Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol: An improved organocatalyst for the asymmetric epoxidation of α,β-enones

Article abstract of DOI:10.1002/adsc.200505370

The asymmetric epoxidation of α,β-enones by the readily available bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol and tert-butyl hydroperoxide (TBHP) is described. Stereoelectronic substitution on the aryl moiety of diaryl-2-pyrrolidinemethanols was f

Full text of DOI:10.1002/adsc.200505370

FULL PAPERS
DOI: 10.1002/adsc.200505370
Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol: an Improved
Organocatalyst for the Asymmetric Epoxidation of a,b-Enones
Alessandra Lattanzi
`
Dipartimento di Chimica, Universita di Salerno, Via S. Allende, 84081 Baronissi, Italy
Fax: (þ39)-089-965-296, e-mail: lattanzi@unisa.it
Received: September 23; 2005; Accepted: December 5, 2005
Abstract: The asymmetric epoxidation of a,b-enones ing (20 mol %) with ees up to 94% for chalcone epox-
by the readily available bis(3,5-dimethylphenyl)-(S)- ides under mild reaction conditions, whereas (S)-di-
pyrrolidin-2-ylmethanol and tert-butyl hydroperoxide phenyl-2-pyrrolidinemethanol afforded a maximum
(TBHP) is described. Stereoelectronic substitution ee of 80%. Interestingly, the methodology is applica-
on the aryl moiety of diaryl-2-pyrrolidinemethanols ble to the epoxidation of more challenging aliphatic
was found to significantly affect the efficiency with re- or enolizable enones with good control of the asym-
spect to the previously reported (S)-diphenyl-2-pyrro- metric induction (up to 87% ee).
lidinemethanol. Improved reactivity and enantiose-
lectivity were achieved with bis(3,5-dimethylphenyl)- Keywords: amino alcohols; asymmetric epoxidation;
(S)-pyrrolidin-2-ylmethanol at reduced catalyst load- a,b-enones; epoxides; organic catalysis
Introduction
ieved by organic chemists.[7] In conjunction with our re-
search interests, we have recently found that commer-
Asymmetric catalysis by small organic molecules, the so- cially available (S)-diphenyl-2-pyrrolidinemethanol
called organocatalysis,[1] is a rapidly growing area, which and tert-butyl hydroperoxide (TBHP) promote the
has led to the development of efficient metal-free meth- enantioselective epoxidation of a,b-enones (Scheme
odologies mainly for C C bond-forming reactions. l- 1).[8]
À
Proline and its derivatives are among the most studied
The epoxides have been obtained in good yields and
organocatalysts reported up to now, which have shown enantioselectivity (up to 80% ee) employing 30 mol %
wide applicability and generally good to high control catalyst loading at room temperature in hexane. We
of the asymmetric induction. With regards to oxidative have suggested a catalytic cycle for the nucleophilic ep-
transformations, few examples have been reported for oxidation, where the amino alcohol plays the role of a bi-
proline-based organocatalysts. Electrophilic epoxida- functional catalyst (Scheme 2). First, it activates via de-
tion of unfunctionalized alkenes, mediated by pyrroli- protonation the alkyl hydroperoxide by the Brønsted-
dines and oxone or dioxirane, afforded the epoxides basic secondary amine, thus generating a tight ion pair.
with up to 66% ee.[2] l-Proline and its analogues cata- Then, the hydroxy group of the catalyst activates and
lyzed the a-oxidation of aldehydes and ketones with orientates the enone toward the attack of the alkyl per-
up to >99% ee.[3] Very recently, the nucleophilic epox- oxide anion to the b-carbon of the enone through hydro-
idation of a,b-unsaturated aldehydes has been realized gen bonding with the carbonyl oxygen atom.
by using an O-protected diaryl-2-pyrrolidinemethanol
and hydrogen peroxide as oxidant.[4] The valuable and
difficult to obtain a,b-epoxy aldehydes have been isolat-
ed in high yields and excellent enantioselectivity (up to
98% ee).
In the past years, we have spent our effortson develop-
ing epoxidation reactions based on renewable sources[5]
or recyclable catalysts.[6] Enantiopure epoxides are im-
portant intermediates for drug design and natural prod-
ucts synthesis, hence new asymmetric versions for their
production represent a fundamental target to be ach- Scheme 1.
Adv. Synth. Catal. 2006, 348, 339 – 346
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339

Alessandra Lattanzi
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Scheme 2. Proposed catalytic cycle for the epoxidation.
The nature of diphenyl-2-pyrrolidinemethanol allows tronic properties of the substituents on the benzene ring
electronic and steric tuning of the catalyst by varying the noticeably influenced the catalytic activity of the diaryl-
substitution pattern on the aryl residue and this can help 2-pyrrolidinemethanols, and electron-donating groups
to shed more light on the factors affecting the catalytic enhanced the conversion to the epoxide, while elec-
activity and the enantioselectivity of this new oxidative tron-withdrawing substituents were detrimental.
system. Herein we report our investigation on the per-
The effects on the asymmetric induction of the nature
formance of different diaryl-2-pyrrolidinemethanols, of the groups are less easily accountable; in fact, it ap-
which led to the development of a more effective system pears that electronic character, steric size and the posi-
for the asymmetric epoxidation[9] of a broad variety of tion of the groups in the benzene ring can be important
a,b-enones under mild and simple reaction conditions.
in affecting the enantioselectivity. On the basis of the
Results and Discussion
Variously substituted diaryl-2-pyrrolidinemethanols
(Figure 1) were readily synthesized starting from l-pro-
line following previously established procedures.[10]
In order to properly compare the efficiency of pro-
moters 3b–g, chalcone 1a was treated under the reac-
tion conditions previously optimized for 3a,[8] employing
30 mol % of catalyst loading, 1.2 equivs. of TBHP in
hexane at room temperature (Table 1).
The p-methoxyphenyl derivative 3b (entry 2) afforded
the (aR,bS)-epoxide 2a, after a substantially reduced re-
action time, in higher yield and similar ee, when com-
pared to 3a (entry 1). A better yield, but enhanced
82% ee, was observed when using more sterically en-
cumbered p-tert-butylphenyl catalyst 3c (entry 3). The
p-phenyl residue on the benzene ring in 3d reduced
the reactivity with only a slight improvement in the
enantioselectivity (entry 4). The sterically demanding
b-naphthyl catalyst 3e was slightly less reactive than
3a, but the ee was not much affected (entry 5). With
the 3,5-dichlorophenyl-modified compound 3f the epox-
idation rate was dramatically reduced, although the ep-
oxide was recovered with improved 81% ee (entry 6). In
contrast, the 3,5-dimethylphenyl catalyst 3g afforded
the epoxide in quantitative yield and 88% ee after the
shortest reaction time (entry 7). It turned out that elec- Figure 1.
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Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol
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Table 1. Asymmetric epoxidation of 1a promoted by 3a–g.
more active than electron-withdrawing substituted 3f,
favouring amine protonation by means of inductive or
electronic effects.[2c,11] Another key factor, which can in-
fluence the catalytic activity, is the enhanced solubility
of alkyl-substituted compounds 3b, c, g in the reaction
solvent. In fact, while reaction mixtures appeared homo-
geneous when using catalysts 3b, c, g, heterogeneous re-
action mixtures were observed employing catalysts 3d,
e, f. It is interesting to note that bis(3,5-dimethylphen-
yl)-(S)-pyrrolidin-2-ylmethanol (3g) has been recently
reported as a very efficient ligand for the highly enantio-
selective cyanosilylation of aldehydes[12] and Diels–Al-
der reaction.[13]
Next, we optimized the parameters for the epoxida-
tion of 1a using the best candidate 3g (Table 2). As pre-
viously observed in the epoxidation promoted by 3a,[8]
apolar solvents provided high enantioselectivity (entries
1 and 2), although the conversion was modest.[14] Hex-
ane was proved to be the best solvent (Table 1, entry
7) and it has to be pointed out that the enantioselectivity
was maintained at the same level when using 10 mol %
of the catalyst (Table 2, entry 3).
Entry
3
Time [h]
Yield [%][a]
ee [%][b]
1[c]
2
3
4
5
3a
3b
3c
3d
3e
3f
94
65
90
90
87
70
60
72
85
79
48
60
26
99
75
76
82
78
77
81
88
6
7
3g
[a]
Yield of isolated product after flash chromatography.
Determined by HPLC on chiral column Daicel Chiralcel
OD. The absolute configuration (aR,bS) was determined
by comparison of the HPLC retention times with those
in the literature.
[b]
[c]
Yield and ee reported in ref.[8]
Under these conditions, a set of experiments was per-
formed in the presence of hydrogen bonding donors as
mechanistic hypothesis proposed for the reaction, additives.[15] The epoxidation was carried out adding
namely the ionic pair made up of the tert-butyl hydroper- 10 mol % of commercially available (4R,5R)-2,2-di-
oxide anion and the ammonium cation being the active methyl-a,a,a’,a’-tetraphenyldioxolane-4,5-dimethanol
species for the epoxidation, increased conversion is ex- [(À)-TADDOL] as a competitive activator of the enone
pected when using more basic pyrrolidinemethanol carbonyl group (entry 4). TADDOLs were recently em-
compounds. Indeed, catalysts with electron-donating ployed as hydrogen bonding donors capable of activat-
substituents on the benzene ring (entries 2, 3 and 7) ing the dienophile carbonyl group in the enantioselec-
were more efficient than unsubstituted 3a and far tive hetero-Diels–Alder reaction.[16] The epoxide was
Table 2. Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol (3g)-catalyzed epoxidation of 1a under various conditions.
Entry
Solvent
Catalyst loading [mol %]
T [8C]
Time [h]
Yield [%][a]
ee [%][b]
1
2
3
toluene
CHCl3
hexane
hexane
hexane
hexane
hexane
hexane
30
30
10
10
10
10
20
20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
À6
4
72
264
95
96
98
96
130
99
40
39
61
65
66
–
86
78
88
85
85
–
4[c]
5[d]
6[e]
7
46
80
94
91
8[f]
[a]
Yield of isolated product after flash chromatography.
[b]
Determined by HPLC on chiral column Daicel Chiralcel OD. The absolute configuration (aR,bS) was determined by com-
parison of the HPLC retention times with those reported in the literature.
The reaction was carried out in the presence of 10 mol % of (À)-TADDOL.
The reaction was carried out in the presence of 10 mol % of phenol.
The reaction was carried out in the presence of 10 mol % of benzoic acid.
The reaction was carried out at C¼0.7 M of 1a instead of C¼0.2 M.
[c]
[d]
[e]
[f]
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Table 3. Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol (3g)-catalyzed asymmetric epoxidation of a,b-enones.
Entry
Substrate 1
Time [h]
Yield [%][a]
ee [%][b]
Catalyst 3a
R1
R2
Yield [%][f]
ee [%][f]
1
2
Ph
p-BrC6H4
m-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
112
217
139
126
178
165
178
90
81
98
70
75
81
90
91
92
89
90 (99)
90
72
72
70
46
–
75
74
78
80
–
3
4[c]
5
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-NO2C6H4
6
92
82 (89)
73
<5
74
–
7[d]
1g
8
Ph
1h
177
80
91
–
–
9[e]
10
11
12
13
Me
Ph
Ph
Ph
Me
Ph
Me
PhCH2CH2
i-Pr
CH3(CH2)4
1j
1k
1i
1l
220
147
160
292
264
60
92
87
83
70
87
75
79
34
74
52
87
–
–
–
79
63
–
–
–
1m
14[d]
1n
1o
284
243
38
16
6[g]
–
–
–
15[d]
75
<5
[a]
Yield of isolated product after flash chromatography.
[b]
Determined by HPLC on Daicel Chiralcel OD and Chiralpak AD chiral columns. The absolute configuration (aR,bS) was
determined by comparison of the HPLC retention times or optical rotation with those in the literature. The value in par-
entheses refers to ee after one recrystallization.
The reaction was carried out at room temperature using 30 mol % of 3g.
The reaction was carried out at room temperature.
[c]
[d]
[e]
[f]
[g]
30 mol % of 3g was used in this reaction.
Yields and ees reported in ref.[8]
The ee was determined by optical rotation measurement. The absolute configuration was (aR,bR).
isolated in comparable yield and slightly decreased À68C, the epoxide was isolated in 94% ee, but the cata-
enantioselectivity with respect to the reaction per- lyst activity was markedly depressed (entry 7). Finally, a
formed in the absence of additive (entry 3). Then, as a right compromise to obtain high asymmetric induction
blank experiment, the epoxidation was performed by us- and conversion in an acceptable reaction time was ach-
ing 10 mol % of pyrrolidine and 10 mol % of (À)-TAD- ieved performing the reaction under more concentrated
DOL, in order to verify if any asymmetric induction conditions at 48C (entry 8).
could be provided when the basic and the hydrogen
The reaction conditions that proved optimal for 1a
bonding donor functionalities were present in separate were found to be general for a variety of a,b-enones
compounds. After 93 h the racemic epoxide was recov- (20 mol % of 3g, 1.2 equivs. of TBHP at 48C in hexane)
ered in 45% yield. The epoxidation was not much affect- and the results are summarized in Table 3. Chalcones
ed when adding 10 mol % of phenol as the additive (en- having either electron-donating or electron-withdraw-
try 5). As expected, when adding 10 mol % of the more ing substituents on the phenyl rings and heteroaromatic
acidic benzoic acid, the epoxidation did not proceed (en- groups were converted into the epoxides in high yield
try 6). When employing 20 mol % of catalyst loading at
and ee (entries 1–8). The less reactive compound 1d
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Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol
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was treated at room temperature with 30 mol % of the nors did not particularly affect the epoxidation (Table 2,
catalyst and the epoxide was thus isolated in good yield entries 4 and 5), indicating the selective and coordinated
and high ee (entry 4). Compound 1g, which did not react action of the basic and hydroxy functionalities of cata-
when using catalyst 3a,[8] was now converted into the ep- lyst 3g in the reaction. When these functionalities are
oxide at room temperature in high yield and very good not in the same molecular scaffold, a reduced reactivity
ee (entry 7). The ees in both cases can be significantly in- and, most of all, a poor control of the asymmetric induc-
creased after one recrystallization (entries 4 and 7). tion can be observed, as demonstrated by carrying out
Thanks to the mild reaction conditions, more challeng- the epoxidation using pyrrolidine/(À)-TADDOL as
ing enones having an alkyl substituent either on the dou- the catalytic system. Furthermore, while prolinol pro-
ble bond or on the carbonyl carbon and aliphatic sub- moted the epoxidation, N-benzylprolinol did not cata-
strates were selectively epoxidized (entry 9–13) with lyze the reaction.[8] It is likely that an intramolecular hy-
good asymmetric induction except when a sterically de- drogen bonding in the ammonium cation, betweþen the
manding alkyl substituent was present (entry 12).[17] In oxygen of the hydroxy group and the proximal N H
À
all the examples (entries 1–13 and 15), diastereoisomer- group, might render the proton of the hydroxy group
ically pure trans-epoxides[18] have been obtained prefer- more acidic. Consequently, it would be more susceptible
entially enriched in the (aR,bS) enantiomer. Bis(3,5-di- to take part in an intermolecular hydrogen bonding with
methylphenyl)-(S)-pyrrolidin-2-ylmethanol (3g) proved the oxygen of the carbonyl moiety, so activating the
superior for the epoxidation of a,b-enones when com- enone and providing the right orientation for the nucle-
pared to the previously employed catalyst 3a (Table 3). ophilic attack.[21] Moreover, since a tertiary ammonium
Finally, in order to point out the influence of the struc- cation was not able to catalyze the reaction, it seems that
tural features of the enones, conformationally fixed simple electrostatic interactions between the ammoni-
s-trans-cyclo-2-hexenone and s-cis-benzylidene-a-tetra- um cation and tert-butyl hydroperoxide anion might
lone were treated under the usual conditions at room not adequately stabilize the ion pair, the protonated sec-
temperature (entries 14 and 15). Both substrates reacted ondary ammonium cation being necessary.[22]
sluggishly, but while the epoxycyclohexanone was ob-
tained in poor ee, the (2R,1’S)-epoxide 2o was isolated
in 75% ee. These results suggest that, in the enantiodif-
ferentiating step, enones could preferentially adopt the
s-cis conformation, although the coplanarity of the aryl
group attached to the carbonyl seems to be detrimental
for the reactivity.
With the intention of gaining better insight into the
mechanism of the reaction, compound 1a was epoxi-
dized under the usual conditions with catalyst 3g,
TBHP (1.2 equivs.) in CDCl3 at room temperature and
the catalyst loading was progressively increased with re-
action time from 30 up to 100 mol %. 1H NMR and 13C
NMR spectra of the reaction mixture were recorded af-
ter each addition up to two days reaction time. Iminium
ion intermediates have not been detected by NMR anal-
yses and the same result has been obtained when carry-
ing out the reaction in C6D6 as the solvent. On the other
hand, the alternative activation of the enone via imini-
um ion formation would be less reasonably expected
to occur under these reaction conditions, given the un-
reactive nature of enone carbonyls and the absence of
an acid catalyst. These observations support that the ep-
oxidation would proceed via the formation of an ion pair
as the true catalytic species (Scheme 2).[19] In the light of
Scheme 3. Postulated transition states.
all results,[20] we propose two hypothetical transition
states A and B to account for the observed sense of
the enantioselectivity (Scheme 3).
Assuming that enones reacted in the preferential s-cis
Hydrogen bonding was shown to be fundamental for conformation, in TS-A a strong steric interaction can be
the reactivity as well as for the asymmetric induction, envisaged between the phenyl ring attached to the car-
as previously demonstrated by the fact that (S)-2-diphe- bonyl function and one of 3,5-dimethylphenyl groups
nylmethylpyrrolidine was a very poor catalyst.[8] Com- of the catalyst, which shields the Re-face of the C C
À
petitive optically pure and achiral hydrogen bonding do- double bond. In TS-B the phenyl ring at the b-position
Adv. Synth. Catal. 2006, 348, 339 – 346
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Alessandra Lattanzi
FULL PAPERS
giving it a wider applicability. Low reaction rates remain
the main drawback, which unfortunately still represent
an aspect in common with several other organocatalytic
processes.
Experimental Section
General Remarks
Figure 2. l-Proline-derived catalysts active in the epoxidation
of enones and enals (TMS ¼ trimethylsilyl).
Reactions were monitored by thin layer chromatography
(TLC) on Merck silica gel plates (0.25 mm) and visualized by
UV light or by 10% H2SO4/ethanol spray test. Flash chroma-
tography was performed on Merck silica gel (60, particle size:
0.040–0.063 mm). 1H NMR and 13C NMR spectra were record-
ed on a Bruker DRX 400 spectrometer at room temperature in
CDCl3 as solvent. Optical rotations were performed on a Jasco
Dip-1000 digital polarimeter using the Na lamp. All commer-
cially available reagents were purchased from Aldrich. a,b-
Enones which were not commercially available were prepared
via aldol condensation using standard conditions.[23] Hexane of
HPLC grade was used as solvent. Catalysts 3b–g, prepared
according toreportedprocedures, havebeen previouslydescrib-
ed in the literature.[10] All epoxides are known compounds,
their analytical data were identical to those reported in the lit-
erature.[17,24] The absolute configuration of the predominant
enantiomer was determined by comparison with the HPLC re-
tention times (Waters 486, UV detector) using Daicel Chiralcel
OD and Daicel Chiralpak AD columns or with optical rota-
tions reported in the literature.[17,24] The enantioselectivities
were determined by chiral HPLC analysis.
points away from the 3,5-dimethylphenyl group, which
effectively shields the opposite face of the enone. TS-B
should be favoured in view of the minimized steric inter-
actions and the attack on the Re-face by the tert-butyl
hydroperoxy anion would afford the (aR,bS)-epoxide
predominantly, as experimentally observed.
It is interesting to note at this point that the structural-
ly and electronically different diaryl-2-pyrrolidineme-
thanols 3g and 4[4] (Figure 2) promote the nucleophilic
asymmetric epoxidation of a,b-enones and a,b-unsatu-
rated aldehydes, respectively. Two distinct pathways
are reasonably involved during the epoxidation reac-
tions. In the last case, the formation of an iminium ion,
by reaction of 4 and aldehyde, was proposed to occur
as the reactive intermediate undergoing the nucleophil-
ic attack of the oxidant at the b-carbon.[4a]
General Procedure for Asymmetric Epoxidation of
a,b-Enones
Conclusion
TBHP (5–6 M decane solution, 33 mL, 0.18 mmol) was added
to a stirred solution of catalyst 3g (9.2 mg, 0.03 mmol) and
In summary, investigations on the stereoelectronic sub-
stitution of the phenyl rings of amino alcohol 3a led to enone 1 (0.150 mmol) in hexane (0.215 mL) at 48C. Stirring
was maintained for the time indicated in Table 3. The crude re-
action mixture was directly purified by flash chromatography
on silica gel (petroleum ether/diethyl ether, 99/1) to provide
the epoxy ketone 2.
the discovery that the easily accessible bis(3,5-dimethyl-
phenyl)-(S)-pyrrolidin-2-ylmethanol (3g) catalyzes the
asymmetric epoxidation of a,b-enones with enhanced
efficiency. The data obtained give better support to the
mechanistic hypothesis proposed for the reaction with
the amino alcohol 3g playing the role of a bifunctional
organocatalyst. Compared to the previously reported
3a, significant improvements have been achieved: 1) re-
duced catalyst loading can be used (20 mol %); 2) high
trans-(2R,3S)-Epoxy-1,3-diphenylpropan-1-one (2a):[17a]
1H NMR (400 MHz): d¼4.08 (d, J¼1.9 Hz, 1H), 4.29 (d, J¼
1.9 Hz, 1H), 7.35–7.63 (m, 8H), 8.00–8.03 (m, 2H); HPLC
(Chiralcel OD, l 254 nm, hexane/i-PrOH 98/2, flow rate
1.0 mL/min): tr(2S,3R)¼17.3 min, tr(2R,3S)¼18.5 min.
trans-(2R,3S)-Epoxy-3-phenyl-1-(4-bromophenyl)propan-
yields and enantioselectivity (up to 94% ee) are ob- 1-one (2b):[24a] 1H NMR (400 MHz): d¼4.05 (d, J¼1.9 Hz,
1H), 4.22 (d, J¼1.9 Hz, 1H), 7.33–7.41 (m, 5H), 7.60–7.65
tained. Attractive features of this organocatalytic trans-
formation, that could be of interest for an industrial
point of view, are that the reactions are carried out under
mild conditions at 48C, with no particular precautions in
the absence of inert atmosphere, anhydrous solvents
and the epoxides are directly isolated by flash chroma-
tography. The epoxidation of aliphatic or enolizable
substrates, apart from chalcones, occurred selectively
(m, 2H), 7.86–7.90 (m, 2H); HPLC (Chiralcel OD, l 254 nm,
hexane/i-PrOH, 95/5, flow rate 0.8 mL/min): tr(2R,3S)¼
20.2 min, tr(2S,3R)¼22.6 min.
trans-(2R,3S)-Epoxy-3-phenyl-1-(3-methylphenyl)propan-
1-one (2c):[24b] 1H NMR (400 MHz): d¼2.41 (s, 3H), 4.07 (d, J¼
1.9 Hz, 1H), 4.29 (d, J¼1.9 Hz, 1H), 7.34–7.82 (m, 9H); HPLC
(Chiralcel OD, l 254 nm, hexane/i-PrOH 30/1, flow rate
0.8 mL/min): tr(2S,3R)¼17.8 min, tr(2R,3S)¼18.8 min.
and with good control of the asymmetric induction,
trans-(2R,3S)-Epoxy-3-(4-methoxyphenyl)-1-phenyl-1-
which is a positive distinguishing feature of this system propanon-1-one (2d):[24a] 1H NMR (400 MHz): d¼3.80 (s, 3H),
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Bis(3,5-dimethylphenyl)-(S)-pyrrolidin-2-ylmethanol
FULL PAPERS
4.02 (d, J¼2.0 Hz, 1H), 4.28 (d, J¼2.0 Hz, 1H), 6.86–6.96 (m,
2H), 7.23–7.34 (m, 2H), 7.40–7.63 (m, 3H), 7.96–8.04 (m, 2H);
HPLC (Chiralcel OD, l 254 nm, hexane/i-PrOH 95/5, flow rate
0.8 mL/min): tr(2S,3R)¼21.7 min, tr(2R,3S)¼23.1 min.
trans-(2R,3S)-Epoxy-3-(4-methylphenyl)-1-phenyl-1-prop-
anon-1-one (2e):[24k] 1H NMR (400 MHz): d¼2.38 (s, 3H), 4.04
(d, J¼1.8 Hz, 1H), 4.27 (d, J¼1.8 Hz, 1H), 7.25–8.10 (m, 9H);
HPLC (Chiralcel OD, l 254 nm, hexane/i-PrOH 95/5, flow rate
0.8 mL/min): tr(2S,3R)¼17.1 min, tr(2R,3S)¼19.6 min.
trans-(2R,3S)-Epoxy-3-(4-chlorophenyl)-1-phenyl-1-prop-
anon-1-one (2f):[24c] 1H NMR (400 MHz): d¼4.06 (d, J¼
1.8 Hz, 1H), 4.24 (d, J¼1.8 Hz, 1H), 7.25–7.68 (m, 7H),
7.97–8.05 (m, 2H); HPLC (Chiralcel OD, l 254 nm, hexane/
i-PrOH, 55/1, flow rate 0.5 mL/min): tr(2S,3R)¼54.5 min,
tr(2R,3S)¼57.0 min.
(dt, J¼8.6, 13.5 Hz, 1H), 2.83 (dd, J¼4.3, 8.6 Hz, 2H), 4.37
(s, 1H), 7.22 (d, J¼7.6 Hz, 1H), 7.34–7.40 (m, 6H), 7.51–7.55
(m, 1H), 8.10–8.14 (m, 1H); HPLC (Chiralpak AD, l
254 nm, hexane/i-PrOH, 90/10, flow rate 0.5 mL/min):
tr(2R,1’S)¼23.3 min, tr(2S,1’R)¼27.9 min.
Acknowledgements
`
Ministero dellꢀUniversita e Ricerca Scientifica e Tecnologica
(MIUR) is gratefully acknowledged for financial support.
References and Notes
trans-(2R,3S)-Epoxy-3-(4-nitrophenyl)-1-phenyl-1-propa-
non-1-one (2g):[24k] 1H NMR (400 MHz): d¼4.21 (d, J¼
1.8 Hz, 1H), 4.27 (d, J¼1.8 Hz, 1H), 7.45–8.30 (m, 9H);
HPLC (Chiralcel OD, l 254 nm, hexane/i-PrOH, 80/20, flow
rate 0.8 mL/min): tr(2S,3R)¼35.9 min, tr(2R,3S)¼40.3 min.
trans-(2R,3S)-Epoxy-3-phenyl-1-(2-furyl)-1-propan-1-one
(2h):[24 g] 1H NMR (400 MHz): d¼4.13 (d, J¼1.8 Hz, 1H), 4.15
(d, J¼1.8 Hz, 1H), 6.59–6.60 (m, 1H), 7.29–7.37 (m, 5H),
7.45–7.47 (m, 1H), 7.66–7.68 (m, 1H); HPLC (Chiralpak
AD, l 254 nm, hexane/i-PrOH 90/10, flow rate 1.0 mL/min):
tr(2S,3R)¼15.3 min, tr(2R,3S)¼16.8 min.
[1] For recent reviews on organocatalysis, see: a) P. I. Dalko,
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Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719; for re-
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trans-(3R,4S)-Epoxy-4-phenylbutan-2-one (2j):[17a,24e] 1H
NMR (400 MHz): d¼2.18 (s, 3H), 3.49 (d, J¼2.0 Hz, 1H),
4.00 (d, J¼2.0 Hz, 1H), 7.19–7.46 (m, 5H); HPLC (Chiralpak
AD, l 254 nm, hexane/i-PrOH, 98/2, flow rate 1.0 mL/min):
tr(3R,4S)¼10.9 min, tr(3S,4R)¼13.7 min.
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Yamaguchi, K. Hibino, M. Shoji, Tetrahedron Lett.
trans-(2R,3S)-Epoxy-1-phenylbutan-1-one (2k):[24d] 1H
NMR (400 MHz): d¼1.52 (d, J¼5.2 Hz, 3H), 3.23 (dq, J¼
2.0, 5.2 Hz, 1H), 3.98 (d, J¼2.0 Hz, 1H), 7.48–7.65 (m, 3H),
7.99–8.03 (m, 2H); HPLC (Chiralcel OD, l 254 nm, hexane/
i-PrOH, 94/6, flow rate 0.8 mL/min): tr(2S,3R)¼10.7 min,
tr(2R,3S)¼11.6 min.
´
`
2003, 44, 8293; d) A. Cordova, H. Sunden, M. Johansson,
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´
Sunden, A. Cordova, Angew. Chem. Int. Ed. 2004, 43,
1109; f) Y. Hayashi, J. Yamaguchi, T. Sumiya, M. Shoji,
Angew. Chem. Int. Ed. 2004, 43, 1112.
trans-(2R,3S)-Epoxy-5-phenylpentanophenone (2i):[24f] 1H
NMR (400 MHz): d¼2.00–2.22 (m, 2H), 2.72–3.00 (m, 2H),
3.20 (ddd, J¼2.0, 5.3, 7.3 Hz, 1H), 3.98 (d, J¼2.0 Hz, 1H),
7.08–7.37 (m, 5H), 7.45 (t, J¼7.5 Hz, 2H), 7.60 (t, J¼7.5 Hz,
1H), 7.83 (d, J¼7.3 Hz, 2H); HPLC (Chiralcel OD, l 254 nm,
hexane/i-PrOH, 20/1 flow rate 1.0 mL/min, tr(2R,3S)¼
16.6 min, tr(2S,3R)¼18.3 min.
´
[4] a) M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang,
K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 6964;
´
´
b) H. Sunden, I. Ibrahem, A. Cordova, Tetrahedron
Lett. 2005, 47, 99.
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Chem. Commun. 2003, 1440; b) A. Lattanzi, M. Cocilo-
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see: a) M. J. Porter, J. Skidmore, Chem. Commun. 2000,
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2002, 35, 47.
[10] a) D. J. Mature, T. K. Jones, L. C. Xavier, T. J. Blacklock,
R. A. Reamer, J. J. Mohan, E. T. T. Turner Jones, K.
trans-(2R,3S)-Epoxy-4-methylpentanophenone (2l):[24e, f]
1H NMR (400 MHz): d¼1.07 (d, J¼6.9 Hz, 3H), 1.11 (d, J¼
6.9 Hz, 3H), 1.72–1.84 (m, 1H), 2.97 (dd, J¼2.0, 6.0 Hz, 1H),
4.07 (d, J¼2.0 Hz, 1H), 7.47–7.56 (m, 2H), 7.58–7.66 (m,
1H), 8.02 (d, J¼8.6 Hz, 2H); HPLC (Chiralcel OD, l 254 nm,
hexane/i-PrOH, 98/2, flow rate 1.0 mL/min): tr(2S,3R)¼
7.5 min, tr(2R,3S)¼8.8 min.
trans-(3R,4S)-Epoxynonan-2-one (2m):[17a,24e] 1H NMR
(400 MHz): d¼0.89 (m, 3H), 1.20–1.75 (m, 8H), 2.06 (s, 3H),
3.07 (dt, J¼2.0, 5.0 Hz, 1H), 3.18 (d, J¼2.0 Hz, 1H); HPLC
(Chiralpak AD, l 280 nm, hexane/i-PrOH, 100/1, flow rate
0.4 mL/min): tr(3R,4S)¼15.6 min, tr(3S,4R)¼17.5 min.
(2R,3R)-Epoxycyclohexan-1-one (2n):[24i, j] [a]D28: þ9.2 (c
1
1.03, CHCl3); H NMR (400 MHz): d¼1.65–1.73 (m, 1H),
1.83–2.14 (m, 3H), 2.23–2.31 (m, 1H), 2.51–2.59 (m, 1H),
3.22 (d, J¼4.0 Hz, 1H), 3.58–3.61 (m, 1H).
(2R,1’S)-Epoxy-2-(1’-phenylmethyl)-1-tetralone (2o):[24e, h]
1H NMR (400 MHz): d¼1.86 (dt, J¼4.3, 13.5 Hz, 1H), 2.45
Adv. Synth. Catal. 2006, 348, 339 – 346
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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346
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 339 – 346