Asymmetric epoxidation of α,β-unsaturated ketones with hydrogen peroxide catalyzed by axially chiral guanidine base

Article abstract of DOI:10.3987/COM-08-S(N)105

The enantioselective epoxidation of α,β-unsaturated ketones with hydrogen peroxide was demonstrated using axially chiral guanidine as a base catalyst. Hydrogen peroxide can be utilized as a cost-effective and atom-efficient oxidant in the present catalyti

Full text of DOI:10.3987/COM-08-S(N)105

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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1049 - 1055. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd April, 2008, Accepted, 12th June, 2008, Published online, 19th June, 2008. COM-08-S(N)105
ASYMMETRIC EPOXIDATION OF α,β-UNSATURATED KETONES
WITH HYDROGEN PEROXIDE CATALYZED BY AXIALLY CHIRAL
GUANIDINE BASE‡
Masahiro Terada* and Megumi Nakano
Department of Chemistry, Graduate School of Science, Tohoku University,
Aoba-ku, Sendai 980-8578, Japan. E-mail: mterada@mail.tains.tohoku.ac.jp
‡Dedication to Professor Ryoji Noyori on the occasion of his 70th birthday
Abstract – The enantioselective epoxidation of α,β-unsaturated ketones with
hydrogen peroxide was demonstrated using axially chiral guanidine as a base
catalyst.
Hydrogen peroxide can be utilized as a cost-effective and
atom-efficient oxidant in the present catalytic epoxidation even under
heterogeneous conditions. The newly developed axially chiral guanidine base
bearing an additional central chirality functions as an efficient catalyst to provide
epoxides in 51-65% ee.
Catalytic asymmetric epoxidation occupies a privileged position in organic synthesis due to the
fundamental importance of enantioenriched epoxides as key synthetic intermediates. A number of
efficient protocols for enantioselective epoxidation using chiral metal catalysts and organocatalysts have
been reported to date.1,2 Julia-Colonna epoxidation is one of the most efficient synthetic methods for the
enantioselective functionalization of α,β-unsaturated ketones using hydrogen peroxide under basic
conditions.3 Since its discovery in 1980, the enantioselective epoxidation of α,β-unsaturated carbonyl
compounds has emerged as an efficient route for preparing highly functionalized synthetic intermediates
in bench-top experiments and industrial processes.4 In recent years, much attention has been devoted to
the utilization of aqueous hydrogen peroxide as the terminal oxidant in enantioselective epoxidation
because of the distinct advantage that its reduction product is water and the fact that it has high active
oxygen content.5,6

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Recently, we successfully developed novel axially chiral guanidines (1) as highly efficient Brønsted base
catalysts for enantioselective carbon-carbon bond and carbon-heteroatom bond forming reactions.7 In
our continuous studies aimed at extending the synthetic applicability of axially chiral guanidine bases (1),
we envisioned the activation of hydrogen peroxide by 1 for the asymmetric epoxidation.8,9 Herein, we
report the enantioselective epoxidation of α,β-unsaturated ketones catalyzed by axially chiral guanidine
bases (1), in which corresponding epoxides were obtained in optically active form by using aqueous
hydrogen peroxide as the ecological and atom-efficient oxidant (eq. 1).
(R)-1 (10 mol%)
O
O
O
30% H2O2 aq.
toluene, rt
Ar
(1)
Ph
R
Ph
R
3
2
H
N
G
N
N
H
Ar
(R)-1
An initial experiment was performed using chalcone (2a) and commercially available 30% hydrogen
peroxide in toluene in the presence of 10 mol% nine-membered axially chiral guanidine catalyst (1aa),
having a phenyl moiety as the aromatic (Ar) substituent introduced at 3,3’-position of the binaphthyl
backbone and an n-propyl group as the alkyl (G) substituent introduced at the nitrogen atom of the
guanidine moiety (eq. 2). To our delight, guanidine catalyst (1aa) accelerated the epoxidation under
heterogeneous conditions, albeit the low enantioselectivity of 17% ee (Table 1, entry 1). We then
explored suitable substituents on axially chiral guanidine bases (1) by changing Ar and G substituents.
As shown in Table 1, the catalytic activities and enantioselectivities were profoundly dependent on Ar
and G substituents. The introduction of substituents at 3,5-position of the phenyl ring (Ar) had negative
effects on both catalytic activities and enantioselectivities, regardless of their electronic properties (entries
2 and 3 vs. entry 1). In contrast, the para-substitution had marked electronic effects. Catalyst (1da)
having an electron withdrawing group, CF3, retarded the reaction markedly (entry 4). In sharp contrast,
tert-butyl substituted catalyst (1ea) accelerated the reaction significantly to provide epoxide (3a) in
excellent yield, even though the enantioselectivity remained low (entry 5). In order to increase % ee, we
further investigated the effect of G substituent introduced at the nitrogen atom of the guanidine moiety
(entries 6 – 10). Since the catalyst bearing 4-tert-butylphenyl moiety as the Ar substituent exhibited the

HETEROCYCLES, Vol. 76, No. 2, 2008
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highest catalytic activity, a series of alkyl groups were employed as the G substituents (entries 6 – 10).
However, neither small nor bulky aliphatic substituents improved enantioselectivities markedly (entries 6
– 8), although good yields were obtained. Benzyl substituted catalyst (1ee) also exhibited a similar
enantioselectivity (entry 9). In contrast, use of sterically congested benzhydryl moiety as the G
substituent, thus 1ef, resulted in enhancement of enantioselectivity at 51% ee (entry 10), although the
yield of product (3a) was low. Further derivatisation of the catalyst bearing benzhydryl moiety and a
4-trifluoromethylphenyl as the Ar substituent, 1df, led to a similar result as observed in the reaction
catalyzed by 1ef (entry 12 vs. 10).
Table 1. Enantioselective epoxidation of chalcone (2a) catalyzed by a series of chiral guanidine bases
(1).a
(R)-1
(10 mol%)
O
O
O
30% H2O2 aq. (5 equiv.)
(2)
Ph
Ph
Ph
Ph
toluene, rt
2a (R = Ph)
3a
entry
1
1 (Ar, G)
time (h)
yield (%)b
ee (%)c
1aa: Ar = C6H5− ,
G = n-Pr
9
58
56
40
62
89
93
79
90
70
27
57
35
17
8
2
1ba: Ar = 3,5-(CF3)2C6H3− , G = n-Pr
1ca: Ar = 3,5-t-Bu2C6H3− , G = n-Pr
24
24
24
7
3
12
19
14
7
4
1da: Ar = 4-CF3C6H4− ,
1ea: Ar = 4-t-BuC6H4− ,
1eb: Ar = 4-t-BuC6H4− ,
1ec: Ar = 4-t-BuC6H4− ,
1ed: Ar = 4-t-BuC6H4− ,
1ee: Ar = 4-t-BuC6H4− ,
1ef: Ar = 4-t-BuC6H4− ,
1de: Ar = 4-CF3C6H4− ,
1df: Ar = 4-CF3C6H4− ,
G = n-Pr
5
G = n-Pr
6
G = Me
7
7
G = c-Hex
G = t-Bu
18
9
26
24
25
51
27
50
8
9
G = PhCH2−
G = Ph2CH−
G = PhCH2−
G = Ph2CH−
24
24
24
24
10
11
12
a
All reactions were carried out using 0.01 mmol of (R)-1 (10 mol%), 0.1 mmol of chalcone (2a), and
30% aqueous hydrogen peroxide (5 equiv.) in 1.0 mL of toluene at room temperature. b Isolated yield of
c
3a.
Enantiomeric excess of 3a was determined by chiral HPLC analysis (DAICEL Chiralpak AD-H).
Absolute stereochemistry of 3a was determined to be 2S,3R.10
It is considered that the low catalytic activity of 1ef and 1df observed in the reaction would be ascribed to
an unfavorable interaction between sterically hindered benzhydryl substituents (G) and reactants 2a. In

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order to evaluate the steric demand of the benzhydryl moiety, we determined the optimized structure of
the guanidinium cation of catalyst 1ef.11 The three-dimensional structure of the lowest energy
conformer of 1ef is illustrated in Figure 1a. One phenyl ring of the benzhydryl moiety is oriented above
and the other below the basal plane of the guanidinium moiety. We hence speculated that these phenyl
substituents would prevent the formation of a transient assembly between chalcone (2a) and ion pairs of
guanidinium cation and hydroperoxide anion. In contrast, simple benzyl-substituted catalyst (1ee and
1de) exhibited lower enantioselectivity (25 - 27% ee) than 1ef and 1df. This result is presumed to be
due to the conformational flexibility around the C-N single bond of the benzyl moiety. We therefore
attempted to introduce chirality at the benzylic position, i.e., phenethyl amine derivatives, to restrict
conformational flexibility around the single bond. Further optimization of G substituents of guanidine
catalysts (1) was performed by combining axial and central chiralities (Figure 1b).
(a)
(b)
t-Bu
NH
NH
∗
N
Ar'
N
N
N
t-Bu
(R)-1eg - 1ei
(R)-1ef
Figure 1. Structure of guanidine catalysts (1). (a) Optimized structure of (R)-1ef. (b) Guanidine
catalysts (1eg – 1ei) bearing axial and central chiralities.
The catalyst bearing 4-tert-butylphenyl substituent was employed in screening chiral G substituents,
because this substituent displayed higher catalytic activity than 4-trifluoromethylphenyl substituent
(Table 1, entry 4 vs. 5). Representative results are summarized in Table 2. As expected, catalytic
activities and enantioselectivities are markedly dependent on the chirality of G substituents.
Introduction of an (R)-phenethyl group to catalyst (1eg) reduced the enantioselectivity, albeit the modest
chemical yield (entry 1). In contrast, diastereomeric catalyst (1eh) exhibited better performance than

HETEROCYCLES, Vol. 76, No. 2, 2008
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1eg in terms of catalytic activity and enantioselectivity (entry 2). Further modification of the substituent
with a more sterically hindered naphthyl ring, i.e., 1ei, which has the same absolute configuration at the
phenethyl moiety as 1eh, resulted in enhancement of catalytic activity with almost the same ee (entry 3 vs.
2). Catalyst (1ei) is applicable to other α,β-unsaturated ketones (2b and c) having alkyl substituents (R
= Me and c-Hex, respectively) (entries 4 and 5). The corresponding products were obtained nearly
quantitative yields and ee reached 65% in the reaction of 2c (R = c-Hex) (entry 5).
Table 2. Enantioselective epoxidation of 2 catalyzed by guanidine bases (1) having axial and central
chiralities.a
entry
1
1
2
time
(h)
Yieldb
(%)
eec
(%)
(Ar, G)
1eg: Ar = 4-t-BuC6H4−, G =
1eh: Ar = 4-t-BuC6H4−, G =
1ei: Ar = 4-t-BuC6H4− , G =
2a
2a
2a
18
18
24
44
57
77
31
50
52
(R)
(S)
2
3
(S)
4
5
1ei
1ei
2b: R= Me
14
14
98
98
51
65
2c: R = c-Hex
a
All reactions were carried out using 0.01 mmol of (R)-1 (10 mol%), 0.1 mmol of chalcone (2a), and
30% aqueous hydrogen peroxide (5 equiv.) in 1.0 mL of toluene at room temperature. b Isolated yield of
c
3.
Enantiomeric excess of 3 was determined by chiral HPLC analysis (Daicel Chiralpak AD-H).
Absolute stereochemistry of either 3a10 or 3b12 was determined to be 2S,3R. Absolute stereochemistry
of 3c was assigned to be 2S,3R by analogy.13
In conclusion, we have demonstrated the enantioselective epoxidation of α,β-unsaturated ketones with
hydrogen peroxide catalyzed by an axially chiral guanidine base. Although the enantioselectivities are
moderate in the series of guanidine catalysts tested, the newly developed axially chiral guanidine base
bearing an additional central chirality functions as an efficient catalyst for asymmetric epoxidation under
heterogeneous conditions. In addition, hydrogen peroxide can be utilized as a cost-effective and
atom-efficient oxidant in the present catalytic epoxidation. The present catalytic method is expected to
contribute to the further development of an environmentally benign process for the asymmetric
epoxidation of α,β-unsaturated carbonyl compounds.14 Further studies to elucidate the mechanisms of
the enantiofacial selection are in progress in our laboratory.

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ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformation of Carbon Resources” (Grant No. 19020006) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. We also acknowledge the Research Fellowship for
Young Scientists (M. N.) from the Japan Society for the Promotion of Science.
REFERENCES AND NOTES
1. For selected reviews on metal-catalyzed asymmetric epoxidations, see: E. McGarrigle and D. G.
Gilheany, Chem. Rev., 2005, 105, 1563; E. N. Jacobsen and M. H. Wu, ‘Comprehensive
Asymmetric Catalysis,’ Vol. 2, ed. by E. N. Jacobsen, A. Pfaltz, and H. Yamamoto, Springer,
Heidelberg, 1999, pp. 649-677; T. Katsuki, ‘Comprehensive Asymmetric Catalysis,’ Vol. 2, ed. by
E. N. Jacobsen, A. Pfaltz, and H. Yamamoto, Springer, Heidelberg, 1999, pp. 621-648.
2. For selected reviews on organocatalytic asymmetric epoxidations, see: P. I. Dalko and L. Moisan,
Angew. Chem. Int. Ed., 2004, 43, 5138; P. Merino and T. Tejero, Angew. Chem. Int. Ed., 2004, 43,
2995; A. Armstrong, Angew. Chem. Int. Ed., 2004, 43, 1460; Y. Shi, Acc. Chem. Res., 2004, 37,
488; D. Yang, Acc. Chem. Res., 2004, 37, 497; A. Berkessel and H. Gröger, ‘Asymmetric
Organocatalysis,’ Wiley-VCH, Weinheim, 2005, pp. 277-313.
3. S. Juliá, J. Masana, and J. C. Vega, Angew. Chem., Int. Ed. Engl., 1980, 19, 929; S. Juliá, J. Guixer,
J. Masana, J. Rocas, S. Colonna, R. Annunziata, and H. Molinari, J. Chem. Soc., Perkin Trans. 1,
1982, 1317.
4. For a recent review on asymmetric epoxidation of α,β-unsaturated carbonyl compounds, see: M. J.
Porter and J. Skidmore, Chem. Commun., 2000, 1215.
5. For leading reviews on epoxidation of olefins with hydrogen peroxide see: G. Grigoropoulou, J. H.
Clark, and J. A. Elings, Green Chem., 2003, 5, 1; R. Noyori, M. Aoki, and K. Sato, Chem.
Commun., 2003, 1977; K. Burgess and B. S. Lane, Chem. Rev., 2003, 103, 2457; I. W. C. E.
Arends, Angew. Chem. Int. Ed., 2006, 45, 6250.
6. For recent examples of organocatalytic asymmetric epoxidations using hydrogen preroxide, see: M.
Marigo, J. Franzén, T. B. Poulsen, W. Zhuang, and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127,
6964; W. Z. Zhuang, M. Marigo, and K. A. Jørgensen, Org. Biom. Chem., 2005, 3883; H.
Sundén, I. Ibrahem, and A. Córdova, Tetrahedron Lett., 2006, 47, 99; G.-L. Zhao, I. Ibrahem, H.
Sundén, and A. Córdova, Adv. Synth. Catal., 2007, 349, 1210; C. P. Burke, L. Shu, and Y. Shi, J.
Org. Chem., 2007, 72, 6320.
7. M. Terada, H. Ube, and Y. Yaguchi, J. Am. Chem. Soc., 2006, 128, 1454; M. Terada, M. Nakano,
and H. Ube, J. Am. Chem. Soc., 2006, 128, 16044; H. Ube, M. Terada, and D. Uraguchi, J.

HETEROCYCLES, Vol. 76, No. 2, 2008
1055
Organomet. Chem., 2007, 692, 545; M. Terada, T. Ikehara, and H. Ube, J. Am. Chem. Soc., 2007,
129, 14112.
8. For reviews of chiral guanidine catalysts, see: T. Ishikawa and T. Isobe, Chem. Eur. J., 2002, 8,
552; T. Ishikawa and T. Kumamoto, Synthesis, 2006, 737.
9. For asymmetric epoxidation promoted by chiral guanidines, see: J. C. McManus, J. S. Carey, and
R. J. K. Taylor, Synlett, 2003, 365; J. C. McManus, T. Genski, J. S. Carey, and R. J. K. Taylor,
Synlett, 2003, 369; M. T. Allingham, A. Howard-Jones, P. J. Murphy, D. A. Thomas, and P. W. R.
Caulkett, Tetrahedron Lett., 2003, 44, 8677; T. Kumamoto, K. Ebine, M. Endo, Y. Araki, Y.
Fushimi, I. Miyamoto, T. Ishikawa, T. Isobe, and K. Fukuda, Heterocycles, 2005, 66, 347; T. Kita,
B. Shin, Y. Hashimoto, and K. Nagasawa, Heterocycles, 2007, 73, 241.
10. B. M. Choudary, M. L. Kantam, K. V. S. Ranganath, K. Mahendar, and B. Sreedhar, J. Am. Chem.
Soc., 2004, 126, 3396; C. L. Elston, R. F. W. Jackson, S. J. F. MacDonald, and P. J. Murray,
Angew. Chem., Int. Ed. Engl., 1997, 36, 410; B. Lygo and P. G. Wainwright, Tetrahedron, 1999,
55, 6289.
11. Geometry optimization was conducted using density functional theory (B3LYP) at the 6-31G* level.
12. O. Meth-Cohn, R. M. Horak, and G. Fouché, J. Chem. Soc., Perkin Trans. 1, 1994, 1517; W.
Adam, P. B. Rao, H.-G. Degen, and C. R. Saha-Möller, J. Am. Chem. Soc., 2000, 122, 5654.
13. S. Arai, Y. Shirai, T. Ishida, and T. Shioiri, Tetrahedron, 1999, 55, 6375.
14. Representative procedure for guanidine-catalyzed asymmetric epoxidation of chalcone (2a): To a
toluene solution (1.0 mL) of guanidine catalyst [(R)-1ei] (7.56 mg, 0.01 mmol) and chalcone (2a)
(20.8 mg, 0.10 mmol) was added H2O2 solution (52 µL, 30% aqueous solution, 0.5 mmol). The
reaction mixture was vigorously stirred at room temperature and the progress of the reaction was
monitored by TLC. The resulting solution was quenched with Na2SO3 aq. and extracted with
AcOEt. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by
column chromatography (hexane/AcOEt = 20/1 to 10/1) to afford trans-epoxy-1,3-
diphenylpropan-1-one (3a) in 77% yield (17.2 mg, 52% ee). Enantiomeric excess was determined
by chiral HPLC analysis. (2S,3R)-3a: HPLC analysis: Daicel Chiralpak AD-H (hexane/EtOH =
85/15, 1.0 mL/min, 254 nm, 10 °C) 21.4 (major), 27.8 (minor) min; and Daicel Chiralcel OJ-H
(hexane/2-propanol = 90/10, 1.0 mL/min, 254 nm, rt) 28.2 (minor), 30.5 (major) min; 1H NMR
(270 MHz, CDCl3) δ 4.07 (1H, d, J = 1.9 Hz), 4.29 (1H, d, J = 1.9 Hz), 7.35-7.63 (8H, m), 8.00-8.03
(2H, m). 13C NMR (67.8 MHz, CDCl3) δ 59.9, 61.5, 126.3, 128.9, 129.3, 129.4, 129.6, 134.5,
136.0, 193.6. These spectral data are consistent with previous reports.10