Biomimetic non-heme iron-catalyzed epoxidation of challenging terminal alkenes using aqueous H2O2 as an environmentally friendly oxidant

Article abstract of DOI:10.3390/molecules24173182

Catalysis mediated by iron complexes is emerging as an eco-friendly and inexpensive option in comparison to traditional metal catalysis. The epoxidation of alkenes constitutes an attractive application of iron(III) catalysis, in which terminal olefins are challenging substrates. Herein, we describe our study on the design of biomimetic non-heme ligands for the in situ generation of iron(III) complexes and their evaluation as potential catalysts in epoxidation of terminal olefins. Since it is well-known that active sites of oxidases might involve imidazole fragment of histidine, various simple imidazole derivatives (seven compounds) were initially evaluated in order to find the best reaction conditions and to develop, subsequently, more elaborated amino acid-derived peptide-like chiral ligands (10 derivatives) for enantioselective epoxidations.

Full text of DOI:10.3390/molecules24173182

molecules
Article
Biomimetic Non-Heme Iron-Catalyzed Epoxidation of
Challenging Terminal Alkenes Using Aqueous H2O2
as an Environmentally Friendly Oxidant
Anja Fingerhut 1, Jorge Vargas-Caporali 2 , Marco Antonio Leyva-Ramírez 2,
Eusebio Juaristi 2,3,
*
and Svetlana B. Tsogoeva 1,
*
1
Department of Chemistry and Pharmacy, Institute of Organic Chemistry I and Interdisciplinary Center for
Molecular Materials (ICMM), Friedrich-Alexander University Erlangen-Nürnberg,
Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany
Department of Chemistry, Centro de Investigación y de Estudios Avanzados,
Av. Instituto Politécnico Nacional 2508, 07360 Ciudad de México, Mexico
El Colegio Nacional, Donceles # 104, Centro Histórico, 06020 Ciudad de México, Mexico
Correspondence: juaristi@relaq.mx (E.J.); svetlana.tsogoeva@fau.de (S.B.T.);
Tel.: +52-55-5747-3722 (E.J.); +49-9131-85-65573 (S.B.T.)
2
3
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Isaac Garcia-Bosch
Received: 10 June 2019; Accepted: 23 August 2019; Published: 1 September 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Catalysis mediated by iron complexes is emerging as an eco-friendly and inexpensive
option in comparison to traditional metal catalysis. The epoxidation of alkenes constitutes an attractive
application of iron(III) catalysis, in which terminal olefins are challenging substrates. Herein,
we describe our study on the design of biomimetic non-heme ligands for the in situ generation of
iron(III) complexes and their evaluation as potential catalysts in epoxidation of terminal olefins.
Since it is well-known that active sites of oxidases might involve imidazole fragment of histidine,
various simple imidazole derivatives (seven compounds) were initially evaluated in order to find
the best reaction conditions and to develop, subsequently, more elaborated amino acid-derived
peptide-like chiral ligands (10 derivatives) for enantioselective epoxidations.
Keywords: non-heme iron-catalysis; peptide-like ligands; enantioselective epoxidation; terminal
olefins; hydrogen peroxide oxidant
1. Introduction
Epoxides are subunits within many natural products or essential biologically active molecules.
Epoxides also represent valuable building blocks, as they are widely used for the synthesis of fine
chemicals and pharmaceuticals due to the broad range of modifications they can undergo [1–7].
In this regard, iron complexes offer potential advantages over other coordination complexes typically
employed in epoxidation reactions because iron is an abundant and relatively non-toxic metal, so in
principle, this element can provide environmentally friendly and economical catalysts for the synthesis
of bulk epoxides [8]. Nature provides numerous efficient examples of iron-based catalysts, such as for
example oxidative enzymes. The synthetic iron complexes mimicking the ability of these enzymes to
promote oxidation processes are usually described as bioinspired catalysts and these can either be heme
(porphyrin) systems or non-heme iron complexes. In particular, cytochrome P450 and other peroxidases
serve as model enzymes for designing oxidation catalysts such as metalloporphyrins [9–11].
While previously studied heme iron catalytic systems were not found to be highly enantioselective [11],
non-heme iron complexes have facilitated the access towards new promising enantioselective oxidizing
catalysts. This goal can be achieved by fine tuning the basic structure of the non-heme ligands and
Molecules 2019, 24, 3182; doi:10.3390/molecules24173182
www.mdpi.com/journal/molecules

Molecules 2019, 24, 3182
2 of 22
with it, their electronic and steric properties. Thus, the combination of an iron center with a given
chiral ligand should result in an efficient and low-cost catalyst for asymmetric synthesis [12].
In principle, non-heme iron catalytic complexes for oxidation reactions can be modelled with the
base on the active site of oxygenases, where imidazole and carboxylate enzymic residues (derived
from e.g., His and Asp) ligate to the iron center and create a chiral environment (see Figure 1).
In a general synthetic strategy, the simple combination of an iron salt with slightly modified
naturally occurring chiral amines, carboxylic acids or amino acids can mimic the active site of an enzyme
to achieve the goal of inducing an enantioselective oxidation.
Figure 1. Examples of active sites in non-heme iron oxygenases: (a) in protocatechuate 3,4-dioxygenase [13]
and (b) in naphthalene dioxygenase [14,15].
Initially, the task described above was carried out in a non-enantioselective approach [16,17].
Subsequently, in 1999 Jacobsen and co-workers came up with one of the main breakthroughs in the
area of enantioselective epoxidations catalyzed by non-heme iron complexes, which were not only
bioinspired but also biomimetic (Figure 2) [18]. Specifically, these workers demonstrated the catalytic
potential of a library of polymer supported peptide-like ligands, which acted in combination with
a variety of metal ions including iron salts. With trans-β-methylstyrene as model substrate, H2O2 as
oxidant, and FeCl2 as iron source up to 78% conversion was recorded in up to 20% enantioselectivity.
Even though the coordination structure of the most efficient catalyst was not provided, it was
proposed that the peptide-based ligand bearing an N2O motif probably formed a biomimetic N2OFeCl2
complex. Further catalytic approaches towards epoxide formation with non-heme iron complexes
and H2O2 or O2 as environmentally friendly oxidants have been reported [19
in 2007 Beller and co-workers developed a remarkable method for the asymmetric epoxidation
of aromatic alkenes using H2O2 as oxidant [21 22]. The chiral iron catalysts were generated in
situ from FeCl3 6H2O, chiral amino-sulfonamides, and pyridine-2,6-dicarboxylic acid (H2Pydic) as
an additive [23]. Various alkenes were evaluated as substrates; however, only sterically hindered olefins
,20]. For example,
,
·
were oxidized with high enantioselectivity [8]. In particular, terminal alkenes afforded products with
8–26% ee.

Molecules 2019, 24, 3182
3 of 22
Figure 2. Biomimetic non-heme iron-catalyzed epoxidations reported by Jacobsen [18], Beller [17],
Costas and Beller [16].
Furthermore, Beller and co-workers developed various non-enantioselective non-heme iron
catalytic systems for olefin epoxidation with H2O2, where the catalyst was also formed in situ.
In particular, small ligands with biomimetic coordination motifs were applied. Illustrative examples are
benzylamine derivatives in combination with pyridin-2,6-dicarboxylic acid (H2Pydic) [23], or various
imidazole derivatives (Figure 2) [17,24,25]. These catalytic systems were able to afford very good yields
of racemic non-terminal and terminal epoxides. In this context, in 2011 Beller, Costas, and co-workers
reported a biomimetic iron catalyst formed in situ for epoxidation reactions, using air as the oxidant
(Figure 2) [16]. Interestingly, by applying a β-keto ester as co-substrate, the O2 activation was similar
to the activation process observed in co-substrate-dependent non-heme oxygenases.
To this date, one of the most successful families of non-heme iron catalysts developed for
asymmetric epoxidation reactions with H2O2 is the one presenting bioinspired octahedral complexes
coordinated to a bis-amino-bis-pyridine ligand. These catalytic systems provide a cis-α-topology and
are chiral at the metal center as consequence of the chiral aliphatic diamine backbone. Nevertheless,
these catalytically active complexes are less closely modeled on enzymes and are not as readily available
as the other previously mentioned examples. Nevertheless, the groups of Que [26
,27], Costas [28–30],
Sun [31 32], Bryliakov and Talsi [33] could obtain very promising results with respect to the yields and
,
enantioselectivities. Regarding the enantioselective epoxidation of terminal olefins, the octahedral
complexes afforded moderate yields and enantioselectivities.
In view of the abovementioned advantages, non-heme iron catalysis is a promising epoxidation
method for eventual large-scale applications in industry, especially in combination with H2O2 as
convenient oxidant. Indeed, this strategy is simple, inexpensive, and environmentally benign since
H2O is the only released side-product [34,35]. As evidenced by the previously mentioned examples,
terminal olefins were found to be challenging substrates for enantioselective non-heme iron catalytic
systems. Nevertheless, terminal olefins represent an important class of substrates; for example,
their chiral epoxides are widespread building blocks in the synthesis of
inhibitors, and polyol and polyene antibiotics, among others [ 36]. The routes by which terminal
epoxides are obtained using non-heme iron complexes and H2O2 are still rare [31 37 38]. Therefore,
the development of new and simple enantioselective biomimetic non-heme iron catalytic systems for
β-blockers, HIV protease
2–6,
,
,

Molecules 2019, 24, 3182
4 of 22
the epoxidation of the challenging terminal alkenes using highly desirable oxidizing agents such as
H2O2 constitutes an attractive and ambitious task.
Herein, we disclose a promising approach towards the preparation of valuable but challenging
terminal oxiranes via enantioselective epoxidation with H2O2 by applying imidazole based peptide-like
ligands in combination with a source of iron(III), representing a highly biomimetic catalyst.
2. Results and Discussion
2-Vinylnaphthalene was chosen as model substrate for the enantioselective epoxidation of terminal
olefins. It turned out to be a challenging but important substrate owing to its bulkiness and relevance
as precursor in drug synthesis [36
catalysts employing H2O2 as the oxidant, only the complex described by Beller and co-workers
which was generated in situ from pyrrolidine, H2Pydic, and FeCl3 6H2O, succeeded in oxidizing
,39,40]. To the best of our knowledge, among all non-heme iron
·
2-vinylnaphthalene with 40% yield, but afforded the desired product as a racemic mixture [41].
In order to test their potential in the preparation of suitable catalysts, several imidazole derivatives
with varying substitution patterns were screened as achiral ligands for iron(III) (Figure 3). The catalysts
were formed in situ from 5 mol% FeCl3 6H2O and 10 mol% of the coordinating imidazole derivative,
·
generating the catalytically active iron species which enables oxygen transfer from H2O2 to the substrate,
affording the target epoxide. This procedure for the in situ formation of the catalytic system is known
to be time-saving, economic, and ecologically friendly, avoiding a laborious preliminary synthetic
manipulation of precatalysts [42,43]. The addition of H2O2 was realized by means of a syringe pump
over the entire reaction period of 1 h. Isolation of the terminal epoxides by column chromatography
had to be avoided because SiO2 was found to catalyze the rearrangement of the product to give
the corresponding aldehyde (see Supplementary Materials). Yield determination was carried out via
1H-NMR measurements using pyrazole as internal standard. The parent unsubstituted imidazole L1
as reference ligand provided the target epoxide with 40% yield (Figure 3).
Figure 3. Screening of imidazole-based ligands: yields of the epoxide products were determined via
1H-NMR using pyrazine as internal standard.
By comparison, N-methylimidazole L2 and N-(trimethylsilyl)-imidazole L3 afforded the epoxide
with 11% and 29% yields, respectively. In the case of the 2,4-disubstituted imidazole derivative L4
only traces of the product could be observed. By contrast, N-butylimidazole L5 afforded 50% yield
of the desired product, even when analogous N-substituted imidazoles L2 and L3 showed modest
catalytic activity. Furthermore, N-benzylimidazole L6, led to a comparable result relative to L3 with
,

Molecules 2019, 24, 3182
5 of 22
30% yield of epoxide. The best result was achieved with N-phenylimidazole L7, which afforded
53% yield of the epoxide product, surpassing the pyrrolidine/H2Pydic system of Beller et al. [41].
Further screening of reaction conditions, such as variation of the reaction temperature, substrate
concentration, reaction time, or adding alternative acidic additives led in some cases to a decrease in
the yield (see Supplementary Materials). Even the use of a co-catalyst was unsuccessful in the goal to
improve the yield of the oxidation reaction. Interestingly, when the reaction was carried out under N2
atmosphere, only traces of the product were detected (see Supplementary Materials). This observation
suggests the participation of the surrounding air in the formation of the catalytically active species.
Initially, it could be suggested the formation of a self-assembled
µ-oxo-iron(III) dimer as the catalytically
active species, as it was previously discussed by Jacobsen and Stack [44
,
45]; however, later on Que and
co-workers demonstrated that this class of dimer would not be efficient in promoting the oxidation
and instead, the formation of this species would correspond to a dead-end intermediate [46]. In situ
generation of the catalyst prior to substrate addition to further ensure self-assembly had no significant
impact on yield (see Supplementary Materials).
Based on this preliminary screening of derivatives of simple imidazoles as constituents of potential
ligands, the most promising one N-phenylimidazole L7 was selected as reference point for the
design of more elaborated chiral ligands and their application in enantioselective epoxidation of
2-vinylnaphthalene. In particular, inspired by Nature (see Figure 1 in the Introduction) we combined L7
with a small chiral peptide-like moiety in order to obtain new ligand L8 (Figure 4). It was anticipated
that this ligand would enable a selective coordination on the iron metal, imitating a catalytically
active enzyme pocket which in turn could effectively orient the substrate toward the activated
oxygen, leading to the selective formation of one enantiomeric epoxide. Similarly, the straightforward
synthesis of L8–L13 and L17 was carried out via EDC coupling using N-Boc-protected l-tert-leucine and
(R)-3,3-dimethyl-2-butylamine as starting materials. Subsequently, the deprotected primary amine was
subjected to a reductive amination with the required imidazole carboxaldehyde derivatives, forming the
different imidazole-based peptide-like ligands. In the case of L16, N-Boc-protected l-proline was
used for EDC coupling instead of l-tert-leucine. The methylation reaction of L10 was carried out with
formaldehyde and sodium triacetoxyborohydride to form ligand L14. In order to generate ligand L15
a reduction of ligand L10 with AlCl3-LiAlH4 was carried out. Thus, we obtained a series of stable
ligands providing a typical [N,N]-binding motif for the coordination to a metal center comparable
,
to that in salalen ligands [47,48]. It is worth mentioning that ligand L10 has already been employed
as chiral promoter in the enantioselective silyl protection of vicinal diols [49
triols [52].
–51] or cyclic and acyclic
On the other hand, it was possible to obtain suitable monocrystals from imine (S,R)-
its subsequent product of reduction, ligand L10, to collect X-ray diffraction data (Figure 5). It can
be appreciated that iminium (N8) and amide (N12) nitrogen atoms in imine (S,R)- -(d) are both
oriented in the same direction (θN8-C9-C10-N12
8.7◦). By contrast, N12 in the amino amide L10 is
V-(d) and
V
=
−
accommodated in opposite direction relative to N8 (θN8-C9-C10-N12 = 127.3◦). Another salient structural
difference is given by C-N bond distances, for instance C7-N8 is equal to 1.265 Å in the imine (Figure 5,
left) while in the amine C7-N8 is 1.456 Å. N8-C9 presents the same length, around 1.46 Å, in both
compounds. Furthermore, amine protons could be located by Fourier difference analysis given the
existence of hydrogen bonds. Likewise, nitrogen atoms N3, N8, and N12 in amino amide L10 are
found forming a sort of cavity, which could suggest its suitability to coordinate an iron cation.

Molecules 2019, 24, 3182
6 of 22
N
N
NaBH4
(3 equiv.)
HCl (cat.)
O
MgSO4.H2O
(0.72 equiv.)
N
N
O
t-Bu
O
t-Bu
O
t-Bu
H
H
H
N
H2N
N
t-Bu
N
N
t-Bu
HN
N
t-Bu
H
+
N
N
N
H
MeOH
0°C, 30 min
rt, 1 h
DCM
rt, overnight
H
N
H
t-Bu
O
t-Bu
O
t-Bu
O
IV-Me-2
(1.3 equiv.)
(S,S,R)-III
84%
(S,S,R)-V-(a)
99%
L17
24%
EDC.HCl
(1.1 equiv.)
HOBt
NaBH4
(3 equiv.)
HCl (cat.)
MgSO4.H2
(0.72 equiv.)
O
N
N
HCl 12 M
(1.3 equiv.)
t-Bu
t-Bu
t-Bu
t-Bu
O
N
N
R
N
H
H
(1.1 equiv.)
H
R
Boc
OH
N
t-Bu
N
t-Bu
H2N
t-Bu
N
t-Bu
+
+
N
H2N
N
N
H
H
N
dioxane
0 °C to rt
1 h
MeOH
0°C, 30 min
rt, 1 h
DIPEA
(3.2 equiv.)
DCM, rt
DCM
rt, overnight
H
R
O
O
O
O
N-Boc-
L-t-Leu
(S,R)-I
92%
IV
L-(3,3-Me2)-BuNH2
(S,R)-V
yield > 90%
Ligands
(1-1.3 equiv.)
+
t-Bu
O
H
N
O
t-Bu
N
HN
N
OH
(S,R)-V-(b)
Boc
H
O
N
N
Ph
N-Boc-
L
-Pro
L8
15%
N
IV-Ph-2
Ph
EDC.HCl
(1.1 equiv.)
HOBt
(1.1 equiv.)
DIPEA
(2.5 equiv.)
DCM, rt, 19 h
t-Bu
a) HCHO
(1.3 equiv.)
AcOH (cat.)
DCM, rt, overnight
H
O
N
N
t-Bu
HN
H
(S,R)-V-(c)
(S,R)-V-(d)
O
N
N
b) STAB (1.5 equiv.)
overnight
Ph
L9
80%
N
N
N
N
IV-Ph-4
t-Bu
H
N
Ph
HCl 12 M
(1.3 equiv.)
dioxane
0 °C to rt
1 h
t-Bu
t-Bu
O
H
O
N
t-Bu
t-Bu
L14
31%
HN
N
H
O
N
NaBH4
(3 equiv.)
HCl (cat.)
H
N
MgSO4.H2O
(0.72 equiv.)
t-Bu
N
AlCl3
(6 equiv.)
LiAlH4
O
L10
33%
N
N
H
N
IV-Me-2
t-Bu
N
N
O
HN
(18 equiv.)
MeOH
0°C, 30 min
rt, 1 h
N
t-Bu
DCM
rt, overnight
H
N
t-Bu
t-Bu
THF (dry)
0 °C, 30 min.
rt, 18 h
H
N
(S,R)-II
99%
L16
27%
N
H
N
O
HN
HN
L15
77%
N
H
O
+
(S,R)-V-(e)
(S,R)-V-(f)
N
N
O
L11
54%
N
N
IV-Me-4
H
N
t-Bu
H
O
IV-Me-2
(1.3 equiv.)
N
t-Bu
t-Bu
N
H
O
N
N
H
L12
44%
NH
IV-H-2
t-Bu
H
O
N
N
HN
H
(S,R)-V-(g)
O
N
N
H
L13
78%
IV-H-4
N
H
Figure 4. Family tree of chiral derivatives synthesized from (R)-3,3-dimethylbutan-2-amine.

Molecules 2019, 24, 3182
7 of 22
Figure 5. X-ray structures corresponding to imine (S,R)-V-(d) [C10-N12 1.336 (2) Å, C10-O11 1.227
(2) Å] (left) and ligand L10 [C10-N12 1.335 (6) Å, C10-O11 1.238 (5) Å] (right) depicted with ellipsoids
at 30% probability.
In this context, the newly designed ligand L8 (1,2-substituted imidazole) contains two tert-butyl
groups, which might induce a substantial effect on enantioselectivity when being compared with other
residues. Indeed, the bulkiness of the tert-butyl group is particularly effective as stereodifferentiating
structural element, as it was discussed for the salen-type ligand in Jacobsen’s catalyst [53]. Application
of ligand L8 to our model reaction led to the isolation of the target epoxide with 27% yield and 34% ee.
Likewise, derivative L9, with a 1,4-substitution pattern, was considered in order to investigate the
effect of the linkage position at the imidazole on the reaction outcome [17]. However, no significant
improvement of yield was observed and actually, a decrease of enantiomeric excess was evident.
N-methylated ligands L10 (1,2-substituted imidazole) and L11 (1,4-substituted imidazole), both sharing
a common coordination motif, were also screened in order to examine the influence of the N-imidazole
residue. While the methylated achiral ligand led to a decrease in yield (compare ligand L2 and L7
,
Figure 3), ligand L10 afforded an improved yield of 44%, with 26% ee. When the reaction was carried
out at lower temperature (0 ◦C) the enantiomeric excess could be improved up to 36%, although the
yield dropped to 23% (Figure 6). On the other hand, ligand L11 (1,4-substituted imidazole) led to the
racemic epoxide in 24% yield. A similar trend relative to that found with the phenylated (L8 and
L9) and methylated (L10 and L11) ligands was observed with N-unsubstituted ligands L12 and L13
With ligand L12, 35% yield and 34% ee were recorded. Again, the enantioselectivity was slightly
improved to 36% when carrying out the reaction at 0 ◦C, although the yield decreased. As it could have
been anticipated, ligand L13 turned out to be less efficient than L12, with an observed decrease in yield
and enantioselectivity. The corresponding screening indicated that ligand L10 was most promising,
both in terms of yield and enantioselectivity. To exclude the possibility that coordination sites of the
iron center were blocked when using a 2:1 molar ratio of ligand to iron, which would suppress H2O2
activation, the amount of ligand L10 was reduced to a 1:1 molar ratio (see Supplementary Materials).
However, the yield was reduced, and the enantiomeric excess remained unchanged. For further
experiments, a 1:1 molar ratio of ligand to iron source with 10 mol% ligand was deemed appropriate
for efficient catalysis.
.
Ligands L14, L15, and L16 were designed in order to examine the effect of structural modifications
on ligand L10. This analysis provided insight on the factors that enable coordination to the iron center
and thereby the activation of the H2O2 oxidant. Indeed, methylation of the secondary aliphatic amine,
which is part of the proposed coordination motif, led to ligand L14 tested as catalyst in the model
oxidation of 2-vinylnaphthalene, affording the target epoxide in a poor 12% yield and in a racemic
manner. It becomes then obvious that the secondary amine in L10 plays a key role in enantioselective
oxygen transfer to the substrate. Furthermore, examination of ligand L15 lacking the carbonyl function,
only afforded traces of the desired product with a negligible enantiomeric excess. This led to the

Molecules 2019, 24, 3182
8 of 22
conclusion that either the carbonyl oxygen or the nitrogen activated by the amide function participate
in the formation of the catalytically active iron complex.
Figure 6. Screening of chiral peptide-like imidazole-based ligands. Yields determined via 1H-NMR
with pyrazine as internal standard; ee values determined via chiral HPLC measurement. (a) 0.33 mmol
of 2-vinylnaphthalene was used.
When the more rigid amino acid l-proline was incorporated instead of l-tert-leucine in compound
L16, only traces of the product were observed in low enantiomeric excess. This corroborated the
intuitive assumption that neither the tertiary nitrogen of the proline moiety nor the less flexible backbone
enables coordination of the ligand to the iron center, in this way preventing H2O2 activation and, hence,
oxygen transfer. To improve the beneficial influence of the l-tert-leucine derived moiety, a second
residue was introduced thus obtaining ligand L17 as an extended version of L10. The enantioselective
epoxidation applying ligand L17 led to 40% yield, which falls in the range exhibited by ligand L10
.
Nevertheless, the observed enantiomeric excess decreased from 26% to 18%.
For further studies of the catalytic system, the influence of (S)-(+)-mandelic acid as additive in
the reaction employing ligand L10 was investigated. Chiral carboxylic acids or carboxylic acids in
general are known for their positive effect as co-catalyst in organo- and metal catalyzed reactions [54,55]
.
As coordinating ligand, the carboxylic acid facilitates the O-O cleavage and promotes the formation
of the active iron oxo species [28,44,45]. However, in the present system there was no change
in enantioselectivity when adding 5 mol% (S)-(+)-mandelic acid to the model reaction system
(see Supplementary Materials). The model epoxidation reaction applying achiral ligand L7 (Figure 3)
showed a decrease of yield to 26% by adding 5 mol% of (S)-(+)-mandelic acid as well, and 2-vinylnaphtyl
oxide (1) was formed as a racemic mixture (see Supplementary Materials). Under modified reaction
conditions with reduced amount of H2O2 and reduced temperature, the addition of 5 mol%
(S)-(+)-mandelic acid led to a slight increase of the enantiomeric excess (Table 1, Entry 1).

Molecules 2019, 24, 3182
9 of 22
Table 1. Screening of chiral peptide-like imidazole-based ligands using (S)-(+)-mandelic acid as additive.
Entry
Ligand L10 (mol%) FeCl3· 6H2O (mol%) (S)-(+)-mandelic acid (mol%) Yield 1 (%) ee 2 (%)
1
2
3
10
5
5
5
5
27
20
43
42
15
10
37
38
20
10
1 Yieldsdeterminedvia1H-NMRwithpyrazineasinternalstandard. 2 eevaluesdeterminedviachiralHPLCmeasurement.
To investigate the effect of (S)-(+)-mandelic acid and the contribution to the complex formed
in situ, the amount was raised to 15 mol% and the quantity of ligand L10 was reduced to 5 mol%
because of the available coordination positions. However, the effect of the modified reaction conditions
was small, and the values of yield and enantiomeric excess were in the same range, as already
described for the prior reaction system with ligand L10 at 0 ◦C (compare Table 1, Entry 2 with Figure 6,
ligand L10). Doubling the amount of catalyst to 20 mol% (Entry 3, Table 1) resulted in 43% yield and
38% enantiomeric excess, which was so far the best result concerning yield and enantioselectivity.
Nevertheless, taking the reaction mass efficiency [56] into account, the aforementioned result was not
as promising for further investigation as the already demonstrated approach at room temperature
(Figure 6, ligand L10).
A further screening of terminal and non-terminal, electron rich and electron deficient olefins
should elucidate the steric and electronic properties of the catalyst by drawing inferences from
substrate preference (Table 2). All tested substrates were found to be oxidized with lower yield than
2-vinylnaphthalene. The reason for this can be on the one hand the good accessibility of the electron-rich
terminal double bond to the iron center due to reduced electronic repulsion, and on the other hand,
due to an enhanced stabilization from the bigger naphthyl fragment. Compared to 2-vinylnaphthyl
oxide, the styrene oxide was obtained with lower yield (Table 2, Entry 2). Styrene derivatives with
electron withdrawing groups like 4-nitrostyrene and 1,2-dichloro-4-vinylbenzene showed lower yield
for their corresponding epoxides compared to unsubstituted styrene (Table 2, Entry 3 and Entry 4).
On the other hand, styrene and its aryl-substituted derivatives (EWGs) led to their corresponding
epoxides with enantioselectivities that fall in the same range of those observed with 2-vinylnaphthalene
oxide (Table 2, Entries 2–4). Unexpectedly, 4-methoxystyrene with its electron donating group,
was oxidized with 5% yield and only 14% enantiomeric excess (Table 2, Entry 5). The result was
surprising because of the expected tendency that electron rich terminal olefins were favored by the
catalyst. This behavior excludes the simple explanation that the oxidizing iron species formed during
the catalytic process is of electrophilic nature. The more sterically demanding double bond of α-methyl
styrene led to 22% yield and decreased enantioselectivity with 16% ee (Table 2, Entry 6). Furthermore,
a benzyl substituted terminal olefin gave just traces of product (Table 2, Entry 7), indicating less activity
of the catalyst for non-conjugated double bonds, even when they are terminal. Thus, we propose
that an aryl moiety directly adjacent to the double bond is highly required to enable the catalyzed
epoxidation process.

Molecules 2019, 24, 3182
10 of 22
Table 2. Screening of substrates.
Entry
Product
Yield 1,2
ee 3
1
44
26 (R)
2
3
30
14
27 (R)
29 (S)
25 (R) 4
4
25
5 4
22
14 (R) 4
16 (S)
5
6
7
8
<5 5
n.d.
6
32
50
9
27
16 (R)
10
<5
27 (2R,3S)
51 (2R,3S)
11 7
7
1
2
Yields determined via 1H-NMR with pyrazine as internal standard. Results already described in literature
for non-heme iron epoxidation employing H2O2 were contrasted in a comparative Table (see Supplementary
3
4
Information). ee values determined via chiral HPLC measurement. ee value determined after derivatization:
5
aminolysis with isopropylamine towards corresponding
n.d.: not determined. in situ catalyst generation with L10 (5 mol%), FeCl3 6H2O (5 mol%), (S)-(+)-mandelic acid
(15 mol%), 1.6 mL 2-Me-2-BuOH, followed by the addition of alkene (0.166 mmol) and 2 eq. H2O2 via syringe pump
β
-aminoalcohol. detected via 1H-NMR and ESI-MS.
6
7
·
at r. t. (3 h reaction).
On the other hand, when β-methylstyrene was used as substrate, the yield of the corresponding
epoxide was 32%, so this result was in the range of that pertaining to the unsubstituted styrene,
even though the enantiomeric excess of 50% was quite high compared to all the other electron-rich
olefins which were tested (Table 2, Entry 8). Thus regarding the enantioselectivity, the epoxidation
system presented herein exceeded Jacobsen’s polymer-supported peptide-based catalyst (Figure 2) [18].
Still no conclusion about the electronic nature of the oxidizing iron species could be drawn, taking the

Molecules 2019, 24, 3182
11 of 22
moderate yield of
β-methylstyrene oxide into account. However, the methyl group at the
β
position
may direct the substrate in a more defined way towards the H2O2 activating iron center within the
chiral catalyst surrounding. In the case of trans-stilbene as representative of nonterminal symmetrically
substituted olefins, the yield was 27% with 16% enantiomeric excess (Table 2, Entry 9). The lower ee in
comparison to styrene oxide could be explained by the difficult access of the catalyst to the double
bond and with it the suppressed transfer of chiral information during the oxygen transferring process.
When the catalytic system was applied on trans-chalcone as an example of a more electron-deficient
nonterminal olefin, only product traces were observed with an ee value of 27% (Table 2, Entry 10).
However, the enantioselectivity was raised to 51% under the modified reaction conditions (described
previously in Table 1) by using (S)-(+)-mandelic acid additive (Table 2, Entry 11). Even though the
yield was quite low, the result was interesting due to the significant influence of the (S)-(+)-mandelic
acid, but only for this substrate. Therefore, we reasoned that the carboxylic acid did not only
favor the formation of the iron oxo species, contrary to what is described in literature [28,44,45].
Possibly, an additional interaction between the chiral acid additive and the carbonyl function of
chalcone raises the enantiomeric excess of the chalcone oxide. Although the substrate screening
revealed that 2-vinylnaphthalene was the most appropriate starting material (regarding yield) the
two non-terminal substrates chalcone and
respect to enantioselectivity.
β-methylstyrene showed the most promising results with
It is worthy of mention that diverse attempts to obtain a suitable monocrystal from L10·FeCl3
and L10·FeCl3
·
[(S)-mandelic acid] in different solvents or mixtures were not fruitful, obtaining
in both cases a dark amber vitreous solid. In order to get insights into the catalyst formation
process, some spectroscopic experiments were conducted. For instance, UV/Vis-spectroscopy
measurements were carried out (see Supplementary Materials). The comparison of the absorption
spectra corresponding to the individually measured compounds, ligand L10 and FeCl3
in 2-Me-2-BuOH, with the spectrum of the mixture (ligand L10 combined with FeCl3 6H2O in
2-Me-2-BuOH) shows a distinct shift of the characteristic FeCl3 6H2O absorption maxima. This indicates
·6H2O
·
·
that the metal interacts with ligand L10 forming a complex. As a further UV/Vis spectrum suggests,
an additional structural change of the previously generated iron complex was taking place when H2O2
was added. This was attributed to the formation of an oxygen transferring iron species. Likewise,
it was possible to identify a species with a mass equivalent to 514.5 Da from a solution of the complex
in methanol by means of LC–ESI-MS. Besides, infrared experiments (ATR) comparing pure L10 versus
the preformed complex L10·FeCl3 showed a noticeable variation in the amide carbonyl band, shifting
from 1651 cm−1 in L10 to 1599 cm−1 in the complex, suggesting that the oxygen preferably coordinates
instead of the amide nitrogen (see Supplementary Materials). In another IR experiment, it could
also be appreciated that it was not the mandelic acid carbonyl group which was participating in the
iron coordination but the hydroxyl oxygen since the intense -OH characteristic band (3440 cm−1
)
disappeared in the spectra of the final complex. Thus, the mandelic acid carbonyl group only slightly
varied (from 1710 to 1735 cm−1, though its transmittance percentage seemed to be reduced). Similarly,
the amide carbonyl band in the complex remained practically unchanged when adding mandelic acid
(from 1599 to 1602 cm−1).
In addition, NMR experiments were run in methanol-d3 solvent. Even though the paramagnetism
of the metal complex made the accumulation of the sample difficult, spectra of L10 significantly changed
upon addition of FeCl3 6H2O [complex concentration = 0.027 M, L10 and Fe(III) in equimolar amount].
·
In particular, a significant broadening of signals in 1H-NMR was observed. Furthermore, in presence
of Fe(III) a remarkable shift for both tert-butyl fragments took place, resulting in a single broad proton
signal at 0.2099 ppm. This contrasted with the clearly defined signals for each fragment of tert-butyl
in the pure ligand (0.937 and 0.915 ppm). The tert-butyl signal broadened even more when adding
an equimolar amount of (S)-mandelic acid, shifting down to 0.325 ppm. These observations may give
−
evidence of the formation of a species in which the degrees of freedom of the tert-butyl fragments are
restricted, i.e., a coordination complex. In accordance with the changes observed by 1H-NMR, the pair

Molecules 2019, 24, 3182
12 of 22
of clearly defined signals for each fragment of tert-butyl in 13C-NMR (25.56 and 26.05 ppm) led to
an intense signal when adding an equimolar amount of FeCl3 6H2O (28.6 ppm) which shifted again
·
to 30.14 ppm in presence of (S)-mandelic acid. Another salient difference in chemical shifts was that
corresponding to the methyl bonded to the stereogenic carbon, moving from 14.95 ppm in the pure
ligand up to 17.87 ppm in the final complex. Less noticeable were the ∆δ corresponding to the carbonyl
carbon: 173.74 ppm in L10 to 171.91 ppm in the final complex including (S)-mandelic acid. On the
other hand, noteworthy changes were also observed for the imidazol fragment, wherein 121.78 and
125.46 ppm shifted to 130.27 and 137.64 ppm, respectively, and Cipso in L10 (146.32 ppm) moves down to
144.65 ppm in the final complex, suggesting that the imidazol fragment could be actively participating
in coordination to iron metal. Figure 7 depicts a plausible structure for the intermediate iron complex.
Figure 7. Possible coordination complex participating as catalyst in the model epoxidation reaction.
3. Materials and Methods
3.1. General Information
Chemicals purchased from commercial sources were used without further purification. All solvents
were purified by distillation, dried according to standard procedures or were purchased in HPLC-quality.
Preparative (flash) column chromatography was performed on Acros Silica gel 60 (0.035–0.070 mm, 60 Å)
as stationary phase. All products were dried in high vacuum (10-3 bar). Thin layer chromatography
(TLC) was performed on precoated aluminium silica gel SIL G/UV254 plates (Macherey-Nagel & Co.,
1
Düren, NRW, Germany). H-NMR (13C-NMR) spectra were recorded at room temperature on a Bruker
Avance 300 or 400 or JEOL JNM GX 400 spectrometer. All chemical shifts are given in ppm scale
and refer to the non-deuterized proportion of the solvent. NMR raw data was processed with the
program MestReNova. Maldi Mass spectra were recorded with Shimadzu Biotech AXIMA Confidence.
ESI Mass spectra were recorded with a Bruker Daltonik maXis 4G, a Bruker Daltonik micrOTOF II focus
or an Agilent 6120 Quadrupole LCMS System. HPLC spectra were recorded at room temperature on
an Agilent Technologies 1200 Series HPLC system. As a stationary phase, the following columns were
utilized: IA, IB, IC, AS, OD. IR spectra were recorded on a Varian IR-660 apparatus. The Absorption is
indicated in wave numbers (cm−1). Optical rotations were determined on a PerkinElmer polarimeter,
model 341, λ = 546 nm.
3.2. General Catalytic Procedure
3.2.1. Catalysis without Additive
To a solution of FeCl3
based ligand (50.0 mol, 10 mol%) was added at room temperature under air. After addition of the
olefin (500 mol), H2O2 (30 wt% in H2O, 170 L, 1.50 mmol) mixed with 830 L 2-Me-2-BuOH was
added via syringe pump over a 1 h period. The reaction was quenched with 50 L saturated aqueous
·
6 H2O (6.8 mg, 25.0 µmol, 5 mol%) in 9 mL 2-Me-2-BuOH, an imidazole
µ
µ
µ
µ
µ
Na2SO3 solution. After extraction with CH2Cl2, the organic phases were combined and evaporated to
dryness. The crude mixture was filtered through a SiO2-plug (1 cm, eluted with CH2Cl2). In order to
determine the yield via 1H-NMR, pyrazine was added in a defined amount as an internal standard.

Molecules 2019, 24, 3182
13 of 22
Afterwards, purification was carried out by means a preparative TLC plate (hexane/ethyl acetate) for
the HPLC sample preparation in order to determine enantioselectivity.
3.2.2. Catalysis with (S)-(+)-Mandelic Acid
A mixture of FeCl3 6 H2O (5–10 mol%), ligand L1 (5–20 mol%), and (S)-(+)-mandelic acid
·
(5–15 mol%) in 1.6 mL of 2-Me-2-BuOH was stirred under air at room temperature for 1 h. Afterwards,
◦
2-vinylnaphtalene (25.6 mg, 166
H2O2 (30 wt% in H2O, 24 L, 249
mixture was stirred for additional 2 h at 0 ◦C. The reaction was quenched with 30
µ
mol) was added and the reaction mixture was cooled to 0 C.
µ
µ
mol) was added via a syringe pump over 1 h. Then the reaction
µ
L of saturated
aqueous Na2SO3 solution. After extraction with CH2Cl2, the organic phases were combined and
evaporated to dryness under reduced pressure. The crude mixture was filtered through a SiO2-plug
(1 cm, eluted with CH2Cl2). In order to determine yield via 1H-NMR, pyrazine was added in a defined
amount as an internal standard. Afterwards, purification was carried out with preparative TLC plate
(hexane/ethyl acetate) for the HPLC sample preparation in order to determine enantioselectivity.
3.2.3. Substrate and Racemic Product References
Olefins like 1-nitro-4-vinylbenzene [57] or 1,2-dichloro-4-vinylbenzene [58] were prepared
according to literature procedure.
The obtained spectroscopic data of 2-phenyloxirane (
2) [59] and 2,3-diphenyloxirane (9) [42] was
in accordance with commercially available 2-phenyloxirane and data from literature.
Oxidation to racemic phenyl(3-phenyloxiran-2-yl)methanone (10) [60] was prepared according to
literature procedure.
For determination of yield and enantioselectivity of product resulting from 4-methoxystyrene,
the volatile epoxide (5) was further converted to the corresponding β-aminoalcohol via
aminolysis by adding 18 equiv. of isopropylamine (instead of addition of saturated aqueous
Na2SO3 soln.) and stirring the reaction mixture for 18 h at 50 ◦C. Then the solvent was
evaporated and the raw material was purified via column chromatography [36]. The racemic
reference of 2-(isopropylamino)-1-(4-methoxyphenyl)ethan-1-ol was synthesized, as described in
procedure 3.2.1 using 1-phenylimidazole as achiral ligand. The obtained spectroscopic data of
2-(isopropylamino)-1-(4-methoxy-phenyl)ethan-1-ol was in accordance with literature [61].
3.3. General Procedure of Olefin Epoxidation with m-CPBA
A mixture of olefin (490
at room temperature. After addition of m-CPBA (77% purity, 0.9–1.2 equiv.) the reaction mixture
was stirred overnight. The obtained spectroscopic data for 2-(naphthalen-2-yl)oxirane ( ) [62],
) [36], 2-Methyl-2-phenyloxirane
) [65] was in accordance with literature.
µmol-7.69 mmol) and NaHCO3 (0.9-1.2 equiv.) was stirred in DCM
1
2-(4-nitrophenyl)oxirane (
) [62], 2-Benzyloxirane (
3
) [63], 2-(3,4-dichlorophenyl)oxirane (4
(6
7
) [64] and 2-Methyl-3-phenyloxirane (8
3.3.1. Synthesis of Ligands
Synthesis of Boc-l-tert-Leucine [66], Boc-l-Proline [67], 1-phenyl-1H-imidazole-2-carbaldehyde [68],
3-methyl-4-formylimidazol, and 1-methyl-4-formylimidazol [69] were prepared according to
reported procedures.
3.3.2. Synthesis of l-Proline or l-tert-Leucine Based Amines
(S)-2-Amino-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethylbutan-amide, (S,R)-
(1.99 g, 9.30 mmol) and (R)-3,3-dimethyl-2-butylamine (1.23 mL, 9.30 mmol) were dissolved in 30 mL
of DCM. To the solution EDC HCl (1.96 g, 10.2 mmol), HOBt (1.57 g, 10.2 mmol), and DIPEA (3.84 g,
I. N-Boc-l-tert-Leucine
·
5.20 mL, 29.7 mmol) were added. The reaction mixture was stirred overnight at room temperature;
then, 10 mL of 10% citric acid was added to quench the reaction. The organic layer was separated and

Molecules 2019, 24, 3182
14 of 22
washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure to afford a white solid. The residue was dissolved in 10 mL
of dioxane, cooled to 0 ◦C. Then, 1 mL of 12 M hydrochloric acid was added dropwise. The mixture
was stirred at room temperature over 1 h and the solution was concentrated under reduced pressure.
The residue was taken up in 5 mL of water and 2 M NaOH solution was added until no further
increase in the amount of precipitate was observed. The resulting solution was washed with DCM
and brine and then dried over anhydrous sodium sulphate. Purification via column chromatography
(SiO2, DCM/MeOH 98:2) afforded the title compound as a white solid (1.83 g, 8.50 mmol, 92%).
The amine was used without further detailed characterization. 1H-NMR (300 MHz, CDCl3, rt):
[ppm] = 6.63 (d, J = 8.4 Hz, 1H), 3.81 (dq, J1 = 6.8 Hz, J2 = 9.7 Hz, 1H), 3.07 (s, 1H), 1.03 (d, J = 6.8 Hz,
δ
3H), 0.99 (s, 9H), 0.88 (s, 9H). 13C-NMR (75 MHz, CDCl3, rt):
δ [ppm] = 172.7, 64.8, 52.4, 34.1, 34.0,
26.9, 26.3, 16.1. HR-MS (ESI) m/z: [M + H]+ calcd. for C12H27N2O: 215.211790; found: 215.212414.
(S)-N-[(R)-3,3-Dimethylbutan-2-yl]pyrrolidine-2-carboxamide [(S,R)-II]. N-Boc-l-proline (620 mg,
2.88 mmol) and (R)-3,3-dimethyl-2-butylamine (0.382 mL, 2.88 mmol) were dissolved in 12 mL DCM.
EDC (608 mg, 3.17 mmol), HOBt (428 mg, 3.17 mmol), and DIPEA (931 mg, 1.25 mL, 7.20 mmol) were
added to the reaction mixture. The mixture was stirred over 19 h at room temperature. Afterwards,
4 mL of 10% citric acid was added to the mixture. The organic layer was removed and washed with
saturated solution of sodium bicarbonate, brine, dried over anhydrous sodium sulfate, ◦filtrated and
concentrated under reduced pressure to afford a yellow oil. This oil was cooled to 0 C and later,
HCl/dioxane (2.1 mL of a 4 M solution) was added over the course of 1 h. The mixture was warmed
to room temperature over 1 h, and the solution was concentrated in vacuo. The unpurified product
was dissolved in water and the solution was basified (pH = 12) by adding a solution of NaOH 3 N.
The resulting solution was extracted with DCM, washed with brine and dried over anhydrous sodium
sulfate. After removal of the solvent in vacuo, raw material of (S,R)-II was obtained as a white solid
and used without further purification or characterization.
(S)-2-Amino-N-{(S)-1-[((R)-3,3-dimethylbutan-2-yl)amino]-3,3-dimethyl-1-oxobutan-2-yl}-3,3-
dimethylbutanamide [(S,S,R)-III]. Boc-L-tert-Leucine [(S)-N-Boc-tLeu, 1.99 g, 9.30 mmol] and
(S)-2-Amino-N-((R)-3,3-dimethylbutan-2-yl)-3,3-dimethylbutan-amide [(S,R)-I, 2.15 g, 9.30 mmol]
were dissolved in DCM (30 mL). EDC HCl (1.96 g, 10.2 mmol), HOBt (1.57 g, 10.2 mmol), and DIPEA
·
(3.84 g, 5.20 mL, 29.7 mmol) were added to the solution. The reaction mixture was stirred overnight at
room temperature; later, 10 mL of 10% citric acid was added to quench the reaction. The organic layer
was separated and washed with saturated aqueous NaHCO3 and 10 mL of brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford a white solid. The residue was dissolved in
dioxane (10 mL), cooled to 0 ◦C, and 1 mL of HCl (12 M) was added dropwise. The mixture was stirred
at room temperature over 1 h and the solution was concentrated under reduced pressure. The residue
was taken up in 5 mL of water, and 2 M NaOH solution was added until no further increase in the
amount of precipitate was observed. The resulting mixture was extracted with DCM, the organic layer
was separated, washed with brine and dried over anhydrous Na2SO4. The product was evaporated to
dryness in vacuo to afford the title compound as a white powder (2.56 g, 84% yield). The raw material
was used without further purification or detailed characterization.
3.3.3. Synthesis of Imidazole Based Aldehyde
1-Phenyl-1H-imidazole-4-carbaldehyde, IV-Ph-4. CuI (93.0 mg, 488
(88.0 mg, 488 mol), tripotassium phosphate (1.56 g, mmol, 7.35 mmol), and 4-imidazolecarboxaldehyde
(330 mg, 3.43 mmol) were placed under inert conditions in a flask with 5 mL of dry DMF. After stirring
µmol), 1,10-phenanthroline
µ
the mixture at room temperature for 10 min, bromobenzene (386 mg, 258 µL, 2.46 mmol) was added.
The reaction mixture was heated to 120 ◦C over 65 h. After cooling to room temperature, the solution
was diluted with ethyl acetate (20 mL) and filtered through silica gel. The organic phase was washed
with brine and then dried over MgSO4. Following to concentration in vacuo, the raw product was

Molecules 2019, 24, 3182
15 of 22
recrystallized from DCM and pentane, which afforded the pure product as a white solid (112 mg,
1
650
µ
mol; 26% yield). The obtained spectroscopic data were in accordance with literature [66]. H-NMR
(300 MHz, CDCl3, rt):
δ
[ppm] = 9.94 (s, 1H), 7.92 (dd, J1 = 14.0 Hz, J2 = 1.3 Hz, 2H), 7.69–7.29 (m, 5H).
3.3.4. Synthesis of Imidazole Based Peptide Like Ligand
General Procedure (GP1): Reductive Amination
The l-Proline or L-tert-Leucine-based amine was dissolved in DCM (2 M), followed by the addition
of the imidazole based aldehyde (1–1.3 equiv.) and MgSO4 H2O (1 g/5 mL solvent). The mixture
·
was stirred overnight at room temperature. Afterwards, solids were removed by filtration and the
resulting solution was concentrated in vacuo. The residue was dissolved in MeOH (2 M) and the
solution was cooled to 0 ◦C. NaBH4 (3 equiv.) and a catalytic amount of conc. HCl were added to this
solution. The mixture was stirred for 30 min at 0 ◦C, and 1 h at room temperature; after this period,
an equal volume of saturated NaHCO3 solution was added to quench the reaction. After washing with
DCM and brine, the organic phase was separated, dried over anhydrous Na2SO4 and concentrated in
vacuo to afford the raw product. Purification of the resulting raw material was carried out via column
chromatography using DCM and MeOH, eluted compound might be subsequently recrystallized from
DCM and pentane.
Ligand L8. The synthesis was carried out according to GP1. The target compound was obtained from
(S)-2-Amino-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethylbutanamide [(S,R)-
1-phenyl-1H-imidazole-2-carbaldehyde ( -Ph-2, 49.7 mg, 289 mol) after purification via column
chromatography (SiO2, DCM/MeOH 98:2) as a white solid (12.1 mg, 33.0
mol; 15%). 1H-NMR
(300 MHz, CD2Cl2, rt): [ppm] = 7.51–7.36 (m, 5H), 7.08 (d, J = 1.3 Hz, 1H), 7.05 (d, J = 1.3 Hz, 1 H),
6.50 (br, J = 9.1 Hz, 1H), 3.80–3.74 (m, 1H), 3.72 (d, J = 14.0 Hz, 1H), 3.53 (d, J = 13.9 Hz, 1H), 2.72
(s, 1H), 0.95 (s, 9H), 0.86 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H). 13C-NMR (100 MHz, CD2Cl2, rt):
[ppm] =
I, 47.6 mg, 222 µmol] and
V
µ
µ
δ
δ
171.7, 146.4, 137.8, 129.9, 128.7, 128.2, 125.9, 121.4, 72.5, 52.8, 44.7, 34.2, 34.0, 27.4, 26.5, 16.2. HR-MS
(ESI) m/z: [M + H]+ calcd. for C22H35N4O: 371.28054; found: 371.28081; m/z: [M + Na]+ calcd. for
C22H34N4NaO: 393.26248; found: 393.26263. [α]D
= 3447, 3193, 3067, 2954, 2905, 2871, 1306, 1644, 1555, 1500, 1470, 1306, 1255, 1141, 1126, 1115, 1082, 962,
= ]
64◦ (c = 0.15, DCM). IR (ATR, solid): ν˜ [cm−1
−
20
915, 818, 764, 734, 693, 569, 540.
Ligand L9. The synthesis was carried out according to GP1. The target compound was obtained
from (S)-2-Amino-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethylbutanamide [(S,R)-
and 1-phenyl-1H-imidazole-4-carbaldehyde ( -Ph-4, 112 mg, 650 mol) after purification via column
chromatography (SiO2, DCM/MeOH 98:2) as a white solid (150 mg, 405
mol; 80%). 1H-NMR (300 MHz,
CDCl3, rt): [ppm] = 7.77 (d, J = 1.4 Hz, 1H), 7.47–7.32 (m, 5H), 7.11 (s, 1H), 7.02 (d, J = 9.8 Hz, 1H),
3.85 (dq, J1 = 6.8 Hz, J2 = 9.8 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.51 (d, J = 13.9 Hz, 1 H), 2.82 (s, 1H),
2.08 (s, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.98 (s, 9H), 0.89 (s, 9H). 13C-NMR (100 MHz, CDCl3, rt):
[ppm]
= 172.4, 141.9, 137.6, 135.7, 130.3, 127.8, 121.6, 115.9, 72.3, 52.9, 46.2, 34.4, 34.0, 27.8, 26.8, 16.6. HR-MS
I, 108 mg, 504 µmol]
V
µ
µ
δ
δ
(ESI) m/z: [M + H]+ calcd. for C22H35N4O: 371.28054; found: 371.28086. [α]D
=
42◦ (c = 0.15, DCM).
−
20
IR (ATR, solid): ν˜ [cm−1] = 3326, 3054, 2958, 2870, 1648, 1600, 1505, 1475, 1365, 1306, 1251, 1130, 1067,
993, 967, 818, 757, 690, 522.
Ligand L10. The synthesis was carried out according to GP1. The target compound was obtained from
(S)-2-Amino-N-((R)-3,3-dimethylbutan-2-yl)-3,3-dimethylbutanamide [(S,R)-I, 973 mg, 4.54 mmol] and
1-methyl-2-imidazolcarbaldehyde (500 mg, 4.54 mmol) after purification via column chromatography
(SiO2, DCM/MeOH 98:2) and recrystallization (DCM/pentane) as a white solid (461 mg, 1.50 mmol;
33%). The obtained spectroscopic data was in accordance with literature [70]. 1H-NMR (300 MHz,
CDCl3, rt):
δ [ppm] = 6.90 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H), 6.49 (br d, J = 9.6 Hz, 1H), 3.88
(dq, J1 = 9.8 Hz, J2 = 6.8 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 3.59 (s, 3H), 3.58 (d, J = 13.9 Hz, 1H), 2.65

Molecules 2019, 24, 3182
16 of 22
(s, 1H), 2.14 (s, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.89 (s, 9H). 13C-NMR (100 MHz, CDCl3, rt):
δ [ppm] = 172.0, 146.1, 127.1, 121.1, 72.0, 52.7, 44.3, 33.9, 33.8, 32.6, 27.1, 26.4, 16.4.
Ligand L11. The synthesis was carried out according to GP1. The target compound was obtained
from (S)-2-Amino-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethylbutanamide [(S,R)-
and 1-methyl-1H-imidazole-4-carbaldehyde ( -Me-4, 44.4 mg, 403 mol) after purification via column
chromatography (SiO2, DCM/MeOH 98:2) as a white solid (67.7 mg, 219
mol; 54%). 1H-NMR
(300 MHz, CDCl3, rt): [ppm] = 7.30 (s, 1H), 7.00 (br d, J = 9.6 Hz, 1H), 6.67 (s, 1H), 3.79 (dq, J1 = 6.8 Hz
J2 = 9.8 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 3.58 (s, 3H), 3.36 (d, J = 14.1 Hz, 1H), 2.73 (s, 1H), 2.34 (s, 1H),
1.00 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.84 (s, 9H). 13C-NMR (100 MHz, CDCl3, rt):
[ppm] = 171.9,
140.5, 137.6, 117.5, 71.7, 52.4, 45.7, 33.9, 33.4, 33.2, 27.4, 26.4, 16.1. HR-MS (ESI) m/z: [M + H]+
I, 86.3 mg, 403 µmol)
V
µ
µ
δ
,
δ
calcd. for C17H33N4O: 309.26489; found: 309.26512. [α]D
=
17◦ (c = 0.15, DCM). IR (ATR, solid):
−
21
ν˜ [cm−1] = 3327, 2956, 2870, 1618, 1508, 1462, 1365, 1307, 1232, 1160, 1131, 991, 816, 738, 618, 482.
Ligand L12. The synthesis was carried out according to GP1. However, in the first
step, MeOH was employed instead of DCM. The target compound was obtained from
(S)-2-Amino-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethylbutanamide [(S,R)-
and 2-imidazolecarboxaldehyde ( -H-2, 48.0 mg, 504 mol). Purification of the resulting material by
recrystallization (DCM/pentane) afforded the desired compound as a white solid (65.0 mg, 221 mol;
44%). 1H-NMR (300 MHz, CDCl3, rt):
[ppm] = 6.91 (s, 2H), 6.70 (d, J = 9.3 Hz, 1H), 3.88 (d, J = 14.8 Hz
1H), 3.84–3.76 (m, 1H), 3.56 (d, J = 14.8 Hz, 1H), 2.66 (s, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H), 0.85
(s, 9H). 13C-NMR (100 MHz, CDCl3, rt):
[ppm] = 172.4, 146.8, 121.7, 71.8, 52.8, 45.4, 34.0, 33.7, 27.1,
I, 108 mg, 504 µmol]
V
µ
µ
δ
,
δ
16.2. HR-MS (ESI) m/z: [M + H]+ calcd. for C16H31N4O: 295.249238; found: 295.249907. [α]D
=
79◦
−
22
(c = 0.15, DCM). IR (ATR, solid): ν˜ [cm−1] = 3352, 3163, 3053, 2955, 2870, 1637, 1526, 1464, 1365, 1248,
1228, 1108, 988, 800, 739, 679, 627, 479.
Ligand L13. The synthesis was carried out according to GP1. The target compound was obtained from
(S)-2-Amino-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethylbutanamide [(S,R)-
4-imidazolecarboxaldehyde ( -H-4, 54.5 mg, 567 mol) without any further purification as a white solid
(99.8 mg, 339
mol; 78%). 1H-NMR (400 MHz, CDCl3, rt):
1H), 6.76 (s, 1H), 3.82 (dq, J1 = 6.8 Hz, J2 = 13.5 Hz, 1H), 3.75 (d, J = 14.0 Hz, 1H), 3.42 (d, J = 14.1 Hz
I, 93.4 mg, 436 µmol] and
V
µ
µ
δ
[ppm] = 7.55 (s, 1H), 6.98 (br, J = 9.0 Hz
,
,
1H), 2.71 (s, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H). 13C-NMR (100 MHz, CDCl3, rt):
δ
[ppm] = 172.6, 136.1, 135.3, 116.4, 70.9, 52.8, 44.3, 34.0, 33.5, 27.3, 26.3, 16.2. MS (MALDI-TOF):
m/z = 295 [M + H]+, 317 [M + Na]+. HR-MS (ESI) m/z: [M + H]+ calcd. for C16H31N4O: 295.24924;
found: 295.24933. [α]D 21◦ (c = 0.15, DCM). IR (ATR, solid): ν˜ [cm−1] = 3314, 3170, 3114, 2958,
2869, 1642, 1516, 1463, 1396, 1365, 1233, 1210, 1130, 987, 933, 818, 731, 661, 623, 495.
=
−
21
Ligand L14. Formaldehyde (37 wt% in H2O, 53.0 L, 650 mol, 1.3 equiv.) was added to L13 (154 mg,
500 mol) in 3 mL DCM. After addition of catalytic drops of glacial acetic acid, the reaction mixture
was stirred overnight at room temperature. Then sodium triacetoxyborohydride (159 mg, 750 mol)
µ
µ
µ
µ
was added to the reaction mixture which was stirred again overnight. Afterwards the reaction was
quenched with 10 mL saturated ammonium chloride solution, and stirred for 1.5 h. The organic layer
was separated and washed with water, dried over Na2SO4, filtered and concentrated. The target
compound was obtained as a white solid (50.0 mg, 155
rt): [ppm] = 6.89 (s, 1H), 6.82 (s, 1H), 6.75 (d, J = 8.3 Hz, 1H), 3.89 (dq, J = 9.5, 6.8 Hz, 1H), 3.78–3.65
(m, 5H), 2.52 (s, 1H), 2.48 (s, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.96 (s, 9H), 0.80 (s, 9H). 13C-NMR (100 MHz,
CDCl3, rt): [ppm] = 168.7, 145.8, 126.6, 121.4, 70.7, 53.3, 52.6, 41.6, 35.0, 33.5, 32.7, 27.3, 26.7, 16.4. MS
(MALDI-TOF): m/z = 323 [M + H]+. HR-MS (ESI) m/z: [M + H]+ calcd. for C18H35N4O: 323.280538;
found: 323.281289. [α]D 168◦ (c = 0.15, DCM). IR (ATR, solid): ν˜ [cm−1] = 3433, 3286, 2954, 2867,
µ
mol; 31% yield). 1H-NMR (300 MHz, CDCl3,
δ
δ
=
−
20
2805, 1649, 1532, 1502, 1451, 1364, 1262, 1178, 1128, 1113, 1013, 965, 811, 743, 708, 667, 626, 472.
Ligand L15. AlCl3 (130 mg, 0.973 mmol) was suspended in 15 mL of dry THF under inert atmosphere
cooled to 0 ◦C. Then 1 M LiAlH4 (2.9 mL, 2.920 mmol) was added and the reaction was stirred for

Molecules 2019, 24, 3182
17 of 22
◦
0.5 h at 0 C. Afterwards, L13 (50 mg, 0.162 mmol) dissolved in 3 mL was added of dry THF and
the reaction mixture was stirred 18 h at room temperature. The reaction mixture was poured onto
ice. After the emulsion reached room temperature, the mixture was filtered through a celite path,
followed by a washing step of celite with warm ethyl acetate. The resulting filtrate was condensed,
and the mixture was then extracted with ethyl acetate. The separated organic phase was treated with
Na2SO4 and afterwards, concentrated under reduced pressure. The crude product was purified via
column chromatography (SiO2, mobile phase gradient from CH2Cl2/(2.5% NH4OH in MeOH) 98:2 to
CH2Cl2/(2.5% NH4OH in MeOH) 9:1. The pure product was obtained as a white solid (37 mg, 77%
yield). 1H-NMR (300 MHz, CDCl3, rt):
δ [ppm] = 6.81 (d, J = 1.4 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H),
4.17–3.88 (m, 2H), 3.49 (s, 3H), 3.17 (dd, J = 11.2, 3.0 Hz, 1H), 2.99–2.71 (m, 2H), 2.64 (d, J = 6.8 Hz, 1H),
1.30 (d, J = 6.8 Hz, 3H), 1.07 (s, 9H), 0.93 (s, 9H). 13C-NMR (100 MHz, CDCl3, rt):
δ [ppm] = 147.45,
125.90, 121.05, 77.20, 66.10, 49.66, 45.28, 35.95, 34.23, 32.34, 26.58, 26.54, 12.68.
Ligand L16
obtained from unpurified raw material of (S)-N-[(R)-3,3-dimethylbutan-2-yl]pyrrolidine-2-carboxamide
[(S,R)-II, 2.88 mmol] and 1-methyl-2-imidazolecarboxaldehyde ( -Me-2, 317 mg, 2.88 mmol) after
recrystallization (DCM/pentane) as a white solid (229 mg, 790
mol; 27%). 1H-NMR (300 MHz, CDCl3,
.
The synthesis was carried out according to GP1. The target compound was
V
µ
rt): δ [ppm] = 7.30 (d, J = 9.8 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 3.93–3.69 (m,
3H), 3.63 (s, 3H), 3.23 (dd, J1 = 4.3 Hz, J2 = 10.1 Hz, 1H), 3.02 (dd, J1 = 4.4 Hz, J2 = 11.2 Hz, 1H),
2.64–2.55 (m, 1H), 2.22–1.67 (m, 4H), 0.93 (d, J = 6.8 Hz, 3H), 0.85 (s, 9H). 13C-NMR (100 MHz, CDCl3,
rt):
δ [ppm] = 173.3, 145.0, 127.6, 121.1, 67.5, 54.4, 51.8, 50.6, 34.3, 32.8, 31.0, 26.1, 24.3, 16.2. MS
(MALDI-TOF): m/z = 293 [M + H]+, 315 [M + Na]+, 607 [2M + Na]+. HR-MS (ESI) m/z: [M + H]+
calcd. for C16H29N4O: 293.233588; found: 293.234407. [α]D
ν˜ [cm−1] = 3354, 3100, 2965, 2870, 2803, 1662, 1511, 1455, 1367, 1285, 1133, 1035, 976, 934, 766, 653, 469.
=
49◦ (c = 0.15, DCM). IR (ATR, solid):
−
23
Ligand L17. The synthesis was carried out according to GP1. The target compound was
obtained from unpurified raw material (S)-2-amino-N-{(S)-1-[((R)-3,3-dimethylbutan-2-yl)amino]-
3,3-dimethyl-1-oxobutan-2-yl}-3,3-dimethylbutanamide [(S,S,R)-IV, 2.51 g, 7.70 mmol] and
1-methyl-2-imidazolecarboxaldehyde (
via column chromatography (SiO2, DCM/2.5% NH4OH in MeOH gradient from 98:2 to 9:1) as a white
solid (795 mg, 1.89 mmol; 24% yield). 1H-NMR (400 MHz, CDCl3, rt):
[ppm] = 7.55 (d, J = 9.8 Hz,
V-Me-2, 1.10 g, 10.0 mmol, 1.3 equiv.) after purification
δ
1H), 6.93 (d, J = 1.3 Hz, 1H), 6.80 (d, J = 1.3 Hz, 1H), 6.21 (d, J = 9.8 Hz, 1H), 4.32 (d, J = 9.8 Hz, 1H),
3.91–3.73 (m, 2H), 3.69 (s, 3H), 3.58 (d, J = 13.3 Hz, 1H), 2.79 (s, 1H), 1.05 (d, J = 6.9 Hz, 3H), 1.01 (s, 8H),
0.99 (s, 9H), 0.83 (s, 9H). 13C-NMR (100 MHz, 3 rt):
δ
[ppm] = 172.49, 170.07, 146.10, 126.78, 121.29,
73.05, 60.72, 52.70, 44.51, 34.33, 34.09, 33.96, 33.01, 27.33, 26.82, 26.16, 16.11. HR-MS (ESI) m/z: [M + H]+
calcd. for C23H44N5O2: 422.348952; found: 422.349351. [α]D
ν˜ [cm−1] = 3356, 3333, 3299, 2949, 2902, 2867, 1642, 1554, 1499, 1364, 1277, 1209, 1118, 918, 831, 758, 720,
=
19◦ (c = 0.15, DCM). IR (ATR, solid):
−
20
705, 666, 628, 559, 483.
3.4. X-ray Crystallographic Studies
Single crystal X-ray diffraction data were collected using a Bruker D8 VENTURE system operated
using the suite APEX 3 and the data collection temperature was controlled at 130 and 140 K using
an Oxford Cryostream system. The crystal structures were solved using ShelxT version 2017 [71],
and refined using ShelxL version 2018/1 [72].
Crystal refinement data for (S)-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethyl-2-[(Z)-(1-methyl-1H-
imidazol-2-yl) methyleneamino]butanamide, (S,R)-V-(d). Colourless crystals, C17H30N4O, M = 306.45,
orthorhombic, space group P212121, a = 6.9534(3), b = 14.0923(5), c = 18.9394(7) Å,
γ = 90◦, V = 1855.86 Å3, Z = 4, T = 140 K, refinement of 216 parameters on 3632 independent reflections
out of 12,787 measured reflections (Rint = 0.0347) led to R1 = 0.0376 (I > 2 (I)), wR2 = 0.0963 (all data).
α = 90, β = 90,
σ
Crystal refinement data for (S)-N-[(R)-3,3-dimethylbutan-2-yl]-3,3-dimethyl-2-[(1-methyl-1H-
imidazol-2-yl)methyl-amino]butanamide, L10. Colourless crystals, C17H33N4O, M = 308.46, monoclinic,

Molecules 2019, 24, 3182
18 of 22
space group P21, a = 8.0138(5), b = 13.0776(8), c = 9.4290(6) Å,
α
= 90,
β
= 108.996(4),
γ
= 90◦,
V = 934.357 Å3, Z = 2, T = 140 K, refinement of 212 parameters on 2823 independent reflections out of
12,635 measured reflections (Rint = 0.0854) led to R1 = 0.0528 (I > 2σ(I)), wR2 = 0.1363 (all data).
Crystallographic data for compounds (S,R)-V-(d) and L10 have been deposited with the Cambridge
Crystallographic Data Centre with deposition numbers CCDC 1858309-1858310, respectively.
4. Conclusions
Herein, we report new enantioselective non-heme iron-catalyzed epoxidations using H2O2,
by applying for the first time chiral imidazole based peptide-like ligands. We synthesized a set of
easily accessible ligands for in situ generation of chiral iron(III) catalysts and studied their ability
towards oxidation of terminal olefins, taking the imidazole substitution pattern, coordinating motif,
and further important functionalities into account. In this context we developed one of the first
biomimetic non-heme iron catalysts for epoxidation of challenging terminal alkenes.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: A.F. and J.V.-C. participated equally in the synthesis of the ligands and their evaluation in
iron(III)-catalyzed epoxidation of alkenes with H2O2. M.A.L.-R. performed the X-ray crystallographic analysis
and solved the structures of compounds (S,R)-V-(d) and ligand L10. E.J. and S.B.T. conceived the study and
supervised the project. All authors contributed to the writing of the manuscript.
Funding: Deutsche Forschungsgemeinschaft (DFG) grant number TS 87/13-1; Consejo Nacional de Ciencia y
Tecnología, CONACYT grant number 220945.
Acknowledgments: We thank the Deutsche Forschungsgemeinschaft (DFG) for research funding by the Grant
TS 87/13-1. Financial support by the Erika Giehrl-Stiftung (doctoral research fellowship) and by the Univ.
Erlangen-Nürnberg, Germany (FFL scholarship, Förderung der Chancengleichheit für Frauen in Forschung und
Lehre) for Anja Fingerhut is gratefully acknowledged. We thank Alexander Penny for synthesis of some ligand
precursors. We also thank the Graduate School Molecular Science (GSMS), Interdisciplinary Center for Molecular
Materials (ICMM) for research support. Financial support from Consejo Nacional de Ciencia y Tecnolog
CONACYT grant number 220945, is gratefully acknowledged. We are also grateful to Dr. Carlos Cruz-Hern
for useful comments.
í
a,
ández
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
2.
Yudin, A.K. (Ed.) Aziridines and Epoxides in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
Beauvais, B.; Sarfati, C.; Challier, S.; Derouin, F. In vitro model to assess effect of antimicrobial agents on
Encephalitozoon cuniculi. Antimicrob. Agents Chemother. 1994, 38, 2440–2448. [CrossRef] [PubMed]
Duffy, J.L.; Kevin, N.J.; Kirk, B.A.; Chapman, K.T.; Schleif, W.A.; Olsen, D.B.; Stahlhut, M.; Rutkowski, C.A.;
Kuo, L.C.; Jin, L.; et al. Synthesis and activity of novel HIV protease inhibitors with improved potency
against multiple PI-resistant viral strains. Bioorg. Med. Chem. 2002, 12, 2423–2426. [CrossRef]
Nachbauer, L.; Brückner, R. Synthesis of a Cn–Cn+6 Building Block Common to Important Polyol, Polyene
Antibiotics from a Divinylcarbinol by a Desymmetrizing Sharpless Epoxidation. Eur. J. Org. Chem. 2013
2013, 6545–6562. [CrossRef]
Nakazawa, M.; Uehara, T.; Nomura, Y. Koningic Acid (a Potent Glyceraldehyde-3-Phosphate Dehydrogenase
Inhibitor)-Induced Fragmentation and Condensation of DNA in NG108-15 Cells. J. Neurochem. 1997
68, 2493–2499. [CrossRef] [PubMed]
Sunohara, K.; Mitsuhashi, S.; Shigetomi, K.; Ubukata, M. Discovery of N-(2,3,5-triazoyl)mycophenolic amide and
mycophenolic epoxyketone as novel inhibitors of human IMPDH. Bioorg. Med. Chem. Lett. 2013, 23, 5140–5144.
[CrossRef] [PubMed]
3.
4.
5.
6.
,
,
7.
8.
Piontek, A.; Bisz, E.; Szostak, M. Iron-catalyzed cross-couplings in the synthesis of pharmaceuticals: In pursuit
of sustainability. Angew. Chem. Int. Ed. 2018, 57, 11116–11128. [CrossRef] [PubMed]
Enthaler, S.; Junge, K.; Beller, M. Sustainable Metal Catalysis with Iron: From Rust to a Rising Star?
Angew. Chem. Int. Ed. 2008, 47, 3317–3321. [CrossRef] [PubMed]

Molecules 2019, 24, 3182
19 of 22
9.
Groves, J.T.; Myers, R.S. Catalytic asymmetric epoxidations with chiral iron porphyrins. J. Am. Chem. Soc.
1983, 105, 5791–5796. [CrossRef]
10. Groves, J.T.; Viski, P. Asymmetric hydroxylation by a chiral iron porphyrin. J. Am. Chem. Soc. 1989, 111, 8537–8538.
[CrossRef]
11. Collman, J.P.; Wang, Z.; Straumanis, A.; Quelquejeu, M.; Rose, E. An Efficient Catalyst for Asymmetric
Epoxidation of Terminal Olefins. J. Am. Chem. Soc. 1999, 121, 460–461. [CrossRef]
12. Darwish, M.; Wills, M. Asymmetric catalysis using iron complexes—‘Ruthenium Lite’? Catal. Sci. Technol.
2012, 2, 243–255. [CrossRef]
13. Schomburg, D.; Schomburg, I.; Chang, A. (Eds.)Class1OxidoreductasesX:EC1.9–1.13; Springer: Berlin/Heidelberg,
Germany, 2007.
14. Karlsson, A.; Parales, J.V.; Parales, R.E.; Gibson, D.T.; Eklund, H.; Ramaswamy, S. Crystal Structure of
Naphthalene Dioxygenase: Side-on Binding of Dioxygen to Iron. Science 2003, 299, 1039–1042. [CrossRef]
[PubMed]
15. Bruijnincx, P.C.; Buurmans, I.L.; Gosiewska, S.; Moelands, M.A.; Lutz, M.; Spek, A.L.; van Koten, G.;
Klein Gebbink, R.J. Iron(II) Complexes with Bio-Inspired N,N,O Ligands as Oxidation Catalysts: Olefin
Epoxidation and cis-Dihydroxylation. Chem. Eur. J. 2008, 14, 1228–1237. [CrossRef] [PubMed]
16. Schroder, K.; Join, B.; Amali, A.J.; Junge, K.; Ribas, X.; Costas, M.; Beller, M. A Biomimetic Iron Catalyst
for the Epoxidation of Olefins with Molecular Oxygen at Room Temperature. Angew. Chem. Int. Ed. 2011
50, 1425–1429. [CrossRef] [PubMed]
,
17. Schroder, K.; Enthaler, S.; Bitterlich, B.; Schulz, T.; Spannenberg, A.; Tse, M.K.; Junge, K.; Beller, M. Design of
and Mechanistic Studies on a Biomimetic Iron–Imidazole Catalyst System for Epoxidation of Olefins with
Hydrogen Peroxide. Chem. Eur. J. 2009, 15, 5471–5481. [CrossRef] [PubMed]
18. Francis, M.B.; Jacobsen, E.N. Discovery of Novel Catalysts for Alkene Epoxidation from Metal-Binding
Combinatorial Libraries. Angew. Chem. Int. Ed. 1999, 38, 937–941. [CrossRef]
19. Hasan, K.; Brown, N.; Kozak, C.M. Iron-catalyzed epoxidation of olefins using hydrogen peroxide. Green Chem.
2011, 13, 1230–1237. [CrossRef]
20. Jiao, M.; Matsunaga, H.; Ishizuka, T. A simple, Iron-Catalyzed, Pyridine-Assisted Hydrogen Peroxide
Epoxidation System. Chem. Pharm. Bull. 2011, 59, 799–801. [CrossRef]
21. Gelalcha, F.G.; Bitterlich, B.; Anilkumar, G.; Tse, M.K.; Beller, M. Iron-Catalyzed Asymmetric Epoxidation of
Aromatic Alkenes Using Hydrogen Peroxide. Angew. Chem. Int. Ed. 2007, 46, 7293–7296. [CrossRef]
22. Gelalcha, F.G.; Anilkumar, G.; Tse, M.K.; Bruckner, A.; Beller, M. Biomimetic Iron-Catalyzed Asymmetric
Epoxidation of Aromatic Alkenes by Using Hydrogen Peroxide. Chem. Eur. J. 2008, 14, 7687–7698. [CrossRef]
23. Bitterlich, B.; Schröder, K.; Tse, M.K.; Beller, M. An Improved Iron-Catalyzed Epoxidation of Aromatic and
Aliphatic Olefins with Hydrogen Peroxide as Oxidant. Eur. J. Org. Chem. 2008, 4867–4870. [CrossRef]
24. Schröder, K.; Tong, X.; Bitterlich, B.; Tse, M.K.; Gelalcha, F.G.; Brückner, A.; Beller, M. Novel biomimetic
iron-catalysts for environmentally benign epoxidations of olefins. Tetrahedron Lett. 2007, 48, 6339–6342.
[CrossRef]
25. Schröder, K.; Junge, K.; Spannenberg, A.; Beller, M. Design of a bio-inspired imidazole-based iron catalyst for
epoxidation of olefins: Mechanistic insights. Catal. Today 2010, 157, 364–370. [CrossRef]
26. Costas, M.; Que, J.L. Ligand Topology Tuning of Iron-Catalyzed Hydrocarbon Oxidations. Angew. Chem.
Int. Ed. 2002, 41, 2179–2181. [CrossRef]
27. Mas-Balleste, R.; Costas, M.; van den Berg, T.; Que, L., Jr. Ligand Topology Effects on Olefin Oxidations by
Bio-Inspired [FeII(N2Py2)] Catalysts. Chem. Eur. J. 2006, 12, 7489–7500. [CrossRef] [PubMed]
28. Cusso, O.; Garcia-Bosch, I.; Ribas, X.; Lloret-Fillol, J.; Costas, M. Asymmetric Epoxidation with H2O2 by
Manipulating the Electronic Properties of Non-heme Iron Catalysts. J. Am. Chem. Soc. 2013, 135, 14871–14878.
[CrossRef] [PubMed]
29. Cusso, O.; Ribas, X.; Lloret-Fillol, J.; Costas, M. Synergistic Interplay of a Non-Heme Iron Catalyst and Amino
Acid Coligands in H2O2 Activation for Asymmetric Epoxidation of α-Alkyl-Substituted Styrenes. Angew.
Chem. Int. Ed. 2015, 54, 2729–2733. [CrossRef]
30. Cusso, O.; Giuliano, M.W.; Ribas, X.; Miller, S.J.; Costas, M. A bottom up approach towards artificial oxygenases
by combining iron coordination complexes and peptides. Chem. Sci. 2017, 8, 3660–3667. [CrossRef]

Molecules 2019, 24, 3182
20 of 22
31. Wu, M.; Miao, C.-X.; Wang, S.; Hu, X.; Xia, C.; Kühn, F.E.; Sun, W. Chiral Bioinspired Non-Heme Iron Complexes
for Enantioselective Epoxidation of
[CrossRef]
α,β-Unsaturated Ketones. Adv. Synth. Catal. 2011, 353, 3014–3022.
32. Wang, B.; Wang, S.; Xia, C.; Sun, W. Highly Enantioselective Epoxidation of Multisubstituted Enones
Catalyzed by Non-Heme Iron Catalysts. Chem. Eur. J. 2012, 18, 7332–7335. [CrossRef]
33. Lyakin, O.Y.; Ottenbacher, R.V.; Bryliakov, K.P.; Talsi, E.P. Asymmetric Epoxidations with H2O2 on Fe and
Mn Aminopyridine Catalysts: Probing the Nature of Active Species by Combined Electron Paramagnetic
Resonance and Enantioselectivity Study. ACS Catal. 2012, 2, 1196–1202. [CrossRef]
34. Lancaster, M. Green Chemistry: An Introductory Text, 3rd ed.; RSC Internet Services: London, UK, 2016.
35. Lane, B.S.; Burgess, K. Metal-Catalyzed Epoxidations of Alkenes with Hydrogen Peroxide. Chem. Rev. 2003
,
103, 2457–2473. [CrossRef] [PubMed]
36. Held, F.E.; Wei, S.; Eder, K.; Tsogoeva, S.B. One-pot route to β-adrenergic blockers via enantioselective
organocatalysed epoxidation of terminal alkenes as a key step. RSC Adv. 2014, 4, 32796–32801. [CrossRef]
37. Fingerhut, A.; Serdyuk, O.V.; Tsogoeva, S.B. Non-heme iron catalysts for epoxidation and aziridination
reactions of challenging terminal alkenes: Towards sustainability. Green Chem. 2015, 17, 2042–2058. [CrossRef]
38. Yeung, H.L.; Sham, K.C.; Tsang, C.S.; Lau, T.C.; Kwong, H.L. A chiral iron-sexipyridine complex as a catalyst
for alkene epoxidation with hydrogen peroxide. Chem. Commun. 2008, 3801–3803. [CrossRef] [PubMed]
39. Hieke, M.; Greiner, C.; Thieme, T.M.; Schubert-Zsilavecz, M.; Werz, O.; Zettl, H. A novel class of dual
mPGES-1/5-LO inhibitors based on the
21, 1329–1333. [CrossRef]
α-naphthyl pirinixic acid scaffold. Bioorg. Med. Chem. Lett. 2011,
40. Shukla, M.R.; Chaudhari, V.D.; Sayyed, M.B.; Phadtare, R.D.; Walke, N.B.; Kulkarni, S.A.; Palle, V.P.;
Kamboj, R.K. Substituted Morpholines as Modulators for the Calcium Sensing Receptor. Patent Number
WO2012120476 A1, 13 Septemper 2012.
41. Bitterlich, B.; Anilkumar, G.; Gelalcha, F.G.; Spilker, B.; Grotevendt, A.; Jackstell, R.; Tse, M.K.; Beller, M.
Development of a General and Efficient Iron-Catalyzed Epoxidation with Hydrogen Peroxide as Oxidant.
Chem. Asian J. 2007, 2, 521–529. [CrossRef]
42. Stingl, K.A.; Weiß, K.M.; Tsogoeva, S.B. Asymmetric vanadium- and iron-catalyzed oxidations: New mild
(R)-modafinil synthesis and formation of epoxides using aqueous H2O2 as a terminal oxidant. Tetrahedron
2012, 68, 8493–8501. [CrossRef]
43. Muñiz, K. Asymmetrische Katalyse mit Metall-Komplexen. Bild oder Spiegelbild? Chem. Unserer Zeit 2006
,
40, 112–124. [CrossRef]
44. White, M.C.; Doyle, A.G.; Jacobsen, E.N. A Synthetically Useful, Self-Assembling MMO Mimic System for
Catalytic Alkene Epoxidation with Aqueous H2O2. J. Am. Chem. Soc. 2001, 123, 7194–7195. [CrossRef]
45. Dubois, G.; Murphy, A.; Stack, T.D. Simple Iron Catalyst for Terminal Alkene Epoxidation. Org. Lett. 2003
,
5, 2469–2472. [CrossRef] [PubMed]
46. Fujita, M.; Que, L., Jr. In situ Formation of Peracetic Acid in Iron-Catalyzed Epoxidations by Hydrogen
Peroxide in the Presence of Acetic Acid. Adv. Synth. Catal. 2004, 346, 190–194. [CrossRef]
47. Yeori, A.; Gendler, S.; Groysman, S.; Goldberg, I.; Kol, M. Salalen: A hybrid Salan/Salen tetradentate
[ONNO]-type ligand and its coordination behavior with group IV metals. Inorg. Chem. Commun. 2004
7, 280–282. [CrossRef]
,
48. Matsumoto, K.; Saito, B.; Katsuki, T. Asymmetric catalysis of metal complexes with non-planar ONNO
ligands: Salen, salalen and salan. Chem. Commun. 2007, 3619–3627. [CrossRef] [PubMed]
49. Zhao, Y.; Mitra, A.W.; Hoveyda, A.H.; Snapper, M.L. Kinetic Resolution of 1,2-Diols through Highly Site-
and Enantioselective Catalytic Silylation. Angew. Chem. Int. Ed. 2007, 46, 8471–8474. [CrossRef]
50. Rodrigo, J.M.; Zhao, Y.; Hoveyda, A.H.; Snapper, M.L. Regiodivergent Reactions through Catalytic
Enantioselective Silylation of Chiral Diols. Synthesis of Sapinofuranone, A. Org. Lett. 2011, 13, 3778–3781.
[CrossRef] [PubMed]
51. Manville, N.; Alite, H.; Haeffner, F.; Hoveyda, A.H.; Snapper, M.L. Enantioselective silyl protection of
alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. Nat. Chem. 2013, 5, 768–774.
[CrossRef] [PubMed]

Molecules 2019, 24, 3182
21 of 22
52. You, Z.; Hoveyda, A.H.; Snapper, M.L. Catalytic Enantioselective Silylation of Acyclic and Cyclic Triols:
Application to Total Syntheses of Cleroindicins D., F., and C. Angew. Chem. Int. Ed. 2009, 48, 547–550.
[CrossRef] [PubMed]
53. Zhang, W.; Loebach, J.L.; Wilson, S.R.; Jacobsen, E.N. Enantioselective epoxidation of unfunctionalized
olefins catalyzed by salen manganese complexes. J. Am. Chem. Soc. 1990, 112, 2801–2803. [CrossRef]
54. Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Additive Effects on Asymmetric Catalysis. Chem. Rev. 2016
116, 4006–4123. [CrossRef]
,
55. Avila-Ortiz, C.G.; López-Ortiz, M.; Vega-Peñaloza, A.; Regla, I.; Juaristi, E. Use of (R)-Mandelic Acid as
Chiral Co-Catalyst in the Michael Addition Reaction Organocatalyzed by (1S,4S)-2-Tosyl-2,5-diazabicyclo
[2.2.1]heptane under Solvent-Free Conditions. Asymmetric Catal. 2015, 2, 37–44. [CrossRef]
56. Dicks, A.P.; Hent, A. Atom Economy and Reaction Mass Efficiency. In Green Chemistry Metrics: A Guide to
Determining and Evaluating Process Grenness; Springer: Heidelberg, Germany, 2015; pp. 17–44.
57. Zhang, C.P.; Wang, Z.L.; Chen, Q.Y.; Zhang, C.T.; Gu, Y.C.; Xiao, J.C. Generation of the CF3 radical from
trifluoromethylsulfonium triflate and its trifluoromethylation of styrenes. Chem. Commun. 2011, 47, 6632–6634.
[CrossRef] [PubMed]
58. Yao, C.Z.; Li, Q.Q.; Wang, M.M.; Ning, X.S.; Kang, Y.B. (E)-Specific direct Julia-olefination of aryl alcohols
without extra reducing agents promoted by bases. Chem. Commun. 2015, 51, 7729–7732. [CrossRef] [PubMed]
59. Kobayashi, Y.; Inukai, S.; Asai, N.; Oyamada, M.; Ikegawa, S.; Sugiyama, Y.; Hamamoto, H.; Shioiri, T.;
Matsugi, M. A comparative study of the asymmetric epoxidation of aromatic olefins using the first generation
manganese salen epoxidation catalysts and their light fluorous variants: An interesting discovery on the use
of benzotrifluoride as a cosolvent. Tetrahedron Asymmetry 2014, 25, 1209–1214. [CrossRef]
60. Yadav, V.K.; Kapoor, K.K. 1,8-diazabicyclo [5.4.0] undec-7-ene: A remarkable base in the epoxidation of
α
,
β
-unsaturated-
[CrossRef]
61. Zandbergen, P.; van den Niewendijk, A.M.C.H.; Brussee, J.; van der Gen, A.; Kruse, C.G. A one-pot
δ-lactones and other enones with anhydrous t-BuOOH. Tetrahedron 1995, 51, 8573–8584.
reduction-transimition-reduction synthesis of N-substituted
1992, 48, 3977–3982. [CrossRef]
β-ethanolamines from cyanohydrins. Tetrahedron
62. Robinson, M.W.; Davies, A.M.; Buckle, R.; Mabbett, I.; Taylor, S.H.; Graham, A.E. Epoxide ring-opening and
Meinwald rearrangement reactions of epoxides catalyzed by mesoporous aluminosilicates. Org. Biomol. Chem.
2009, 7, 2559–2564. [CrossRef]
63. Pedragosa-Moreau, S.; Morisseau, C.; Zylber, J.; Archelas, A.; Baratti, J.; Furstoss, R. Microbiological
Transformations. 33. Fungal Epoxide Hydrolases Applied to the Synthesis of Enantiopure Para-Substituted
Styrene Oxides. A Mechanistic Approach. J. Org. Chem. 1996, 61, 7402–7407. [CrossRef]
64. Grigg, R.D.; Rigoli, J.W.; Pearce, S.D.; Schomaker, J.M. Synthesis of Propargylic and Allenic Carbamates via
the C–H Amination of Alkynes. Org. Lett. 2012, 14, 280–283. [CrossRef]
65. Fristrup, P.; Dideriksen, B.B.; Tanner, D.; Norrby, P.O. Probing Competitive Enantioselective Approach
Vectors Operating in the Jacobsen
J. Am. Chem. Soc. 2005, 127, 13672–13679. [CrossRef]
−
Katsuki Epoxidation: A Kinetic Study of Methyl-Substituted Styrenes.
66. Alvaro, G.; D
é
cor, A.; Fontana, S.; Hamprecht, D.; Large, C.; Marasco, A. Imidazolidinedione Derivatives.
Patent Number WO2011069951 A1, 16 June 2011.
67. Huy, P.; Neudorfl, J.M.; Schmalz, H.G. A Practical Synthesis of Trans-3-Substituted Proline Derivatives
through 1,4-Addition. Org. Lett. 2011, 13, 216–219. [CrossRef] [PubMed]
68. Gebert, U.; Kerékjártó
, B.V. Modellreaktionen für die enzymatische Katalyse, IV1) Untersuchungen zur
Struktur-Wirkung-Beziehung neuer Transaminatoren mit Imidazol-, Thiazol- und Benzimidazolgerüst.
Justus Liebigs Ann. Chem. 1974, 1974, 644–654. [CrossRef]
69. Kodera, M.; Terasako, N.; Kita, T.; Tachi, Y.; Kano, K.; Yamazaki, M.; Koikawa, M.;
Tokii, T. Synthesis, Crystal Structures, and Catalytic Activity of Dicopper(II) Complexes with
Dinucleating Tetraimidazole Ligands [Cu2(RO)(mbipl)](ClO4)2 (R = Me, Et, 2-Pr; Hmbipl =
1,5-Bis[bis[(1-methyl-4-imidazolyl)methyl]amino]-3-pentanol) and [Cu2(MeO)(pbipl)](ClO4)2 (Hpbipl =
1,5-Bis[bis[(1-isopropyl-4-imidazolyl)methyl]amino]-3-pentanol). Inorg. Chem. 1997, 36, 3861–3868.
70. Zhao, Y.; Rodrigo, J.; Hoveyda, A.H.; Snapper, M.L. Enantioselective silyl protection of alcohols catalysed by
an amino-acid-based small molecule. Nature 2006, 443, 67–70. [CrossRef] [PubMed]

Molecules 2019, 24, 3182
22 of 22
71. Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Crystallogr. Sect.
A Found. Crystallogr. 2015, 71, 3–8. [CrossRef] [PubMed]
72. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C Cryst. Struct. Commun.
2015, 71, 3–8. [CrossRef] [PubMed]
Sample Availability: Samples of the ligands (S,R)-I, L10 and L17 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).