Quest for Efficient Catalysts based on Zinc tert-Butyl Peroxides for Asymmetric Epoxidation of Enones: C2- vs C1-Symmetric Auxiliaries

Article abstract of DOI:10.1002/adsc.201500764

Zinc tert-butyl peroxide-based catalysts for the asymmetric epoxidation of enones using tert-butyl hydroperoxide as an oxidant have been developed. A comparative study of chiral monoanioninc N,N′-bidentate ligands, C₂-symmetric bisoxazolinates and C₁-symmetric enaminooxazolinates, revealed excellent performance of C₁-symmetric auxiliary ligands on catalytic asymmetric epoxidation of enones (up to 96% yield, 91% ee).

Full text of DOI:10.1002/adsc.201500764

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DOI: 10.1002/adsc.201500764
Very Important Publication
Quest for Efficient Catalysts based on Zinc tert-Butyl Peroxides
for Asymmetric Epoxidation of Enones: C2- vs C1-Symmetric
Auxiliaries
Abdul Raheem Keeri,a,b Iwona Justyniak,c Janusz Jurczak,a,d,*
b,
´
and Janusz Lewinski *
a
Faculty of Chemistry, University of Warsaw, Pasteura-1, 02093 Warsaw, Poland
Fax: (+48)-22-632.6681; phone: (+48)-22-343-2330; e-mail: jjurczak@chem.uw.edu.pl
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego-3, 00664 Warsaw, Poland
b
E-mail: lewin@ch.pw.edu.pl (home page: http://lewin.ch.pw.edu.pl)
Institute of Physical Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01224 Warsaw, Poland
Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01224 Warsaw, Poland
c
d
Received: August 14, 2015; Revised: October 29, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500764.
Abstract: Zinc tert-butyl peroxide-based catalysts
for the asymmetric epoxidation of enones using
tert-butyl hydroperoxide as an oxidant have been
developed. A comparative study of chiral mono-
anioninc N,N’-bidentate ligands, C2-symmetric bi-
soxazolinates and C1-symmetric enaminooxazoli-
nates, revealed excellent performance of C1-sym-
metric auxiliary ligands on catalytic asymmetric ep-
oxidation of enones (up to 96% yield, 91% ee).
highly enantioselective epoxidation of enones remains
elusive. In 1996, Enders et al.[11] reported the first stoi-
chiometric asymmetric epoxidation of a,b-unsaturated
ketones mediated by a Zn alkyl peroxide, which was
generated in situ from Et2Zn, (R,R)-N-methylpseu-
doephedrine and O2. Under such conditions, trans-
chalcone epoxidation was completed in 16 h with
61% ee. Since then, various structurally ill-defined Zn
catalysts possessing a BINOL moiety in combination
with tert-butyl hydroperoxide (TBHP) or cumene hy-
droperoxide (CMHP) have been developed for the
catalytic asymmetric epoxidation of a variety of
enones, providing the corresponding epoxides in good
yields and with very high enantiomeric excesses up to
96%.[5a–d]
Keywords: asymmetric catalysis; chiral auxiliaries;
epoxidation of enones; ligand design; zinc
In 2003, our group reported the first structurally au-
Asymmetric catalytic oxidation of olefins is a power- thenticated Zn alkyl peroxides[12] and demonstrated
ful tool to synthesize optically active epoxides, which that one of them, namely [(BDI)ZnOOEt]2 (BDI=b-
are a common motif in many biologically important diketiminate ligand), exhibits high efficiency in the
compounds and biosynthetic intermediates.[1] The stoichiometric epoxidation of trans-chalcone.[12a]
highly enantioselective epoxidation of a,b-unsaturat- More recently, these findings were extended to a
ed ketones is of particular interest because it offers catalytic system with TBHP as an oxidant using
an efficient route to many useful enantioenriched [(t-BuOO)Zn(ATI)]2 [ATI=(S,S)-N,N’-di-(1-phenyl-
products by selective functionalization of both car- ethyl)-aminotroponiminate] as a chiral catalyst. The
bonyl and epoxy groups. Over the last two decades, trans-chalcone was oxidized within 4 h at 08C to the
several methods have been developed to synthesize corresponding epoxide in 60% yield, but with low
this type of chiral epoxide that use chiral metal com- enantiomeric excess (29%).[5e] The latter studies[5e,12]
plexes as well as organocatalysts.[2] Reported catalytic provided the first structurally well-defined system for
metal-mediated systems include complexes of Li,[3] the epoxidation of trans-chalcone, so its further devel-
Mg,[4] Zn,[5] Fe,[6] and lanthanides (e.g., La,[7] Sm,[8] opment is highly desirable. Here, we report the cata-
and Yb[9]).
lytic enantioselective epoxidation of various a,b-unsa-
In terms of green and sustainable science, develop- turated ketones mediated by new Zn alkyl peroxides
ing catalytic systems with non-toxic metals such as Zn supported by monoanionic C2- and much less
is of great interest.[10] Nevertheless, despite continuous common C1-symmetric N,N-bidentate ligands.[13] Two
interest in this area, the well-defined Zn-catalyzed C2-symmetric bisoxazolinate ligands, 1a and 1b, and
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Quest for Efficient Catalysts based on Zinc tert-Butyl Peroxides
Table 1. Catalytic enantioselective epoxidation of trans-chal-
cone.[a]
Entry
Catalyst 3
Conversion [%][b]
ee [%][c,d]
Figure 1. Selected C2- and C1-symmetric monoanionic li-
gands for asymmetric epoxidation.
1
2
3
4
3a
3b
3c
3d
80
80
90
96
54
68
32
68
[a]
The reaction was performed with 10 mol% 3, 0.1 mmol
trans-chalcone and 1.2 equiv. TBHP at 08C for 1 h.
Determined by 1H NMR.
Determined by chiral HPLC.
The absolute configuration was assigned to be (2S,3R)
based on optical rotation reported.
[b]
[c]
[d]
Scheme 1. One-pot procedure for the synthesis of our cata-
lysts.
two electronically and sterically asymmetric enami-
nooxazolinates with C1-symmetry, 1c and 1d, were se- benchmark epoxidation reaction (Table 1). After 1 h,
lected to study the factors affecting the title reaction the epoxy chalcone was formed in high yield in the
(Figure 1).
reactions catalyzed by the enaminooxazolinate com-
The new Zn tert-butyl peroxides were prepared by plexes 3c and 3d (up to 96%) and with slightly lower
a slightly modified version of the previously reported conversion (80%) in the case of bisoxazolinate cata-
two-step procedure.[12a] The corresponding N,N-proli- lysts 3a and 3b. Strikingly, the most sterically hindered
gands were treated with 1 equiv. of (t-Bu)2Zn in tolu- catalyst 3d showed the highest activity and was the
ene for 2 h at room temperature, then the resulting al- most active catalyst of the oxazolinate 3b and enami-
kylzinc complexes 2a–d were exposed to dry air at nooxazolinate 3d catalysts bearing sterically demand-
À208C (Scheme 1) to give Zn tert-butyl peroxides 3a– ing substituents (68% ee; Table 1, entries 2 and 4),
d (Figure 2).
whereas the less hindered catalyst 3c gave the lowest
Initially, trans-chalcone 4a was used as a model sub- enantioselectivity (32% ee; Table 1, entry 3). These
strate to investigate the catalytic activities of Zn tert- observations indicate that both the symmetry of the
butyl peroxides 3a–d generated in situ. A catalytic auxiliary ligand (i.e., C1 vs C2) and electronic factors
amount of the Zn tert-butyl peroxide at À608C was arising from the characteristics of the ligand backbone
added to a mixture of trans-chalcone and TBHP[14] in have minor effects on the enantioselectivities in the
toluene. The mixture was then warmed to 08C to studied reactions, whereas the steric environment in
afford the 2S,3R isomer of epoxy chalcone.[15] The close proximity to the coordinating center seems to
alkyl peroxides 3a–d exhibited high activities in the be crucial.
With an efficient catalyst for the asymmetric epoxi-
dation of trans-chalcone in hand, we started to evalu-
ate the substrate scope of this reaction using various
a,b-unsaturated ketones with different substitution
patterns, including a diketone (Table 2). The most
active C1-symmetric catalyst 3d was selected for fur-
ther studies. Enones 4b–g were all oxidized in excel-
lent yields under the reaction conditions studied. The
introduction of a strong electron-withdrawing group
such as a nitro moiety at the para-position of the aro-
matic ring on the carbonyl side of the enone resulted
in a marked increase in enantioselectivity (89% ee)
and excellent yield (98%) of oxazolinate 3b and en-
aminooxazolinate 3d catalysts (Table 2, entry 2). Con-
versely, an electron-donating para-OMe group on the
same aromatic ring decreased both the selectivity and
yield to 56% and 85%, respectively (Table 2, entry 3).
Substituting the aromatic ring of the olefin side of the
enone with an electron-withdrawing halogen (para-
Figure 2. Schematic representation of Zn tert-butyl perox-
ides 3a–d.
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Table 2. Catalytic enantioselective epoxidation of a,b-unsa-
turated ketones.[a]
Entry
R
R1
5
Yield [%][b] ee [%][c]
1
2
3
4
C6H5
C6H5
C6H5
4-BrC6H4 C6H5
4-MeC6H4 C6H5
C6H5
5a 96
68
89
56
81
71
21
91
4-NO2C6H4 5b 98
4-OMeC6H4 5c 85
5d 97
5e 98
5f 90
5g 80
5
6[d]
7[e]
i-Pr
C6H5
(CO)C6H5 C6H5
Figure 3. Molecular structure of 3d; hydrogen atoms are
omitted for clarity. Selected bond lengths (Š) and angles
[a]
Reaction was performed with 10 mol% 3d, 0.1 mmol
enone and 1.2 equiv. TBHP at 08C for 1 h.
Yield after column chromatography.
The ee value was determined by chiral HPLC. The abso-
lute configuration was assigned to be (2S,3R) based on
optical rotation reported.
The 2R,3S isomer was obtained.
Reaction was performed at À208C.
À
À
À
(8): O1 O2=1.485(8), O3 O4 1.473(8), Zn1 O1 2.077(6),
[b]
[c]
À
À
À
Zn1 O3 1.951(6), Zn2 O1 1.969(6), Zn2 O3 2.041(6),
À
À
À
À
Zn1 N1 1.962(8), Zn1 N2 1.970(7), Zn2 N3 1.968(8), Zn2
N4 1.963(7).
[d]
[e]
bromo) or an electron-donating para-Me group led to
the same yields as in the cases of 5a and 5b. While
the reaction yields were constant, the bromo and Me
substituents caused the enantioselectivities to de-
crease to 81% and 71% ee, respectively (Table 2, en-
tries 4 and 5). Moreover, the ee decreased to 21% for
aliphatic (i-Pr) enone 4f. These results suggest that
electron-deficient enones could be epoxidized asym-
metrically and efficiently under the studied reaction
conditions. For example, trans-1,2-dibenzoylethylene
gave an excellent enantioselectivity (91% ee).
To confirm the structure of the catalytic species, we
isolated a single crystal of the most efficient catalyst
3d from the reaction system outlined in Scheme 1 and
subjected it to single-crystal X-ray diffraction.[16] The
molecular structure of 3d consists of a dinuclear ag-
gregate with monomeric 3d units joined by the m2-
bridging oxygen atoms of the t-BuOO groups
(Figure 3). Dimeric 3d has C2 crystallographic symme-
try and distorted tetrahedral geometry about the Zn
Scheme 2. Proposed catalytic cycle for the enantioslective
epoxidation of enones.
À
centers. The average peroxo O O bond length is
À
1.479 Š and the Zn N bond lengths vary from
1.962(8) to 1.970(7) Š. All these distances are similar
to the corresponding bond lengths found for Zn m2- assume that under the reaction conditions the mono-
alkyl peroxide complexes supported by N,N,-bidentate meric form (N,N’)ZnOO-t-Bu acts as the true catalyst.
ligands.[12a,13,17]
In the first step the carbonyl oxygen of the enone is
In Scheme 2 we propose a catalytic cycle for the being coordinated to the metal center followed by
enantioselective epoxidation of enones mediated by a nucleophilic attack of oxygen[18] from the si-side of
the Zn t-Bu peroxide and TBHP as oxidant. In our the activated enone, which affords 2S,3R epoxide as
previous study involving the related zinc alkyl perox- the major product. The cycle is completed by ex-
ide catalytic system, the diffusion ordered spectrosco- change of the O-t-Bu ligand in the resulting alkoxide
py experiments revealed that the catalyst most likely (N,N’)ZnO-t-Bu moiety with tert-butyl peroxide origi-
existed as a monomeric species in solution,[5e] so we nating from TBHP.
866
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Quest for Efficient Catalysts based on Zinc tert-Butyl Peroxides
J. Stiller, T. Naicker, H. Jiang, K. A. Jørgensen, Angew.
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In summary, useful insights to allow further devel-
opment of catalytic systems for the epoxidation of
enones mediated by Zn alkyl peroxides have been
presented. An appropriate choice of C2-symmetric bi-
soxazolinate and C1-symmetric enaminooxazolinate
auxiliaries showed that the steric effects of the sub-
stituents in close proximity of the binding site had
a major influence on the enantioselectivities of the
studied reactions. The most active and selective C1-
symmetric enaminooxazolinate gave epoxides of both
aliphatic and aromatic enones in excellent yields and
with good enantioselectivities; for example, up to
96% yield and 91% ee for aromatic enones. Thus, the
data show that C2 symmetry is not a requirement for
obtaining high enantioselectivity. We believe that our
results will enable the rational development of new
efficient and environmentally benign catalysts for the
asymmetric epoxidation of enones.
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Experimental Section
General Procedure
(t-Bu)2Zn (0.01 mmol) was added to a Schlenk flask contain-
ing a solution of pro-ligand 1 (0.01 mmol) in toluene
(0.5 mL) under inert conditions at À608C. The resulting so-
lution was stirred at room temperature for 2 h. The Zn com-
plex 2 generated in situ was exposed to dry air at À208C for
1 h to afford Zn alkyl peroxide 3. To the resulting solution
of 3 cooled at À608C was added a toluene solution of
TBHP (4M, 0.12 mmol) followed by enone (0.1 mmol) in
toluene (1 mL). The reaction was warmed to 08C within
10 min, then stirred for 1 h. Volatile solvents were removed
under high vacuum. The crude product was dissolved in di-
ethyl ether (5 mL), and filtered through a pad of silica gel.
The resulting residue was further purified by silica-gel
column chromatography (hexane:ethyl acetate 9:1) to give
the desired epoxy products 5.
[10] For recent selected reviews, see: a) Zinc Catalysis: Ap-
plications in Organic Synthesis, (Eds.: S. Enthaler, X.-F.
Wu), Wiley-VCH, Weinheim, 2015; b) D. Łowicki, S.
Acknowledgements
We acknowledge the European Union and Regional Develop-
ment Fund within a project of Foundation for Polish Science
(MPD/2010/13; A. R. K.) and the National Science Centre
(grant DEC-2012/04A/ST5/00595; I. J., J. L.) for financial
support.
´
Bas, J. Młynarski, Tetrahedron 2015, 71, 1339; c) T.
Bauer, Coord. Chem. Rev. 2015, 299, 83; d) X.-F. Wu,
H. Neumann, Adv. Synth. Catal. 2012, 354, 3141; e) X.-
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be the optimal oxidant, whereas CMHP was less effi-
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these issues require further investigations and will be
published in due course).
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