Revisiting the Juliá-Colonna enantioselective epoxidation: Supramolecular catalysis in water

Article abstract of DOI:10.1039/c7cc01168g

We describe an efficient epoxidation process leading to chiral epoxyketones using the reusable homo-oligopeptide poly-l-leucine (PLL) in pure water, without any organic co-solvent. A range of substituted epoxyketones can be accessed with good conversions and high enantioselectivities. Based on the experimental results and computational studies, we propose a mechanism that demonstrates the importance of both the α-helical structure and the presence of a hydrophobic groove of the homo-oligopeptide catalyst for reactivity and selectivity.

Full text of DOI:10.1039/c7cc01168g

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Revisiting the Juliá-Colonna enantioselective epoxidation:
supramolecular catalysis in water
Received 00th January 20xx,
Accepted 00th January 20xx
a†
b†
b
a
Christopher Bérubé , Xavier Barbeau , Patrick Lagüe and Normand Voyer
DOI: 10.1039/x0xx00000x
www.rsc.org/
We describe an efficient epoxidation process leading to chiral conditions,6h,7 on solid-support8 and in phase-transfer9
epoxyketones using the reusable homo-oligopeptide poly-L- conditions. Despite this significant progress, all the systems
Leucine (PLL) in pure water, without any organic co-solvent. A developed so far with natural homo-oligopeptides require the
range of substituted epoxyketones can be accessed with good use of miscible or immiscible organic solvents for efficiency.
conversions and high enantioselectivities. Based on the Interestingly, mechanistic investigations have provided insights
experimental results and computational studies, we propose a on the process. A mechanism has been proposed, supported
10
mechanism that demonstrates the importance of both the α- by significant data. It requires an
α-helical structure and
helical structure and the presence of a hydrophobic groove of the terminal hydrogen bonding groups, which serve to maintain
homo-oligopeptide catalyst for reactivity and selectivity.
the substrates in a chiral environment. Still, the proposed
mechanism cannot explain all the data observed and certain
aspects remain elusive.
Developing new bioinspired catalytic systems as green and
scalable processes that use environmentally friendly reagents
under mild conditions is an exciting area of research. As with
enzymes, performing efficient reactions in pure water without
organic solvents could reduce chemical wastes by 85% in large
scale processes, which is both economically and
6f,10b
Herein, we describe an ecofriendly process to prepare chiral
α,β-epoxyketones by the utilization of homo-oligopeptides in
pure water for the Juliá-Colonna asymmetric epoxidation. We
also describe mechanistic investigations that demonstrate the
supramolecular origin of catalysis and enantioselectivity of the
process, which involve both the hydrophobic and
conformational features of the oligopeptide catalyst.
1
environmentally appealing. However, achieving efficient
organic enantioselective transformations in pure water brings
some challenges of solubility, reactivity, and selectivity.
2
Towards solving these problems, the use of peptide catalysts
has attracted considerable attention.3 Probably the best
example, reported in the early 1980s by Juliá and Colonna, is
the asymmetric epoxidation of electron-deficient enones to
useful enantioenriched epoxyketones4 in high yields and
optical purities catalyzed by homo-oligopeptides.5 This
supramolecular catalytic process, initially described as a
triphasic system, requires an aqueous oxidant phase, an
organic immiscible solvent, and an insoluble homo-
oligopeptide as a catalyst and chirality source. Over the years,
the Juliá-Colonna epoxidation has been studied and further
improved, notably as a biphasic system,4 under homogenous
We chose to investigate poly-L-leucine (PLL) and poly-L-alanine
(
PLA), as they gave the highest yields and enantioselectivities
5b
in the classic Juliá-Colonna epoxidation. We also evaluated
poly-L-isoleucine (PLI) and poly-L-valine (PLV) to study the
importance of conformation and hydrophobicity for the
reaction. These two oligopeptides bear a substituent on the
carbon of their side chain. They prefer to adopt a -structure
β-
β
rather than a helical one in solution and in the solid-state.
Homo-oligopeptides are readily available from the
11
corresponding amino acids N-carboxyanhydrides. These
a,6
activated amino acids can be polymerized readily with 1,3-
diaminopropane as a nucleophilic initiator, leading to PLL, PLA,
PLI and PLV in good overall yields and with a sufficient degree
a.Département de Chimie and PROTEO, Université Laval, Faculté des sciences et de
génie, 1045 avenue de la Médecine, Québec, QC, G1V OA6, Canada. E-mail :
normand.voyer@chm.ulaval.ca
of polymerisation (DPn = 19, 18, 17, 16 for PLL, PLA, PLI and
11-12
PLV) respectively by MALDI mass sprectrometry.
Also,
b.
Département de biochimie, microbiologie et bioinformatique and PROTEO,
NMR studies showed no detectable peaks other than those of
the homo-oligopeptides.11
Université Laval, Faculté des sciences et de génie, 1030 avenue de la Médecine,
Québec, QC, G1V OA6
†
These authors contributed equally to manuscript.
Electronic Supplementary Information (ESI) available: [Homo-oligopeptides
synthesis, Epoxidation procedure, HPLC analysis, NMR and IR sprectra, Molecular
modeling]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1 Optimisation of reaction conditionsa
possesses specific characteristics conveying unique catalytic
activity. We studied the reusability of the PLL in our water
View Article Online
DOI: 10.1039/C7CC01168G
process. The insoluble PLL in the buffer solution was easily
recovered between each run by a simple filtration. The
recovered PLL was then reused under the same conditions in
the epoxidation of
showed very good reusability: up to 96% conversion and 96%
ee of were obtained, with 94% of the original PLL mass
1. After the first recycling experiment, PLL
1
recovered. For the second and third recycling experiments,
PLL showed good reusability where enantiomeric excesses
remained almost the same (93% and 87% ee) with a decrease
of conversion (30% and 10%) of the starting material. The
decrease in conversion is most probably due to the loss of PLL
and partial unfolding.
Entry
Catalyst (mol %)
Buffer
Yield (%)b
ee (%)b
1
2
3
4
5
6
7
8
9
-
-
-
8
10
12
8
10
12
8
8
8
8
8
<5
18
10
38
48
53
48
61
97
<5
<5
<5
0
0
0
95
80
75
96
96
97
0
PLL (1)
PLL (1)
PLL (1)
PLL (2.5)
PLL (5)
PLL (10)
PLA (10)
PLI (10)
PLV (10)
Using the optimized conditions, we explored the generality of
the process with different α,β-unsaturated ketones. The
results are summarized in Table 2. Using optimized conditions
with an electron-withdrawing chloro group on the β-phenyl
moiety led to a 42% yield and 90% ee of (2R,3S)-epoxide 2b
(Table 2, entry 2). We also verified the effect of a para-fluoro
and para-trifluoro substitution on the α-phenyl moiety of the
chalcone. Reactions with these substrates led to high yields
(87% and 91%) and high enantioselectivities such as 96% and
1
1
1
0
1
2
0
0
8
a
Unless otherwise note, the reaction performed using 1 (0.1 mmol) and PLL
in 1 mL of buffer solution and 30% H
Determined by chiral HPLC.
2
O for 48 hours.
2
b
9
0% of (2R,3S)-epoxides 2c and 2d respectively (Table 2,
The process investigated is shown in Table 1 and uses
hydrogen peroxide which is a mild oxidant, safe to handle,
atom-efficient, and produces water and oxygen as byproducts.
Results are reported in Table 1. First, the background reaction,
without oligopeptides, led to very low conversion of 2a at pH
entries 3,4). Comparable results were obtained with chalcone
having a para-fluoro substitution on the β-phenyl moiety,
leading to both a high yield (83%) and enantioselectivities,
such as 93% of (2R,3S)-epoxide 2e (Table 2, entry 5). Bi-
substituted enones led to a lower yield (53%), but high
enantioselectivity (94%) of (2R,3S)-epoxide 2f (Table 2, entry
8
, 10 and 12, although the reaction is more important at the
two highest pH tested (Table 1, entries 1-3). Then, we
investigated 1 mol% of PLL at the same three pH (Table 1,
entries 4-6). Surprisingly, we observed 38% yield
6
). It is possible that the presence of two electon-withdrawing
groups deactivates the substrates. Substitutions at different
positions on the β-phenyl moiety with the strong electron-
withdrawing nitro group led to variable results (Table 2,
entries 7-9). Comparable enantioselectivities were obtained
with para and meta substitutions leading to 75% and 79% of
2R,3S)-epoxide 2g and 2h, respectively. However, the yield
and enantioselectivity are lower in the case of the ortho-nitro
substituted 2i (Table 2, entry 9). In this case, both electronic
and 95% ee of (2R,3S)-epoxychalcone 2a at pH 8, even though
the solubility of both the oligopeptide and the substrate is
almost negligible. This result represents the first example of
Julia-Colona epoxidation of electron-deficient olefins in pure
water with a high enantiomeric excess. It suggests that PLL
acts as both chiral source and solubilizing agent for the
substrate in absence of organic co-solvent. At the same
catalyst loading (Table 1, entries 4-6), increasing the pH
increased the yields from 38% to 48% and 53%. However, the
enantioselectivity dropped from 95% to 80% and 75%,
respectively. This phenomenon can be attributed to the
enhanced background reaction occurring at higher pH. It is
also possible that the lower enantioselectivities obtained using
(
Table 2 Substrate scope in the epoxidation process catalyzed by PLL
Yield (%)b
97
ee (%)b
97
90
96
90
93
94
75
79
more alkaline aqueous solutions could be due to a slow
degradation of PLL;5
Entry
1
2
3
4
5
6
7
8
R
Ph
p-Cl-Ph
p-F-Ph
1
R
Ph
Ph
Ph
Ph
2
No
2a
2b
2c
2d
2e
2f
2g
2h
2i
c,6a
pH has a significant influence on the
42
87
91
83
53
58
28
17
yield and the enantioselectivity of the process.. Having
identified pH 8 as the optimal pH, we verified the catalyst
loading up to 10 mol% (Table 1, entries 7-9). Higher catalyst
loadings maintain high enantioselectivity and significantly
increase the chemical yield. The use of 10 mol % of PLL
provides highest enantioselectivities and quantitative
conversion of (2R,3S)-epoxychalcone 2a (97%). Noteworthy of
mention, using these optimized conditions with PLA, PLI, and
PLV did not provide 2a in any significant yield. Clearly, PLL
p-CF
3
-Ph
Ph
p-F-Ph
p-NO
m-NO
o-NO
p-F-Ph
p-CH
3
Ph
Ph
Ph
Ph
-Ph
2
-Ph
-Ph
-Ph
2
9
2
50
75
10
p-OMe-Ph
2j
13
a
Unless otherwise noted, the reactions are performed using electron-
deficient enones (0.05 mmol) and PLL in 1 mL of buffer solution and 30%
b
H
O
2 2
for one week. Determined by chiral HPLC
2
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7CC01168G
Fig. 2 Angular distribution of angle θ between trans-chalcone
carbonyl (red) and PLL helix. The angle between the PLL helix axis and
the trans-chalcone carbonyl vector was calculated from the inverse
cosine of the scalar product of these two vectors. PLL is represented in
1 (green)
1
Fig. 1 A) Interaction of trans-chalcone
are represented in gray cartoon. Leucine side chains interacting with
trans-chalcone are represented as spheres. B) Contact surface area
) between trans-chalcone and PLL (red) or PLA (black).
1
with PLL and PLA. PLL and PLA
gray cartoon. Leucine side chains interacting with trans-chalcone 1 are
represented as spheres.
1
(
Å
1
stable complex where the trans-chalcone
1 inserts in the non-
polar groove formed by the leucine side chains and the alpha
helix main chain (Figure 1A). A short video presenting the
and steric effects can be evoked to explain the significant
decrease in reactivity. Predictably, substitution with a para-
methoxy electron-donating group on the β-phenyl moiety
afforded (2R,3S)-epoxide 2j with a very low conversion
interaction of trans-chalcone
the supplementary information. To further characterize the
interaction between trans-chalcone and PLL, we calculated
the orientation of with respect to the PLL helix. The angular
1 with PLL and PLA is available in
1
2
1
(
13%),probably due to enone lower electrophilicity. However,
the reaction proceeded with good enantioselectivity (75%)
Table 2, entry 10). Again, steric and electronic effects are
1
distribution is presented in Figure 2 and shows that trans-
chalcone 1, when bound to PLL, adopts a wide range of
orientations, with no preference for the side exposed to the
solvent and accessible to the nucleophilic species (Fig. 2). Thus,
the enantioselectivity observed from the experimental results
does not appear to result from nucleophilic attack of a loose
hydroperoxide anion coming from the solvent; a ratio close to
(
probable factors that led to the poor reactivity in this case. In
summary, studies with different substrates strongly suggest
that both steric hindrance and electronic factors of chalcones
play a crucial role in the outcomes of the process, especially on
the chemical yields. On the other hand, the well-established
mechanism described in the literature for the triphasic system
cannot explain the results obtained here in pure water.
Indeed, Kelly and Roberts proposed that hydrogen bonding of
the three terminal amidic N-H groups, near the N-terminus,
acts as an oxy-anion hole for the resonance-stabilized
hydroperoxide enolate intermediate.1 Considering that PLA
5
0% of each epoxide enantiomer would be observed if that
was the case. Rather, we suggest a mechanism where the
hydroperoxide anion would be concentrated at the N-terminal
of the PLL. The trans-chalcone
1 would slide in the leucine side
chain’s hydrophobic groove until it reaches the N-terminal to
react with the hydroperoxide anion. This “groove sliding”
mechanism would lead to a reactive supramolecular complex
0d
presents a high percentage of
α-helical conformation in the
1
2
solid-state and in an aqueous suspension, there should have
been a certain level of enantioselectivity in the reaction.
Furthermore, hydrogen bonding interactions are minimized in
pure water. Clearly, hydrophobic interactions must be involved
somehow in favouring the transformation, and other factors
must therefore being considered to explain the results
obtained in the actual process. Using computational tools, we
formed by the PLL, the trans-chalcone
hydroperoxide, as represented in Figure 3. Depending on the
orientation of with respect to the PLL, four different
1
and the
1
complexes are possible. To test this assumption, the four
complexes were built and energy-minimized using quantum
12
mechanics calculations.
The resulting structures are
represented in Figure 3. Of the four supramolecular
complexes, only the complex depicted in Figure 3A has a
modelled PLL and PLA oligomers of 20 residues with an
α-
helical conformation, their preferred conformation based on
ATR-FTIR results.12 PLL with a helical conformation creates nice
hydrophobic chiral grooves, regularly distributed along the
helical axis. MD Simulations, used to study the interactions of
distance of 2.5
hydroperoxide anion and trans-chalcone
corresponding to reactive trans-chalcone
Å
and an angle of 98° between the
reactive atoms,
which leads to the
1
1
trans-chalcone
chalcone fits perfectly within the PLL groove, as illustrated in
Figure 1A. 50 ns trajectories were recorded for each peptide in
the presence of one trans-chalcone molecule, contact was
1 with PLL and PLA, showed that trans-
1
1
observed 88% of the time between trans-chalcone
and only 33% of the time between trans-chalcone
1
1
and PLL,
and PLA.
Figure 1B shows the surface of contact between trans-
Fig.3 Supramolecular complexes proposed for the “groove sliding”
mechanism. Trans-chalcone and PLL are represented in sticks and
and PLA were transient and lead to a stable and ribbon respectively. Hydroperoxide is in red spheres. Only the complex
depicted in A has a distance of 2.5 and a 98° angle between the
hydroperoxide and trans-chalcone 1 reactive atoms.
chalcone
chalcone
1 and PLL or PLA. The contacts between trans-
1
1
Å
defined supramolecular complex. By contrast, contacts
between trans-chalcone and PLL were lasting and led to a
1
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corresponding (2R,3S)-epoxide 2a obtained experimentally.
Based on the experimental results described above and the
computational results of previous pertinent mechanistic
studies, we propose that in pure water, both a helical
conformation and hydrophobic interactions are responsible for
the chiral catalytic effect of PLL. Interestingly, more
hydrophobic and less hindered enones demonstrate higher
yields and enantioselectivity ratios than those with larger polar
substituents, which have a lower affinity for the hydrophobic
Wang, R. G. Cornwall and Y. Shi, Chem. Rev., 2014, V1ie1w4,Ar8tic1l9e 9O;nl(inee)
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1
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in a predictable manner the substrate, leading to high yields
Masana and A. Alvarez, Tetrahedron, 1983, 39, 1635; (d) S. Banfi,
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4
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and enantioselectivities in the epoxidation of
α,β-conjugated
6
enones in pure water, without an organic co-solvent. Although
the outcomes of the process vary with the structure of the
substrates, PLL efficiently catalyzes the epoxidation of a variety
of
electron-deficient
enones,
leading
to
high
1
997, 3297; (c) W.-p. Chen, A. L. Egar, M. B. Hursthouse, K. M.
enantioselectivities. Both the conformation and hydrophobic
nature of oligopeptide catalysts are essential in order to act as
efficient biomimetic catalyst. This new process in water opens
the way to easily and rapidly access a variety of chiral
Abdul Malik, J. E. Mathews and S. M. Roberts, Tetrahedron Lett.,
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Skidmore, J. Smith and N. Williamson, Chem. Commun., 1998,
epoxyketones
through
environmentally
benign
enantioselective processes.
We are grateful to NSERC of Canada and to FRQNT of Québec
for financial support. CB also thanks FRQNT for a graduate
scholarship and PROTEO for a travel award. The authors wish
to thank François Otis for his technical assistance with chiral
HPLC and François Paquet-Mercier for help with ATR-FTIR
spectroscopy.
1
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