guidelines for epoxidation

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Guidelines for Asymmetric Epoxidation

Prepared by O. Andrea Wong 2009

For reviews on chiral ketone-catalyzed asymmetric epoxidation, see: (a) Wong, O.A.;

Shi, Y. Chem. Rev. 2008, 108, 3958. (b) Shi, Y. Acc. Chem. Res. 2004, 37 , 488.

I. Catalyst Selection

1a. Substrate Scope of Ketone 1

O

OO

OO

O

1

PhPh

O

85% yield98% ee

C6H13

C6H13

89% yield95% ee

O

Ph

O

94% yield96% ee

trans-olefins

PhPh

O

54% yield97% ee

PhO

Ph

94% yield98% ee

C10H21

O

94% yield89% ee

trisubstituted olefins

Ph

O

OH

85% yield94% ee

Ph

O

90% yield91% ee

OH

hydroxyalkenes

O

82% yield90% ee

OH

Ph

TMSO

74% yield94% ee

TMSO

51% yield90% ee

2,2-disubstituted vinylsilanes

HO TMS

O

71% yield93% ee

Ph

O

77% yield97% ee

Ph

conjugated dienes and enynes

O

78% yield93% ee

O

82% yield95% ee

OEt

OBzOO

Ph

OAcO

82% yield93% ee

66% yield91% ee

enol esters

BzOO

87% yield91% ee

Trans- and trisubstituted olefins: Wang, Z-X.; Tu, Y.; Frohn, M.; Zhang, J-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.

Enol esters: (a) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819. (b)Zhu, Y.; Manske, K.J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 4080. (c) Feng, X.; Shu, L.;Shi, Y. J. Am. Chem. Soc. 1999, 121, 11002. (d) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org.

Chem. 2001, 66 , 1818.

Hydroxyalkenes: Wang, Z-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.



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2,2-Disubstituted vinyl silanes: Warren, J.D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.

Conjugated Dienes: Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z-X.; Shi, Y. J. Org.

Chem. 1998, 63, 2948.

Conjugated Enynes: (a) Cao, G-A.; Wang, Z-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. (b) Wang, Z-X.; Cao, G-A; Shi, Y. J. Org. Chem. 1999, 64, 7646.

1b. Synthesis of Ketone 1 and ent-1

O

OO

OO

O

O

HOOH

OHOH

OH

O

OO

OO

OH

O

D-Fructose1

H+

[O]

Tu, Y.; Frohn, M.; Wang, Z-X.; Shi, Y. Org. Synth. 2003, 80, 1.

OOH

HO OH

OH

OH OMe

OMe

DME, SnCl2

O OO

O

O OH

MsCl, py O OO

O

O OMs

1) H2SO4, rt2) NaOH

3) NaOH, 90-100 oC

4) H2SO4, 70-80o

C

O

HOOH

OHOH

OH

L-Fructose

O

OO

OO

O

O

OO

OO

OH

O

ent- 1

H+

[O]

L-Sorbose

Zhao, M-X.; Shi, Y. J. Org. Chem. 2006, 71, 5377.

1c. Commercial Sources of Ketone 1 (CAS #18422-53-2)

a. Alfar Aesar (1 g, 5 g) b. Aldrich (5g)



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1d. Representative Epoxidation Procedure (small-scale, Oxone/K 2CO3 , see Figures 1

and 2)

trans-β-Methylstyrene (0.118 g, 1 mmol) was dissolved in acetonitrile-DMM (15 mL, 1:2

v/v). Buffer (10 mL, 0.05 M solution of Na2B4O7·10H2O in 4 x 10-4 M aqueous

Na2EDTA, tetrabutylammonium hydrogen sulfate (15 mg, 0.04 mmol), and ketone 1

(0.0774 g, 0.3 mmol) were added with stirring. The mixture was cooled to about –10 oC

(inside) (bath temperature was about –12 to –15 oC) using an NaCl-ice bath. A solution

of Oxone (0.85 g, 1.38 mmol) in aqueous Na2EDTA (4 x 10-4, 6.5 mL) and a solution of

K 2CO3 (0.8 g, 5.8 mmol) in water (6.5 mL) were added dropwise separately over a period

of 2 h (via syringe pump). At this point, the reaction was immediately quenched by the

addition of pentane and water. The mixture was extracted with pentane (3 x 30 mL),

washed with brine, dried over Na2SO4, purified by flash column chromatography [thesilica gel was buffered with 1% Et3 N in pentane; pentane-ether (1:0 to 50:1 v/v) was used

as eluent] to afford trans-β-methylstyrene oxide as a colorless liquid (0.126 g, 94% yield,

95.5% ee). Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc.

1997, 119, 11224. See Section VI for general tips and troubleshooting information.

Note:

(a) 0.05 M Na2B4O7·10H2O solution can be replaced by K 2CO3-AcOH (pH = 9.3)

buffer, see Section III for buffer preparation procedures. References: (a) Cao, G-

A.; Wang, Z-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. (b) Wang, Z-

X.; Cao, G-A; Shi, Y. J. Org. Chem. 1999, 64, 7646.

Additional references: (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.

Chem. Soc. 1997, 119, 11224. (b) Warren, J.D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.(c) Wang, Z-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099. (d) Frohn, M.; Dalkiewicz, M.;Tu, Y.; Wang, Z-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. (e) Wang, Z-X.; Cao, G-A;

Shi, Y. J. Org. Chem. 1999, 64, 7646. (f) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem.2001, 66 , 1818.



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with 1 M aqueous Na2S2O3 and brine, dried (Na2SO4), filtered, concentrated, and purified

by chromatography (silica gel was buffered with 1% Et3 N in hexanes, using

hexanes/ether 50/1 as eluent) to afford trans-stilbene oxide as a white solid (0.151 g, 77

% yield, 99% ee). Shu, L.; Shi, Y. Tetrahedron 2001, 57 , 5213. See Section VI for

general tips and troubleshooting information.

Note:

(a) Vigorous stirring is crucial for epoxidation efficiency in the H2O2 epoxidation,

particularly for less reactive (i.e. nonpolar) substrates.

(b) Mixed solvent systems such as MeCN-EtOH-DCM, MeCN-nPrOH-DCM,

MeCN-nPrOH-PhCH3, and MeCN-nPrOH-PhH are beneficial for olefins with

poor solubility.

(c) The quality of H2O2 is important. Old or contaminated H2O2 cannot providemaximum conversion.

Additional references: (a) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721. (b) Shu, L.;Shi, Y. Tetrahedron 2001, 57 , 5213. (c) Wang, Z-X.; Shu, L.; Frohn, M.; Tu, Y.; Shi, Y.Org. Synth. 2003, 80, 9.

1g. Examples of Synthetic Applications of Ketone 1

OMe

OMe

O O

Ketone 1

OMe

OMe

O O

OH

OMe

OMe

N O

(-)-Mesembrine

Oxone

OMe

OMe

O O

OMgCl

73% two steps

96% ee

H

Taber, D.F.; He, Y. J. Org. Chem. 2005, 70, 7711.



6

OH O

O

Ph

HOH

1) Ketone 1Oxone

2) Nicotinic acidDCC, DMAP

O O

O

Ph

HO

O

N

O

ON

(+)-Nigellamine A2

51% two steps

Bian, J.; Van Wingerden, M.; Ready, J.M. J. Am. Chem. Soc. 2006, 128, 7428.

OMe

MeH

MeMe

TMSO

H

H

ent -Abudinol

O

HHO

MeMe H

Me

OMeH

ent -Nakorone

Me Me

Me

Me

SO2Tol

TMS Me Me

Me

Me

SO2Tol

TMS

O OKetone 1

Oxone76%

OMe

MeH

MeMe

HO

H

H OH

MeH

OH

MeMe

>20:1 dr

Tong, R.; Valentine, J.C.; McDonald, F.E.; Cao, R.; Fang, X.; Hardcastle, K.I. J. Am.

Chem. Soc. 2007, 129, 1050.



7

OH

HOOH

OH OH

HOOH

OH

O O

O OKetone 1

Oxone

O

O O

OO

OHOH

HMe

HMe

H

HMe

HMe

H

3 steps

Glabrescol

66%

(a) Corey, E.J.; Xiong, Z. J. Am. Chem. Soc. 2000, 122, 4831. (b) Corey, E.J.; Xiong, Z. J. Am. Chem. Soc. 2000, 122, 9328.

H H

HH

H Me

Me H

Me

O

H H

HH

H Me

Me

O

H

Me

O O O O1) BF3

.OEt2

2) Ac2Opyridine O

O

O

O

O

O

H H MeMe

OAcH

Me

Me H H

Ketone 1

O

O

Me2N

O

Me2N

OxoneH H

HH

H Me

Me H

MeHO

1) SharplessEpoxidation

2) n-BuLiMe2NC(O)Cl

(a) McDonald, F.E.; Wang, X.; Do, B.; Hardcastle, K.I. Org. Lett. 2000, 2, 2917. (b)McDonald, F.E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh, M.; Rodríguez, J.R.; Do, B.; Neiwert, W.A.; Hardcastle, K.I. J. Org. Chem. 2002, 67 , 2515. (c) Bravo, F.; McDonald,F.E.; Neiwert, W.A.; Do, B.; Hardcastle, K.I. Org. Lett. 2003, 5, 2123. (d) Valentine,J.C.; McDonald, F.E.; Neiwert, W.A.; Hardcastle, K.I. J. Am. Chem. Soc. 2005, 127 ,4586.



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O

TBSOH

H

O

O

O

H HH

H HH

MeKetone 1

Oxone O

TBSOH

H

MeO

O

O

OMe

HOH

H

TBAF

THF

H2O

70 oC, 72 h

71%O

HO H

H

MeO

O

O

Vilotijevic, I.; Jamison, T.F. Science 2007, 317 , 1189.


Ph

O

92% yield81% ee

OCl

74% yield83% ee

O

90% yield85% ee

ClPh

O

78% yield95% ee

styrenes trisubstituted olefins

PhO

55% yield80% ee

Ph

O

87% yield91% ee

O

76% yield92% ee

O

74% yield92% ee

F

O

88% yield83% ee 88% yield

84% ee

O

O

NCO

61% yield91% ee

conjugated cis-olefins

O

Ph

O

nC6H13

82% yield91% ee

77% yield87% ee

O

O

OO

O

O

O

O

O

61% yield97% ee

47% yield96% ee

88% yield94% ee

unconjugated olefins

F

OO

73% yield86% ee

O

61% yield81% ee

Cl

n-C5H11

O

O

O

76% yield92% ee

O

93% yield71% ee

n-C6H13

MeO

O

79% yield61% ee

71% yield85% ee

Me

OO

O

OO

NBocO

O

O

2



9

Styrenes: (a) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. (b) Tian, H.;She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67 , 2435.

Trisubstituted, conjugated cis-olefins, unconjugated olefins: (a) Tian, H.; She, X.;Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551. (b) Tian, H.; She, X.; Yu,

H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67 , 2435. (c) Burke, C.P.; Shi, Y. Org. Lett.2009, 11, 5150.

2b. Synthesis of Ketone 2

O

OH

OH

HO OH

OH

D-glucose

O

OH

HO OH

OHNBn2

(MeO)3CH

CH3COCH3

HCl

O

OH

OHNBn2

OO

H2, Pd/C

HOAc

O

OH

OHNH3OAc

OO

COCl2

NaHCO3

O

O

O

NBocO

O

O

O

OO

NHO

OH

O

PDC

Bn2NH

HOAc

(Boc)2O

DMAP

O

OO

NBocO

OH

O

Shu, L.; Shen, Y.M.; Burke, C.; Goeddel, D.; Shi, Y. J. Org. Chem. 2003, 68, 4963.

2c. Representative Epoxidation Procedure (small-scale, Oxone/K 2CO3 , see Figures 1

and 2)

To a solution of cis-β-methylstyrene (0.059 g, 0.5 mmol) and ketone 2 (0.026 g, 0.075

mmol) in DME-DMM (3:1, v/v) (7.5 mL) were added buffer (0.2 M K 2CO3-AcOH in 4 x

10-4

M aqueous Na2EDTA, buffer pH = 8.0) (5 mL) and Bu4 NHSO4 (0.0075 g, 0.02mmol) with stirring. After the mixture was cooled to about –10 oC (bath temperature)

using an NaCl-ice bath, a solution of Oxone (0.21 M in 4 x 10 –4 M aqueous Na2EDTA,

4.2 mL) (0.548 g 0.89 mmol) and K 2CO3 (0.48 M in 4 x 10-4 M aqueous Na2EDTA, 4.2

mL) (0.278 g, 2.01 mmol) were added dropwise separately over a period of 3.5 h via

syringe pump. The reaction was then quenched with the addition of pentane and



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extracted with pentane. The combined organic layers were washed with brine, dried

(Na2SO4), filtered, concentrated, and purified by flash chromatography [the silica gel was

buffered with 1% Et3 N in pentane; pentane-ether (1/0 to 50/1) was used as eluent] to give

cis-β-methylstyrene oxide as a colorless liquid (0.058 g, 87% yield, 91% ee). Tian, H.;

She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551. See Section VI for

general tips and troubleshooting information.

Additional references: (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc.

2000, 122, 11551. (b) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. (c)Tian, H., She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67 , 2435.



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3a. Substrate Scope of Ketones 3

Ph

O

99% conv.84% ee

cis- β ββ β -methylstyrenes

O

100% conv.88% ee

Me

O

94% conv.96% ee

NC

2,2-dimethylchromenes

O

O

O

ONC

100% conv.84% ee

83% conv.93% ee

O

O

95% conv.88% ee

CN

O

72%yield86% ee

styrenes

O

86%yield90% ee

NC

benzylidenecyclobutanes and 2-aryl-cyclopentanones

48% yield91% ee

H

O

O

H

Ar via

O

benzylidenecyclopropanes

54% yield87% ee

Me

O

O

Me

Ar viaO

CO2EtO

O

CO2Et

74% yield94% ee

64% yield94% ee

cis-dienes and trienes

PhO

66% yield85% ee

O

78% yield93% ee

Ph

O

Ph76% yield93% ee

cis-enynesO

O

O

O

54% yield87% ee

unconjugated olefins

O

nHex

OH

89% yield82% ee

O

nHex

HO

71% yield79% ee

O

OH

n-C5H11

O

75% yield91% ee

O

OO

NO

O

O

R

3a = Me3b = Et3c = nBu

Ph

OR O

R

Ph

Et2AlCl

R=H, 93% (90% ee)R=Me, 94% (84% ee)

R=H, 90% (90% ee)R=Me, 93% (84% ee)

O

82% conv.93% ee

Br

O

nHex

52% yield64% ee

O

OCl

100% conv.93% ee

cis-β-Methylstyrenes: Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115.

Unconjugated Olefins: Burke, C.P.; Shi, Y. Org. Lett. 2009, 11, 5150.

2,2-Dimethylchromenes: Wong, O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973.

Styrenes: Goeddel, D.; Shu, L.; Yuan, Y.; Wong, O. A.; Wang, B.; Shi, Y. J. Org. Chem.

2006, 71, 1715.



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Benzylidenecyclobutanes and 2-Aryl-Cyclopentanones: (a) Shen, Y.-M.; Wang, B.;Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 1429. (b) Shen, Y.-M.; Wang, B.; Shi, Y.Tetrahedron Lett. 2006, 47 , 5455.

Benzylidenecyclopropanes: Wang, B.; Shen, Y.-M.; Shi, Y. J. Org. Chem. 2006, 71,9519.

cis-Enynes: Burke, C. P.; Shi, Y. J. Org. Chem. 2007, 72, 4093.

cis-Dienes and Trienes: Burke, C. P.; Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 4475.

3b. Synthesis of Ketones 3

O OHOH

OH

HO OH

1) ArNH2

HOAc

2) CH(OMe)3acetoneH2SO4

D-Glucose

OOH

OHOO

NHAr 1) COCl2

2) PDC

O NO

O

O

O

O

3

R

(a) Goeddel, D.; Shu, L.; Yuan, Y.; Wong, O.A.; Wang, B.; Shi, Y. J. Org. Chem. 2006,71, 1715. (b) Zhao, M-X.; Goeddel, D.; Li, K.; Shi, Y. Tetrahedron 2006, 62, 8064.

3c. Commercial Sources of Ketone 3a (CAS #403501-30-4)

Aldrich (100 mg, 500 mg)

3d. Representative Epoxidation Procedure (small-scale, Oxone/K 2CO3 , see Figures 1

and 2)

To a mixture of 2,2-dimethylchromene (0.4 mmol), Bu4 NHSO4 (0.001 g, 0.003 mmol),

and ketone 3b (0.028 g, 0.08 mmol) was added DME/DMM (v/v 3:1) (6.0 mL). After the

mixture was stirred at rt for 20 min, buffer (0.1 M K 2CO3-AcOH in 4 x 10-4 M aqueous

Na2EDTA, pH 9.3) (4.0 mL) was added. After being stirred at rt for 10 additional min,

the mixture was cooled using an ice bath (0 °C). Oxone (5.04 mL, 0.212 M in 4 x 10-4 M

aqueous Na2EDTA) and K 2CO3 (5.04 mL, 0.84 M in 4 x 10-4 M aqueous Na2EDTA)

were added simultaneously and separately via syringe pump over 6 hours. The reaction

was quenched by the addition of diethyl ether and extracted with diethyl ether. The



13

combined organic layers were washed with brine, dried over Na2SO4, filtered,

concentrated, and purified by flash chromatography (silica gel was buffered with 1%

NEt3) to afford the corresponding epoxide. Wong, O.A.; Shi, Y. J. Org. Chem. 2006, 71,

3973. See Section VI for general tips and troubleshooting information.

3e. Representative Epoxidation Procedure (MeCN/H 2O2 , see Figure 6)

A mixture of 2-methyl-1-phenyl-1-propene (0.135 g, 1.00 mmol) and ketone 3b (0.051

g, 0.15 mmol) in n-BuOH (3.0 mL) was cooled to 0 °C with an ice bath. CH3CN (0.20

mL, 3.8 mmol) and 0.30 M K 2CO3 in 4 x 10-4 M aqueous Na2EDTA (3.0 mL) were then

added, followed by H2O2 (30%, 0.30 mL, 3.0 mmol) with vigorous stirring at 0 °C. The

mixture was stirred at 0 °C for 24 h and was then poured into petroleum ether andextracted with petroleum ether. The combined organic layers were washed with water

and saturated aqueous Na2S2O3, dried (Na2SO4), filtered, concentrated, and purified by

flash chromatography (silica gel was buffered with 1% Et3 N in petroleum ether;

petroleum ether was used as eluent) to give 2,2-dimethyl-3-phenyloxirane as a colorless

oil (0.121 g, 82% yield, 92% ee). Burke, C.P.; Shu, L.; Shi, Y. J. Org. Chem. 2007, 72,

6320. See Section VI for general tips and troubleshooting information.

Notes:

a) The quality of the ketone catalyst is very important when H2O2 is used as the

oxidant. For example, it was observed that lower conversions were obtained with

the ketones 3a-c prepared from the TEMPO-bleach oxidation of the alcohol

precursor. It appears that some residual impurities from TEMPO-bleach

oxidation somehow affect the epoxidation.

b) Vigorous stirring is crucial for epoxidation efficiency in the H2O2 epoxidation,

particularly for less reactive (i.e. nonpolar) substrates.

c) The quality of H2O2 is important. Old or contaminated H2O2 cannot providemaximum conversion.



14


O OO

AcO O

AcO 4

OOBz

97% yield95% ee

O

PhPh

63% yield93% ee

78% yield86% ee

NO

nBu

O

O

trans and trisubstituted olefins

Ph

O

TBS

60% yield90% ee

Ph

O

OTBS

62% yield70% ee

O

O

O

ONC

75% yield88% ee

73% conv.90% ee

cis-olefins

95% yield75% ee

NO

nBu

O

O

PhCO2Et

O

73% yield96% ee

CO2EtO

MeO57% yield90% ee

PhCO2Et

O

93% yield96% ee

O

CO2Et

CO2Et

O

Ph

CO2Et

O

77% yield93% ee

96% yield94% ee

64% yield82% ee

αααα,ββββ-unsaturated esters fluoroolefins

Ph

O

86% yield91% ee

60% yield90% ee

Ph

O

68% yield92% ee

Ph

F

F

Ph

OF

n-Bu

O

77% yield91% ee

n-Bu

F

trans, cis, and Trisubstituted Olefins: Wang, B.; Wu, X.-Y.; Wong, O.A.; Nettles, B.;Zhao, M.-X.; Chen, D.; Shi, Y. J. Org. Chem. 2009, 74, 3986.

α,β-Unsaturated Esters: Wu, X-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124,

8792.

Fluoroolefins: Wong, O.A.; Shi, Y. J. Org. Chem., 2009, 74, 8377-8380



15

4b. Synthesis of Ketone 4 (hydrate of ketone 4, 4 • •• • H 2O, can be used in place of ketone 4)

O OO

AcO OAcO

4

O

OO

OO

O

1

DDQ, MeCN/H2O

H2O, Ac2O

Ac2O, DMAPO O

O

HO OOH

O OO

AcOOH

AcO4.H2O

O

OO

OO

O

1

AcOH, ZnCl2

H2O, Ac2O

OH

OR

Wang, B.; Wu, X.-Y.; Wong, O.A.; Nettles, B.; Zhao, M.-X.; Chen, D.; Shi, Y. J. Org.Chem. 2009, 74, 3986.


and 2)

To a solution of trans-β-methylstyrene (0.059 g, 0.5 mmol), ketone 4·H2O (0.015 g,

0.046 mmol), and tetrabutylammonium hydrogen sulfate (0.01 g, 0.03 mmol) in MeCN-

DMM (v/v, 1/2) (9 mL) was added buffer (0.05 M aq Na2HPO4-0.05 M aq KH2PO4, pH

7.0) (3 mL) with stirring. Upon cooling to 0 oC, a solution of Oxone (0.212 M in 4 x 10-4

M aq Na2EDTA, 4.8 mL) and a solution of K 2CO3 (0.42 M in 4 x 10-4 M aq Na2EDTA,

4.8 mL) were added dropwise simultaneously and separately over 8 h via syringe pump.

The reaction was quenched by addition of pentane and extracted with pentane. The

combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by

flash chromatography (silica gel was buffered with 1% Et3 N in organic solvent, first

pentane, then pentane/Et2O = 20/1) to give the epoxide as a colorless oil (0.054 g, 81%

yield, 86% ee). Wang, B.; Wu, X.-Y.; Wong, O.A.; Nettles, B.; Zhao, M.-X.; Chen, D.;Shi, Y. J. Org. Chem. 2009, 74, 3986. See Section VI for general tips and

troubleshooting information.



16

4d. Representative Epoxidation Procedure (NaHCO3 /Oxone, see Figure 7)

Aqueous Na2(EDTA) (1×10-4 M, 2.5 mL) and a catalytic amount of tetrabutylammonium

hydrogen sulfate (0.010 g, 0.03 mmol) were added to a solution of ethyl trans-4-

methylcinnamate (0.095 g, 0.5 mmol) in CH3CN (2.5 mL) with vigorous stirring at 0 ˚C.

A mixture of Oxone (1.537 g, 2.5 mmol) and NaHCO3 (0.651 g, 7.75 mmol) was

pulverized, and a small portion of this mixture was added to the reaction mixture to bring

pH to >7.0. Then a solution of ketone 4 (0.038 g, 0.125 mmol) in CH3CN (1.25 mL) was

added. The remainder of the Oxone and NaHCO3 was added to the reaction mixture

portionwise over a period of 4.5 h. Upon stirring for an additional 7.5 h at 0 oC and 12 h

at rt, the resulting mixture was diluted with water, and extracted with ethyl acetate. The

combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and

purified by flash chromatography (silica gel, hexane/EtOAc = 1/0 to 95/5) to give the

epoxide as a colorless oil (0.094 g, 91% yield, 97% ee). Wu, X-Y.; She, X.; Shi, Y. J.

Am. Chem. Soc. 2002, 124, 8792. See Section VI for general tips and troubleshooting

information.



17


5

O

Ph

60% yield62% ee

O

Ph

62% yield77% ee

O

Ph

43% yield86% ee

OF

72% yield88% ee

OOH

Ph

93% yield77% ee

OOH

Ph

76% yield87% ee

Me Me

OOH

nC6H13

78% yield60% ee

Me Me

1,1-disubstituted olefins

Ph

O

60% yield85% ee

O

ONC

87% yield84% ee

O

Ph

89% yield80% ee

PhO

56% yield90% ee

cis-olefins

OOH

Ph

86% yield88% ee

O

OO

O

N

O

O

1,1-Disubstituted Olefins and cis-Olefins: Wang, B.; Wong, O.A.; Zhao, M.-X.; Shi, Y. J. Org. Chem. 2008, 73, 9539.



18

5b. Synthesis of Ketone 5

O OH

OH

OH

HO

OH

D-Glucose

p-Toluidine

H+

OOH

NHTol- p

OH

OH

HO

Me2C(OMe)2

acetoneH2SO4

O

Br Br

Et3N, NaH

OOH

O

O

NHTol- p

OH

OO

O

O

NTol- p

OH

O

OO

O

O

NTol- p

O

O

PDC

CH2Cl25

Wang, B.; Wong, O.A.; Zhao, M.-X.; Shi, Y. J. Org. Chem. 2008, 73, 9539.


and 2)

To a solution of α-methylstyrene (0.024 g, 0.20 mmol), tetrabutylammonium hydrogen

sulfate (0.0038 g, 0.010 mmol), and ketone 5 (0.0208 g, 0.06 mmol) in dioxane (3 mL)

was added buffer (0.1 M K 2CO3-AcOH in 4 x 10-4 M aqueous Na2EDTA, pH = 9.3; 2

mL) with stirring. After the mixture was cooled to -10 oC (bath temperature), a solution

of Oxone (0.20 M in 4 x 10-4 M aqueous Na2EDTA, 1.6 mL) (0.197 g, 0.32 mmol) and a

solution of K 2CO3 (0.84 M in 4 x 10-4 M aqueous Na2EDTA, 1.6 mL) (0.185 g, 1.344

mmol) were added separately and simultaneously via syringe pump over a period of 2 h.

The reaction mixture was quenched with hexane, extracted with EtOAc, dried over

Na2SO4, filtered, concentrated, and purified by flash chromatography (silica gel was

buffered with 1% Et3 N in organic solvent) to give α-methylstyrene oxide (60% yield,

62% ee). Wang, B.; Wong, O.A.; Zhao, M.-X.; Shi, Y. J. Org. Chem. 2008, 73, 9539.

See Section VI for general tips and troubleshooting information.



19

II. General Guidelines for Epoxidation Setup

Small-scale epoxidation set up (Figures 1 and 2)

Figure 1. Epoxidation using Oxone/K 2CO3 (syringe)

a) Fill with Oxone dissolved in 4x10-4

M aq. Na2EDTA b) Fill with K 2CO3 dissolved in 4x10-4 M aq. Na2EDTAc) Syringes are taped together for stability.d) Rubber tubing and plastic tip, do not use metal.e) Holes are spaced to prevent mixing at the tube tips and to

prevent the solutions from dripping down the side of theflasks where they freeze.

Figure 2. Epoxidation using Oxone/K 2CO3

a) Syringe pump. Oxone and K 2CO3 should be added at aconstant rate over the desired reaction time. Air at the tip of



20

the syringe should be pushed out to ensure thesimultaneous addition of Oxone and K 2CO3 as pH controlis important for the epoxidation reactions. It has beenfound that the oxidation activity of the purchased Oxoneoccasionally varies with different batches.

b) Reaction flask is suspended into Dewar with a clamp. Allglassware should be washed with soap to be free of anytrace metals, which catalyze the decomposition of Oxone.Cap should not be airtight.

c) Dewar flask. For –10 oC epoxidations, bath temperatureshould not be below –15 oC which will freeze the reaction.Low conversions will result from frozen reactions.

d) Stir plate. Stirring should be vigorous but withoutsplashing.

Large-scale epoxidation set up (Figures 3-5)

Figure 3. Epoxidation using Oxone/ K 2CO3

a) Fill with Oxone dissolved in 4x10-4 M aq. Na2EDTA b) Fill with K 2CO3 dissolved in 4x10-4 M aq. Na2EDTAc) Ice bath. For –10 oC epoxidations, bath temperature should

not be below –15 oC which will freeze the reaction. Lowconversions will result from frozen reactions.

d) Stir plate. Stirring should be vigorous but withoutsplashing.



21

Figure 4. Epoxidation using Oxone/ K 2CO3 or Oxone/ KOH

a) Fill with Oxone dissolved in 4x10-4 M aq. Na2EDTA b) Fill with KOH or K 2CO3 dissolved in 4x10-4 M aq.

Na2EDTAc) Ice bath. For –10 oC epoxidations, bath temperature should

not be below –15 oC which will freeze the reaction. Low

conversions will result from frozen reactions.d) Stir plate. Stirring should be vigorous but without

splashing.



22

Figure 5. Epoxidation using Oxone/ K 2CO3 or Oxone/ KOH (addition funnel)

a) Addition funnel equipped with needle stopcock is preferredfor precise addition-rate control.

Figure 6. Epoxidation using MeCN/H2O2

a) The ketones 3a-c used in the H2O2 epoxidation weresynthesized by the PDC oxidation. It was observed thatlower conversions were obtained with the ketones preparedfrom the TEMPO-bleach oxidation of the alcohol precursor. It appears that some residual impurities fromTEMPO-bleach oxidation somehow affect the epoxidation.



23

b) Vigorous stirring is crucial for epoxidation efficiency in theH2O2 epoxidation, particularly for less reactive (i.e.nonpolar) substrates.

c) For the H2O2 epoxidation with ketone 1, a mixed solventsuch as MeCN-EtOH-DCM is beneficial for olefins with

poor solubility.

Figure 7. Epoxidation using Oxone/NaHCO3 (solid mixture)

a) Oxone needs to be pulverized before use. b) The pH of the reaction mixture needs to be >7 before

adding ketone.c) For substrates with poor solubility, the amount of organic

solvent used can be doubled.



24

III. Buffer Preparations

Buffer solution Ratio of components

pH 9.3 buffer

(0.05 M Na2B2O7.10H2O)

1.907 g Na2B2O7·10H2O,

100 mL 4 x 10 –4 M aq Na2(EDTA) solution

pH 9.3 buffer (0.1 M K 2CO3-AcOH)

13.82 g K 2CO3 and 4.80 mL AcOH in 1L H2O

pH 8.0 buffer (0.1 M K 2CO3-AcOH)

13.82 g K 2CO3 and 5.96 mL AcOH in 1L H2O

pH 7.0 buffer 7.1 g Na2HPO4, 6.8 g KH2PO4 in 1L H2O

IV. K 2CO3 Concentration Chart (Oxone concentration = 0.21 M)

Catalyst K 2CO3 Concentration (M)

1 0.89

2 0.48

3a-c 0.84

4·H2O 0.42

5 0.84



25

V. Preparation of Buffers for pH Study

Buffer solution Ratio of components

pH 8.0 buffer 13.82 g K 2CO3 and 5.96 mL AcOH in 1 L H2O








26

VI. General Tips and Troubleshooting Information

a) Oxone and K 2CO3 should be added at a constant rate over the desired reaction

time. Air at the tip of the syringe should be pushed out to ensure the simultaneous

addition of Oxone and K 2CO3 as pH control is important for the epoxidation

reactions. It has been found that the oxidation activity of the purchased Oxone

occasionally varies with different batches.

b) Reaction flask is suspended into Dewar with a clamp. All glassware should be

washed with soap to be free of any trace metals, which catalyze the

decomposition of Oxone. Avoid using metal needles for the addition of aqueous

Oxone solution.

c) For –10 oC epoxidations, bath temperature should not be below –15 oC which willfreeze the reaction. Even momentary freezing will result in low conversions.

d) Stirring should be vigorous but without splashing.

e) Relatively insoluble substrates should be stirred in only organic solvent at room

temperature for about 20-30 min before adding buffer and cooling to ensure

maximum conversion.

f) For less reactive substrates, conversion can also usually be improved with a

slower addition of Oxone and/or higher reaction temperature (0 °C or rt).

However, a decrease of ee may result from higher reaction temperature.

g) Purification columns are usually performed with solvents buffered with 1% Et3 N

as the epoxides are acid-sensitive. However, it was found that certain epoxides

decompose in the presence of Et3 N (e.g. Fluoroepoxides: Wong, O. A.; Shi, Y. J.

Org. Chem., 2009, 74, 8377-8380). Moreover, Et3 N maybe difficult to

completely remove for extremely volatile epoxides.

h) The quality of H2O2 is important in the case where H2O2 is used as the oxidant .

Old or contaminated H2O2 cannot provide maximum conversion.

i) The quality of the ketone catalyst is very important when H2O2 is used as the

oxidant. For example, it was observed that lower conversions were obtained with

the ketones 3a-c prepared from the TEMPO-bleach oxidation of the alcohol



precursor. It appears that some residual impurities from TEMPO-bleach

oxidation somehow affect the epoxidation.

j) Certain reactive olefins may contain racemic epoxide resulting from oxidation

during storage. To ensure maximum enantioselectivities, those olefins should be

purified before asymmetric epoxidation.

guidelines for epoxidation

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