Synthesis of enantiomerically enriched α,α-disubstituted β,γ-epoxy esters using hydrolytic kinetic resolution catalyzed by salenCo(III)

Article abstract of DOI:10.1016/j.tetasy.2010.03.036

Novel α,α-disubstituted epoxy esters were prepared in enantiopure form by hydrolytic kinetic resolution (HKR) of the corresponding racemic mixtures using chiral salenCo(III) as catalyst. The methodology provides a convenient route to enantioenriched β,γ-epoxy esters 2a, 2c and 2d.

Full text of DOI:10.1016/j.tetasy.2010.03.036

Tetrahedron: Asymmetry 21 (2010) 631–635
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiomerically enriched a,a-disubstituted b,c-epoxy esters
using hydrolytic kinetic resolution catalyzed by salenCo(III)
*
Ignacio Viera, Eduardo Manta, Lucía González, Graciela Mahler
Departamento de Química Orgánica, Cátedra de Química Farmacéutica, Universidad de la República, Avda. General Flores 2124, CC1157 Montevideo, Uruguay
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel
a,a-disubstituted epoxy esters were prepared in enantiopure form by hydrolytic kinetic resolution
Received 12 March 2010
Accepted 31 March 2010
Available online 27 April 2010
(HKR) of the corresponding racemic mixtures using chiral salenCo(III) as catalyst. The methodology pro-
vides a convenient route to enantioenriched b,
c-epoxy esters 2a, 2c and 2d.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
R
R
O
O
OH
As part of our efforts in the synthesis of new bioactive
compounds based on simplifications of the natural product myco-
thiazole 1 (Fig. 1)1 we were interested in the development of a
general and scalable procedure for the preparation of enantiopure
ADH
OEt
O
R
R
β-hydroxybutanolide
a)
a,a
-disubstituted epoxy esters 2, as building blocks for these
analogues.
O
O
OH
O
EtO
N
R
R
O
(R)-2epoxiester
S
1
N
H
OMe
b)
HKR
OH
R
O
R
O
O
O
Br
OEt
EtO
EtO
R
R
R
R
bromohydrine
S-2
Scheme 1. Retrosynthetic epoxy ester 2 approach.
Figure 1. (ꢀ)-Mycothiazole 1 and
a,a-disubstituted b,c-epoxy ester (S)-2.
Epoxides are versatile building blocks that have been exten-
sively used in the synthesis of complex organic compounds. Most
of the methods available for their preparation include the oxida-
tion of alkenes with peracids or the cyclization of the correspond-
ing halohydrins catalyzed by base.2 Their utility as valuable
intermediates has been further expanded upon with the advent
of asymmetric catalytic methods for their synthesis. One reported
The hydrolytic kinetic resolution (HKR) seems to be an ideal
methodology for the synthesis of enantiopure b,c-epoxy esters.
The process developed by Jacobsen is used to synthesize terminal
diols and their corresponding epoxides in virtually enantiomeri-
cally pure form.4 This methodology employs water as the only re-
agent, small amounts of solvent and a high loading of recyclable
chiral cobalt(III)-based complexes 3 (Fig. 2) to afford the terminal
epoxides and 1,2-diols in high yield and high enantiomeric excess.
An important number of building blocks for the synthesis of com-
plex natural products and pharmaceuticals have been prepared
using this methodology.5 However, most reports of successful
HKR are related to simple non-functionalized terminal epoxides.6
Herein we report our findings with regarding to the synthesis of
method for the preparation of enantiomerically pure b,c-epoxy
esters has been described by the chemoselective ring opening of
b-hydroxybutanolides with trimethylsilyliodide, followed by cycli-
zation of the resulting iodohydrines with silver oxide (Scheme 1,
route a).3 However, no general and convenient methods are avail-
able for their preparation.
chiral
a,a-disubstituted epoxides 2, by exploring two alternatives:
* Corresponding author. Tel.: +598 2 9290290; fax: +598 2 9241906.
E-mail address: gmahler@fq.edu.uy (G. Mahler).
(a) asymmetric synthesis of enantiopure b-hydroxybutanolides
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.036

632
I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635
O
O
O
O
i)
H
N
H
N
EtO
EtO
H2O
Co
OAc
Et
Et
4d
O
ii); iii); iv)
O
v)
O
O
EtO
5
Et Et
O
O
Et
O
Me3SiI, Ag2O
(S,S)-3
EtO
Et
(S)-2d
Et
Et
Figure 2. SalenCo(III).
6
OH
25% ee
followed by ring opening and (b) HKR using catalytic chiral salen-
Scheme 2. Reagents and conditions: (i) K2CO3, Bu4N+Iꢀ, EtBr (2 equiv), DMF, rt,
85%; (ii) NaBH4, EtOH, 0 °C to rt, 73%; (iii) TsCl, Py, 4 °C, overnight; (iv) DBU, 140 °C,
3 h 62%; (v) tBuOH/H2O, 0 °C, 24 h, 35%, 25% ee.
Co(III) of racemic epoxides
(Scheme 1, route b).
2 prepared from bromohydrins
2. Results and discussion
ethyl acetoacetate with different alkyl groups afforded ketones 4a–
e in good yields (65–93%). Bromoketones 7a–e were then obtained
As shown in Scheme 2, we initially attempted to prepare a b,c-
epoxy ester using the Sharpless asymmetric dihydoxylation (ADH)
reaction.7 Ethyl acetoacetate was dialkylated with ethyl bromide to
by
a-bromination of ketones 4a–e in yields ranging from 66% to
give the
a,a
-disubstituted ketone 4d, using Bu4N+Iꢀ as a phase
80%. Reduction of the resulting bromoketones 7a–e with NaBH4
followed by cyclization of the corresponding bromohydrins in ba-
sic media led to racemic epoxides 2a–e in excellent yields (80–
89%).
Epoxides 2a–e were then subjected to HKR with salenCo(III)-3
as a catalyst (Scheme 4). Substrates 2a, c and d, bearing the di-
methyl, cyclopentyl and diethyl substituents, underwent resolu-
tion in high yield (45–48%) and ee (92–99%), using either the
(S,S)- or (R,R)-enantiomers of 3, (Table 1, entries 1, 2, 5–8).10
In the case of cyclopropyl derivative 2b, low yield and poor res-
olution were achieved (Table 1, entries 3 and 4). This can be attrib-
uted to the instability of 2b, which decomposed into a complex
mixture of products under HKR conditions. When we attempted
transfer catalyst.8 Olefin 5 was prepared by the reduction of ketone
4d followed by tosylation of the corresponding alcohol and elimi-
nation (44% overall yield). Oxidation of alkene 5 under ADH condi-
tions took place in low yield and poor stereoselectivity to give b-
hydroxybutanolide 6 (35%, 25% ee). It is important to note that
according to literature reports terminal olefins can sometimes re-
act slower AD-mix and lead to low ee.9 Taking also into account
the limitations associated with scale-up costs, this route was not
suitable for our purposes.
We therefore turned our attention to the HKR of racemic
a,a-
disubstituted epoxides using Jacobsen’s catalyst. The synthesis of
this class of epoxides by cyclization of bromohydrins has been
optimized by our group as part of the synthesis of mycothiazole
HKR on
a,a-dibenzyl epoxide 2e, no resolution was observed and
analogues.1 Therefore, racemic
a,a-disubstituted epoxides were
the recovered starting material had a very low ee, even when we
increased the amount of catalyst to 5% and the reaction time to
synthesized by the sequence shown in Scheme 3. Dialkylation of
O
O
O
O
O
ii)
i)
EtO
EtO
EtO
R
R
4a (68%), R = Me;
4b (85%), R = (CH2)2;
4c (83%), R = (CH2)4; 4d (70%) R = Et;
4e (65%), R = Bn
O
R
O
iii)
iv)
O
Br
EtO
R
R
R
7a (70%), R = Me;
7b (66%), R = (CH2)2 2a (88%), R = Me;
2b (80%), R = (CH2)2
7c (67%), R = (CH2)4; 7d(73%), R = Et;
7e (80%), R = Bn
2c (83%) R = (CH2)4, 2d (88%), R = Et;
2e (89%), R = Bn
Scheme 3. Reagents and conditions: (i) K2CO3, Bu4NI, R-Br, DMF, rt; (ii) Br2, EtOH, 0 °C to rt; (iii) NaBH4, EtOH, 0 °C to rt; (iv) K2CO3, EtOH.
O
O
OH
O
O
1-2% (S,S)-3
OH
OH
EtO
EtO
EtO
EtO
+
H2O (0.5 eq)
R
S-2
O
R
R
O
R
R
O
R
O
EtO
OH
R
(RS)-2
1-2% (R,R)-3
+
R
R
R
R-
H2O (0.5 eq)
2
Scheme 4. HKR of epoxide 2.

I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635
633
Table 1
carrier gas He, provided with capillary column on tert-butyldimeth-
ylsilyl b-cyclodextrin PS086.
Hydrolytic kinetic resolution of substrates 2a–e
Entry
Substrate
R
Catalyst
Time (h)
% eea
Yield %
4.2. Synthesis of a,a-alkylacetoacetates 4a–e: general procedure
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
Me
Me
2%, (S,S)-3
2%, (R,R)-3
1%, (S,S)-3
1%, (S,S)-3
2%, (S,S)-3
2%, (R,R)-3
2%, (S,S)-3
2%, (R,R)-3
5%, (S,S)-3
5%, (R,R)-3
21
21
24
24
24
24
24
24
72
72
>99
92
30
25
95
>99
95
98
5
45
47
17
20
47
45
48
48
65
70
(CH2)2
(CH2)2
(CH2)4
(CH2)4
Et
Et
Bn
Bn
4.2.1. Ethyl 2,2-dibenzyl-3-oxobutanoate 4e
To a stirred suspension of dry K2CO3 (5.2 g, 0.015 mol) in DMF
(35 mL) were added under N2 ethyl acetoacetate (2 g, 0.015 mol),
benzylchloride (3.54 mL, 0.030 mol) and (nBu)4NI (0.6 g,
0.0016 mol) and stirred at room temperature overnight. To the
mixture was added brine solution (70 mL) at 4 °C and extracted
with Et2O (200 mL ꢁ 4). The combined organic layers were washed
with H2O (2 ꢁ 70 ml), dried over Na2SO4 and concentrated in va-
cuo. The residual oil was purified by flash chromatography (SiO2,
AcOEt/hexane; 1:9) to give 4e as an oil (2.59 g, 65%): 1H NMR
(CDCl3) 1.19 (t, J = 7.1 Hz, 3H), 1.97 (s, 3H), 2.12 (br t, J = 6.4 Hz,
4H), 3.23 (s, 6H), 4.12 (q, J = 7.1 Hz, 2H), 7.15–7.28 (m, 10H); 13C
NMR (CDCl3) 14.4, 29.4, 61.7, 66.5, 127.3, 128.7, 130.5, 136.8
173.9, 204.4.
10
4
a
The ee % was determined by chiral GLC.
72 h (Table 1, entry 10). It is likely that the bulky benzyl groups at
the -position prevent the approach of the catalysts, leading to
a
slow hydrolysis and hence poor resolution.
Finally, we were able to scale up the reaction successfully using
epoxide 2a as a test case. HKR of 4 g of racemic 2a resulted in the
desired enantiopure compound (S)-2a in excellent yield (46%) and
ee (99%).
Overall and with the exception of acid-sensitive or bulky epox-
ides (2c and 2e, respectively) HKR provided a practical, cost-effec-
tive and efficient route for the preparation of enantiopure epoxides
2a, 2c and 2d.
4.2.2. Ethyl 2,2-dimethyl-3-oxobutanoate 4a
Prepared in 68% yield as a colourless oil analogous to the route
described for 4e. 1H NMR (CDCl3) 1.28 (t, J = 7.0 Hz, 3H), 1.36 (s,
6H), 2.16 (s, 3H), 4.23 (q, J = 7.0 Hz, 2H).
4.2.3. Ethyl 2-cyclopropyl-3-oxobutanoate 4b
Prepared in 85% yield as a colourless oil analogous to the route
described for 4e. 1H NMR (CDCl3) 1.30 (t, J = 7.1 Hz, 3H), 1.46 (s,
4H), 2.47 (s, 3H), 4.20 (q, J = 7.1 Hz, 2H).
3. Conclusions
In conclusion, we have explored the preparation of enantiopure
a,a-disubstituted epoxy esters using either Sharpless ADH or HKR
4.2.4. Ethyl 2,2-cyclopentyl-3-oxobutanoate 4c
Prepared in 83% yield as a colourless oil analogous to the route
described for 4e. 1H NMR (CDCl3) 1.27 (t, J = 7.1 Hz, 3H), 1.63–1.69
(m, 4H), 2.12 (t, J = 6.4 Hz, 4H), 2.17 (s, 3H), 4.20 (q, J = 7.1 Hz, 2H);
13C NMR (CDCl3) 14.4, 26.1, 26.8, 33.4, 61.7, 67.3, 173.9, 204.4.
with salenCo(III) catalyst. The use of the HKR seems to have clear
advantages over ADH, including the minimization of synthetic
operations, easy preparation of the catalyst, nominal solvent use,
excellent chemical yields and high ee. While not all the substrates
were suitable for HKR, we were also able to show that the method
could be easily scaled up.
4.2.5. Ethyl 2,2-diethyl-3-oxobutanoate 4d
Prepared in 70% yield as a colourless oil analogous to the route
described for 4e. 1H NMR (CDCl3) 0.78 (t, J = 7.6 Hz, 6H), 1.29 (t,
J = 7.1 Hz, 3H), 1.88 (m, 4H), 2.13 (s, 3H), 4.16 (q, J = 7.1 Hz, 3H).
4. Experimental part
4.1. General methods
4.3. Ethyl 2,2-diethyl-3-butenoate 511
The reactions were monitored by analytical thin layer chroma-
tography 0.25 mm silica gel plastic sheets (Macherey-Nagel, Poly-
gramÒ SIL G/UV 254). Flash chromatography on Silica Gel 60 (J. T.
The compound was prepared according Ref. 11, in 44% overall
yield. 1H NMR (CDCl3) 0.82 (t, J = 7.5 Hz, 6H), 1.27 (t, J = 7.1 Hz,
3H), 1.74 (q, J = 7.5 Hz, 4H), 4.17 (q, J = 7.1 Hz, 2H), 5.10 (d,
J = 17.7 Hz, 1H), 5.20 (d, J = 11.0 Hz, 1H), 5.98 (dd, J = 11.1,
17.7 Hz, 1H). 13C NMR (CDCl3) 8.9, 14.4, 14.5, 22.9, 23.0, 28.6,
53.3, 60.7, 114.7, 140.2, 175.7.
Baker, 40 lm average particle diameter) was used to purify the
crude reaction mixtures. NMR spectra were recorded at 400 MHz,
100 MHz (1H NMR, 13C NMR) using a Bruker AVANCE at 21 °C.
Chemical shifts (d) are reported as follows: chemical shift, multi-
plicity, coupling constant and integration. IR spectra were obtained
on a Perkin Elmer 1310 and FTIR 8101A Shimadzu spectrometer,
unit cmꢀ1. High-resolution mass spectra were measured on VG
AutoSpect spectrometer (EIS mode). Melting points were deter-
mined using a Laboratory Devices Gallenkamp apparatus. Optical
rotations were measured using a Kruss Optronic GmbH P8000
polarimeter with a 0.5-mL cell (concentration c given as g/
100 mL). Liquid chromatography was performed with a Shimadzu
LC 20 AT provided with UV (SPD-M20A) detection. All solvents were
purified according to the literature procedures. All reactions were
carried out in dry, freshly distilled solvents under anhydrous condi-
tions unless otherwise stated. Yields are reported for chromato-
graphic and spectroscopic (1H and 13C NMR) pure compounds.
Enantiomeric excess was calculated by gas chromatography (GLC)
using a GC-17A Shimadzu with a flame ionization detector (FID),
4.4. (RS)-2,2-Diethyl-3-hydroxybutanolide 612
t
To a mixture of AD-mix-
a
(833 mg) in 6 mL BuOH/H2O (1:1)
cooled at 0 °C was added compound 5 (0.10 g, 0.59 mmol) and stir-
red for 24 h. While the mixture was stirred at 0 °C, solid sodium
sulfite (0.9 g) was added and the mixture was allowed to warm
to room temperature and stirred for 60 min. The aqueous phase
was extracted with AcOEt (5 ꢁ 20 mL) and the combined organic
extract was dried over Na2SO4 and concentrated in vacuo. The
residual oil was purified by flash chromatography (SiO2, Et2O/hex-
ane; 1:9) to give 6 (32 mg, 35% yield, 25% ee) as an oil 1H NMR
(CDCl3) 0.93 (t, J = 7.5 Hz, 6H), 1.57 (q, J = 7.5 Hz, 4H), 4.13 (dd,
J = 4.5, 10.0 Hz, 1H), 4.20 (dd, J = 3.2, 10.0 Hz, 1H), 4.55 (dd,
J = 3.2, 4.5 Hz, 1H); 13C NMR (CDCl3) 9.0, 9.7, 21.9, 22.8, 45.6,
69.8, 75.7, 179.9.

634
I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635
4.5. Synthesis of bromoketones 7a–e: general procedure
J = 7.1 Hz, 3H), 2.67 (dd, J1 = 2.8, J2 = 4.5 Hz, 1H), 2.71 (dd, J1 = 4.0,
J2 = 4.5 Hz, 1H), 3.17 (dd, J1 = 2.8, J2 = 4.0 Hz, 1H), 4.17 (q,
J = 7.1 Hz, 2H). 13C NMR (CDCl3) 14.5, 20.6, 21.6, 42.8, 44.3, 56.8,
61.2, 176.1.
4.5.1. Ethyl 2,2-dibenzyl-4-bromo-3-oxobutanoate 7e
To a stirred solution of ethyl 2,2-dibenzyl-3-oxobutanoate (1 g,
3.2 mmol) in dry EtOH (12 ml) at 0 °C was added Br2 (0.18 mL,
3.5 mol) dropwise. The mixture was warmed to room temperature
and stirred for 24 h. The solvent was removed in vacuo and the
crude is poured into NaHCO3 saturated solution (30 ml). The mix-
ture was extracted with Et2O (200 mL ꢁ 4) and the combined or-
ganic layers were washed with H2O (2 ꢁ 70 ml), dried over
Na2SO4 and concentrated in vacuo. The residual oil was purified
by flash chromatography (SiO2, AcOEt/hexane; 1:9) to give 4c
(0.96 g, 80%) as a solid mp 113–114 °C: 1H NMR (CDCl3) 1.21 (t,
J = 7.2 Hz, 3H), 3.31 (s, 4H), 3.75 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H),
7.14 (m, 4H), 7.28 (m, 6H); 13C NMR 14.2, 29.4, 41.8, 62.0, 127.7,
128.8, 130.5, 136.1, 171.4, 200.1.
4.6.3. (RS)-Ethyl 2,2-cyclopropyl-3,4-epoxybutanoate 2b
Prepared in 80% yield as a colourless oil analogous to the route
described for 2e. 1H NMR (CDCl3) 0.78 (dt, J = 3.5, 7.0 Hz, 1H), 0.93
(dt, J = 3.5, 7.0 Hz, 1H), 1.03 (dt, J = 3.5, 7.0 Hz, 1H), 1.24 (m, 1H),
1.29 (t, J = 7.1 Hz, 2H), 2.44 (dd, J = 2.6, 4.8 Hz, 1H), 2.81 (dd,
J = 4.0, 4.8 Hz, 1H), 3.58 (dd, J = 2.6, 4.0 Hz, 1H), 4.18 (q, J = 7.1 Hz,
1H); 13C NMR (CDCl3) 10.8, 13.7, 14.6, 24.5, 46.5, 50.0, 52.4, 53.8,
61.4, 174.0; EIMS (ESI) m/z calcd for C8H13O3 [M+H+]+ 157.0786,
found 157.0799.
4.6.4. (RS)-Ethyl 2,2-cyclopentanyl-3,4-epoxybutanoate 2c
Prepared in 83% yield as a colourless oil analogous to the route
described for 2e. 1H NMR (CDCl3) 1.25 (t, J = 7.1 Hz, 2H), 1.49 (m,
1H), 1.65 (m, H 5), 1.89 (m, 1H), 2.09 (m, 1H), 2.55 (dd,, J = 2.8,
4.6 Hz, 1H), 2.71 (dd, J = 7.0, 7.0 Hz, 1H), 3.23 (dd, J = 2.7, 4.1 Hz,
1H), 4.16 (q, J = 7.1 Hz, 1H); 13C NMR (CDCl3) 9.2, 14.6, 25.9, 31.0,
33.7, 44.6, 54.2, 55.3, 61.9, 176.2; EIMS (EIS) m/z calcd for
C10H17O3 [M+H]+ 185.1099, found 185.1109.
4.5.2. Ethyl 4-bromo-2,2-dimethyl-3-oxobutanoate 7a
Prepared in 70% yield as a colourless oil analogous to the route
described for 7e. 1H NMR (CDCl3) 1.29 (t, J = 7.1 Hz, 6H), 1.47 (s,
6H), 4.14 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H); 13C NMR (CDCl3) 14.5,
22.2, 22.8, 31.7, 55.4, 62.2, 173.2, 199.8.
4.5.3. Ethyl 4-bromo-2,2-cyclopropyl-3-oxobutanoate 7b
Prepared in 66% yield as a colourless oil analogous to the route
described for 7e. 1H NMR (CDCl3) 1.32 (t, J = 7.1 Hz, 3H), 1.60 (dt,
J = 5.9, 9.4 Hz, 4H), 4.24 (q, J = 7.1 Hz, 2H), 4.50 (s, 2H). 13C NMR
(CDCl3) 14.4, 26.0, 26.7, 34.3, 62.1, 67.3, 173.9, 204.4.
4.6.5. (RS)-Ethyl 2,2-diethyl-3,4-epoxybutanoate 2d
Prepared in 88% yield as a colourless oil analogous to the route
described for 2e. 1H NMR (CDCl3) 1H NMR (CDCl3) 0.80 (t,
J = 7.5 Hz, 6H), 1.27 (t, J = 7.1 Hz, 4H), 1.89 (dt, J = 7.5, 15.0 Hz,
2H), 1.99 (dt, J = 7.5, 15.0 Hz, 2H), 4.09 (s, 2H), 4.21 (q, J = 7.1 Hz,
2H), 1.65–1.72 (m, 3H), 2.72–2.77 (m, 2H), 3.16 (dd, J = 3.0,
4.0 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H); 13C NMR (CDCl3) 9.2, 14.9,
25.3, 26.2, 44.6, 50.0, 55.4, 61.0, 174.7; HRMS (ESI) m/z calcd for
C10H18O3 186.1256, found 186.1258.
4.5.4. Ethyl 4-bromo-2,2-cyclopentyl-3-oxobutanoate 7c
Prepared in 67% yield as a colourless oil analogous to the route
described for 7e. 1H NMR (CDCl3) 1.32 (t, J = 7.1 Hz, 3H), 1.68 (m,
4H), 4.25 (t, J = 7.1 Hz, 2H), 4.51 (s, 2H); 13C NMR (CDCl3) 14.4,
21.4, 33.6, 35.3, 61.9, 170.7, 197.9.
4.5.5. Ethyl 4-bromo-2,2-diethyl-3-oxobutanoate 7d
4.7. Hydrolytic kinetic resolution of ethyl 2,2-dimethyl-3,4-
epoxybutanoate 2a13
Prepared in 73% yield as a colourless oil analogous to the route
described for 7e. 1H NMR (CDCl3) 0.82 (t, J = 7.5 Hz, 6H), 1.28 (t,
J = 7.1 Hz, 4H), 1.89 (dt, J = 7.5, 15.0 Hz, 2H), 1.99 (dt, J = 7.5,
15.0 Hz, 2H), 4.10 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H); 13C NMR (CDCl3)
8.5, 14.5, 24.9, 25.1, 33.0, 61.9, 172.3, 199.2.
4.7.1. Preparation of the active catalyst (S,S)-3
To a stirred suspension of (S,S)-N,N-bis(3,5-di-tert-butylsalicy-
lidene)-1,2-cyclohexane-diamino cobalt-(II) (2 mg, 3.3 ꢁ 10ꢀ3
mmol) in PhMe (1 mL) was added a solution of 25% AcOH in PhMe
4.6. Synthesis of epoxides 2a–e: general procedure
(20 lL) and stirred under air for 1 h. The solvent was removed with
nitrogen and the dark brown residue was dried under vacuum and
used directly in the kinetic resolution.
4.6.1. (RS)-Ethyl 2,2-dibenzyl-3,4-epoxybutanoate 2e
To a stirred solution of bromoketone 7e (1 g, 2.6 mmol) in EtOH
(12 mL) at room temperature was added in portions NaBH4
(0.097 g, 2.7 mmol). After 3 h, the solvent was removed and to
the crude was added HCl 5% until pH 7. The aqueous layer was ex-
tracted with AcOEt (5 ꢁ 30 mL) and the combined organic layer
was dried over Na2SO4, filtered and concentrated in vacuo. The res-
idue was used without purification in the next reaction; to it was
added MeOH (5 mL), K2CO3 (3.0 mmol) and stirred overnight. The
mixture reaction was quenched with HCl 5% until pH 7, extracted
with AcOEt (5 ꢁ 30 mL) and the combined organic layer was dried
over Na2SO4, filtered and concentrated in vacuo. The crude was
purified (SiO2, AcOEt/n-hexanes, 1:2) to afford 2e (0.63 g, 89%) as
an oil: 1H NMR (CDCl3) 1.20 (t, J = 7.1 Hz, 3H), 2.76 (dd, J = 4.3,
4.3 Hz, 1H), 2.89 (dd, J = 4.3, 4.3 Hz, 1H), 2.92 (m, 2H), 2.10 (m,
3H), 4.13 (q, J = 7.1 Hz, 2H), 7.24 (m, 10H); 13C NMR (CDCl3) 14.4,
39.8, 40.5, 45.7, 51.3, 54.8, 61.2, 127.0, 127.1, 128.5, 130.8, 130.9,
137.1, 137.2, 173.5; EIMS (EIS), m/z calcd for C20H22O3 310.1569,
found 310.1347.
4.7.2. (S)-Ethyl 2,2-dimethyl-3,4-epoxybutanoate (S)-2a
To the active catalyst prepared previously were added the race-
mic epoxide 2a (0.260 g, 1.64 mmol) and H2O (16 lL, 0.93 mmol)
and stirred at rt for 21 h. The reaction mixture was purified by flash
chromatography (AcOEt/hexanes; 1:9) to give the epoxide S-2a
(129 mg, 45%), ½a D23
¼ þ16:1 (c 0.98, CH2Cl2), ee >99%. Spectro-
ꢂ
scopic data were identical with those of the racemate 2a. Enantio-
meric excess was determined by GLC, the oven temperature
programme was ramped from 60 °C, 5 min, 2 °C/min to 75 °C, held
for 20 min, 5 °C/min to 150 °C, held for 15 min. The injector and
detector temperatures were 180 °C, the peaks were identified in
the following order: (S)-2a: tR = 44.7 min, (R)-2a: tR = 45.2 min.
4.7.3. (R)-Ethyl 2,2-dimethyl-3,4-epoxybutanoate (R)-2a
Prepared in 47% yield, 92% ee as a colourless oil analogous to the
route described for (S)-2a using 2% of (RR)-3. ½a D23
¼ ꢀ15:3 (c 1.01,
ꢂ
CH2Cl2).
4.6.2. (RS)-Ethyl 2,2-dimethyl-3,4-epoxybutanoate 2a
4.7.4. (S)-Ethyl, 2,2-cyclopropyl-3,4-epoxybutanoate (S)-2b
Prepared in 17% yield and 30% ee as a colourless oil analogous to
the route described for (S)-2a using 1% of (SS)-3. % Ee was
Prepared in 88% yield as a colourless oil analogous to the route
described for 2e. 1H NMR (CDCl3) 1.12 (s, 3H), 1.20 (s, 3H), 1.29 (t,

I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635
635
determined using the same method as for (S)-2a, the peaks were
identified in the following order: (S)-2b: tR = 32.8 min, (R)-2b:
tR = 33.2 min.
4.7.9. (R)-Ethyl 2,2-diethyl-3,4-epoxybutanoate (R)-2d
Prepared in 48% yield and 98% ee as a colourless oil analogous to
the route described for (S)-2a using 2% of (RR)-3. ½a D22
¼ ꢀ58:1 (c
ꢂ
0.5 1, CH2Cl2).
4.7.5. (R)-Ethyl, 2,2-cyclopropyl-3,4-epoxybutanoate (R)-2b
Prepared in 20% yield and 25% ee as a colourless oil analogous to
the route described for (S)-2a using 1% of (RR)-3. Spectroscopic
data were identical with those of the racemate 2b.
Acknowledgements
This research was supported by grant from Fondo Clemente
Estable FCE9002. We thank Prof. Sonia Rodríguez for chiral GLC
facilities. We appreciate greatly Prof. G. Moyna for valuable sugges-
tions to this paper.
4.7.6. (S)-Ethyl, 2,2-cyclopentyl-3,4-epoxybutanoate (S)-2c
Prepared in 47% yield and 95% ee as a colourless oil analogous to
the route described for (S)-2a using 2% of (SS)-3. Spectroscopic data
were identical with those of the racemate 2c; ee was determined
using the same method as for (S)-2a, the peaks were identified in
the following order: (S)-2c: tR = 41.5 min, (R)-2c: tR = 42.2 min;
References
1. Mahler, G.; Serra, G.; Domínguez, L.; Saldana, J.; Dematteis, S.; Manta, E. Bioorg.
Med. Chem. Lett. 2006, 16, 1309–1311.
2. (a) Smith, J. G. Synthesis 1984, 629; (b) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G.
Tetrahedron 1983, 39, 2323.
½
a 2D3
ꢂ
¼ þ1:8 (c 1.02, CH2Cl2).
3. Larchêveque, M.; Henrot, S. Tetrahedron 1990, 46, 4277.
4. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936.
5. For a review of this field see: Kumar, P.; Naidu, V.; Gupta, P. Tetrahedron 2007,
63, 2745–2785.
6. Chow, S.; Kitching, W. Tetrahedron: Asymmetry 2002, 13, 779.
7. Kolb, H.; VanNieuwenhze, V.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
8. Muthusamy, S.; Gnanaprakasam, B. Tetrahedron Lett. 2005, 46, 635–638.
9. Rauhala, V.; Nättinen, K.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005,
4119–4126.
4.7.7. (R)-Ethyl, 2,2-cyclopentyl-3,4-epoxybutanoate (R)-2c
Prepared in 45% yield and 99% ee as a colourless oil analogous to
the route described for (S)-2a using 2% of (RR)-3. % Ee was
determined using the same method as for (S)-2a, the peaks were
identified in the following order: (S)-2c: tR = 41.5 min, (R)-2c:
tR = 42.2 min; ½a 2D3
¼ ꢀ2:1 (c 1.05, CH2Cl2).
ꢂ
10. The absolute configuration is based on the accepted mnemonic for the
Jacobsen’s HKR: Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K.; Gould, A.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
1307–1315.
11. Hayashi, Y.; Orikasa, S.; Tanaka, K.; Kanoh, K.; Kiso, Y. J. Org. Chem. 2000, 65,
8402.
12. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.
S.; Kwong, H.; Morikawa, K.; Wang, Z. M. J. Org. Chem. 1992, 57, 2768.
13. Savle, P. S.; Lamoreaux, M. J.; Berry, J. F.; Gandour, R. D. Tetrahedron: Asymmetry
1998, 9, 1843–1846.
4.7.8. (S)-Ethyl 2,2-diethyl-3,4-epoxybutanoate (S)-2d
Prepared in 48% yield and 95% ee as a colourless oil analogous to
the route described for (S)-2a using 2% of (SS)-3. Spectroscopic data
were identical with those of the racemate 2c; ee was determined
using the same method as for (S)-2a, the peaks were identified in
the following order: (S)-2d: tR = 47.5 min, (R)-2d: tR = 48.4,
½
a 2D3
ꢂ
¼ þ61:0 (c 0.22, CH2Cl2).