Myers Shi Asymmetric Epoxidation Reaction Chem 115

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 H3C
General Transformation: H3C Ph
H3C CH3
H3C
CH3 26% ee 79% ee 81% ee 98% ee
O
R1 O O oxone, pH 10.5, base R1
R3 R3 2. Effect of larger R3 (also: "L-branch").
O
R2 H2O, CH3CN R2
O O
O H3C H3C H3C CH3
H3C Ph C10H21
CH3 CH3 CH3 H3C H3C CH3
1
Useful for epoxidation of trans-disubstituted olefins (ketone 1), trisubstituted olefins (ketone 1), 76% ee 86% ee 91% ee
conjugated cis-disubstituted olefins (ketone 2, see p. 3), and styrenes (ketone 2, see p. 3).
3. Comparing the size of R1 and R3.
Catalyst Conditions:
H3C Ph
Ph CH3
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 CH3 CH3
readily available L-sorbose. 76% ee 97% ee
Ketone 1 can be used catalytically (2030 mol %).
Oxone (a commercial mixture of 2:1:1 KHSO5:KHSO4:K2SO4) is used as the stoichiometric Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 19, 1122411235.
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 Proposed Catalytic Cycle:
decompose. However, at pH 78 the Shi catalyst decomposes due to competing Baeyer-
Villiger reaction. By increasing the pH to 10.5 (by addition of K2CO3), the amount of ketone R1
R3
used can be reduced to a catalytic amount (30 mol %) and the amount of Oxone can be O
R2 H3C
reduced to a stoichiometric amount (1.5 equiv), suggesting that at this pH the ketone is CH3 HSO5
sufficiently reactive to compete with Oxone decomposition. R1 O
Dimethoxymethane (DMM) and CH3CN (2:1 v/v) solvent mixtures generally provide higher R3 O O
ee's. R2
Reaction temperatures range from 10 to 20 C. O O
It is proposed that the Shi epoxidation proceeds through a dioxirane intermediate and a spiro O
transition state and that a so-called planar transition state is a main competing pathway. The H3C H3C
spiro transition state is believed to be electronically favored as a result of a stabilizing interaction CH3 CH3 H3C
CH3
between an oxygen lone pair of the dioxirane with the !* orbital of the olefin. O
O O O
O O
H3C CH
3 O
H3C CH
3 OH
O O
O O O O O
O O O
R3
R1 H3C O
H3C SO3
O R O R CH3
1 3 CH3
R2 R2 H3C
O O CH3
O O
O O O O O
O O
H3C CH3 H3C CH3
SO4 2 O
Spiro O O O
Planar
O
H3C SO3
Higher ee's are observed with smaller R1 and larger R3 substituents. CH3 Soojin Kwon

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Myers Shi Asymmetric Epoxidation Reaction Chem 115
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 Product Yield ee (%)

O TMS 1, Oxone, K2CO3, O O

Ph Ph 73% 95% Ph TMS + TMS
Ph Ph Ph Ph
R CH3CN, DMM R R

O 61% 93%
Ph Cl
Ph Cl Yield ee Ratio
R=H 31% 95% 1:1
O R = CH3 77% 92% 14:1
O 41% 93%
O
Ph O
Ph O

O Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 29482953.
n-C10H21 CH3 94% 89%
n-C10H21 CH3
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 TMS
1, Oxone, K2CO3, O
Ph Ph
CH3CN, DMM
CH3 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 bis- 64%, 94% ee
epoxidation. Vinyl silanes and allylic silyl ethers are deactivated towards epoxidation
(attributed to sterics and inductive deactivation, respectively).

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 CH3
25 mol % 1, Oxone, K2CO3
OTBS OTBS
H3C H3C 1,1-Disubstituted epoxides can be synthesized enantioselectively by Shi epoxidation of
CH3CN, DMM O trisubstituted vinyl silanes followed by TBAF-mediated desilyation.

81%, 96% ee

CH3 CH3 CH3

1, Oxone, K2CO3
H3C CH3 20 mol % 1, Oxone, K2CO3 H3C CH3 TMS TMS TBAF
O
CH3CN, DMM O 82% O
H3C OCH3 H3C OCH3
CH3CN, DMM
74%, 94% ee 94% ee
65%, 89% ee

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

Soojin Kwon

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Myers Shi Asymmetric Epoxidation Reaction Chem 115
A modified catalyst is useful for epoxidation of cis-disubstituted olefins and styrenes. Enol esters can be used as substrates for the preparation of !-hydroxyketones in either
enantiomeric form.
O
O CH3
O NBoc CH3 O
K2CO3, MeOH
O O O O CH3
O Ph
O CH3 66%, 91% ee CH3
O Ph Ph OH
H3C O 90%
H
CH3 2 O
H 91% ee 94% ee
Oxone, K2CO3, DME, DMM
Ph CH3 Ph CH3
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 O
K2CO3, MeOH
CH3 CH3
Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 1155111552. Ph Ph
OAc OH

O 88% ee
O
O NBoc
Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 78197822.
O O
O
H3C Kinetic resolution of racemic 1,3- and 1,6-disubstituted cyclohexenes can provide optically
CH3 O
2 enriched allylic silyl ethers.

Oxone, K2CO3, DME, DMM

100%, 81% ee
OTMS OTMS OTMS
Ph 35 mol % 1 Ph Ph
Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 19291931. O
Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 24352446.
49% conversion
96% ee trans:cis >20:1
95% ee trans
In both cases, it is proposed that the "-substituent of the substrate prefers to be proximal to the spiro
oxazolidinone. OTBS OTBS OTBS
35 mol % 1
O O
O Ph 70% conversion Ph Ph
NBoc
O R" 99% ee trans:cis 4:1
R 81% ee trans
O O 1
O O
CH3 CH3
Frohn, M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 77187719.

Soojin Kwon

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Myers Shi Asymmetric Epoxidation Reaction Chem 115
The original Shi catalyst decomposes (via the Baeyer-Villiger pathway) faster than it reacts with Cryptophycin 52:
electron-deficient !,"-unsaturated esters. A second-generation catalyst, incorporating electron-
withdrawing acetate groups, slows the Baeyer-Villiger decomposition. The Shi epoxidation system provided the desired epoxide in a 6:1 diastereomeric ratio, while
other epoxidation methods never exceeded a 2:1 ratio.
H3C CH3 CH3 CH3
O O
O O O Conditions O

OH HN Cl OH HN R
AcO O
OAc O O O OCH3 O O
CO2Et CO2Et
Ph Ph
73%, 96% ee CCl3 CCl3
Conditions ",! ratio
Ketone 1 6.5:1
Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 87928793. m-CPBA 1.5:1

Applications in Synthesis: O OH
H3C O

H3C O NHFmoc
Glabrescol: H3C CH3

asymmetric HO CH3 CH3 CH3 DMAP, DCC, CH2Cl2

squalene CH3 71% (2 steps)
dihydroxylation H 3C
OH CH3 CH3 CH3
73% CH3
88% ee O
O
1, Oxone, DMM, O O HN Cl
piperidine, DMF H3C O
CH3CN, H2O, CH3
pH 10.5, 0 C, 1.5 h 79% H3C O CH3 O O OCH3

CCl3
CH3 CH3 NHFmoc
HO CH3
O O O CH3
CH3 O
H3C O
O O
OH CH3 CH3 CH3
O O HN Cl
H3C O
CSA, toluene, 0 C, 1 h
H3C O N O OCH3
31% (2 steps) H
H3C CH3

OH OH Cryptophycin 52
H3C CH3
O O O O O
H3C H CH3 H CH3 H H CH3 H CH3 H 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

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Myers Shi Asymmetric Epoxidation Reaction Chem 115
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 Ph3P, AcOH
CO2CH3
TBSO TBSO
80 C, 8 h
CH3 CH3
85% 1. NBS, THF, H2O, 67%
H3C OAc H3C OAc
30 mol % 1, Oxone H
2. catalyst 1, Oxone, O
K2CO3, 0 C, 6 h DMM, CH3CN, H2O,
45 % H3C pH 10.5, 58% HO
H3C Br
CH3 farnesyl acetate CH3
OTBS 1. Me3Al; H2O, 30 C,
O cat. CSA
CO2CH3 2 h, 82%
TBSO CO2CH3
TBSO Et2O
CH3 2. TBDMSCl, Im, 23 C, 50%
2 d, 84% 9096% ee

CH3
CH3 H3C CH3
H3C CH3 O OAc
O H3C OH
H3C OH H
OAc H
H
H Br
O Br
OTBS O (proposed) HO
O O OH
TBSO H O t-BuOOH, cat. Ti(O-i-Pr)4
CH3
CH3 CH3 (+)-diethyl tartrate, CH2Cl2
CH3 CH3 CH3 99%
Octalactin A

CH3
H3C CH3 O
O OH
H3C OAc
Bluet, G.; Campagne, J.-M. Synlett 2000, 1, 221222. H
H
Br >95% de
(proposed)
H3C
HO CH3 H3C H
O CH3
CH3 O
H3C H HO H HO CH3
O
H3C O
H H
H
Br Thyrsiferol

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