Enantioselective epoxidation of α,β-enones promoted by α,α-diphenyl-L-prolinol as bifunctional organocatalyst

Article abstract of DOI:10.1021/ol050694m

(Chemical Equation Presented) An operationally simple and mild protocol for the catalytic enantioselective epoxidation of α,β-unsaturated ketones has been established using commercially available α,α- diphenyl-L-prolinol as bifunctional organocatalyst and tert-butyl hydroperoxide (TBHP) as oxidant. The epoxides have been obtained in good yields and with up to 80% ee.

Full text of DOI:10.1021/ol050694m

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2579-2582
Enantioselective Epoxidation of
r
,
,
â
r
-Enones Promoted by
-Diphenyl- -prolinol as Bifunctional
r
L
Organocatalyst
Alessandra Lattanzi*
Dipartimento di Chimica, UniVersita` di Salerno, Via S. Allende, I-84081 Baronissi,
Salerno, Italy
lattanzi@unisa.it
Received April 1, 2005
ABSTRACT
An operationally simple and mild protocol for the catalytic enantioselective epoxidation of
r
,
â
-unsaturated ketones has been estabilished
using commercially available -diphenyl-L-prolinol as bifunctional organocatalyst and tert-butyl hydroperoxide (TBHP) as oxidant. The epoxides
r,r
have been obtained in good yields and with up to 80% ee.
The development of efficient methods for the asymmetric
epoxidation of R,â-enones is a major goal in organic
synthesis since optically active epoxy ketones are among the
most versatile building blocks for access to several natural
products and pharmaceuticals.1 A variety of valuable systems
have been proposed for this reaction based on chirally
modified metal alkyl peroxides2 and optically pure alkyl
hydroperoxides.3 Hydrogen peroxide and various polyamino
acids1c,4 have also been used in this capacity, as have
hydrogen peroxide and cinchona alkaloid combinations.5
Asymmetric reactions promoted by small organic molecules
is an emerging and still scarsely investigated area.6 Being
interested in the development of mild and convenient
methodologies of epoxidation using renewable sources7 or
(5) (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.; Lee, K.; Lah, M.-S.; Park, H.-G. Angew. Chem., Int. Ed. 2005,
44, 2.
(6) For reviews on organocatalysis, see: (a) List, B. Synlett 2001, 1675.
(b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (c) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5183. (d) Special Issue:
Asymmetric Organocatalysis, Acc. Chem. Res. 2004, 37, 487. (e) Seayad,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719. For examples on enantio-
selective oxidations promoted by L-proline and its derivatives, see: (a)
Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc. 2003, 125,
7596. (b) Sunde`n, H.; Engqvist, M.; Casas, J.; Ibrahem, I.; Co´rdova, A.
Angew. Chem., Int. Ed. 2004, 43, 6532.
(1) For recent reviews, see: (a) Porter, M. J.; Skidmore, J. Chem.
Commun. 2000, 1215. (b) Lauret, C. Tetrahedron: Asymmetry 2001, 12,
2359. (c) Lauret, C.; Roberts, S. M. Aldrichim. Acta 2002, 35, 47.
(2) (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996,
35, 1725. (b) Elston, C. L.; Jackson, W. R. F.; MacDonald, S. J. F.; Murray,
P. J. Angew. Chem., Int. Ed. Engl. 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.
(3) (a) Adam, W.; Bheema Rao, P.; Degen, H.-G.; Saha-Mo¨ller, C. R.
J. Am. Chem. Soc. 2000, 122, 5654. (b) Dwyer, C. L.; Gill, C. D.; Ichihara,
O.; Taylor, R. J. K. Synlett 2000, 704.
(4) (a) Julia`, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl.
1980, 19, 929. (b) Julia`, 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.
(7) (a) Lattanzi, A.; Iannece, P.; Scettri, A. Tetrahedron Lett. 2002, 43,
5629. (b) Lattanzi, A.; Iannece, P.; Vicinanza, A.; Scettri, A. Chem.
Commun. 2003, 1440. (c) Lattanzi, A.; Cocilova, M.; Iannece, P.; Scettri,
A. Tetrahedron: Asymmetry 2004, 15, 3751.
10.1021/ol050694m CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/25/2005

recyclable catalysts,8 we were intrigued by the possibility
that easily accessible amino alcohols could be exploited as
bifunctional catalysts for the nucleophilic enantioselective
epoxidation of R,â-enones. Herein, we report the first
successful example of this transformation using commercially
available R,R-diphenyl-L-prolinol and TBHP as the asym-
metric oxidant.
Table 1. Optimization of Reaction Conditions for the
Epoxidation of 4aa
yield (%)
of 5ab
ee (%) of
5ac (config)d
entry catalyst solvent oxidant t (h)
1
2
3
4
5f
6
7
8
9g
10f,h
11i
12
2
2
2
2
2
2
2
2
2
2
2
3
CHCl3
CH2Cl2 TBHP 144
THF TBHP 144
CH3CN TBHP 170
CH3OH TBHP 120
TBHP
96
5
4
5
65
55
17
nde
30
76
76
55
70
78
67
23
L-Prolinol 19 (Figure 1) was first examined for its ability
trace
11
53
46
51
71
80
27
22
hexane TBHP
c-C6H12 TBHP
hexane CHP
hexane TBHP
48
48
94
62
hexane TBHP 102
hexane TBHP 44
hexane TBHP 140
Figure 1. L-Proline-derived organocatalysts.
a Unless otherwise specified, the reaction was carried out at room
temperature with 1.2 equiv of TBHP in the presence of 30 mol % of catalyst
at C ) 0.2 M of 4a. b Yield of isolated product. c Enantiomeric excess was
determined by HPLC analysis by using the chiral column Daicel Chiralcel
OD. d Absolute configuration of 5a was determined to be (2R,3S) by
comparison of the HPLC retention times with those reported in the literature
(see the Supporting Information). e Not determined. f 50 mol % catalyst was
used in this reaction. g The reaction was performed at C ) 1 M of 4a. h The
reaction was performed at 4 °C. i 30 mol % of tetrabutylammonium acetate
was added.
to promote the epoxidation of trans-chalcone 4a with TBHP
(1.2 equiv) in toluene at room temperature (Scheme 1).
Scheme 1. Epoxidation of trans-Chalcone 4a by Catalysts
1 and 2
substantial improvement in the yield and a slightly reduced
ee was observed under more concentrated reaction conditions
(entry 9). Performing the epoxidation with 50 mol % of 2 at
4 °C had only a minimal effect on the level of selectivity,
although a very good conversion was achieved (entry 10).
When the reaction was carried out in the presence of the
ionic additive tetrabutylammonium acetate (entry 11), the
reaction rate was lowered (compare with entry 6) and the
enantioselectivity moderately reduced. Notably, when the
epoxidation was performed with catalyst 3 having no
hydroxyl group, under conditions otherwise identical to those
reported in entry 6, a dramatic loss was noted in both the
catalytic activity and asymmetric induction (entry 12).
Having improved the reaction conditions to practically
useful levels of stereocontrol, the optimized protocol,
employing catalyst 2, TBHP in hexane at room temperature,
was applied to a variety of R,â-enones to study the general
scope and limitations of the epoxidation method (Table 2).
In all of the examples (entries 1-10), diastereoisomerically
pure trans-(2R,3S)-epoxides were obtained starting from
trans-R,â-unsaturated ketones. Different types of electronic
substitution on the phenyl ring of the carbonyl function
furnished results comparable to those achieved in the
epoxidation of 4a (entries 2 and 3). More hindered â-naph-
thyl derivative was slowly converted to the epoxide in 64%
ee (entry 4). Enones having para electron-donating or
electron-withdrawing substituents on the â-phenyl group led
to satisfactory results (entries 5 and 6), except for the p-NO2-
substituted chalcone, which did not react (entry 7).
Catalytic loadings of 1 (30 mol %) afforded racemic
epoxide in modest yield. When R,R-diphenyl-L-prolinol 2
was used, diastereoisomerically pure trans-(2R,3S)-5a was
isolated in 69% ee, although in low yield. Encouraged by
this result, we screened various reaction conditions with a
view to improving the efficiency of the epoxidation of model
compound 4a (Table 1).
The reaction was performed using 30 mol % of 2 in
different solvents (entries 1-7). The epoxidation carried out
in chloroform or dichloromethane (entries 1 and 2) was very
sluggish, but satisfactory levels of enantioselectivity were
observed. Tetrahydrofuran, polar and protic solvents afforded
comparable results in terms of conversion, but the epoxide
showed a poor ee (entries 3-5).
Since apolar and noncoordinating solvents furnished better
results, the reaction was performed in hexane (entry 6). We
were pleased to isolate, in reduced reaction time, (2R,3S)-
5a in 53% yield and improved 76% ee. Cyclohexane proved
to be equally efficient (entry 7). Hexane was then employed
as the solvent of choice in further investigations of this
reaction. More hindered cumene hydroperoxide (CHP) gave
reduced conversion and enantioselectivity (entry 8). A
Interestingly, the protocol can be successfully extended
to substrates having an alkyl substituent either on the double
bond or on the carbonyl carbon and to aliphatic R,â-
unsaturated ketones (entries 8-10).
(8) Lattanzi, A.; Leadbeater, N. E. Org. Lett. 2002, 4, 1519.
(9) Amino alcohols have been previously reported to promote, in
stoichiometric amounts, the epoxidation of electron-deficient alkenes to
racemic epoxides: Masahiko, Y.; Noboru, K.; Satomi, T. Jpn. Patent JP
06092950 A2, 1994.
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Org. Lett., Vol. 7, No. 13, 2005

Table 2. Catalytic Enantioselective Epoxidation of R,â-Enones
Promoted by 2 and TBHPa
Figure 2. Linear effect in the R,R-diphenyl-L-prolinol-mediated
epoxidation of chalcone 4a. R ) correlation coefficient.
On the basis of the experimental data, we suggest that R,R-
diphenyl-L-prolinol serves as bifunctional catalyst giving rise
to the simultaneous activation of the enone and the alkyl
hydroperoxide by the hydroxy and amino groups, respec-
tively (Scheme 2).12
Scheme 2. Proposed Catalytic Cycle
a Unless otherwise specified, the reaction was carried out with 1.2 equiv
of TBHP in the presence of 30 mol % of 2 at C ) 0.2 M of 4. b Yield of
isolated product. c Enantiomeric excess was determined by HPLC analysis
using chiral columns Daicel Chiralcel OD and Chiralpak AD. d Absolute
configurations of 5 were determined by comparison of the HPLC retention
times or optical rotations with those reported in the literature (see the
Supporting Information). e The reaction was carried out at C ) 0.6 M of 4.
f Not determined. g 50 mol % catalyst was used in this reaction.
Catalyst 2 activates the nucleophile by deprotonation of
TBHP,13 thus generating tert-butyl hydroperoxide anion and
the corresponding ammonium cation 6, which in hexane
constitute a tight ion pair.
The conformationally fixed s-cis-â-benzilidene-R-tetralone
(entry 11) proved to be completely unreactive, while the rigid
s-trans vitamin K3 was fairly converted to the (2S,3R)-
epoxide although in low ee (entry 12).10 These data indicate
that stereoelectronic requirements and conformational pre-
requisites of enones are important features for the reactivity
and the enantiocontrol.
To gain insight into the mechanism of the epoxidation,
we next investigated nonlinear effects11 using R,R-diphenyl-
L-prolinol 2 of different degrees of optical purity (Figure
2).
Within experimental error, a linear effect in the epoxidation
of 4a was observed under the conditions reported in Table
1, entry 6. This correlation strongly indicates that a single
molecule of the catalyst is involved in the enantiodifferen-
tiating step.
The hydroxyl group of the diarylmethanol moiety of 2
appears to activate the enone by hydrogen bonding to the
carbonyl group.14,15 The polar-electrostatic interactions of the
three partners provide a valuable organizational template that
(11) (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 4000.
(b) Kagan, H. B. AdV. Synth. Catal. 2001, 343, 227. (c) Blackmond, D. G.
Acc. Chem. Res. 2000, 33, 402.
(12) Activation of the enone via iminium ion formation is less reasonably
expected to occur under these reaction conditions, given the unreactive
nature of enone carbonyls and the absence of an acid catalyst.
(13) (a) pKa of pyrrolidine) 11.3: Ohwada, T.; Hirao, H.; Ogawa, A.
J. Org. Chem. 2004, 69, 7486. (b) pKa of TBHP) 12.4: Richardson, W.
H.; Hodge, V. F. J. Org. Chem. 1970, 35, 4012.
(14) Wynberg first reported a transition-state complex comprising all
three species (thiol, enone, and the catalyst) in the asymmetric Michael
addition of thiols to cyclic enones mediated by quinine as bifunctional
catalyst: Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
(15) For studies on hydrogen bonds acting in a Lewis acid fashion, see:
(a) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062. (b) Huang, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662. (c) Scheiner, P. R.;
Wittkopp, A. Org. Lett. 2002, 4, 217. (d) Bordwell, F. G.; Ji, G. J. Am.
Chem. Soc. 1991, 113, 8398. (e) Kelly, T. R.; Kim, M. H. J. Am. Chem.
Soc. 1994, 116, 7072.
(10) The s-trans conformation of the enone moiety might be preferentially
adopted in the epoxidation reaction, although a noncoplanar enone geometry
cannot be excluded.
Org. Lett., Vol. 7, No. 13, 2005
2581

correctly positions the enone for conjugate addition of the
tert-butyl hydroperoxide anion. The hydrogen-bond-stabilized
enolate then attacks the O-O bond intramolecularly giving
rise to epoxide ring closure and elimination of the tert-butoxy
anion, according to the accepted mechanism for the nucleo-
philic epoxidation.16 Finally, the tert-butoxy anion regener-
ates catalyst 2.17
It is noteworthy that good facial control was observed in
the epoxide formation, taking into account that no covalent
bonds are involved in the activation of both reagents by such
a small organocatalyst. This proposition is confirmed by the
dramatic solvent effects displayed in the epoxidation (Table
1). In fact, polar, protic and coordinating solvents, which
solvate the ion pair, disrupt its rigidity, giving rise to a
conformationally flexible system of much less efficiency and
selectivity.
butylammonium acetate (Table 1, entry 11). Hydrogen
bonding has been shown to be fundamental for the catalytic
efficiency and the enantiocontrol, as clearly demonstrated
when employing R,R-diphenyl-L-proline 3, which proved to
be a very poor catalyst (Table 1, entry 12).
In conclusion, we have disclosed a new methodology for
the catalytic asymmetric epoxidation of a broad variety of
R,â-enones mediated by the bifunctional organocatalyst R,R-
L-diphenyl prolinol. The reaction is operationally simple and
does not require inert atmospheres or temperature manipula-
tion, and the epoxides are readily isolated by flash chroma-
tography without further workup to obtain good enantio-
selectivity. Moreover, depending on the choice of both
commercially available, R,R-L- or R,R-D-diphenylprolinol,
either enantiomer of the epoxide can be prepared. Research
efforts are now directed at improving the reaction by
employing stereoelectronically modified R,R-L-diarylproli-
nols, which should help to better define the elements crucial
for the reactivity and asymmetric induction.
The competitive formation by exchange of the unreactive
ion pair made of ammonium cation 6/acetate anion and the
low-reacting ion pair made of sterically hindered quaternary
tetrabutylammonium cation/tert-butyl hydroperoxy anion18
explains the suppressed reactivity and the slightly decreased
enantioselectivity observed when using the additive tetra-
Acknowledgment. We thank the Italian Ministero
dell’Istruzione, Universita` e Ricerca (MIUR), for financial
support.
(16) (a) Bunton, C. A.; Minkoff, G. J. J. Chem. Soc., Chem. Commun.
1979, 665. (b) House, H. O.; Ro, R. S. J. Am. Chem. Soc. 1958, 80, 2428.
(c) Wynberg, H.; Pluim, H. J. Org. Chem. 1980, 45, 2498.
(17) Background oxidation of catalyst 2 was checked in absence of the
enone [2 (30 mol %)/TBHP (1.2 equiv) in hexane at room temperature for
115 h]. 1H NMR analysis of the crude reaction mixture showed no significant
degradation of 2 under the reaction conditions.
Supporting Information Available: Experimental pro-
cedures, ee determination of chiral epoxy ketones by HPLC,
and 1H NMR and 13C NMR spectra of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) The epoxidation of 4a with the tertiary N-benzyl L-prolinol under
the usual conditions (rt, hexane, TBHP, 90 h) furnished traces of the epoxide.
OL050694M
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Org. Lett., Vol. 7, No. 13, 2005