Diaryl-2-pyrrolidinemethanols catalyzed enantioselective epoxidation of α,β-enones: new insight into the effect of structural modification of the catalyst on reaction efficiency

Article abstract of DOI:10.1016/j.tet.2006.10.005

Catalytic enantioselective epoxidation of α,β-unsaturated ketones promoted by diaryl-2-pyrrolidinemethanols and tert-butyl hydroperoxide (TBHP) is described. Investigation on structural modifications of the diaryl-2-pyrrolidinemethanols showed that fine t

Full text of DOI:10.1016/j.tet.2006.10.005

Tetrahedron 62 (2006) 12264–12269
Diaryl-2-pyrrolidinemethanols catalyzed enantioselective
epoxidation of a,b-enones: new insight into the effect of structural
modification of the catalyst on reaction efficiency
*
Alessandra Lattanzi and Alessio Russo
Dipartimento di Chimica, Universit aꢀ di Salerno, Via Ponte don Melillo, 84084-I Fisciano, Italy
Received 28 July 2006; revised 18 September 2006; accepted 5 October 2006
Available online 27 October 2006
Abstract—Catalytic enantioselective epoxidation of a,b-unsaturated ketones promoted by diaryl-2-pyrrolidinemethanols and tert-butyl hy-
droperoxide (TBHP) is described. Investigation on structural modifications of the diaryl-2-pyrrolidinemethanols showed that fine tuning of the
stereoelectronics of the substituents on the aryl moiety is important to achieve high efficiency. By employing a structurally optimized organo-
catalyst, significantly reduced loading (10 mol %) can be used to produce the epoxides in high yield and up to 90% ee at room temperature.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
OH-free prolinols have met with poor success as promoters
because of the formation of unreactive cyclic N,O-acetals
9
Enantiomerically enriched a,b-epoxy ketones are versatile
intermediates in organic synthesis and important synthetic
pharmaceuticals. Efficient asymmetric epoxidation reac-
tions of a,b-unsaturated ketones, mainly chalcones, have
been reported using chiral metal alkyl hydroperoxide sys-
tems. Moreover, polyaminoacids and cinchona alkaloids
have been used in the presence of hydrogen peroxide as an
oxygen source under basic conditions. The development of
simple, catalytic and environmentally benign methodologies
to access optically pure compounds is a fundamental goal of
with carbonyl compounds. Very recently, the asymmetric
vinylogous Michael addition reaction has been promoted
by diaryl-2-pyrrolidinemethanols through the formation of
1
1
0
iminium intermediates. We have recently discovered that
commercially available (S)-diphenyl-2-pyrrolidinemethanol
2a and TBHP oxidize unsaturated a,b-ketones into the cor-
responding epoxides in good yield and enantioselectivity (up
to 80% ee), using 30 mol % catalyst loading at room temper-
2
3
4
1
1
ature (Scheme 1).
5
current organic synthesis. Asymmetric organocatalysis
OH
Ph
satisfies most of these requirements; low cost and easily
accessible chiral organic molecules are able to catalyze an
ever-increasing number of reactions under operational sim-
plicity and mild conditions. In order to achieve good yields
of products and satisfactory level of enantioselectivity, in
most of the reactions, e.g., those promoted by proline-based
compounds, 20–30 mol % of catalyst loading is generally
employed. Thus, one of the most challenging goals in orga-
nocatalysis is to reduce catalyst loading to the level used in
metal-catalyzed asymmetric synthesis (ꢀ10 mol %).
N
H Ph
O
R
O
O
2
a 30 mol %
R1
R1
R
TBHP, hexane, rt
46-87%
63-80% ee
Scheme 1.
In exploring the effects of structural modification on catalyst
activity, investigation on stereoelectronic substitution on the
phenyl moiety gave improved understanding of mechanism
and more importantly a remarkable enhancement of the re-
Chiral diaryl-2-pyrrolidinemethanol ethers have been
successfully employed as organocatalysts in different
transformations such as C–C bond forming reactions,
functionalizations of carbonyl compounds and epoxidation
of a,b-unsaturated aldehydes. On the other hand, the
1
2
action efficiency. Indeed, bis(3,5-dimethylphenyl)-((S)-
pyrrolidin-2-yl)methanol 2b, when employed at 20 mol %
6
7
ꢁ
and ee (up to 92% ee). Nonlinear effects (NLE) investiga-
loading and 4 C, afforded the epoxides in higher yield
8
13
tion using (S)-diphenyl-2-pyrrolidinemethanol 2a, at differ-
ent degrees of optical purity, afforded a linear relationship,
suggesting the involvement of a single molecule of the
catalyst in the enantiodifferentiating step. The postulated
Keywords: Epoxidation; a,b-Enones; Asymmetric organocatalysis; Epox-
ides.
*
Corresponding author. Tel.: +39 089 969563; e-mail: lattanzi@unisa.it
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.005

A. Lattanzi, A. Russo / Tetrahedron 62 (2006) 12264–12269
12265
OH
Ph
OH
Ph
substituted compound 1d was obtained in 48% yield. This
was probably due to the bigger steric congestion of the
o-methyl substituent with respect to o-methoxy group at
the reactive site of the organometallic reagent, which pre-
vented the addition. Catalyst 2d was isolated in 25% yield
after hydrolysis. Next, sterically more encumbered groups
were introduced at the meta positions and the corresponding
compounds 2e,f were obtained in 49% and 31% yield for the
two steps, respectively. Finally, compound 2g was obtained
in good overall 68% yield.
+
t-BuOO
+
t-BuOOH
N
H
N
Ph
H
H Ph
O
t-BuOH
R
R1
Ph
Ph
O
δ- H
O
N
δ
O
OH
Ph
H
- H
+
t-BuO
N
O
H
H
Ph
O
O
R
R1
R1
R
Catalysts 2d–g were then checked under the optimal condi-
tions (TBHP 1.2 equiv, +4 C, 20 mol % catalyst loading)
ꢁ
12
previously found for catalyst 2b on trans-chalcone 3a
(Table 1, entry 1).
Figure 1. Proposed catalytic cycle for the epoxidation.
catalytic cycle for the epoxidation involves the formation
of a ionic pair, made of tert-butyl hydroperoxide anion and
ammonium cation, as the active species (Fig. 1).
1
1
The epoxidation of 3a, using the o,p-dimethoxy substituted
catalyst 2d, afforded 4a in very low yield and low enantio-
selectivity (entry 2). Although we expected the trisubstituted
catalyst 2e to be less reactive than 2b, because of electron-
withdrawing inductive effect of the methoxy groups at
meta positions, the slightly bigger m-methoxy substituents
were not beneficial for the enantioselectivity (entry 3). Inter-
estingly, the activity of catalyst 2f, bearing sterically en-
coumbered m-tert-butyl groups, was completely inhibited
(entry 4). These results showed that ortho-type substitution
is detrimental in all respects, probably because of steric ef-
fect on the OH group, which prevented activation via hydro-
gen bonding with the enone carbonyl moiety. Substitution at
the meta positions proved to be crucial for catalyst perfor-
mance. Small or major modifications of the substituent
nature, with respect to the methyl group of 2b, were delete-
rious (entries 3 and 4). Thus, methyl substitution at the meta
positions would seem optimal to achieve high enantioselec-
tivity. We then studied the epoxidation with the trisubstituted
promoter 2g. This compound should have had improved ac-
tivity with respect to 2b due to the introduction of additional
electron-donating p-methoxy groups and had a comparable
impact on enantioselectivity. The epoxidation was carried
Further understanding of the catalyst activity, through fine-
tuned stereoelectronic modifications on the phenyl ring, is
important for the development of a more efficient and prac-
tical epoxidation reaction. Hence, in this study, novel mod-
ified diaryl-2-pyrrolidinemethanols were synthesized and
tested as promoters for the epoxidation, which was success-
fully improved by using a more active organocatalyst at
significantly reduced loading.
2
. Results and discussion
1
2
Our preliminary investigation on the effect of substituents
on the phenyl ring showed that (i) electron-donating substit-
uents at para and meta positions enhanced catalyst activity;
(
ii) substitution at meta positions was found to be beneficial
for the enantioselectivity. These results reinforced the mech-
anistic hypothesis involving the ionic pair as active species
(
Fig. 1). In fact, the equilibrium for its formation would be
favoured for those catalysts having electron-donating
groups, which through inductive or mesomeric effects can
increase amine basicity. In order to further improve our
oxidative system, a more detailed analysis of the stereo-
electronic effects on catalyst activity was undertaken. In
Table 1. Asymmetric epoxidation of 3a by 2/TBHP system
1
2
the light of previous results, ortho-substituted and meta-
disubstituted catalysts with electron-donating groups were
thought to be the most suitable compounds to prepare and
check in the epoxidation. (S)-Diaryl-2-pyrrolidinemethanols
are readily accessible starting from L-proline according to
OH
N
Ar
O
H Ar
O
O
2
Ph
Ph
Ph
Ph
TBHP, hexane
3a
4a
1
4
the general established procedures (Scheme 2).
ꢁ
a
b
Entry
2 (mol %)
T ( C)
t (h)
Yield 4a (%)
ee 4a (%)
c
Ar
OH
Ar
1
b (20)
d (20)
e (20)
f (20)
g (15)
g (10)
b (10)
a (30)
g (5)
+4
+4
+4
+4
+4
rt
rt
rt
rt
rt
112
112
86
90
9
91 (aR,bS)
43 (aR,bS)
86 (aR,bS)
—
92 (aR,bS)
89 (aR,bS)
88 (aR,bS)
75 (aR,bS)
88 (aR,bS)
83 (aR,bS)
i
ii
iii
CO2H
COOMe
CO2Et
N
H
N
N
Ar
2
3
4
5
6
N
H
O
37
<5
70
93
61
72
77
47
Ar
O
90
1
2
106
110
95
94
120
120
Ar=o-methyl-p-methoxyphenyl (c)
Ar=o,p-dimethoxyphenyl (d) 12%
c
7
Ar=m,m'-dimethoxy-p-methoxyphenyl (e) 49%
Ar=m,m'-di-t-butylphenyl (f) 31%
Ar=m,m'-dimethyl-p-methoxyphenyl (g) 68%
d
8
9
1
0
g (2)
Scheme 2. Reagents and conditions: (i) ethyl chloroformate, K
2
CO
MeOH, 0 C to rt, 97%; (ii) ArMgBr, THF, 0–60 C; (iii) KOH, EtOH/
O, reflux.
3
,
a
ꢁ
ꢁ
Yield of isolated product after flash chromatography.
b
Determined by HPLC on chiral column. Absolute configuration (aR,bS)
was determined by comparison of the HPLC retention times with those
in the literature.
Yield and ee are reported in Ref. 12.
Yield and ee are reported in Ref. 11.
H
2
c
Grignard addition to (S)-proline-N-ethyl carbamate methyl
ester did not furnish compound 1c, while the o,p-dimethoxy
d

12266
A. Lattanzi, A. Russo / Tetrahedron 62 (2006) 12264–12269
out at lower catalyst loading (15 mol %) under the same con-
ditions and the epoxide was isolated in good yield and high
ee (entry 5). A better comparison on catalysts activity can be
gained by comparing the results obtained at 10 mol % load-
ing, working at room temperature (entries 6 and 7). After
similar reaction times, the epoxide was isolated in compara-
ble ee, but a higher yield was achieved when using catalyst
2g. The relevance of the substitution pattern on catalyst effi-
ciency can be clearly observed when comparing the results
with those obtained using the original promoter 2a at
3. Conclusion
In summary, careful choice of stereoelectronic phenyl sub-
stitution is necessary in order to improve the activity of
diaryl-2-pyrrolidinemethanols as promoters in asymmetric
epoxidation of a,b-enones. Electron-rich derivative 2g, eas-
ily obtained in good overall yield from L-proline, proved to
be a more active catalyst than previously reported analogues
and it could be employed at 10 mol % level, which is consid-
erably lower than firstly reported (30 mol % loading). The
optimized catalytic epoxidation reaction afforded epoxides
in good to high yield and high ee at room temperature.
3
0 mol % (entry 8). It is worth noting that the amount of cat-
alyst 2g could be further reduced to 2 mol % (entries 9 and
0) without particularly affecting the enantioselectivity,
1
although the yield of 4a decreased.
4. Experimental
Having established that 2g proved about equal to 2b (com-
pare entries 1 and 6), but at half the catalyst loading
4.1. General
(10 mol %) we next screened a series of a,b-enones under
the conditions reported in entry 6 of Table 1 (Table 2).
All reactions requiring dry or inert conditions were con-
ducted in flame dried glassware under a positive pressure
of argon. THF was freshly distilled before use from LiAlH4.
Reactions were monitored by thin layer chromatography
(TLC) on Merck silica gel plates (0.25 mm) and visualized
by UV light or by 10% H SO /ethanol spray test. Flash chro-
Epoxides of chalcones bearing electron-donating or with-
drawing groups on the phenyl rings were obtained in good
to high yield and high ee (entries 1–8). Predictably, the
conversion was somewhat decreased for chalcones having
electron-donating substituent on the b-phenyl ring (entries
2
4
matography was performed on Merck silica gel (60, particle
1
13
4
and 5). Although the epoxide of the o-substituted b-phenyl
size: 0.040–0.063 mm). H NMR and C NMR spectra
were recorded on Bruker DRX 400 spectrometer at room
temperature in CDCl as solvent. Optical rotations were per-
ring 4i was obtained with decreased ee (entry 9), it is worth
noting that the same reaction when carried out by 30 mol %
of the commercial promoter 2a was considerably slower and
the product was obtained in modest yield and significantly
reduced ee (entry 10). Finally, the epoxidation of more chal-
lenging alkyl substituted a,b-unsaturated ketones led to the
formation of the epoxides in good ee (entries 11–13).
3
formed on a Jasco Dip-1000 digital polarimeter using the Na
lamp. FTIR spectra were recorded as a thin film on NaCl
plates using Bruker Vector 22 spectrometer and absorption
ꢂ1
maxima are reported in wavenumber (cm ). ESI-MS was
performed using a Bio-Q triple quadrupole mass spectrome-
ter (Micromass, Manchester, UK) equipped with an electro-
spray ion source. All commercially available reagents were
purchased from Aldrich. Petrol ether (PE) refers to light
a
Table 2. Catalytic asymmetric epoxidation of 3 by 2g/TBHP system
OH
ꢁ
CH3
petroleum ether (bp 40–60 C). a,b-Enones which were
not commercially available were prepared via aldol conden-
sation using standard conditions. Hexane of HPLC grade
N
H
OCH3
CH3
15
was used as solvent for the epoxidation. The absolute config-
uration of the predominant enantiomer of epoxides was
determined by comparison with the HPLC retention times,
using Daicel Chiralcel OD and Daicel Chiralpak AD
columns, as reported in the literature. (S)-Proline-N-ethyl
carbamate ethyl ester was prepared according to the
H3C
CH3
O
O
2
g
OCH3
O
R
R1
R1
R
TBHP, hexane, rt
3
4
1
b
c
Entry
R, R
3
t (h)
Yield 4 (%)
ee 4 (%)
1
6
1
2
3
4
Ph, Ph
p-BrC
m-CH
Ph, p-CH
Ph, p-OCH
Ph, p-CN
2-Furyl, Ph
Ph, p-Cl
Ph, o-Cl
Ph, o-Cl
a
b
c
d
e
f
g
h
i
i
j
k
l
110
172
137
153
120
170
179
167
76
143
216
119
162
93
98
87
80
61
65
78
88
70
45
55
95
80
89
86
89
86
87
86
90
87
69
34
83
67
71
literature.
6
H
4
, Ph
3
C
6
H
4
, Ph
4.2. General procedure for the preparation of carba-
mates 1 from (S)-proline-N-ethyl carbamate methyl
ester
3
d
5
3
6
7
8
Magnesium turnings (251 mg, 10.3 mmol) were placed in
a dried two-necked round-bottom flask attached with a reflux
condenser under argon atmosphere. After adding dry THF
(3 mL) and few iodine crystals to the reaction vessel, the
turnings were left under stirring for 2 h. Aryl bromide
(9.4 mmol) in dry THF (8 mL) was added dropwise in
15 min. The mixture was then refluxed under stirring for
e
9
f
10
11
12
13
d
CH
Ph, CH
2 2
Ph, (CH ) Ph
3
, Ph
3
a
b
c
Molar ratios: 3/2g/TBHP 1:0.10:1.2.
Yield of isolated product after flash chromatography.
Determined by HPLC on chiral columns. Absolute configuration (aR,bS)
was determined by comparison of the HPLC retention times with those in
the literature.
ꢁ
45 min. After cooling the reaction mixture at 0 C, a solution
of (S)-proline-N-ethyl carbamate methyl ester (805 mg,
4 mmol) in THF (18 mL) was cannulated into the reaction
vessel. The resulting mixture was warmed up to room tem-
d
e
f
2
0 mol % was used in this reaction.
5 mol % was used in this reaction.
The reaction was carried out with 30 mol % of 2a.
1
ꢁ
perature gradually and then heated up to 60 C. After stirring

A. Lattanzi, A. Russo / Tetrahedron 62 (2006) 12264–12269
12267
overnight, the reaction was quenched with saturated ammo-
nium chloride solution (50 mL) extracted with CHCl3
4.3. General procedure for the hydrolysis of carbamates
to (S)-diaryl-2-pyrrolidinemethanols 2
(
3ꢃ50 mL). The combined organic layer was washed with
brine and dried over anhydrous sodium sulfate and concen-
trated under reduced pressure. Purification by flash chroma-
tography typically eluting with mixtures of PE/ethyl acetate
A solution of 1 (2.2 mmol), KOH (2.4 g, 43 mmol), EtOH
ꢁ
(10 mL) and H O (2.0 mL) was heated overnight at 80 C
2
(in some examples up to two days time was necessary to
complete conversion of starting material as assessed by
TLC analysis). After cooling to room temperature, EtOH
was removed under reduced pressure, and the aqueous layer
9
0/10 to 50/50 afforded the corresponding carbamate 1.
4
.2.1. Carbamate 1d. Compound 1d was obtained in 48%
2
4
yield as white gum; [a] ꢂ118.1 (c 1.25, CHCl ); nmax/
was extracted with CHCl (3ꢃ50 mL). The combined or-
D
3
3
ꢂ1
cm 2945, 1743, 1463, 1209, 798, 750; dH (400 MHz,
CDCl ) 7.36 (1H, d, J¼8.5 Hz), 6.94 (1H, d, J¼8.5 Hz),
ganic layer was washed with brine and dried over anhydrous
sodium sulfate and concentrated under reduced pressure. Pu-
rification by flash chromatography typically eluting with
mixtures of PE/ethyl acetate 80/20 to pure ethyl acetate
afforded compounds 2.
3
6
.51–6.43 (3H, m), 6.39–6.34 (1H, m), 4.53 (1H, dd,
J¼9.6, 6.6 Hz), 3.82 (3H, s), 3.78 (3H, s), 3.74 (3H, s),
3
2
1
1
9
.73 (3H, s), 3.67–3.59 (1H, m), 3.30–3.22 (1H, m), 2.09–
.00 (1H, m), 1.98–1.89 (1H, m), 1.75–1.68 (1H, m),
.50–1.42 (1H, m); dC (100 MHz, CDCl ) 160.6, 159.8,
4.3.1. Bis(2,4-dimethoxyphenyl)((S)-pyrrolidin-2-yl)me-
thanol 2d. Compound 2d was obtained in 25% yield as yel-
3
57.6, 129.7, 128.3, 124.1, 120.6, 103.9, 103.5, 99.1,
9.0, 86.7, 69.4, 55.4, 55.2, 55.1, 44.9, 28.0, 25.9; MS
2
4
ꢂ1
low gum; [a]D ꢂ83.5 (c 1.08, CHCl ); nmax/cm 3463,
3
+
+
+
(
ESI , m/z): 422 [(M+Na ), 28%], 438 [(M+K ), 35%],
2938, 1462, 1209, 1031, 833, 754; d (400 MHz, CDCl )
H
3
+
4
C, 66.15; H, 6.31; N, 3.51. Found: C, 66.29; H, 6.20; N,
3
00 [(M+H ), 20%]; Anal. Calcd (%) for C H NO :
7.67 (1H, d, J¼8.7 Hz), 7.54 (1H, d, J¼8.7 Hz), 6.56–6.51
(1H, m), 6.49–6.45 (1H, m), 6.36–6.25 (2H, m), 5.13 (1H,
t, J¼8.4 Hz), 3.75 (3H, s), 3.73 (3H, s), 3.63 (3H, s), 3.51
2
2
25
6
.42.
(3H, s), 3.09–3.00 (2H, m), 1.91–1.76 (3H, m), 1.58–1.55
4
.2.2. Carbamate 1e. Compound 1e was obtained in 59%
(1H, m); d (100 MHz, CDCl ) 160.1, 157.6, 156.5, 131.4,
C 3
2
4
yield as dark yellow gum; [a] ꢂ134.3 (c 1.06, CHCl );
129.6, 127.8, 127.6, 124.4, 123.1, 104.3, 103.7, 99.8, 99.1,
76.9, 62.0, 55.7, 55.4, 55.2, 47.4, 26.8, 25.2; MS (ESI ,
D
3
ꢂ1
+
nmax/cm 2940, 1749, 1418, 1128, 756; dH (400 MHz,
+
CDCl ) 6.73 (2H, s), 6.58 (2H, s), 4.47 (1H, dd, J¼10.5,
m/z): 374 [(M+H ), 18%], 356 [(Mꢂ17), 100%]; Anal.
3
5
3
1
.4 Hz), 3.84 (12H, s), 3.83 (6H, s), 3.80–3.71 (1H, m),
.30–3.25 (1H, m), 2.06–1.98 (1H, m), 1.93–1.86 (1H, m),
.79–1.73 (1H, m), 1.25–1.15 (1H, m); dC (100 MHz,
Calcd (%) for C H NO : C, 67.54; H, 7.29; N, 3.75.
2
1
27
5
Found: C, 67.68; H, 7.20; N, 3.61.
CDCl ) 160.3, 153.2, 153.0, 138.7, 138.1, 137.3, 135.6,
3
4.3.2. Bis(3,4,5-trimethoxyphenyl)((S)-pyrrolidin-2-yl)-
methanol 2e. Compound 2e was obtained in 83% yield as
1
2
3
03.6, 102.8, 85.8, 77.3, 69.3, 60.8, 56.3, 56.2, 46.1, 29.0,
4.8; MS (ESI , m/z): 498 [(M+K ), 12%], 460 [(M+H ),
5%]; Anal. Calcd (%) for C H NO : C, 62.73; H, 6.36;
+
+
+
23
ꢂ1
yellow gum; [a]D ꢂ60.3 (c 1.17, CHCl ); nmax/cm
3
3450, 2940, 1458, 1128, 756; d (400 MHz, CDCl ) 6.81
H 3
2
4
29
8
N, 3.05. Found: C, 62.60; H, 6.49; N, 3.14.
(2H, s), 6.73 (2H, s), 4.14 (1H, t, J¼7.8 Hz), 3.85 (6H, s),
.84 (6H, s), 3.80 (6H, s), 3.04–2.90 (2H, m), 1.77–1.53
(4H, m); d (100 MHz, CDCl ) 152.9, 152.7, 143.5, 140.7,
3
4
.2.3. Carbamate 1f. Compound 1f was obtained in 65%
C
3
2
5
yield as yellow gum; [a] ꢂ82.2 (c 1.0, CHCl ); nmax/
136.7, 136.5, 103.7, 103.2, 102.8, 72.9, 64.8, 60.7, 56.2,
D
3
ꢂ1
+
+
cm 2963, 1749, 1476, 1248, 754; d (400 MHz, CDCl )
H
56.1, 46.6, 26.4, 25.3; MS (ESI , m/z): 434 [(M+H ),
10%], 416 [(Mꢂ17), 100%]; Anal. Calcd (%) for
C H NO : C, 63.73; H, 7.21; N, 3.23. Found: C, 63.62,
3
7
(
5
.38 (2H, d, J¼1.4 Hz), 7.35–7.33 (1H, m), 7.30–7.28
1H, m), 7.24 (2H, d, J¼1.4 Hz), 4.48 (1H, dd, J¼10.5,
.3 Hz), 3.77–3.70 (1H, m), 3.26–3.20 (1H, m), 2.01–1.95
2
3
31
7
H, 7.30; N, 3.15.
(
(
1H, m), 1.94–1.85 (1H, m), 1.84–1.74 (1H, m), 1.29
36H, s), 1.16–1.10 (1H, m); d (100 MHz, CDCl ) 160.9,
4.3.3. Bis(3,5-di-tert-butylphenyl)((S)-pyrrolidin-2-yl)-
methanol 2f. Compound 2f was obtained in 48% yield as
C
3
1
1
50.7, 150.4, 143.4, 139.6, 122.1, 122.0, 121.0, 119.7,
19.6, 86.8, 70.7, 45.9, 34.9, 31.4, 29.3, 24.8; MS (ESI ,
+
22
ꢂ1
yellow gum; [a]D ꢂ58.2 (c 1.01, CHCl ); nmax/cm
3
+
+
m/z): 526 [(M+Na ), 12%], 504 [(M+H ), 35%]; Anal.
Calcd (%) for C H NO : C, 81.06; H, 9.80; N, 2.78.
Found: C, 81.18; H, 9.68; N, 2.66.
3417, 2963, 1392, 1248, 757; d (400 MHz, CDCl ) 7.52
H 3
(2H, d, J¼1.4 Hz), 7.35 (2H, d, J¼1.4 Hz), 7.26 (1H, s),
3
4
49
2
7.18 (1H, s), 4.73 (1H, t, J¼7.8 Hz), 2.33–2.27 (1H, m),
2.25–2.15 (1H, m), 1.94–1.88 (1H, m), 1.75–1.55 (3H, m),
4
.2.4. Carbamate 1g. Compound 1g was obtained in 84%
1.32 (18H, s), 1.24 (18H, s); d (100 MHz, CDCl ) 150.7,
C 3
2
4
yield as yellow gum; [a] ꢂ168.8 (c 1.54, CHCl ); nmax/
150.4, 143.1, 142.4, 122.1, 120.5, 119.9, 119.2, 78.2, 66.2,
46.2, 35.0, 34.9, 31.6, 26.6, 24.7; MS (ESI , m/z): 478
D
3
ꢂ1
+
cm 2947, 1752, 1484, 1227, 1012, 756; dH (400 MHz,
CDCl ) 7.14 (2H, s), 6.98 (2H, s), 4.50 (1H, dd, J¼10.5,
+
[(M+H ), 100%], 460 [(Mꢂ17), 60%]; Anal. Calcd (%)
3
5
.5 Hz), 3.75–3.68 (1H, m), 3.69 (6H, s), 3.26–3.20 (1H,
for C H NO: C, 82.96; H, 10.76; N, 2.93. Found: C,
3 51
3
m), 2.27 (6H, s), 2.25 (6H, s), 2.01–1.94 (1H, m), 1.93–
.82 (1H, m), 1.70–1.55 (1H, m), 1.14–1.07 (1H, m); dC
100 MHz, CDCl ) 160.7, 156.7, 156.1, 138.6, 135.6,
82.85; H, 10.66; N, 2.85.
1
(
4.3.4. Bis(3,5-dimethyl-4-methoxyphenyl)((S)-pyrrol-
idin-2-yl)methanol 2g. Compound 2g was obtained in
3
1
1
1
7
30.8, 130.6, 126.2, 125.7, 85.5, 59.6, 46.0, 28.9, 24.7,
+
+
+
25
6.3; MS (ESI , m/z): 434 [(M+K ), 15%], 396 [(M+H ),
00%]; Anal. Calcd (%) for C H NO : C, 72.89; H,
.39; N, 3.54. Found: C, 72.73; H, 7.27; N, 3.44.
81% yield as pale yellow gum; [a]D ꢂ48.1 (c 1.15,
ꢂ1
CHCl ); nmax/cm 3446, 2946, 1484, 1224, 1136, 756; dH
3
2
4
29
4
(400 MHz, CDCl ) 7.18 (2H, s), 7.09 (2H, s), 4.18 (1H, t,
3

12268
A. Lattanzi, A. Russo / Tetrahedron 62 (2006) 12264–12269
J¼7.6 Hz), 3.66 (6H, s), 3.00–2.89 (2H, m), 2.25 (6H, s),
.24 (6H, s), 1.75–1.67 (2H, m), 1.62–1.53 (2H, m); d
4.5.9. trans-(2R,3S)-Epoxy-3-(2-chlorophenyl)-1-phenyl-
1-propan-1-one 2i. HPLC (Chiralpak AD): l 254 nm, hex-
4
f
2
C
(
100 MHz, CDCl ) 155.3, 155.2, 143.3, 140.6, 130.1,
3
ane/i-PrOH 96/4, flow rate 1.0 mL/min, t (2R,3S)¼
R
1
2
3
29.8, 126.8, 126.7, 126.0, 125.7, 76.4, 64.5, 59.4, 46.6,
6.2, 25.4, 16.3; MS (ESI , m/z): 370 [(M+H ), 10%],
52 [(Mꢂ17), 100%]; Anal. Calcd (%) for C H NO :
10.1 min, t (2S,3R)¼11.5 min.
R
+
+
2
c
4.5.10. trans-(3R,4S)-Epoxy-4-phenylbutan-2-one 4j.
HPLC (Chiralpak AD): l 254 nm, hexane/i-PrOH 98/2,
flow rate 1.0 mL/min, t (3R,4S)¼10.9 min, t (3S,4R)¼
2
3
31
3
C, 74.76; H, 8.46; N, 3.79. Found: C, 74.65; H, 8.53; N,
3
.70.
R
R
1
3.7 min.
4.4. General procedure for the asymmetric epoxidation
of a,b-enones
2
2
4.5.11. trans-(2R,3S)-Epoxy-1-phenylbutan-1-one 4k.
HPLC (Chiralcel OD): l 254 nm, hexane/i-PrOH 94/6,
flow rate 0.8 mL/min, t (2S,3R)¼10.7 min, t (2R,3S)¼
To a stirred solution of catalyst 2g (5.5 mg, 0.015 mmol) and
a,b-enone 3 (0.150 mmol) in hexane (300 mL) at room tem-
perature was added TBHP (5–6 M decane solution, 33 mL,
R
R
11.6 min.
0
.18 mmol). Stirring was maintained for the time indicated
4.5.12. trans-(2R,3S)-Epoxy-5-phenylpentanophenone
4l. HPLC (Chiralcel OD): l 254 nm, hexane/i-PrOH 20/
1, flow rate 1.0 mL/min, t (2R,3S)¼16.6 min, t (2S,3R)¼
2
3
in Table 2. The crude reaction mixture was directly purified
by flash chromatography on silica gel (PE/diethyl ether 99/1)
to provide the epoxy ketone 4. Epoxides data were as
R
R
18.3 min.
2
c,11,12,17–23
described previously.
4.5. Determination of enantiomeric excess for epoxy
ketones 4
Acknowledgements
Ministero Italiano dell’Universit ꢀa e Ricerca Scientifica e
Tecnologica (MIUR) is gratefully acknowledged for finan-
cial support.
4
4
2
1
.5.1. trans-(2R,3S)-Epoxy-1,3-diphenylpropan-1-one
a. HPLC (Chiralcel OD): l 254 nm, hexane/i-PrOH 98/
, flow rate 1.0 mL/min, t (2S,3R)¼17.3 min, t (2R,3S)¼
2
c
R
R
8.5 min.
References and notes
4.5.2. trans-(2R,3S)-Epoxy-3-phenyl-1-(4-bromophenyl)-
propan-1-one 4b. HPLC (Chiralcel OD): l 254 nm,
1
7
1. (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley:
New York, NY, 2000; For a recent review on asymmetric epox-
idation, see: Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su,
K.-X. Chem. Rev. 2005, 105, 1603.
hexane/i-PrOH 95/5, flow rate 0.8 mL/min, t (2R,3S)¼
R
2
0.2 min, t (2S,3R)¼22.6 min.
R
4.5.3. trans-(2R,3S)-Epoxy-3-phenyl-1-(3-methylphenyl)-
propan-1-one 4c. HPLC (Chiralcel OD): l 254 nm,
2. (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. 1996,
35, 1725; (b) Elston, C. L.; Jackson, R. F. W.; MacDonald,
S. J. F.; Murray, P. J. Angew. Chem., Int. Ed. 1997, 36, 410;
(c) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329; (d) Yu,
H.-B.; Zheng, X.-F.; Lin, Z.-M.; Hu, Q.-F.; Huang, W.-S.;
Pu, L. J. Org. Chem. 1999, 64, 8149; (e) Nemoto, T.;
Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 2725; (f) Tanaka, Y.; Nishimura, K.;
Tomioka, K. Tetrahedron 2003, 59, 4549; (g) Adam, W.;
Bheema Rao, P.; Degen, H.-G.; Saha-M €o ller, C. R. J. Am.
Chem. Soc. 2000, 122, 5654; (h) Dwyer, C. L.; Gill, C. D.;
Ichihara, O.; Taylor, R. J. K. Synlett 2000, 704.
3. (a) Juli ꢀa , S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed.
Engl. 1980, 19, 929; (b) Juli ꢀa , S.; Guixer, J.; Masana, J.;
Rocas, J.; Colonna, S.; Annunziata, R.; Molinari, H. J. Chem.
Soc., Perkin Trans. 1 1982, 1317; (c) Geller, T.; Roberts,
S. M. J. Chem. Soc., Perkin Trans. 1 1999, 1397.
4. (a) Helder, R.; Hummelen, J. C.; Laane, R. W. P. M.; Wiering,
J. S.; Wynberg, H. Tetrahedron Lett. 1976, 21, 1831; (b) Lygo,
B.; Wainwright, P. G. Tetrahedron Lett. 1998, 38, 1599; (c)
Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39,
7563; (d) MacDonald, G.; Alcaraz, L.; Lewis, N. J.; Taylor,
R. J. K. Tetrahedron Lett. 1998, 39, 5433; (e) Corey, E. J.;
Zhang, F. Y. Org. Lett. 1999, 1, 1287; (f) Arai, S.; Tsuge, H.;
Oku, M.; Miura, M.; Shioiri, T. Tetrahedron 2002, 58, 1623;
(g) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am.
Chem. Soc. 2004, 126, 6844; (h) Jew, S.-S.; Lee, J. H.; Jeong,
B. S.; Yoo, M. S.; Kim, M. J.; Lee, Y. J.; Lee, J.; Choi, S.-H.;
4
f
hexane/i-PrOH 30/1, flow rate 0.8 mL/min, t (2S,3R)¼
R
1
7.8 min, t (2R,3S)¼18.8 min.
R
4
1
.5.4. trans-(2R,3S)-Epoxy-3-(4-methylphenyl)-1-phenyl-
-propan-1-one 4d. HPLC (Chiralcel OD): l 254 nm,
1
8
hexane/i-PrOH 95/5, flow rate 0.8 mL/min, t (2S,3R)¼
R
1
7.1 min, t (2R,3S)¼19.6 min.
R
4.5.5. trans-(2R,3S)-Epoxy-3-(4-methoxyphenyl)-1-phen-
yl-1-propan-1-one 4e. HPLC (Chiralcel OD): l 254 nm,
1
7
hexane/i-PrOH 95/5, flow rate 0.8 mL/min, t (2S,3R)¼
R
2
1.7 min, t (2R,3S)¼23.1 min.
R
4
1
.5.6. trans-(2R,3S)-Epoxy-3-(4-cyanophenyl)-1-phenyl-
-propan-1-one 4f. HPLC (Chiralpak AD): l 254 nm,
1
9
hexane/i-PrOH 90/10, flow rate 0.9 mL/min, t (2S,3R)¼
R
3
5.0 min, t (2R,3S)¼38.3 min.
R
4
.5.7. trans-(2R,3S)-Epoxy-3-phenyl-1-(2-furyl)-1-
propan-1-one 4g. HPLC (Chiralpak AD): l 254 nm, hex-
2
0
ane/i-PrOH 90/10, flow rate 1.0 mL/min, t (2S,3R)¼
R
1
5.3 min, t (2R,3S)¼16.8 min.
R
4
1
.5.8. trans-(2R,3S)-Epoxy-3-(4-chlorophenyl)-1-phenyl-
-propan-1-one 2h. HPLC (Chiralcel OD): l 254 nm,
2
1
hexane/i-PrOH 55/1, flow rate 0.5 mL/min, t (2S,3R)¼
R
5
4.5 min, t (2R,3S)¼57.0 min.
R

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2
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1
1
1
3
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