Myers

Chem 115

Shi Asymmetric Epoxidation Reaction

Reviews:

Examples:

Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 39583987.

1. Effect of smaller R1 (also known as "T-branch"; phenyl groups can be considered smaller than
methyl).

Shi, Y. Acc. Chem. Res. 2004, 37, 488496.

Frohn, M.; Shi, Y. Synthesis 2000, 14, 19792000.

H3C

General Transformation:
H3C
R1

R3
R2

CH3
O

R1
R2

R3

Useful for epoxidation of trans-disubstituted olefins (ketone 1), trisubstituted olefins (ketone 1),
conjugated cis-disubstituted olefins (ketone 2, see p. 3), and styrenes (ketone 2, see p. 3).
Catalyst Conditions:

H3C CH
3

H3C CH
3

O
H3C

O
O

CH3

Spiro

R3

O R
3

R2
O

H3C

R1
R2

Planar

Higher ee's are observed with smaller R1 and larger R3 substituents.

98% ee

CH3

H3C H3C CH3

91% ee

3. Comparing the size of R1 and R3.

Ph

Ph
CH3

76% ee

CH3
CH3
97% ee

Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 19, 1122411235.
Proposed Catalytic Cycle:
R1
R2
R1

R3
H3C
O

R3

CH3

HSO5

R2
O

O
H3C
O

H3C

CH3

H3C

O
H3C

CH3

O
O

O
H3C

CH3

H3C

CH3

H3C

C10H21
86% ee

O
O

81% ee

CH3

76% ee

H3C
Ketone 1 can be readily prepared from D-fructose ($15/kg) by ketalization (acetone, HClO4, 0
C, 53%) and oxidation (PCC, 23 C, 93%). L-Fructose can be prepared in 3 steps from
readily available L-sorbose.
Ketone 1 can be used catalytically (2030 mol %).
Oxone (a commercial mixture of 2:1:1 KHSO5:KHSO4:K2SO4) is used as the stoichiometric
oxidant but H2O2/CH3CN can also be used (peroxyimidic acid is the proposed oxidant).
Generally, the optimum pH for dioxirane epoxidation is 78. At higher pH, Oxone tends to
decompose. However, at pH 78 the Shi catalyst decomposes due to competing BaeyerVilliger reaction. By increasing the pH to 10.5 (by addition of K2CO3), the amount of ketone
used can be reduced to a catalytic amount (30 mol %) and the amount of Oxone can be
reduced to a stoichiometric amount (1.5 equiv), suggesting that at this pH the ketone is
sufficiently reactive to compete with Oxone decomposition.
Dimethoxymethane (DMM) and CH3CN (2:1 v/v) solvent mixtures generally provide higher
ee's.
Reaction temperatures range from 10 to 20 C.
It is proposed that the Shi epoxidation proceeds through a dioxirane intermediate and a spiro
transition state and that a so-called planar transition state is a main competing pathway. The
spiro transition state is believed to be electronically favored as a result of a stabilizing interaction
between an oxygen lone pair of the dioxirane with the !* orbital of the olefin.

O R
1

H3C

Ph
CH3

79% ee

2. Effect of larger R3 (also: "L-branch").

H3C

O
CH3

Ph

H3C

26% ee
oxone, pH 10.5, base
H2O, CH3CN

O
H3C

H3C

H3C CH3

O
SO42

CH3
O

OH
O O
SO3

CH3
O

O
H3C

O
CH3

O
CH3

O O
SO3
Soojin Kwon

Myers

Chem 115

Shi Asymmetric Epoxidation Reaction

Examples of Shi Epoxidations:

Regioselectivity increases when either olefin of a 1,3-diene is trisubstituted. It is proposed that

the trisubstituted olefin prevents full conjugation of the diene due to A1,2 strain, causing each
olefin to present an individual steric or electronic environment, as if each were isolated.

Substrate
Ph

Product
O

Ph
Ph

CH3

TMS

Ph

1, Oxone, K2CO3,
CH3CN, DMM

TMS +

Ph

O
Ph

TMS

93%

41%

93%

94%

89%

Yield

ee

Ratio

R=H

31%

95%

1:1

R = CH3

77%

92%

14:1

Ph

CH3

95%

61%

Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 29482953.

O
n-C10H21

73%

Cl

Ph

O
Ph

ee (%)

R
O

Cl

Ph

Ph

Yield

n-C10H21

CH3
CH3

Epoxidation of enynes occurs selectively at the CC double bond.

Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 98069807
and Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 1122411235.

TMS
Ph
CH3

Monoepoxidation of conjugated dienes favors the more electron-rich or less sterically hindered
olefin. The amount of catalyst used must be properly controlled (0.20.3 equiv) to prevent bisepoxidation. Vinyl silanes and allylic silyl ethers are deactivated towards epoxidation
(attributed to sterics and inductive deactivation, respectively).

1, Oxone, K2CO3,

TMS

Ph

CH3CN, DMM

CH3

64%, 94% ee

Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 44254428.
Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 76467650.
CH3
OTBS

H3C

CH3

25 mol % 1, Oxone, K2CO3

CH3CN, DMM

OTBS

H3C

1,1-Disubstituted epoxides can be synthesized enantioselectively by Shi epoxidation of

trisubstituted vinyl silanes followed by TBAF-mediated desilyation.

81%, 96% ee
CH3
H3C
H3C

CH3
OCH3

20 mol % 1, Oxone, K2CO3

CH3CN, DMM
65%, 89% ee

O
H3C

H3C

CH3
OCH3

TMS

1, Oxone, K2CO3
CH3CN, DMM

CH3
O

74%, 94% ee

Warren, J.D.; Shi, Y. J. Org. Chem. 1999, 64, 76757677.

TMS TBAF
82%

CH3
O
94% ee

Soojin Kwon

Myers

A modified catalyst is useful for epoxidation of cis-disubstituted olefins and styrenes.

O
O

CH3

CH3

CH3

CH3

NBoc
O

H3C

Enol esters can be used as substrates for the preparation of !-hydroxyketones in either
enantiomeric form.

Ph

Chem 115

Shi Asymmetric Epoxidation Reaction

Ph

O
CH3

66%, 91% ee

Ph

Ph

OH

90%

CH3

CH3

Ph

91% ee

Oxone, K2CO3, DME, DMM

K2CO3, MeOH

O
CH3

94% ee

195 C, 0.5 h

82%, 91% ee

92%

The enantiomeric excess is generally high for cyclic olefins and for acyclic olefins conjugated with
an alkynyl or aromatic group.

O
Ph

Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 1155111552.

CH3

K2CO3, MeOH

CH3

Ph

OAc

OH

O
O

88% ee

NBoc
Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 78197822.
O

O
H3C

O
CH3

Kinetic resolution of racemic 1,3- and 1,6-disubstituted cyclohexenes can provide optically
enriched allylic silyl ethers.

Oxone, K2CO3, DME, DMM

100%, 81% ee
OTMS
Ph
Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 19291931.
Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 24352446.

In both cases, it is proposed that the "-substituent of the substrate prefers to be proximal to the spiro
oxazolidinone.

NBoc
R"

R
O O 1
O
O
CH3 CH3

OTMS
Ph

OTMS
Ph
O

49% conversion

OTBS

96% ee

trans:cis >20:1
95% ee trans

OTBS

OTBS

35 mol % 1

O
O

35 mol % 1

Ph

70% conversion

Ph
99% ee

O
Ph
trans:cis 4:1
81% ee trans

Frohn, M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 77187719.
Soojin Kwon

Myers

Chem 115

Shi Asymmetric Epoxidation Reaction

The original Shi catalyst decomposes (via the Baeyer-Villiger pathway) faster than it reacts with
electron-deficient !,"-unsaturated esters. A second-generation catalyst, incorporating electronwithdrawing acetate groups, slows the Baeyer-Villiger decomposition.
H3C
O

Cryptophycin 52:
The Shi epoxidation system provided the desired epoxide in a 6:1 diastereomeric ratio, while
other epoxidation methods never exceeded a 2:1 ratio.

CH3

CH3

Ph

OAc

CO2Et

Cl

OH

73%, 96% ee

CO2Et

Ph

OCH3

CCl3

Applications in Synthesis:

Conditions

",! ratio

Ketone 1
m-CPBA

6.5:1
1.5:1

H3C

dihydroxylation

CH3

HO CH3

CH3

OH

CH3

O
1, Oxone, DMM,

CH3

H3C

CH3CN, H2O,

piperidine, DMF

pH 10.5, 0 C, 1.5 h

79%

CH3

CH3

CH3

CSA, toluene, 0 C, 1 h
31% (2 steps)
OH
CH3

OH
H3C

CH3 H

H3C

CH3
H3C

H3C

H3C

CH3
O
O
O

HN
CH3
CH3 O
NHFmoc

CH3

OH

OH
O

71% (2 steps)

CH3

CH3

88% ee

HO CH3

CCl3

DMAP, DCC, CH2Cl2

CH3

H 3C

73%

HN

NHFmoc
O
H3C CH3

H3C
Glabrescol:
asymmetric

Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 87928793.

squalene

CH3

Conditions

HN

OH
AcO

CH3 H

O
O
CH3 H CH3 H

H3C

Cl
O

OCH3

CCl3

CH3
O
O

HN

N
O
H
H3C CH3

Cl
O

OCH3

Cryptophycin 52

CH3

originally proposed structure of Glabrescol

Hoard, D. W.; Moher, E. D.; Martinelli, M. J.; Norman, B. H. Org. Lett. 2002, 4, 18131815.
Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 48314832.

Soojin Kwon

Myers

Chem 115

Shi Asymmetric Epoxidation Reaction

Thyrsiferol:

Octalactin A:

Post epoxidation, only one bromohydrin diastereomer cyclized to the bromotetrahydropyran. The
unreactive diastereomer was separated from the cyclization product and isolated in 30% yield.
CO2CH3
TBSO

Ph3P, AcOH

CO2CH3

TBSO

80 C, 8 h

CH3

CH3

85%
H3C

30 mol % 1, Oxone

OAc

H3C
CH3

OTBS
CO2CH3

TBSO

1. Me3Al; H2O, 30 C,
2 h, 82%

O
TBSO

CH3

2. TBDMSCl, Im, 23 C,
2 d, 84%

(proposed)

HO

TBSO
CH3

OAc

Br
CH3
cat. CSA

CO2CH3

Et2O
50%

9096% ee

H
Br

O
O

HO
H3C

farnesyl acetate

H3C
H3C
OTBS

H3C
O

2. catalyst 1, Oxone,
DMM, CH3CN, H2O,
pH 10.5, 58%

K2CO3, 0 C, 6 h
45 %

1. NBS, THF, H2O, 67%

CH3
CH3 CH3

OH
CH3

CH3

CH3
H

OAc

H3C
H3C

OH

CH3

CH3
H

H
Br

OAc

OH

t-BuOOH, cat. Ti(O-i-Pr)4

(+)-diethyl tartrate, CH2Cl2

CH3

99%

Octalactin A

Bluet, G.; Campagne, J.-M. Synlett 2000, 1, 221222.

H3C
H3C
H
Br

CH3
H

OAc

CH3
O
OH

>95% de
(proposed)
H3C
H3C
H3C

CH3

H
Br

McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593595.

HO CH3 H3C
H

H
O

HO H

CH3

HO CH3

H
Thyrsiferol

Soojin Kwon