Crown-ether-modified cyclic dipeptides as supramolecular chiral catalysts

Article abstract of DOI:10.1080/10610278.2017.1392521

With the objective to develop supramolecular catalysts for useful chemical transformations, we report here a rapid and efficient solid-phase synthesis of novel cyclic dipeptides (crown-CDPs) with a diversity of L-DOPA derived crown ether substituents and

Full text of DOI:10.1080/10610278.2017.1392521

Supramolecular Chemistry
ISSN: 1061-0278 (Print) 1029-0478 (Online) Journal homepage: http://www.tandfonline.com/loi/gsch20
Crown-ether-modified cyclic dipeptides as
supramolecular chiral catalysts
Christopher Bérubé & Normand Voyer
To cite this article: Christopher Bérubé & Normand Voyer (2017): Crown-ether-modified
cyclic dipeptides as supramolecular chiral catalysts, Supramolecular Chemistry, DOI:
10.1080/10610278.2017.1392521
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Date: 23 October 2017, At: 12:36

Supramolecular chemiStry, 2017
https://doi.org/10.1080/10610278.2017.1392521
Crown-ether-modified cyclic dipeptides as supramolecular chiral catalysts
Christopher Bérubé and Normand Voyer
Département de chimie and proteo, université laval, Québec, canada
ABSTRACT
ARTICLE HISTORY
received 9 September 2017
accepted 11 october 2017
With the objective to develop supramolecular catalysts for useful chemical transformations, we
report here a rapid and efficient solid-phase synthesis of novel cyclic dipeptides (crown-CDPs)
with a diversity of L-DOPA derived crown ether substituents and stereochemistry. We prepared and
characterized 14 crown-CDPs and evaluated their efficiency as supramolecular epoxidation catalysts
in a water/hexanes biphasic system. Yields increase significantly in the presence of the crown-CDPs,
though enantioselectivity depends on the nature of the substituents. The results reported constitute
a useful approach for chiral epoxides of interest and further illustrate the potential of cyclic peptides
as supramolecular catalysts.
KEYWORDS
artificial amino acids;
crown ethers; cyclic
dipeptide; chiral receptors;
supramolecular catalysis
1. Introduction
We also demonstrated that some structural features
are required for efficient conversion and, more impor-
tantly, induction of chirality into the products. Very sub-
tle changes in the CDPs can lead to significant drops in
efficiency. Among all the CDPs prepared, the most effi-
cient one was derived from L-Leucine, leading to 70% ee
in the epoxidation process. Computational studies pro-
vided insight into the functional supramolecular inter-
facial complex between cyclo(L-Leu-L-Leu), the enone, a
sodium cation and a hydroperoxide ion, which is required
for good enantioselectivity, consistent with the experi-
mental data (11).
Cyclic dipeptides (CDPs) are an excellent, easily accessi-
ble scaffold for producing supramolecular receptors and
catalysts (1–9). CDPs have two chiral side chains on a flat
cyclic dipeptide ring, which allows a rich diversity of sub-
stituents to be added with a preferential orientation. We
recently reported an example of interfacial supramolecular
catalysis, the asymmetric epoxidation of electron-deficient
ketones catalysed by several CDPs in a water/hexanes
media (10,11). Good enantioselectivities were obtained,
though conversions were good to moderate after 48 h.
CONTACT Normand Voyer
Normand.voyer@chm.ulaval.ca
Supplemental data for this article can be accessed https://doi.org/10.1080/10610278.2017.1392521.
© 2017 informa uK limited, trading as taylor & Francis Group

2
C. BÉRUBÉ AND N. VOYER
Thus, the well-defined supramolecular complex located
depicted in Figure 1. Also, Závada et al. synthesized three
crown-CDPs (6–8) with a spiro-crown ether attached to
the α-carbons (Figure 1) (23).
at the interface with a cation inspired us to develop a sec-
ond generation of CDP catalysts. We hypothesized that
incorporating one or two crown ethers as cation ligands
onto the cyclic dipeptide core could enhance both reac-
tion rate and enantioselectivity, thus acting as supramolec-
ular phase-transfer catalysts. Crown ethers are well known
phase-transfer catalysts used efficiently in numerous pro-
cesses (12). Interestingly, Bakó et al. reported the use of
monoaza-[15]-crown-5 derived from monosaccharides as
an asymmetric phase-transfer catalyst in the epoxidation
of electron-deficient enones (13–17) and other further the-
oretical studies have been described (18). Also, chiral crown
ethers have been examined for asymmetric phase-transfer
epoxidation of olefins (19,20). Herein, we report our results
on the efficiency of mono- and bis- L-DOPA derived crown
ether cyclic dipeptides (crown-CDPs) using different oxi-
dant systems.
Our strategy to prepare crown-CDPs with one crown
ether side chain involved using one proteogenic amino
acid and one L-DOPA-derived crown ether. We use leu-
cine, alanine and phenylalanine, based on our previous
results (11). In addition, we investigated crown-CDPs with
two crown ether side chains in an attempt to exploit a
cooperative binding of metal cations, which in turn could
facilitate the migration of the hydroperoxide anion at the
interface. This could lead to an increase of the epoxidation
reaction rate and enantioselectivity.
Recently, we reported a rapid and efficient parallel syn-
thetic procedure toward optically pure CDPs, using enanti-
opure N-t-butyloxycarbonyl (N-Boc) protected amino acids
(11,24). We used a Kaiser oxime resin with an N-Boc pro-
tection strategy to prepare linear dipeptides, which were
cleaved from the resin by an intramolecular cyclization to
yield highly pure CDPs. Using this synthetic strategy, we
report herein the preparation of novel enantiopure crown-
CDPs bearing one or two crown ether side chains and their
utilization as asymmetric supramolecular catalysts in the
epoxidation of electron-deficient ketones.
Early examples of similar crown-CDPs were reported by
Sonveaux et al. In their studies, five crown-CDPs were pre-
pared in solution by the condensation of one N-Boc pro-
tected amino acid and a crown DOPA methyl ester (21,22).
A further cyclization step of the linear dipeptide in solu-
tion led to cis (1–2), trans (3–4) and bis (5) crown-CDPs, as
Figure 1. previous work by Sonveaux and Závada.

SUPRAMOLECULAR CHEMISTRY
3
2.2. Cyclic dipeptide synthesis
2. Results and discussion
Fourteen new crown-CDPs were prepared by solid-phase
synthesis using Kaiser oxime resin (27,28). Taking advan-
tage of the availability of natural and unnatural chiral
amino acids as chiral synthons, the crown-CDPs were
synthesized with a variety of substituents and stere-
ochemistry. The key step of this rapid method is the
concomitant cyclization and cleavage of a linear dipep-
tide from the oxime ester linkage from resin, as previ-
ously reported (10,11,24,29,30). The first amino acid was
coupled for three hours using diisopropylcarbodiimide
(DIC) as a coupling reagent. The N-Boc protecting group
was removed using a mixture of 1:1 trifluoroacetic acid
(TFA)/dichloromethane, while the second amino acid
was activated with 6-Chloro-1-hydroxybenzotriazole
2.1. Crown ether amino acids synthesis
The binding selectivity of crown ethers depends on their
size and on the number of oxygen atoms each contains.
Hence, we devised a general synthetic strategy for enanti-
opure crown ether amino acids with different macrocycle
sizes (25). The synthetic procedure starts with commer-
cially available 3,4-dihydroxy-L-phenylalanine, L-DOPA
(9). Taking advantage of the catechol function, macrocy-
cles were formed in solution from fully protected L-DOPA
11 and dibromo-oligo(ethylene glycol) synthons 12–14,
leading to a variety of crown ether amino acids 15–17
(Figure 2). The acid function was then deprotected using
NaOH in methanol to provide the desired N-Boc protected
amino acids 18–20, which were used in peptide synthesis.
Overall, the N-Boc crown ether L-phenylalanines 18, 19
and 20 were prepared in five steps with respectively 35,
42 and 53% isolated yields from L-DOPA. The crown ethers
were optically pure, as established previously (26).
(6-Cl-HOBt)
and
O-(6-Chlorobenzotriazol-1-yl)-
N,N,N′,N′-tetramethyluronium hexafluorophosphate
(HCTU). After deprotection, the linear dipeptide was
treated with diisopropylethylamine (DIEA; 2.5 equiv.)
Figure 2. Synthetic procedure for crowned Dopa amino acid derivatives 18–20.

4
C. BÉRUBÉ AND N. VOYER
Figure 3. Synthetic procedure for crown-cDps.
Table 1. Novel synthesized crown-cDps.
Entry
R1
R2
Crown-CDPs
Yield (%)
1
2
3
4
5
6
7
8
(S)-ch2ch(ch3)2
(R)-ch2ch(ch3)2
(S)-ch2ch(ch3)2
(R)-ch2ch(ch3)2
(S)-ch2ch(ch3)2
(R)-ch2ch(ch3)2
(S)-ch3
(S)-Dopa(18-c-6)
(S)-Dopa(18-c-6)
(S)-Dopa(21-c-7)
(S)-Dopa(21-c-7)
(S)-Dopa(15-c-5)
(S)-Dopa(15-c-5)
(S)-Dopa(18-c-6)
(S)-Dopa(18-c-6)
(S)-Dopa(15-c-5)
(S)-Dopa(18-c-6)
(S)-Dopa(21-c-7)
(S)-Dopa(18-c-6)
(S)-Dopa(21-c-7)
(S)-Dopa(21-c-7)
21
22
23
24
25
26
27
28
29
30
31
32
33
34
65
43
72
67
81
74
40
67
72
59
64
40
63
50
(S)-ch2ph
9
(S)-Dopa(15-c-5)
(S)-Dopa(15-c-5)
(S)-Dopa(15-c-5)
(S)-Dopa(18-c-6)
(S)-Dopa(18-c-6)
(S)-Dopa(21-c-7)
10
11
12
13
14
and acetic acid (AcOH; 5 equiv.) in dichloromethane
to cause simultaneous cyclization and cleavage from
the resin, leading to high-purity crown-CDPs 21–34
(Table 1) with control over substitution patterns and
the stereochemistry.
In this way, we successfully synthesized cis and trans
analogues of crown-CDPs with a variety of crown ether
side chains. We also prepared all possible combinations
of crown-CDPs bearing two crown ether side chains using
N-Boc amino acids 18–20. Overall, 14 crown-CDPs were
prepared in good yields (40–81%) with between 80 and
92% purity by a simple treatment of the crude cyclization
products with Amberlite IR-120 and trituration with ether.
The purity of all crown-CDPs was sufficient to be used as-is
in the epoxidation reactions. It is worth mentioning that
the overall synthesis proceeds with very low racemization
(5% or less), as measured by NMR signals of the diastere-
omeric crown-CDPs (24).

SUPRAMOLECULAR CHEMISTRY
5
the organic solvent and 10 mol% of 21 as the catalyst
loading (Table 2, entries 6 and 7). In both cases, racemic
epoxychalcone was obtained, pointing to the importance
of sodium peroxide and the formation of a supramolecular
complex.
2.3. Use of crown-CDPs in the epoxidation of
electron-deficient enones
2.3.1. Optimization of reaction conditions
With a series of diverse enantiopure crown-CDPs in hand,
we investigated their efficacy in the asymmetric epoxida-
tion of a model substrate, the trans-chalcone 35, produc-
ing the epoxychalcone 36a. At first, we investigated the
epoxidation using cis crown-CDP 21, which has a ben-
zo-18-crown-6 side chain and an isobutyl side chain. The
epoxidation of 35 was carried out in a liquid-liquid tolu-
ene/water biphasic system employing aqueous sodium
hydroxide in 30% hydrogen peroxide as a reagent, with
10 mol% of catalyst 21 (Table 2, entries 1–2).
These experiments revealed that a higher concentra-
tion of sodium hydroperoxide increases the reaction rate.
The use of dichloromethane instead of toluene led to a
lower yield and provided racemic epoxychalcone 36a
(Table 2, entry 3). Both diethyl ether and hexanes led to
high yields, though only hexanes yielded enantio-en-
riched 36a, albeit with a low 9% ee (Table 2, entries 4–5).
Overall, hexanes were found to be the most adequate
organic solvent in terms of rate and enantioselectivity
(Table 2, entry 5).
We then explored the impact of counter cations on the
process. Lithium, potassium and cesium ions were investi-
gated (Table 2, entries 8–12). The lithium cation was more
efficient than other cations in providing epoxychalcone
with higher enantioselectivity (37% ee), which replicates
a phenomena observed by others (31,32). Interestingly, we
observed a higher reaction rate at a lower base concen-
tration using lithium hydroxide. This could be due to the
ability of the benzo-18-crown-6 to more efficiently bind
sodium and potassium ions, hence possibly decreasing
the stability of the supramolecular complex necessary for
catalysis. In fact, the nature of the counter cation signifi-
cantly impacts the chemical yield and the enantioselectiv-
ity at lower concentrations.
An attempt to enhance the enantioselectivity by low-
ering the reaction temperature to zero degrees led to a
slightly increased enantioselectivity, from 37% to 39% ee
of epoxychalcone 36a (Table 2, entry 13). Finally, using
5 mol% of catalyst loading (crown-CDP-21) led to compa-
rable epoxidation results, with 31% conversion and 36%
ee (Table 2, entry 14).
Further investigations were done with different oxi-
dation reagents such as tert-butyl hydroperoxide (TBHP)
and sodium hypochlorite (NaOCl), keeping hexanes as
Table 2. optimization of epoxidation conditionsa.
Entry
Crown-CDP-21 (mol%)
Oxidant system
Solvent
Yield (%)b
ee (%)b
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
5
8% Naoh/30% h2o2
20% Naoh/30% h2o2
20% Naoh/30% h2o2
20% Naoh/30% h2o2
20% Naoh/30% h2o2
20% Naoh/70% tBhp
13% Naoclc
8% lioh/30% h2o2
8% Koh/30% h2o2
20% Koh/30% h2o2
20% K2co3/30% h2o2
20% cs2co3/30% h2o2
8% lioh/30% h2o2
8% lioh/30% h2o2
phme
phme
Dcm
et2o
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
16
70
13
93
98
98
6
46
25
98
25
25
27
31
0
0
0
0
9
0
0
37
0
5
0
0
39
36
9
10
11
12
13d
14
aunless otherwise noted, the reaction was performed as a biphasic system using 35 (0.1 mmol) and 21 (0.01 mmol) in solvent (0.3 ml) and a solution (0.2 ml) b of
base in 30% h2o2 for 24 h.
bDetermined by chiral hplc.
c0.5 ml was used.
dreaction performed at 0 °c.

6
C. BÉRUBÉ AND N. VOYER
Table 3. evaluation of crown-cDps synthesized in the optimized asymmetric reaction conditionsa.
Entry
Crown-CDPs
Yield (%)b
ee (%)b
1
2
3
4
5
6
7
8
cyclo[l-leu-l-Dopa(18-c-6)] 21
cyclo[D-leu-l-Dopa(18-c-6)] 22
cyclo[l-leu-l-Dopa(21-c-7)] 23
cyclo[D-leu-l-Dopa(21-c-7)] 24
cyclo[l-leu-l-Dopa(15-c-5)] 25
cyclo[D-leu-l-Dopa(15-c-5)] 26
cyclo[l-ala-l-Dopa(18-c-6)] 27
cyclo[l-phe-l-Dopa(18-c-6)] 28
cyclo-bis[l-Dopa(15-c-5)] 29
cyclo[l-Dopa(15-c-5)-l-Dopa(18-c-6)] 30
cyclo[l-Dopa(15-c-5)-l-Dopa(21-c-7)] 31
cyclo-bis[l-Dopa(18-c-6)] 32
cyclo[l-Dopa(18-c-6)-l-Dopa(21-c-7)] 33
cyclo-bis[l-Dopa(21-c-7)] 34
93
85
99
88
67
88
99
92
91
53
76
93
86
93
34
7
11
8
0
0
9
5
6
8
4
0
4
4
9
10
11
12
13
14
aunless otherwise noted, the reaction was performed as a triphasic system using 35 (0.1 mmol) and catalyst in hexanes (0.3 ml) using a solution (0.2 ml) of 8%
lioh in 30% h2o2 for 48 h.
bDetermined by chiral hplc.
In general, as reported previously (11), cis crown-CDPs
provided better asymmetric induction than trans crown-
CDPs. Moreover, crown-CDPs with only one crown ether
side chain were more efficient in asymmetric induction
than crown-CDPs bearing two crown ethers in the epox-
idation process. These results point to the importance of
having a higher dissymmetry in the supramolecular cata-
lyst to induce higher enantioselectivity.
2.3.2. Investigation of the efficacy of crown-CDPs
prepared
Using the optimized conditions, we investigated the supra-
molecular catalytic ability of all the crown-CDPs prepared.
First, cis crown-CDP-21, bearing isobutyl and benzo-18-
crown-6 side chains, provided a higher enantioselectivity
of (2R,3S)-epoxychalcone 36a (34%) than the trans dias-
tereoisomer crown-CDP-22 (7%) (Table 3, entries 1–2).
Using crown-CDPs with a benzo-21-crown-7 (23–24) or
a benzo-15-crown-5 (25–26), high yields of epoxide 36a
were obtained, though lower enantioselectivities were
observed (0–11% ee), especially using trans crown-CDPs.
In order to verify the steric impact of side chains in
the epoxidation process, further investigations were per-
formed with crown-CDPs bearing a methyl (27) or a benzyl
(28) side chain and both having a benzo-18-crown-6 side
chain. Using crown-CDPs with methyl or benzyl moieties
gave lower enantioselectivities as compared to an isobutyl
group (Table 3, entries 7–8). We also investigated crown-
CDPs bearing two different crown ethers. In all cases,
regardless of the combination of crown ether side chains,
crown-CDP 29–34 yielded epoxychalcone 36a with low
enantiomeric excesses (up to 8%).
2.3.3. Reaction scope using crown-CDP 21
We next investigated the substrate scope of the crown-
CDP catalyzed epoxidation under optimal conditions, but
using only 5 mol% of CDP-21 for 72 h. Under those con-
ditions, epoxidation of trans-chalcone 35 provided a high
yield (93%) and 34% ee of (2R,3S)-epoxide 36a (Table 4,
entry 1). Epoxidation of chalcone with electron-withdraw-
ing chloro group on the β-phenyl moiety led to moderate
yield (32%) and 27% ee of (2R,3S)-epoxide 36b (Table 4,
entry 2).
We also verified the effect of a para-fluoro substitution
on the α-phenyl moiety of the chalcone. Reaction with this
substrate led to 31% yield and 30% ee of (2R,3S)-epoxide
36c (Table 4, entry 3). A higher reaction rate was obtained

SUPRAMOLECULAR CHEMISTRY
7
Table 4. reaction scope in the epoxidation processa catalyzed by 21.
Entry
R1
ph
p-cl-ph
p-F-ph
ph
p-F-ph
p-No2-ph
m-No2-ph
o-No2-ph
p-ome-ph
2-naphtyl
R2
ph
ph
No
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
36a
36b
36c
36d
36e
36f
93
32
31
67
54
81
54
43
10
45
34
27
30
18
40
21
15
6
ph
p-F-ph
p-ch3-ph
ph
ph
ph
ph
ph
36g
36h
36i
13
19
10
36j
aunless otherwise noted, the reaction was performed as a biphasic system using a chalcone (0.1 mmol) and 21 (0.005 mmol) in hexanes (0.3 ml) using a solution
(0.2 ml) of 8% lioh in 30% h2o2 for 72 h.
bDetermined by chiral hplc.
with chalcone having a para-fluoro substitution on the
β-phenyl moiety, leading to a good yield (67%). However,
a decrease of enantioselectivity to 18% of (2R,3S)-epoxide
36d is observed (Table 4, entry 4) in that case. Epoxidation
of the bi-substituted chalcone 36e led to a good yield
(54%) and to the highest enantioselectivity observed in
this study, 40% ee of (2R,3S)-epoxide 36e (Table 4, entry 5).
Substitutions at different positions on the β-phenyl
moiety with the strong electron-withdrawing nitro group
led to variable results (Table 4, entries 6–8). The yield (81%)
and enantioselectivity (21%) are highest in the case of the
para-nitro substitution of (2R,3S)-epoxide-36f (Table 4,
entry 6). Yields and enantioselectivities decrease with meta
and ortho substitutions leading to 15% and 6% respec-
tively of (2R,3S)-epoxide 36g and (2R,3S)-epoxide 36h. In
this case, both electronic and steric effects explain the sig-
nificant decrease of reactivity. Lower electrophilicity of the
enone with a para methoxy electron-donating group on
the β-phenyl moiety afforded (2R,3S)-epoxide 36i with a
low yield (10%) and enantioselectivity (13%) (Table 4, entry
9). On the other hand, using a 2-napthyl substitution on
the enone led to a good yield (45%) and low enantiomeric
excess (19%) of (2R,3S)-epoxide 36j (Table 4, entry 10).
In summary, studies with different substrates strongly
suggest that both the steric hindrance and electronic
factors of chalcones play a crucial role in the outcomes
of the process. The level of enantioselectivity observed is
highly variable, and seems to rely on many parameters.
In all cases, the supramolecular catalysis of crown-CDPs
led to (2R,3S)-epoxides, which shows that the same type
of supramolecular complex is involved in the catalysis.
Though multiple orientations of the substrate are possible,
it has been previously demonstrated that in phase-transfer
epoxidations, the chiral crown ethers complex the cation,
which in turn brings the hydroperoxide anion to the inter-
face for a nucleophilic 1,4-addition on the enone (33). In
this study, we demonstrated that incorporating crown-
DOPA derivatives into cyclic dipeptides does not improve
the efficiency of the supramolecular catalytic epoxidation
of electron-deficient enones. The results illustrate the dif-
ficulties in designing highly efficient supramolecular cat-
alysts, at least for epoxidation processes.
3. Conclusion
In summary, we have prepared 14 new cis, trans crown-
CDPs by taking advantage of solid-phase peptide synthesis
and of the chemical reactivity of the Kaiser oxime resin.
Crown-CDPs were obtained with good yields and high
purities. We demonstrated the versatility of the method-
ology by preparing several crown-CDPs bearing various
sizes of crown ethers and covering both of the substitution
patterns that are possible with crown-CDPs. In a model
epoxidation reaction, we showed that a catalytic amount
(5 mol%) of crown-CDP can significantly enhance con-
version yields (up to 99%) and introduce chirality in the
process (up to 40%). Though the enantiomeric excesses
obtained so far are low to moderate, the results reported
illustrate the potential of this approach to prepare useful

8
C. BÉRUBÉ AND N. VOYER
supramolecular phase-transfer catalysts by combining the
advantages of chiral crown ethers and of cyclic dipeptides.
We are currently exploring the use of the crown-CDPs in
other important chemical transformations.
filtered under vacuum and the resin was washed [DMF (3
× 15 mL), MeOH (3 × 15 mL), DMF (3 × 15 mL), MeOH (3 ×
15 mL)] and dried under reduced pressure.
4.2.2. Acetylation of unreacted sites on oxime resin
The resin was treated three times with DMF (3 × 20 mL).
A solution of 50% v/v DMF/acetic anhydride (15 mL) and
DIEA (1.5 mL) were added to the peptide synthesis vessel
and shaken for 1 h. Then, the mixture was filtered under
vacuum and the resin was washed [DMF (3 × 15 mL), MeOH
(3 × 15 mL), DMF (3 × 15 mL), MeOH (3 × 15 mL)] and dried
under reduced pressure.
4. Experimental section
4.1. General information
Oxime resin (1.12 mmol/g), coupling reagents, and N-Boc-
protected amino acids were purchased from Matrix
Innovation (Québec City, QC, Canada). Unless otherwise
indicated, other starting materials were purchased from
commercial sources (Sigma-Aldrich and VWR) and used
without further purification. The reagents and the solvents
were dried and purified before use by the usual proce-
dures and kept under argon. All reagents were assembled
under an inert atmosphere. 1H and 13C-NMR spectra were
recorded on an Agilent DD2 500 MHz spectrometer and
Varian Inova 400 MHz. The coupling constants are reported
in hertz (Hz). Splitting patterns are designated as s (singlet),
d (doublet), dd (doublet of doublet), t (triplet), q (quartet),
brs (broad singlet), ddt (doublet of doublet of triplets), and
m (multiplet). Melting points were taken using a Stanford
Research Systems OptiMelt MPA 100 instrument. Mass
spectra were obtained on an Agilent 6210 LCTime of Flight
Mass Spectrometer in direct injection mode. IR spectra
were recorded onThermo Scientific Nicolet 380 FT-IR using
ZnSe crystal. HPLC purities data were measured on Agilent
1260 Infinity instrument with a C18 column (GraceVydac)
and a DAD detector (λ = 280 nm). Retention time is in min-
utes, followed by the percentage integration of the total
chromatogram. All solvents were degassed, using a gradi-
ent of (100% H2O) to (46.4% H2O/54.4% CH3CN) in 35 min
followed by 100% H2O between 35 and 42 min. Optical
rotations were measured at ambient temperature on a
Jasco DIP-360 digital polarimeter using a sodium lamp.
Crown amino acids were prepared following reported
procedures (25). Their synthesis and characterization are
reported in the SI.
4.2.3. Removal of the N-Boc protecting group
The resin was treated three times with CH2Cl2 (15 mL).
A 50% v/v solution of trifluoroacetic acid (TFA) in CH2Cl2
was added to the peptide synthesis vessel and shaken for
30 min. Then, the mixture was filtered under vacuum and
the resin was washed with DMF (3 × 15 mL), MeOH (3 ×
15 mL), DMF (3 × 15 mL), MeOH (3 × 15 mL) and with a
solution of 10% v/v DIEA in CH2Cl2 (15 mL).
4.2.4. Coupling of the second N-Boc protected
α-amino acid
The amino acid (3.0 equiv.) was dissolved in DMF in a
100 mL flask. The solution was cooled to 0 °C, then HCTU
(3.0 equiv.) and HOBt (3.0 equiv.) were added. The mixture
was poured into the peptide synthesis vessel, in which the
resin was previously treated with CH2Cl2. DIEA (6.0 equiv.)
was also added to the vessel and the mixture was shaken
for 3 h. After filtration under vacuum, the resin was washed
[DMF (3 x 15 mL), MeOH (3 × 15 mL), DMF (3 × 15 mL) and
MeOH (3 × 15 mL)] and dried under reduced pressure. The
Kaiser ninhydrin test was performed to monitor the effi-
ciency of the coupling, and the coupling procedure was
repeated as needed.
4.2.5. Cyclization/cleavage from the resin
First, the N-Boc group was removed using the procedure
described in (4.2.3), but without the 10% v/v DIEA/CH2Cl2
washing step. After drying, CH2Cl2 and DIEA (2.5 equiv.)
were added to the peptide synthesis vessel and the mix-
ture was shaken for 2 min. Acetic acid (5.0 equiv.) was
added and the contents were shaken for 24 h. Then the
filtrate was collected and the resin was rinsed several times
with CH2Cl2 and MeOH. All the filtrates were combined and
evaporated, and the resulting solid was dissolved in CH2Cl2.
Amberlite IR-120 was introduced to the solution to remove
the remaining traces of DIEA. The mixture was stirred for
a few minutes and filtered. The filtrate was evaporated to
give compounds 21–34. Trituration in a minimum of cold
ether was performed and led to the desired compounds
with satisfying purity.
4.2. Preparation of crown-CDPs
4.2.1. Coupling of the first N-Boc protected α-amino
acid on oxime resin
A desired quantity of oxime resin (1.12 mmol/g) was added
to a peptide synthesis vessel. The resin was treated three
times with CH2Cl2. Amino acid (3.0 equiv.) and 6-Cl-HOBt
(3.0 equiv.) were dissolved in DMF in a 100 mL flask and the
mixture was stirred for few minutes at 0 °C. DIC (3.0 equiv.),
DIEA (3.0 equiv.) and DMAP (0.1 equiv.) were added, and
the mixture was introduced into the peptide synthesis
vessel and stirred mechanically for 3 h. The mixture was

SUPRAMOLECULAR CHEMISTRY
9
1
4.2.5.1. cyclo[L-Leu-L-DOPA(18-C-6)](21). Yellow
powder, 65% yield. mp 150 °C. [ꢀ]2D2 + 27.8° (c 0.1 in
MeOH). ATR (ZnSe) 3102, 3052, 2870, 1663, 1513, 1457,
1265, 1123, 799 cm−1. 1H NMR (500 MHz, DMSO-d6) δ 8.08
(d, J = 2.3 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 8.2 Hz,
1H), 6.72 (d, J = 1.8 Hz, 1H), 6.63 (dd, J = 8.2, 1.8 Hz, 1H),
4.10 (brt, 1H), 4.06–3.95 (m, 5H), 3.76–3.69 (m, 4H), 3.62–
3.57 (m, 4H), 3.56–3.50 (m, 8H), 3.03 (dd, J = 13.5, 3.8 Hz,
1H), 2.75 (dd, J = 13.6, 4.8 Hz, 1H), 1.49–1.41 (m, 1H), 1.30–
1.22 (m, 2H), 0.65 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 6.6 Hz, 3H).
13C NMR (126 MHz, DMSO-d6) δ 167.8, 166.8, 148.3, 147.9,
128.9, 123.1, 116.3, 113.4, 70.3, 69.2, 69.1, 68.8, 68.7, 56.0,
52.8, 44.2, 38.5, 23.4, 23.2, 21.9. HRMS (ESI) m/z calcd for
C25H42N3O8 (M + NH4)+: 512.2955, found 512.2971. HPLC
(Retention time, purity): 20.74 min, 87%.
1458, 1260, 1120 cm−1. H NMR (500 MHz, DMSO-d6) δ
8.02–8.00 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 2 Hz,
1H), 6.69 (dd, J = 8.2, 2.0 Hz, 1H), 4.09 (brt, 1H), 4.03–4.00
(m, 4H), 3.74–3.71 (m, 4H), 3.61–3.58 (m, 4H), 3.56–3.53
(m, 4H), 3.51 (s, 8H), 3.03 (dd, J = 13.6, 4.1 Hz, 1H), 2.97–
2.94 (m, 1H), 2.79 (dd, J = 13.6, 4.7 Hz, 1H), 1.73–1.68
(m, 1H), 1.47–1.42 (m, 1H), 1.40–1.34 (m, 1H), 0.78 (d,
J = 6.6 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz,
DMSO-d6) δ 168.3, 167.9, 148.0, 147.6, 129.0, 123.0, 116.0,
113.4, 70.7, 70.3, 69.4, 69.3, 68.7, 68.6, 55.8, 52.4, 41.9,
38.1, 23.8, 23.2, 22.4. HRMS (ESI) m/z calcd for C47H46N3O9
(M + NH4)+: 556.3229, found 556.3443. HPLC (Retention
time, %): 19.30 min, purity 91% .
4.2.5.5. cyclo[L-Leu-L-DOPA(15-C-5)](25). Brown
powder, 81% yield. mp 161 °C.[ꢀ]2D2 + 6.3° (c 0.1 in MeOH).
ATR (ZnSe) 3180, 3054, 2919, 2869, 1666, 1530, 1452,
1256, 1123 cm−1. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (d,
J = 2.7 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 8.2 Hz,
1H), 6.71 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.1, 2.0 Hz, 1H),
4.11–4.09 (m, 1H), 4.01–3.93 (m, 4H), 3.75–3.72 (m, 4H),
3.61–3.58 (m, 8H), 3.49–3.46 (m, 1H), 3.03 (dd, J = 13.5,
3.8 Hz, 1H), 2.73 (dd, J = 13.5, 3.8 Hz, 1H), 1.45–1.41 (m,
1H), 1.26–1.23 (m, 2H), 0.65 (d, J = 6.5 Hz, 3H), 0.63 (d,
J = 6.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 167.9,
166.7, 148.7, 148.3, 129.1, 123.4, 116.9, 113.9, 70.9, 70.4,
69.4, 69.2, 56.0, 52.7, 44.2, 38.5, 23.3, 21.9, 21.5. HRMS
(ESI) m/z calcd for C23H35N2O7 (M + H)+: 451.2439, found
451.2438. HPLC (Retention time, %): 17.98 min, purity
80%.
4.2.5.2. cyclo[D-Leu-L-DOPA(18-C-6)] (22). Pale yellow
powder, 43% yield. mp 164 °C. [ꢀ]2D2 + 42.6° (c 0.1 in
MeOH). ATR (ZnSe) 3183, 3054, 2921, 2867, 1668, 1514,
1
1455, 1263, 1124 cm−1. H NMR (500 MHz, DMSO-d6). δ
7.99 (s, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 1.7 Hz, 1H),
6.69 (dd, J = 8.1, 1.6 Hz, 1H), 4.09 (brt, 1H), 4.02–3.99 (m,
5H), 3.75–3.72 (m, 4H), 3.61–3.58 (m, 4H), 3.55–3.52 (m,
8H), 3.03 (dd, J = 13.6, 4.1 Hz, 1H), 2.97 (t, J = 6.1 Hz, 1H),
2.80 (dd, J = 13.6, 4.7 Hz, 1H), 1.75–1.67 (m, 1H), 1.48–1.43
(m, 1H), 1.40–1.34 (m, 1H), 0.78 (d, J = 6.6 Hz, 3H), 0.74
(d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 168.9,
167.9, 148.1, 147.6, 128.9, 122.9, 116.0, 113.3, 70.3, 70.2,
69.2, 69.1, 68.6, 55.8, 52.4, 41.9, 38.1, 23.9, 23.2, 22.4. HRMS
(ESI) m/z calcd for C25H42N3O8 (M + NH4)+: 512.2966, found
512.2948. HPLC (Retention time, purity): 19.68 min, 92%.
4.2.5.6. cyclo[D-Leu-L-DOPA(15-C-5)](26). Brown
powder, 74% yield. mp 169 °C. [ꢀ]2D2 + 24.9° (c 0.1 in
MeOH). ATR (ZnSe) 3179, 3051, 2927, 2877, 1669, 1518,
4.2.5.3. cyclo[L-Leu-L-DOPA(21-C-7)] (23). Pale orange
powder, 72% yield. mp 140 °C. [ꢀ]2D2 + 10.2° (c 0.1 in
MeOH). ATR (ZnSe) 3183, 3051, 2869, 1661, 1511, 1458,
1266, 1121, 801 cm−1. 1H NMR (500 MHz, DMSO-d6) δ
8.09 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 2.3 Hz, 1H), 6.84 (d,
J = 8.2 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.63 (dd, J = 8.2,
1.8 Hz, 1H), 4.10 (br, 1H), 4.04–3.96 (m, 4H), 3.75–3.69
(m, 4H), 3.64–3.57 (m, 4H), 3.57–3.52 (m, 4H), 3.51–3.46
(m, 9H), 3.03 (dd, J = 13.5, 3.8 Hz, 1H), 2.74 (dd, J = 13.5,
4.7 Hz, 1H), 1.44 (ddt, J = 15.6, 13.2, 6.4 Hz, 1H), 0.85–0.80
(m, 1H), 0.64 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 6.6 Hz, 3H),
0.25–0.16 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 168.0,
166.8, 148.3, 147.9, 128.9, 123.2, 116.5, 113.5, 70.7, 70.3,
69.4, 69.3, 68.9, 68.8, 56.0, 52.7, 44.2, 38.7, 23.4, 23.2,
21.8. HRMS (ESI) m/z calcd for C47H46N3O9 (M + NH4)+:
556.3229, found 556.3263. HPLC (Retention time, purity):
21.40 min, 90%.
1
1461, 1258, 1122 cm−1. H NMR (500 MHz, DMSO-d6) δ
8.02 (m, 2H), 6.63 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.0 Hz,
1H), 6.69 (dd, J = 8.1, 2.0 Hz, 1H), 4.10–4.08 (m, 1H), 3.99–
3.96 (m, 5H), 3.75–3.72 (m, 4H), 3.61–3.59 (m, 8H), 3.03
(dd, J = 13.6, 4.1 Hz, 1H), 2.79 (dd, J = 13.7, 4.8 Hz, 1H),
1.71–1.68 (m, 1H), 1.26–1.23 (m, 2H), 0.77 (d, J = 6.6 Hz,
3H), 0.73 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6)
δ 168.9, 167.9, 148.5, 148.0, 129.1, 123.1, 116.6, 114.0,
70.9, 70.3, 69.3, 69.0, 55.8, 52.3, 41.8, 38.1, 23.8, 23.2, 22.3.
HRMS (ESI) m/z calcd for C23H35N2O7 (M + H)+: 451.2439,
found 451.2438. HPLC (Retention time, %): 18.58 min,
purity 86%.
4.2.5.7. cyclo[L-Ala-L-DOPA(18-C-6)] (27). Pale yellow
powder, 40% yield. mp 169 °C.[ꢀ]2D2 + 30° (c 0.1 in MeOH).
ATR (ZnSe) 3183, 3045, 2921, 1664, 1512, 1461, 1264,
1
4.2.5.4. cyclo[D-Leu-L-DOPA(21-C-7)] (24). Pale yellow
powder, 67% yield. mp 148 °C. [ꢀ]2D2 + 15.6° (c 0.1 in
MeOH). ATR (ZnSe) 3180, 3049, 2921, 2870, 1665, 1515,
1125, 877 cm−1. H NMR (500 MHz, DMSO-d6) δ 8.05 (d,
J = 1.3 Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 6.85 (d, J = 8.2 Hz,
1H), 6.75 (d, J = 1.8 Hz, 1H), 6.65 (dd, J = 8.2, 1.8 Hz, 1H),

10
C. BÉRUBÉ AND N. VOYER
4.11 (brt, 1H), 4.05–4.00 (m, 5H), 3.76–3.70 (m, 4H), 3.61–
3.57 (m, 4H), 3.56–3.52 (m, 4H), 3.52 (s, 4H), 3.02 (dd,
J = 13.5, 3.8 Hz, 1H), 2.77 (dd, J = 13.5, 4.6 Hz, 1H), 0.58
(d, J = 7.0 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 168.2,
166.5, 148.3, 147.7, 129.0, 123.2, 116.4, 113.8, 70.3, 69.2,
69.1, 68.7, 68.6, 55.9, 50.2, 38.3, 20.3. HRMS (ESI) m/z calcd
for C22H36N3O8 (M + NH4)+: 470.2497, found 470.2514.
HPLC (Retention time, purity): 17.03 min, 84%.
(ESI) m/z calcd for C36H50N2NaO13 (M + Na)+: 741.3205,
found 741.3232. HPLC (Retention time, %): 20.22 min,
purity 89%.
4.2.5.11. cyclo[L-DOPA(15-C-5)-L-DOPA(21-C-7)]
(31). Brown oil, 64% yield. [ꢀ]2D2 − 57.7° (c 0.1 in MeOH).
ATR (ZnSe) 3181, 3051, 2917, 2853, 1667, 1515, 1453,
1258, 1123 cm−1. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (d,
J = 2.6 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 6.87 (d, J = 2.1 Hz,
1H), 6.86 (d, J = 2.1 Hz, 1H), 6.54–6.50 (m, 2H), 4.02–3.91
(m, 10H), 3.76–3.68 (m, 12H), 3.60–3.48 (m, 20H), 2.60 (dd,
J = 13.6, 4.4 Hz, 2H), 2.15 (dd, J = 12.6, 5.6 Hz, 1H), 2.02 (dd,
J = 15.6, 7.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 166.7,
162.8, 148.9, 148.4, 147.9, 147.4, 129.7, 129.6, 122.7, 122.5,
116.1, 115.6, 114.5, 113.9, 70.9, 70.8, 70.7, 70.6, 70.4, 70.3,
69.4, 69.3, 69.2, 68.9, 68.8, 68.7, 56.0. HRMS (ESI) m/z calcd
for C38H54N2NaO14 (M + Na)+: 785.3467, found 785.3508.
HPLC (Retention time, %): 20.67 min, purity 80%.
4.2.5.8. cyclo[L-Phe-L-DOPA(18-C-6)] (28). Pale yellow
powder, 67% yield. mp 170 °C. [ꢀ]2D2 − 83.1° (c 0.1 in
MeOH). ATR (ZnSe) 3188, 3053, 2875, 1665, 1513, 1452,
1261, 1121, 799 cm−1. 1H NMR (500 MHz, DMSO-d6) δ 7.91
(d, J = 1.9 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.25 (t, J = 7.3 Hz,
2H), 7.18 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 7.5 Hz, 2H), 6.81 (d,
J = 8.1 Hz, 1H), 6.55 (s, 1H), 6.46 (d, J = 8.3 Hz, 1H), 4.01–
3.94 (m, 5H), 3.86 (brt, 1H), 3.76–3.63 (m, 4H), 3.60–3.55
(m, 2H), 3.53–3.49 (m, 2H), 3.47–3.42 (m, 8H), 2.60 (dd,
J = 13.4, 4.7 Hz, 1H), 2.50 (dd, J = 13.8, 4.5 Hz, 1H), 2.30
(dd, J = 13.5, 6.0 Hz, 1H), 1.94 (dd, J = 13.5, 6.9 Hz, 1H).
13C NMR (126 MHz, DMSO-d6) δ 166.7, 166.5, 148.3, 147.4,
136.9, 130.3, 129.3, 128.6, 127.0, 122.4, 115.2, 113.6, 70.3,
70.2, 69.1, 68.6, 68.4, 56.0, 55.8. HRMS (ESI) m/z calcd for
C28H40N3O8 (M + NH4)+: 546.2810, found 546.3151. HPLC
(Retention time, purity): 23.79 min, 82%.
4.2.5.12. cyclo[L-DOPA(18-C-6)-L-DOPA(18-C-6)]
(32). Pale yellow powder; 40% yield. mp 64 °C.
[ꢀ]2D2 − 58.0° (c 0.1 in MeOH). ATR (ZnSe) 2922, 2856,
1
1667, 1515, 1454, 1265, 1123, 1051, 946 cm−1. H NMR
(500 MHz, DMSO-d6) δ 7.84 (s, 2H), 6.87 (d, J = 8.2 Hz,
2H), 6.62 (s, 2H), 6.52 (d, J = 8.0 Hz, 2H), 4.03–4.01 (m,
8H), 3.93 (brt, 2H), 3.78–3.74 (m, 4H), 3.71–3.68 (m, 4H),
3.62–3.58 (m, 4H), 3.57–3.53 (m, 8H), 3.53–3.49 (m, 12H),
2.60 (dd, J = 13.6, 4.3 Hz, 2H), 2.09 (dd, J = 13.5, 6.7 Hz,
2H). 13C NMR (126 MHz, DMSO-d6) δ 166.7, 148.5, 147.5,
129.5, 122.5, 115.5, 113.8, 70.3, 70.2, 70.0, 69.2, 68.8, 68.7,
56.0. HRMS (ESI) m/z calcd for C38H58N3O14 (M + NH4)+:
780.3913, found 780.3917. HPLC (Retention time, purity):
22.77 min, 89%.
4.2.5.9. cyclo[L-DOPA(15-C-5)-L-DOPA(15-C-5)](22)
(29). White powder, 72% yield. mp 116 °C. [ꢀ]2D2 − 28.0°
(c 0.1 in MeOH). ATR (ZnSe) 3177, 3052, 2918, 2855, 1671,
1513, 1450, 1260, 1119 cm−1. 1H NMR (500 MHz, DMSO-d6)
δ 7.86 (d, J = 2.2 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.62 (d,
J = 1.7 Hz, 2H), 6.52 (dd, J = 8.1, 2.0 Hz, 2H), 4.01–3.97 (m,
8H), 3.94–3.92 (m, 2H), 3.77–3.69 (m, 8H), 3.61–3.54 (m,
16H), 2.59 (dd, J = 13.5, 4.0 Hz, 2H), 2.09 (d, J = 13.6, 6.6 Hz,
2H). 13C NMR (126 MHz, DMSO-d6) δ 166.7, 148.9, 147.9,
122.7, 116.0, 114.5, 70.9, 70.8, 70.3, 69.3, 68.9, 56.0. HRMS
(ESI) m/z calcd for C34H47N2O12 (M + H)+: 675.3124, found
675.3123. HPLC (Retention time, %): 19.36 min, purity
88%.
4.2.5.13. cyclo[L-DOPA(18-C-6)-L-DOPA(21-C-7)]
(33). Yellow gummy oil, 63% yield. [ꢀ]2D2 − 41.4° (c 0.1 in
MeOH). ATR (ZnSe) 3177, 3051, 2920, 2853, 1668, 1518,
1
1452, 1259, 1119 cm−1. H NMR (500 MHz, DMSO-d6) δ
7.85 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 6.86 (s,
1H), 6.85 (s, 1H), 6.62 (d, J = 1.8 Hz, 2H), 6.52–6.50 (m, 2H),
4.03–4.00 (m, 8H), 3.93–3.91 (m, 2H), 3.75–3.68 (m, 12H),
3.60–3.49 (m, 24H), 2.60 (dd, J = 14.1, 4.7 Hz, 2H), 2.08 (dd,
J = 13.5, 6.8 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.7,
162.8, 148.5, 148.4, 147.5, 147.4, 129.6, 129.5, 122.6, 122.5,
115.7, 115.5, 114.0, 113.8, 70.7, 70.7, 70.6, 70.3, 70.3, 70.2,
70.2, 69.4, 69.2, 68.9, 68.7, 68.7, 68.6. HRMS (ESI) m/z calcd
for C40H58N2NaO15 (M + Na)+: 829.3729, found 829.4056.
HPLC (Retention time, %): 21.68 min, purity 93%.
4.2.5.10. cyclo[L-DOPA(15-C-5)-L-DOPA(18-C-6)]
(30). Brown oil, 59% yield. [ꢀ]2D2 − 47.4° (c 0.1 in MeOH).
ATR (ZnSe) 3181, 3050, 2930, 2850, 1669, 1510, 1454,
1
1259, 1121 cm−1. H NMR (500 MHz, DMSO-d6) δ 7.87 (d,
J = 2.6 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 6.87 (d, J = 2.1 Hz,
1H), 6.86 (d, J = 2.2 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 6.61 (d,
J = 2.0 Hz, 1H), 6.53 (dd, J = 8.1, 2.0 Hz, 1H), 6.51 (dd, J = 8.2,
2.0 Hz, 1H), 4.03–3.98 (m, 10H), 3.76–3.68 (m, 8H), 3.60–
3.50 (m, 20H), 2.61–2.58 (m, 2H), 2.15 (dd, J = 13.5, 6.6 Hz,
1H), 2.03 (dd, J = 12.8, 6.0 Hz, 1H). 13C NMR (126 MHz,
DMSO-d6) δ 166.7, 162.8, 148.9, 148.4, 147.9, 147.5, 129.7,
129.5, 122.7, 122.5, 116.1, 115.4, 114.5, 113.8, 70.9, 70.8,
70.3, 70.3, 70.2, 70.2, 69.3, 69.2, 68.9, 68.7, 68.5, 56.0. HRMS
4.2.5.14. cyclo-bis[L-DOPA(21-C-7)](34). Orange
gummy oil, 50% yield. [ꢀ]2D2 − 53.4° (c 0.1 in MeOH).
ATR (ZnSe) 3179, 3050, 2919, 2852, 1666, 1517, 1454,
1
1262, 1122 cm−1. H NMR (500 MHz, DMSO-d6) 7.84 (d,

SUPRAMOLECULAR CHEMISTRY
11
J = 2.6 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 6.63 Hz,
2H), 6.52 (dd, J = 8.2, 2.0 Hz, 2H), 4.04–4.00 (m, 8H), 3.93
(brt, 2H), 3.76–3.68 (m, 10H), 3.62–3.60 (m, 4H), 3.56–3.54
(m, 8H), 3.52–3.48 (m, 18H), 2.60 (dd, J = 13.7, 4.5 Hz,
2H), 2.09 (dd, J = 13.6, 6.7 Hz, 2H). 13C NMR (126 MHz,
DMSO-d6) δ 166.7, 148.4, 147.7, 129.6, 122.6, 115.7, 114.0,
70.7, 70.3, 70.3, 69.4, 68.9, 68.7, 56.0. HRMS (ESI) m/z calcd
for C42H62N2NaO16 (M + Na)+: 873.3992, found 873.3967.
HPLC (Retention time, %): 21.89 min, purity 89%.
4.3.4. trans-(2R,3S)-2,3-epoxy-3-phenyl-1-(4-
fluorophenyl)propan-1-one (10,35,38) (36d)
The ee of epoxide 36d was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 18.95 min, tR major (2R,3S)
= 20.89 min.
4.3.5. trans-(2R,3S)-2,3-epoxy-1-(4-methylphenyl)-3-
(4-fluorophenyl)propan-1-one (10,35,39) (36e)
The ee of epoxide 36e was determined by HPLC analy-
sis using a Chiralcel AD-H column (0.25 cm × 0.46 cm
ID), conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 38.75 min, tR major (2R,3S)
= 42.07 min.
4.3. General procedure for epoxidation of
unsaturated ketones
The catalyst 21 (0.005 mmol, 0.05 equiv.) was added to
a solution of enone (0.1 mmol) in 0.3 mL of hexanes and
stirred at room temperature for 30 min. Then, 0.2 mL of a
solution of 8% LiOH (m/v) in 30% H2O2 (w/w) was added
and the mixture was stirred at room temperature for
48 h. Twenty-five microliter of H2O2 30% were added to
the solution after 24 h. The conversion and the enantio-
meric excess of the corresponding epoxide were deter-
mined by chiral HPLC using a Hewlett Packard series 1050
instrument. Each epoxidation reaction was duplicated and
the reported results correspond to the mean of the two
experiments (conversions and enantiomeric excesses).
The absolute configuration of epoxides 36a–36k was
determined by comparison of the HPLC retention times
and the elution order of the corresponding epoxides with
literature values.
4.3.6. trans-(2R,3S)-Epoxy-3-(4-nitrophenyl)-1-
phenyl-1-propan-1-one (10,34,35) (36f)
The ee of epoxide 36g was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 61.98 min, tR major (2R,3S)
= 67.98 min.
4.3.7. trans-(2R,3S)-Epoxy-3-(3-nitrophenyl)-1-
phenyl-1-propan-1-one (10,35) (36g)
The ee of epoxide 36h was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 48.75 min, tR major (2R,3S)
= 55.02 min.
4.3.1. trans-(2R,3S)-Epoxy-1,3-diphenylpropan-1-one
(10,34,35) (36a)
4.3.8. trans-(2R,3S)-Epoxy-3-(2-nitrophenyl)-1-
phenyl-1-propan-1-one (10,35) (36h)
The ee of epoxide 36i was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR major (2R,3S) = 44.55 min, tR minor (2S,3R)
= 50.27 min.
The ee of epoxide 36a was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 16.99 min, tR major (2R,3S)
= 18.70 min.
4.3.2. trans-(2R,3S)-Epoxy-3-(4-chlorophenyl)-1-
phenyl-1-propan-1-one (10,35,36) (36b)
4.3.9. trans-(2R,3S)-Epoxy-3-(4-methoxyphenyl)-1-
phenyl-1-propan-1-one (10,35,36) (36i)
The ee of epoxide 36b was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 18.32 min, tR major (2R,3S)
= 19.74 min.
The ee of epoxide 36j was determined by HPLC analysis
using a Chiralcel OD-H column (0.25 cm × 0.46 cm ID),
conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 22.59 min, tR major (2R,3S)
= 25.07 min.
4.3.10. trans-(2R,3S)-Epoxy-3-(naphthyl)-1-phenyl-1-
propan-1-one (35,40) (36j)
4.3.3. trans-(2R,3S)-Epoxy-3-(4-fluorophenyl)-1-
phenyl-1-propan-1-one (10,35,37) (36c)
The ee of epoxide 36k was determined by HPLC analy-
sis using a Chiralcel AD-H column (0.25 cm × 0.46 cm
ID), conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 27.69 min, tR major (2R,3S)
= 32.15 min.
The ee of epoxide 36c was determined by HPLC analy-
sis using a Chiralcel AD-H column (0.25 cm × 0.46 cm
ID), conditions: λ 254 nm, hexanes/i-PrOH 95/5, flow rate
0.6 mL/min, tR minor (2S,3R) = 33.00 min, tR major (2R,3S)
= 35.73 min.

12
C. BÉRUBÉ AND N. VOYER
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The authors thank François Otis for his technical assistance with
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Disclosure statement
No potential conflict of interest was reported by the authors.
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Funding
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