Interfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides

Article abstract of DOI:10.1080/10610278.2016.1236197

We synthesised a library of cis- and trans-cyclic dipeptides and evaluated their efficacy as catalysts in the asymmetric Weitz-Scheffer epoxidation of trans-chalcone. A thorough investigation relying on structure-activity studies and computational studies provided insights into the mechanism of the process. Our results revealed some structural features required for efficient conversion and for introduction of chirality into the product. The cyclic dipeptide acts as a catalyst by templating a supramolecular arrangement at the aqueous-organic interface required for efficient transformations to occur. Among all cyclic dipeptides investigated, cyclo(Leu-Leu) was the most efficient supramolecular catalyst.

Full text of DOI:10.1080/10610278.2016.1236197

Supramolecular Chemistry
ISSN: 1061-0278 (Print) 1029-0478 (Online) Journal homepage: http://www.tandfonline.com/loi/gsch20
Interfacial supramolecular biomimetic epoxidation
catalysed by cyclic dipeptides
Christopher Bérubé, Xavier Barbeau, Sébastien Cardinal, Pierre-Luc
Boudreault, Corinne Bouchard, Nicolas Delcey, Patrick Lagüe & Normand
Voyer
To cite this article: Christopher Bérubé, Xavier Barbeau, Sébastien Cardinal, Pierre-
Luc Boudreault, Corinne Bouchard, Nicolas Delcey, Patrick Lagüe & Normand Voyer
(2016): Interfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides,
Supramolecular Chemistry, DOI: 10.1080/10610278.2016.1236197
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Date: 11 November 2016, At: 01:28

Supramolecular chemiStry, 2016
http://dx.doi.org/10.1080/10610278.2016.1236197
Interfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides
Christopher Bérubéa, Xavier Barbeaub, Sébastien Cardinala, Pierre-Luc Boudreaulta, Corinne Boucharda, Nicolas
Delceya, Patrick Lagüeb and Normand Voyera
b
aDépartement de chimie and proteo, université laval, Québec, canada; Département de Biochimie, microbiologie et Bioinformatique and
protÉo, université laval, Québec, canada
ABSTRACT
ARTICLE HISTORY
received 3 august 2016
accepted 7 September 2016
We synthesised a library of cis- and trans-cyclic dipeptides and evaluated their efficacy as catalysts
in the asymmetric Weitz-Scheffer epoxidation of trans-chalcone. A thorough investigation relying
on structure-activity studies and computational studies provided insights into the mechanism
of the process. Our results revealed some structural features required for efficient conversion
and for introduction of chirality into the product. The cyclic dipeptide acts as a catalyst by
templating a supramolecular arrangement at the aqueous-organic interface required for efficient
transformations to occur. Among all cyclic dipeptides investigated, cyclo(Leu-Leu) was the most
efficient supramolecular catalyst.
KEYWORDS
cyclic dipeptides; interfacial
epoxidation; supramolecular
catalysis
addition, Cis CDPs create a concave cavity that could serve
as a receptor to bind a substrate in a chiral environment.
Along those lines, we recently reported the asymmet-
ric epoxidation of α,β-unsaturated ketones in a triphasic
system using insoluble CDPs located at the interface.
Asymmetric epoxidation of a model substrate trans-
chalcone (1) into epoxychalcone (2) using a catalytic
amount of cyclo[Leu-Leu] (3a and 3b) led to 70% ee as
described in Figure 1 (14). Interestingly, only a modest 15%
ee was obtained when the linear L-Leucine dipeptide was
used (15).
We wanted to develop more efficient supramolecular
catalysts for asymmetric biomimetic epoxidation of a vari-
ety of α,β-unsaturated ketones, and to gain insights into the
mechanism of the process. Therefore, we have prepared a
library of CDPs and investigated their properties as supra-
molecular chiral catalysts. We also report modelling stud-
ies that aim at identifying the origin of the supramolecular
catalysis. Our studies revealed some important supramolec-
ular and structural features required for efficient conversion
and more importantly, to create chiral products.
1. Introduction
Numerous reports describe the use of chiral receptors as
chirality sources in chemical transformations. Although
some efficient processes have been developed, most used
the chiral receptors in stoichiometric amounts in organic
solvents and the efficiency, in terms of yield, rate and enan-
tioselectivity, is often moderate. The possibility of using
chiral receptors as organocatalysts in greener solvents is
highly desirable and has attracted considerable interest
recently (1–4).
Notably, some supramolecular catalysts have been used
successfully in aqueous media (5). Among those, cyclic
dipeptides (CDPs) (which are 2,5-diketopiperazines), form
supramolecular structures that could be useful in asym-
metric catalysis (6–11). These compounds have well-ori-
ented hydrogen bond donors and acceptors through their
cis-amide functionality. Thus, CDPs form highly ordered
supramolecular structures such as linear one-dimensional
(1-D) hydrogen-bonded tapes and hydrogen-bonded
dimers and multimers. Their properties could be exploited
for efficient supramolecular chiral catalysis (12, 13). In
CONTACT Normand Voyer
normand.voyer@chm.ulaval.ca
Supplemental data for this article can be accessed here. [http://dx.doi.org/10.1080/10610278.2016.1236197]
© 2016 informa uK limited, trading as taylor & Francis Group

2
C. BéruBé eT AL.
Figure 1. catalyst rigidity effect in the asymmetric epoxidation of 1.
Figure 2. Synthetic strategy towards cDps.
to high-purity CDPs 3–35. using the synthetic procedure
described here, we successfully synthesised CDPs with a
variety of chiral cis (Figures 3 and 4) and trans (Figure 5) side
chains. Analogues with isopropyl, benzyl, dibenzyl, ali-
phatic, benzyloxymethyl groups and tricyclic derivatives
have been prepared with high yields (>90%). A total of
2. Results and discussion
2.1. Cyclic dipeptides synthesis
We synthesised a library of cyclic dipeptides with a variety
of substituents and stereochemistries, by taking advan-
tage of the availability of natural and synthetic amino acids
to be chiral synthons. This library will facilitate the study
of the structural features required for efficient conversion
and enantioselectivity. Our synthetic procedure involves
the condensation of two N-Boc amino acids using oxime
resin (16, 17) and standard peptide solid-phase synthetic
strategies (Figure 2) (18).
58 CDPs were prepared and characterised by 1H NMr, 13
C
NMr and mass spectrometry analyses. The procedure is
robust and efficient, allowing the quick preparation
of CDPs with purity sufficient to be used as-is, even on
larger scales.
Briefly, the first amino acid was coupled for three hours
using diisopropylcarbodiimide (DIC) as coupling reagent.
The N-Boc protecting group was removed using a mix-
ture of 1:1 trifluoroacetic acid (TFA)/dichloromethane,
while the second amino acid was activated with hydroxy-
benzotriazole (HOBt) and (2-(6-Chloro-1H-benzotriazole-
1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate
(HBTu). After deprotection, the linear dipeptide was
simultaneously cyclised and cleaved from the resin in the
presence of diisopropylethylamine (DIeA; 2.5 equiv) and
acetic acid (AcOH; 5 equiv) in dichloromethane, leading
2.2. Evaluation of CDPs efficacy in the epoxidation
of trans-chalcone
2.2.1. cis-(L,L) CDPs
As in a preliminary study (14), we chose trans-chalcone
1 as a model substrate for the present investigation. We
used optimised conditions: 25% sodium hydroxide (NaOH)
in hydrogen peroxide (30% H2O2) as an oxidant system,
and 10 mol% of CDPs for 48 h at room temperature with
hexanes as the organic phase (14). To evaluate the impor-
tance of the structure of CDPs on their catalytic efficiency,

SuPrAMOLeCuLAr CHeMISTry
3
Figure 3. cis-(l,l) cDps synthesised.
Figure 4. cis-(D,D) cDps synthesised.

4
C. BéruBé eT AL.
Figure 5. trans-(D,l) cDps synthesised.
Table 1. catalytic efficiency of cis-(l,l) cDp in the triphasic epoxidation of trans-chalcone 1.
entry
Supramolecular catalyst
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
cyclo[l-leu-l-leu]3a
cyclo[l-leu-l-ala] 4a
33
22
20
19
26
18
34
26
30
44
22
14
22
24
18
25
23
99
13
24
23
20
21
22
12
24
22
24
19
22
18
22
18
70
19
6
9
0
9
0
50
0
28
5
0
0
22
0
0
15
0
0
0
0
5
0
6
0
5
0
9
0
0
0
13
0
cyclo[l-leu-l-Val] 5a
cyclo[l-leu-l-phe] 6a
cyclo[l-leu-l-phe(No2)] 7a
cyclo[l-leu-l-Ser(Bzl)] 8a
cyclo[l-leu-l-tyr(Bzl)] 9a
cyclo[l-leu-l-pro] 10a
9
cyclo[l-leu-l-trp(cho)] 11a
cyclo[l-leu-l-arg(No2)] 12a
cyclo[l-phe-l-ala] 13a
cyclo[l-phe-l-Val] 14a
cyclo[l-phe-l-Ser(Bzl) 15a
cyclo[l-phe-l-lys(Z)] 16a
cyclo[l-tyr(Bzl)-l-Val] 17a
cyclo[l-phe-l-trp(cho)] 18a
cyclo[l-phe-l-phe] 19a
cyclo[l-phe-l-phe(No2)] 20a
cyclo[l-tyr(Bzl)-l-phe] 21a
cyclo[l-tyr(Bzl)-l-phe(No2)] 22a
cyclo[l-ala-l-ala] 23a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
cyclo[l-Val-l-Val] 24a
cyclo[l-ile-l-ile] 25a
cyclo[l-Ser(Bzl)-l-Ser(Bzl)] 26a
cyclo[l-thr(Bzl)-l-thr(Bzl)] 27a
cyclo[l-Val-l-Ser(Bzl)] 28a
cyclo[l-ile-l-Ser(Bzl)] 29a
cyclo[l-ala-l-Gln] 30a
cyclo[l-pro-l-pro] 31a
cyclo[l-thz-l-thz] 32a
cyclo[Gly-l-leu] 33a
cyclo[Gly-l-phe] 34a
cyclo[Gly-l-Ser(Bzl)] 35a
we studied CDPs 3a-12a that possess at least one isobutyl
group (Table 1, entries 1–10). The model catalyst CDP 3a
led to 70% ee of (2R,3S)-epoxychalcone 2 (Table 1, entry
1). In all other cases, lower enantiomeric excesses were
obtained when the CDPs had other aliphatic side chains,
such as methyl (4a) and isopropyl (5a), which led to 22%
and 6% ee of (2R,3S)-epoxychalcone 2, respectively (Table
1, entries 2 and 3).

SuPrAMOLeCuLAr CHeMISTry
5
CDP 6a, with one benzyl side chain, provided 2 with
only 9% ee (Table 1, entry 4). Interestingly, using CDP 7a,
which has an electron-withdrawing nitro group in the
para position of the benzyl moiety of 6a, provided race-
mic epoxychalcone with a slight increase in the conversion
rate (Table 1, entry 5). using CDPs bearing benzyloxyme-
thyl (8a) and p-benzyloxybenzyl (9a) side chains led to 9%
ee and racemic epoxide 2, respectively (Table 1, entries
6 and 7). Good enantiomeric excess was obtained using
CDP 10a with a pyrrolidine side chain, with up to 50% ee
of (2R,3S)-epoxychalcone 2 (Table 1, entry 8). The 2-indolyl
carbaldehyde side chain CDP 11a led to the racemic prod-
uct (Table 1, entry 9). using the nitroguanidine substituent
of CDP 12a improved the conversion to 44% and the enan-
tiomeric excess up to 28% (Table 1, entry 10).
The results of these experiments demonstrate that
the two isobutyl side chains are the best combination
for higher yield and enantioselectivity. They also point
out that very subtle changes lead to significant drops
in efficiency. Clearly, the structure of the supramolecu-
lar complex relevant to catalysis involves more than just
hydrophobic interactions at the interface and is not a sim-
ple phase transfer catalysis.
In a second series, we evaluated CDPs 13a–18a with an
isobutyl and a more hindered β-phenyl side chain (Table
1, entries 11–16). Catalyst 13a, with a benzyl and a methyl
side chain, provided (2R,3S)-epoxychalcone 2 with a low
5% ee (Table 1, entry 11). The analogues with one benzyl
group and either an isopropyl (14a) or a benzyloxyme-
thyl moiety (15a) led to racemic epoxychalcone in both
cases (Table 1, entries 12 and 13). However, 16a with a Cbz
protected aminobutyl side chain was efficient to induce
chirality to (2R,3S)-epoxychalcone 2 up to 22% ee (Table
1, entry 14). On the other hand, CDP (17a) with a p-ben-
zyloxybenzyl and an isopropyl chiral side chains and CDP
18a substituted by a benzyl and a 2-indolyl carbaldehyde
led to racemic epoxide (Table 1, entries 15 and 16).
We also investigated CDPs 19a–22a, which have two
benzyl side chains with different functional groups in
the para position. CDP 19a provided 15% ee of (2R,3S)-
epoxychalcone 2 (Table 1, entry 17). Compared to 19a,
using CDP 20a with a p-nitro group on one phenyl moi-
ety dramatically enhanced the reaction rate leading
to quantitative conversion of racemic epoxychalcone
2 (Table 1, entry 18). In this case, the presence of the
electron-withdrawing group seems to activate the sub-
strate trans-chalcone 1. Perhaps the nitro group on 20a
Considering previous results obtained with CDP 20a, it
was assumed that introducing a p-nitrobenzyl group in
22a should enhance the reaction rate and induce chirality
in the process. However, we obtained a low conversion
rate and only 9% ee of (2R,3S)-epoxychalcone 2 (Table 1,
entry 20).
Further investigations were performed with CDPs
that have two identical aliphatic side chains such as
methyl (23a), isopropyl (24a) and sec-butyl (25a) (Table
1, entries 21–23). In all three cases, racemic epoxychal-
cone 2 was obtained in roughly 20% yields. These results
are surprising, especially in the case of CDP 25a, which
has two sec-butyl side chains. Indeed, we observed a
complete loss of enantioselectivity compared to CDP 3a
having two isobutyl groups from L-Leucine. Hence,
it appears that β-substitutions on the side chains
significantly affect the formation of a stable supramolec-
ular complex between the CDP and the substrate. In the
case of 23a with a two methyl side chains, it is possible that
the lower steric hindrance created by the CDP allows the
formation of multiple supramolecular complexes yielding
racemic epoxides.
We also evaluated CDPs with one or two benzyloxyme-
thyl group side chains (26a–29a) (Table 1, entries 24–27).
Only CDPs 26a and 28a produced epoxides with low
enantiomeric excesses (6 and 5%, respectively) (Table 1,
entries 24 and 26). Again, for a CDP with a β-substitution
on the side chain, 27a, a very low conversion and racemic
epoxide 2 were obtained. These results further support the
importance of the β-position for functional and efficient
CDP catalysts. Introducing a hydrogen bond donor group
into a CDP (30a) provided (2R,3S)-epoxychalcone 2 with
only 9% ee (Table 1, entry 28). This result illustrates that
the CDP side chains are involved in the enantioselectivity
through steric interactions rather than through hydrogen
bonding. On the other hand, tricyclic CDP 31a (Table 1,
entry 29) and its thio derivative 32a (Table 1, entry 30) led
to racemic epoxychalcone 2 in both cases.
Finally, with 33a–35a we verified the efficiency of CDPs
with only chiral side chains on the cyclic core (Table 1,
entries 31–33). Interestingly, CDP with one isobutyl 33a
provided racemic epoxychalcone. The same result was
obtained using 35a with a benzyloxymethyl group. From
that series, only CDP 34a with a benzyl side chain led to
low enantioselectivity (Table 1, entry 32).
In summary, these screening experiments showed
that using cis-(L,L) CDPs led to the (2R,3S)-epoxychalcone
enantiomer 2 in all cases. The best enantioselectivity was
observed with CDPs with at least one isobutyl (leucine)
side chain. Notably, the presence of a substituent at the
β-position is highly detrimental to the enantioselectivity
and efficiency. The best CDP catalyst 3a has a C2 symmetric
facilitates the formation of interfacial supramolecular com
-
plexes with 1, which renders it more electrophilic and in
close proximity to a hydroperoxide ion.
CDP with p-benzyloxybenzyl and benzyl substituents
(21a) led to racemic epoxychalcone (Table 1, entry 19).

6
C. BéruBé eT AL.
Table 2. catalytic efficiency of cis-(D,D) cDp in the triphasic epoxidation of trans-chalcone 1.
entry
Supramolecular catalyst
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
cyclo[D-leu-D-leu] 3b
cyclo[D-leu-D-ala] 4b
35
23
17
24
21
30
20
17
17
19
21
17
24
23
22
20
18
70
17
6
9
8
0
5
0
0
0
10
0
0
5
5
5
0
cyclo[D-leu-D-Val] 5b
cyclo[D-leu-D-phe] 6b
cyclo[D-leu-D-Ser(Bzl)] 8b
cyclo[D-leu-D-tyr(Bzl)] 9b
cyclo[D-phe-D-ala] 13b
cyclo[D-phe-D-Val] 14b
cyclo[D-phe-D-Ser(Bzl)] 15b
cyclo[D-tyr(Bzl)-D-Val] 17b
cyclo[D-phe-D-phe] 19b
cyclo[D-tyr(Bzl)-D-phe] 121b
cyclo[D-ala-D-ala] 23b
cyclo[D-Val-D-Val] 24b
9
10
11
12
13
14
15
16
17
cyclo[D-Ser(Bzl)-D-Ser(Bzl)] 26b
cyclo[D-Val-D-Ser(Bzl)] 28b
cyclo[D-pro-D-pro] 31b
structure. However, CDPs 23a–25a, also C2 symmetric, are
inefficient.
2.2.3. trans-(L,D) CDPs
We continued our investigation by evaluating the effi-
ciency of trans-(L,D) CDPs in the asymmetric epoxidation
of 1. Thus, CDPs 3c, 5c, 10c, 15c, 19c, 23c, 26c, and 31c
were prepared starting from the corresponding D and
L-amino acids. results of their efficacy are reported inTable
3. For CDPs 3c, 19c, 23c, 26c, and 31c, having the same
side chain substituents with opposite configuration led as
expected to racemic epoxychalcone 2 due to their achiral
structure (Table 3, entries 1, 5–8). CDP 5c, which has an
isobutyl and an isopropyl side chains facilitated the forma-
tion of (2R,3S)-epoxychalcone 2 with 5% ee, although with
a very low 13% conversion (Table 3, entry 2). Interestingly,
trans CDP 10c provided (2R,3S)-2 with 23% ee, the same
enantiomer obtained with its cis analogue 10a, albeit less
efficiently (50% ee of (2R,3S)-2, Table 1, entry 3). This result
demonstrates well that spatial orientation of side chains
significantly impacts the stereochemical outcome of the
process. CDP 15c provided (2R,3S)-epoxychalcone 2 with
14% ee (Table 3, entry 4), an improvement as compared
with its L,L analogue 15a (Table 1, entry 13).
Overall, the above results illustrate that several param-
eters influence the formation of well-defined supra-
molecular complexes required for obtaining efficient
enantioselective epoxidation of trans-chalcone (1) in high
yields.
2.2.2. cis-(D,D) CDPs
To learn more about the mechanism and with the objec-
tive to access both enantiomers of epoxychalcone 2, we
evaluated cis-(D,D) CDPs in the asymmetric epoxidation of
trans-chalcone 1. For comparison with the cis-(L,L) CDPs
described in Section 2.2.1, we synthesised the same CDPs
starting from D-amino acids. results are reported in Table
2. When tested in the same process under the same con-
ditions, CDPs that led to racemic epoxychalcone 2 with
the L,L series, led to racemic epoxychalcone 2 as expected
(Table 2, entries 6, 8–10, 12–13, 17). However, CDPs that
induced chirality in the asymmetric epoxydation of 1 were
also effective catalysts, leading essentially to the same
enantiomeric excesses, but with opposite chirality, pro-
viding (2S,3R)-epoxychalcone 2.
Overall, CDPs with isobutyl side chains led to
higher enantioselectivities than those with one or two

SuPrAMOLeCuLAr CHeMISTry
7
Table 3. catalytic efficiency of trans-(D,l) cDp in the triphasic epoxidation of trans-chalcone 1.
entry
Supramolecular catalyst
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
cyclo[D-leu-l-leu] 3c
cyclo[D-Val-l-leu] 5c
16
13
23
25
22
24
20
15
0
5 (2R,3S)
cyclo[D-pro-l-leu] 5c
25 (2R,3S)
cyclo[D-Ser(Bzl)-l-phe] 15c
cyclo[D-phe-l-phe] 19c
cyclo[D-ala-l-ala] 23c
cyclo[D-Ser(Bzl)-l-Ser(Bzl)] 26c
cyclo[D-pro-l-pro] 31c
14 (2R,3S)
0
0
0
0
O
O
a,b
N
NH
N
HN
85%
O
O
36
3a
84% c,d
e
NH
N
N
HN
74%
37
38
a) NaH (3.0 equiv), DMF, 0 oC, 0.5 h. b) MeI (5.0 equiv), r.t., 3h. c) LiAlH4 (12.0 equiv), THF, 0 oC to
reflux, 48h d) Na2SO4 10 H2O, 0 oC to reflux, 0.5 h. e) HCOOH (50 equiv), HCOH (33 equiv), 70 oC, 0.5h
al
Figure 6. (colour online) Functional groups modification of cDp 3a.
aromatic side chains. This phenomenon, observed
with leucine analogues, could be due to their ability
to create more defined supramolecular catalytic
superstructures at the interface. This is supported by
the fact that their concave shape formed with cis sub-
stituents is essential for reactivity and introduction of
chirality.
demonstrating the importance of the amide moiety to cre-
ate supramolecular catalytic structures by hydrogen bond-
ing. This is further supported by the results obtained with
CDP 10a (with one secondary amide), which catalysed the
formation of epoxide 2 with up to 50% ee. Substituting a
leucine for a glycine in CDP leads to a significant drop in
enantioselectivity.
In addition, results with the tricyclic CDP 31a with-
out any NH groups led to racemic epoxychalcone 2,
Thus, it appears that two chiral side chains are essential
to efficiently induce enantioselectivity.

8
C. BéruBé eT AL.
dynamic (MD) simulations. For this purpose, five 45-ns
trajectories were recorded for each of CDP 3a and trans-
chalcone 1 in a water/hexane system. The results demon-
strate that both molecules are located at the interface and
adopt a limited range of conformations. Moreover, the two
entities showed only 10% of non-specific contacts, sug-
gesting that a sodium cation and/or a hydroperoxide anion
are essential for the formation of a well-defined supramo-
lecular complex.
Figure 7. (colour online) Frequency distributions of the
SaSa(hexane)/SaSa(water) ratio for cDp 3a (blue) and trans-
chalcone 1 (red). Frequencies for each molecule sums to 100%.
a ratio of one denotes an equal exposure to hexane and water.
To further characterise the location and orientation of
both CDP 3a and trans-chalcone 1 at the interface, we used
the trajectories to calculate the solvent-accessible surface
area (SASA) exposed by each molecule to each solvent.
The ratio, SASA (hexane)/SASA(water), reveals the location
respective to the interface. A ratio of 1 represents an inter-
facial positioning where the molecular surface is in equal
contact with hexane and water, while a ratio higher than
1 indicates a greater exposure to hexane and a ratio lower
than 1, a greater exposure to water. Figure 7 presents the
frequency distribution of the SASA (hexane)/SASA (water)
ratio for both molecules as calculated from the trajecto-
ries. The distributions show that both CDP 3a and trans-
chalcone 1 are located at the interface with a slightly higher
exposure to hexane, in agreement with the predominance
of non-polar functions present on each molecule. For CDP
3a, the isobutyl side chains are in the hexane phase and the
polar CDP ring is in the water phase (Figure 8). For trans-
chalcone 1, the preferred conformation is roughly planar at
the interface with the carbonyl in the water phase. The inter-
facial location of CDP 3a allows this molecule to position its
hydrophilic functional groups, such as carbonyl and amide,
in water while keeping the nonpolar functional groups, the
isobutyl side chains, in contact with hexane (Figure 8).
Then, we measured the orientation of CDP 3a and
trans-chalcone 1 with respect to the interface obtained
2.2.4. CDP structure modifications
To further decipher the mechanism of the supramolecular
process, we prepared structural analogues of the most effi-
cient CDP 3a (Figure 6) by modifying the NH and carbonyls
groups. First, we used sodium hydride and methyl iodide
to produce the N-methylated CDP 36, with no hydrogen
donor groups (19). We prepared the 14-piperazine 37
without hydrogen bond acceptor groups from 3a with
lithium aluminium hydride (LiAlH4). Finally, we prepared
N,N-dimethylpiperazine 38, which lacks both hydrogen
bond donors and acceptors (Figure 6) (20). Interestingly,
using 36–38 in the process led to racemic epoxychalcone
2 with conversions near background reaction (<15%), con-
firming the results reported above and further supporting
the necessity of amide moieties for the formation of effi-
cient supramolecular catalytic complexes.
2.2.5. Mechanistic investigations using
computational approaches
With the experimental results in hand and with the objec-
tive to elucidate the mechanism of this novel triphasic
asymmetric epoxidation of acyclic enones, we performed
thorough computational studies. First, the location and
orientation of CDP 3a and trans-chalcone 1 at the water/
hexane interface were investigated using molecular
����⃗
from the simulations. We used one vector (V1) for CDP 3a
����⃗
����⃗
and two vectors (V2 and V3) for trans-chalcone 1. Figure 8
Figure 8. (colour online) orientation of cDp 3a (left) and trans-chalcone 1 (right) with respect to the interface. orientation is expressed as
���⃗ ���⃗
���⃗
a distribution of angle Θ between the Z axis (normal of the interface) and each vectorV1, V2 and V3. Frequency for distribution profiles
sums to 100%.

SuPrAMOLeCuLAr CHeMISTry
9
presents the angular deviation of these vectors from the
normal of the interface (defined as Z axis). The V1 vec-
mimic the interfacial positioning. The sodium hydrop-
eroxide anion was inserted in the middle at 2.3 Å (21)
between the sodium cation, the CDP 3a carbonyl and the
trans-chalcone 1 carbonyl. An arbitrary distance of 2.5 Å
and an angle of 107° were set to respect the Dunitz angle
(22, 23) for nucleophilic attack between the hydroperoxide
nucleophilic oxygen and the enone’s reactive sp2 carbon
of trans-chalcone 1. Figure 9 presents the proposed model
for the functional supramolecular complex for CDP 3a and
trans-chalcone 1 resulting from energy minimisation. The
geometry of the model is in agreement with a nucleophilic
attack of the hydroperoxide anion on the chalcone enone.
Furthermore, the proposed model is consistent with the
orientation of hydrophilic and hydrophobic functional
groups at the hexane/water interfacial position.
����⃗
tor presents an angular distribution between 0° and 40°
with respect to the interfacial normal (Figure 8, left). This
result suggests that the diketopiperazine ring of CDP 3a
lies almost parallel to the interface, as depicted in Figure
8 (top left). It also suggests that the fluctuations around
this orientation are small, with the carbonyls going toward
����⃗
����⃗
the water phase. The angular distributions of V2 and V3
, presented in Figure 8 (right), indicate that the orienta-
tion of trans-chalcone 1 fluctuates more with respect to
the interfacial normal. With a maximum distribution of
����⃗
����⃗
~90° for V2, and ~0° for V3, the most visited orientation
of trans-chalcone 1 is almost parallel to the interface with
its carbonyl pointing into the water phase.
Because CDP 3a is located at the interface with a small
range of accessible orientations, the resulting supra-
molecular complex with a hydroperoxide anion and a
sodium cation would retain its structure at the interface.
Asymmetric epoxidation would occur upon efficient col-
lision between this CDP 3a complex and trans-chalcone
1, also located at the interface with a planar orientation.
A reactive collision requires the trans-chalcone 1
carbonyl to interact with the sodium cation while hav-
ing the enone reactive carbon on the same side as the
hydroperoxide anion at a reactive distance as depicted in
Figure 9 (left). Because of its unsymmetrical shape, trans-
chalcone 1 can indiscriminately adopt two orientations
at the interface. While one is reactive, the second is not,
as shown in Figure 9 (right). With the latter orientation,
the trans-chalcone 1 carbonyl interacts with the sodium
cation, placing the enone’s reactive carbon on the oppo-
site side of the hydroperoxide anion, too far for reaction
to occur. Consequently, only one enantiomer results from
this supramolecular functional complex. The other enan-
tiomer comes from the background reaction without the
CDP intervention.
2.2.5.1. Interfacial supramolecular assembly mediating
enantioselective epoxidation. From experimental
results, the CDP amide groups are essential for reactivity,
both for their carbonyl (H-bond acceptor) or NH
(H-bond donor). It is also reasonable to assume that the
hydroperoxide anion tightly interacts with the sodium
cation. From MD simulations, the CDP 3a and trans-
chalcone 1 do not interact together, suggesting that
supramolecular complex formation is mediated by other
species. On the basis of this information, we propose
that the functional supramolecular complex involved in
the catalysis consists of a bidentate system, in which the
hydroperoxide anion and the sodium cation pair with the
complementary donor and acceptor amide functions of
the CDP. Then, trans-chalcone 1, with its carbonyl group,
interacts with the sodium cation. This latter interaction
allows the molecule to position the reactive enone
carbon close to the hydroperoxide (Figure 9).
To test this hypothesis, we built the following model.
First, based on the results from the simulations, CDP 3a
and trans-chalcone 1 were placed on the same plane to
Figure 9. (colour online) (Left) optimised supramolecular complex proposed as model for the enantioselective epoxidation of 1 catalysed
by cDp. cDp 3a (green), trans-chalcone 1 (cyan), hydroperoxyde are in sticks and sodium is represented as a sphere. only hydrogens
involved in polar interactions are represented. the polar interactions are identified with dashed yellow lines. a grey dashed line is
arbitrarily placed to represent the hexane/water interface. (Right) illustration of the productive and non-productive supramolecular
complexes.

10
C. BéruBé eT AL.
Figure 10. (colour online) comparison of the calculated models for functional supramolecular complex of cDp 3a and cDp 25a. (Left)
cDp 3a (green), cDp 25a (orange), trans-chalcone 1 (cyan) and hydroperoxide are in sticks, sodium is a sphere. only hydrogen involved in
polar interactions are represented. the polar interactions are identified with dashed yellow lines. a grey dashed line is arbitrarily placed
to represent the hexane/water interface. clash between the ethyl chain on beta carbon of cDp 25a (orange) with trans-chalcone 1 is
shown with orange lines. (Right) Superimposition of the optimised supramolecular complex obtained with cDp 3a in green and cDp 25a
in orange showing the two calculated position for 1, the orange structure is located in water.
2.2.5.2. Impact of substitution at beta carbon. Figure
10 (left) presents the superimposition of cyclo[L-Ile-L-Ile],
CDP 25a, over the proposed functional supramolecular
complex of CDP 3a. According to the calculated structure,
the ethyl chains on the beta carbon of CDP 25a would
clash with trans-chalcone 1. The optimisation of the CDP
25a supramolecular complex, as described in Section
2.2.5.1, resulted in a loose assembly. Figure 10 (right)
shows a superimposition of the CDP 3a (green) and CDP
25a (orange) optimised supramolecular complexes.
Considering the functional complex geometry proposed,
for CDP 25a to be positioned at the interface with the
hydroperoxide anion and sodium cation in the water
epoxide product. Depending on the side chain chirality of
the CDPs, both enantiomers could be obtained. Our results
showed that CDPs with their side chains in a cis relation-
ship have higher reactivity. reactivity was also influenced
by the nature of the side chains. The level of enantiose-
lectivity observed was highly variable, and seemed to rely
on many parameters. Computational studies provided
insights into the functional supramolecular interfacial
complex that led to high enantioselectivity. The model we
propose is consistent with the experimental data. On the
basis of the reported results, we are working to improve
the supramolecular catalytic efficiency of CDPs and to
apply the concepts to various important organic reactions.
phase, the trans-chalcone
1 would be positioned
completely in the water phase. This orientation is not
favourable in a hexane/water system. Consequently,
CDP 25a is not functional and only a 15% yield of 2 is
observed presumably originating from the background
reaction without any enantioselectivity.
4. Experimental
4.1. General information
Oxime resin, coupling reagents and N-Boc-protected
amino acids were purchased from Matrix Innovation
(Québec City, QC, Canada). resin with a substitution level
of 1.12 mmol/g of oxime group was used. All chemicals
were purchased from commercial sources and used
directly, unless indicated otherwise. Nuclear magnetic
resonance (NMr) spectra were recorded using Varian
Inova 400 MHz and NMr Agilent DD2 500 MHz spectrom-
eters. The coupling constants are reported in hertz (Hz).
Chemical shifts are reported in parts per million downfield
fromTMS. Splitting pattern sare designated as s (singlet), d
(doublet), dd (doublet of doublets), t (triplet), q (quartet),
brs (broad singlet), brt (broad triplet), brq (broad quadru-
plet) and m (multiplet). Mass spectra were obtained on
an Agilent 6210 LC Time of Flight Mass Spectrometer in
direct injection mode.
3. Conclusion
In summary, we have developed an efficient and rapid
solid-phase synthesis using natural and synthetic amino
acids to produce a library of CDPs. All of these CDPs were
tested in the enantioselective epoxidation of enones in a
two-phase system. Although most of the CDPs were not
efficient in facilitating the process, some were effective
catalysts for the epoxidation of trans-chalcone, leading to
up to 70% ee in a triphasic system where the insoluble
CDP resides at the water-hexane interface. The best CDP
in our experiments was one derived from L-leucine. Our
results revealed some structural features required for effi-
cient conversion, and more importantly, to create a chiral

SuPrAMOLeCuLAr CHeMISTry
11
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 then
added and the content was shaken for 24 h. Then the fil-
trate 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 remaining traces of DIeA. The mixture was stirred
for a few minutes and filtered. The filtrate was evaporated
to give compounds 3 to 35. Trituration in a minimum of
cold ether was performed and led to desired compounds
with satisfying purity.
4.2. Preparation of CDPs (3-35)
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 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 filtered under vacuum and the resin was
washed (DMF (3 × 100 mL), MeOH (3 × 100 mL), DMF
(3 × 100 mL), MeOH (3 × 100 mL)) and dried under reduced
pressure.
4.3. Spectral data of CDPs synthesised
4.3.1. (3S,6S)-3,6-diisobutylpiperazine-2,5-dione (14,
20) (3a)
4.2.2. Acetylation of unreacted sites on oxime resin
The resin was treated three times with DMF (3 × 50 mL).
A solution of 50% v/v DMF/acetic anhydride (80 mL) and
DIeA (1 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 × 100 mL),
MeOH (3 × 100 mL), DMF (3 × 100 mL), MeOH (3 × 100 mL))
and dried under reduced pressure.
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.81 (d,
J = 6.5 Hz, 6H), 0.84 (d, J = 6.5 Hz, 6H), 1.35–1.45 (m, 2H),
1.49–1.57 (m, 2H), 1.70–1.81 (m, 2H), 3.64–3.69 (m, 2H), 8.14
(s, 2H). 13C NMR (101 MHz, DMSO-d6): δ = 22.3, 23.7, 24.3,
44.3, 53.3, 169.2. HRMS (eSI-TOF, m/z): calcd for C12H23N2O2
(M+H)+ = 227.1754, found 227.1762.
4.3.2. (3R,6R)-3,6-diisobutylpiperazine-2,5-dione (14,
20) (3b)
4.2.3. Removal of the N-Boc protecting group
The resin was treated three times with CH2Cl2 (100 mL). A
50% v/v solution ofTFA 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 × 100 mL), MeOH (3 × 100 mL), DMF (3 × 100 mL),
MeOH (3 × 100 mL) and with a solution of 10% v/v DIeA
in CH2Cl2 (100 mL).
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.81 (d,
J = 6.5 Hz, 6H), 0.84 (d, J = 6.5 Hz, 6H), 1.35–1.45 (m, 2H),
1.49–1.57 (m, 2H), 1.70–1.81 (m, 2H), 3.64–3.69 (m, 2H), 8.14
(s, 2H). 13C-NMR (101 MHz, DMSO-d6): δ = 22.3, 23.7, 24.3,
44.3, 53.3, 169.2. HRMS (eSI-TOF, m/z): calcd for C12H23N2O2
(M+H) + = 227.1754, found 227.1764.
4.3.3. (3R,6S)-3,6-diisobutylpiperazine-2,5-dione (14,
20) (3c)
4.2.4. Coupling of the second N-Boc protected
α-amino acid
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.81
(d, J = 6.3 Hz, 6H), 0.83 (d, J = 6.3 Hz, 6H), 1.40–1.59 (m,
4H), 1.69–1.83 (m, 2H), 3.67–3.74 (m, 2H), 8.08 (s, 2H). 13C-
NMR (101 MHz, DMSO-d6): δ = 22.6, 23.5, 24.2, 42.0, 53.1,
169.4. HRMS (eSI-TOF, m/z): calcd for C12H23N2O2 (M+H)
+ = 227.1754, found 227.1762.
The amino acid (3.0 equiv) was dissolved in DMF in a
100 mL flask. The solution was cooled to 0 °C, then HBTu
(3.0 equiv) and HOBt (3.0 equiv) were added. The mixture
was poured into the peptide synthesis vessel in which the
resin has been 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 × 100 mL), MeOH (3 × 100 mL), DMF
(3 × 100 mL) and MeOH (3 × 100 mL)) and dried under
reduce pressure. The Kaiser ninhydrin test was performed
to monitor the efficiency of the coupling, and the coupling
procedure was repeated if needed.
4.3.4. (3S,6S)-3-isobutyl-6-methylpiperazine-2,5-
dione (24) (4a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.80 (d,
J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H), 1.21 (d, J = 7.1 Hz,
3H), 1.37–1.45 (m, 1H), 1.52–1.60 (m, 1H), 1.71–1.74 (m,
1H), 3.68–3.75 (m, 1H), 3.78–3.85 (m, 1H), 8.06 (s, 1H), 8.08
(s, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 20.2, 22.5, 23.6,
24.3, 43.2, 50.5, 53.2, 169.0, 169.5. HRMS (eSI-TOF, m/z):
calcd for C9H17N2O2 (M+H) + = 185.1245, found 185.1301.
4.2.5. Cyclisation/cleavage from the resin
First, N-Boc group was removed using procedure described
in (Section 4.2.3), but without the 10% v/v DIeA/CH2Cl2

12
C. BéruBé eT AL.
4.3.5. (3R,6R)-3-isobutyl-6-methylpiperazine-2,5-
dione (4b)
4.3.10. (3R,6R)-3-benzyl-6-isobutylpiperazine-2,5-
dione (6b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.80 (d,
J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H), 1.21 (d, J = 7.1 Hz,
3H), 1.37–1.45 (m, 1H), 1.52–1.60 (m, 1H), 1.71–1.74 (m,
1H), 3.68–3.75 (m, 1H), 3.78–3.85 (m, 1H), 8.06 (s, 1H),
808 (s, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 20.2, 22.5,
23.6, 24.3, 43.2, 50.5, 53.2, 169.0, 169.5. HRMS (eSI-TOF,
m/z): calcd for C9H17N2O2 (M+H)+ = 185.1245, found
185.1292.
1H-NMR (400 MHz, DMSO-d6): δ = 0.01–0.08 (m, 1H), 0.54
(d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H), 0.65–0.83 (m,
3H), 1.28–1.41 (m, 1H), 3.08 (dd, J = 13.6, 3.7 Hz, 1H), 3.38–
3.45 (m, 1H), 4.09–4.15 (m, 1H), 7.05–7.25 (m, 5H), 802 (s,
1H), 804 (s, 1H) 13C-NMR (101 MHz, DMSO-d6): δ = 22.0,
23.5, 23.5, 39.1, 44.3, 52.9, 56.1, 127.4, 128.7, 131.1, 136.7,
166.8, 168.1 HRMS (eSI-TOF, m/z): calcd for C15H21N2O2
(M+H)+ = 261.1598, found 261.1607.
4.3.6. (3S,6S)-3-isobutyl-6-isopropylpiperazine-2,5-
dione (24) (5a)
4.3.11. (3S,6S)-3-isobutyl-6-(4-nitrobenzyl)
piperazine-2,5-dione (7)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.79 (d,
J = 3.0 Hz, 3H), 0.80 (d, J = 3.0 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H), 0.89 (d, J = 6.8 Hz, 3H), 1.34–1.43 (m, 1H), 1.52–1.62
(m, 1H), 1.79–1.85 (m, 1H), 2.05–2.12 (m, 1H), 3.55–3.59 (m,
1H), 3.68–3.74 (m, 1H), 8.01 (s, 1H), 8.14 (s, 1H). 13C-NMR
(101 MHz, DMSO-d6): δ = 18.0, 19.4, 22.4, 23.8, 24.2, 32.1,
44.6, 53.0, 60.2, 167.5, 169.1. HRMS (eSI-TOF, m/z): calcd for
C11H21N2O2 (M+H)+ = 213.1598, found 213.1608.
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.16–0.25
(m, 1H), 0.48 (d, J = 6.5 Hz, 3H), 0.55 (d, J = 6.5 Hz, 3H), 0.76–
0.84 (m, 1H), 1.29–1.39 (m, 1H), 2.95 (dd, J = 12.9, 5.1 Hz,
1H), 3.21 (dd, J = 13.4, 4.0 Hz, 1H), 3.46–3.52 (m, 1H), 4.22–
4.26 (m, 1H), 7.37 (d, J = 8.4 Hz, 2H), 8.11–8.17 (m, 4H). 13C-
NMR (101 MHz, DMSO-d6): δ = 22.1, 23.3. 23.5, 38.7, 44.3,
52.8, 55.7, 123.7, 132.3, 145.3, 147.3, 166.4, 168.1. HRMS
(eSI-TOF, m/z): calcd for C15H20N2O4 (M+H)+ = 306.1448,
found 306.1456.
4.3.7. (3R,6R)-3-isobutyl-6-isopropylpiperazine-2,5-
dione (20) (5b)
4.3.12. (3S,6S)-3-(benzyloxymethyl)-6-
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.79 (d,
J = 3.0 Hz, 3H), 0.80 (d, J = 3.0 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H), 0.89 (d, J = 6.8 Hz, 3H), 1.34–1.43 (m, 1H), 1.52–1.62
(m, 1H), 1.79–1.85 (m, 1H), 2.05–2.12 (m, 1H), 3.55–3.59 (m,
1H), 3.68–3.74 (m, 1H), 8.01 (s, 1H), 8.14 (s, 1H). 13C-NMR
(101 MHz, DMSO-d6): δ = 18.0, 19.4, 22.4, 23.8, 24.2, 32.1,
44.6, 53.0, 60.2, 167.5, 169.1. HRMS (eSI-TOF, m/z): calcd for
C11H21N2O2 (M+H)+ = 213.1598, found 213.1601.
isobutylpiperazine-2,5-dione (8a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.64 (d,
J = 6.5 Hz, 3H), 0.70 (d, J = 6.5 Hz, 3H), 1.37–1.51 (m, 2H),
1.62–1.72 (m, 1H), 3.49 (dd, J = 9.9, 2.7 Hz, 1H), 3.58–3.64
(m, 1H), 3.73 (dd, J = 9.4, 3.2 Hz, 2H), 3.86–3.89 (m, 1H),
4.42 (s, 2H), 7.21–7.30 (m, 5H), 8.04 (d, J = 2.5 Hz, 1H), 8.22
(d, J = 2.8 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 22.2,
23.6, 23.8, 45.0, 53.3, 56.1, 128.2, 128.3. 128.8, 138.6,
166.3, 168.8. HRMS (eSI-TOF, m/z): calcd for C16H23N2O3
(M+H)+ = 291.1703, found 291.1701.
4.3.8. (3R,6S)-3-isobutyl-6-isopropylpiperazine-2,5-
dione (5c)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.78–0.83
(m, 9H), 0.91 (d, J = 6.9 Hz, 3H), 1.44–1.59 (m, 2H), 1.71–1.84
(m, 1H), 2.10–2.20 (m, 1H), 3.60 (s, 1H), 3.67–3.74 (m, 1H),
7.96 (s, 1H), 8.08 (s, 1H). 13C-NMR (101 MHz, DMSO-d6):
δ = 17.5, 19.0. 22.7, 23.5, 24.1, 31.9, 42.4, 53.0, 59.9,
168.1, 169.5. HRMS (eSI-TOF, m/z): calcd for C11H21N2O2
(M+H)+ = 213.1598, found 213.1607.
4.3.13. (3R,6R)-3-(benzyloxymethyl)-6-
isobutylpiperazine-2,5-dione (8b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.64 (d,
J = 6.5 Hz, 3H), 0.70 (d, J = 6.5 Hz, 3H), 1.37–1.51 (m, 2H),
1.62–1.72 (m, 1H), 3.49 (dd, J = 9.9, 2.7 Hz, 1H), 3.58–3.64
(m, 1H), 3.73 (dd, J = 9.4, 3.2 Hz, 2H), 3.86–3.89 (m, 1H),
4.42 (s, 2H), 7.21–7.30 (m, 5H), 8.04 (d, J = 2.5 Hz, 1H), 8.22
(d, J = 2.8 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 22.2,
23.6, 23.8, 45.0, 53.3, 56.1, 128.2, 128.3. 128.8, 138.6,
166.3, 168.8. HRMS (eSI-TOF, m/z): calcd for C16H23N2O3
(M+H)+ = 291.1703, found 291.1709.
4.3.9. (3S,6S)-3-benzyl-6-isobutylpiperazine-2,5-
dione (20) (6a)
White powder. H-NMR (400 MHz, DMSO-d6): δ = 0.01–
1
0.08 (m, 1H), 0.54 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz,
3H), 0.65–0.83 (m, 3H), 1.28–1.41 (m, 1H), 3.08 (dd, J = 13.6,
3.7 Hz, 1H), 3.38–3.45 (m, 1H), 4.09–4.15 (m, 1H), 7.05–
7.25 (m, 5H), 8.02 (s, 1H), 8.04 (s, 1H). 13C-NMR (101 MHz,
DMSO-d6): δ = 22.0, 23.5, 23.5, 39.1, 44.3, 52.9, 56.1, 127.4,
128.7, 131.1, 136.7, 166.8, 168.1. HRMS (eSI-TOF, m/z): calcd
for C15H21N2O2 (M+H)+ = 261.1598, found 261.1608.
4.3.14. (3S,6S)-3-(4-(benzyloxy)benzyl)-6-
isobutylpiperazine-2,5-dione (20) (9a)
1
White powder. H-NMR (400 MHz, DMSO-d6): δ = 0.08–
0.15 (m, 1H), 0.58 (d, J = 6.7 Hz, 3H), 0.60 (d, J = 6.7 Hz,
3H), 0.70–0.77 (m, 1H), 1.32–1.45 (m, 1H), 2.71 (dd, J = 136,
49 Hz, 1H), 3.03 (dd, J = 13.6, 4.9 Hz, 2H), 3.38–3.42 (m, 1H),

SuPrAMOLeCuLAr CHeMISTry
13
4.04–4.08 (m, 1H), 4.97 (s, 2H), 6.87 (d, J = 8.6 Hz, 2H), 7.00
(d, J = 8.6 Hz, 2H), 7.23–7.38 (m, 5H), 8.04 (d, J = 2.7 Hz,
1H), 8.02 (d, J = 2.2 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6):
δ = 21.8, 23.4, 23.6, 38.3, 52.9, 56.3, 69.9, 115.0, 128.3, 128.5.
128.8, 129.1, 132.0, 137.8, 158.2, 166.8, 168.1. HRMS (eSI-
TOF, m/z): calcd for C22H27N2O3 (M+H)+ = 367.2016, found
367.2026.
131.9, 161.8, 167.1, 167.9. HRMS (eSI-TOF, m/z): calcd for
C18H22N3O3 (M+H)+ = 328.1656, found 328.1659.
4.3.19. 1-(3-((2S,5S)-5-isobutyl-3,6-dioxopiperazin-2-
yl)propyl)-3-nitroguanidine (24) (12a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.86
(dd, J = 12.6, 6.6 Hz, 6H), 1.42–1.48 (m, 1H), 1.53–1.61
(m, 4H), 1.69–1.75 (m, 1H), 1.76–1.85 (m, 1H), 3.15 (brq,
2H), 3.72–3.77 (m, 2H), 8.15 (d, J = 2.3 Hz, 1H), 8.20 (d,
J = 2.3 Hz, 1H), 8.56 (s, 1H), 9.42 (s, 1H), 11.14 (s, 1H). 13C-
NMR (101 MHz, DMSO-d6): δ = 22.2, 23.5, 24.1, 31.4, 40.7,
43.8, 53.0, 54.3, 159.8, 168.3, 168.8. HRMS (eSI-TOF, m/z):
calcd for C12H23N6O4 (M+H)+ = 315.1775, found 315.1774.
4.3.15. (3R,6R)-3-(4-(benzyloxy)benzyl)-6-
isobutylpiperazine-2,5-dione (20) (9b)
1
White powder. H-NMR (400 MHz, DMSO-d6): δ = 0.08–
0.15 (m, 1H), 0.58 (d, J = 6.7 Hz, 3H), 0.60 (d, J = 6.7 Hz,
3H), 0.70–0.77 (m, 1H), 1.32–1.45 (m, 1H), 2.71 (dd, J = 136,
4.9 Hz, 1H), 3.03 (dd, J = 13.6, 4.9 Hz, 2H), 3.38–3.42 (m, 1H),
4.04–4.08 (m, 1H), 4.97 (s, 2H), 6.87 (d, J = 8.6 Hz, 2H), 7.00
(d, J = 8.6 Hz, 2H), 7.23–7.38 (m, 5H), 8.04 (d, J = 2.7 Hz,
1H), 8.02 (d, J = 2.2 Hz, 1H). 13C-NMR (101 MHz, DMSO-d6):
δ = 21.8, 23.4, 23.6, 38.3, 52.9, 56.3, 69.9, 115.0, 128.3, 128.5,
128.8, 129.1, 132.0, 137.8, 158.2, 166.8, 168.1. HRMS (eSI-
TOF, m/z): calcd for C22H27N2O3 (M+H)+ = 367.2016, found
367.2022.
4.3.20. (3S,6S)-3-benzyl-6-methylpiperazine-2,5-
dione (26) (13a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.40 (d,
J = 6.9 Hz, 3H), 2.80 (dd, J = 13.7, 4.9 Hz, 1H), 3.08 (dd,
J = 13.5, 5.6 Hz, 1H), 3.53–3.60 (m, 1H), 4.15–4.10 (m, 1H),
7.07–7.15 (m, 2H), 7.14–7.26 (m, 3H), 7.97 (s, 1H), 8.07 (s,
1H). 13C-NMR (101 MHz, DMSO-d6): δ = 20.4, 39.0, 50.4,
56.0, 127.3, 128.7, 131.0, 136.7, 166.5, 168.4. HRMS (eSI-
TOF, m/z): calcd for C12H15N2O2 (M+H)+ = 219.1128, found
219.1139.
4.3.16. (3S,8S)-3-isobutylhexahydropyrrolo[12-a]
pyrazine-14-dione (10a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.82 (dd,
J = 6.5, 3.5 Hz, 6H), 1.24–1.36 (m, 1H), 1.65–1.92 (m, 5H),
2.01–2.12 (m, 1H), 3.24–3.37 (m, 3H), 3.95 (t, J = 5.7 Hz, 1H),
4.14 (t, J = 8.0 Hz, 1H), 7.97 (s, 1H). 13C-NMR (101 MHz,
DMSO-d6): δ = 22.3, 22.9, 23.2, 24.5, 27.8, 38.2, 45.3, 53.0,
58.9, 166.9, 170.8. HRMS (eSI-TOF, m/z): calcd for C11H19N2O2
(M+H)+ = 211.1441, found 211.1438.
4.3.21. (3R,6R)-3-benzyl-6-methylpiperazine-2,5-
dione (20) (13b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.40 (d,
J = 6.9 Hz, 3H), 2.80 (dd, J = 13.7, 4.9 Hz, 1H), 3.08 (dd,
J = 13.5, 5.6 Hz, 1H), 3.53–3.60 (m, 1H), 4.15–4.10 (m, 1H),
7.07–7.15 (m, 2H), 7.14–7.26 (m, 3H), 7.97 (s, 1H), 8.07 (s,
1H). 13C-NMR (101 MHz, DMSO-d6): δ = 20.4, 39.0, 50.4,
56.0, 127.3, 128.7, 131.0, 136.7, 166.5, 168.4. HRMS (eSI-
TOF, m/z): calcd for C12H15N2O2 (M+H)+ = 219.1128, found
219.1138.
4.3.17. (3R,8S)-3-isobutylhexahydropyrrolo[12-a]
pyrazine-14-dione (25) (10c)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.87 (d,
J = 6.3 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 1.35–1.45 (m, 1H),
1.50–1.60 (m, 1H), 1.63–1.90 (m, 4H), 2.05–2.18 (m, 1H),
3.25–3.50 (m, 2H), 3.55–3.65 (m, 1H), 4.17 (dd, J = 8.7, 6.8 Hz,
1H), 8.35 (s, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 21.5,
21.9, 23.0, 23.8, 28.5, 42.0, 44.8, 55.0, 57.5, 168.7. HRMS
(eSI-TOF, m/z): calcd for C11H19N2O2 (M+H)+ = 211.1441,
found 211.1438.
4.3.22. (3S,6S)-3-benzyl-6-isopropylpiperazine-2,5-
dione (26) (14a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.19 (d,
J = 7.0 Hz, 3H), 0.59 (d, J = 7.0 Hz, 3H), 1.60–1.70 (m, 1H),
2.81 (dd, J = 13.8, 4.7 Hz, 1H), 3.10 (dd, J = 13.8, 4.7 Hz, 1H),
3.46–3.50 (m, 1H), 4.13–4.19 (m, 1H), 7.09–7.22 (m, 5H), 7.87
(s, 1H), 8.08 (s, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 16.8,
18.9, 31.7, 38.4, 55.7, 59.8, 127.1, 128.6, 131.0, 137.0,
167.1, 167.2. HRMS (eSI-TOF, m/z): calcd for C14H19N2O2
(M+H)+ = 247.1441, found 247.1449.
4.3.18. 3-(((2S,5S)-5-isobutyl-3,6-dioxopiperazin-2-yl)
methyl)-1H-indole-1-carbaldehyde (11a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.45 (d,
J = 6.5 Hz, 3H), 0.55 (d, J = 6.5 Hz, 3H), 0.87 (dd, J = 14.5,
6.5 Hz, 1H), 1.24 (dd, J = 13.8, 7.0 Hz, 1H), 3.03 (dd, J = 14.4,
4.8 Hz, 1H), 3.23 (dd, J = 14.4, 3.5 Hz, 1H), 3.51 (s, 1H), 4.21
(s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.67 (d, J = 7.8 Hz,
1H), 8.10 (s, 1H), 8.16 (d, J = 1.9 Hz, 1H), 9.30 (s, 1H). 13C-
NMR (101 MHz, DMSO-d6): δ = 21.9, 23.1, 29.0, 44.3,
52.9, 55.2, 111.1, 115.5, 117.6, 120.5, 124.5, 125.1, 126.3,
4.3.23. (3R,6R)-3-benzyl-6-isopropylpiperazine-2,5-
dione (14b)
1
White powder. H-NMR (400 MHz, DMSO-d6): δ = 0.19
(d, J = 7.0 Hz, 3H), 0.59 (d, J = 7.0 Hz, 3H), 1.60–1.70
(m, 1H), 2.81 (dd, J = 13.8, 4.7 Hz, 1H), 3.10 (dd, J = 13.8
et 4.7 Hz, 1H), 3.46–3.50 (m, 1H), 4.13–4.19 (m, 1H),

14
C. BéruBé eT AL.
7.09–7.22 (m, 5H), 7.87 (s, 1H), 8.08 (s, 1H). 13C-NMR
(101 MHz, DMSO-d6): δ = 16.8, 18.9, 31.7, 38.4, 55.7, 59.8,
127.1, 128.6, 131.0, 137.0, 167.1, 167.2. HRMS (eSI-TOF,
m/z): calcd for C14H19N2O2 (M+H)+ = 247.1441, found
247.1459.
4.3.28. (3S,6S)-3-(4-(benzyloxy)benzyl)-6-
isopropylpiperazine-2,5-dione (17a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.22 (d,
J = 7.0 Hz, 3H), 0.60 (d, J = 7.0 Hz, 3H), 1.59–1.71 (m, 1H),
2.75 (dd, J = 14.0, 4.8 Hz, 1H), 3.03 (dd, J = 14.0, 48 Hz, 1H),
3.44–3.49 (m, 1H), 4.07–4.13 (m, 1H), 5.05 (s, 2H), 6.83 (d,
J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 7.23–7.38 (m, 5H),
7.83 (s, 1H), 8.01 (s, 1H). 13C-NMR (101 MHz, DMSO-d6):
δ = 16.8, 18.9, 31.7, 37.6, 55.8, 59.8, 69.7, 115.1, 128.1, 128.3,
129.0, 129.1, 131.9, 137.9, 157.9, 167.1, 167.3. HRMS (eSI-
TOF, m/z): calcd for C21H25N2O3 (M+H)+ = 353.1860, found
353.1865.
4.3.24. (3S,6S)-3-benzyl-6-(benzyloxymethyl)
piperazine-2,5-dione (20) (15a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.59 (dd,
J = 9.7, 6.4 Hz, 1H), 2.86 (dd, J = 13.9, 50 Hz, 1H), 3.04 (dd,
J = 13.5, 57 Hz, 1H), 3.23 (dd, J = 9.6, 3.0 Hz, 1H), 3.76–3.81
(m, 1H), 4.02–4.08 (m, 1H), 4.26 (s, 2H), 7.03 (d, J = 6.9 Hz,
2H), 7.13–7.32 (m, 8H), 8.07 (s, 2H). 13C-NMR (101 MHz,
DMSO-d6): δ = 40.1, 55.6, 56.1, 72.2, 72.8, 127.2, 128.2,
128.3, 128.8, 128.9, 130.7, 137.1, 138.6, 165.7, 167.1. HRMS
(eSI-TOF, m/z): calcd for C19H21N2O3 (M+H)+ = 325.1547,
found 325.1555.
4.3.29. (3R,6R)-3-(4-(benzyloxy)benzyl)-6-
isopropylpiperazine-2,5-dione (17b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.22 (d,
J = 7.0 Hz, 3H), 0.60 (d, J = 7.0 Hz, 3H), 1.59–1.71 (m, 1H),
2.75 (dd, J = 14.0, 4.8 Hz, 1H), 3.03 (dd, J = 14.0, 48 Hz, 1H),
3.44–3.49 (m, 1H), 4.07–4.13 (m, 1H), 5.05 (s, 2H), 6.83 (d,
J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 7.23–7.38 (m, 5H),
7.83 (s, 1H), 8.01 (s, 1H). 13C-NMR (101 MHz, DMSO-d6):
δ = 16.8, 18.9, 31.7, 37.6, 55.8, 59.8, 69.7, 115.1, 128.1, 128.3,
129.0, 129.1, 131.9, 137.9, 157.9, 167.1, 167.3. HRMS (eSI-
TOF, m/z): calcd for C21H25N2O3 (M+H)+ = 353.1860, found
353.1867.
4.3.25. (3R,6R)-3-benzyl-6-(benzyloxymethyl)
piperazine-2,5-dione (15b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.59 (dd,
J = 9.7, 6.4 Hz, 1H), 2.86 (dd, J = 13.9, 50 Hz, 1H), 3.04 (dd,
J = 13.5, 57 Hz, 1H), 3.23 (dd, J = 9.6, 3.0 Hz, 1H), 3.76–3.81
(m, 1H), 4.02–4.08 (m, 1H), 4.26 (s, 2H), 7.03 (d, J = 6.9 Hz,
2H), 7.13–7.32 (m, 8H), 8.07 (s, 2H). 13C-NMR (101 MHz,
DMSO-d6): δ = 40.1, 55.6, 56.1, 72.2, 72.8, 127.2, 128.2,
128.3, 128.8, 128.9, 130.7, 137.1, 138.6, 165.7, 167.1. HRMS
(eSI-TOF, m/z): calcd for C19H21N2O3 (M+H)+ = 325.1547,
found 325.1552.
4.3.30. 3-(((2S,5S)-5-benzyl-3,6-dioxopiperazin-2-yl)
methyl)-1H-indole-1-carbaldehyde (18a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 1.80 (dd,
J = 13.5, 7.2 Hz, 1H), 2.41 (dd, J = 13.6, 4.7 Hz, 1H), 2.48
(dd, J = 12.8, 3.8 Hz, 1H), 2.76 (dd, J = 14.5, 4.1 Hz, 1H),
3.81 (brt, 1H), 3.93 (brt, 1H), 6.63–6.69 (m, 2H), 6.91–6.96
(m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 7.08–7.17 (m, 3H), 7.28 (d,
J = 8.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.87 (s,
1H), 10.85 (s, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 30.1,
55.7, 56.0, 109.2, 111.7, 118.8, 121.3, 124.8, 126.8, 128.4,
130.1, 136.4, 136.9, 166.6, 167.2. HRMS (eSI-TOF, m/z): calcd
for C21H20N3O3 (M+H)+ = 362.4085, found 362.1505.
4.3.26. (3R,6S)-3-benzyl-6-(benzyloxymethyl)
piperazine-2,5-dione (15c)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.83
(dd, J = 13.8, 4.7 Hz, 1H), 3.10 (dd, J = 13.8, 4.7 Hz, 1H),
3.39 (dd, J = 9.6, 2.6 Hz, 1H), 3.63 (dd, J = 9.6, 2.6 Hz, 1H),
3.88–3.95 (m, 1H), 4.08–4.12 (m, 1H), 4.39 (dd, J = 4.4,
12.3 Hz, 1H), 7.12–7.31 (m, 10H), 7.98 (s, 1H), 8.16 (s, 1H).
13C-NMR (101 MHz, DMSO-d6): δ = 38.4, 55.5, 55.6, 71.4,
73.1, 127.3, 127.9, 128.7, 128.7, 128.9, 130.5, 136.8, 138.8,
166.8, 166.9. HRMS (eSI-TOF, m/z): calcd for C19H21N2O3
(M+H)+ = 325.1547, found 325.1557.
4.3.31. (3S,6S)-3,6-dibenzylpiperazine-2,5-dione (20)
(19a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.18 (dd,
J = 14.1, 6.1 Hz, 2H), 2.52 (dd, J = 13.6, 4.9 Hz, 2H), 3.89–
3.95 (m, 2H), 6.96–7.01 (m, 4H), 7.13–7.26 (m, 6H), 8.03 (s,
2H). 13C-NMR (101 MHz, DMSO-d6): δ = 40.0, 56.1, 127.2,
128.9, 130.5, 137.2, 166.8. HRMS (eSI-TOF, m/z): calcd for
C18H19N2O2 (M+H)+ = 295.1441, found 295.1445.
4.3.27. Benzyl4-((2S,5S)-5-benzyl-3,6-dioxopiperazin-
2-yl)butylcarbamate (16a)
1
White powder. H-NMR (500 MHz, DMSO-d6): δ = 0.50–
0.85 (m, 2H), 0.98–1.16 (m, 4H), 2.75–2.87 (m, 3H), 3.14 (dd,
J = 13.4, 3.7 Hz, 1H), 3.36 (s, 1H), 3.55 (brs, 1H), 4.18 (brq, 1H),
5.00 (s, 2H), 7.11–7.26 (m, 6H), 7.28–7.39 (m, 4H), 8.02 (s,
1H), 8.14 (s, 1H). 13C-NMR (126 MHz, DMSO-d6): δ = δ 21.3,
29.4, 33.5, 38.6, 40.7, 54.2, 55.7, 65.6, 127.1, 128.2, 128.4,
128.8, 130.81, 136.5, 137.7, 156.4, 166.6, 167.4. HRMS (eSI-
TOF, m/z): calcd for C23H28N3O4 (M+H)+ = 410.2074, found
410.2092.
4.3.32. (3R,6R)-3,6-dibenzylpiperazine-2,5-dione (20)
(19b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.18 (dd,
J = 14.1, 6.1 Hz, 2H), 2.52 (dd, J = 13.6, 4.9 Hz, 2H), 3.89–
3.95 (m, 2H), 6.96–7.01 (m, 4H), 7.13–7.26 (m, 6H), 8.03 (s,

SuPrAMOLeCuLAr CHeMISTry
15
2H). 13C-NMR (101 MHz, DMSO-d6): δ = 40.0, 56.1, 127.2,
128.9, 130.5, 137.2, 166.8. HRMS (eSI-TOF, m/z): calcd for
C18H19N2O2 (M+H)+ = 295.1441, found 295.1450.
2.67 (dd, J = 13.7, 4.9 Hz, 1H), 2.76 (dd, J = 13.7, 4.4 Hz,
1H), 3.99 (t, J = 6.3 Hz, 1H), 4.08 (t, J = 4.4 Hz, 1H), 5.04
(s, 2H), 6.91–6.94 (m, 2H), 6.99–7.01 (m, 2H), 7.20 (d,
J = 8.7 Hz, 2H), 7.25–7.30 (m, 3H), 7.35–7.37 (m, 2H), 8.00
(d, J = 2.2 Hz, 1H), 8.07–8.10 (m, 2H), 8.14 (d, J = 2.0 Hz, 1H).
13C-NMR (125 MHz, DMSO-d6): δ = 37.9, 40.1, 40.2, 55.3,
55.8, 69.5, 114.9, 123.6, 127.9, 128.1, 128.7, 128.8, 131.3,
131.6, 137.6, 145.7, 146.6, 157.7, 166.4, 166.8. HRMS (eSI-
TOF, m/z): calcd for C25H24N3O5 (M+H)+ = 446.1710, found
446.1694
4.3.33. (3R,6S)-3,6-dibenzylpiperazine-2,5-dione (20)
(19c)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ 2.67 (dd,
J = 14.0, 8.0 Hz, 2H), 2.95 (dd, J = 12.0, 4.0 Hz, 2H), 3.33 (br,
2H), 7.06–7.09 (m, 4H), 7.16–7.22 (m, 6H), 8.01 (s, 2H). 13C-
NMR (101 MHz, DMSO-d6): δ 32.2, 55.0, 127.0, 128.4, 130.1,
136.3, 167.3. HRMS (eSI-TOF, m/z): calcd for C18H19N2O2
(M+H)+ = 295.1441, found 295.1452.
4.3.38. (3S,6S)-3,6-dimethylpiperazine-2,5-dione (27)
(23a)
4.3.34. (3S,6S)-3-benzyl-6-(4-nitrobenzyl)piperazine-
2,5-dione (20a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 1.19 (d,
J = 6.9 Hz, 6H), 3.79–3.89 (m, 2H), 8.04 (s, 2H). 13C-NMR
(101 MHz, DMSO-d6): δ = 19.2, 50.4, 169.8. HRMS (eSI-
TOF, m/z): calcd for C6H11N2O2 (M+H)+ = 143.0815, found
143.0822.
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.16 (dd,
J = 13.5, 6.5 Hz, 1H), 2.48 (dd, J = 13.5, 5.3 Hz, 1H), 2.66
(dd, J = 13.8, 5.1 Hz, 1H), 2.79 (dd, J = 13.6, 4.0 Hz, 1H),
3.95–4.01 (m, 1H), 4.07–4.12 (m, 1H), 7.02 (d, J = 7.4 Hz, 2H),
7.07–7.23 (m, 5H), 7.97–8.03 (m, 3H), 8.13 (s, 1H), 13C-NMR
(101 MHz, DMSO-d6): δ = 38.8, 39.4, 55.5, 55.9, 123.8, 127.1,
128.7, 130.8, 131.5, 136.4, 145.7, 166.6, 166.7. HRMS (eSI-
TOF, m/z): calcd for C18H18N3O4 (M+H)+ = 340.1292, found
340.1300.
4.3.39. (3R,6R)-3,6-dimethylpiperazine-2,5-dione
(23b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 1.19 (d,
J = 6.9 Hz, 6H), 3.79–3.89 (m, 2H), 8.04 (s, 2H). 13C-NMR
(101 MHz, DMSO-d6): δ = 19.2, 50.4, 169.8. HRMS (eSI-
TOF, m/z): calcd for C6H11N2O2 (M+H)+ = 143.0815, found
143.0819.
4.3.35. (3S,6S)-3-benzyl-6-(4-(benzyloxy)benzyl)
piperazine-2,5-dione (20) (21a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.14 (dd,
J = 13.8, 6.1 Hz, 1H), 2.22 (dd, J = 13.8, 6.1 Hz, 1H), 2.48–2.57
(m, 2H), 3.84–3.89 (m, 1H), 3.90–3.95 (m, 1H), 5.00 (s, 2H), 6.84–
6.92 (m, 4H), 6.99 (d, J = 6.7 Hz, 2H), 7.12–7.35 (m, 8H), 7.84
(m, 2H). 13C-NMR (101 MHz, DMSO-d6): δ = 39.1, 42.4, 56.1,
56.2, 69.8, 115.2, 127.1, 128.1, 128.4, 128.9, 129.0, 129.3, 130.5,
131.5, 137.3, 137.8, 157.8, 166.9, 166.9. HRMS (eSI-TOF, m/z):
calcd for C25H25N2O3 (M+H)+ = 401.1860, found 401.1865.
4.3.40. (3S,6R)-3,6-dimethylpiperazine-2,5-dione (28)
(23c)
1
White powder. H-NMR (400 MHz, DMSO) : δ = 1.25 (d,
J = 7.0 Hz, 6H), 3.83–3.90 (m, 2H), 8.10 (s, 2H). 13C-NMR
(400 MHz, DMSO): δ = 19.4, 50.3, 169.1. HRMS (eSI-TOF,
m/z): calcd for C6H11N2O2 (M+H)+ = 143.0815, found
143.0818.
4.3.41. (3S,6S)-3,6-diisopropylpiperazine-2,5-dione
(29) (24a)
4.3.36. (3R,6R)-3-benzyl-6-(4-(benzyloxy)benzyl)
piperazine-2,5-dione (21b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.79
(d, J = 6.9 Hz, 6H), 0.91 (d, J = 6.9 Hz, 6H), 2.06–2.19 (m,
2H), 3.61–3.66 (m, 2H), 7.90 (s, 2H). 13C-NMR (101 MHz,
DMSO-d6): δ = 17.9, 19.3, 31.7, 59.8, 168.1, HRMS (eSI-
TOF, m/z): calcd for C10H19N2O2 (M+H)+ = 199.1441, found
199.1447 = (M+H)+
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.14 (dd,
J = 13.8, 6.1 Hz, 1H), 2.22 (dd, J = 13.8, 6.1 Hz, 1H), 2.48–2.57
(m, 2H), 3.84–3.89 (m, 1H), 3.90–3.95 (m, 1H), 5.00 (s, 2H),
6.84–6.92 (m, 4H), 6.99 (d, J = 6.7 Hz, 2H), 7.12–7.35 (m,
8H), 7.84 (m, 2H). 13C-NMR (101 MHz, DMSO-d6): δ = 39.1,
42.4, 56.1, 56.2, 69.8, 115.2, 127.1, 128.1, 128.4, 128.9, 129.0,
129.3, 130.5, 131.5, 137.3, 137.8, 157.8, 166.9, 166.9. HRMS
(eSI-TOF, m/z): calcd for C25H25N2O3 (M+H)+ = 401.1860,
found 401.1869.
4.3.42. (3R,6R)-3,6-diisopropylpiperazine-2,5-dione
(24b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.79
(d, J = 6.9 Hz, 6H), 0.91 (d, J = 6.9 Hz, 6H), 2.06–2.19 (m,
2H), 3.61–3.66 (m, 2H), 7.90 (s, 2H). 13C-NMR (101 MHz,
DMSO-d6): δ = 17.9, 19.3, 31.7, 59.8, 168.1. HRMS (eSI-
TOF, m/z): calcd for C10H19N2O2 (M+H)+ = 199.1441, found
199.1451.
4.3.37. (3S,6S)-3-(4-(benzyloxy)benzyl)-6-(4-
nitrobenzyl)piperazine-2,5-dione (22a)
1
White powder. H-NMR (500 MHz, DMSO-d6): δ = 2.14
(dd, J = 13.6, 6.7 Hz, 1H), 2.20 (dd, J = 13.7, 6.1 Hz, 1H),

16
C. BéruBé eT AL.
13C-NMR (101 MHz, DMSO-d6): δ = 17.3, 18.9, 55.6, 60.1,
71.8, 73.1, 127.9, 128.1, 128.9, 138.8, 167.4, 168.3. HRMS
(eSI-TOF, m/z): calcd for C15H21N2O3 (M+H)+ = 277.1547,
found 277.1561.
4.3.43. (3S,6S)-3,6-di-sec-butylpiperazine-2,5-dione
(30) (25a)
White powder. 1H-NMR (400 MHz, DMSO): δ = 0.79 (t,
J = 7.4 Hz, 6H), 0.89 (d, J = 7.1 Hz, 6H), 1.09–1.23 (m, 2H),
1.30–1.44 (m, 2H), 1.81–1.86 (m, 2H), 3.71 (t, J = 2.0 Hz, 2H),
7.88 (s, 2H). 13C-NMR (400 MHz, DMSO): δ = 12.4, 15.4, 24.7,
38.1, 58.8, 167.9 HRMS (eSI-TOF, m/z): calcd for C12H23N2O2
(M+H)+ = 227.1754, found 227.1630.
4.3.49. (3R,6R)-3-(benzyloxymethyl)-6-
isopropylpiperazine-2,5-dione (20) (28b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.78 (d,
J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 2.08–2.17 (m, 1H),
3.53 (dd, J = 9.7, 2.8 Hz, 1H), 3.58–3.60 (m, 1H), 3.76 (dd,
J = 9.7, 2.8 Hz, 1H), 3.89–3.92 (m, 1H), 4.45 (dd, J = 15.5,
9.3 Hz, 1H), 7.20–7.32 (m, 5H), 8.06 (s, 1H), 8.07 (s, 1H). 13C-
NMR (101 MHz, DMSO-d6): δ = 17.3, 18.9, 55.6, 60.1, 71.8,
73.1, 127.9, 128.1, 128.9, 138.8, 167.4, 168.3. HRMS (eSI-
TOF, m/z): calcd for C15H21N2O3 (M+H)+ = 277.1547, found
277.1567.
4.3.44. (3S,6S)-3,6-bis(benzyloxymethyl)piperazine-
2,5-dione (31) (26a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 3.51 (dd,
J = 9.7, 3.2 Hz, 2H), 3.62 (dd, J = 9.7, 3.2 Hz, 2H), 3.88–3.93
(m, 2H), 4.32 (s, 4H), 7.21–7.30 (m, 10H), 8.21 (s, 2H). 13C-
NMR (101 MHz, DMSO-d6): δ = 55.9, 72.5, 72.9, 128.1,
128.2, 128.9, 138.6, 166.2. HRMS (eSI-TOF, m/z): calcd for
C20H23N2O4 (M+H)+ = 355.1652, found 355.1662.
4.3.50. (3S,6S)-3-(benzyloxymethyl)-6-s-
butylpiperazine-2,5-dione (29a)
4.3.45. (3R,6R)-3,6-bis(benzyloxymethyl)piperazine-
2,5-dione (26b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.65 (t,
J = 7.4 Hz, 3H), 0.82 (d, J = 7.1 Hz, 3H), 1.20 (q, J = 6.0 Hz,
2H), 1.73–1.85 (m, 1H), 3.05–3.12 (m, 2H), 3.55 (dd, J = 9.5,
2.9 Hz, 1H), 3.72 (dd, J = 9.6, 4.1 Hz, 1H), 4.33–4.51 (m,
2H), 7.17–7.33 (m, 5H), 8.05 (s, 1H), 8.08 (s, 1H). 13C-NMR
(101 MHz, DMSO-d6): δ = 12.0, 15.5, 24.6, 38.7, 53.9, 59.3,
70.9, 72.9, 127.8, 127.9, 128.5, 138.5, 166.0, 167.0. HRMS
(eSI-TOF, m/z): calcd for C16H23N2O3 (M+H)+ = 291.1703,
found 291.1710.
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 3.51 (dd,
J = 9.7, 3.2 Hz, 2H), 3.62 (dd, J = 9.7, 3.2 Hz, 2H), 3.88–3.93
(m, 2H), 4.32 (s, 4H), 7.21–7.30 (m, 10H), 8.21 (s, 2H). 13C-
NMR (101 MHz, DMSO-d6): δ = 55.9, 72.5, 72.9, 128.1,
128.2, 128.9, 138.6, 166.2. HRMS (eSI-TOF, m/z): calcd for
C20H23N2O4 (M+H)+ = 355.1652, found 355.1659.
4.3.46. (3R,6S)-3,6-bis(benzyloxymethyl)piperazine-
2,5-dione (31) (26c)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 3.54 (dd,
J = 9.6, 2.3 Hz, 2H), 3.77 (dd, J = 9.6, 3.0 Hz, 2H), 3.89 (s,
2H), 4.45 (s, 4H), 7.22–7.34 (m, 10H), 8.16 (s, 2H). 13C-NMR
(400 MHz, DMSO): δ = 55.7, 71.1, 72.8, 127.7, 127.8, 128.7,
138.6, 167.0. HRMS (eSI-TOF, m/z): calcd for C20H23N2O4
(M+H)+ = 355.1652, found 355.1670.
4.3.51. 3-((2S,5S)-5-methyl-3,6-dioxopiperazin-2-yl)
propanamide (33) (30a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 1.25
(d, J = 7.0 Hz, 3H), 1.79–1.97 (m, 2H), 2.03–2.25 (m, 2H),
3.84–3.91 (m, 2H), 6.76 (s, 1H), 7.29 (s, 1H), 8.06 (s, 1H), 8.14
(s, 1H). 13C-NMR (101 MHz, DMSO-d6): δ = 19.6, 28.7, 30.7,
50.2, 54.0, 168.1, 169.4, 174.1. HRMS (eSI-TOF, m/z): calcd
for C8H14N3O3 (M+H)+ = 200.1030, found 200.1025.
4.3.47. (3S,6S)-3,6-bis((S)-1-(benzyloxy)ethyl)
piperazine-2,5-dione (32) (27a)
White powder. 1H-NMR (400 MHz, DMSO): δ = 1.08 (d,
J = 6.3 Hz, 6H), 3.57 (dd, J = 5.1, 3.6 Hz, 2H), 3.72–3.85 (m,
2H), 4.09 (d, J = 11.9 Hz, 2H), 4.26 (d, J = 11.9 Hz, 2H), 7.16–
7.27 (m, 10H), 8.17 (s, 2H), 8.23 (s, 1H). 13C-NMR (400 MHz,
DMSO): δ = 16.7, 60.3, 70.4, 76.6, 127.7, 127.9, 128.5,
138.9, 166.4. HRMS (eSI-TOF, m/z): calcd for C6H11N2O2
(M+H)+ = 143.0815, found 143.0822.
4.3.52. (3S,6S)-1,6-3,4-bis(propylidene)-1,4-
piperazine-2,5-dione (34) (31a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 1.86–1.95
(m, 2H), 1.97–2.07 (m, 2H), 2.12–2.23 (m, 2H), 2.26–2.35 (m,
4H), 3.46–3.56 (m, 2H), 4.13–4.19 (t, J = 7.9 Hz, 2H). 13C-NMR
(101 MHz, DMSO-d6): δ = 23.6, 27.9, 45.4, 60.8, 166.6. HRMS
(eSI-TOF, m/z): calcd for C10H15N2O2 (M+H)+ = 195.1128,
found 195.1057.
4.3.48. (3S,6S)-3-(benzyloxymethyl)-6-
isopropylpiperazine-2,5-dione (28a)
4.3.53. (3R,6R)-1,6-3,4-bis(propylidene)-1,4-
piperazine-2,5-dione (31b)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 0.78 (d,
J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 2.08–2.17 (m, 1H),
3.53 (dd, J = 9.7, 2.8 Hz, 1H), 3.58–3.60 (m, 1H), 3.76 (dd,
J = 9.7, 2.8 Hz, 1H), 3.89–3.92 (m, 1H), 4.45 (dd, J = 15.5,
9.3 Hz, 1H), 7.20–7.32 (m, 5H), 8.06 (s, 1H), 8.07 (s, 1H).
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 1.86–1.95
(m, 2H), 1.97–2.07 (m, 2H), 2.12–2.23 (m, 2H), 2.26–2.35 (m,
4H), 3.46–3.56 (m, 2H), 4.13–4.19 (t, J = 7.9 Hz, 2H). 13C-NMR
(101 MHz, DMSO-d6): δ = 23.6, 27.9, 45.4, 60.8, 166.6. HRMS

SuPrAMOLeCuLAr CHeMISTry
17
(eSI-TOF, m/z): calcd for C10H15N2O2 (M+H)+ = 195.1128,
found 195.1054.
The temperature was cooled down to 0 °C and NaH
(3 equiv, 3 mmol). The mixture was stirred for 30 min
and methyl iodide (5 equiv, 5 mmol) was added. The
reaction mixture was allowed to warm at room temper-
ature and stirred for 3 h. Water was added to the mix-
ture and extracted three times with etOAc. The organic
layers were combined, washed with water and brine,
dried with Na2SO4, concentrated in vacuo and purified
by trituration using et2O yielding 254 mg (85%) of 8 as
4.3.54. (3S,6R)-1,6-3,4-bis(propylidene)-1,4-
piperazine-2,5-dione (31c)
1
White powder. H-NMR (400 MHz, DMSO-d6): δ = 1.70–
1.84 (m, 2H), 1.85–1.99 (m, 2H), 1.99–2.01 (m, 2H), 2.40–
2.49 (m, 2H), 3.28–3.37 (m, 2H), 3.95–4.03 (m, 4H). 13C-NMR
(101 MHz, DMSO-d6): δ = 23.5, 27.8, 45.4, 60.7, 166.6. HRMS
(eSI-TOF, m/z): calcd for C10H15N2O2 (M+H)+ = 195.1128,
found 195.1057.
1
a pale yellow solid. H-NMR (400 MHz, CDCl3): δ = 0.94
(d, J = 6.6 Hz, 6H), 0.98 (d, J = 6.6 Hz, 6H), 1.51–1.58 (m,
2H), 1.64–1.71 (m, 2H), 1.83–1.98 (m, 2H), 2.93 (s, 6H),
3.79 (dd, J = 8.7, 5.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3):
δ = 22.0, 23.0, 25.2, 32.7, 43.7, 60.8, 166.8. HRMS (eSI-
TOF, m/z) calcd for C14H27N2O2 (M+H)+ = 255.2067, found
255.2071.
4.3.55. (5aR,10aR)-tetrahydrodithiazolo[3,4-a:3’,4’-d]
pyrazine-5,10(3H,8H)-dione (35) (32a)
White powder. 1H-NMR (400 MHz, CDCl3): δ = 4.76 (d,
J = 10.0 Hz, 2H), 4.42–4.53 (m, 4H), 3.33–3.44 (M, 4H). 13C-
NMR (101 MHz, CDCl3): δ = 32.6, 48.5, 62.7, 163.7. HRMS
(eSI-TOF, m/z): calcd for C8H11N2O2S2 (M+H)+ = 231.0256,
found 231.0256.
4.4.2. Preparation of (2S,5S)-2,5-diisobutylpiperazine
(20) (37)
The CDP 3a was partially dissolved in anhydrous THF in
an oven-dried three-neck flask under argon. The solution
was cooled to 0 °C and LiAlH4 (1.0 M THF, 12 eq) was added
dropwise. The mixture was allowed to warm at room tem-
perature and the reaction was refluxed overnight. The
mixture was then cooled to 0 °C and treated with Na2SO4
decahydrate. The suspension obtained was refluxed for
30 min and then filtered. The solvent was evaporated
under reduced pressure and the crude product was dried
under vacuum yielding 9 as a pale oil (66% yield). (2S,5S)-
2,5-diisobutylpiperazine (37); 1H NMR (400 MHz, DMSO-d6):
δ 0.80 (d, J = 6.4 Hz, 12H), 1.21–1.41 (m, 4H), 1.53–1.62 (m,
2H), 2.52 (dd, J = 12.1, 5.7 Hz, 2H), 2.74–2.82 (m, 4H), 7.76 (s,
2H). 13C NMR (101 MHz, DMSO) δ 22.9, 23.1, 24.2, 45.2, 50.0.
HRMS (eSI-TOF, m/z) calcd for C12H27N2 (M+H)+ = 199.2129,
found 199.2258.
4.3.56. (S)-3-isobutylpiperazine-2,5-dione (36) (33a)
White powder. 1H-NMR (500 MHz, CDCl3): δ = 0.86 (d,
J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 1.49–1.56 (m, 2H),
1.70–1.80 (m, 1H), 3.58–3.70 (m, 2H), 3.80–3.84 (m, 1H), 7.96
(s, 1H), 8.22 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ = 21.6,
22.2, 23.3, 42.6, 44.7, 53.4, 166.7, 169.1. HRMS (eSI-TOF,
m/z): calcd for C8H15N2O2 (M+H)+ = 171.1128, found
171.1133.
4.3.57. (S)-3-benzylpiperazine-2,5-dione (26) (34a)
White powder. 1H-NMR (400 MHz, DMSO-d6): δ = 2.71 (d,
J = 17.4 Hz, 1H), 2.83 (dd, J = 13.5, 4.0 Hz, 1H), 3.04 (dd,
J = 13.5, 4.5 Hz, 1H), 3.32 (d, J = 2.8 Hz, 1H), 4.01 (brs, 1H),
7.11–7.13 (m, 2H), 7.17–7.26 (m, 3H). 13C-NMR (101 MHz,
DMSO-d6): δ = 39.2, 44.0, 55.9, 127.2, 128.5, 130.5, 136.4,
166.0, 167.5. HRMS (eSI-TOF, m/z): calcd for C11H13N2O2
(M+H)+ = 205.0972, found 205.0946.
4.4.3. Preparation of (2S,5S)-2,5-diisobutyl-1,4-
dimethylpiperazine (20) (38)
4.3.58. (S)-3-(benzyloxymethyl)piperazine-2,5-dione
(37) (35a)
Without purification, the 14-piperazine 37 from previous
step was dissolved in formic acid (50 eq) in a regular round
bottom flask and stirred for a few minutes. Formaldehyde
(33 eq, 37% v/v in water) was added and the mixture was
stirred at 70 °C for 30 min. etOAc was used to dilute the reac-
tion mixture and a saturated NaHCO3 solution was added
dropwise until no further gas formation was observed. The
reaction mixture was extracted three times with etOAc.
The organic layers were combined, dried with Na2SO4, fil-
tered, concentrated in vacuo and purified by flash chroma-
tography using (90:5:5) CH2Cl2/MeOH/AcOH) yielding 10
as a red oil (17% yield). 1H-NMR (400 MHz, CDCl3): δ = 0.87
(d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 1.31–1.41 (m, 4H),
1.49–1.61 (m, 2H), 2.27 (s, 6H), 2.29–2.50 (m, 6H). 13C-NMR
(100 MHz, CDCl3): δ = 22.2, 24.2, 26.0, 36.2, 42.8, 56.8, 59.2.
Orange powder 1H-NMR (400 MHz, DMSO-d6): δ = 3.48–
3.86 (m, 5H), 445 (s, 2H), 7.20–7.33 (m, 5H), 803 (s, 1H), 813
(s, 1H) 13C-NMR (100 MHz, DMSO-d6): δ = 41.5, 52.7, 69.2,
73.1, 127.8, 128.1, 128.9, 130.5, 138.8, 167.0, 167.2 HRMS
(eSI-TOF, m/z): calcd for C12H15N2O3 (M+H)+ = 235.1077,
found 235.1084
4.4. Modification of CDP 3a
4.4.1. Preparation of (3S,6S)-3,6-diisobutyl-1,4-
dimethylpiperazine-2,5-dione (19) (36)
At room temperature, 3a was partially dissolved in
DMF in an oven-dried three neck flask under argon.

18
C. BéruBé eT AL.
HRMS (eSI-TOF, m/z) calcd for C14H31N2 (M+H)+ = 227.2482,
The topology and parameters for the trans-chalcone 1 are
found 227.2490.
provided as supplementary material.
4.6.2. System preparation
4.5. Typical procedure for the asymmetric
epoxidation of trans-chalcone 1
CDP 3a was built in MOe and prepared for MD simula-
tions using the charmm-gui web server (46) Two orthog-
onal boxes of dimension x = y = 40 Å and z = 30 Å, one
composed of water and the other of hexane, were joined
together using packmol version 15084 (47) yielding a sys-
tem of dimension x = y = 40 Å and z = 60 Å CDP 3a and
trans-chalcone 1 were initially positioned in the water and
hexane phases, respectively, with their respective geomet-
ric centre at 105 Å of the interface and at 21 Å of each other
Na+ and Cl− were added to the water phase at a concen-
tration of 015 M and neutral net charge.
The catalyst (0.01 mmol, 0.1 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 25% NaOH (m/v) in 30% H2O2 (w/w) was added and the
mixture was stirred in the dark at room temperature for
48 h. 25 μL of H2O2 30% were added to the solution after
24 h. The conversion and the enantiomeric excess of the
corresponding epoxychalcone were determined by chiral
HPLC using a Hewlett Packard series 1050 using the follow-
ing conditions: trans-(2R,3S)-Epoxy-1,3-diphenylpropan-1-
one (2). HPLC (Chiralcel OD-H): λ 254 nm, hexanes/i-PrOH
95/5, flow rate 0.6 mL/min, tR (2S,3R) = 19.23 min, tR (2R,3S)
= 21.29 min (14, 38). each epoxidation reaction has been
done at least in duplicate and the reported results corre-
spond to the means of the experiments (conversions and
enantiomeric excesses).
4.6.3. Simulations
All the MD simulations were performed using NAMD 2.9
(48) using the CHArMM36 force field (49), TIP3 waters (50,
51), periodic boundary conditions and a timestep of 2 fs for
long-range electrostatics and 1 fs for all other potentials.
Cut-offs for the short-range electrostatics and the Lennard-
Jones interactions were 12 Å with the latter smoothed via
a switching function over the range of 10 to 12 Å. Long-
range electrostatics were calculated via the Particle Mesh
ewald method (52, 53) using a sixth-order interpolation
and a grid spacing of ≈1 Å NPT ensembles were generated
Langevin damping with a coefficient of 1 ps−1 was used
to maintain a constant temperature of 37 °C, and the pres-
sure was controlled by a Nosé-Hoover Langevin piston at
1 atm. The length of the bonds between hydrogens and
heavy atoms were constrained using the SeTTLe (54) for
water molecules, and SHAKe (55) for all other molecules
The x–y plane area was kept constant allowing fluctuation
of the z axis Nonbonded pair lists were updated every 10
steps The systems were minimised for 300 steps prior to
MD simulations. Five 45 ns trajectories were recorded, for
a total of 225 ns of trajectories, and the coordinates were
saved every 100 ps for analysis with the first 3 ns of each
trajectory considered as equilibration.
4.6. MD simulations
4.6.1. Trans-chalcone 1 parametrisation
Trans-chalcone 1 molecule was built in MOe (www.chem-
comp.com). Initial parameters for the CHArMM general
force field (CGenFF v 3.0.1) (39, 40), were automatically
assigned using the CGenFF paramchem server (cgenff.par-
amchem.org) (41, 42). Parameters for charges, angles and
dihedral angles with penalties above 10 were optimised
using the Force Field Toolkit (FFTK) (43) implemented in
VMD 1.9.2. (44) Figure S1 shows the optimised parame-
ters on the trans-chalcone 1 molecule. Target quantum
mechanical (QM) data were computed with Gaussian 03
(45) using the input files generated through the FFTK
workflow using default parameters. Charges were opti-
mised using default FFTK procedure until convergence.
The first round of optimisation for the angle used an angle
deviation of 2.0°, a constant K upper Bound of 60 kcal/
mol with the simulated annealing protocol. The obtained
bond constant was further optimised until convergence
using an angle deviation of 0 and the downhill algorithm.
First round of dihedral angles optimisation used a kmax of 3
with the simulated annealing protocol and default param-
eters. The obtained dihedral angle constants were further
refined with the downhill protocol until convergence to
a rMSe of 0.105°. Figure S2 presents the target potential
energy surface from QM used for dihedral angles para-
metrisation, the PSe using missing parameters with k = 0
and the PSe with optimised dihedral angles parameters.
4.6.4. Analysis
Solvent accessible surface area (SASA) was calculated for
CDP 3a and trans-chalcone 1 using the measure function in
VMD with a radius (srad) of 14 Å. The distributions of orien-
tations adopted by the molecules relative to the normal of
the interface (Z axis) were calculated using one vector for
����⃗
����⃗
the CDP 3a (V1) and two vectors the trans-chalcone 1 (V2
����⃗
����⃗
and V3) (see Figure 8). For CDP 3a, V1 was defined as the
cross product of the vector between the two amide nitro-
gens and the vector between the two carbonyl oxygens.
����⃗
The first vector of trans-chalcone 1 (V2) was defined as

SuPrAMOLeCuLAr CHeMISTry
19
by the geometric centres of the two benzene rings, while
Funding
����⃗
����⃗
V3 was defined as the cross product of V2 and the vector
described by the bond between the carbonyl carbon and
oxygen (Figure 8).
This work was supported by the NSerC of Canada, the FQrNT of
Quebec, PrOTeO and université Lava.
References
4.7. Establishment of the functional
supramolecular complex model
(1) raj, M.; Singh, V.K. Chem. Commun. 2009, 44, 6687–6703.
(2) Gruttadauria, M.; Giacalone, F.; Noto, r. Adv. Synth. Catal.
2009, 351, 33–57.
All molecules were initially built and individually opti-
mised in MOe using default parameters. The supramolec-
ular complex was composed of CDP 3a, trans-chalcone
1, sodium cation and hydroperoxide anion. Based on the
interfacial positioning of the molecules observed from MD
simulations, CDP 3a and trans-chalcone 1 were started on
the same plane. Sodium cation and hydroperoxide anion
were placed in between the molecules, with a separation
distance of 2.3 Å (21) between the sodium cation and the
CDP 3a carbonyl, the trans-chalcone 1 carbonyl and the
hydroperoxide anion. In addition, the hydroperoxide was
positioned at a distance of 2.5 Å (arbitrary) and an angle of
107° between the hydroperoxide anionic oxygen and the
enone reactive carbon of trans-chalcone 1, according to
the dunitz angle for nucleophilic attack (22, 23). This initial
positioning was then optimised using density functional
theory (DFT) calculations at the B97-D3 (56)/Def2-SVP (57)
level. The resulting complex was further optimised with-
out constraint at the B97-D3 (56) / Def2-TZVP (57) level.
The above procedure was also used to build the supra-
molecular complex with CDP 25a. Finally, a relaxed scan
of the distance between hydroperoxide anionic oxygen
and the enone reactive carbon of trans-chalcone 1 (from
2.3 to 1.3 Å), was realised for the supramolecular CDP 3a
complex. This scan confirmed the reactivity of this com-
plex and the absence of transition state on the potential
energy surface for this supramolecular complex. All QM
calculations were performed using Orca 3.0.3 software (58)
and used the empirical D3 correction (59, 60), (denoted by
the suffix -D3), and the Becke-Johnson damping poten-
tial (61), and the rIJCOSX approximation (62), as recom-
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Acknowledgements
The authors thank François Otis for his technical assistance with
liquid chromatography and in peptide synthesis. This work was
supported by the NSerC of Canada, the FQrNT of Quebec, PrO-
TeO and université Laval. C.B. is also indebted to FrQNT for a
postgraduate scholarship.
Disclosure statement
No potential conflict of interest was reported by the authors.

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