Highly Enantioselective Epoxidation of α,β-Unsaturated Ketones Using Amide-Based Cinchona Alkaloids as Hybrid Phase-Transfer Catalysts

Article abstract of DOI:10.1021/acs.orglett.0c03272

A series of 20 one chiral epoxides were obtained with excellent yields (up to 99%) and enantioselectivities (up to >99% ee) using hybrid amide-based Cinchona alkaloids. Our method is characterized by low catalyst loading (0.5 mol %) and short reaction times. Moreover, the epoxidation process can be carried out in 10 cycles, without further catalyst addition to the reaction mixture. This methodology significantly enhance the scale of the process using very low catalyst loading.

Full text of DOI:10.1021/acs.orglett.0c03272

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Letter
Highly Enantioselective Epoxidation of α,β-Unsaturated Ketones
Using Amide-Based Cinchona Alkaloids as Hybrid Phase-Transfer
Catalysts
Maciej Majdecki,† Agata Tyszka-Gumkowska,† and Janusz Jurczak*
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ABSTRACT: A series of 20 one chiral epoxides were obtained with excellent yields (up to 99%) and enantioselectivities (up to
>99% ee) using hybrid amide-based Cinchona alkaloids. Our method is characterized by low catalyst loading (0.5 mol %) and short
reaction times. Moreover, the epoxidation process can be carried out in 10 cycles, without further catalyst addition to the reaction
mixture. This methodology significantly enhance the scale of the process using very low catalyst loading.
compounds, peptides, guanidine salts, prolines, etc., have also
been used, albeit without high enantioselectivities.17
atalytic enantioselective epoxidation of allylic alcohols,
1
Cintroduced by Sharpless
in the 1980s, has been
Despite recent spectacular progress in asymmetric epoxida-
tion of E-chalcones, there are several issues that prevent their
general applicability. The main disadvantages of the methods
discussed are as follows: multistep synthesis of catalysts, high
catalyst loading, a frequent necessity to use special techniques,
and long reaction times. Therefore, there is a strong need for
research on rationally designed and efficient PTC catalysts,
especially chiral ones, which meet additional requirements
related to the possibility of their reuse. Herein, we report our
own approach to enantioselective epoxidation by introducing a
readily available and finely tunable library of hybrid Cinchona
alkaloid-based catalysts, the potential application of which we
have previously demonstrated in studies on alkylation of imino
glycine esters.18
recognized as one of the most significant tools in asymmetric
synthesis, since epoxides are considered versatile building blocks
and intermediates in asymmetric organic transformations.2,3
This fundamental discovery has significantly expanded over the
last 40 years, especially in the field of metal catalysis4 and
organocatalysis.5 With the growing demand for green and
sustainable chemistry, the development of environmentally
benign and cheap catalysts remains a great challenge in
stereocontrolled organic synthesis.6 In this area, phase-transfer
catalysis (PTC) has become established as a comprehensive
method,7 owing to mild reaction conditions, operational
simplicity, and no use of heavy metals. Particular attention in
such work has been devoted to the asymmetric epoxidation of
α,β-unsaturated ketones,3a,8−10 as an extension of the pioneering
work by Wynberg et al.11 on epoxidation of E-chalcones using
quinine salts as catalysts. However, successful examples of highly
enantioselective synthesis of epoxyketones still remain few in
number. The most representative continuations of Wynberg’s
discovery were published in the 1990s by the Lygo12 and
Corey13 groups. Alternative methods to improving the abilities
of Cinchona-based catalysts were presented by the Park14 and
Siva15 groups, who showed that adding surfactants to reaction
mixtures or using ultrasound support increased the enantiomeric
excess of products formed. On the other hand, Maruoka et al.16
introduced efficient, but expensive, BINOL-based catalysts.
Furthermore, other types of PTC catalysts, such as macrocyclic
We began the present study with epoxidation of model E-
chalcone S1 using cinchonidine-based catalyst C1, leading to
product P1 with high yield (91%), but low enantioselectivity
(29% ee), as shown in Scheme 1. Next, we carried out catalyst
screening under the given conditions, and we found that
Received: September 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03272
© XXXX American Chemical Society
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a
Scheme 1. Scope of Hybrid Cinchona-Based Catalysts
Scheme 2. Asymmetric Epoxidation of α,β-Unsaturated
a
Ketones S1−S21 Using Catalyst C5
a
The ee values were determined by HPLC analysis using a chiral
column Kromasil OD-H or Chiralcel AD-H and OB-H.
compound C5 allows the desired epoxides to be obtained with
high yield (99%) and promising enantiomeric excess (71% ee).
Also, reactions with catalysts based on the other Cinchona
alkaloids give the desired products with excellent yield, but in
racemic form.
Subsequently, we started to optimize the reaction conditions
using C5 as the catalyst, and we noted that the ratio of hydrogen
peroxide and aqueous solution of NaOH strongly affected the
enantioselectivity. We postulate that the oxidant/base ratio
affects the rate of hydrogen peroxide decomposition and
formation of the reactive HOO− ion. Moreover, instead of
toluene we found that a mixture of Et2O/toluene (1:1) was the
best solvent for most of these reactions. Finally, we showed that
epoxidation of chalcone S1 under the newly found conditions
was very efficient and proceeded for 1 h with an excellent
enantiomeric excess (99% ee), using only 0.5 mol % of catalyst at
5 °C temperature. Lower catalyst loading resulted in decreased
yield and ee value. All details of the optimization process are
presented in the Supporting Information (Tables S2−S6).
Under such optimal conditions we examined the reactivity and
selectivity of α,β-unsaturated ketones S1−S21 as shown in
Scheme 2.
All of the epoxides P1−P21 were obtained from the
corresponding substrates S1−S21 with both excellent yield
and excellent enantioselectivity. For substrates S1−S13, with
various electron-differentiating substituents on the carbonyl
group side, no significant changes in the extremely high
selectivities (95−99% ee) were observed. Due to lower solubility
of epoxides P6, P10, and P12 in the diethyl ether, reactions
should be carried out longer (up to 48 h). Slightly lower
enantiomeric excesses were noted for epoxidation of E-
chalcones with an electron-differentiating substituents in the
phenyl ring on the double bond side S14−S17. In those four
cases, achievement of complete conversion required the use of 1
mol % of the catalyst and the reactions were carried out in
toluene (P13−P16 marked green, Scheme 2), but we noted very
high yields and ee values (92−99%, 90−96% ee). With more
challenging substrates S18−S21 we performed the epoxidation
reactions with 3 mol % of the catalyst C5 and also in these cases
we choose toluene as an optimal solvent (P18−P21 marked
purple, Scheme 2). Epoxidation of S20 was conducted 72 h
a
The ee values were determined by HPLC analysis using a chiral
b
column Kromasil OD-H or Chiralcel AD and OB-H. The ee values
were determined by HPLC analysis using a chiral column Kromasil
OD-H or Chiralcel AD and OB-H. Reactions were carried out in
toluene, and 1 mol % of C5 was used.
c
leading to product with moderate yield 71% and high
enantiomeric excess 97% ee. It is worth mentioning the great
results obtained for (2E,4E)-1,5-diphenylpenta-2,4-dien-1-one
S18 (95% yield, 96% ee) and α,β-unsaturated ketone S21
containing aliphatic substituent (98% yield, 99% ee). In
addition, all epoxides, except P20, can be isolated from organic
layer using simple filtration by silica gel pad. Such results
indicate a fairly universal character of the developed method,
and to the best of our knowledge it is a first example of successful
epoxidation such substrates using organocatalysts.
The obtained results may indicate a competitive π-stacking
effect originating from the phenyl system on the double bond
side, which may adversely affect the formation of the
diastereomeric complex with the catalyst C5. In order to explain
such high selectivity, we obtained monocrystals of C5 by slowly
evaporation of its saturated solution in wet acetone. Next, we
performed a successful single-crystal X-ray diffraction analysis of
catalyst C5 (for details see the Supporting Information), which
revealed its distinctive three-dimensional structure (Figure 1).
Let us consider one of the catalyst molecules as it occurs in a
single crystal. The C5 molecule has an aromatic ring stacked in
the direction determined by the amide function. Importantly,
the arrangement of the phenyl group in the amide arm is nearly
perpendicular, this conformational information creating an
attractive chiral reaction cavity around the amide function. This
B
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The above results turned our attention to the possibility of
further improving our reaction. After confirming the stability of
catalyst C5 under PTC-epoxidation conditions, we decided to
investigate the possibility of its reuse. Scheme 3 presents our
concept of conducting 10 epoxidation cycles under subsequent
conditions. The chalcone S1, in the presence of 1 mol % of
catalyst C5, was used for the first reaction cycle.
After completion of the reaction, another portion of hydrogen
peroxide and aqueous NaOH, accompanied by chalcone S1
were added (the second cycle). This procedure was repeated
after each reaction cycle in order to maintain full conversion of
the reaction. Thus, we were able to carry out epoxidation of
chalcone S1 on a 5 g scale, after 10 reaction cycles, and the
product was obtained in total with 97% yield and >99% ee. Note
that during eight reaction cycles, the model catalytic reaction did
not lose any efficiency or enantioselectivity; however, we
terminated the experiment after the tenth cycle due to the
slightly lowering of the conversion (to 97%). Given that the
epoxidation reaction is very clean, after isolation of the desired
product P1, we were also able to recover the catalyst C5 from a
postreaction mixture with 99% efficiency, simply by precipitat-
ing it with the addition of diethyl ether. Given these advantages,
the discussed procedure is an excellent solution for epoxidation
on a multigram scale, as only 0.1 mol % of the catalyst was used,
based on the final amount of the product obtained. Note that
when such catalyst loading under classical batch conditions
(without sequential addition of reagents) was used, the products
were obtained in the form of a racemate with low yield. Such
high efficiency of sequential addition of reagents is observed due
to the continuous presence of 1 mol % of catalyst in the reaction
mixture, which does not lose its activity over time or in the
presence of the product.
Figure 1. X-ray structure of selected molecule of catalyst C5. The
solvent molecules, anions, and nonacidic protons were omitted for
clarity, and thermal ellipsoids are drawn at the 50% probability level.
strongly implies that the expected hydrogen-bonding interaction
would indeed bring an enone inside the cavity to provide an ideal
proximity to the hydrogen peroxide ion. This hypothesis is
supported by studies with N-methylated catalyst C5 in which we
obtained a racemic epoxide P1. Our proposed model of the
transition state (Figure 2) posits that the chalcone substrate is
stabilized by the hydrogen bond from the amide function of a
catalyst.
Figure 2. Proposed transition-state model for catalyst C5 with E-
chalcone.
In summary, we have developed an efficient method for the
preparation of enantiomerically pure epoxyketones using hybrid
amide-based Cinchona alkaloids as catalysts under PTC
conditions. The low loading (0.5 mol %) of highly effective
catalysts allowed us to obtain a wide range of such chiral
epoxyketones with very high yields and with excellent
enantioselectivity (up to 99% and 99% ee, respectively). To
the best of our knowledge, these are unique results as compared
to those obtained with application of known catalysts, while
maintaining such low catalyst loading. Additionally, for the first
A key element determining the high enantioselection of the
reaction is the phenyl ring from the amide arm which has a π−π
stacking interaction with the β-phenyl group of substrate. Such
interactions block one of the E-chalcone faces. Moreover, the
hydroxyl group of the catalyst forms an ionic pair with the
hydrogen peroxide ion (HOO−) via a hydrogen bond.
Consequently, the hydrogen peroxide can reach the β-carbon
atom of an enone exclusively from above to afford the αS,βR-
product of epoxidation.
Scheme 3. Multigram Synthesis of Epoxide P1 Using Subsequent Epoxidation Reactions
C
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time we presented the possibility of reusing Cinchona derivatives
in the synthesis of optically pure epoxy ketones by follow-up
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between subsequent reactions. This approach could be highly
valuable in the synthesis of potential building blocks in the field
of medicinal, agrochemical, and material chemistry on a large
scale. Further work on applying our catalyst library to
asymmetric epoxidation with other enones is in progress.
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ASSOCIATED CONTENT
* Supporting Information
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Oligopeptides as catalysts for asymmetric epoxidation. Biopolymers
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Asymmetric Epoxidation of Olefins Catalyzed by Chiral Ketones and
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covalent Organocatalytic Approach in the Asymmetric Epoxidation of
Electron-Poor Alkenes: Recent Developments Frontiers of Green Catalytic
Selective Oxidations; Springer: Singapore, 2019. (e) Triandafillidi, I.;
Tzaras, D. I.; Kokotos, Ch. G. Green Organocatalytic Oxidative
Methods using Activated Ketones. ChemCatChem 2018, 10, 2521−
2535.
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sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03272.
General remarks, experimental procedures, character-
ization of products, NMR spectra, and HPLC chromato-
grams (PDF)
Accession Codes
CCDC 2016792 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(6) (a) Tavakolian, M.; Vahdati-Khajeh, S.; Asgari, S. Recent
Advances in Solvent-Free Asymmetric Catalysis. ChemCatChem
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Oxygenations with the Environmentally Benign Oxidants H. Chem. Rev.
2017, 117, 11406−11459.
(7) For recent reviews on asymmetric phase-transfer catalysis, see:
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Phase-Transfer Catalysis with Achiral Schiff Base Esters. Acc. Chem. Res.
2004, 37, 506. (b) Jew, S-s.; Park, H-h. Cinchona-based phase-transfer
catalysts for asymmetric synthesis. Chem. Commun. 2009, 14, 7090−
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AUTHOR INFORMATION
Corresponding Author
■
Janusz Jurczak − Institute of Organic Chemistry, Polish Academy
of Sciences, 01-224 Warsaw, Poland; orcid.org/0000-0002-
0351-6614; Email: jurczak_group@icho.edu.pl
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03272
Author Contributions
†M.M. and A.T.-G. contributed equally.
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Epoxidation of α,β-Enones Promoted by α,α-Diphenyl-l-prolinol as
Bifunctional Organocatalyst. Org. Lett. 2005, 7, 2579−2582. (b) Li, Y.;
Liu, X.; Yang, Y.; Zhao, G. 4-Substituted- α,α-diaryl-prolinols Improve
the Enantioselective Catalytic Epoxidation of α,β-Enones. J. Org. Chem.
2007, 72, 288−291. (c) Bondzic, B. P.; Urushima, T.; Ishikawa, H.;
Hayashi, Y. Asymmetric Epoxidation of α-Substituted Acroleins
Catalyzed by Diphenylprolinol Silyl Ether. Org. Lett. 2010, 12, 5434−
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L.; Lin, L. L.; Feng, X. M. Asymmetric catalytic epoxidation of α,β-
unsaturated carbonyl compounds with hydrogen peroxide: Additive-
free and wide substrate scope. Chem. Sci. 2012, 3, 1996−2000.
(b) Wang, B.; Miao, C. X.; Wang, S. F.; Xia, C. G.; Sun, W. Manganese
Catalysts with C1-Symmetric N4 Ligand for Enantioselective
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(c) Nishikawa, Y.; Yamamoto, H. Iron-Catalyzed Asymmetric
Epoxidation of β,β-Disubstituted Enones. J. Am. Chem. Soc. 2011,
133, 8432−8435. (d) Qian, Q.; Tan, Y.; Zhao, B.; Feng, T.; Shen, Q.;
Yao, Y. Asymmetric Epoxidation of Unsaturated Ketones Catalyzed by
Heterobimetallic Rare Earth-Lithium Complexes Bearing Phenoxy-
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge Poland’s National Science Centre (Project
2016/21/B/ST5/03352) for financial support.
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