (400 MHz, CDCl ) δ 1.24 (d, J = 6.4 Hz, 6H),
3
1.37 (t, J = 7.2 Hz, 6H), 2.76 (dd, J = 2.8 Hz, 10.4 Hz, 2H), 2.86-2.91 (m, 1H),
3.18-3.22 (m, 2H), 3.62-3.70 (m, 2H), 4.18 (q, J = 7.2 Hz, 4H), 4.87-4.89 (m, 2H),
6.59 (d, J = 15.6 Hz, 2H), 6.93-6.95 (m, 8H), 7.18 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0
1
3
Hz, 2H), 7.43 (d, J = 8.4 Hz, 4H), 7.51 (d, J = 15.6 Hz, 2H); C NMR (100 MHz,
CDCl ) δ 14.8, 24.0, 33.4, 58.0, 59.0, 66.5, 81.8, 115.8, 118.2, 118.8, 118.9, 125.2,
3
1
27.5, 130.0, 130.3, 131.7, 143.9, 144.0, 154.7, 156.9, 159.7; HRMS (ESI) m/z calcd
+
D
for C H NO S [M+H] 748.2608, found 748.2621. [α]21 = -17.9 (c = 0.53, CHCl3).
4
0
45
9 2
5
.1.15 General procedure for 10a-12a:
To stirred
a
solution
of
diethyl
2
,2'-((((3R,4R)-pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethane-
1
-sulfonate) (7a) (1.0 equiv.) and HBTU (1.2 equiv.) in DCM under argon at room
temperature were added substituted benzoic acid (1.2 equiv.) and DMAP (1.5 equiv.)
sequentially. The reaction mixture was stirred at room temperature for 24 h before
concentration. The residue was dissolved in EtOAc, washed with 5% HCl, saturated
aqueous NaHCO and brine, dried over anhydrous Na SO , concentrated, and purified
3
2
4
by flash chromatography (petroleum ether:EtOAc:DCM = 4:1:1) to afford the target
product.

ACCEPTED MANUSCRIPT
5
.1.15.1
diethyl
2
,2'-((((3R,4R)-1-benzoylpyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis
(ethene-1-sulfonate) (10a)
1
White solid (45%). M.p.: 79-81 °C. H NMR (400 MHz, CDCl ) δ 1.37 (t, J = 7.2
3
Hz, 6H), 3.75 (d, J = 10.8 Hz, 1H), 3.97-4.10 (m, 2H), 4.16-4.24 (m, 5H), 4.97-5.03
(m, 2H), 6.58-6.65 (m, 2H), 6.92 (dd, J = 8.4 Hz, 28.0 Hz, 4H), 7.38-7.56 (m, 11H);
1
3
C NMR (100 MHz, CDCl ) δ 14.9, 49.8, 52.5, 66.7, 78.8, 115.9(2), 119.5(2), 126.0,
3
1
27.2, 128.4, 130.4, 130.5, 135.7, 143.6(2), 158.5(2), 170.3; HRMS (ESI) m/z calcd
+
D
for C H NO S [M+H] 628.1669, found 628.1689. [α]22 = -8.2 (c = 0.18, CHCl3).
3
1
33
9 2
5
.1.15.2
diethyl
2
,2'-((((3R,4R)-1-(4-phenoxybenzoyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))
(1E,1'E)-bis(ethene-1-sulfonate) (11a)
1
White solid (42%). M.p.: 84-86 °C. H NMR (400 MHz, CDCl ) δ 1.39 (t, J = 7.2
3
Hz, 6H), 3.80 (d, J = 10.8 Hz, 1H), 3.98 (d, J = 10.8 Hz, 1H), 3.98-4.12 (m, 2H),
4
.20-4.22 (m, 4H), 4.99 (d, J = 12.0 Hz, 2H), 6.60-6.64 (m, 2H), 6.88-7.04 (m, 8H),
1
3
7
.17 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 8.4 Hz, 2H), 7.45-7.55 (m, 8H); C NMR (100
MHz, CDCl ) δ 14.9, 49.9, 52.6, 66.7, 78.8, 115.9, 117.7, 119.6, 119.7, 124.3, 126.0,
3
1
29.4, 129.9, 130.0, 130.5, 143.6, 155.8, 158.6(2), 159.6, 169.7; HRMS (ESI) m/z
+
D
calcd for C H NO S [M+H] 720.1932, found 720.1943. [α]21 = -7.7 (c = 0.77,
3
7
37
10 2
CHCl3).
5
2
1
.1.15.3
diethyl
,2'-((((3R,4R)-1-(4-(4-isopropylphenoxy)benzoyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,
-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (12a)
1
White solid (55%). M.p.: 81-83 °C. H NMR (400 MHz, CDCl ) δ 1.23 (d, J = 6.8
3
Hz, 6H), 1.35 (t, J = 7.2 Hz, 6H), 2.83-2.91 (m, 1H), 3.79 (d, J = 10.8 Hz, 1H), 3.96
(d, J = 10.8 Hz, 1H), 3.98-4.12 (m, 2H), 4.17-4.19 (m, 4H), 5.00 (d, J = 12.0 Hz, 2H),
13
6
.60-6.64 (m, 2H), 6.91-6.95 (m, 8H), 7.18-7.20 (m, 2H), 7.47-7.52 (m, 8H); C
NMR (100 MHz, CDCl ) δ 14.7, 23.9, 33.3, 49.8, 52.4, 66.6, 78.7, 115.8, 117.2, 119.4,
3

ACCEPTED MANUSCRIPT
119.5, 125.8, 127.6, 129.2, 129.5, 130.4, 143.5, 144.8, 153.4, 158.5, 159.8, 169.6;
+
D
HRMS (ESI) m/z calcd for C H NO S [M+H] 762.2401, found 762.2423. [α]22
=
4
0
43
9 2
-6.1 (c = 0.63, CHCl3).
5
.1.16 General procedure for 13a-15a:
To stirred
a
solution
of
diethyl
2
1
,2'-((((3R,4R)-pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethane-
o
-sulfonate) (7a) (1.0 equiv.) and Et N (2.2 equiv.) in DCM under argon at 0 C was
3
added triphosgene (0.35 equiv.). The reaction mixture was stirred for 30 min at room
temperature before cooled to 0 °C again, and then substituted arylamine (1.0 equiv.)
was added. The mixture was allowed to warm to room temperature and stirred for
another 1 h. Then the mixture was washed with 5% HCl, saturated aqueous NaHCO3
and brine, dried over anhydrous Na SO , concentrated, and purified by flash
2
4
chromatography (petroleum ether: EtOAc:DCM = 4:1:1) to afford the target product.
5
2
1
.1.16.1
diethyl
,2'-((((3R,4R)-1-(phenylcarbamoyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(
E,1'E)-bis(ethene-1-sulfonate) (13a)
1
White solid (35%). M.p.: 88-90 °C. H NMR (400 MHz, CDCl ) δ 1.37 (t, J = 7.2
3
Hz, 6H), 3.82 (d, J = 12.0 Hz, 2H), 3.96-4.00 (m, 2H), 4.19 (q, J = 7.2 Hz, 4H), 5.01
d, J = 4.0 Hz, 2H), 6.29 (s, 1H), 6.59 (d, J = 15.0 Hz, 2H), 6.91 (d, J = 8.4 Hz, 4H),
(
7
6
1
.00 (t, J = 7.2 Hz, 1H), 7.22-7.26 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.43-7.51 (m,
1
3
H); C NMR (100 MHz, CDCl ) δ 14.9, 49.5, 66.7, 78.3, 115.9, 119.4, 119.7, 123.3,
3
25.9, 128.9, 130.5, 138.5, 143.7, 153.8, 158.6; HRMS(ESI) m/z calcd for
+
D
C H N O S [M+H] 643.1778, found 643.1790. [α]22 = -13.4 (c = 0.16, CHCl3).
31
34
2
9 2
5
.1.16.2
diethyl
2
,2'-((((3R,4R)-1-((4-phenoxyphenyl)carbamoyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-
phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (14a)
1
White solid (37%). M.p.: 91-93 °C. H NMR (400 MHz, CDCl ) δ 1.37 (t, J = 7.2
3

ACCEPTED MANUSCRIPT
Hz, 6H), 3.82 (d, J = 12.0 Hz, 2H), 3.96-4.00 (m, 2H), 4.19 (q, J = 7.2 Hz, 4H), 5.01
(d, J = 3.6 Hz, 2H), 6.31 (s, 1H), 6.59 (d, J = 15.2 Hz, 2H), 6.91 (d, J = 8.4 Hz, 8H),
13
7
.04 (t, J = 7.2 Hz, 1H), 7.24-7.33 (m, 4H), 7.43-7.51 (m, 6H); C NMR (100 MHz,
CDCl ) δ 14.9, 49.5, 66.7, 78.4, 115.9, 118.2, 119.6, 119.7, 121.7, 122.9, 126.0, 129.7,
3
1
30.5, 134.0, 143.6, 152.8, 154.0, 157.6, 158.6; HRMS (ESI) m/z calcd for
+
D
C H N O S [M+H] 735.2041, found 735.2052. [α]22 = -12.1 (c = 0.14, CHCl3).
37
38
2
10 2
5
.1.16.3
diethyl
2
,2'-((((3R,4R)-1-((4-(4-isopropylphenoxy)phenyl)carbamoyl)pyrrolidine-3,4-diyl)bis(
oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (15a)
1
White solid (30%). M.p.: 90-91 °C. H NMR (400 MHz, CDCl ) δ 1.26-1.41 (m,
3
1
7
6
6
2H), 2.84-2.92 (m, 1H), 3.84 (d, J = 12.0 Hz, 2H), 3.99-4.03 (m, 2H), 4.22 (q, J =
.2 Hz, 4H), 5.05 (d, J = 3.6 Hz, 2H), 6.20 (s, 1H), 6.62 (d, J = 15.2 Hz, 2H),
.88-6.96 (m, 8H), 7.15 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.47-7.56 (m,
1
3
H); C NMR (100 MHz, CDCl ) δ 14.9, 24.1, 29.7, 49.5, 66.7, 78.4, 115.9, 118.2,
3
119.4, 119.6, 121.7, 126.0, 127.5, 130.5, 133.7, 143.6, 143.6, 153.3, 154.0, 155.4,
+
1
58.6; HRMS (ESI) m/z calcd for C H N O S [M+H] 777.2510, found 777.2516.
40 44 2 10 2
D
[
α]22 = -12.3 (c = 0.26, CHCl3).
5
.1.17 General procedure for 16a-28a:
To stirred
a
solution
of
diethyl
2
,2'-((((3R,4R)-pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethane-
1
-sulfonate) (7a) (1.5 g, 2.68 mmol) and Et N (0.41 g, 4.02 mmol) in 50 mL DCM
3
under argon at 0 °C was added ethyl oxalyl monochloride (0.40 g, 2.91 mmol). The
reaction mixture was stirred for 8 h at room temperature, then washed with 5% HCl,
saturated aqueous NaHCO3 and brine, dried over anhydrous Na SO , and
2
4
concentrated. The residue was redissolved in 10 mL THF and to it was added 2M
aqueous of LiOH (2.7 mL, 5.40 mmol). The mixture was stirred for 30 min at room
temperature, and then evaporated to move most of THF. The resulted precipitate was
filtered and purified by flash chromatography (DCM:MeOH = 30:1) to afford

ACCEPTED MANUSCRIPT
2
-((3R,4R)-3,4-bis(4-((E)-2-(ethoxysulfonyl)vinyl)phenoxy)pyrrolidin-1-yl)-2-oxoace
tic acid as yellow solid (1.26 g, 72%).
To
-((3R,4R)-3,4-bis(4-((E)-2-(ethoxysulfonyl)vinyl)phenoxy)pyrrolidin-1-yl)-2-oxoace
a
stirred
solution
of
2
tic acid (1.0 equiv.) and HBTU (1.2 equiv.) in DMF under argon at room temperature
was added substituted arylamine (1.2 equiv.) and DMAP (1.5 equiv.) sequentially. The
reaction mixture was stirred at room temperature for 24 h, then washed with 5% HCl
and brine, dried over anhydrous Na SO , concentrated, and purified by flash
2
4
chromatography (petroleum ether:EtOAc:DCM = 4:1:1) to afford the target product.
5
.1.17.1
diethyl
2
,2'-((((3R,4R)-1-(2-oxo-2-(phenylamino)acetyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-
phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (16a)
1
White solid (39%). M.p.: 92-94 °C. H NMR (400 MHz, CDCl ) δ 1.36-1.40 (m,
3
6H), 4.07 (s, 2H), 4.20-4.25 (m, 4H), 4.47 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d, J =
14.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63 (dd, J = 4.4 Hz, 15.6 Hz,
2H), 6.92-6.96 (m, 4H), 7.15 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.46-7.52
1
3
(
m, 5H), 7.55 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 9.40 (s, 1H); C NMR
(
100 MHz, CDCl ) δ 14.8, 51.6, 52.2, 66.7, 75.9, 79.2, 115.9(2), 119.6(2), 119.7,
3
1
25.2, 126.0(2), 129.1, 130.5, 136.4, 143.6, 157.3, 158.4, 159.4; HRMS (ESI) m/z
+
D
calcd for C H N O S [M+H] 671.1728, found 671.1730. [α]22 = -23.3 (c = 0.66,
3
2
34
2
10 2
CHCl3).
5
.1.17.2
diethyl
2
,2'-((((3R,4R)-1-(2-oxo-2-((4-phenoxyphenyl)amino)acetyl)pyrrolidine-3,4-diyl)bis(o
xy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (17a)
1
White solid (24%). M.p.: 93-95 °C. H NMR (400 MHz, CDCl ) δ 1.39 (t, J = 7.2
3
Hz, 6H), 4.07 (s, 2H), 4.20-4.25 (m, 4H), 4.48 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d,
J = 14.0 Hz, 1H), 5.00 (s, 1H), 5.10 (s, 1H), 6.63 (dd, J = 4.4 Hz, 15.6 Hz, 2H),
6
.92-7.00 (m, 8H), 7.09 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.47-7.57 (m,

ACCEPTED MANUSCRIPT
1
3
8
H), 9.40 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.9, 51.6, 52.2, 66.7, 75.9, 79.2,
3
1
15.9(2), 118.6, 119.4, 119.7(2), 121.4, 123.3, 126.1(2), 129.7, 130.5, 131.9, 143.5,
54.3, 157.1, 157.2, 158.4, 159.4; HRMS (ESI) m/z calcd for C H N O S
11 2
1
3
8
38
2
+
D
[
M+Na] 785.1809, found 785.1814. [α]23 = -22.7 (c = 0.53, CHCl3).
5
2
3
.1.17.3
diethyl
,2'-((((3R,4R)-1-(2-((4-(4-isopropylphenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-
,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (18a)
1
Light yellow solid (27%). M.p.: 92-94 °C. H NMR (400 MHz, CDCl ) δ 1.24 (d, J
3
=
7.2 Hz, 6H), 1.37-1.41 (m, 6H), 2.87-2.91 (m, 1H), 4.06 (s, 2H), 4.20-4.25 (m, 4H),
.47 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J
3.6 Hz, 1H), 6.63 (dd, J = 4.8 Hz, 15.6 Hz, 2H), 6.90-6.99 (m, 8H), 7.17 (d, J = 8.4
4
=
1
3
Hz, 2H), 7.47-7.55 (m, 8H), 9.38 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.9, 24.1,
3
3
3.4, 51.6, 52.2, 66.7, 75.9, 79.2, 115.9(2), 118.6, 119.1, 119.7(2), 121.3, 126.1(2),
27.6, 130.5, 131.5, 143.5, 144.0, 154.8, 154.8, 157.1, 158.4, 159.5; HRMS (ESI) m/z
1
+
D
calcd for C H N O S [M+Na] 827.2279, found 827.2277. [α]23 = -21.4 (c = 0.55,
4
1
44
2
11 2
CHCl3).
5
.1.17.4
diethyl
2
,2'-((((3R,4R)-1-(2-((4-(4-ethylphenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-3,4-d
iyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (19a)
1
Brown solid (22%). M.p.: 91-93 °C. H NMR (400 MHz, CDCl ) δ 1.23 (t, J = 7.2
3
Hz, 3H), 1.37-1.41 (m, 6H), 2.62 (q, J = 7.2 Hz, 2H), 4.07 (s, 2H), 4.20-4.25 (m, 4H),
4
.47 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J
3.6 Hz, 1H), 6.63 (dd, J = 4.8 Hz, 15.6 Hz, 2H), 6.89-6.98 (m, 8H), 7.14 (d, J = 8.0
=
1
3
Hz, 2H), 7.47-7.55 (m, 8H), 9.38 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.9, 15.6,
3
2
8.1, 51.6, 52.2, 66.7, 75.9, 79.2, 115.9(2), 118.8, 119.0, 119.7(2), 121.3, 126.1(2),
29.0, 130.5, 131.5, 139.4, 143.5, 154.8, 154.8, 157.1, 158.4, 159.4; HRMS (ESI) m/z
1
+
D
calcd for C H N O S [M+Na] 813.2122, found 813.2130. [α]23 = -21.5 (c = 0.40,
4
0
42
2
11 2
CHCl3).

ACCEPTED MANUSCRIPT
5
.1.17.5
diethyl
2
,2'-((((3R,4R)-1-(2-((4-(4-(tert-butyl)phenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine
-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (20a)
1
Brown solid (18%). M.p.: 95-97 °C. H NMR (400 MHz, CDCl ) δ 1.31 (s, 9H),
3
1
1
4
9
7
1
.37-1.41 (m, 6H), 4.06 (s, 2H), 4.20-4.25 (m, 4H), 4.47 (dd, J = 3.6 Hz, 14.0 Hz,
H), 4.65 (d, J = 14.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63 (dd, J =
.8 Hz, 15.5 Hz, 2H), 6.91-7.00 (m, 8H), 7.33 (d, J = 8.4 Hz, 2H), 7.47-7.55 (m, 8H),
1
3
.39 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.9, 31.4, 34.3, 51.6, 52.2, 66.7, 75.9,
3
9.2, 115.9(2), 118.2, 119.2, 119.7(2), 121.3, 126.1(2), 126.5, 130.5, 131.6, 143.5,
46.3, 154.6, 154.7, 157.1, 158.4, 159.5; HRMS (ESI) m/z calcd for C H N O S
11 2
4
2
46
2
+
D
[
M+Na] 841.2435, found 841.2430. [α]23 = -21.1 (c = 0.39, CHCl3).
5
.1.17.6
diethyl
2
,2'-((((3R,4R)-1-(2-((4-(4-fluorophenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-3,4-
diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (21a)
1
White solid (28%). M.p.: 96-97 °C. H NMR (400 MHz, CDCl ) δ 1.37-1.40 (m,
3
6
1
2
H), 4.07 (s, 2H), 4.18-4.24 (m, 4H), 4.47 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d, J =
4.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63 (dd, J = 4.8 Hz, 15.5 Hz,
1
3
H), 6.92-7.01 (m, 10H), 7.47-7.56 (m, 8H), 9.39 (s, 1H); C NMR (100 MHz,
CDCl ) δ 14.9, 51.6, 52.2, 66.7, 75.9, 79.2, 115.9(2), 116.2 and 116.4, 118.8, 119.7(2),
3
1
1
20.2(2), 121.4, 126.1(2), 130.5, 131.8, 143.5, 152.8(2), 154.7, 157.2, 157.6 and
+
60.0, 158.4, 159.4; HRMS (ESI) m/z calcd for C H FN O S [M+Na] 803.1715,
38
37
2
11 2
D
found 803.1706. [α]23 = -20.2 (c = 0.64, CHCl3).
5
.1.17.7
diethyl
2
,2'-((((3R,4R)-1-(2-((4-(4-chlorophenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-3,4
-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (22a)
1
White solid (34%). M.p.: 92-94 °C. H NMR (400 MHz, CDCl ) δ 1.37-1.41 (m,
3
6
H), 4.06 (s, 2H), 4.20-4.25 (m, 4H), 4.47 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d, J =

ACCEPTED MANUSCRIPT
1
2
4.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63 (dd, J = 4.8 Hz, 15.6 Hz,
1
3
H), 6.89-7.00 (m, 8H), 7.07-7.32 (m, 2H), 7.48-7.58 (m, 8H), 9.40-9.41 (m, 1H); C
NMR (100 MHz, CDCl ) δ 14.9, 51.6, 52.2, 66.7, 75.9, 79.2, 115.9(2), 118.6,
3
119.5(2), 119.7, 119.8, 121.4(2), 123.3, 126.1, 128.3, 129.7(2), 130.5, 131.9(2), 143.5,
1
53.9, 154.3 and 155.9, 157.1(2), 158.4, 159.4(2); HRMS (ESI) m/z calcd for
+
D
C H ClN O S [M+Na] 819.1420, found 819.1428. [α]23 = -20.1 (c = 0.74, CHCl3).
38
37
2
11 2
5
.1.17.8
diethyl
2
,2'-((((3R,4R)-1-(2-((4-(4-bromophenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-3,4
-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (23a)
1
Yellow solid (38%). M.p.: 94-95 °C. H NMR (400 MHz, CDCl ) δ 1.37-1.41 (m,
3
6
1
2
H), 4.08(s, 2H), 4.19-4.24 (m, 4H), 4.48 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.65 (d, J =
4.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63 (dd, J = 4.8 Hz, 15.6 Hz,
1
3
H), 6.84-7.00 (m, 8H), 7.40-7.58 (m, 10H), 9.40 (s, 1H); C NMR (100 MHz,
CDCl ) δ 14.9, 51.6, 52.2, 66.7, 75.9, 79.2, 115.7, 115.9(2), 119.6, 119.7(2), 120.2,
3
1
21.4, 126.1(2), 130.5, 132.3, 132.7, 143.5, 153.7, 156.4, 157.2, 158.4, 159.4; HRMS
+
D
(
ESI) m/z calcd for C H BrN O S [M+Na] 863.0914, found 863.0923. [α]23
=
3
8
37
2
11 2
-19.7 (c = 0.52, CHCl3).
5
.1.17.9
diethyl
2
,2'-((((3R,4R)-1-(2-((4-([1,1'-biphenyl]-4-yloxy)phenyl)amino)-2-oxoacetyl)pyrrolidi
ne-3,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (24a)
1
White solid (34%). M.p.: 109-111 °C. H NMR (400 MHz, CDCl ) δ 1.37-1.41 (m,
3
6
1
2
H), 4.09 (s, 2H), 4.19-4.25 (m, 4H), 4.48 (dd, J = 3.6 Hz, 14.0 Hz, 1H), 4.67 (d, J =
4.0 Hz, 1H), 5.01 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63 (dd, J = 4.8 Hz, 15.5 Hz,
1
3
H), 6.93-7.06 (m, 8H), 7.30-7.60 (m, 15H), 9.41 (s, 1H); C NMR (100 MHz,
CDCl ) δ 14.9, 51.6, 52.2, 66.7, 75.9, 79.2, 115.9(2), 118.8, 119.6, 119.7(2), 121.4,
3
1
1
26.1(2), 126.8, 127.0, 128.4, 128.7, 130.5, 132.0, 136.4, 140.4, 143.6, 154.2, 156.7,
+
57.2, 158.4, 159.4; HRMS (ESI) m/z calcd for C H N O S [M+Na] 861.2122,
44
42
2
11 2
D
found 861.2118. [α]23 = -21.6 (c = 0.37, CHCl3).

ACCEPTED MANUSCRIPT
5
2
3
.1.17.10
diethyl
,2'-((((3R,4R)-1-(2-((4-(naphthalen-2-yloxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-
,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (25a)
1
White solid (31%). M.p.: 111-113 °C. H NMR (400 MHz, CDCl ) δ 1.37 (t, J =
3
7
4
2
1
.2 Hz, 6H), 4.06 (s, 2H), 4.20 (q, J = 7.2 Hz, 4H), 4.46 (dd, J = 14.4Hz, 4.0 Hz, 1H),
.64 (d, J = 14.4 Hz, 1H), 4.99 (s, 1H), 5.08 (d, J = 4.0 Hz, 1H), 6.61 (dd, J = 15.6Hz,
.4 Hz, 2H), 6.88-6.97 (m, 4H), 7.00-7.08 (m, 2H), 7.18-7.28 (m, 2H), 7.35-7.61 (m,
1
3
0H), 7.66 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.4 Hz, 4.4 Hz, 2H), 9.43 (s, 1H); C
NMR (100 MHz, CDCl ) δ 14.9, 51.6, 52.2, 66.7, 75.8, 79.2, 113.8, 115.8, 119.6,
3
1
19.7, 121.4, 124.7, 126.0, 126.5, 127.0, 127.7, 129.9, 130.1, 130.5, 132.1, 134.2,
43.6, 154.1, 155.0, 157.2, 158.4, 159.4; HRMS (ESI) m/z calcd for C H N O S
11 2
1
4
2
40
2
+
D
[
M+Na] 835.1966, found 835.1958. [α]23 = -23.9 (c = 0.36, CHCl3).
5
.1.17.11
diethyl
2
,2'-((((3R,4R)-1-(2-((4-hexylphenyl)amino)-2-oxoacetyl)pyrrolidine-3,4-diyl)bis(oxy)
)bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (26a)
1
White solid (34%). M.p.: 84-85 °C. H NMR (400 MHz, CDCl ) δ 0.86 (m, 3H),
3
1.27-1.29 (m, 6H), 1.40 (td, J = 7.2 Hz, 2.4 Hz, 6H), 1.53-1.59 (m, 2H), 2.56 (t, J =
8.4 Hz, 2H), 4.07 (s, 2H), 4.22 (qd, J = 7.2 Hz, 2.4 Hz, 4H), 4.47 (dd, J = 14.0 Hz,
3.6 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 5.01 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H), 6.63
(dd, J = 4.4 Hz, 15.6 Hz, 2H), 6.93 (t, J = 8.4 Hz, 4H), 7.14 (d, J = 8.4 Hz, 2H),
1
3
7
3
1
.47-7.56 (m, 8H), 9.35 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.0, 14.9, 22.5, 28.8,
3
1.4, 31.6, 35.3, 51.5, 52.2, 66.7, 75.8, 79.1, 115.8, 119.5(2), 119.6, 125.9(2), 129.0,
30.5, 134.0, 140.1, 143.6, 157.1, 158.4(2), 159.5; HRMS (ESI) m/z calcd for
+
D
C H N O S [M+Na] 777.2486, found 777.2474. [α]23 = -22.6 (c = 0.68, CHCl3).
38
46
2
10 2
5
.1.17.12
diethyl
2
,2'-((((3R,4R)-1-(2-((4-decylphenyl)amino)-2-oxoacetyl)pyrrolidine-3,4-diyl)bis(oxy)
)bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (27a)

ACCEPTED MANUSCRIPT
1
White solid (36%). M.p.: 76-78 °C. H NMR (400 MHz, CDCl ) δ 0.87 (t, J = 7. 2
3
Hz, 3H), 1.21-1.28 (m, 14H), 1.39 (td, J = 7.2 Hz, 2.4 Hz, 6H), 1.54-1.58 (m, 2H),
2
1
6
7
2
.56 (t, J = 8.4 Hz, 2H), 4.07 (s, 2H), 4.22 (qd, J = 7.2 Hz, 2.4 Hz, 4H), 4.47 (dd, J =
4.0 Hz, 3.6 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 5.00 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H),
.63 (dd, J = 4.4 Hz, 15.6 Hz, 2H), 6.94 (t, J =8.4 Hz, 4H), 7.15 (d, J =8.0 Hz, 2H),
13
.47-7.56 (m, 8H), 9.34 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.1, 14.9, 22.6, 29.2,
3
9.3, 29.4, 29.5, 29.6, 31.4, 31.8, 35.4, 51.6, 52.2, 66.7, 75.8, 79.1, 115.8, 119.5(2),
119.6, 126.0(2), 129.0, 130.5, 134.0, 140.1, 143.6, 157.1, 158.4(2), 159.5; HRMS
+
D
(
ESI) m/z calcd for C H N O S [M+Na] 833.3112, found 833.3090. [α]23 = -21.8
42 54 2 10 2
(c = 0.50, CHCl3).
5
.1.17.13
diethyl
2
,2'-((((3R,4R)-1-(2-((4-dodecylphenyl)amino)-2-oxoacetyl)pyrrolidine-3,4-diyl)bis(o
xy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (28a)
1
White solid (33%). M.p.: 74-76 °C. H NMR (400 MHz, CDCl ) δ 0.87 (t, J = 7. 2
3
Hz, 3H), 1.24-1.29 (m, 18H), 1.40 (td, J = 7.2 Hz, 2.4 Hz, 6H), 1.55-1.60 (m, 2H),
2
1
6
7
2
.57 (t, J = 8.4 Hz, 2H), 4.08 (s, 2H), 4.22 (qd, J = 7.2 Hz, 2.4 Hz, 4H), 4.47 (dd, J =
4.0 Hz, 3.6 Hz, 1H), 4.66 (d, J = 14.0 Hz, 1H), 5.01 (s, 1H), 5.10 (d, J = 3.6 Hz, 1H),
.63 (dd, J = 4.4 Hz, 15.6 Hz, 2H), 6.94 (t, J =8.4 Hz, 4H), 7.15 (d, J =8.0 Hz, 2H),
13
.47-7.56 (m, 8H), 9.33 (s, 1H); C NMR (100 MHz, CDCl ) δ 14.1, 14.9, 22.7, 29.2,
3
9.3, 29.5, 29.5, 29.6, 29.6, 29.6, 31.4, 31.9, 35.4, 51.6, 52.2, 66.7, 75.8, 79.1,
115.9(2), 119.5(2), 119.7, 126.0(2), 129.0, 130.5, 134.0, 140.2, 143.6, 157.1, 158.4(2),
+
1
59.5; HRMS (ESI) m/z calcd for C H N O S [M+Na] 861.3425, found 861.3392.
44 58 2 10 2
D
[
α]23 = -21.5 (c = 0.87, CHCl3).
5
.1.18 General procedure for 16b-28b:
Compounds 16b-28b were synthesized according to the above method for the
synthesis of 16a-28a.
5
.1.18.1
diethyl

ACCEPTED MANUSCRIPT
2
,2'-((((3S,4R)-1-(2-oxo-2-(phenylamino)acetyl)pyrrolidine-3,4-diyl)bis(oxy))bis(4,1-
phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (16b)
1
White solid (46%). M.p.: 86-88 °C. H NMR (400 MHz, CDCl ) δ 1.40 (t, J = 7.2
3
Hz, 6H), 3.97-4.02 (m, 1H), 4.10-4.13 (m, 1H), 4.21-4.23 (m, 4H), 4.40-4.46 (m, 1H),
4
7
1
1
.69-4.72 (m, 1H), 5.11 (d, J = 3.6 Hz, 2H), 6.58-6.63 (m, 2H), 6.95-6.97 (m, 4H),
1
3
.16-7.19 (m, 1H), 7.35-7.61 (m, 10H), 9.36 (s, 1H); C NMR (100 MHz, CDCl ) δ
3
4.9, 50.1, 51.2, 66.7, 73.4, 75.9, 116.1, 119.3(2), 119.7, 125.3, 125.8, 129.2, 130.3,
36.4, 143.8, 157.1, 159.3, 159.6(2); HRMS (ESI) m/z calcd for C H N O S
10 2
3
2
34
2
+
[
M+Na] 693.1547, found 693.1534.
5
.1.18.2
diethyl
2
,2'-((((3S,4R)-1-(2-oxo-2-((4-phenoxyphenyl)amino)acetyl)pyrrolidine-3,4-diyl)bis(o
xy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (17b)
1
Light brown solid (54%). M.p.: 94-96 °C. H NMR (400 MHz, CDCl ) δ 1.39 (t, J
3
=
7.2 Hz, 6H), 3.97-4.00 (m, 1H), 4.10-4.14 (m, 1H), 4.20-4.22 (m, 4H), 4.41-4.45 (m,
1
7
H), 4.68-4.71 (m, 1H), 5.11 (s, 2H), 6.60 (d, J = 14.8 Hz, 2H), 6.93-7.01 (m, 8H),
1
3
.10 (t, J = 8.0 Hz, 1H), 7.31-7.57 (m, 10H), 9.36 (s, 1H); C NMR (100 MHz,
CDCl ) δ 14.9, 50.1, 51.2, 66.7, 73.4, 75.9, 116.2, 118.6, 119.3, 119.5, 121.3, 123.4,
3
1
25.8, 129.8, 130.3, 131.8, 143.8, 154.3, 157.0, 157.1, 159.3, 159.6(2); HRMS (ESI)
+
m/z calcd for C H N O S [M+Na] 785.1809, found 785.1800.
3
8
38
2
11 2
5
2
3
.1.18.3
diethyl
,2'-((((3S,4R)-1-(2-((4-(4-isopropylphenoxy)phenyl)amino)-2-oxoacetyl)pyrrolidine-
,4-diyl)bis(oxy))bis(4,1-phenylene))(1E,1'E)-bis(ethene-1-sulfonate) (18b)
1
Yellow solid (39%). M.p.: 97-99 °C. H NMR (400 MHz, CDCl ) δ 1.24 (d, J = 7.2
3
Hz, 6H), 1.39 (t, J = 7.2 Hz, 6H), 2.87-2.91 (m, 1H), 3.97-4.00 (m, 1H), 4.09-4.14 (m,
1
2
H), 4.18-4.23 (m, 4H), 4.41-4.45 (m, 1H), 4.67-4.72 (m, 1H), 5.11 (d, J = 3.6 Hz,
13
H), 6.58-6.62 (m, 2H), 6.91-7.19 (m, 10H), 7.43-7.56 (m, 8H), 9.34 (s, 1H); C
NMR (100 MHz, CDCl ) δ 14.9, 24.1, 33.4, 50.1, 51.2, 66.7, 73.4, 75.9, 116.1, 118.7,
3
119.1, 119.3, 121.3, 125.8, 127.6, 130.3, 131.5, 143.7, 144.0, 154.7, 154.8, 157.0,