Highly efficient asymmetric synthesis of α,β-epoxy esters via one-pot organocatalytic epoxidation and oxidative esterification

Article abstract of DOI:10.1039/c3ob00056g

Highly enantioselective synthesis of α,β-epoxy esters was achieved via one-pot organocatalytic epoxidation and consequent oxidative esterification. Excellent enantioselectivities (up to 99% ee) and good yields were obtained for a variety of α,β-epoxy esters. The method was readily scaled. Furthermore the product was applied towards the synthesis of (-)-clausenamide with excellent enantioselectivities (>99% ee).

Full text of DOI:10.1039/c3ob00056g

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Highly efficient asymmetric synthesis of α,β-epoxy
esters via one-pot organocatalytic epoxidation and
oxidative esterification†
Cite this: Org. Biomol. Chem., 2013, 11,
1815
Received 10th January 2013,
Accepted 29th January 2013
Yi-ning Xuan,*a Han-Sen Lina and Ming Yan*b
DOI: 10.1039/c3ob00056g
www.rsc.org/obc
Highly enantioselective synthesis of α,β-epoxy esters was achieved aldehydes with good yields and high enantioselectivities.10
via one-pot organocatalytic epoxidation and consequent oxi- However due to the high strain of the epoxy group, α,β-epoxy
dative esterification. Excellent enantioselectivities (up to 99% ee) aldehydes are susceptible to ring opening reactions. The direct
and good yields were obtained for a variety of α,β-epoxy esters. transformation of α,β-epoxy aldehydes to α,β-epoxy esters is
The method was readily scaled. Furthermore the product was still challenging. Here we report an efficient approach for the
applied towards the synthesis of (−)-clausenamide with excellent highly enantioselective synthesis of α,β-epoxy esters by a one-
enantioselectivities (>99% ee).
pot organocatalytic asymmetric epoxidation of α,β-unsaturated
aldehydes and oxidative esterification.11,12
Chiral α,β-epoxy esters are important intermediates for the syn-
thesis of drugs and complex molecules.1 Many efforts have
been devoted to enantioselective synthesis of α,β-epoxy
esters.2–5 Among them, asymmetric epoxidation of prochiral
α,β-unsaturated esters presents an attractive strategy. The
manganese–salen complexes are effective catalysts for the
epoxidation of (Z)-cinnamates.1j,6 Shi et al. developed chiral
ketone catalysts for the asymmetric epoxidation of α,β-unsatu-
rated esters.7 However, high catalyst loading (20–30 mol%) and
excess oxone (5 equiv.) are necessary for achieving acceptable
yields and enantioselectivities. Shibasaki reported highly enantio-
selective epoxidation of α,β-unsaturated esters catalyzed by an
yttrium–biphenyldiol complex,8 but the diethylene ether-
linked biphenyldiol ligands are difficult to synthesize. In
addition, highly toxic triphenylarsine is required as an addi-
tive. Although other indirect synthetic methods of chiral
α,β-epoxy esters were also developed, the development of
efficient synthetic methods of α,β-epoxy esters with high enantio-
selectivity is still highly desirable.
We initially explored a model reaction of cinnamaldehyde
1a with hydrogen peroxide in the presence of organocatalyst 4
in dichloromethane at room temperature (Table 1, entry 1). As
expected, the reaction resulted in the desired α,β-epoxy
Table 1 Optimization studies on the one-pot enantioselective synthesis of 3aa
Entry Catalyst Timeb (h) Additive
Yieldc,d (%) eee (%)
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
5
6
16
16
16
12
12
12
3
3
3
3
—
Et3N
—
—
—
44
53
52
61
25
24
73
—
—
—
90
90
90
90
90
88
95
Proton spongef
NaHCO3
Li2CO3
NaOAc
Na2CO3
K2CO3
In recent decades asymmetric organocatalysis has emerged
as a powerful tool for the synthesis of valuable chiral com-
pounds.9 Córdova and Jørgensen have independently reported
the organocatalytic asymmetric epoxidation of α,β-unsaturated
9
Na2CO3
Na2CO3
10g
aCollege of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006,
China. E-mail: xuanyn@mail3.sysu.edu.cn; Fax: +86-20-39352139;
Tel: +86-20-39352139
bIndustrial Institute of Fine Chemicals and Synthetic Drugs, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
E-mail: yanming@mail.sysu.edu.cn; Fax: +86-20-39943049; Tel: +86-20-39943049
a Unless otherwise stated, all reactions were performed at room
temperature with 1a (0.5 mmol), H2O2 (30 wt% in H2O) (0.6 mmol),
and a catalyst (0.05 mmol) in 0.5 mL of CH2Cl2 for 3 h. Then CH3OH
(1 mL), NBS (0.65 mmol) and additive (0.65 mmol) were added. b Time
for the oxidative esterification step. c Overall yield of two steps by GC
analysis. d Yield of the trans product. e ee values were determined by
chiral HPLC. f 1,8-Bis(dimethylamino)naphthalene. g Epoxidation was
performed with 10 mol% catalyst 6 for 2 h.
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob00056g
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aldehydes 2a. Due to the chemical instability of 2a, in situ
transformation of 2a to the corresponding ester 3a via oxi-
dative esterification was attempted. After the mixture was
diluted with methanol, 1.3 equiv. of N-bromosuccinimide
(NBS) was added. However, no anticipated α,β-epoxy esters 3a
were found. We doubted that the intermediate α,β-epoxy alde-
hyde may undergo ring opening reaction with methanol. This
side reaction is promoted by HBr produced during the course
of the reaction. Therefore basic additives were added. When
Et3N or a proton sponge (1.3 equiv.) is used as the acid scaven-
ger, no desired 3a was obtained (Table 1, entries 2 and 3). To
our delight, when NaHCO3 was used as the additive, the
process proceeds smoothly to give α,β-epoxy esters 3a in 44%
yield and 90% ee. Further screening of base additives indi-
cated Na2CO3 as the best additive. Full conversion was
achieved within 3 hours and α,β-epoxy esters 3a were obtained
with 61% overall yield and excellent enantioselectivity
(entry 7).
Two other organocatalysts 5 and 6 were also examined in
the reaction. Chiral amine catalyst 6 was found to be more
effective than 4 and 5. The epoxidation step could be com-
pleted in 2 hours and epoxy ester 3a was obtained in 73%
yield. In addition, the enantioselectivity was improved further
(entry 10).
As shown in Table 2, this one-pot epoxidation/oxidative
esterification can be extended to a variety of α,β-unsaturated
aldehydes. α,β-Epoxy esters were obtained in moderate to good
yields and with excellent enantioselectivities (Table 2, entries
1–10). The ortho-, meta-, and para-substitutions on the phenyl
ring were tolerated very well. The electronic property of the
substituent seemed to have a slight effect on the yield and
enantioselectivity. In contrast to direct asymmetric epoxidation
Scheme 1 Proposed mechanism for the oxidative esterification of α,β-epoxy
aldehyde.
of α,β-unsaturated esters,7,8,13 this method is very effective for
the synthesis of α,β-epoxy esters with a strong electron-with-
drawing substituent. Substrates with nitro, nitrile or trifluoro-
methyl groups on the phenyl ring all proceeded smoothly to
afford the α,β-epoxy esters 1g–1j with good yield and enantio-
selectivity (Table 2, entries 7–10). β-Alkyl unsaturated aldehydes
were also examined. The epoxidation step took place smoothly,
but subsequent oxidative esterification gave low yields. The
absolute configuration of 3a was determined to be 2S,3R by
comparing the optical rotation with reported data.8 By
analogy, the other α,β-epoxy esters were proposed to have the
same absolute configurations. A proposed mechanism for
the oxidative esterification step is depicted in Scheme 1. The
α,β-epoxy aldehyde reacted with methanol to give the corres-
ponding hemiacetal. This intermediate underwent SN2 substi-
tution with NBS to form the hemiacetal hypobromite.
Subsequent elimination promoted by a base such as Na2CO3
afforded the α,β-epoxy ester product.
Table 2 Synthesis of chiral α,β-epoxy esters from a variety of α,β-unsaturated
aldehydesa
The reaction was readily scaled up and performed on a
gram scale. A reaction with 1a (3.96 g, 30 mmol) proceeded
efficiently to afford 3a in a similar yield and enantioselectivity.
3a could be further applied for the synthesis of (−)-clausen-
amide 7d, which is an antiamnaesic agent with potent hepato-
protective activity (Scheme 2).14,15 3a was converted to the
amide 7a in 80% yield using racemic 2-methylamino-1-phenyl-
ethanol. Oxidation of 7a provided 7b in 86% yield. Base-
Entry
R
Product, yieldb,c (%)
eed (%)
1
2
3
4
5
6
7
8
9
Ph, 1a
3a, 72
3b, 54
3c, 55
3d, 71
3e, 62
3f, 69
3g, 67
3h, 63
3i, 73
3j, 63
95
96
97
93
96
96
97
99
95
96
4-Me-C6H4, 1b
2-Cl-C6H4, 1c
3-Cl-C6H4, 1d
4-Cl-C6H4, 1e
4-Br-C6H4, 1f
2-NO2-C6H4, 1g
4-NO2-C6H4, 1h
4-NC-C6H4, 1i
4-CF3-C6H4, 1j
10
a Unless otherwise stated, all reactions were performed at room
temperature with 1 (0.5 mmol), H2O2 (30 wt% in H2O) (0.6 mmol), and
a catalyst (0.05 mmol) in 0.5 mL of CH2Cl2 for 2 h. Then CH3OH
(1 mL), NBS (0.65 mmol) and Na2CO3 (0.65 mmol) were added and the
mixture was stirred for 3 h. b Isolated yield for the overall two steps.
c Yield for the trans product. d ee values were determined by chiral
HPLC.
Scheme 2 Synthesis of (−)-clausenamide 7d from 3a.
1816 | Org. Biomol. Chem., 2013, 11, 1815–1817
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catalyzed cyclization of 7b furnished lactam 7c in 45% yield.
Reduction of 7c with NaBH4 gave (−)-clausenamide 7d in 90%
yield and excellent enantioselectivity (>99% ee). This method
is also potentially applicable for the preparation of clausen-
amide derivatives.
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Conclusions
In summary, we have developed a convenient and efficient
method for the asymmetric synthesis of α,β-epoxy esters. The
one-pot organocatalytic epoxidation of α,β-unsaturated alde-
hydes and consequent oxidative esterification provided
α,β-epoxy esters in good yields and enantioselectivities. The
readily available catalyst, the simple procedure and the scale
up potential make the method attractive for the practical syn-
thesis of chiral α,β-epoxy esters.
Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (No. 21172270) and the Guangdong Engineer-
ing Research Center of Chiral Drugs is gratefully
acknowledged.
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