Synthesis of carbohydrate based macrolactones and their applications as receptors for ion recognition and catalysis

Article abstract of DOI:10.3390/molecules26113394

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functional

Full text of DOI:10.3390/molecules26113394

molecules
Article
Synthesis of Carbohydrate Based Macrolactones and Their
Applications as Receptors for Ion Recognition and Catalysis
Surya B. Adhikari, Anji Chen and Guijun Wang *
Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA;
sbadhika@odu.edu (S.B.A.); achen@odu.edu (A.C.)
*
Correspondence: g1wang@odu.edu; Tel.: +1-757-683-3781; Fax: +1-757683-4628
Abstract: Glycomacrolactones exhibit many interesting biological properties, and they are also
important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to
be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-
based macrocycles containing triazole and lactone moieties have been designed and synthesized. The
synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step.
In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization.
Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen
different macrocycles have been synthesized and characterized, of which eleven macrocycles are
from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others
from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones
have unique structures and demonstrate interesting anion binding properties, especially for chloride.
The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective
ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition,
several macrocycles show some selectivity for different alkynes.
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ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Citation: Adhikari, S.B.; Chen, A.;
Wang, G. Synthesis of Carbohydrate
Based Macrolactones and Their
Keywords: glycomacrocycles; glucosamine; macrolactonization; click chemistry; triazole; copper
Applications as Receptors for Ion
Recognition and Catalysis. Molecules
catalyst; anion binding
2
021, 26, 3394. https://doi.org/
1
0.3390/molecules26113394
1
. Introduction
Macrocyclic compounds are important classes of molecules with many biological ap-
plications and useful for drug discovery [ ]. Carbohydrate-based macrocyclic compounds
have unique molecular architectures and many practical applications [ ]. Naturally exist-
ing and synthetic carbohydrate-based macrocycles have been utilized in drug discovery,
molecular recognition, and as advanced functional materials [ ]. Among the different
Academic Editors: Roman Dembinski
and Igor Alabugin
1,2
3,4
Received: 16 April 2021
Accepted: 24 May 2021
Published: 3 June 2021
1,3,5–7
classes of macrocycles, macrolactones are especially unique compounds that exhibit biolog-
ical activities and often function as enzyme inhibitors; they also showed applications in
molecular recognition for supramolecular chemistry. For example, macrolactones synthe-
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
sized from cholesterol derivatives have shown utility for molecular recognitions [
synthetic macrodilactone exhibited enantioselective recognition of amino alcohols, as well
as metal ions [ ]. Naturally existing carbohydrate-based macrolactones or macrolides often
exhibit many desirable biological activities for drug development [10 12]. The structures
of several macrolactones are shown in Figure 1. Erythromycin ( ) is a sugar-containing
macrolide antibiotic. Ipomoeassina F ( ) and analogs are macrolactones containing a dis-
accharide unit, which exhibit anticancer activities and recently have been identified as
protein-translocation inhibitors [ 13]. Glucolipsin A ( ) and analogs are natural products
8], and a
9
–
1
2
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
5
,
3
containing sugar dilactones—they are inhibitors for dual specific phosphatase Cdc25A [14].
This compound was synthesized from the corresponding hydroxy acids through a macrodi-
lactonization reaction mediated by 2-chloro-1,3-dimethylimidazolinium chloride.
Using a hexapyranose as the scaffold, a variety of synthetic macrolactones can be
prepared depending on the cyclization patterns from different positions of the sugar
4
.0/).
Molecules 2021, 26, 3394. https://doi.org/10.3390/molecules26113394
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3394
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ring. The lactonization could be introduced at an earlier stage and a different method
for the macrocyclization utilized later [12,15]. For instance, the glycomacrolactones with
azobenzene functionality have been synthesized through the cyclization from the C-2 to C-3
or C-4 to C-6 positions of D-glucose and D-mannose derivatives. These glycomacrolactones
have exhibited applications in supramolecular chemistry for the design of chemosensors
and other functional molecular assemblies [16,17]. A macrocyclic sialyl Lewis X (SLeX)
mimic synthesized by lactonization via Mitsunobu reaction from the C-1 to C-6 position
of the L-galactoside, was 1000 fold more potent for the inhibition of P-selectin than the
tetrasaccharide SLeX [18].
Triazole-based macrocyclic frameworks are important structural features in many
bioactive compounds and pharmaceuticals [19
cycloaddition reactions (CuAAC), the “click chemistry”, many classes of 1,4-disubstituted
,2,3-triazole derivatives have been synthesized and studied. There are also many stud-
–21]. Using Cu (I) catalyzed azide-alkyne
1
ies towards the effective transformation of [3+2] azide-alkyne cycloaddition reactions,
and triazole functions have been used as ligands for catalysis, including the CuAAC
reactions [22
–
26]. Besides being medicinally important, the macrocycles containing the
1
,2,3-triazole moieties are also useful in forming host-guest complexes and recognitions for
ions [27–30]. The 1,2,3-triazole functional groups can act as Lewis bases to coordinate with
metal cations, and the triazoles can also recognize halides through the triazole C-H—anion
hydrogen bonds [30 31]. Triazole-containing macrocycles have shown interesting binding
,
properties for both anions and cations; some of them are also ditopic ion-pair receptors,
typically with rigid aromatic structures [31].
The synthesis of triazole-containing glycomacrocycles can be accomplished by many
different methods. Using click chemistry, several series of glycomacrocycles have been
synthesized and analyzed [32
–34]. Several sugar-based bistriazole-containing macrocycles
(
4
) were synthesized, and they are effective ligands in accelerating the CuSO mediated
4
azide-alkyne cycloaddition (AAC) reactions [35]. The macrocycles with different ring sizes
showed different selectivity and catalytic effect for 1-octyne and phenylacetylene. Because
of the importance and potential applications of triazole-based glycomacrocycles, in this
study, we designed and synthesized two series of macrolactones with the general structures
5A and 5B, as shown in Figure 1.
Figure 1. Structures of several carbohydrate-based macrocycles.

Molecules 2021, 26, 3394
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These compounds contain either one or two triazole moieties and are expected to
have properties in binding to guest molecules or ions, resulting in useful structures and
applications.
2. Results and Discussion
As shown in Scheme 1, the macrolactones with general structures 5A can be synthe-
sized starting from the intermediate 3S, which was prepared from N-acetyl-D-glucosamine
NAG) [35]. By installing a suitable leaving group at the C-6 position and a nucleophile,
such as a long-chain and triazole-containing carboxylate linked to the anomeric center, an
(
intramolecular S 2 reaction of the carboxylate with the leaving group is expected to form
N
the macrolactones. The carboxylate intermediate can be prepared using click chemistry to
include one or two triazole functional groups.
To test the feasibility of this route to synthesize the glycomacrolactones, several dif-
ferent sulfonate leaving groups towards the macrocyclization were evaluated to obtain
suitable conditions for the cyclization reactions. Common aryl sulfonyl chlorides were
selected for the derivatiazation of the C-6-primary hydroxyl group of S3—these include
p-bromobenzene-, p-chlorobenzene-, p-tolyl-, and 1-naphthyl-sulfonyl chloride. Methane-
sulfonyl chloride was not selected, since it typically reacts with both the C-4 and C-6
hydroxyl groups readily [36]. The C-6 primary hydroxyl group of S3 was then converted
to different sulfonate leaving groups selectively to afford 6a–6d. The intermediates 6a–6c
were treated with benzoyl chloride to afford the corresponding dibenzoates 7, with both
the C-3 and C-4 positions benzoylated. However, the naphthyl derivative 6d afforded
mainly the C-3 monobenzoylation product, presumably due to steric hindrance.
Scheme 1. Macrolactonization using different sulfonates as the leaving groups.
The 4-bromobenzenesulfonate 6a was converted to the corresponding dibenzoate 7a
followed by a click reaction to afford the intermediate 8a. The intramolecular macrolac-

Molecules 2021, 26, 3394
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tonization reaction led to the monomeric lactone LM28 in 72% yield, together with 20%
dimeric lactonization product DLM28. The 4-chlorosulfonate 6b was converted to chloride
during the benzoylation step to afford the chloride 7b. Using a similar protocol, compound
7b was converted the LM28 in 67% yield together with 17% DLM28; and the tosylate 8c
led to 82% LM28 and no dimer was isolated. Based on these, the tosyl group was superior
to other leaving groups, and this was selected to synthesize a series of other macrocycles
containing monotriazole and bis-triazoles (Schemes 2 and 3).
As shown in Scheme 2, treating 7c and 9 [35] with different alkynoic acids 10a-c uti-
lizing click reaction gave the carboxylic acids 11a–12c. The intramolecular S 2 reaction
N
◦
was carried out using K CO as the base in DMF at 75 C to afford monotriazole macro-
2
3
lactones 13a–13c, 14a–14c with different ring sizes in excellent yields. The synthesis of
bis-triazole-containing macrolactones is shown in Scheme 3. Using a similar method and
the triazole-containing alkynoic acids 10d-e, the desired macrocycles 16a-d were obtained
in 78–90% yields. The concentrations of the cyclization step for both monotriazole and bis-
triazole-containing macrocycles were typically ~10 mM or 0.01 M of the reactants, which
are not super dilute conditions; therefore, the method should be practical for possible
large-scale synthesis.
Besides using DMF as the solvent, for the intramolecular lactonization reaction, ace-
tonitrile was also used as the solvent; similar macrolactonization results were typically
obtained through the reactions that required a longer time to complete. The monotriazole
derivative LM28 was obtained in 77% yield in acetonitrile (9 mM concentration 6 h). The
bistriazole-based macrocycles were also prepared in acetonitrile overnight to afford the
macrocycle products in 71–78% yields. The typical concentration for cyclization for small
scale reactions was about 4–6 mM; though the yields were slightly lower than those reac-
tions when DMF was used, the lower boiling point of acetonitrile makes it easier to remove
during work up. In addition, in acetonitrile, no dimerization was observed, perhaps due to
reduced nucleophilicities of the carboxylate in acetonitrile than DMF.
Scheme 2. Synthesis of monotriazole-based macrocycles.

Molecules 2021, 26, 3394
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Scheme 3. Synthesis of bis-triazole-based macrocycles.
Using the macrolactonization method developed above, several macrocycles with
the general structure 5B can be synthesized. As shown in Scheme 4, the azido sugar
derivative 17 [37] was converted to the key intermediate tosylate 20 in three steps. For
the benzoylation step of compound 19, pyridine was found to be a more effective solvent.
The yields of the dibenzoylated products improved from 74% in DCM/pyridine to 91%
in pyridine. The intermediate azide 20 was treated with different alkyne-containing acids
to generate the precursors for macrolactonizations. As a proof of principle, here, only
two alkynyl acids 10c and 10d, were used. The intermediate 21 was converted to the
monolactonziation product 22 in good yield under similar conditions. Which indicated
that the macrolactonization methods are applicable to the synthesis of glycomacrolactones
of different positions to the C-6.
The bistriazole derivative 23 was subjected to macrolactonization using different
bases to obtain suitable conditions for monocyclization. Three different carbonate bases
in anhydrous DMF were screened, and the results are shown in Table 1. It seems that the
cations used can affect the ratio of the monomer versus the dimer; all conditions showed
100% conversion of the starting materials based on the disappearance of the tosylate signal.
Using sodium and potassium carbonate, the monolactone 24 was obtained, and when
using cesium carbonate, mainly the dimeric-lactone 25 was isolated. In 5% MeOH/DCM,
the monolactone was slightly more polar than the dilactone, which showed an opposite
trend to the C1-series. Using either Na CO or K CO , the monolactonization products
2
3
2
3
were obtained in good yields for the C2 series macrocycles.

Molecules 2021, 26, 3394
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OTs
OTs
OH
Ph
O
HO
HO
O
O
BzO
BzO
O
HO
O
O
BzCl, Py
HOAc/H2O HO
TsCl, Py
HO
NH
NH
OMe
NH
OMe
OMe 0 °C, 1.5 h
91%
NH
0 °C, 1.5 h
81%
OMe 75 °C, 4 h
5%
O
O
O
O
8
N3
N3
N3
N3
1
9
20
1
7
O
O
1
8
OTs
O
BzO
BzO
OBz
OBz
Click reaction
7%
NH
K2CO3, DMF
HO
O
2
0 +10c
O
OMe
5 oC, 2 h
80%
7
6
O
MeO
N
HN
N
N
N
O
N
O
N
2
1
22 (C2ML)
O
N
N
N
BzO
OH
O
O
BzO
O
O
N
Na2CO3 or BzO
K2CO3 or
O
N
N
O
N
N
NH OMe
N
N
OTs
N
Click reaction
N Cs CO
2
3
BzO
OMe
O
O
2
0 +10d
BzO
BzO
N
N
N
MeO HN
O
DMF
HN
8
3%
O
OBz
0 oC, 2 h
7
NH
OMe
5
1 - 83%
N
O
O
N
N
N
OBz
N
N
N
O
N
N
2
4 (C2DML)
25 (C2DDL)
2
3
Scheme 4. Synthesis of macrocycles 5B by cyclization from C2 to C-6 positions.
Table 1. Macrolactonization of the intermediate 23 using different bases.
Yield %
Mono 24 Di 25
Amount Concentration
Base
2.0 equiv
DMF
(mL)
Temp
( C)
Entry
◦
(
mg)
(mM)
1
2
3
100
75
100
9.7
8.7
9.7
Cs CO
12
10
12
70
70
70
0
77
83
51
0
0
2
3
K CO
2
3
Na CO
2
3
2
.1. Anion Binding Studies of the Macrocycles with Tetrabutyl Ammonium Halides
As mentioned earlier, triazole derivatives in rigid macrocycles have shown strong
binding to chloride ions from the C-H bond [38 39]. In order to understand the anion
,
binding capacities of the macrocycles, several representative macrocycles, including the C1
series monotriazole LM28, bistriazole DM35, and C-2 series monotriazole 22 and bistriazole
2
4
, were studied. The tetrabutylammonium halides (TBAX), including TBACl, TBABr, and
1
TBAI, were used to study halide binding. The H NMR spectra of the macrocycles with
different amounts of halides were obtained, and possible anion recognitions were analyzed.
The structures and H NMR spectra of several representative macrocycles with TBACl are
1
shown in Figures 2–5 and Figures S1–S22 on pages S80–S90.
Figure 2. Structures of several macrocycles and the protons assigned.

Molecules 2021, 26, 3394
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1
The H NMR spectra of LM28 with TBACl are shown in Figure 3, Figures S1 and S2.
The triazole C-H and the amide NH signals of LM28 showed significant chemical shift
changes upon adding halides. From 0 to 10.0 equiv of TBACl, the NH showed the most
significant downfield shift of 0.59 ppm—this indicated strong hydrogen bonding with the
chloride. The triazole signal also shifted downfield, with 2.0 equiv of TBACl, the Ha moved
downfield by 0.16 ppm; interestingly, this signal only shifted another 0.04 ppm when 10.0
equiv of chloride was added. The significant downfield change of triazole and NH signals
with increasing amounts of chloride indicated that they were affected by forming hydrogen
bonds with chloride and by anion-π interactions. Other protons were less affected by
chloride additions and showed small upfield shifts. The anomeric proton shifted upfield
by 0.04 ppm, H by 0.05 ppm, and H by 0.10 ppm. Without chloride, the Hb, Hc, and Hd
3
4
are multiplets centered at
δ
4.73, 4.57, and 4.39 ppm, respectively, and the Hb and Hc each
showed doublet of triplet splitting pattern (dt). However, with 10.0 equiv of TBACl, the Hb
and Hc merged to a pseudo triplet. These changes indicated that the chloride binding to
the ring caused significant chemical and magnetic environment changes for the macrocycle
protons. The anion binding did not affect the conformation of the sugar ring much, but did
change the dihedral angles of anomeric methylene groups (Figure 2).
1
Figure 3. H NMR spectra of LM28 with different amounts of TBACl from 0 to 10.0 equiv.
1
The H NMR spectra of LM28 with TBABr and TBAI are shown in Figures S3–S8; the
patterns are similar to those of chloride, but with much smaller chemical shift changes.
From 0 to 5.0 equiv of TBABr, the triazole signal showed about 0.10 ppm downfield shift,
and the NH signal shifted downfield by 0.19 ppm, the anomeric proton showed a small
upfield shift of 0.03 ppm. These results showed that the bromide also forms hydrogen
bonds with the triazole hydrogen, amide hydrogen cooperatively. But the bromide binding
is apparently weaker than chloride. TBAI had even less influence on chemical shift changes
(
Figures S6–S8). From 0 to 5.0 equiv of TBAI, the triazole and the NH signals only showed
small downfield changes of 0.03 and 0.06 ppm, respectively. This indicated that iodide
didn’t form strong interactions with the triazole and the macrocycle.
1
The H NMR spectra of DM35 with different TBAX are shown in Figures S9–S17. For 0
to 5.0 equiv of TBACl (Figures S9–S11), the amide NH signal showed a 0.14 ppm downfield
shift, and the anomeric proton showed a similar upfield change of 0.04 ppm. The triazole
signals showed a small downfield shift of 0.04 ppm when adding up to 2 equiv of TBACl
(Figure S10); however, not much change was observed after adding additional TBACl. This
could be due to the conformation change caused by the anion binding with the sugar ring.
A similar trend was observed for TBABr, as shown in Figures S12–S14, from 0 to 5 equiv
of TBAB, the NH signal moved downfield by 0.04 ppm, and the anomeric proton showed

Molecules 2021, 26, 3394
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an upfield change of 0.03 ppm. The triazole signals showed concentration dependence.
Upon addition of one equiv of TBABr, the two triazole signals showed 0.08 ppm downfield
change; after further addition of TBABr, the triazole signals did not move (Figure S13). This
indicates that possibly one bromide is hydrogen bonding with both triazole protons, and
bromide formed stronger interactions than chloride did. TBAI did not cause significant
chemical shift changes (Figures S15–S17).
1
The H NMR spectra of the C-2 series macrocycles 22 are shown in Figure 4,
Figures S18 and S19. The triazole signal showed a small downfield (0.03 ppm) change
after adding one equiv of TBACl. From 0 to 10.0 equiv of TBACl, the amide NH showed a
larger downfield change of 0.19 ppm, the other protons from the sugar ring also showed
significant changes (Figure 4). The anomeric proton showed an upfield shift of 0.07 ppm.
The protons at C-3 and C-4 positions became more resolved into two triplets, and the
methylene Hb and Hc merged from two separate doublets to a pseudo quartet. This
indicated the chemical environment of the two protons become very similar.
1
Figure 4. H NMR spectra of C2-monotriazole compound 22 at different concentrations of TBACl.
The C2-bistriazole macrocycle 24 binding to chloride was also studied, as shown in
Figure 5 and Figures S20–S22. The triazole, anomeric, NH, and many other signals changed
significantly upon adding TBACl. From 0 to 10.0 equiv of TBACl, the triazole proton
Ha at 7.49 ppm shifted downfield by 0.10 ppm; and Hb at 7.37 shows a small downfield
(0.03 ppm) change, the amide NH shifted downfield by 0.31 ppm. This indicated that
the amide participated in intermolecular hydrogen bonding significantly, and one of the
triazole hydrogen atoms also formed a stronger hydrogen bond with chloride than the
other. The H and H appeared as a pseudo triplet; H shifted upfield by 0.05 ppm, while
3
4
4
H stayed the same. The methylene Hc and Hd changed from a pseudo quartet to a broad
3
singlet, indicating that they have a similar chemical and the magnetic environment with
5.0–10.0 equiv of TBACl. These shifts showed that the macrocycle can bind to chloride, and
the binding of anions resulted in a conformational change of the macrocycle.

Molecules 2021, 26, 3394
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1
Figure 5. The H NMR spectra of compound 24 with different amounts of TBACl.
The binding properties of the macrocycles LM28
using several macrolactones and H NMR spectroscopy at variable temperatures. The
H NMR spectra of DM35 and its complex with CuSO4 5H O are shown in Figure 6 and
,
DM35 with Cu2+ were also studied
1
1
·
2
Figures S23–S25. In the complex, the two sharp triazole singlets at 7.70 and 7.69 ppm
disappeared or became broadened and shifted downfield to around 7.81 ppm. The triazole
signals were very broadened due to the paramagnetic properties of Cu (II) binding to
triazole [40]. Typically, protons within 0.9 nm of the Cu (II) were not observed due to fast
paramagnetic relaxation, and the protons in the outer shell between 0.9–1.7 nm from the
copper showed chemical shift changes and broad resonances [41]. The signals far away
from Cu (II) were not affected as much (Figure S23). This showed that the copper ion is in
close vicinity to the triazoles.
1
II
Figure 6. The H NMR spectra of DM35 and its Cu complex with CuSO ·5H O in d -DMSO.
4
2
6
1
The H NMR spectra of the copper complex with DM35 were also evaluated at
◦
different temperatures, from 30 to 60 C (Figure 7, Figures S24 and S25), the triazole
signals showed upfield shift to a broad signal, but more defined peak at around 7.71 ppm,
this is close to the chemical shifts of macrocycle without Cu (II), which indicates that
the Cu (II) is more dissociated from the binding to the two triazole nitrogen atoms at
◦
elevated temperatures. The anomeric proton appeared broad singlet at 30 C, at 4.79 ppm,
and shifted to 4.81 to a doublet (Figure S24a). The amide NH signal shifted upfield at
higher temperature indicates that amide participates in intermolecular hydrogen bonding.
◦
The process is reversible as when the same NMR sample was cooled from 60 to 30 C
(
Figure S25), the signals for triazoles and amide reverted to the original pattern.

Molecules 2021, 26, 3394
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1
Figure 7. Stacked H NMR spectra of DM35 complex with CuSO4
·
5H O at different temperatures.
2
The signal for triazole and amides are labeled.
1
The H NMR spectra of the complex of DM35 with Cu(OAc) are shown in
2
Figures S26–S28. These are similar to the copper sulfate complex, but showed more
significant broadening; this indicated that the macrocycle formed a strong complex with
the Cu (II) through interactions with the nitrogen of the triazole ring, and the copper ion is
in close proximity with several other hydrogens. The complex of the monotriazole LM28
with CuSO4
·
5H O (Figure S29) showed a similar trend; the triazole signal appeared as a
2
1
broad singlet, but still visible, unlike in the bistriazole complexes. The H NMR spectra of
the copper complex at different temperatures showed some chemical shift changes for the
NH and triazole signals (Figure S31). These results showed that for monotriazoles, such as
LM28, the copper ion was not bonded to the triazole as tightly as comparing to bistriazoles.
The complex of the C2 bistriazole derivative 24 with CuSO4
the H NMR spectra showed similar trends (Figures S32–S34).
·
5H O was also prepared and
2
1
2.2. Effect of the Macrocycles as Ligands for CuAAC Reactions
Besides the binding studies, the effect of these macrocycles on CuAAC reactions was
also studied as shown in Scheme 5. Using the anomeric sugar azide 26 as the substrate, a
series of reactions were carried out with different alkynes, including the aliphatic alkyne
1
1
-octyne, aromatic alkynes, such as phenylacetylene, 4-t-Bu-phenylacetylene, and 5-phenyl-
-pentyne. The results are summarized in Tables 2–5 and SI Tables S1–S8, Figures S35–S42.
For phenylacetylene, when using 2.5 mol% macrocycle and copper sulfate as the
catalyst (Table 2a), at 2 h, all C1-series macrocycles (MCs), including both monotriazole
and bis-triazole derivatives, were able to accelerate the reaction to over 50% conversion
versus 15% conversion without the macrocycles. The most effective macrocycles are the
bistriazole macrocycles DM25 and DM35, which reached 100% conversion within 5 h. The
reactions in the presence of the monotriazole derivatives LM34, LM36, LM26 reached over
7
5% conversion at 5 h and almost completed after 9 h. When the monotriazoles (Table 2b)
were increased to 5.0 mol%, LM26 and LM34 were both effective in catalyzing the reactions,
reaching almost full conversions at 5 h. The C2 series macrocycles were not as effective as
the C-1 series; only the bistriazole derivative C2DML (24) showed some acceleration for
the reaction.

Molecules 2021, 26, 3394
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Scheme 5. Cycloaddition reactions of sugar azide with different acetylenes.
Table 2. Effect of the macrocycles on catalyzing the click reactions of phenylacetylene.
Conversion (%)
mol% of
Isolated
Yields for 28
Entry
MC Code
MC
(a) 1 h, (b) 0.5 h
2 h
5 h
9 h
(
a)
1
2
3
4
5
6
7
8
9
None
LM24
LM26
LM28
LM34
LM36
LM38
DM24
DM25
DM34
DM35
0
15
50
61
61
66
60
49
51
84
60
81
21
57
78
67
79
77
51
54
100
61
N/A
68
85
79
93
89
51
58
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
38
57
57
55
56
49
51
68
53
68
70%
82%
80%
92%
96%
65
1
0
100
(
1
1
1
1
1
1
1
1
1
b)
None
LM26
LM34
LM36
DM24
DM25
DM34
DM35
C2ML
C2DLM
0
18
74
51
34
56
59
54
42
10
27
21
100
94
87
70
100
68
100
20
1
2
3
4
5
6
7
8
9
5.0
5.0
5.0
2.5
2.5
2.5
2.5
2.5
2.5
51
42
27
43
46
46
35
88%
79%
93%
94%
40, 10 h
79, 10 h
56
Condition (a): Sugar azide (1.0 equiv, 40.0 mg), CuSO4·5H
2
O (0.2 equiv, 5.4 mg), phenylacetylene (1.2 equiv,
4.0 L), EtOH/H O (v/v 1:1, 2.0 mL), macrocycle, NaAsc (0.4 equiv, 8.5 mg). Condition (b) The same as (a)
1
µ
2
except 1.5 equiv of alkynes and 0.5 equiv of NaAsc were used.
When using 1-octyne as the substrate, different macrocycles showed very different re-
sults. As shown in Table S3, with 2.5 mol% macrocycles, 1.2 equiv of 1-octyne and 0.1 equiv
of CuSO , only DM34 was effective at catalyzing the reaction, reaching 93% conversion at
4
2
h; the other macrocycles didn’t show improvement over the control experiment. When
increasing the 1-octyne from 1.2 to 1.5 equiv, the reaction completed within 1 h in the
presence of 2.5 mol% of DM34. Increasing the loading of MCs for LM26 LM34, and LM36
,
to 5.0 mol% did not improve the conversions (Table 3 and Table S4). The experiments
confirmed that DM34 was particularly efficient at catalyzing the click reaction of 1-octyne.

Molecules 2021, 26, 3394
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Table 3. Effect of the macrocycle on catalyzing the click reaction of 1-octyne (R = n-Hexyl).
Conversion Conversion Conversion
Isolated
Yield 29
Entry
MC Code
mol% MC
(%) at 1 h
(%) at 2 h
(%) at 5 h
1
2
3
4
5
6
7
8
None
LM26
LM34
LM36
DM24
DM25
DM34
DM35
0
11
8
14
12
18
14
35
25
20
25
28
23
46
57
5.0
5.0
5.0
2.5
2.5
2.5
2.5
16
12
27
12
100
20
87%
22
37
Condition: Sugar azide (1 equiv, 40.0 mg), CuSO4·5H
2
O (0.1 equiv, 2.7 mg), 1-octyne (1.5 equiv, 23.7 µL),
EtOH/H2O (v/v 1:1, 2.0 mL), NaAsc (0.3 equiv, 6.4 mg).
5-Phenyl-1-pentyne was found to be much more reactive in comparison to the other
alkynes screened. Several experiments were carried out to analyze the effect of the macro-
cycles with reduced copper loading. A few summarized results are shown in Table 4 and
Tables S5 and S6. Without macrocycles, at 2 h the reaction of the alkyne with 26 reached
1
00% (0.1 equiv of CuSO ) and 51% conversion when using 0.05 equiv copper sulfate. Fur-
4
ther reduction of copper to 1 mol%, at 2 h only 5% conversion was observed; however, with
added 2.5 mol% of DM35, the reaction reached 52% conversion. From these results, we
selected either 2.0 or 5.0 mol% of copper to evaluate the MC ligands. As shown in Table 4
,
1
.0–2.5% mol of the bis-triazole macrocycles were effective at accelerating the reactions
significantly, reaching 100% conversion at about 1–5 h. When using 2 mol% Cu(OAc)2
as the catalyst, the control reaction reached 13% conversion, but the reaction with DM35
reached 100% conversion at 2 h (Table S5).
Table 4. Effect of the macrocycles on CuAAC of sugar azide with 5-phenyl-1-pentyne.
Conversion (%)
mol%
of MC
CuSO4
(equiv)
Isolated
Yield 30
Entry
Macrocycle
1 h
2 h
5 h
1
2
3
4
5
6
7
8
None
None
DM35
DM35
DM24
DM25
DM34
DM35
0
0
0.01
0.05
0.01
0.02
0.02
0.05
0.05
0.05
2
33
29
58
62
77
100
100
5
27
51
52
88
88
98
2.5
1.0
2.5
1.0
2.5
2.5
74
100
100
86%
79%
86%
77%
87%
Conditions: Sugar azide (1.0 equiv, 40.0 mg), CuSO4·5H
pentyne (1.5 equiv, 24.5 L), EtOH/H O (v/v 1:1, 2.0 mL), macrocycle (1.0–2.5 mol%), NaAsc (three folds of the
molar amount of copper sulfate).
2
O (0.05 equiv, 1.3 mg or other amount), 5-phenyl-1-
µ
2
For 4-t-butylphenylacetylene (Table 5 and Tables S7 and S8), using 0.1 equiv of copper
sulfate, the reactions were slow; only DM25 and DM35 helped the reaction to full conver-
sion at 20 h; when the CuSO loading was increased, the reactions in the presence of the
4
two MCs reached full conversions at 5 h. DM34 and DM24 were not that effective, giving
similar conversion compared to the control experiment. DM25 was much more efficient
than the isomer DM34—apparently, the positions of the triazoles in the macrocycle had an
influence towards the catalysis of the reaction.

Molecules 2021, 26, 3394
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Table 5. Effect of the macrocycles on copper-mediated click reaction of sugar azide with 4-tert-
butylphenylacetylene (R = p-t-Bu-C H -).
6
4
Conversion (%)
mol%
of MC
CuSO4
(equiv)
Isolated
Yield 31
Entry Macrocycle
2 h
5 h
10 h
20 h
a
1
2
3
4
None
DM25
DM34
DM35
0
0.1
0.1
0.1
0.1
4
10
80
34
45
17
100
70
a
2.5
2.5
2.5
47
15
28
91%
86%
a
a
100
0.2 b
5
6
7
8
9
None
DM24
DM25
DM25
DM34
DM35
0
42
61
30
43
48
68
62
78
100
100
75
83
87
b
5.0
2.5
5.0
5.0
5.0
0.2
0.2
0.2
0.2
b
93%
95%
b
b
84
100
b
1
0
0.2
98
89%
a
Condition : Sugar azide (1.0 equiv), CuSO4·5H
2 2
O (0.1 equiv), p-t-butyl-phenylacetylene (1.5 equiv), EtOH/H O
b
(
v/v 1:1, 2.0 mL), NaAsc (0.3 equiv); Condition : The same as “a” except 0.2 equiv of CuSO4·
2
H O and 0.4 equiv
of NaAsc were used.
The energy minimized conformations of two macrocycles DM25 and DM34 are shown
in Figure 8 [35]. These two compounds have the same molecular weight and ring sizes—the
only difference is that the triazole is located at a different position to the anomeric center.
The two MCs adopted quite different conformations in which the triazoles rings are more
parallel in DM25, but at a dihedral angle about 30 degrees to each other for DM34. The two
triazole rings can adopt different conformations upon binding with copper, and possibly
have a cooperative effect when both triazole rings are embedded in the macrocycles. The
conformation difference of these MCs perhaps is correlating with the selectivity among
different alkynes. DM25 is more selective for phenylacetylene; it is also more effective
for t-Bu-phenylacetylene, while DM34 was the most effective MC for 1-octyne, but not
as good as other MCs for phenylacetylenes. The interesting selectivity towards different
alkynes may be useful in differentiating acetylenes when reacting with the azide; this could
be useful for other selective reactions.
Figure 8. The energy minimized conformations of (a) DM25 and (b) DM34.
3
. Experimental Section
General Methods
All reactions were carried out under normal conditions, reagents and solvents were
obtained commercially from Sigma-Aldrich, VWR, and Fisher and used directly with-
out purifications. All reactions, unless otherwise noted, were carried out in oven-dried
glassware under a nitrogen atmosphere. All purifications were conducted by flash chro-
matography using 230–400 mesh silica gel with a gradient of solvent systems. Thin-layer
chromatography (TLC) analysis was performed with aluminum-backed TLC plates with
UV and fluorescence indicator and visualized using UV lamp at 254 nm, then stained
with PMA solution. 1H NMR and proton-decoupled C NMR spectra were obtained
with Bruker 400 MHz NMR spectrometer in DMSO-d , D O, or CDCl . The chemical
13
6
2
3
shifts were reported using CDCl /DMSO-d as internal standard at 7.26/2.50 ppm and at
3
6

Molecules 2021, 26, 3394
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77.0/39.5 ppm, respectively. 2D NMR experiments (HSQC, COSY) were also conducted
to assist the compound characterizations. Melting point measurements were carried out
using a Fisher Jones melting point apparatus. The molecular mass was measured using
LC-MS on an Agilent LC1260 system and 6120B Single Quad Mass Spectrometer or with
Shimadzu LCMS-2020. HRMS data were obtained using positive electrospray ionization
on a Bruker 12T APEX-Qe FTICR-MS with an Apollo II ion source.
For compounds synthesized by similar methods, the procedures for the first com-
pound are included in detail. For the rest, only the amount used, purification method, and
the characterization data are provided.
Synthesis of compound 6a. Compound S3 (200.0 mg, 0.69 mmol, 1.0 equiv) was added
to a 50 mL round bottomed flask (RBF) with a drying tube and nitrogen balloon, pyridine
◦
(
(
4.0 mL) was added and the flask was cooled to 0 C, then 4-bromobenzenesulfonyl chloride
◦
352.1 mg, 1.37 mmol, 2.0 equiv) was added and the mixture was stirred at 0 C for 20 min
1
and the ice bath was removed. The mixture was stirred at rt for 20 h, at which time H
NMR spectrum showed about 95% conversion. The reaction was stopped, and solvent was
removed, the crude product was purified on silica gel using a gradient of dichloromethane
(
DCM) and methanol, from DCM up to 10% MeOH/DCM (R = 0.31 in 10% MeOH/DCM).
f
1
The desired product 6a was obtained as a colorless liquid (232.0 mg, 66%). H NMR
(
400 MHz, CDCl3)
δ 7.78 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 6.21 (d, J = 8.8 Hz, 1H),
4
.78 (d, J = 3.6 Hz, 1H), 4.38–4.29 (m, 2H), 4.11–4.04 (m, 1H), 3.87–3.78 (m, 2H), 3.71–3.65
1
3
(
(
m, 1H), 3.60–3.54 (m, 1H), 3.53–3.46 (m, 2H), 3.37–3.29 (m, 1H), 2.02 (s, 3H); C NMR
100 MHz, CDCl3)
δ
172.3, 134.8, 132.6, 129.5, 129.2, 97.7, 73.4, 70.5, 69.9, 69.7, 67.2, 53.2,
+
50.5, 23.2. HRMS m/z calcd for C H BrN O SNa [M + Na] 531.0156, found 531.0155.
16
21
4
8
Synthesis of compound 6b. Compound S3 (100.0 mg, 0.35 mmol), pyridine (1.5 mL),
4
-chlorobenzene sulfonyl chloride (147.7 mg, 0.69 mmol), 12 h. Purified by flash chro-
matography (DCM to 2% MeOH/DCM) to obtain a colorless liquid (122.0 mg, 76%) as
1
the desired compound. (R = 0.27 in 10% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
f
3
7.86 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 6.12 (d, J = 8.7 Hz, 1H), 4.79 (d, J = 3.6 Hz,
1
(
H), 4.39–4.25 (m, 2H), 4.11–4.03 (m, 1H), 3.90–3.83 (m, 1H), 3.83–3.77 (m, 1H), 3.71–3.64
m, 1H), 3.61–3.45 (m, 3H), 3.38–3.29 (m, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
1
72.2, 140.6, 134.3, 129.6, 129.4, 97.7, 72.8, 70.3, 69.9, 69.8, 67.2, 53.2, 50.4, 23.1. LC-MS (ESI+)
+
+
calcd for C H ClN O S [M+H] 465 found 465. HRMS (ESI+) ([M + Na] ) m/z calcd for
16
22
4
8
C H ClN O SNa, 487.0661, found 487.0665.
16
21
4
8
Synthesis of compound 6d. Compound S3 (200.0 mg, 0.69 mmol), pyridine (4.0 mL),
-naphthalenesulfonyl chloride (312.4 mg, 1.37 mmol), 20 h to see 90% conversion. Purified
1
by flash chromatography (DCM to 10% MeOH/DCM) to obtain a white foam (211.0 mg,
1
6
4%) as the desired product. (R = 0.33 in 10% MeOH/DCM). H NMR (400 MHz, CDCl )
f
3
δ
8.63 (d, J = 7.9 Hz, 1 H), 8.29 (dd, J = 8.4, 7.0 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.95 (d,
J = 8.0 Hz, 1H), 7.74–7.55 (m, 3H), 5.92 (d, J = 8.3 Hz, 1H), 4.61 (d, J = 3.7 Hz, 1H), 4.40–4.31
(
(
1
2
m, 1H), 4.28–4.20 (m, 1H), 3.98–3.89 (m, 1H), 3.90–3.67 (m, 2H), 3.64–3.54 (m, 1H), 3.49–3.34
m, 3H), 3.27–3.18 (m, 1H), 2.01 (s, 3H); 13C NMR (400 MHz, CDCl3)
172.1, 135.3, 134.1,
31.1, 130.4, 128.8, 128.5, 128.4, 127.2, 125.0, 124.0, 97.4, 72.7, 70.4, 69.9, 69.8, 66.9, 53.1, 50.3,
δ
+
3.1. HRMS m/z calcd for C H N O SNa [M + Na] 503.1207, found 503.1208.
20
24
4
8
Synthesis of compound 7a. Compound 6a (100.0 mg, 0.2 mmol, 1.0 equiv) was added
to a 50 mL round bottom flask with a drying tube and nitrogen balloon attached, the
◦
reaction flask was cooled to 0 C, then dichloromethane (2.5 mL), pyridine (5.0 equiv) and
benzoyl chloride (0.06 mL, 0.5 mmol, 2.5 equiv) were added to the solution. The reaction
◦
mixture was stirred at to 0 C and then stirred at rt for about 12 h. At this time, TLC and
1
H NMR indicated full conversion to the product. The reaction was stopped, and solvent
was removed under vacuum using a rotovap. The crude product was purified using flash
chromatography on silica gel using a solvent gradient of ethyl acetate and hexane from
1
7
4
:4 to 3:2 ratio. The desired product was obtained as a colorless viscous liquid (112.0 mg,
1
9% yield). (R = 0.38 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.90–7.83 (m,
f
3
H), 7.70 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.55–7.47 (m, 2H), 7.39–7.32 (m, 4H),

Molecules 2021, 26, 3394
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5
.90 (d, J = 9.1 Hz, 1H), 5.64 (t, J = 10.9 Hz, 1H), 5.38 (t, J = 9.9 Hz, 1H), 4.97 (d, J = 3.6 Hz,
1
(
H), 4.56–4.49 (m, 1H), 4.28–4.16 (m, 3H), 4.00–3.94 (m, 1H), 3.72–3.65 (m, 1H), 3.62–3.55
m, 1H), 3.45–3.38 (m, 1H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
170.1, 166.9, 165.1,
1
6
34.5, 133.7, 133.5, 132.5, 129.9, 129.8, 129.4, 129.3, 128.7, 128.5, 128.4, 97.6, 71.0, 68.8, 68.5,
+
8.4, 67.8, 52.0, 50.4, 23.0. HRMS m/z calcd for C H BrN O SNa [M + Na] 739.0680,
30
29
4
10
found 739.0676.
Synthesis of compound 7b. Compound 6b (100.0 mg, 0.22 mmol), DCM (3.0 mL) and
benzoyl chloride (0.06 mL, 0.54 mmol), 12 h. The crude was purified using flash chro-
matography on silica gel using a solvent gradient of DCM to 3% MeOH/DCM) to obtain
1
brown oil (96.0 mg, 86%) as the desired product. (R = 0.32 in 5% MeOH/DCM). H
f
NMR (400 MHz, CDCl3)
δ 7.96–7.87 (m, 4H), 7.53–7.45 (m, 2H), 7.40–7.30 (m, 4H), 5.96 (d,
J = 9.3 Hz, 1H), 5.68 (t, J = 10.9 Hz, 1H), 5.47 (t, J = 9.9 Hz, 1H), 5.06 (d, J = 3.6 Hz, 1H),
4
2
.65–4.55 (m, 1H), 4.26–4.18 (m, 1H), 4.12–4.03 (m, 1H), 3.78–3.71 (m, 1H), 3.71–3.63 (m,
H), 3.63–3.56 (m, 1H), 3.48–3.39 (m, 1H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3)
170.1,
δ
1
5
67.0, 165.2, 133.6, 133.5, 129.83, 129.81, 128.7, 128.6, 128.5, 128.4, 97.5, 71.2, 70.5, 70.3, 67.7,
+
2.1, 50.4, 43.6, 23.0. LC-HRMS m/z calcd for C H ClN O Na [M + Na] 539.1304, found
24
25
4
7
5
39.1301.
Synthesis of compound 8a. To a 50 mL RBF, 7a (100.0 mg, 0.14 mmol, 1.0 equiv) in
t-BuOH: THF: H O (v:v:v 1:1:1, 3.0 mL) and 10-undecynoic acid (33.1 mg, 0.18 mmol,
2
1
.3 equiv), CuSO4 5H O (7.0 mg, 0.028 mmol, 0.2 equiv) and sodium ascorbate (NaAsc)
·
2
(11.1 mg, 0.056 mmol, 0.4 equiv) was added sequentially as described and stirred at rt
1
for 16 h. The reaction was monitored after 16 h by H NMR to see the consumption of
starting material and TLC to see no starting material at all. Further purified by flash
chromatography using DCM to 2% MeOH/DCM to obtain a white foam (112.0 mg, 89%) as
1
the desired product. (R = 0.26 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.88–7.79
f
3
(m, 4H), 7.68 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.53–7.44 (m, 3H), 7.38–7.30 (m, 4H),
6
.15 (d, J = 9.0 Hz, 1H), 5.52 (t, J = 10.1 Hz, 1H), 5.32 (t, J = 9.8 Hz, 1H), 4.87 (d, J = 3.6 Hz,
1
2
H), 4.60 (s, 2H), 4.53–4.44 (m, 1H), 4.20–4.06 (m, 3H), 4.02–3.94 (m, 1H), 3.92–3.84 (m, 1H),
1
3
.70 (s, 2H), 2.30 (t, J = 7.3 Hz, 2H), 1.86 (s, 3H), 1.68–1.54 (m, 4H), 1.26 (m, 8H); C NMR
177.7, 170.6, 166.8, 165.0, 134.3, 133.6, 133.4, 132.5, 129.8, 129.7, 129.4,
(
100 MHz, CDCl3)
δ
1
2
29.2, 128.6, 128.5, 128.40, 128.37, 97.5, 71.1, 68.7, 68.4, 68.3, 66.6, 51.8, 49.6, 33.9, 29.2, 29.0,
+
8.91, 28.86, 25.5, 24.7, 22.9. HRMS m/z calcd for C H BrN O SNa [M + Na] 921.1990,
41
47
4
12
found 921.1994.
Synthesis of compound 8b. Compound 7b (90.0 mg, 0.17 mmol), t-BuOH: THF: H O
2
(
0
v:v:v 1:1:1, 2.5 mL), 10-undecynoic acid (31.7 mg, 0.17 mmol), CuSO4
.02 mmol), NaAsc (10.6 mg, 0.05 mmol), 5 h. The crude was purified by flash chromatog-
·
5H O (6.7 mg,
2
raphy (DCM to 3% MeOH/DCM) to obtain a colorless oil (68 mg, 56%) as the desired
1
product. (R = 0.24 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.94–7.86 (m, 4H),
f
3
7
9
.54–7.46 (m, 2H), 7.44 (s, 1H), 7.40–7.32 (m, 4H), 6.13 (d, J = 9.2 Hz, 1H), 5.58 (dd, J = 10.7,
.6 Hz, 1H), 5.41 (t, J = 9.6 Hz, 1H), 4.96 (d, J = 3.6 Hz, 1H), 4.70–4.59 (m, 2H), 4.59–4.51 (m,
1
H), 4.31–4.20 (m, 1H), 4.03–3.89 (m, 2H), 3.68–3.57 (m, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.33 (t,
13
J = 7.3 Hz, 2H), 1.88 (s, 3H), 1.69–1.58 (m, 4H), 1.29 (m, 8H); C NMR (100 MHz, CDCl3)
δ
1
70.6, 167.0, 165.2, 133.6, 133.5, 129.9, 129.8, 128.73, 128.65, 128.5, 128.4, 97.5, 71.4, 70.5, 70.3,
6
6.6, 52.0, 49.5, 43.6, 29.2, 28.9, 28.8, 28.7, 25.6, 23.0. HRMS m/z calcd for C H ClN O Na
35
43
4
9
+
[
M + Na] 721.2611, found 721.2609.
Synthesis of compound 8c. Compound 7c (360.0 mg, 0.55 mmol), t-BuOH: THF: H O
2
(
0
v:v:v 1:1:1, 6.0 mL), 10-undecynoic acid (138.0 mg, 0.72 mmol), CuSO4 5H O (18.0 mg,
.108 mmol, 0.2 equiv), NaAsc (44.0 mg, 0.22 mmol), 12 h. Purified by flash chromatography
·
2
(
DCM to 5% MeOH/DCM) to afford the colorless a semi-solid (378.0 mg, 82%) as the
1
desired product (R = 0.65 in 10% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.89–7.81
f
3
(
2
m, 4H), 7.70 (d, J = 8.3 Hz, 2H), 7.55–7.43 (m, 3H), 7.40–7.30 (m, 4H), 7.21 (d, J = 8.1 Hz,
H), 6.07 (d, J = 9.2 Hz, 1H), 5.54 (dd, J = 10.8, 9.6 Hz, 1H), 5.30 (t, J = 9.6 Hz, 1H), 4.86 (d,
J = 3.6 Hz, 1H), 4.65–4.56 (m, 2H), 4.51–4.43 (m, 1H), 4.22–4.04 (m, 4H), 3.93–3.85 (m, 1H),
.72 (t, J = 7.7 Hz, 2H), 2.36 (s, 3H), 2.32 (t, J = 7.4 Hz, 2H), 1.86 (s, 3H), 1.71–1.57 (m, 4H),
2

Molecules 2021, 26, 3394
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1
1
.29 (m, 8H); 13C NMR (100 MHz, CDCl3)
33.4, 132.3, 130.0, 129.9, 129.81, 129.78, 128.7, 128.6, 128.4, 128.0, 121.3, 97.5, 71.3, 68.9, 68.7,
δ
177.0, 170.5, 166.9, 165.1, 148.8, 145.0, 133.6,
6
8.2, 66.7, 51.9, 49.5, 33.8, 29.3, 29.0, 28.84, 28.82, 25.6, 24.7, 23.0, 21.6; HRMS m/z calcd for
+
C H N O SNa [M + Na] 857.3038, found 857.3039.
42
50
4
21
Synthesis of compound LM28 (13c). Compound 8c (100.0 mg, 0.12 mmol, 1.0 equiv),
K CO (33.0 mg, 0.24 mmol, 2.0 equiv) and DMF (14 mL) were added to a 50 mL RBF. The
2
3
◦
1
reaction mixture was stirred at 70 C for 3 h, at which time H NMR spectrum and TLC
indicated the full conversion of starting materials. The reaction was stopped and solvent
was removed. The crude was purified via flash chromatography using an eluent of DCM
to 5% MeOH/DCM to obtain the desired product as a white solid (65.0 mg, 82%), R = 0.29
f
◦
◦
1
in 5% MeOH/DCM), m.p. 196.0 C-198.0 C; H NMR (400 MHz, CDCl )
(
(
1
(
δ
ppm 7.95–7.86
m, 4H), 7.54–7.45 (m, 2H), 7.42 (s, 1H), 7.40–7.31 (m, 4H), 6.00 (d, J = 9.2 Hz, 1H), 5.62
dd, J = 10.9, 9.7 Hz, 1H), 5.45 (t, J = 9.7 Hz, 1H), 4.77–4.69 (m, 1H), 4.66 (d, J = 3.5 Hz,
H), 4.62–4.54 (m, 1H), 4.51–4.43 (m, 1H), 4.41–4.34 (m, 1H), 4.13–4.01 (m, 4H), 2.87–2.78
m, 1H), 2.77–2.67 (m, 1H), 2.31–2.20 (m, 1H), 2.19–2.09 (m, 1H), 1.93 (s, 3H), 1.79–1.60 (m,
H), 1.56–1.43 (m, 2H), 1.29–1.09 (m, 8H); 13C NMR (100 MHz, CDCl3)
173.4, 170.2, 167.2,
65.4, 133.52, 133.47, 129.9, 129.8, 128.9, 128.8, 128.5, 128.4, 121.3, 97.7, 71.4, 70.2, 68.0, 65.0,
3
2
δ
1
6
3.2, 52.6, 46.6, 33.7, 30.2, 28.20, 28.19, 28.1, 27.7, 27.2, 24.9, 24.4, 23.1; HRMS (ESI+) ([M +
+
Na] ) m/z calcd for C H N O Na, 685.2844, found 685.2825.
35
42
4
9
Synthesis of compounds LM28 and DLM28. Compound 8a (100.0 mg, 0.11 mmol,
.0 equiv), DMF (7.0 mL), and K CO (30.7 mg, 0.22 mmol, 2.0 equiv) were added to
1
2
3
◦
1
a 50 mL RBF. The reaction mixture was stirred at 75 C for 5 h, the H NMR and TLC
samples showed complete conversion of the starting materials. The crude was purified
by flash chromatography using DCM to 5% MeOH DCM to obtain the desired compound
LM28 (53.0 mg, 0.080 mmol, 72%) along with some later fraction which was identified as
the dimerization product DLM28 as a white solid (15.0 mg, 0.011 mmol, 20% based on
starting material conversion). The chloro compound 8b was cyclized by similar conditions,
using compound 8b (50.0 mg, 0.07 mmol, 1.0 equiv), DMF (7.0 mL), and K CO (19.8 mg,
2
3
0
.14 mmol, 2.0 equiv). The desired compound LM28 (31.7 mg, 0.048 mmol, 67%) and
DLM28 (8.0 mg, 0.006 mmol, 17% based on starting material conversion) were obtained.
◦
1
Characterization for DLM28: R = 0.18 in 5% MeOH/DCM. m.p. 236.0–238.0 C; H
f
NMR (400 MHz, CDCl3)
J = 9.1 Hz, 2H), 5.58 (dd, J = 10.3, 9.5 Hz, 2H), 5.43 (t, J = 9.8 Hz, 2H), 4.89 (d, J = 3.5 Hz, 2H),
.63–4.50 (m, 6H), 4.21–4.11 (m, 6H), 3.95–3.88 (m, 4H), 2.72 (t, J = 7.6 Hz, 4H), 2.27–2.22
δ 7.92–7.87 (m, 8H), 7.51–7.46 (m, 6H), 7.37–7.31 (m, 8H), 6.06 (d,
4
1
3
(m, 4H), 1.89 (s, 6H), 1.70–1.66 (m, 4H), 1.59–1.54 (m, 4H), 1.33–1.23 (m, 16H); C NMR
(
100 MHz, CDCl3) 173.2, 170.3, 166.9, 165.2, 133.5, 133.4, 129.83, 129.77, 128.87, 128.85,
δ
1
2
28.4, 121.3, 97.7, 71.4, 69.3, 68.6, 66.8, 62.6, 52.0, 49.5, 34.0, 29.2, 28.93, 28.88, 28.8, 25.6, 24.7,
+
3.1. HRMS m/z calcd for C H N O Na [M + Na] 1347.5796, found 1347.5797.
70
84
8
18
Synthesis of compound 10d. 3-azido propionic acid (200.0 mg, 1.74 mmol, 1.0 equiv)
and 1,7-octadiyne (276.0 mg, 2.6 mmol, 1.5 equiv) were dissolved in t-BuOH: THF: H O
2
(
0
v:v:v 1:1:1, 25.0 mL), then CuSO4
.68 mmol, 0.4 equiv) were added to the reaction mixture. The reaction was stirred at rt
·
5H O (84.8 mg, 0.34 mmol, 0.2 equiv), NaAsc (134.7 mg,
2
1
for 24 h, at which time the reaction was completed as indicated by H NMR and TLC. The
reaction was stopped, and solvent was removed using a rotovap, the residue was diluted
with EtOAc and acidified using 0.1 N HCl (5.0 mL) followed by water wash. The organic
layer was collected and dried over anhydrous Na SO and solvent was removed under
2
4
vacuum to obtain the crude, which was further purified with flash chromatography using
eluent of hexanes to 60% EtOAc/Hexanes to obtain the desired product as a yellowish solid
◦
272.0 mg, 71%), R = 0.48 in 80% EtOAc/Hexanes, m.p. 93.5–94.5 C; H NMR (400 MHz,
f
1
(
CDCl3)
δ 8.98 (br s, 1H), 7.47 (s, 1H), 4.66 (t, J = 6.5 Hz, 2H), 3.02 (t, J = 6.5 Hz, 2H), 2.75 (t,
J = 7.6 Hz, 2H), 2.23–2.18 (m, 2H), 1.92 (t, J = 2.6 Hz, 1H), 1.82–1.73 (m, 2H), 1.62–1.54 (m,
1
3
2
1
H); C NMR (100 MHz, CDCl ) δ 173.2, 147.7, 121.8, 84.2, 68.5, 45.7, 34.7, 28.3, 27.9, 24.9,
3
+
8.1. HRMS m/z calcd for C H N O Na [M + Na] 244.1056, found 244.1056.
11
15
3
2

Molecules 2021, 26, 3394
17 of 26
Synthesis of compound 10e. The same procedure for compound 10d was used, 3-
azido propionic acid (200.0 mg, 1.74 mmol), t-BuOH: THF: H O (v:v:v 1:1:1, 25.0 mL),
2
1
0
3
,8-nonadiyne (313.3 mg, 2.6 mmol), CuSO4 5H O (84.8 mg, 0.34 mmol), NaAsc (134.7 mg,
·
2
.68 mmol), 24 h. The product was purified using flash chromatography (Hexanes to
0% EtOAc/Hexanes) to obtain a yellowish solid (306.0 mg, 75%) as the desired product
◦
1
(
R = 0.5 in 80% EtOAc/Hexanes). m.p. 137.5–139.0 C; H NMR (400 MHz, CDCl ) 7.39
f
3
(
2
s, 1H), 4.62 (t, J = 6.5 Hz, 2H), 3.02 (t, J = 6.5 Hz, 2H), 2.71 (t, J = 7.7 Hz, 2H), 2.23–2.13 (m,
1
3
H), 1.93 (t, J = 2.7 Hz, 1H), 1.72–1.64 (m, 2H), 1.59–1.51 (m, 2H), 1.50–1.43 (m, 2H);
C
NMR (100 MHz, CDCl3)
HRMS (ESI+) m/z calcd for C H N O Na [M + Na] 258.1213, found 258.1212.
δ
173.0, 148.0, 121.6, 84.5, 68.3, 45.5, 34.6, 28.8, 28.3, 28.2, 25.4, 18.3.
+
12
17
3
2
Synthesis of compound 11a. Compound 7c (100.0 mg, 0.15 mmol), t-BuOH: THF:
H O (v:v:v 1:1:1, 3.0 mL), 6-heptynoic acid (25.2 mg, 0.2 mmol), CuSO 5H O (7.7 mg,
·
2
4
2
0
.03 mmol), NaAsc (12.1 mg, 0.06 mmol), 16 h. Purified by flash chromatography (DCM
to 3% MeOH/DCM) to obtain a colorless slurry (96.0 mg, 81%) as the desired product
1
(
R = 0.32 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.88–7.83 (m, 4H), 7.70 (d,
f
3
J = 8.2 Hz, 2H), 7.67 (s, 1H), 7.55–7.47 (m, 3H), 7.40–7.32 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H),
.45 (d, J = 8.8 Hz, 1H), 5.62 (t, J = 10.1 Hz, 1H), 5.31 (t, J = 9.4 Hz, 1H), 4.90 (d, J = 3.6 Hz,
H), 4.70–4.59 (m, 2H), 4.57–4.49 (m, 1H), 4.22–4.07 (m, 4H), 3.97–3.90 (m, 1H), 2.85–2.77 (m,
H), 2.43–2.34 (m, 5H), 1.85 (s, 3H), 1.81–1.68 (m, 4H); 13C NMR (100 MHz, CDCl3)
176.5,
70.6, 167.5, 165.1, 145.1, 133.8, 133.6, 132.3, 129.9, 129.8, 128.53, 128.46, 128.0, 97.2, 71.6, 69.1,
8.5, 68.3, 66.4, 51.8, 32.8, 27.8, 24.9, 23.5, 22.9, 21.6. HRMS m/z calcd for C H N O SNa
6
1
2
δ
1
6
38
42
4
12
+
[
M + Na] 801.2412, found 801.2406.
Synthesis of compound 11b. Compound 7c (100.0 mg, 0.15 mmol), t-BuOH: THF: H O
2
(
v:v:v 1:1:1, 3.0 mL), 8-nonynoic acid (30.7 mg, 0.2 mmol), CuSO4
·
5H O (7.7 mg, 0.03
2
mmol), NaAsc (12.1 mg, 0.06 mmol), 16 h. Purified by flash chromatography (DCM to 3%
MeOH/DCM) to obtain a colorless slurry (109.0 mg, 88%) as the desired product (R = 0.38
f
1
in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.88–7.82 (m, 4H), 7.70 (d, J = 8.0 Hz,
3
2
5
4
H), 7.54–7.45 (m, 3H), 7.38–7.30 (m, 4H), 7.21 (d, J = 7.9 Hz, 2H), 6.15 (d, J = 6.9 Hz, 1H),
.55 (t, J = 10.1 Hz, 1H), 5.29 (t, J = 8.6 Hz, 1H), 4.86 (d, J = 2.4 Hz, 1H), 4.60 (br s, 2H),
.52–4.43 (m, 1H), 4.20–4.05 (m, 4H), 3.90–3.84 (m, 1H), 2.73 (br s, 2H), 2.35 (s, 3H), 2.31
(
t, J = 7.2 Hz, 2H), 1.86 (s, 3H), 1.72–1.58 (m, 4H), 1.38–1.33 (m, 4H); 13C NMR (100 MHz,
CDCl3)
δ 176.6, 169.6, 165.9, 164.1, 144.1, 132.6, 132.5, 131.3, 128.9, 128.8, 127.7, 127.6, 127.4,
1
27.0, 96.5, 70.3, 67.9, 67.6, 67.3, 65.5, 50.8, 32.7, 27.47, 27.45, 23.5, 20.6. HRMS m/z calcd for
+
C H N O SNa [M + Na] 829.2725, found 829.2722.
40
46
4
12
Synthesis of compound 12a. Compound
H O (v:v:v 1:1:1, 2.5 mL), 6-heptynoic acid (24.6 mg, 0.19 mmol), CuSO
.03 mmol), NaAsc (11.8 mg, 0.06 mmol), 24 h. Purified by flash chromatography (DCM
9
(100.0 mg, 0.15 mmol), t-BuOH: THF:
5H O (7.5 mg,
·
2
4
2
0
to 2% MeOH/DCM) to obtain a colorless slurry (98.0 mg, 82%) as the desired product
1
(
(
R = 0.22 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.92–7.83 (m, 4H), 7.69
f
3
d, J = 8.3 Hz, 2H), 7.56–7.46 (m, 3H), 7.40–7.32 (m, 4H), 7.21 (d, J = 8.2 Hz, 2H), 6.43 (d,
J = 9.2 Hz, 1H), 5.61 (t, J = 10.1 Hz, 1H), 5.32 (t, J = 10.0 Hz, 1H), 4.88 (d, J = 3.6 Hz, 1H),
.66–4.57 (m, 1H), 4.54–4.42 (m, 2H), 4.31–4.23 (m, 1H), 4.21–4.08 (m, 2H), 3.82–3.74 (m,
H), 3.43–3.33 (m, 1H), 2.79 (t, J = 6.7 Hz, 2H), 2.42–2.33 (m, 5H), 2.29–2.19 (m, 2H), 1.93 (s,
H), 1.81–1.64 (m, 4H); 13C NMR (100 MHz, CDCl3)
176.4, 170.9, 167.1, 165.2, 148.1, 145.0,
33.6, 132.3, 129.9, 129.8, 128.7, 128.6, 128.5, 128.4, 128.0, 121.3, 97.1, 71.5, 69.1, 68.5, 68.4,
4.5, 52.1, 46.8, 33.1, 29.6, 28.2, 25.0, 23.8, 23.0, 21.6. HRMS m/z calcd for C H N O SNa
4
1
3
δ
1
6
39
44
4
12
+
[
M + Na] 815.2569, found 815.2564.
Synthesis of compound 12b. Compound 9 (100.0 mg, 0.15 mmol), t-BuOH: THF: H O
2
(
v:v:v 1:1:1, 2.5 mL), 8-nonynoic acid (30.1 mg, 0.19 mmol), CuSO4
·
5H O (7.5 mg, 0.03 mmol),
2
NaAsc (11.8 mg, 0.06 mmol), 24 h. Purified by flash chromatography (DCM to 2%
MeOH/DCM) to obtain a colorless slurry (106.0 mg, 86%) as the desired product (R = 0.23
f
1
in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.92–7.84 (m, 4H), 7.69 (d, J = 8.2 Hz,
3
2
5
H), 7.56–7.46 (m, 2H), 7.41–7.31 (m, 5H), 7.21 (d, J = 8.2 Hz, 2H), 6.38 (d, J = 9.2 Hz, 1H),
.60 (t, J = 10.0 Hz, 1H), 5.31 (t, J = 9.9 Hz, 1H), 4.84 (d, J = 3.5 Hz, 1H), 4.67–4.57 (m, 1H),

Molecules 2021, 26, 3394
18 of 26
4.55–4.43 (m, 2H), 4.31–4.24 (m, 1H), 4.20–4.07 (m, 2H), 3.87–3.78 (m, 1H), 3.40–3.31 (m, 1H),
2
.74 (t, J = 7.5 Hz, 2H), 2.38–2.18 (m, 7H), 1.95 (s, 3H), 1.74–1.59 (m, 4H), 1.42–1.32 (m, 4H);
13
C NMR (100 MHz, CDCl3)
29.9, 129.8, 128.8, 128.7, 128.4, 128.0, 120.9, 97.5, 71.5, 69.2, 68.6, 68.5, 64.8, 52.0, 46.9, 33.5,
9.9, 28.9, 28.44, 28.37, 25.2, 24.5, 23.0, 21.6. HRMS m/z calcd for C H N O SNa [M +
δ 176.9, 170.8, 167.0, 165.2, 148.5, 145.0, 133.54, 133.48, 132.3,
1
2
41
48
4
12
+
Na] 843.2882, found 843.2876.
Synthesis of compound 12c. Compound
9 (100.0 mg, 0.15 mmol), t-BuOH: THF: H O
2
(
0
v:v:v 1:1:1, 2.5 mL), 10-undecynoic acid (35.5 mg, 0.19 mmol), CuSO4 5H O (7.5 mg,
.03 mmol), NaAsc (11.8 mg, 0.06 mmol), 24 h. Purified by flash chromatography using
·
2
(
DCM to 2% MeOH/DCM) to obtain a colorless slurry (98.0 mg, 77%) as the desired
1
product (R = 0.27 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.91–7.84 (m, 4H),
f
3
7
(
4
1
(
1
.69 (d, J = 8.2 Hz, 2H), 7.55–7.44 (m, 2H), 7.41–7.30 (m, 5H), 7.20 (d, J = 8.2 Hz, 2H), 6.44
d, J = 9.2 Hz, 1H), 5.59 (t, J = 10.1 Hz, 1H), 5.31 (t, J = 9.8 Hz, 1H), 4.83 (d, J = 3.5 Hz, 1H),
.70–4.57 (m, 1H), 4.56–4.43 (m, 2H), 4.32–4.23 (m, 1H), 4.20–4.06 (m, 2H), 3.89–3.80 (m,
H), 3.40–3.28 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.37–2.17 (m, 7H), 1.94 (s, 3H), 1.71–1.55
m, 4H), 1.39–1.24 (m, 8H); 13C NMR (100 MHz, CDCl3)
177.8, 170.8, 166.9, 165.2, 148.9,
45.0, 133.5, 133.4, 132.3, 129.84, 129.79, 129.77, 128.8, 128.6, 128.4, 128.1, 128.0, 120.7, 97.5,
δ
7
1.4, 69.2, 68.5, 68.4, 64.8, 51.9, 46.8, 33.9, 29.9, 29.2, 28.92, 28.89, 28.85, 25.5, 24.6, 23.0, 21.6;
+
HRMS m/z calcd for C H N O SNa [M + Na] 871.3195, found 871.3192.
43
52
4
12
Synthesis of compound 13a (LM24). Compound 11a (74.0 mg, 0.095 mmol, 1.0 equiv),
◦
DMF (13.0 mL), K CO (26.3 mg, 0.19 mmol, 2.0 equiv, 75 C for 2 h. Purified by flash
2
3
chromatography using (DCM to 3% MeOH/DCM) to obtain a white solid (51.0 mg, 88%)
◦
1
as the desired product (R = 0.32 in 5% MeOH/DCM). m.p. 123.0–125.0 C; H NMR (400
f
MHz, CDCl3)
H), 5.62 (dd, J = 10.9, 9.6 Hz, 1H), 5.36 (t, J = 9.9 Hz, 1H), 5.02 (d, J = 3.6 Hz, 1H), 4.87–4.77
m, 1H), 4.64–4.55 (m, 1H), 4.50–4.42 (m, 1H), 4.22 (dd, J = 11.9, 4.4 Hz, 1H), 4.13–3.94 (m,
H), 3.63–3.55 (m, 1H), 2.96–2.86 (m, 1H), 2.72–2.61 (m, 1H), 2.30–2.21 (m, 1H), 2.01–1.93
m, 1H), 1.91 (s, 3H), 1.63–1.48 (m, 4H); 13C NMR (100 MHz, CDCl3)
172.3, 170.2, 167.2,
65.5, 148.6, 133.6, 133.5, 129.91, 128.87, 128.8, 128.7, 128.5, 128.4, 120.6, 97.2, 71.0, 70.4, 69.1,
8.6, 64.5, 52.8, 50.0, 33.7, 28.2, 24.7, 23.2, 23.1; HRMS m/z calcd for C H N O Na [M +
δ 7.98–7.86 (m, 4H), 7.54–7.46 (m, 3H), 7.41–7.32 (m, 4H), 6.18 (d, J = 8.6 Hz,
1
(
3
(
δ
1
6
31
34
4
9
+
Na] 629.2218, found 629.2222.
Synthesis of compound 13b (LM26). Compound 11b (100.0 mg, 0.12 mmol), DMF
◦
(
10.0 mL), K CO (34.3 mg, 0.24 mmol), 75 C for 5 h. Purified by flash chromatography
2
3
(
(
DCM to 5% MeOH/DCM) to obtain a white solid (60.0 mg, 76%) as the desired product
◦
1
R = 0.29 in 5% MeOH/DCM). m.p. 108.0–110.0 C; H NMR (400 MHz, CDCl )
δ
7.97–
f
3
7
.87 (m, 4H), 7.54–7.45 (m, 3H), 7.41–7.31 (m, 4H), 6.21 (d, J = 9.1 Hz, 1H, -NH), 5.62
(
4
dd, J = 10.9, 9.5 Hz, 1H, H-3), 5.37 (t, J = 9.8 Hz, 1H, H-4), 4.99 (d, J = 3.6 Hz, 1H, H–1),
.72–4.67 (m, 2H, -O-CH -CH -N), 4.59–4.50 (m, 1H, H-2), 4.22–4.02 (m, 3H, H-6 , H-6b,
-CH -N), 4.00–3.93 (m, 1H, -O-CH -CH -N), 3.87–3.78 (m, 1H, H-5), 2.90–2.71 (m,
2
2
a
-O-CH
a
2
b
2
2
H, -HC=C-CH -CH -), 2.16–1.98 (m, 2H, -OOC-CH -CH -), 1.90 (s, 3H), 1.80–1.68 (m, 1H),
2
2
2
2
13
1
.67–1.55 (m, 1H), 1.54–1.40 (m, 2H), 1.28–1.07 (m, 4H); C NMR (100 MHz, CDCl3)
70.1, 167.0, 165.3, 148.5 (HC=C-), 133.5, 129.83, 128.79, 128.7, 128.44, 128.42, 120.8 (HC=C-),
7.3 (C-1), 71.1 (C-3), 70.4 (C-4), 68.5 (C-5), 67.1 (-O-CH -CH -N), 64.1 (C-6), 52.3 (C-2), 49.6
δ 173.3,
1
9
2
2
(
[
-O-CH -CH -N), 32.9, 27.9, 27.4, 25.9, 24.7, 23.7, 23.1; HRMS m/z calcd for C H N O Na
M + Na] 657.2531, found 657.2529.
2
2
33 38
4
9
+
Synthesis of compound 14a (LM34). Compound 12a (96.0 mg, 0.12 mmol), DMF
◦
(
10.0 mL), K CO (33.5 mg, 0.24 mmol), 75 C for 2 h. Purified by flash chromatogra-
2
3
phy (DCM to 3% MeOH/DCM) to obtain a colorless liquid which turns into a white solid
over time (66.3 mg, 88%) as the desired product (R = 0.2 in 5% MeOH/DCM). m.p. 117.0–
f
◦
1
1
(
18.0 C; H NMR (400 MHz, CDCl )
δ
7.97–7.85 (m, 4H), 7.54–7.45 (m, 2H), 7.42–7.31
m, 5H), 5.88 (d, J = 9.2 Hz, 1H), 5.65 (t, J = 10.2 Hz, 1H), 5.31 (t, J = 9.6 Hz, 1H), 4.93 (d,
J = 3.6 Hz, 1H), 4.75–4.66 (m, 1H), 4.57–4.42 (m, 2H), 4.19–4.01 (m, 3H), 3.55–3.37 (m, 2H),
.90–2.70 (m, 2H), 2.43–2.16 (m, 4H), 1.87 (s, 3H), 1.79–1.72 (m, 2H), 1.69–1.62 (m, 2H),
.53–1.45 (m, 2H); 13C NMR (100 MHz, CDCl3)
172.4, 169.9, 167.2, 165.3, 147.3, 133.5,
3
2
1
δ

Molecules 2021, 26, 3394
19 of 26
1
2
29.9, 129.8, 128.7, 128.5, 126.9, 121.2, 97.4, 71.4, 69.5, 68.6, 64.8, 64.0, 52.3, 46.6, 41.0, 34.3,
+
9.8, 27.3, 24.4, 23.3, 23.2; HRMS m/z calcd for C H N O Na [M + Na] 643.2375, found
32
36
4
9
643.2374.
Synthesis of compound 14b (LM36). Compound 12b (86.0 mg, 0.10 mmol), DMF
◦
(
10.0 mL), K CO (28.9 mg, 0.20 mmol), 75 C for 2 h. Purified by flash chromatogra-
2
3
phy (DCM to 3% MeOH/DCM) to obtain a white solid (56.6 mg, 83%) as the desired
◦
1
product (R = 0.3 in 5% MeOH/DCM). m.p. 97.0–98.0 C; H NMR (400 MHz, CDCl )
δ
f
3
7
.98–7.86 (m, 4H), 7.53–7.46 (m, 2H), 7.40–7.31 (m, 5H), 5.95 (d, J = 9.1 Hz, 1H), 5.67 (t,
J = 10.2 Hz, 1H), 5.35 (t, J = 9.7 Hz, 1H), 4.98 (d, J = 3.6 Hz, 1H), 4.69–4.60 (m, 1H), 4.55–4.48
(
(
(
m, 1H), 4.47–4.39 (m, 1H), 4.24–4.09 (m, 3H), 3.66–3.51 (m, 2H), 2.86–2.68 (m, 2H), 2.43–2.24
m, 2H), 2.08 (t, J = 7.0 Hz, 2H), 1.88 (s, 3H), 1.74–1.64 (m, 2H), 1.61–1.47 (m, 2H), 1.33–1.16
m, 4H); 13C NMR (100 MHz, CDCl3)
δ
173.2, 169.9, 167.2, 165.4, 148.1, 133.53, 133.51,
1
3
6
30.0, 129.84, 128.79, 128.7, 128.46, 128.45, 120.9, 98.0, 71.4, 70.0, 68.5, 65.5, 63.8, 52.6, 46.6,
+
2.4, 30.3, 27.4, 26.6, 25.7, 24.6, 23.5, 23.2; HRMS m/z calcd for C H N O Na [M + Na]
34
40
4
9
71.2688, found 671.2686.
Synthesis of compound 14c (LM38). Compound 12c (90.0 mg, 0.11 mmol), DMF (10.0 mL),
◦
K CO (30.4 mg, 0.20 mmol), 75 C for 2 h. Purified by flash chromatography (DCM to
2
3
2
% MeOH/DCM) to obtain a white solid (59.5 mg, 83%) as the desired product (R = 0.32
f
◦
1
in 5% MeOH/DCM). m.p. 87.0–89.0 C; H NMR (400 MHz, CDCl )
δ
7.97–7.88 (m, 4H),
3
7
.54–7.47 (m, 2H), 7.41–7.31 (m, 5H), 6.12 (d, J = 8.8 Hz, 1H), 5.62 (t, J = 10.6 Hz, 1H), 5.44
(
(
4
t, J = 9.8 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.61–4.42 (m, 3H), 4.33–4.12 (m, 3H), 3.71–3.61
m, 1H), 3.46–3.36 (m, 1H), 2.88–2.71 (m, 2H), 2.33–2.04 (m, 4H), 1.93 (s, 3H), 1.75–1.68 (m,
H), 1.56–1.47 (m, 2H), 1.28–1.15 (m, 8H); 13C NMR (100 MHz, CDCl3)
δ
173.4, 170.2, 167.2,
1
65.4, 133.52, 133.47, 129.9, 129.8, 128.9, 128.8, 128.5, 128.4, 121.3, 97.7, 71.4, 70.2, 68.0, 65.0,
6
3.2, 52.6, 46.6, 33.7, 30.2, 28.20, 28.19, 28.14, 27.7, 27.2, 24.9, 24.4, 23.1; HRMS m/z calcd for
+
C H N O Na [M + Na] 699.3001, found 699.3000.
36
44
4
9
Compounds 15a-b and 16a-b were prepared similarly as compound 8a.
Synthesis of compound 15a. Compound 7c (200.0 mg, 0.31 mmol, 1.0 equiv), t-BuOH:
THF: H O (v:v:v 1:1:1, 3.0 mL), 10d (89.2 mg, 0.4 mmol, 1.3 equiv), CuSO4 5H O (15.5 mg,
·
2
2
0
.062 mmol, 0.2 equiv), NaAsc (24.6 mg, 0.124 mmol, 0.4 equiv), 24 h. Purified by flash
chromatography (DCM to 3% MeOH/DCM) to obtain a yellowish slurry (209.0 mg, 78%) as
1
the desired product (R = 0.5 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.86–7.80
f
3
(
(
m, 4H), 7.68 (d, J = 8.3 Hz, 2H), 7.54–7.46 (m, 2H), 7.45 (s, 1H), 7.41 (s, 1H), 7.38–7.29
m, 4H), 7.20 (d, J = 8.0 Hz, 2H), 6.26 (d, J = 9.1 Hz, 1H), 5.54 (t, J = 10.8 Hz, 1H), 5.28 (t,
J = 9.6 Hz, 1H), 4.84 (d, J = 3.6 Hz, 1H), 4.63–4.55 (m, 4H), 4.49–4.42 (m, 1H), 4.20–4.04
m, 4H), 3.89–3.83 (m, 1H), 2.91 (t, J = 6.2 Hz, 2H), 2.76–2.66 (m, 4H), 2.34 (s, 3H), 1.82 (s,
H), 1.75–1.62 (m, 4H); 13C NMR (100 MHz, CDCl3)
172.6, 171.0, 166.7, 165.1, 148.2, 147.3,
45.1, 133.6, 133.4, 132.3, 129.9, 129.81, 129.75, 128.7, 128.6, 128.4, 128.0, 122.2, 121.6, 97.5,
(
3
δ
1
7
1.2, 68.9, 68.6, 68.2, 66.7, 51.9, 49.6, 45.9, 35.1, 28.5, 28.3, 25.2, 25.0, 22.8, 21.6. HRMS m/z
+
calcd for C H N O SNa [M + Na] 896.2896, found 896.2886.
42
47
7
12
Synthesis of compound 15b. Compound 7c (100.0 mg, 0.15 mmol, 1.0 equiv), t-BuOH:
THF: H O (v:v:v 1:1:1, 3.0 mL), 10e (46.8 mg, 0.19 mmol, 1.3 equiv), CuSO4 5H O (7.3 mg,
·
2
2
0
.03 mmol, 0.2 equiv), NaAsc (12.3 mg, 0.06 mmol, 0.4 equiv), 24 h. Purified by flash
chromatography (DCM to 2% MeOH/DCM) to obtain a yellowish slurry (108.0 mg, 79%)
1
as the desired product (R = 0.41 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
f
3
7
7
.88–7.81 (m, 4H), 7.69 (d, J = 8.3 Hz, 2H), 7.54–7.47 (m, 2H), 7.45 (s, 1H), 7.40 (s, 1H),
.38–7.30 (m, 4H), 7.21 (d, J = 7.9 Hz, 2H), 6.11 (d, J = 9.1 Hz, 1H), 5.53 (t, J = 10.8 Hz,
1
4
H), 5.28 (t, J = 9.6 Hz, 1H), 4.86 (d, J = 3.6 Hz, 1H), 4.64–4.58 (m, 4H), 4.50–4.42 (m, 1H),
.21–4.07 (m, 4H), 3.93–3.86 (m, 1H), 2.91 (t, J = 6.2 Hz, 2H), 2.73–2.65 (m, 4H), 2.35 (s, 3H),
.83 (s, 3H), 1.70–1.59 (m, 4H), 1.36–1.28 (m, 2H); 13C NMR (100 MHz, CDCl3)
172.5, 170.8,
1
1
1
δ
66.8, 165.1, 148.4, 147.5, 145.1, 133.6, 133.5, 132.3, 129.83, 129.77, 128.7, 128.6, 128.4, 128.0,
22.2, 121.6, 97.5, 71.2, 68.9, 68.7, 68.2, 66.6, 51.9, 49.6, 45.8, 35.1, 29.0, 28.4, 28.0, 25.3, 25.0,
+
2
2.9, 21.6. HRMS m/z calcd for C H N O SNa [M + Na] 910.3052, found 910.3043.
43
49
7
12

Molecules 2021, 26, 3394
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Synthesis of compound 15c. To a 50 mL RBF, compound
9
(100.0 mg, 0.15 mmol,
1
.0 equiv), t-BuOH: THF: H O (v:v:v 1:1:1, 3.0 mL), 10d (43.1 mg, 0.19 mmol, 1.3 equiv),
2
CuSO4 5H O (7.3 mg, 0.03 mmol, 0.2 equiv), NaAsc (12.3 mg, 0.06 mmol, 0.4 equiv), 16 h.
·
2
Purified by flash chromatography (DCM to 5% MeOH/DCM) to obtain a yellowish slurry
1
(
116.0 mg, 87%) as the desired product (R = 0.41 in 5% MeOH/DCM). H NMR (400 MHz,
f
CDCl3)
m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 6.39 (d, J = 9.1 Hz, 1H), 5.59 (t, J = 9.7 Hz, 1H), 5.31 (t,
J = 9.7 Hz, 1H), 4.84 (d, J = 3.5 Hz, 1H), 4.68–4.56 (m, 3H), 4.54–4.42 (m, 2H), 4.33–4.24
δ 7.91–7.85 (m, 4H), 7.68 (d, J = 8.3 Hz, 2H), 7.56–7.46 (m, 2H), 7.43 (s, 1H), 7.40–7.31
(
(
2
m, 1H), 4.20–4.07 (m, 2H), 3.86–3.78 (m, 1H), 3.34–3.26 (m, 1H), 2.88 (t, J = 5.9 Hz, 2H),
.78–2.66 (m, 4H), 2.35 (s, 3H), 2.32–2.16 (m, 2H), 1.94 (s, 3H), 1.80–1.59 (m, 4H); C NMR
1
3
(
100 MHz, CDCl3)
δ
171.2, 166.9, 165.2, 148.3, 147.3, 145.0, 133.5, 133.4, 132.3, 129.9, 129.8,
1
2
9
28.8, 128.7, 128.4, 128.0, 122.4, 120.9, 97.5, 71.4, 69.1, 68.6, 68.4, 64.8, 52.1, 46.8, 46.0, 35.4,
+
9.7, 28.5, 28.3, 25.04, 24.96, 23.0, 21.6. HRMS m/z calcd for C H N O SNa [M + Na]
43 49 7 12
10.3052, found 910.3043.
Synthesis of compound 15d. Compound
9
(100.0 mg, 0.15 mmol, 1.0 equiv), t-BuOH:
5H O
THF: H O 1:1:1 (v:v:v 1:1:1, 3.0 mL), 10e (45.9 mg, 0.19 mmol, 1.3 equiv), CuSO4
·
2
2
(
7.3 mg, 0.03 mmol, 0.2 equiv), NaAsc (11.9 mg, 0.06 mmol, 0.4 equiv), 16 h. Purified by
flash chromatography (DCM to 5% MeOH/DCM) to obtain a yellowish slurry (113.0 mg,
1
8
3%) as the desired product (R = 0.46 in 5% MeOH/DCM). H NMR (400 MHz, CDCl )
f
3
δ
7.90–7.84 (m, 4H), 7.69 (d, J = 8.3 Hz, 2H), 7.56–7.45 (m, 2H), 7.44–7.30 (m, 6H), 7.21 (d,
J = 8.2 Hz, 2H), 6.36 (d, J = 9.1 Hz, 1H), 5.59 (t, J = 9.7 Hz, 1H), 5.31 (t, J = 9.7 Hz, 1H),
.84 (d, J = 3.5 Hz, 1H), 4.66–4.57 (m, 3H), 4.54–4.46 (m, 2H), 4.31–4.25 (m, 1H), 4.20–4.08
m, 2H), 3.87–3.80 (m, 1H), 3.38–3.20 (m, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.73–2.65 (m, 4H),
4
(
2
1
3
.35 (s, 3H), 2.32–2.19 (m, 2H), 1.93 (s, 3H), 1.73–1.59 (m, 4H), 1.36–1.25 (m, 2H); C NMR
(
100 MHz, CDCl3)
δ
170.8, 167.0, 165.2, 148.6, 147.5, 145.0, 133.54, 133.46, 132.3, 129.9, 129.8,
1
2
28.8, 128.7, 128.4, 128.0, 122.2, 121.0, 97.5, 71.5, 69.1, 68.6, 68.4, 64.8, 52.0, 47.0, 45.9, 35.2,
+
9.9, 29.0, 28.4, 28.0, 25.2, 25.0, 23.0, 21.6. HRMS m/z calcd for C H N O SNa [M + Na]
44 51 7 12
9
24.3209, found 924.3213.
Compounds 16a-d 22, 24 were prepared similarly as for compound 13c. The amount
,
of all chemicals, reaction time, yield, R value, and characterization of the product are listed,
f
respectively. The macrocycles were typically obtained first as a clear waxy liquid, which
upon standing for a few days, turned to a white solid.
Synthesis of compound 16a (DM24). Compound 15a (75.0 mg, 0.086 mmol), DMF
◦
(
12.0 mL), K CO (23.7 mg, 0.17 mmol), 85 C for 4.0 h. The crude was purified by flash
2
3
chromatography (DCM to 2% MeOH/DCM) to obtain a white solid (54.0 mg, 90%) as the
desired product 16a (R = 0.14 in 5% MeOH/DCM). The reaction was also carried out using
f
CH CN as the solvent: Compound 15a (50.0 mg, 0.057 mmol) was dissolved in CH CN
3
3
(
7
12.0 mL), then K CO (15.8 mg, 0.11 mmol) was added, the reaction mixture was stirred at
2 3
◦
5 C for 11.0 h. The solvent was removed using a rotavap, and the crude was purified
◦
using flash column similarly to give the pure product (31.0 mg, 77%). m.p. 127.0–129.0 C;
1
H NMR (400 MHz, CDCl3) δ 7.94–7.86 (m, 4H), 7.54–7.44 (m, 2H), 7.39–7.32 (m, 5H), 7.30
(
s, 1H), 5.96 (d, J = 9.3 Hz, 1H), 5.55 (t, J = 10.8 Hz, 1H), 5.38 (t, J = 9.9 Hz, 1H), 4.73 (d,
J = 3.5 Hz, 1H), 4.70–4.58 (m, 4H), 4.51–4.43 (m, 1H), 4.21–4.14 (m, 1H), 4.13–4.00 (m, 3H),
.88–3.78 (m, 1H), 3.02–2.93 (m, 1H), 2.89–2.82 (m, 1H), 2.80–2.70 (m, 2H), 2.66–2.53 (m, 2H)
.92 (s, 3H), 1.67–1.55 (m, 4H); 13C NMR (100 MHz, CDCl3)
170.3, 170.1, 166.8, 165.2, 148.8,
47.9, 133.6, 133.4, 129.8, 129.7, 128.8, 128.7, 128.5, 128.4, 121.6, 120.7, 98.2, 70.9, 69.2, 68.1,
6.9, 62.8, 51.9, 50.3, 45.5, 34.8, 27.7, 24.8, 24.7, 23.2; HRMS m/z calcd for C H N O Na
3
1
1
6
[
δ
35
39
7
9
+
M + Na] 724.2701, found 724.2704.
Synthesis of compound 16b (DM25). Compound 15b (68.0 mg, 0.077 mmol), DMF
◦
(
(
(
12.0 mL), K CO (21.2 mg, 0.15 mmol), 80 C for 2.0 h. Purified by flash chromatography
2
3
DCM to 2% MeOH/DCM) to obtain a white solid (48.0 mg, 88%) as the desired product
R = 0.2 in 5% MeOH/DCM). The reaction was also carried out in acetonitrile: Compound
f
1
2
5b (50.0 mg, 0.05 mmol, 1.0 equiv), CH CN (10.0 mL), K CO (15.6 mg, 0.11 mmol,
.0 equiv), 75 C for 14.0 h, yield 28.5 mg, 71%. M.p. 239.0–240.0 C; H NMR (400 MHz,
3
2
3
◦
◦
1

Molecules 2021, 26, 3394
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CDCl3)
δ
7.92–7.85 (m, 4H), 7.62 (s, 1H), 7.54–7.47 (m, 2H), 7.46 (s, 1H), 7.39–7.30 (m, 4H),
5
1
(
4
1
6
.91 (d, J = 9.3 Hz, 1H), 5.56 (t, J = 9.5 Hz, 1H), 5.30 (t, J = 9.9 Hz, 1H), 4.67 (d, J = 3.5 Hz,
H), 4.65–4.55 (m, 4H), 4.51–4.45 (m, 1H), 4.36–4.30 (m, 1H), 4.16–4.08 (m, 2H), 4.02–3.95
m, 1H), 3.93–3.87 (m, 1H), 3.03–2.90 (m, 2H), 2.79–2.70 (m, 4H), 1.91 (s, 3H), 1.75–1.66 (m,
H), 1.32–1.25 (m, 2H); 13C NMR (100 MHz, CDCl3)
170.1, 169.9, 166.9, 165.4, 148.2, 147.6,
33.6, 133.5, 129.83, 129.81, 128.8, 128.6, 128.5, 128.4, 122.2, 121.6, 97.9, 71.2, 69.6, 68.6, 66.8,
3.4, 52.0, 49.6, 45.2, 34.3, 27.5, 27.3, 26.1, 24.5, 23.2; HRMS m/z calcd for C H N O Na
δ
36
41
7
9
+
[
M + Na] 738.2858, found 738.2862.
Synthesis of compound 16c (DM34). Compound 15c (120.0 mg, 0.14 mmol), DMF
◦
(
15.0 mL), K CO (37.3 mg, 0.27 mmol), 75 C for 2.0 h. Purified by flash chromatography
2
3
(
DCM to 3% MeOH/DCM) to obtain a white solid (82.0 mg, 85%) as the desired product,
R = 0.21 in 5% MeOH/DCM. The reaction was also carried out in acetonitrile: Compound
f
1
5c (50.0 mg, 0.05 mmol, 1.0 equiv), CH CN (8.0 mL), K CO (15.7 mg, 0.11 mmol, 2.0
3 2 3
◦
◦
1
equiv), 75 C for 14.0 h, yield 31.5 mg, 78%, m.p. 99.0–101.0 C; H NMR (400 MHz, CDCl )
3
δ
7.93–7.89 (m, 4H), 7.54–7.47 (m, 2H), 7.39–7.34 (m, 6H), 6.09 (d, J = 8.8 Hz, 1H), 5.54 (t,
J = 10.6 Hz, 1H), 5.46 (t, J = 9.6 Hz, 1H), 4.77 (d, J = 3.7 Hz, 1H), 4.60–4.44 (m, 5H), 4.33–4.26
(
(
m, 1H), 4.17–4.03 (m, 2H), 3.59–3.49 (m, 1H), 3.30–3.21 (m, 1H), 2.83–2.70 (m, 6H), 2.33–2.20
m, 2H), 1.94 (s, 3H), 1.80–1.69 (m, 2H), 1.69–1.59 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ
1
1
70.3, 170.1, 167.1, 165.3, 148.2, 147.8, 133.6, 133.5, 129.9, 129.7, 128.8, 128.76, 128.5, 128.4,
21.7, 121.2, 97.7, 71.3, 69.7, 67.7, 64.8, 63.2, 52.4, 46.4, 45.4, 34.8, 29.6, 28.0, 25.1, 24.8, 23.1;
+
HRMS m/z calcd for C H N O Na [M + Na] 738.2858, found 738.2855.
36
41
7
9
Synthesis of compound 16d (DM35). Compound 15d (90.0 mg, 0.10 mmol), DMF
◦
(
12.0 mL), K CO (27.5 mg, 0.19 mmol), 80 C for 3.0 h. The crude was purified by
2
3
flash chromatography (DCM to 3% MeOH/DCM) to obtain a white solid upon standing
57.0 mg, 78%) as the desired product (R = 0.26 in 5% MeOH/DCM). The reaction was
(
f
also carried out using CH CN as the solvent: Compound 15d (50.0 mg, 0.055 mmol),
3
◦
CH CN (8.0 mL), K CO (15.3 mg, 0.11 mmol), 75 C for 15.0 h, yield 30.0 mg, 74%. m.p.
3
2
3
◦
1
9
1
2.0–94.0 C; H NMR (400 MHz, CDCl )
δ
7.94–7.89 (m, 4H), 7.55–7.46 (m, 2H), 7.42 (s,
H), 7.41 (s, 1H), 7.38–7.32 (m, 4H), 6.10 (d, J = 9.0 Hz, 1H), 5.57 (t, J = 9.6 Hz, 1H), 5.40 (t,
J = 9.8 Hz, 1H), 4.84 (d, J = 3.7 Hz, 1H), 4.61–4.44 (m, 5H), 4.36–4.28 (m, 1H), 4.25–4.15 (m,
H), 3.76–3.65 (m, 1H), 3.44–3.33 (m, 1H), 2.99–2.81 (m, 2H), 2.80–2.73 (m, 2H), 2.73–2.67
3
2
(
(
1
1
3
m, 2H), 2.36–2.23 (m, 2H), 1.93 (s, 3H), 1.74–1.65 (m, 4H), 1.34–1.27 (m, 2H); C NMR
100 MHz, CDCl3) 170.3, 169.8, 167.0, 165.4, 148.3, 147.7, 133.6, 133.5, 129.9, 129.83, 128.80,
28.7, 128.5, 128.4, 122.0, 121.4, 97.6, 71.5, 69.7, 68.4, 65.6, 63.7, 52.3, 46.9, 45.3, 34.5, 29.9,
δ
+
2
8.1, 27.8, 26.7, 24.8, 24.8, 23.1; HRMS m/z calcd for C H N O Na [M + Na] 752.3014,
37 43 7 9
found 752.3011.
Synthesis of compound 18. To a 50 mL RBF, compound 17 (200.0 mg, 0.55 mmol) was
◦
dissolved in HOAc: H O (v:v 4:1, 5.0 mL) and heated at 75 C for 4 h. The reaction was
2
stopped, and solvent was dried under vacuum to afford the crude, which was purified by
flash chromatography using eluent from DCM to 3% MeOH/DCM to obtain a colorless
1
liquid (129 mg, 85%) as the desired product (R = 0.3 in 10% MeOH/DCM). H NMR
f
(
400 MHz, DMSO-d6)
δ
7.97 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 5.6 Hz, 1H), 4.80 (d, J = 5.7 Hz,
1
3
H), 4.56 (d, J = 3.5 Hz, 1H), 4.50 (t, J = 6.0 Hz, 1H), 3.87–3.77 (m, 2H), 3.73–3.61 (m, 2H),
.52–3.40 (m, 2H), 3.35–3.31 (m, 1H), 3.25 (s, 3H), 3.18–3.10 (m, 1H); C NMR (100 MHz,
13
DMSO-d6)
δ
167.5, 97.7, 72.7, 70.73, 70.65, 60.7, 54.2, 53.9, 50.5. LC-MS (ESI+) calcd for
+
C H N O [M + H] 277.1, found 277.1.
9
16
4
6
Synthesis of compound 19. In a 50 mL RBF, compound 18 (500 mg, 1.81 mmol) was
taken and dissolved in pyridine (5.0 mL). To this solution, tosyl chloride (862.7 mg, 4.52
◦
mmol) dissolved in pyridine (5.0 mL) was added dropwise at 0 C. The reaction was
monitored in 1.5 h to see full conversion. Pyridine was dried under vacuum and crude
was coated on silica gel and isolated by flash chromatography using eluent from DCM to
2
% MeOH/DCM to obtain a sticky colorless slurry (628 mg, 81%) as the desired product
1
(R = 0.51 in 10% MeOH/DCM). H NMR (400 MHz, CDCl )
δ
7.80 (d, J = 8.3 Hz, 2H),
f
3
7.34 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 1H), 4.63 (d, J = 3.7 Hz, 1H), 4.36–4.27 (m, 2H),

Molecules 2021, 26, 3394
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4
3
.11–3.99 (m, 3H), 3.78–3.71 (m, 1H), 3.67 (t, J = 9.6 Hz, 1H), 3.49 (t, J = 9.4 Hz, 1H), 3.35 (s,
H), 3.06 (br s, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.3, 145.0, 132.8, 129.9,
1
28.0, 98.2, 73.4, 70.6, 69.5, 69.0, 55.4, 53.3, 52.4, 21.6. LC-MS (ESI+) calcd for C H N O S
16 22 4 8
+
[
M + H] 431.1, found 431.1.
Synthesis of compound 20. In a 50 mL RBF, compound 19 (628 mg, 1.46 mmol, 1.0 equiv),
pyridine (3.0 mL) and benzoyl chloride (0.51 mL, 4.38 mmol, 3.0 equiv) was added at
◦
0
C dropwise and let it stir for 1.5 h to see full conversion. The reaction mixture was
extracted with DCM (25.0 mL) and washed with NH Cl (10.0 mL) and NaHCO (10.0 mL)
4
3
followed by brine (10.0 mL). The organic layer was then dried over anhydrous Na SO
2
4
and concentrated under reduced pressure to obtain the crude. Crude was purified by
flash chromatography using eluent from pure hexanes to 40% EtOAc/Hexanes to obtain a
colorless liquid (850 mg, 91%) as the desired product (R = 0.35 in 40% EtOAc/Hexanes).
f
1
H NMR (400 MHz, CDCl3)
.39–7.31 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 9.4 Hz, 1H), 5.56 (dd, J = 10.8, 9.5 Hz,
H), 5.36 (t, J = 9.6 Hz, 1H), 4.78 (d, J = 3.5 Hz, 1H), 4.50–4.42 (m, 1H), 4.23–4.16 (m, 2H),
.15–4.09 (m, 1H), 3.85 (d, J = 16.6 Hz, 1H), 3.73 (d, J = 16.6 Hz, 1H), 3.45 (s, 3H), 2.37 (s,
δ 7.91–7.81 (m, 4H), 7.72 (d, J = 8.3 Hz, 2H), 7.55–7.45 (m, 2H),
7
1
4
3
13
H); C NMR (100 MHz, CDCl ) δ 166.72, 166.69, 165.1, 144.9, 133.52, 133.46, 132.5, 129.9,
3
1
29.7, 128.7, 128.6, 128.4, 128.0, 97.9, 71.3, 68.8, 68.11, 68.05, 55.7, 52.5, 52.2, 21.6. LC-MS
+
(
ESI+) calcd for C H N O S [M + H] 639.2, found 639.2.
30
31
4
10
Synthesis of compound 21. Compound 20 (110.0 mg, 0.17 mmol, 1.0 equiv) in t-BuOH:
THF: H O (v:v:v 1:1:1, 3.0 mL) and 10-undecynoic acid 10c (40.8 mg, 0.22 mmol, 1.3 equiv),
2
CuSO4 5H O (8.6 mg, 0.034 mmol, 0.2 equiv), NaAsc (13.7 mg, 0.069 mmol, 0.4 equiv) and
·
2
Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) (18.3 mg, 0.03 mmol, 0.2 equiv)
was added and the reaction mixture was stirred at rt for 7 h. The reaction was stopped,
and solvent was dried under vacuum to afford the crude, which was purified by flash
chromatography using eluent from DCM to 2% MeOH/DCM to obtain white solid (95 mg,
◦
7%) as the desired product (R = 0.5 in 5% MeOH/DCM). m.p. 74.5–77.0 C. H NMR
f
1
6
(
(
5
400 MHz, CDCl3)
m, 4H), 7.21 (d, J = 7.9 Hz, 2H), 7.11 (s, 1H), 6.20 (d, J = 9.3 Hz, 1H), 5.54–5.48 (m, 1H),
.34 (t, J = 9.6 Hz, 1H), 4.91 (d, J = 16.5 Hz, 1H), 4.83 (d, J = 16.5 Hz, 1H), 4.74 (d, J = 3.6
Hz, 1H), 4.49–4.41 (m, 1H), 4.22–4.09 (m, 3H), 3.40 (s, 3H), 2.72–2.61 (m, 2H), 2.36 (s, 3H),
δ 7.89–7.79 (m, 4H), 7.71 (d, J = 8.3 Hz, 2H), 7.54–7.47 (m, 2H), 7.38–7.32
13
2
.33 (t, J = 7.4 Hz, 2H), 1.69–1.54 (m, 4H), 1.36–1.29 (m, 8H); C NMR (100 MHz, CDCl3) δ
1
1
78.4, 178.1, 166.5, 165.5, 165.0, 149.0, 144.9, 133.5, 132.5, 129.9, 129.8, 128.61, 128.58, 128.5,
28.4, 128.0, 121.9, 97.8, 71.5, 68.7, 68.1, 68.0, 55.8, 52.6, 52.4, 33.91, 33.88, 29.1, 29.01, 28.97,
2
8.96, 28.93, 28.89, 28.87, 28.6, 28.4, 25.5, 24.71, 24.66, 21.6, 18.4. LC-MS (ESI+) calcd for
+
C H N O S [M + H] 821.3, found 821.4.
41
49
4
12
Synthesis of compound 23. Compound 20 (100 mg, 0.16 mmol) was mixed with THF:
H O: t-BuOH (v:v:v 1:1:1, 3.0 mL). To this solution, 10d (45.0 mg, 0.20 mmol), CuSO4 5H O
·
2
2
(
7.8 mg, 0.031 mmol) and NaAsc (12.4 mg, 0.063 mmol) were added and the reaction
mixture was stirred at rt for 12 h. The reaction was stopped, and solvent was dried under
vacuum, and the crude was purified by flash chromatography using eluent from DCM to
2
5
% DCM/MeOH to obtain a white solid (112 mg, 83%) as the desired product (R =0.27 in
f
◦
1
% MeOH/DCM). m.p. 93.5–95.5 C; H NMR (400 MHz, CDCl ) δ 7.84–7.77 (m, 4H), 7.70
3
(
d, J = 8.3 Hz, 2H), 7.53–7.44 (m, 3H), 7.37–7.28 (m, 4H), 7.20 (d, J = 8.1 Hz, 2H), 7.14 (br
s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 5.55 (t, J = 10.3 Hz, 1H), 5.37 (t, J = 9.7 Hz, 1H), 4.99–4.84
m, 2H), 4.77 (d, J = 3.3 Hz, 1H), 4.66–4.57 (m, 2H), 4.49–4.42 (m, 1H), 4.21–4.15 (m, 2H),
(
4
2
.14–4.08 (m, 1H), 3.39 (s, 3H), 2.92 (t, J = 5.3 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.62–2.53 (m,
H), 2.34 (s, 3H), 1.72–1.47 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ
172.4, 166.5, 165.7, 165.0,
1
1
48.3, 147.1, 145.0, 133.6, 132.4, 129.81, 129.76, 129.7, 128.6, 128.53, 128.45, 128.4, 128.0, 122.6,
22.3, 97.8, 71.6, 68.6, 68.0, 55.8, 52.5, 52.4, 45.9, 34.9, 28.3, 27.7, 24.9, 24.8, 21.6. LC-MS (ESI+)
+
calcd for C H N O S [M + H] 860, found 860.
41
46
7
12
Synthesis of compound 22 (C2ML). Compound 21 (70.0 mg, 0.085 mmol), DMF (14.0 mL)
◦
and K CO (23.5 mg, 0.17 mmol), 75 C, 2 h. Purification by flash chromatography (DCM to
2
3
1
% MeOH/DCM) to obtain 22 as a white solid (80%, 44 mg). R = 0.64 in 5% MeOH/DCM.
f

Molecules 2021, 26, 3394
23 of 26
◦
1
m.p. 207.5–210.0 C. H NMR (400 MHz, CDCl )
δ
7.98–7.88 (m, 4H), 7.55–7.48 (m, 3H),
3
7
.41–7.34 (m, 4H), 5.55 (d, J = 9.3 Hz, 1H), 5.42–5.34 (m, 2H), 4.98 (d, J = 16.0 Hz, 1H), 4.80
(
2
d, J = 16.0 Hz, 1H), 4.47–4.27 (m, 4H), 3.91–3.81 (m, 1H), 3.37 (s, 3H), 2.84 (t, J = 6.1 Hz,
H), 2.29–2.07 (m, 2H), 1.78–1.67 (m, 2H), 1.67–1.49 (m, 2H), 1.39–1.19 (m, 8H); C NMR
1
3
(
100 MHz, CDCl3)
δ
173.3, 166.6, 166.0, 165.6, 149.6, 133.5, 129.9, 129.8, 129.7, 129.0, 128.9,
1
2
28.5, 128.4, 122.5, 97.8, 72.6, 70.2, 68.7, 62.4, 56.0, 53.7, 53.4, 52.3, 34.2, 31.5, 30.4, 29.9, 29.6,
+
8.7, 25.4, 25.0. LC-MS (ESI+) calcd for C H N O [M + H] 649, found 649.
34
41
4
9
Synthesis of compound 24 (C2DLM). Compound 23 (75.0 mg, 0.087 mmol), K CO
24.1 mg, 0.17 mmol), DMF (10.0 mL), 70 C, 2.0 h. Purification by flash chromatography
2
3
◦
(
(DCM to 2% MeOH/DCM) to obtain a white solid (46 mg, 77%) as the desired product.
Using Na CO as the base: Compound 23 (100.0 mg, 0.12 mmol, 1.0 equiv), Na CO
3
2
3
2
◦
24.6 mg, 0.23 mmol, 2.0 equiv), DMF (12 mL), 70 C, 2.0 h. The pure compound 24
(
◦
1
was obtained in 83% yield, 66 mg. R = 0.4 in 5% MeOH/DCM. m.p. 83.5–85.0 C; H
f
NMR (400 MHz, CDCl3)
δ7.97–7.87 (m, 4H), 7.57–7.46 (m, 3H), 7.43–7.32 (m, 5H), 5.54 (d,
J = 9.2 Hz, 1H), 5.35–5.28 (m, 1H), 5.24 (t, J = 9.9 Hz, 1H), 4.93 (d, J = 16.2 Hz, 1H), 4.83
(
5
d, J = 16.2 Hz, 1H), 4.67–4.51 (m, 2H), 4.38–4.25 (m, 4H), 3.70–3.62 (m, 1H), 3.01–2.90 (m,
H), 2.89–2.71 (m, 4H), 2.07–1.92 (m, 2H), 1.83–1.71 (m, 2H); C NMR (100 MHz, CDCl3) δ
13
1
1
70.7, 166.5, 165.7, 165.6, 149.2, 147.3, 133.6, 133.4, 129.88, 129.85, 128.9, 128.7, 128.5, 128.4,
22.2, 121.8, 97.4, 72.2, 69.7, 68.3, 63.6, 55.3, 53.4, 52.0, 45.5, 34.8, 29.4, 27.6, 26.1, 25.2. LC-MS
+
(
ESI+) calcd for C H N O [M + H] 688, found 688.
34
38
7
9
Synthesis of compound 25 (C2DDL). Compound 23 (100.0 mg, 0.12 mmol), Cs CO
75.8 mg, 0.23 mmol), DMF (12 mL), 70 C, 2.0 h. After solvent was removed, the crude
2
3
◦
(
was purified by flash chromatography (DCM to 5% MeOH/DCM) to obtain the dimeric
macrodilactone compound 25 as a white solid (41 mg, 51 %). R = 0.32 in 5% MeOH/DCM).
f
◦
1
m.p. 257.0–258.0 C; H NMR (400 MHz, CDCl )
δ
8.03–7.97 (m, 4H), 7.96–7.91 (m, 4H),
3
7
2
4
2
.54–7.48 (m, 6H), 7.47 (s, 2H), 7.42–7.33 (m, 8H), 5.31–5.21 (m, 4H), 5.16 (t, J = 9.9 Hz,
H), 5.09 (d, J = 16.8 Hz, 2H), 4.73–4.64 (m, 4H), 4.56–4.49 (m, 2H), 4.47 (d, J = 4.1 Hz, 2H),
.38–4.27 (m, 6H), 3.56–3.47 (m, 2H), 3.07 (s, 6H), 2.99–2.92 (m, 4H), 2.88–2.69 (m, 8H),
.06–1.95 (m, 4H), 1.77–1.68 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ
169.9, 166.7, 165.7,
1
65.4, 149.3, 148.8, 133.5, 133.4, 132.1, 130.0, 129.9, 128.86, 128.85, 128.5, 128.4, 122.8, 97.4,
7
2.7, 70.0, 68.6, 63.6, 55.5, 53.1, 51.8, 50.4, 33.9, 29.8, 27.1, 26.1, 25.3. LC-MS (ESI+) calcd for
+
C H N O Na [M + Na] 1398 found 1398.
68
74 14 18
Synthesis of compound 31 and a general procedure and example in Table 5.
Sugar azide 26 (40.0 mg, 0.11 mmol, 1.0 equiv) and 4-t-butylphenylacetylene (29.0
µL,
0
.16 mmol, 1.5 equiv) were dissolved in EtOH:H O (v 1:1, 2.0 mL), then CuSO
·
5H O
2
4
2
(5.36 mg, 0.021 mmol, 0.2 equiv) and sodium ascorbate (8.51 mg, 0.043 mmol, 0.4 equiv)
were added to the reaction mixture. To this mixture, macrocycle DM25 (3.86, 5.0 mol%)
was added. The reaction was stirred rt for 5.0 h to at which time the starting material was
1
full converted to product, as indicated by H NMR. The reaction was stopped, and solvent
was removed using a rotavap, to obtain the crude, which was further purified with flash
chromatography using eluent of DCM to 1% MeOH/DCM to obtain the desired product
1
as white solid (54 mg, 95%), R = 0.35 in 5% MeOH/DCM. H NMR (400 MHz, CDCl )
δ
f
3
8.08 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.41 (d, J = 9.1 Hz, 1H), 6.11 (d,
J = 9.9 Hz, 1H), 5.52 (dd, J = 10.3, 9.5 Hz, 1H), 5.26 (t, J = 9.7 Hz, 1H), 4.64 (q, J = 9.8 Hz,
1
9
H), 4.35–4.27 (m, 1H), 4.19–4.12 (m, 1H), 4.05–3.97 (m, 1H), 2.07 (s, 9H), 1.76 (s, 3H), 1.34 (s,
13
H); C NMR (100 MHz, CDCl3)
δ 170.70, 170.66, 170.6, 169.3, 151.8, 148.0, 126.9, 125.9,
1
25.7, 118.8, 85.9, 75.0, 72.4, 68.0, 61.7, 53.6, 34.7, 31.3, 22.8, 20.7, 20.60, 20.58. LC-MS (ESI+)
+
calcd for C H N O Na [M + Na] 553 found 553.
26
34
4
8
4. Conclusions
In summary, we have synthesized several series of novel N-acetyl-D-glucosamine
and triazole-derived macrolactones through intramolecular S 2 reactions in short steps
N
and high efficiency. The macrocyclization did not require high dilution and was carried
out at about 10 mM concentrations, affording the mono-macrolactones in 76–90% yields.

Molecules 2021, 26, 3394
24 of 26
Eleven macrolactones cyclized from C1 to C6, and three macrocycles cyclized from C2 to
C6 were synthesized and characterized. The macrocycles showed interesting anion binding
properties with tetrabutylammonium halides. TBACl showed the strongest complexation
with the macrocycles. Moreover, several bistriazole-containing macrolactones also formed
1
complexes with Cu (II) ions. As indicated by H NMR spectra, the amide proton and
triazole signals exhibited significant chemical shift changes, which indicated that the Cu
(II) or anions are binding to the macrolactones in a specific manner and may be useful for
molecular recognition. The applications of these macrocycles as ligands for copper ions for
the cycloaddition reactions of azide and alkynes (AAC) were explored. Interestingly the
bis-triazole-containing macrocycles were highly efficient ligands for accelerating the AAC
reactions significantly, and the monotriazole-based macrolactones were not as effective.
The rate accelerating effects of macrocycles were also selective towards different acetylenes.
The methods of synthesizing these novel sugar-based macrocycles should apply to other
carbohydrate derivatives.
Supplementary Materials: The following are available online. Synthesis of compounds S2-S5
6e, 7c and 9
,
6c
; H and C NMR spectra for all compounds, 2D HSQC and COSY NMR spectra for
compounds 8c 11a-b 12a-c 13a-c 14a-c 15a 16a-d DLM28 18 19 20 21 22 23 24 25 and 31;
,
1
13
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
anion binding studies for TBAX are included in Figures S1–S22; stacked NMR spectra for copper
complexes are included in Figures S23–S34; screening reactions conditions and stacked NMR spectra
are included on page S97, Tables S1–S8 and Figures S35–S42; FTIR spectra for macrocycles are on
pages S111–S118.
Author Contributions: Conceptualization, G.W.; Data curation, S.B.A. and A.C.; Formal analysis,
S.B.A., A.C. and G.W.; Funding acquisition, G.W.; Investigation, G.W.; Methodology, G.W., S.B.A.
and A.C.; Supervision, G.W.; Validation, S.B.A. and A.C.; Writing—original draft, G.W. and S.B.A.;
Writing—review & editing, G.W., S.B.A. and A.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was supported by a grant from National Science Foundation CHE#1808609.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: We thank Lalith P. Samankumara for his help with the preparation of some
starting materials and intermediates.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
2
.
.
Yu, X.; Sun, D. Macrocyclic drugs and synthetic methodologies toward macrocycles. Molecules 2013, 18, 6230–6268. [CrossRef]
Madsen, C.M.; Clausen, M.H. Biologically Active Macrocyclic Compounds—From Natural Products to Diversity-Oriented
Synthesis. Eur. J. Org. Chem. 2011, 2011, 3107–3115. [CrossRef]
3.
4.
5.
6.
Xie, J.; Bogliotti, N. Synthesis and Applications of Carbohydrate-Derived Macrocyclic Compounds. Chem. Rev. 2014, 114,
7
678–7739. [CrossRef] [PubMed]
Singh, K.; Tripathi, R.P. An Overview on Glyco-Macrocycles: Potential New Lead and their Future in Medicinal Chemistry. Curr.
Med. Chem. 2020, 27, 3386–3410. [CrossRef] [PubMed]
Zong, G.; Barber, E.; Aljewari, H.; Zhou, J.; Hu, Z.; Du, Y.; Shi, W.Q. Total Synthesis and Biological Evaluation of Ipomoeassin F
and Its Unnatural 11R-Epimer. J. Org. Chem. 2015, 80, 9279–9291. [CrossRef]
Toure, S.; Barthelemy, M.; Sorres, J.; Genta-Jouve, G.; Dusfour, I.; Eparvier, V.; Stien, D. Mucorolactone, a Macrolactone from
Mucor sp. SNB-VECD13A, a Fungus Isolated from the Cuticle of a Vespidae Species. Org. Lett. 2018, 20, 3780–3783. [CrossRef]
[
PubMed]
Fürstner, A. Total Syntheses and Biological Assessment of Macrocyclic Glycolipids. Eur. J. Org. Chem. 2004, 2004, 943–958.
CrossRef]
7.
8.
9.
[
Wu, J.; Lu, J.; Liu, J.; Zheng, C.; Gao, Y.; Hu, J.; Ju, Y. A deoxycholic acid-based macrocycle: Recognition of mercury ion and
cascade enantioselective sensing toward amino acids. Sens. Actuatorsb 2017, 241, 931–937. [CrossRef]
Xiao, W.; Mo, Y.; Guo, J.; Su, Z.; Dong, S.; Feng, X. Catalytic enantioselective synthesis of macrodiolides and their application in
chiral recognition. Chem. Sci. 2021, 12, 2940–2947. [CrossRef]

Molecules 2021, 26, 3394
25 of 26
1
1
0. Peng, D.; Lin, X.; Jiang, L.; Huang, J.; Zeng, G.; Deng, X.; Zhou, Y. Five macrocyclic glycosides from Schoenoplectus tabernaemon-
tani. Nat Prod Res 2019, 33, 427–434. [CrossRef]
1. Desmond, R.T.; Magpusao, A.N.; Lorenc, C.; Alverson, J.B.; Priestley, N.; Peczuh, M.W. De novo macrolide-glycolipid macro-
lactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles. Beilstein J. Org. Chem. 2014, 10,
2
215–2221. [CrossRef] [PubMed]
2. Li, Y.; Sun, J.; Gong, Y.; Yu, B. Synthesis of Oligomeric 4-(Glycosyloxy)benzoate Macrocyclic Glycosides. J. Org. Chem. 2011, 76,
654–3663. [CrossRef] [PubMed]
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3. Zong, G.; Hu, Z.; O’Keefe, S.; Tranter, D.; Iannotti, M.J.; Baron, L.; Hall, B.; Corfield, K.; Paatero, A.O.; Henderson, M.J.; et al.
Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation. J. Am. Chem. Soc. 2019, 141, 8450–8461. [CrossRef] [PubMed]
4. Fuerstner, A.; Ruiz-Caro, J.; Prinz, H.; Waldmann, H. Structure Assignment, Total Synthesis, and Evaluation of the Phosphatase
Modulating Activity of Glucolipsin A. J. Org. Chem. 2004, 69, 459–467. [CrossRef]
5. Si, D.; Peczuh, M.W. Synthesis and structure of a carbohydrate-fused [15]-macrodilactone. Carbohydr. Res. 2016, 434, 113–120.
[CrossRef]
6. Lin, C.; Maisonneuve, S.; Theulier, C.; Xie, J. Synthesis and Photochromic Properties of Azobenzene-Derived Glycomacrolactones.
Eur. J. Org. Chem. 2019, 2019, 1770–1777. [CrossRef]
7. Lin, C.; Maisonneuve, S.; Metivier, R.; Xie, J. Photoswitchable Carbohydrate-Based Macrocyclic Azobenzene: Synthesis, Chiropti-
cal Switching, and Multi-stimuli-Responsive Self-Assembly. Chem. Eur. J. 2017, 23, 14996–15001. [CrossRef]
8. Tsai, C.Y.; Huang, X.; Wong, C.H. Design and synthesis of cyclic sialyl Lewis X mimetics: A remarkable enhancement of inhibition
by pre-organizing all essential functional groups. Tetrahedron Lett. 2000, 41, 9499–9503. [CrossRef]
9. Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem. 2017, 71, 30–54.
[CrossRef]
0. Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click Chemistry for Drug Development and Diverse Chemical-Biology Applications.
Chem. Rev. 2013, 113, 4905–4979. [CrossRef]
1. Barlow, T.M.A.; Tourwe, D.; Ballet, S. Cyclisation To Form Small, Medium and Large Rings by Use of Catalysed and Uncatalysed
Azide-Alkyne Cycloadditions (AACs). Eur. J. Org. Chem. 2017, 2017, 4678–4694. [CrossRef]
2. Singh, M.S.; Chowdhury, S.; Koley, S. Advances of azide-alkyne cycloaddition-click chemistry over the recent decade. Tetrahedron
2
016, 72, 5257–5283. [CrossRef]
3. Haldon, E.; Nicasio, M.C.; Perez, P.J. Copper-catalysed azide-alkyne cycloadditions (CuAAC): An update. Org. Biomol. Chem.
015, 13, 9528–9550. [CrossRef]
4. Zhang, X.; Liu, P.; Zhu, L. Structural determinants of alkyne reactivity in copper-catalyzed azide-alkyne cycloadditions. Molecules
016, 21, 1697. [CrossRef] [PubMed]
2
2
5. Tiwari, V.K.; Mishra, B.B.; Mishra, K.B.; Mishra, N.; Singh, A.S.; Chen, X. Cu-Catalyzed Click Reaction in Carbohydrate Chemistry.
Chem. Rev. 2016, 116, 3086–3240. [CrossRef]
6. Wang, G.; Wang, D.; Bietsch, J.; Chen, A.; Sharma, P. Synthesis of Dendritic Glycoclusters and Their Applications for Supramolec-
ular Gelation and Catalysis. J. Org. Chem. 2020, 85, 16136–16156. [CrossRef]
7. Singh, A.; Khatri, V.; Malhotra, S.; Prasad, A.K. Sugar-based novel chiral macrocycles for inclusion applications and chiral
recognition. Carbohydr. Res. 2016, 421, 25–32. [CrossRef] [PubMed]
8. Pathigoolla, A.; Sureshan, K.M. Reverse-CD mimics with flexible linkages offer adaptable cavity sizes for guest encapsulation.
Chem. Commun. 2014, 50, 317–319. [CrossRef]
9. Bodine, K.D.; Gin, D.Y.; Gin, M.S. Highly Convergent Synthesis of C3-or C2-Symmetric Carbohydrate Macrocycles. Org. Lett.
2
005, 7, 4479–4482. [CrossRef] [PubMed]
0. Peng, R.; Xu, Y.; Cao, Q. Recent advances in click-derived macrocycles for ions recognition. Chin. Chem. Lett. 2018, 29, 1465–1474.
CrossRef]
1. Picot, S.C.; Mullaney, B.R.; Beer, P.D. Ion-pair recognition by a heteroditopic triazole-containing receptor. Chem.-Eur. J. 2012, 18,
230–6237. [CrossRef]
[
6
2. Yu, Y.; Bogliotti, N.; Tang, J.; Xie, J. Synthesis and Properties of Carbohydrate-Based BODIPY-Functionalized Fluorescent
Macrocycles. Eur. J. Org. Chem. 2013, 2013, 7749–7760. [CrossRef]
3. Chandrasekhar, S.; Rao, C.L.; Nagesh, C.; Reddy, C.R.; Sridhar, B. Inter and intramolecular copper(I)-catalyzed 1,3-dipolar
cycloaddition of azido-alkynes: Synthesis of furanotriazole macrocycles. Tetrahedron Lett. 2007, 48, 5869–5872. [CrossRef]
4. Maurya, S.K.; Rana, R. An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-
derived building blocks. Beilstein J. Org. Chem. 2017, 13, 1106–1118. [CrossRef] [PubMed]
5. Chen, A.; Samankumara, L.P.; Dodlapati, S.; Wang, D.; Adhikari, S.; Wang, G. Syntheses of Bis-Triazole Linked Carbohydrate
Based Macrocycles and Their Applications for Accelerating Copper Sulfate Mediated Click Reaction. Eur. J. Org. Chem. 2019
019, 1189–1194. [CrossRef]
6. Nie, X.; Wang, G. Synthesis of a Ring-Oxygenated Variant of the 2-Carboxy-6-hydroxyoctahydroindole Core of Aeruginosin
98-A from Glucose. J. Org. Chem. 2005, 70, 8687–8692. [CrossRef]
,
2
3
3
2
7. Wang, G.; Chen, A.; Mangunuru, H.P.R.; Yerabolu, J.R. Synthesis and characterization of amide linked triazolyl glycolipids as
molecular hydrogelators and organogelators. Rsc Adv. 2017, 7, 40887–40895. [CrossRef]

Molecules 2021, 26, 3394
26 of 26
3
3
4
4
8. Liu, Y.; Zhao, W.; Chen, C.-H.; Flood, A.H. Chloride capture using a C-H hydrogen-bonding cage. Sci. (Wash. Dcu. S.) 2019, 365,
59–161.
9. Chen, Y.; Wu, G.; Chen, L.; Tong, L.; Lei, Y.; Shen, L.; Jiao, T.; Li, H. Selective Recognition of Chloride Anion in Water. Org. Lett.
020, 22, 4878–4882. [CrossRef]
0. Deraedt, C.; Pinaud, N.; Astruc, D. Recyclable Catalytic Dendrimer Nanoreactor for Part-Per-Million CuI Catalysis of “Click”
Chemistry in Water. J. Am. Chem. Soc. 2014, 136, 12092–12098. [CrossRef]
1. Ubbink, M.; Lian, L.Y.; Modi, S.; Evans, P.A.; Bendall, D.S. Analysis of the 1H-NMR chemical shifts of Cu(I)-, Cu(II)- and
Cd-substituted pea plastocyanin. Metal-dependent differences in the hydrogen-bond network around the copper site. Eur. J.
Biochem. 1996, 242, 132–147. [CrossRef] [PubMed]
1
2