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

Tetrahedron: Asymmetry 21 (2010) 631–635

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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: Received 12 March 2010 Accepted 31 March 2010 Available online 27 April 2010

Novel a,a-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 b,c-epoxy esters 2a, 2c and 2d. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction

R

As part of our efforts in the synthesis of new bioactive compounds based on simplifications of the natural product mycothiazole 1 (Fig. 1)1 we were interested in the development of a general and scalable procedure for the preparation of enantiopure a,a-disubstituted epoxy esters 2, as building blocks for these analogues.

N 1

OH

OH

O ADH

OEt

O β-hydroxybutanolide

R

R

a) O

O

EtO R R (R)-2epoxiester

O

S N H O

R

O

OMe

HKR

R R S-2 Figure 1. ()-Mycothiazole 1 and a,a-disubstituted b,c-epoxy ester (S)-2.

Epoxides are versatile building blocks that have been extensively used in the synthesis of complex organic compounds. Most of the methods available for their preparation include the oxidation of alkenes with peracids or the cyclization of the corresponding 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 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 cyclization of the resulting iodohydrines with silver oxide (Scheme 1, route a).3 However, no general and convenient methods are available for their preparation. * Corresponding author. Tel.: +598 2 9290290; fax: +598 2 9241906. E-mail address: [email protected] (G. Mahler). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.03.036

OH

O

O

EtO

b) O

EtO R

R

Br

O

OEt R R bromohydrine

Scheme 1. Retrosynthetic epoxy ester 2 approach.

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 enantiomerically pure form.4 This methodology employs water as the only reagent, 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 complex 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 chiral a,a-disubstituted epoxides 2, by exploring two alternatives: (a) asymmetric synthesis of enantiopure b-hydroxybutanolides

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I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635

O H N O

H H2O

O

O i)

EtO

N

EtO

ii); iii); iv)

EtO 5 Et

O Et

O

(S,S)-3

Me3SiI, Ag2O

6

OH

Et

O O EtO Et

(S)-2d

25% ee

followed by ring opening and (b) HKR using catalytic chiral salenCo(III) of racemic epoxides 2 prepared from bromohydrins (Scheme 1, route b).

v)

Et

Et Figure 2. SalenCo(III).

Et 4d

Et

O

Co O OAc

O

Scheme 2. Reagents and conditions: (i) K2CO3, Bu4N+I, 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.

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 by a-bromination of ketones 4a–e in yields ranging from 66% to 80%. Reduction of the resulting bromoketones 7a–e with NaBH4 followed by cyclization of the corresponding bromohydrins in basic 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 dimethyl, cyclopentyl and diethyl substituents, underwent resolution 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 resolution were achieved (Table 1, entries 3 and 4). This can be attributed to the instability of 2b, which decomposed into a complex mixture of products under HKR conditions. When we attempted HKR on a,a-dibenzyl epoxide 2e, no resolution was observed and the recovered starting material had a very low ee, even when we increased the amount of catalyst to 5% and the reaction time to

As shown in Scheme 2, we initially attempted to prepare a b,cepoxy ester using the Sharpless asymmetric dihydoxylation (ADH) reaction.7 Ethyl acetoacetate was dialkylated with ethyl bromide to give the a,a-disubstituted ketone 4d, using Bu4N+I as a phase transfer catalyst.8 Olefin 5 was prepared by the reduction of ketone 4d followed by tosylation of the corresponding alcohol and elimination (44% overall yield). Oxidation of alkene 5 under ADH conditions took place in low yield and poor stereoselectivity to give bhydroxybutanolide 6 (35%, 25% ee). It is important to note that according to literature reports terminal olefins can sometimes react 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,adisubstituted 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 analogues.1 Therefore, racemic a,a-disubstituted epoxides were synthesized by the sequence shown in Scheme 3. Dialkylation of

O

O

O

O ii)

i)

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

O

EtO R

O

iii)

Br R

O

EtO

iv)

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; 2c (83%) R = (CH2)4, 2d (88%), R = Et; 7e (80%), R = Bn 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 1-2% (S,S)-3

O

O

EtO

H2O (0.5 eq)

R R (RS)-2

O 1-2% (R,R)-3 H2O (0.5 eq)

+

R R S-2

EtO

O

O

R R R-2

Scheme 4. HKR of epoxide 2.

OH

EtO R O

O

EtO

+

OH R OH OH

EtO R

R

I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635

carrier gas He, provided with capillary column on tert-butyldimethylsilyl b-cyclodextrin PS086.

Table 1 Hydrolytic kinetic resolution of substrates 2a–e

a

Entry

Substrate

R

Catalyst

1 2 3 4 5 6 7 8 9 10

2a 2a 2b 2b 2c 2c 2d 2d 2e 2e

Me Me (CH2)2 (CH2)2 (CH2)4 (CH2)4 Et Et Bn Bn

2%, 2%, 1%, 1%, 2%, 2%, 2%, 2%, 5%, 5%,

(S,S)-3 (R,R)-3 (S,S)-3 (S,S)-3 (S,S)-3 (R,R)-3 (S,S)-3 (R,R)-3 (S,S)-3 (R,R)-3

633

Time (h) 21 21 24 24 24 24 24 24 72 72

% eea

Yield %

>99 92 30 25 95 >99 95 98 5 4

45 47 17 20 47 45 48 48 65 70

The ee % was determined by chiral GLC.

72 h (Table 1, entry 10). It is likely that the bulky benzyl groups at the a-position prevent the approach of the catalysts, leading to 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 epoxides (2c and 2e, respectively) HKR provided a practical, cost-effective and efficient route for the preparation of enantiopure epoxides 2a, 2c and 2d.

3. Conclusions

4.2. Synthesis of a,a-alkylacetoacetates 4a–e: general procedure 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 vacuo. 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. 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).

In conclusion, we have explored the preparation of enantiopure

a,a-disubstituted epoxy esters using either Sharpless ADH or HKR 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.

4.2.4. 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); 13 C NMR (CDCl3) 14.4, 26.1, 26.8, 33.4, 61.7, 67.3, 173.9, 204.4.

4. Experimental part

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).

4.1. General methods

4.3. Ethyl 2,2-diethyl-3-butenoate 511

The reactions were monitored by analytical thin layer chromatography 0.25 mm silica gel plastic sheets (Macherey-Nagel, PolygramÒ SIL G/UV 254). Flash chromatography on Silica Gel 60 (J. T. 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, multiplicity, coupling constant and integration. IR spectra were obtained on a Perkin Elmer 1310 and FTIR 8101A Shimadzu spectrometer, unit cm1. High-resolution mass spectra were measured on VG AutoSpect spectrometer (EIS mode). Melting points were determined 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 conditions unless otherwise stated. Yields are reported for chromatographic 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),

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. 4.4. (RS)-2,2-Diethyl-3-hydroxybutanolide 612 To a mixture of AD-mix-a (833 mg) in 6 mL tBuOH/H2O (1:1) cooled at 0 °C was added compound 5 (0.10 g, 0.59 mmol) and stirred 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/hexane; 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.

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4.5. Synthesis of bromoketones 7a–e: general procedure 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 mixture was extracted with Et2O (200 mL  4) and the combined organic 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. 4.5.2. 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. 4.5.4. 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 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. 4.6. Synthesis of epoxides 2a–e: general procedure 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 extracted with AcOEt (5  30 mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue 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. 4.6.2. (RS)-Ethyl 2,2-dimethyl-3,4-epoxybutanoate 2a 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,

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. 4.6.3. (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. 4.6.5. (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. 4.7. Hydrolytic kinetic resolution of ethyl 2,2-dimethyl-3,4epoxybutanoate 2a13 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-butylsalicylidene)-1,2-cyclohexane-diamino cobalt-(II) (2 mg, 3.3  103 mmol) in PhMe (1 mL) was added a solution of 25% AcOH in PhMe (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. 4.7.2. (S)-Ethyl 2,2-dimethyl-3,4-epoxybutanoate (S)-2a To the active catalyst prepared previously were added the racemic 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%), ½a23 D ¼ þ16:1 (c 0.98, CH2Cl2), ee >99%. Spectroscopic data were identical with those of the racemate 2a. Enantiomeric 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. ½a23 D ¼ 15:3 (c 1.01, CH2Cl2). 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

I. Viera et al. / Tetrahedron: Asymmetry 21 (2010) 631–635

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. 4.7.5. (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. 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; ½a23 D ¼ þ1:8 (c 1.02, CH2Cl2). 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; ½a23 D ¼ 2:1 (c 1.05, CH2Cl2). 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, ½a23 D ¼ þ61:0 (c 0.22, CH2Cl2).

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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. ½a22 D ¼ 58:1 (c 0.5 1, CH2Cl2). 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 suggestions to this paper. 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. 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. 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.