Highly enantioselective epoxidation catalyzed by cinchona thioureas: Synthesis of functionalized terminal epoxides bearing a quaternary stereogenic center

Article abstract of DOI:10.1002/chem.201200500

A brilliant debut! Cinchona thioureas have been reported for the first time as catalysts in the area of asymmetric oxidations. They efficiently promote an unprecedented highly enantioselective epoxidation of deactivated 1,1-disubstituted alkenes to terminal epoxides containing a quaternary stereogenic center (see scheme). Copyright

Full text of DOI:10.1002/chem.201200500

DOI: 10.1002/chem.201200500
Highly Enantioselective Epoxidation Catalyzed by Cinchona Thioureas:
Synthesis of Functionalized Terminal Epoxides Bearing a Quaternary
Stereogenic Center
Alessio Russo,[a] Gerardina Galdi,[a] Gianluca Croce,[b] and Alessandra Lattanzi*[a]
Catalytic enantioselective epoxidation of alkenes occupies
a venerable position in asymmetric synthesis.[1] Over the last
decades, the preparation of chiral epoxides received consid-
erable attention due to the highly versatile nature of epox-
ides as building blocks and synthetic intermediates to con-
struct vicinal stereogenic centers in a well-defined fashion.[2]
Pivotal examples in the area of chiral metal-complex based
epoxidation include those reported by Katsuki–Sharpless[3]
and Jacobsen[4] that enable access to a variety of structurally
different epoxides. Moreover, a wide substrate applicability
has been successfully demonstrated by chiral dioxirane
based systems.[5] Important advances in the epoxidation of
electron-poor alkenes have also been reported.[6] Notably,
organocatalytic systems have recently solved long-standing
problems such as the asymmetric epoxidation of enals and
cyclic and acyclic dialkyl enones by using secondary and pri-
mary chiral non-racemic amines.[7] However, despite these
impressive contributions, few examples of efficient and
highly enantioselective epoxidation reactions of terminal al-
kenes have been disclosed.[8] Indeed, they represent the
most challenging class of alkenes to epoxidize and the devel-
opment of effective methods are highly desirable in consid-
eration of their huge potential for further elaboration in
target-oriented synthesis.[9]
Since the seminal reports by the groups of Soꢀs, Connon,
and Dixon,[10] readily accessible cinchona thioureas have
been shown to be excellent organocatalysts in a wide array
of highly stereoselective transformations.[11] However, to the
best of our knowledge, they have not been used as catalysts
in the area of asymmetric oxidations. We have recently
shown that simple Schreinerꢁs thiourea efficiently catalyzed
the oxidation of sulfides to sulfoxides with tert-butyl hydro-
peroxide (TBHP).[12] Motivated by our interest in develop-
ing organocatalytic asymmetric epoxidation reactions of
electron-poor alkenes,[13] we questioned whether we could
epoxidize, in an enantioselective manner, deactivated 1,1-
disubstituted alkenes of type 1 by using cinchona thioureas
and TBHP as oxygen source (Scheme 1). We planned to
Scheme 1. Cinchona thiourea catalyzed enantioselective epoxidation of
electron-poor terminal alkenes.
achieve this highly ambitious goal, namely the formation of
terminal epoxides containing
a quaternary stereogenic
center,[14] by considering the known ability of cinchona thio-
ureas to generate enolates of 1,3-dicarbonyl compounds in
a chiral environment and their bifunctional nature as pro-
moters. According to the Weitz–Scheffer mechanism of ep-
oxidation, cinchona thioureas were supposed to be able to
deprotonate TBHP to form the peroxyanion, followed by its
conjugate addition to alkene 1. The prochiral peroxyenolate
formed, hydrogen-bonded by the thiourea group of the cata-
lyst, could have resulted in preferential ring-closure to give
the enantiomerically enriched epoxide.
We describe herein a novel catalytic cinchona thiourea/
TBHP system, which has been successfully applied in unpre-
cedented asymmetric epoxidation of electron-poor terminal
alkenes 1. The corresponding functionalized epoxides 2,
containing a quaternary stereogenic center, have been ob-
tained in good to excellent yield and enantioselectivity. The
elaboration of epoxides 2 to a variety of synthetically valua-
ble and difficult to access derivatives can be envisaged by
straightforward epoxide ring-opening.
At the outset of our study, we choose to react a-benzoyl
N-phenylacrylamide 1a as model alkene with TBHP and
different cinchona alkaloid derivatives in toluene at room
temperature (Table 1).
[a] Dr. A. Russo, G. Galdi, Prof. Dr. A. Lattanzi
Dipartimento di Chimica e Biologia
Universitꢂ di Salerno
Via Ponte don Melillo, 84084 Fisciano (Italy)
Fax : (+39)089-969603
E-mail: lattanzi@unisa.it
[b] Dr. G. Croce
DISIT–Universitaꢁ del Piemonte Orientale
Viale T. Michel, 11; 15121 Alessandria (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200500.
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Chem. Eur. J. 2012, 18, 6152 – 6157

COMMUNICATION
Table 1. Screening of catalysts and reaction parameters in the epoxida-
improvement of ee value up to 97% (Table 1, entries 6–10).
Cumyl hydroperoxide was shown to be a slightly less effec-
tive oxidant than TBHP (Table 1, entry 11), whereas the ee
value significantly dropped to 54% when using hydrogen
peroxide as terminal oxidant (Table 1, entry 12). Pleasingly,
the eQNT loading could be reduced as low as 5 mol% with-
out affecting the process when employing TBHP as the oxi-
dant (Table 1, entries 13 and 14). A brief screening of low
polarity solvents, such as p-xylene, chloroform, and diethyl
ether, confirmed toluene to be the optimum medium for the
epoxidation (Table 1, entries 15–17).
tion of a-benzoyl-N-phenylacrylamide 1a.[a]
The scope and limitation of the asymmetric epoxidation
was next investigated with respect to the nature of substitu-
ents and carbonyl residue present in the starting alkene
1 using eQNT at 5 mol% loading with TBHP at room tem-
perature (Table 2).
Entry
Cat.
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CN
CD
QN
QD
2
1
1
1
93
97
92
98
98
98
98
98
98
98
96
90
98
98
98
98
98
61
À59
À33
À12
À13
À97
À96
95
Electron-donating groups at different position in the a-
aroyl moiety and a larger naphthoyl residue in alkenes
1 were well tolerated leading to epoxides in excellent yield
and ee value (Table 2, entries 2–6). Compounds 1 with elec-
tron-withdrawing groups at the the a-aroyl moiety proved
to be very reactive and suffered easy decomposition. Never-
theless, when the epoxidation was carried out on compound
1 f, containing a methoxy group at the meta position, the
product was recovered in good yield and 98% ee (Table 2,
entry 7). Alkenes with electron-withdrawing groups in the
aromatic residue of the amide group were smoothly convert-
ed into the product in very high enantioselectivity (Table 2,
entry 8). Aliphatic substituted alkenes 1i–l, either at the
amido, ketone, or both moieties, gave the epoxide with high
to excellent ee values (Table 2, entries 9–12). The corre-
sponding a-benzoyl acrylates 1m–n were converted into the
product after prolonged reaction times using 10 mol% load-
ing of eHQNT as the catalyst (see the Supporting Informa-
tion). The epoxides were obtained in good yield and 74%,
77% ee, respectively (Table 2, entries 13 and 14). The enan-
tioselectivity could be improved to a good level by perform-
ing the reaction at À208C (Table 2, entry 15). Mixed sub-
strates, such as carbamoyl acrylates 1o–p smoothly reacted,
affording the product in good yield and enantioselectivity
(Table 2, entries 16 and 17). Interestingly, alkene 1q contain-
ing a tertiary amide group, treated under otherwise identical
conditions, even after prolonged reaction times, proved to
be unreactive (Table 2, entry 18). This result clearly indi-
(DHQD)2PHAL
2
eQNT
eQDT
eCDT
eCNT
eHQNT
eQNT
eQNT
eQNT
eQNT
eQNT
eQNT
eQNT
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
9
À95
10
11[d]
12[e]
13[f]
14[g]
15[f,h]
16[f,i]
17[f,j]
96
93
54
96
84
96
90
55
1
1
[a] Reactions performed on 0.1 mmol scale, with 1a/TBHP 1/1.2 ratio at
[1a]0 =0.1m. [b] Isolated yield after silica gel chromatography. [c] Deter-
mined by HPLC analysis using a chiral column. [d] Cumyl hydroperoxide
was used. [e] 50% H2O2 was used. [f] 5 mol% catalyst was used.
[g] 2 mol% catalyst was used. [h] p-Xylene as solvent. [i] CHCl3 as sol-
vent. [j] Et2O as solvent.
Interestingly, when cinchonine (CN) was employed at
10 mol% loading, the epoxide was isolated in high yield and
61% enantiomeric excess (ee) after a short reaction time
(Table 1, entry 1). In our opinion this is a remarkable result
for different reasons: 1) it represents the first example of
a natural cinchona alkaloid catalyzed asymmetric epoxida-
tion; 2) the reaction was clean. Indeed, the epoxide was ob-
tained in high yield, considering the reactive nature of com-
pound 1a as a Michael acceptor and the competing polymer-
ization that could have occurred as a side reaction. The
pseudoenantiomeric cinchonidine (CD) afforded the oppo-
site enantiomer of 2a in comparable yield and asymmetric
induction (Table 1, entry 2). Quinine (QN) and quinidine
(QD) proved to be equally effective in terms of product
yield, although significantly less enantioselective catalysts
(Table 1, entries 3 and 4). The dimeric derivative
(DHQD)2PHAL gave almost quantitatively the epoxide,
albeit with only 13% ee (Table 1, entry 5). To our great de-
light, the epoxidation mediated by commonly used cinchona
thioureas, proceeded rapidly to give epoxide 2a, of both ab-
solute configurations, in excellent yield and with a notable
À
cates the crucial role of the amide N H proton in the pro-
cess. Finally, 2-alkylidene-1,3-dione 1r reacted sluggishly to
give the epoxide in low yield and poor ee value (Table 2,
entry 19).
To better understand the role of the promoter in the cat-
alysis, the epoxidation was further investigated (Table 3).
Model compound 1a was treated with 10 mol% of Schrein-
erꢁs thiourea[11a] and TBHP in toluene at room temperature
(Table 3, entry 1). After 1 hour, the conversion to epoxide
was very low in comparison to the data reported in Table 1
(entries 6–10). The reaction catalyzed by 20 mol% of 1,8-di-
azabicycloundec-7-ene (DBU) likewise proceeded to
a lesser extent when compared with the use of cinchona thi-
Chem. Eur. J. 2012, 18, 6152 – 6157
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6153

A. Lattanzi et al.
Table 2. Asymmetric epoxidation of terminal alkenes 1 by eQNT/TBHP system.[a]
confirmed the hypothesis of a nucleophilic epoxida-
tion process.
The high level of enantiocontrol observed in the
epoxidation of acrylamide derivatives 1a–l suggests
a catalyst–reagent associated complex.[15] This as-
sumption is consistent with the fast conversion pro-
vided by the bifunctional organocatalyst and the ab-
sence of any intermediate species detected. To shed
light on the origin of the enantioselectivity, we de-
cided to build a plausible model by quantum me-
chanical calculations using density functional
theory. a-Benzoyl N-phenylacrylamide (1a), TBHP,
and a simplified eQNT catalyst were employed. To
reduce computational costs, the methoxy group on
quinoline, the vinyl fragment of the quinuclidine
and the trifluoromethyl groups in the thiourea
moiety were removed, assuming their limited
impact on the enantiocontrol based on the observa-
tions reported in entries 6–10 of Table 1.
Entry
R1
R2
t [h]
2
ee [%][c]
AHCTUNGTERNNUNG )
(Yield [%][b]
1
2
3
4
5
6
7
8
Ph
NHPh
NHPh
NHPh
NHPh
NHPh
NHPh
NHPh
NH(3-CF3C6H4)
NHBn
NHPh
NHPh
NHCH2CH
OMe
OEt
1
1
1
1.5
1.5
2
1
1
1
1.5
6
16
70
70
113
6
25
2a (98)
2b (98)
2c (97)
2d (96)
2e (98)
2 f (97)
2g (84)
2h (98)
2i (98)
2j (98)
2k (98)
2l (92)
2m (50)
2n (79)
2n (74)
2o (78)
2p (74)
2q (<10)
2r (40)[g]
96
93
96
99
96
98
98
97
94
91
99
99
74
77
86
80
80
n.d.
20
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2-naphthyl
3-MeOC6H4
Ph
Ph
iPr
tBu
tBu
Ph
Ph
Ph
MeO
EtO
9
10
11
12[d]
13[e]
14[e]
15[e,f]
16[e]
17[e]
18[e]
19[e]
(CH3)2
OEt
NHBn
NHBn
NMeBn
tBu
A neutral ternary complex, formed among cata-
lyst, alkene, and TBHP was calculated.[16] The opti-
mized reactive hydrogen-bonded complex found is
illustrated in Figure 1.[17] The secondary amide
group of the alkene plays a crucial role either in the
preorganization and activation of the substrate
MeO
Ph
72
120
[a] Reactions performed on 0.1 mmol scale, with 1/TBHP 1/1.2 ratio at [1]0 =0.1m.
[b] Isolated yield after silica gel chromatography. [c] Determined by HPLC analysis
using chiral columns (see the Supporting Information). [d] 10 mol% catalyst was used.
[e] 10 mol% of eHQNT was used. [f] Reaction performed at À208C. [g] Conversion
1
determined by H NMR spectroscopy.
Table 3. Epoxidation of alkene 1a by using achiral promoters.
Entry Cat.
mol% t [min] Conv. [%][a]
1
10
60
15
2
3
DBU
–
20
–
40
60
50
31
Figure 1. Optimized neutral ternary complex among simplified eQNT
catalyst, TBHP and 1a. All hydrogen atoms, except those involved in hy-
drogen bonding (lengths of hydrogen bond in ꢄ), were removed for clari-
ty.
1
[a] Conversion determined by H NMR spectroscopy.
oureas (Table 3, entry 2). A blank experiment demonstrated
that the epoxide formation is not a negligible process in the
absence of a catalyst (Table 3, entry 3). From these findings
it is evident that the bifunctional nature of the cinchona thi-
ourea greatly accelerates the process by synergic activation
of both reagents.
through intramolecular hydrogen bonding with the carbonyl
group. This is also supported by the unreactive nature of
compound 1q with
a tertiary amide moiety (Table 2,
Model epoxidation on compound 1a, carried out under
conditions reported in entry 1 of Table 1, was monitored by
1H NMR spectroscopy in deuterated toluene at room tem-
perature. The reaction proved to be so fast that the conver-
sion to the epoxide was complete after the few minutes nec-
essary to process the NMR experiment. The same analysis
was performed on the less reactive acrylate 1n. In this case,
we were able to detect the postulated peroxy adduct illus-
trated in Scheme 1 (see the Supporting Information), which
entry 18). The quinuclidine nitrogen is engaged in a hydro-
gen-bonding interaction with the pronucleophile TBHP.
Both NH hydrogen atoms of the thiourea moiety are in-
volved in double hydrogen-bonding with the nitrogen and
the oxygen atoms of the amide group.[18] On the basis of this
model, it can be predicted that, once formed, the hydrogen-
bonded prochiral Re-peroxy enolate would preferentially
give ring closure to (R)-epoxide 2a.
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Enantioselective Epoxidation Catalyzed by Cinchona Thioureas
COMMUNICATION
Terminal epoxides of type 2 can be transformed into a va-
riety of synthetically important linear a-hydroxylated a-sub-
stituted 1,3-dicarbonyl derivatives by regioselective ring-
opening. Indeed, a limited number of methods, exclusively
focused on the a-hydroxylation of the corresponding linear
a-substituted b-ketoesters, provided access to the products
with good levels of enantioselectivity.[19] An alternative ap-
proach to these compounds has been recently developed by
Maruoka and co-workers, exploiting a phase-transfer-cata-
lyzed asymmetric alkylation of a-benzoyloxy-b-ketoesters.[20]
The versatile nature of compounds 2 as intermediates was
demonstrated in the synthesis of novel diversely functional-
ized linear a-hydroxylated a-substituted b-ketoamides.
Alkene 1a was conveniently transformed into compound 3a
Scheme 3. Synthetic elaboration of epoxide 2a to the N-Boc-a-hydroxy-
b-amino acid derivative 5a.
Scheme 3. Ring-opening of enantioenriched epoxide 2a with
NaN3 in the presence of LiClO4 gave the 1,2-azido alcohol
4a in 61% yield (Scheme 3).
through
a
one-pot epoxidation/ring-opening sequence
(Scheme 2).[21]
One-pot sequential Staudinger reaction on compound 4a
followed by protection of the primary amine with di-tert-bu-
tyldicarbonate afforded N-Boc-5a in 57% overall yield and
without erosion of the enantiomeric excess.
In conclusion, we have documented, for the first time, the
ability of cinchona thioureas as catalysts in the area of asym-
metric oxidations, further expanding their potential in orga-
nocatalysis. Specifically, the easily accessible cinchona thio-
urea/TBHP system enabled an unprecedented and challeng-
ing asymmetric epoxidation of electron-poor terminal al-
kenes bearing different carbonyl groups. The corresponding
epoxides, containing a quaternary stereocenter, were isolat-
ed in good to excellent yield and enantioselectivity. The ep-
oxides, available in both absolute configurations, represent
a class of valuable intermediates to prepare an array of
highly enantioenriched linear a-hydroxylated a-substituted
1,3-dicarbonyl derivatives hitherto not accessible by other
methods. We believe that this system will pave the way for
further interesting applications in asymmetric organocatalyt-
ic oxidations.
Scheme 2. One-pot asymmetric epoxidation/ring-opening sequence to
give compound 3a.
The asymmetric epoxidation, followed by regioselective
ring-opening of the intermediate epoxide 2a, by means of
the addition of phenyl thiol and a catalytic amount of trieth-
yl amine, afforded the desired tertiary alcohol 3a in 96%
yield and 97% ee.
The absolute configuration of compound 3a was unambig-
uously determined to be R by single-crystal X-ray analysis
as illustrated in Figure 2.[22] This enabled the assignment of
the absolute configuration of epoxide 2a as R at the quater-
nary stereocenter, which was found to be in agreement with
that predictable by the model in Figure 1.
A facile approach to highly functionalized chiral non-rac-
emic a-hydroxy-b-amino acid derivatives[23] is illustrated in
Experimental Section
General procedure for the asymmetric epoxidation: TBHP (22 mL,
0.12 mmol) was added to
a sample vial charged with the alkene
(0.10 mmol) and appropriate cinchona thiourea derivative (0.0050 mmol
or 0.010 mmol) in anhydrous toluene (1.0 mL) and the solution was
stirred at room temperature for the indicated time. The reaction mixture
was directly loaded onto silica gel and purified by flash chromatography
(petroleum ether/ethyl acetate 9:1) to give the corresponding epoxide 2.
The enantiomeric excess was determined by chiral HPLC analysis.
Acknowledgements
Financial support from the MIUR, National Projects PRIN 2008 is grate-
fully acknowledged. We thank Prof. Zanasi and Dr. Monaco for comput-
er facilities and Dr. P. Iannece for mass spectra analyses.
Keywords: alkenes
thioureas · epoxides · organocatalysis
·
asymmetric synthesis
·
cinchona
6155
Figure 2. X-ray crystal structure of (R)-3a with ellipsoids set at 30%
probability.
Chem. Eur. J. 2012, 18, 6152 – 6157
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A. Lattanzi et al.
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Chem. Eur. J. 2012, 18, 6152 – 6157

Enantioselective Epoxidation Catalyzed by Cinchona Thioureas
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Received: February 15, 2012
Published online: April 18, 2012
Chem. Eur. J. 2012, 18, 6152 – 6157
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6157