Enantioselective epoxidation of α,β-enones by electrophilic activation with a BINOL-zinc catalyst

Article abstract of DOI:10.1002/ejoc.200500606

The combination of BINOL and a dialkylzinc reagent R₂Zn affords, in situ, a catalyst for homogeneous epoxidation of (E)-α,β-enones to the corresponding trans-epoxy ketones. tert-Butyl hydroperoxide (TBHP) and cumene hydroperoxide (CMHP) are eff

Full text of DOI:10.1002/ejoc.200500606

FULL PAPER
DOI: 10.1002/ejoc.200500606
Enantioselective Epoxidation of α,β-Enones by Electrophilic Activation with a
BINOL–Zinc Catalyst
Ana Minatti[a] and Karl Heinz Dötz*[a]
Keywords: Asymmetric catalysis / Enantioselectivity / Enones / Epoxidation / Zinc
The combination of BINOL and a dialkylzinc reagent R2Zn
affords, in situ, a catalyst for homogeneous epoxidation of
(E)-α,β-enones to the corresponding trans-epoxy ketones.
tert-Butyl hydroperoxide (TBHP) and cumene hydroperoxide
(CMHP) are effective terminal oxidants for this process. En-
antiomeric excesses of up to 96% can be achieved conve-
niently at room temperature. Mechanistic investigations
point towards an electrophilic activation of the substrates by
the chiral BINOL–zinc catalyst and a subsequent nucleo-
philic attack of the oxidant. This mechanistic proposal is sup-
ported additionally by a non-linear effect, the absolute prod-
uct configuration as well as NMR studies.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
The enantioselective synthesis of α,β-epoxy ketones is of
major interest to organic synthesis in general and medicinal
chemistry in particular as the resulting chiral compounds
are versatile precursors to many natural products and phar-
maceuticals.[1] Since the seminal work of Weitz and Scheffer
on the epoxidation of electron-deficient alkenes,[2] several
asymmetric variants of this reaction have been developed.[3]
Juliá and Colonna were the first to report on the use of
poly-l-alanine as a catalyst for the enantioselective epoxid-
ation of chalcone.[4] Since then, a variety of valuable proto-
cols based on poly(amino acid) catalysts (e.g. I in Scheme 1)
have been established for a variety of α,β-enones.[5] Re-
cently, even a monomeric proline-derived catalyst (II) has
proved to be effective in the enantioselective epoxidation of
enones.[6] Phase-transfer catalysis derived from Chinchona
alkaloids (e.g. V) have also been found to catalyse the enan-
tioselective epoxidation of a wide range of enones in the
presence of, for example, sodium hypochlorite.[7] Another
important contribution originated from the employment of
optically pure hydroperoxides (VI).[8]
Nevertheless, a broad scope of developments can be
found in the field of chiral ligand–metal peroxides for this
enantioselective oxidative transformation. Enders et al.
have reported that (E)-α,β-unsaturated ketones can be
epoxidised in an enantioselective fashion using stoichiomet-
ric amounts of diethylzinc and (R,R)-N-methylpseudo-
ephedrine, under oxygen (Scheme 2).[9] The initially formed
chiral ethylzinc alkoxide is oxidised to the corresponding
chiral ethylperoxyzinc alkoxide, which attacks the si-face of
Scheme 1. Different strategies for the enantioselective epoxidation
of α,β-unsaturated ketones.
the enone in an oxa-Michael type addition to give the trans-
epoxy ketone.
Later, Pu et al. employed a binaphthyl polymer as a chi-
ral ligand, and by additional replacement of molecular oxy-
gen by tert-butyl hydroperoxide (TBHP) turned the epoxid-
ation into a catalytic process (Scheme 3).[10]
Shibasaki et al. introduced chiral lanthanide–BINOL
catalysts (e.g. III in Scheme 1) and studied the effect of se-
veral additives on the course of the epoxidation reaction.[11]
Finally, Jackson has developed the catalytic enantioselective
epoxidation of aryl- and alkyl-substituted enones using tar-
trate-derived magnesium alkoxides (IV in Scheme 1).[12]
In a preliminary report, we have recently described a new
method for the enantioselective epoxidation of α,β-enones
with a chiral zinc–BINOL catalyst using tert-butyl hydro-
peroxide (TBHP) or cumene hydroperoxide (CMHP) as the
terminal oxidant.[13] In this paper, we wish to report the
optimisation of this catalytic reaction and discuss its mech-
[a] Kekulé-Institut für Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms Universität Bonn,
Gerhard-Domagk-Str. 1, 53112 Bonn, Germany
E-mail: doetz@uni-bonn.de
268
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Enantioselective Epoxidation of α,β-Enones by Electrophilic Activation
FULL PAPER
Scheme 2. Zinc-mediated aerobic enantioselective epoxidation in the presence of (R,R)-N-methylpseudoephedrine.
Scheme 3. Enantioselective epoxidation of enones catalysed by a chiral polybinaphthyl–zinc complex.
anistic background. Furthermore, a NMR spectroscopic
study of the catalytically active species will be presented.
Results and Discussion
Scheme 4. Enantioselective catalytic epoxidation of chalcone.
In a first set of experiments the dependence of the epox-
idation on various reaction parameters was analysed with
Diethyl ether turned out to be the solvent of choice, as
chalcone as the model substrate (Scheme 4, Table 1). This the reactions conducted in this solvent provided the best
includes the study of solvent dependence (Table 1, en- results both with TBHP (80% yield, 47% ee) as well as
tries 1–7), catalyst loading (Table 1, entries 7–9), the nature with CMHP (99% yield, 68% ee) as the terminal oxidant
of the diorganozinc species (Table 1, entries 10–12), and fi- (Table 1, entries 4 and 7). The trans-epoxide was formed ex-
nally the nature of the terminal oxidant (Table 1, entries 13 clusively in all cases, rendering this reaction a completely
and 14).
diastereoselective process. The superiority of CMHP to
Table 1. Optimisation of reaction conditions for the epoxidation of chalcone.
Entry
Solvent
Oxidant
ZnR2 [mol-%]
Yield [%][a]
de [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
THF
TBHP/CMHP
TBHP
TBHP
ZnEt2 [36]
ZnEt2 [36]
ZnEt2 [36]
ZnEt2 [36]
ZnEt2 [36]
ZnEt2 [36]
ZnEt2 [36]
ZnEt2 [18][e]
ZnEt2 [9][f]
ZnMe2 [36]
ZnPh2 [36]
ZnPh2 [36]
ZnEt2 [36]
ZnEt2 [36]
–
–
–
CH2Cl2
toluene
Et2O
CH2Cl2
toluene
Et2O
Et2O
Et2O
Et2O
Et2O
Ͻ5
Ͻ5
80
95
95
99
99
99
99
–
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
–
nd
nd
47
5
71
68
67
58
76
–
TBHP
CMHP
CMHP
CMHP
CMHP
CMHP
CMHP
CMHP
CMHP
H2O2
9
10
11
12
13
14
toluene
Et2O
Et2O
–
–
–
–
–
–
–
–
–
[g]
mCPBA
[a] Yield of epoxide isolated. [b] Only the trans-isomer is formed, as determined from the 1H NMR coupling constant of the vicinal
protons on the oxirane ring. [c] Determined by HPLC analysis on a chiral stationary phase. [d] The absolute configuration of the major
enantiomer was determined to be (2S,3R) by comparison of the optical rotation and HPLC retention times with those reported in the
literature.[14] [e] 10 mol-% (R)-BINOL. [f] 5 mol-% (R)-BINOL. [g] Traces of (E)-β-benzoyloxystyrene were isolated.
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TBHP was already noticeable in these early experiments as product can be explained by a Baeyer–Villiger oxidation of
only traces of the product were detected in dichloromethane chalcone.[15]
and toluene with TBHP (Table 1, entries 2 and 3) and ne-
arly quantitative epoxidation was observed in dichloro- cation of the substrate was investigated by changing the
methane, toluene and diethyl ether for CMHP (Table 1, en- para-substituent on the β-phenyl ring (Scheme 5,
The sensitivity of the reaction towards electronic modifi-
X
tries 5–7). The extent of the asymmetric induction, however, Table 2). Additionally, the epoxidation of each substrate
varied strongly, as the enantiomeric excesses ranged from was performed following two different methods A and B,
71% and 68% in the case of toluene and diethyl ether, which differ in the ZnEt2/(R)-BINOL ratio (A: 1.8:1; B: 1:1)
respectively, to 5% in the case of dichloromethane. No and concentration {A: c = 0.01 [mmol (R)-BINOL/mL
epoxidation at all was observed when the reaction was con- Et2O]; B: c = 0.05 [mmol (R)-BINOL/mL Et2O]}.
ducted in tetrahydrofuran, irrespective of the oxidising rea-
The results shown in Table 2 reveal that rendering the
gent in use (Table 1, entry 1). Performing the reaction in unsaturated bond in the enone more electron-rich by replac-
diethyl ether with half of the catalyst loading [10 mol-% ing X = H with OMe or even a substituent with only a
(R)-BINOL and 18 mol-% ZnEt2] did not have any negative slightly positive inductive effect, such as Me, causes a com-
influence on the result (Table 1, entry 8). However, a further plete inhibition of the epoxidation (Table 2, entries 1 and
decrease to 10 mol-% ZnEt2 and 5 mol-% (R)-BINOL de- 2). On the other hand, enhancing the electron-deficiency of
creased the enantiomeric excess slightly to 58% (Table 1, the double bond with a substituent like Br resulted in an
entry 9). Variation of the diorganozinc species caused a re- increase in the ee up to 71 and 72%, irrespective of whether
markable increase of the enantiomeric excess up to 76% in TBHP or CMHP was used as oxidant (Table 2, entries 6
diethyl ether when dimethylzinc was used (Table 1, en- and 7). Unexpectedly, this tendency was not sustained for
try 10). In contrast to the dialkylzinc species, which were the much more electron-withdrawing group NO2 − the en-
employed as solutions, diphenylzinc was added as a solid to antiomeric excesses decreased to 60% and 62%, respectively
a solution of (R)-BINOL. No dissolution and therefore no (Table 2, entries 9 and 10). CMHP provided significantly
epoxidation at all was observed in diethyl ether or toluene higher yields than TBHP in all cases and increased the reac-
(Table 1, entries 11 and 12). Finally, hydrogen peroxide and tion rate, resulting in shorter reaction times. An exceptional
m-chloroperbenzoic acid were tested as terminal oxidants. increase of the enantiomeric excesses and acceleration of
No epoxide formation was observed with either oxidant, the reaction was found for the chalcone derivatives when
although a small amount of the chalcone enol ester was the epoxidation was run under conditions B. After a reac-
isolated in the case of the peracid. The formation of this tion time of only one hour, complete epoxidation of all
Scheme 5. Enantioselective catalytic epoxidation of substituted chalcones.
Table 2. Enantioselective catalytic epoxidation of substituted chalcones.
Entry
Enone (X)
Method[a]
Oxidant
t [h]
Yield [%][b]
de [%][c]
ee [%][d,e]
1
2
3
4
5
6
7
8
1 (OMe)
2 (Me)
3 (H)
A
A
A
A
B
A
A
B
TBHP/CMHP
TBHP/CMHP
TBHP
CMHP
CMHP
TBHP
CMHP
CMHP
TMHP
12
12
12
4
–
–
–
–
–
–
80
99
99
50
95
99
Ͻ10
86
99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
47
68
90
71
72
92
60
62
76
3 (H)
3 (H)
1
4 (Br)
12
2.5
1
12
12
1
4 (Br)
4 (Br)
9
10
11
5 (NO2)
5 (NO2)
5 (NO2)
A
A
B
CMHP
CMHP
[a] Method A: 20 mol-% (R)-BINOL, 36 mol-% ZnEt2, 0 °C, 15 min, 1.2 equiv. oxidant, c = 0.01 [mmol (R)-BINOL/mL Et2O]; Method
B: 20 mol-% (R)-BINOL, 20 mol-% ZnEt2, 0 °C, 3 h, 1.2 equiv. oxidant, c = 0.05 [mmol (R)-BINOL/mL Et2O]. [b] Yield of epoxide
isolated. [c] Only the trans-isomer is formed, as determined from the 1H NMR coupling constant of the vicinal protons on the oxirane ring.
[d] Determined by HPLC analysis on a chiral stationary phase. [e] The absolute configuration of the major enantiomer was determined to
be (2S,3R) by comparison of the optical rotation and HPLC retention times with those reported in the literature.[14]
270
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Enantioselective Epoxidation of α,β-Enones by Electrophilic Activation
FULL PAPER
three substrates (3–5) was observed and the enantiomeric times decreased from 12 h to 5 h (R = tBu) or even 1.5 h
excesses of the corresponding epoxides were determined to (R = Me), the epoxides were isolated in very high yields
be 90% (3), 92% (4) and 76% (5) (Table 2, entries 5, 8 and (83–99%) and the enantiomeric excesses increased approxi-
11). This striking increase in ee renders protocol B the most mately up to 20% in every case (Table 3, entries 3, 6, 9, 12
convenient and efficient one.
This pronounced effect was also encountered when the enantiomeric excess (96%).
present protocols were successfully extended to substrates The fact that the s-cis conformation of the enone moiety
bearing β-alkyl substituent on the double bond is a conformational prerequisite for a successful epoxidation
and 15). The tBu-substituted enone 10 provided the highest
a
(Scheme 6). The steric bulk at the enone was varied by in- was proven by the unreactivity of 2-cyclohexanone as a typ-
troducing different alkyl chains (R) in the β-position ical representative of an s-trans-enone.
(Table 3).
To gain insight into the mechanism of this epoxidation
reaction, we next investigated the possible existence of non-
linear effects using BINOL of different degrees of optical
purity (Figure 1).[16]
Scheme 6. Enantioselective catalytic epoxidation of alkyl-substi-
tuted enones.
When performing the epoxidations under conditions A
with TBHP as oxidant the asymmetric induction increases
with the length of the alkyl chain. This tendency is reversed
for CMHP as the enantiomeric excess decreases from 54%
for R = Me to 40% for R = nPr (Table 3, entries 2 and 8).
As an exception, the ee obtained for R = iPr does not follow
this rule (Table 3, entries 10 and 11). A possible explanation
for this phenomenon may be the conformational flexibility
Figure 1. Asymmetric amplification in the epoxidation of chalcone
at c = 0.05 catalysed by the Zn–BINOL catalyst generated in situ.
Within experimental error, asymmetric amplification was
of iPr. The bulky substituent tBu is conformationally fixed observed for the epoxidation of chalcone under conditions
and furnished an ee of 80%, irrespective of the oxidising B. This correlation points towards the preferential forma-
reagent used (Table 3, entries 13 and 14). In general, the tion of heterodimeric or -oligomeric zinc BINOLate com-
reactions with CMHP proceeded with significantly higher plexes, which are less reactive than the monomeric ones.
yields than with TBHP in all cases.
Two striking differences between our experimental data
As expected, performing the epoxidations under condi- and the results obtained in the zinc-mediated enantioselec-
tions B led again to a significant improvement. The reaction tive epoxidations by Enders[9a,9b] and Pu[10] prompted us to
Table 3. Enantioselective catalytic epoxidation of alkyl-substituted enones.
Entry
Enone (R)
Method[a]
Oxidant
t [h]
Yield [%][b]
de [%][c]
ee [%][d,e]
1
2
3
4
5
6
7
8
6 (Me)
6 (Me)
6 (Me)
7 (Et)
A
A
B
A
A
B
A
A
B
A
A
B
TBHP
CMHP
CMHP
TBHP
CMHP
CMHP
TBHP
CMHP
CMHP
TBHP
CMHP
CMHP
TBHP
CMHP
CMHP
12
12
1.5
12
12
2.5
12
12
4
12
12
1.5
12
12
5
24
60
99
28
79
99
72
78
90
36
75
90
Ͻ10
73
83
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
40
54
68
48
50
73
60
40
64
54
40
68
80
80
96
7 (Et)
7 (Et)
8 (nPr)
8 (nPr)
8 (nPr)
9 (iPr)
9 (iPr)
9 (iPr)
10 (tBu)
10 (tBu)
10 (tBu)
9
10
11
12
13
14
15
A
A
B
[a] Method A: 20 mol-% (R)-BINOL, 36 mol-% ZnEt2, 0 °C, 15 min, 1.2 equiv. oxidant, c = 0.01 [mmol (R)-BINOL /mL Et2O]; Method
B: 20 mol-% (R)-BINOL, 20 mol-% ZnEt2, 0 °C, 3 h, 1.2 equiv. oxidant, c = 0.05 [mmol (R)-BINOL/mL Et2O]. [b] Yield of epoxide
isolated. [c] Only the trans-isomer is formed, as determined from the 1H NMR coupling constant of the vicinal protons on the oxirane ring.
[d] Determined by HPLC analysis on a chiral stationary phase. [e] The absolute configuration of the major enantiomer was determined to
be (2S,3R) by comparison of the optical rotation and HPLC retention times with those reported in the literature.[14]
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A. Minatti, K. H. Dötz
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Figure 2. Proposed catalytic cycle for the enantioselective epoxidation with the Zn–(R)-BINOL catalyst.
suggest a different reaction mechanism to the commonly
stated one (Schemes 2 and 3).
Pu obtained (2R,3S)-configured epoxy ketones when
using (R)-binaphthol polymeric zinc complexes and both
Enders and Pu have reported the successful epoxidation of
enones bearing an electron-donating group at the para-posi-
tion on the β-phenyl ring. As a consequence, we postulate
the mechanism depicted in Figure 2 for the enantioselective
epoxidation of enones catalysed by a zinc (R)-BINOLate
complex.
The zinc (R)-BINOLate complex formed in situ acts so-
Figure 4. Proposed mechanism for the oxygen transfer.
lely as a Lewis acid and activates the enone function for
nucleophilic attack by complexing the carbonyl function-
ality. The final configuration of the obtained epoxy ketone
(2S,3R) suggests that the (R)-BINOLate complex blocks the
si-face of the enone (Figure 3).
The resulting epoxy ketone is readily displaced by an-
other enone molecule to close the overall catalytic cycle as,
due to the conjugated system, the carbonyl oxygen of the
enone displays a higher electron density than the carbonyl
oxygen of the epoxy ketone.
Our control experiments rule out background reactions
like the epoxidation in the absence of ZnEt2 or (R)-BINOL.
The inertness of p-OMe- or p-Me-substituted chalcone de-
rivatives can be rationalised by considering that these en-
ones undergo electronic stabilisation through the arene do-
nor substituent, which decreases their Michael acceptor
character. Thus, the nucleophilicity of the peroxides is not
sufficient to initiate oxidation. The acceleration of the reac-
Figure 3. Face-selectivity in the enantioselective epoxidation with
the Zn–(R)-BINOL catalyst.
This observation is in complete agreement with the gene- tion rate and the increased yields observed for CMHP as
ral rule for (R)-binaphthyl metal complexes interacting with terminal oxidant reflects the better leaving-group character
carbonyl functionalities.[17] For the present oxidation, Lewis of PhMe2CO– as compared to tBuO– [pka(tBuOH, DMSO)
acidic activation by the zinc catalyst renders the β-carbon = 29.4; pka(PhMe2COH, DMSO) = 14.3].[18]
atom of the vinylogous substrate positively charged. This
The formation of a “white precipitate” was observed
electrophilic position can then be attacked by the weakly upon mixing one equivalent of (R)-BINOL with one equiv-
nucleophilic hydroperoxide, which transfers an oxygen atom alent of ZnEt2 solution (conditions B).[19] A simple stoi-
within the chiral environment to yield the (2S,3R)-epoxy chiometric experiment proved this species to be the catalyti-
ketone and the corresponding alcohol (Figure 4).
cally active species, or at least the immediate precatalyst, as
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Enantioselective Epoxidation of α,β-Enones by Electrophilic Activation
FULL PAPER
1
filtering the precipitate off and performing an epoxidation
A comparison of the aromatic section of the H NMR
with the solid resulted in complete conversion and forma- spectra of a) and c) (Figure 6) suggests the formation of a
tion of the epoxy ketone in 99% yield, Ͼ99% de and 90% C2-symmetric complex present in b) characterised by only
ee (Scheme 7, case I). No reaction, however, was observed six multiplets (corresponding to 2 H atoms each); the mul-
when the filtrate was used instead (Scheme 7, case II).
tiplet fine-structures are identical to those of the parent (R)-
1H NMR spectroscopic experiments were undertaken to BINOL signals. The coordination of diethylzinc to (R)-
visualise the chemical reaction between (R)-BINOL and BINOL with concomitant loss of ethane is supported by
ZnEt2. A comparison of the NMR spectra before and after both the missing OH signals and the distinct upfield shift
the addition of one equivalent of ZnEt2 (solution in tolu- of the aromatic protons (6.47 Ͻ δ Ͻ 7.91 ppm) compared
ene) to a solution of (R)-BINOL in CDCl3 reveals that the to those in free (R)-BINOL (7.16 Ͻ δ Ͻ 7.95 ppm), which
hydroxy protons (δ = 5.1 ppm) have disappeared [Figure 5, is most noticeable for H3, H4 and H8, as expected for zinc–
parts a) and b)]. Interestingly, spectrum b) shows very BINOLate chelation.
broad signals, which suggests the formation of zinc (R)-
Based on these results, we conclude a pronounced role
BINOLate aggregates. This is in agreement with the obser- of a BINOL–Zn catalyst, readily generated in situ from
vation that the solution in the NMR tube turned very vis- ZnR2 and BINOL as a white precipitate when both compo-
cous until a white gel was formed. Simple shaking of the nents are mixed in a 1:1 ratio. This complex, even when
NMR probe, however, caused the solution to turn clear present in minor amounts, is suggested to dominate the ki-
again, and the recorded NMR spectrum c) reveals sharp netic activation of the enone carbonyl group and, thus, the
signals again, indicating efficient deaggregation.
enantioselective oxidation pathway. The role of the alkyl hy-
Scheme 7. Reactivity of the “white precipitate”.
1
1
Figure 5. H NMR spectrum of (R)-BINOL (CDCl3) (a), H NMR spectrum of (R)-BINOL + 1 equiv. ZnEt2 (CDCl3, toluene) white
1
precipitate (b), and H NMR spectrum of (R)-BINOL + 1 equiv. ZnEt2 (CDCl3, toluene) clear solution (c).
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A. Minatti, K. H. Dötz
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1
Figure 6. Enlarged aromatic sections of the H NMR spectra labeled a) and c) in Figure 5.
and 13C NMR spectra were recorded on a 300 MHz spectrometer.
The chemical shifts are reported in ppm relative to TMS. GC-MS
was performed with a Hewlett–Packard 5890 Series-II Gas Chro-
matograph with 5972 Series-Mass Selective Detector, using an HP-
5 column. All yields given refer to isolated yields. The dia-
stereomeric ratio of the epoxides was determined by 1H NMR
analysis of the crude reaction mixtures. The enantiomeric excess of
the epoxides was determined by HPLC on a chiral stationary phase
(Chiracel OD/OD-H column with n-hexane/2-propanol as eluent
and a 254 nm UV detector). The absolute configurations of the
epoxides were assigned by comparison of their optical rotation with
literature values and the elution order of the two enantiomers on
the HPLC column. (R)-BINOL, (S)-BINOL, ZnEt2, TBHP,
CMHP and chalcone were used as commercial reagents without
further purification. The epoxidations were allowed to proceed un-
til the substrates had been totally consumed, as monitored by TLC,
or until no further consumption was observed. The syntheses of
some of the α,β-enones have been described previously: 1,[20] 2,[21]
4,[21] 5,[20] 6,[22] 7,[9b] 8,[9b] 9,[9b] 10.[23]
droperoxide is characterised by a nucleophilic attack at the
β-carbon atom of the enone.
Conclusions
In summary, we have demonstrated that the combination
of enantiomerically pure BINOL and a dialkylzinc reagent
provides an effective catalyst for the enantioselective epox-
idation of α,β-enones. Under optimised conditions, the
catalytic epoxidation proceeds for a variety of enones in
very high yields, with excellent enantiomeric excesses up to
96% and complete diastereoselectivity, yielding exclusively
the trans-epoxide. The efficiency of the reaction depends on
the nature of the oxidant, and CMHP proved to be the
oxidant of choice. Since both (R)- and (S)-BINOL, are
commercially available, either enantiomer of the resulting
epoxides is accessible. The ease of performance, the com-
mercial availability of all reagents and the easy recovery of
General Procedures for the Enantioselective Epoxidation of α,β-En-
the chiral ligand render the described procedure an attract- ones. A: (R)-BINOL (57 mg, 0.2 mmol) was dissolved in the corre-
sponding solvent (20 mL) in a 50-mL Schlenk flask equipped with
a magnetic stirring bar under an inert atmosphere. After cooling
to 0 °C in an ice-bath, ZnEt2 (0.33 mL, 0.36 mmol, 1.1 m solution
in toluene) was added whilst stirring. After 15 min the α,β-unsatu-
rated ketone (1 mmol) and the oxidant (0.24 mL, 1.2 mmol, 5–6 m
in decane in the case of TBHP; 0.22 mL, 1.2 mmol, 80% solution
in cumene in the case of CMHP) were added, and the resulting
mixture was warmed to room temperature overnight. The reaction
was quenched with aq. sat. NaHSO3 and extracted with EtOAc
and the organic layer was washed with aq. Na2CO3 and brine. The
ive synthetic methodology.
Experimental Section
General Remarks: All reactions were carried out using standard
Schlenk techniques under an inert atmosphere. Solvents were dried
and purified by conventional methods prior to use. Diethyl ether
(Et2O), tetrahydrofuran (THF) and toluene were freshly distilled
from benzophenone ketyl radical under argon. Dichloromethane
was distilled from CaH2 under argon. Column chromatography was combined organic layers were dried with MgSO4, and the solvent
performed with silica gel 60 (0.063–0.2 mm). Optical rotations [c =
g/100 mL] were measured on a Perkin–Elmer 431 polarimeter. H
was evaporated in vacuo. The residue was purified by column
chromatography. CH2Cl2 was used as eluent in all cases, and re-
1
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Enantioselective Epoxidation of α,β-Enones by Electrophilic Activation
FULL PAPER
maining starting material and the α,β-epoxy ketone were isolated
in this sequence. (R)-BINOL was recovered almost quantitatively
as the last fraction.
73% ee. [α]2D6 = –7.8 (c = 0.94, CH2Cl2). Literature value for the
other enantiomer (2R,3S): [α]2D6 = +13.8 (c = 1.4, CH2Cl2, ee =
91%).[9b]
B: (R)-BINOL (57 mg, 0.2 mmol) was dissolved in Et2O (4 mL) in
a 50-mL Schlenk flask equipped with a magnetic stirring bar under
an inert atmosphere. After cooling to 0 °C in an ice-bath, ZnEt2
(0.18 mL, 0.2 mmol, 1.1 m solution in toluene) was added whilst
stirring. After 3 h the complete precipitation of an amorphous
white solid was observed and α,β-unsaturated ketone (1 mmol) and
CMHP (0.22 mL, 1.2 mmol, 80% solution in cumene) were added;
stirring of the reaction mixture at room temperature was main-
tained for the indicated time. The reaction was quenched with aq.
sat. NaHSO3 and extracted with EtOAc. The organic layer was
washed with aq. Na2CO3 and brine. The combined organic layers
were dried with MgSO4, and the solvent was evaporated in vacuo.
The residue was purified by column chromatography. CH2Cl2 was
used as eluent in all cases and remaining starting material and the
α,β-epoxy ketone were isolated in this sequence. (R)-BINOL was
recovered almost quantitatively as the last fraction.
(E)-Phenyl-(3-propyloxiran-2-yl)methanone:[9b]
1H
NMR
(300 MHz, CDCl3): δ = 1.01 (t, J = 7.4 Hz, 3 H, CH3), 1.48–1.83
(m, 4 H, CH2CH2), 3.15 (m, 1 H, Hβ), 4.03 (d, J = 2 Hz, 1 H, Hα),
7.47–7.65 (m, 3 H), 8.01 (m, 2 H) ppm. GCMS: m/z = 189 [M+
–
H], 147 [M+ – C3H7], 131 [M+ – C3H7O], 105 [C7H5O+]. HPLC
(Chiracel OD, n-hexane/2-propanol, 90:10, 0.5 mLmin–1): tR
=
11.88 min (2S,3R-enantiomer, major), tR = 12.60 min (2R,3S-en-
antiomer, minor), 64% ee. [α]2D6 = –1.3 (c = 0.9, CH2Cl2). Literature
value for the other enantiomer (2R,3S): [α]2D6 = +1.7 (c = 1.0,
CH2Cl2, ee = 76%).[10]
(E)-(3-Isopropyloxiran-2-yl)phenylmethanone:[9b]
1H
NMR
(300 MHz, CDCl3): δ = 1.07 (d, J = 6.7 Hz, 3 H, CH3), 1.10 (d, J
= 6.7 Hz, 3 H, CH3), 1.79 (m, 1 H, CH), 2.96 (dd, J = 6.7 Hz,
2.0 Hz, 1 H, Hβ), 4.07 (d, J = 2.0 Hz, 1 H, Hα), 7.47–7.64 (m, 3
H), 8.02 (m, 2 H) ppm. GCMS: m/z = 189 [M+ – H], 174 [M+ – O],
147 [M+ – C3H7], 105 [C7H5O+]. HPLC (Chiracel OD, n-hexane/2-
propanol, 90:10, 0.5 mLmin–1): tR = 11.08 min (2S,3R-enantiomer,
major), tR = 12.18 min (2R,3S-enantiomer, minor), 68% ee.
[α]2D6 = –21.9 (c = 1.2, CH2Cl2). Literature value for the other
enantiomer (2R,3S): [α]2D6 = +32 (c = 1.3, CH2Cl2, ee = 92%).[10]
(E)-Phenyl-(3-phenyloxiran-2-yl)methanone:[24]
1H
NMR
(300 MHz, C6D6): δ = 4.04 (d, J = 1.8 Hz, 1 H, Hβ), 4.06 (d, J =
1.8 Hz,1 H, Hα), 6.97–7.15 (m, 8 H), 7.81 (m, 2 H) ppm. GCMS:
m/z = 224 [M+], 207 [M+ – OH], 105 [C7H5O+]. HPLC (Chiracel
OD, n-hexane/2-propanol, 95:5, 0.7 mLmin–1): tR = 15.17 min
(2S,3R-enantiomer, major), tR = 16.35 min (2R,3S-enantiomer,
minor), 90% ee. [α]2D6 = +207.7 (c = 0.78, CH2Cl2). Literature value
for the other enantiomer (2R,3S): [α]2D6 = –130.0 (c = 1.1, CH2Cl2,
ee = 61%).[9b]
(E)-(3-tert-Butyloxiran-2-yl)phenylmethanone:[29]
1H
NMR
(300 MHz, CDCl3): δ = 1.02 [s, 9 H, C(CH3)3], 2.94 (d, J = 2.2 Hz,
1 H, Hβ), 4.09 (d, J = 2.2 Hz, 1 H, Hα), 7.45–7.60 (m, 3 H), 7.97–
8.01 (m, 2 H) ppm. GCMS: m/z = 204 [M+], 189 [M+ – CH3], 173
[M+ – CH3O], 147 [M+ – C4H9], 105 [C7H5O+]. HPLC (Chiracel
OD, n-hexane/2-propanol, 90:10, 0.4 mLmin–1): tR = 12.38 min
(2S,3R-enantiomer, major), tR = 14.23 min (2R,3S-enantiomer,
minor), 96% ee. [α]2D6 = –18.0 (c = 1.3, CHCl3). Literature value
for the other enantiomer (2R,3S): [α]2D6 = +14 (c = 0.36, CH2Cl2,
ee = 64%).[10]
(E)-β-Benzoyloxystyrene:[30] 1H NMR (300 MHz, CDCl3): δ = 6.51
(d, J = 12.76 Hz, 1 H, Hβ), 7.17 (m, 1 H), 7.26 (m, 2 H), 7.32 (m,
2 H), 7.41 (m, 2 H), 7.53 (m, 1 H), 8.01 (d, J = 12.76 Hz, 1 H, Hα),
8.07 (m, 2 H) ppm. GCMS: m/z = 224 [M+], 105 [C7H5O+].
(E)-[3-(p-Bromophenyl)oxiran-2-yl]phenylmethanone:[25] 1H NMR
(300 MHz, CDCl3): δ = 3.95 (d, J = 1.8 Hz, 1 H, Hβ), 4.15 (d, J =
1.8 Hz, 1 H, Hα), 7.14 (d, J = 8.5 Hz, 2 H), 7.37–7.55 (m, 5 H),
7.90 (d, J = 7 Hz, 2 H) ppm. GCMS: m/z = 302 [C15H1179BrO2+],
+
286 [C15H1179BrO2 – O], 105 [C7H5O+]. HPLC (Chiracel OD-H,
n-hexane/2-propanol, 90:10, 0.4 mLmin–1): tR = 27.08 min (2S,3R-
enantiomer, major), tR = 29.12 min (2R,3S-enantiomer, minor),
90% ee. [α]2D6 = +137.2 (c = 1.22, CH2Cl2).
(E)-[3-(p-Nitrophenyl)oxiran-2-yl]phenylmethanone:[26] 1H NMR
(300 MHz, CDCl3): δ = 4.11 (d, J = 1.8 Hz, 1 H, Hβ), 4.17 (d, J =
1.8 Hz, 1 H, Hα), 7.29 (d, J = 9 Hz, 1 H), 7.44 (t, J = 8 Hz, 4 H),
7.91 (d, J = 7 Hz, 2 H), 8.16 (d, J = 8.9 Hz, 2 H) ppm. GCMS:
m/z = 269 [M+], 165 [M+ – C7H5O+], 105 [C7H5O+]. HPLC (Chira-
Acknowledgments
cel OD-H, n-hexane/2-propanol, 75:25, 0.5 mLmin–1): tR
=
We thank the Fonds der Chemischen Industrie for a doctoral fel-
lowship (Ana Minatti) and for financial support.
31.38 min (2S,3R-enantiomer, major), tR = 34.37 min (2R,3S-en-
antiomer, minor), 76% ee. [α]2D6 = +156.8 (c = 0.98, CH2Cl2). Lit-
erature value for the other enantiomer (2R,3S): [α]2D5 = –274.0 (c =
2.0, CH2Cl2, ee = 99%).[27]
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(E)-(3-Ethyloxiran-2-yl)phenylmethanone:[9b] 1H NMR (300 MHz,
CDCl3): δ = 1.09 (t, J = 7.4 Hz, 3 H. CH3), 1.69–1.90 (m, 2 H,
CH2), 3.15 (m, 1 H, Hβ), 4.04 (d, J = 2.0 Hz, 1 H, Hα), 7.47–7.65
(m, 3 H), 8.02 (m, 2 H) ppm. GCMS: m/z = 176 [M+], 147 [M+
–
C2H5], 131 [M+ – C2H5O], 105 [C7H5O+]. HPLC (Chiracel OD, n-
hexane/2-propanol, 90:10, 0.5 mLmin–1): tR = 12.47 min (2S,3R-
enantiomer, major), tR = 13.37 min (2R,3S-enantiomer, minor),
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A. Minatti, K. H. Dötz
FULL PAPER
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276
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