myers sharpless asymmetric epoxidation reaction chem...

Chem 115Sharpless Asymmetric Epoxidation ReactionMyers

Reivews:Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–300.

Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp. 103–158.

Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming,I., Eds., Pergamon Press: New York, 1991, Vol. 7, pp. 389–436.

Pfenninger, A. Synthesis 1986, 89–116.

Substitution patterns:

Asymmetric Epoxidation of Allylic Alcohols:

R2

R1

R3OH

Ti(Oi-Pr)4, (+)-DET

t-BuOOH, 3Å-MSCH2Cl2, –20 °C

R2

R1

R3OH

O

• 5–10 mol% catalyst in the presence of 3- or 4Å-MS.• 10–20 mol% excess tartrate vs. Ti(OiPr)4 required.• (+)- and (–)-DET are readily available and inexpensive.• (+)- and (–)-DIPT, diisopropyl tartrate, are also available and sometimes lead to higher selectivity.

Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.

Mnemonic for selectivity:

L-(+)-DET "O"

D-(–)-DET "O"

Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.Application of Mnemonic:

OH

CH3

OH

CH3O OH

CH3O

AE-(–)-DET

97%, 86% ee

AE-(+)-DET

97%, 86% ee

OH OH

OH

OHOH OH OH

• Z-disubstituted olefins are least reactive and selective.OH

Examples of Sharpless Epoxidation:

product Ti(%) tartarate(%) °C h yield (%) ee (%)

OHO 5 (+)-DIPT (6.0) 0 2 65 90

OHO 5 (+)-DIPT (7.0) –20 3 89 >98Ph

OHO 4.7 (+)-DET (5.9) –12 11 88 95

Pr

OHO

10 (+)-DET (14) –10 29 74 86

C7H15

OHO 5 (+)-DIPT (7.5) –35 2 79 >98Ph

CH3

OHO 100 (+)-DET (142) –20 14 80 80

CH3

BnO

OHO

5 (+)-DET (7.4) –20 0.75 95 91CH3

H3C

CH3

OHO

120 (–)-DET (150) –20 5 90 94PhCH3

Ph

From: Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780 and Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp. 103–158.

R1

R2 R3

HO

EtO2C

OH

OH

CO2Et(+)-DET =

M. Movassaghi

1

Chiral Substrate: Kinetic Resolution:

• Products are diastereomeric.• Sense of induction is dominated by the catalyst.• The C4 center reinforces and erodes this in "MATCHED" and "MISMATCHED" cases, respectively, as shown.

Homoallylic, bishomoallylic and trishomoallylic:

Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1984, 49, 3707–3711.

OHO

O

H3CCH3

OHO

O

H3CCH3

OOH

OO

H3CCH3

O

Reagent Ratio (syn : anti)

m-CPBAVO(acac)2-TBHPTi(OiPr)4-TBHPTi(OiPr)4-(-)-DIPT-TBHPTi(OiPr)4-(+)-DIPT-TBHP

1 : 1.4 1 : 1.8 1 : 2.3 1 : 90 22 : 1

MATCHEDMISMATCHED

Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A., III; Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245–264.

• Rates of epoxidation are usually slower.• Enantiofacial selectivity of the catalyst is reversed for all three.• Enantiofacial selectivity is generally lower.

R1

R2 R3

HO

(+)-DET "O"

H3C OHTi(Oi-Pr)4 (1.0 equiv)(+)-DET (1.2 equiv)

TBHP, –20 °C1–4 d

50%, 41% ee

H3C OHO

CH3

OH

Ti(Oi-Pr)4 (1.0 equiv)(+)-DET (1.2 equiv)

TBHP, 0 °C48 h

22%, 29% ee

O

OH

HCH3

H

Hosokawa, T.; Kono, T.; Shinohara, T.; Murahashi, S.-I. J. Organometal. Chem. 1989, 370,C13–C16.For other examples see: Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis,Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158.and Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–300.

• Products are diastereomeric.• Using the Sharpless mnemonic, contact between the C1 substituent (R) and the catalyst predicts the slow-reacting isomer.

RH

R1

R2 R3

HO

(+)-DET "O"

HR

slow fastkrel = kfast/kslow

• With the exception of Z-disubstituted allylic alcohols, krel > 25.• When krel = 25, the ee of unreacted alcohol is essentially 100% at 60% conversion.• Allylic tertiary alcohols are not successfully expoxidized under Sharpless conditions.• Factors may combine for high selectivity:

H3C

OH (–)-DIPT

40% conversion H3C

OHO

70% yield>95% ee

• Disubstituted olefin is more reactive than monosubstituted olefin (krel ~ 100).• kfast/kslow for chiral E-propenylcarbinols is ~100.

Excercice: Apply the Sharpless mnemonic to predict the stereochemistry of this product.

Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S.M.; Walker, F. J.; Woodard, S. S. Pure Appl. Chem. 1983, 55, 589–604.

• Allylic 1,2-diols do not follow the Sharpless mnemonic:

OH

OH

(+)-DIPTOH

OH

OOH

OH

O+

71%90% ee

10%90% ee

Excercice: What isomer would you have predicted using the Sharpless mnemonic?

Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am. Chem. Soc. 1991, 113, 2786–2787. M. Movassaghi


(±)

2

C2-Symmetric Substrates:

M. Movassaghi

Venustatriol:

OBn

OH O O

H3C CH3

OH

OBn OBn

OH O O

H3C CH3

OH

OBnOmeso 89%

(+)-DIPT

Applications in Synthesis:

L-Hexoses:

RO OH

R = CHPh2

Ti(Oi-Pr)4, (+)-DIPT

TBHP, –20 ºCRO OH

O 92%, >95% ee

PhSH, NaOHH2O/t-BuOH, !

71%

RO SPh

OH

OH

1. 2,2-dimethoxypropane

2. m-CPBA, –78 ºC3. Ac2O, NaOAc, !

cat, POCl3

93%, 3-steps

SPh

OAcRO

OO

CH3H3C

H

ORO

OO

CH3H3C

H

ORO

OO

CH3H3C

syn anti

K2CO3CH3OH25 ºC

100%

DIBAL-HCH2Cl2–78 ºC

91%

• Any minor diastereomer that is produced is rapidly removed by bis-epoxidation.Exercise: Why?

Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525–1529.Schreiber, S. L.; Goulet, M. T.; Schulte, G. J. Am. Chem. Soc. 1987, 109, 4718–4720.

• HWE-olefination, reduction, and AE provides an iterative route to the synthesis of polyols.

Ko, S. Y.; Lee, A. W. M.; Masamune, S; Reed, L. A., III; Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245–264. Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171–3174.

H3C

H3C

CH3

CH3

OHTi(Oi-Pr)4, (–)-DET

TBHP, 3Å-MS–20 ºC

92%

H3C

H3C

CH3

CH3

OHO

H3C

H3C

CH3

OH3C

HOH

CNH

Ti(Oi-Pr)4, (–)-DET

TrOOH, 3Å-MS0 " 23 ºC, 15 h

74%

H3C

H3C

CH3

OH3C

HOH

CNH

O

Br

OH3C

OH

CNH

HOH3C

H3CH3C

H

+ OO O

HCH3CH3H

Li

CH3

H3C

HO

CH3

O CH3

H3C

HO

CH3

Ti(Oi-Pr)4, (–)-DET

TBHP 3Å-MS–23 ºC

92%

Br

OH3C

OHH

OH3C

H3CH3C

H

H

OHH

OCH3

H3C H

OHH OHCH3

Venustatriol


3

Ferensimycin B:

M. Movassaghi

(+)-Neocarzinostatin Chromophore:

(–)-7-Deacetoxyalcyonin Acetate:

N

O

CH3

H3CO

EtOH

H3C

CH3 N NCH3

CH3

CH3 EtLi

Et2O CH3 EtOH

H3C

CH3 N NCH3

CH3

CH3OLiO

NH3C

H3C

EtEt

OH

EtEt

OHO

EtEt

OOMgBr

1. Et2NLi(1.5 equiv)THFNaHSO4, H2O2.

(+)-DET, Ti(Oi-Pr)4

TBHP

76% of TY,90% ee

EtMgBr

OEt

OH

Et

H3C

OHO

CH3

H3C

HEt

O

CH3

OEt

OH

Et

H3C

OHO

CH3

H3C

HEt

O

CH3

OH

CH3H

CH3H3C

OHHO2C

CH3

Ferensimycin B

Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613–7630.

MacMillan, D. W. C.; Overman, L, E. J. Am. Chem. Soc. 1995, 117, 10391–10392.

O

CH3H3C

H3C

H H

H HH3C

OH TMS

O

CH3H3C

H3C

H H

H HH3C

OH TMS

O

O

CH3H3C

H3C

H H

H HH3C

OH TMS

HOO

CH3H3C

H3C

H HH HH3C

HO

AcO H

1. (+)-DET, Ti(Oi-Pr)4TBHP, –20 ºC

CH2Cl2

2. Red-Al, THF – 15 ºC; H2O79% (two steps)

(–)-7-Deacetoxyalcyonin Acetate

H

O

H

TBSH

HO

HO H

TBSH

TBDPSO

HO O

H

TBSH

HO

HO O

OH

OO

O

•

O

O

CH3OH

HO

NH3CH

OH O

CH3

OCH3

94%, !95% de1. TDSCl, Et3N, DMAP

CH2Cl2, 0 ºC

2. (–)-DET, Ti(Oi-Pr)4 TBHP, –20 ºC, CH2Cl2 4Å-MS

(+)-DET, Ti(Oi-Pr)4TBHP, –20 ºC

CH2Cl2, 4Å-MS

70%, !95% de

(+)-Neocarzinostatin Chromophore

•

Myers, A. G.; Hammond, M.; Wu, Y.; Xiang, J.-N.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1996, 118, 10006–10007.

Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.; Yusheng, W.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120, 5319–5320.


A further example of anomalous stereochemistry in AE of an allylic diol (no reaction with (–)-DIPT).

4

Examples of the Sharpless Asymmetric Epoxidation Reaction in Industry:

• In this example, excess TBHP was quenched with triethylphosphite instead of FeII sulfate.

• In this example, a stoichiometric amount of titanium and DIPT was necessary for high conversion.

Jesse Teske, Andy Flick, Daniel Schmitt

OH OHO(–)-DIPT, Ti(Oi-Pr)4, TBHP

NaOH

OEtOH

58% (2 steps), 98% ee

OO

NH

H

(S,S)-Reboxetine succinatea norepinephrine uptake inhibitor

EtOAc, –15 oC97% conversion

Henegar, K. E.; Cebula, M. Org. Proc. Res. Dev. 2007, 11, 354–358.

OH

N3 (–)-DIPT, Ti(Oi-Pr)4TBHP, 4Å-MS

OH

N3O

90% ee 95%, 98% ee

N N

OO

OH

CO2CH3H3CO2C

HIV-1 protease inhibitor

Jadhav, P. K.; Man, H. W. Tetrahedron Lett. 1996, 37, 1153–1156.

NHCbz

OH

NHCbz

OH

O N O

O

NHAcH3C

O

An antibacterial agent

Gleave, D. M.; Brickner, S. J. J. Org. Chem. 1996, 61, 6470–6474.

F

F

OHF

FOH

O

Saksena, A. K.; Girijavallabhan, V. M.; Lovey, R. G.; Pike, R. E.; Desai, J. A.; Ganguly, A. K.; Hare, R. S.; Loebenberg, D.; Cacciapuoti, A.; Parmegiani, R. M. Bioorg. Med. Chem. Lett. 1994, 4, 2023–2028.

CH2Cl2, –15 ºC

An antifungal agent

(–)-DIPT, Ti(Oi-Pr)4TBHP, 4Å-MS

CH2Cl2, 84%, >95% ee

F

FOHO

O N N NNN

O

CH3

H3C

CH3

OH

Geraniol

CH3

H3C

CH3

OHO

(–)-DET, Ti(Oi-Pr)4TBHP, 4Å-MS

CH2Cl2, –10 ! 20 ºC99%, 91% ee

NBoc

CO2HH3CHO

Noe, M. C.; Hawkins, J. M.; Snow, S. L.; Wolf-Gouveia, L. J. Org. Chem. 2008, 73, 3295–3298.

N-Boc-(2R,3R)-3-methyl-3-hydroxypipecolic acid


O

OHOH

OEt

(150 g)

(187.3 g)

• In the following example, the minor enantiomer was unreactive, leading to enantiomeric enrichment:

CH3H

CH3

(+)-Tartrate, Ti(Oi-Pr)4TBHP, 4Å-MS

CH2Cl2, >95%, 88–92% ee

OEt

HO2CCO2H

•

(The choice of tartrate was not specified)

5

R'R

OCH3

CH3

NC

O

O

OCH3

CH3

ONC

O

O

O

O

R'R

O HHt-Bu

t-Bu

N N

t-Bu

t-BuOOMn

Cl

HH

Ph

CH3

Ph

H

R'

H

R

t-Bu

t-Bu

N N

t-Bu

t-BuOO

Mn

HHO

R'

H

R

HPh

Ph

Ph

H3C

Ph

Ph

Ph

PhO

H3C

Ph

PhO

Ph

Ph

PhO

R

R"

H

R'

Ph

CH3

PhO

H

Chem 115Jacobsen Asymmetric Epoxidation ReactionMyersReviews:

Jacobsen, E. N. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993;

pp. 159-202.

Linker, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2060-2062.

(S,S)-1

(S,S)-1 (4 mol %)

NaOCl(aq)

CH2Cl2, 4 °C

olefin yield, % ee, % equiv (S,S)-1

96

63

97

94

0.03

0.15

79 84 0.006a

• Selectivity is determined through nonbonded interactions.

• Terminal olefins are poor substrates.

• Addition of substoichiometric amounts of 4-phenylpyridine N-oxide improves both catalyst

aReaction carried out in the presence of 4-phenylpyridine N-oxide.

• The observed selectivities are explained

• cis-Disubstituted conjugated olefins are epoxidized with high levels of enantioselectivity.

• trans-Disubstituted olefins react more slowly and with diminished selectivity.

epoxide

• In general, R is aryl, alkenyl or alkynyl and R' is a bulky group.

From: Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991,

113, 7063-7064.

by a side-on approach of olefin:

selectivity and turnover numbers.

(S,S)-1 "O"

(R,R)-1 "O"

Mnemonics for the observed selectivities:

cis-olefin trisubstituted olefin

(S,S)-1 "O"

(R,R)-1 "O"

• cis-Olefins: Place Aryl, alkenyl or alkynyl substituent in upper-left quadrant (R) and the

corresponding trans hydrogen atom in the lower-right quadrant.

• trans-Olefins are poor substrates.

• Trisubstituted olefins: Place the hydrogen atom in the lower-right quadrant.

Trisubstituted olefins:

• Trisubstituted alkenes are excellent substrates for the Jacobsen asymmetric epoxidation.

69 93

91 95

97 92

From: Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378-4380.

(R,R)-1 (3 mol %)

NaOCl(aq)

CH2Cl2 or TBME

4-Phenylpyridine N-oxide

0 °C

87%, 88% ee

olefin yield, % ee, %epoxidea

M. Movassaghi

CO2CH3RO

ROCO2CH3

O 3

CO2CH3

O

CH3

3

3

CH3PhPh

CH3O

Ph CH3

ON N

OO

Mn

Cl

HH

R

t-Bu

N

Ph

N

Ph

t-Bu

ROO

Mn

Cl

CO2EtPh Ph

CO2EtO

Ph CO2Et

O

O

TMS

TMSTMS

O

O

Br

CH3

CH3

CH3

CH3O

H3C

CH3Br

CH3

CH3

O

O

CH3Br

CH3

CH3

OCH3CH2

O

Br

CH2CH3

CH3

CH3

CH3

H3C

CH3

OCH3

CH3

CH3

CH3

H3C

CH3

O

Ph

Ph

Ph

CH3 CH3

Ph

Ph

PhO

Tetrasubstituted Olefins:

R = CH3, (S,S)-2R = OCH3, (S,S)-3

(S,S)-4

• High enantioselectivities are not yet general but may be attained in certain cases with catalysts

olefin epoxide yield, % ee, %catalyst

(S,S)-2

(S,S)-2

(S,S)-3

(R,R)-3

(S,S)-4

84 96

81 97

45 65

37 35

12 46

From: Brandes, B. D.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5123-5126.

From: Jacobsen, E. N. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993; pp. 159-202 and Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063-7064.

0.08

0.04

0.04

• cis-!-Substituted styrene derivatives afford cis-epoxides as major products while cis-enynes and

olefinequiv (S,S)-1

• Rotation of a radical intermediate is proposed to account for the cis " trans isomerization.

R = COCH2OPh(R,R)-1 (4 mol %)

4-Phenylpyridine N-oxideNaOClpH 11.3

Leukotriene A4 methyl ester

Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993, 58, 6939-6941.

62% (trans:cis, 8:1), 82% ee (trans)

cis-dienes produce trans-epoxides.

77, 92

52, 97

10, 64

6.7, 83

15, 78

55, 98

cis-epoxide trans-epoxideyield (%), ee (%) yield (%), ee (%) • Chromene derivatives undergo epoxidation with higher enantioselectivity as compared to indene

shown.

derivatives.

epoxide

M. Movassaghi

R1 R3O

OOO

OO

CH3

CH3

H3C

H3C

OOO

OO

CH3H3C

CH3H3C

OO

R1 R2

R3 OOO

OO

CH3H3C

CH3H3C

OO

R3 R2

R1

R1 R3O

H3C PhCH3

H3C PhCH3

H3C

H3C CH3

SO42–

O

OO

OO

CH3

CH3

H3C

H3CO

O

H3C C10H21CH3

Ph CH3CH3

H3C

O

OO

OO

CH3

CH3

H3C

H3C

O–

O OSO3–

O

OOO

OO

CH3

CH3

H3C

H3C

H3C

H3C

CH3

CH3H3C

H3C

HSO5–

Ph

O

OO

OO

CH3

CH3

H3C

H3C

OHO O

SO3–

Soojin Kwon

Chem 115Shi Asymmetric Epoxidation Reaction

Reviews:

Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987. Shi, Y. Acc. Chem. Res. 2004, 37, 488–496. Frohn, M.; Shi, Y. Synthesis 2000, 14, 1979–2000.

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.

•

General Transformation:

oxone, pH 10.5, base

H2O, CH3CN

Myers

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 (20–30 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 7–8. At higher pH, Oxone tends to decompose. However, at pH 7–8 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 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.

•

••

•

•

•

Spiro Planar

1

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

Proposed Catalytic Cycle:

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:

Examples:

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

26% ee 79% ee 81% ee 98% ee

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

3. Comparing the size of R1 and R3.

76% ee 86% ee 91% ee

76% ee 97% ee

Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 19, 11224–11235.

R2 R2

R1 R3R2

R1 R3OR2

1

H3C OTBSCH3

H3C OCH3

H3C CH3

H3C OCH3

H3C CH3O

H3C OTBSCH3

O

TMSCH3

TMSCH3

O

Ph TMS

RPh TMSO

R

Ph

TMS

CH3

Ph TMSO

R

Ph

TMSO

CH3

CH3

O

Soojin Kwon

Monoepoxidation of conjugated dienes favors the more electron-rich or less sterically hindered olefin. The amount of catalyst used must be properly controlled (0.2–0.3 equiv) to prevent bis-epoxidation. Vinyl silanes and allylic silyl ethers are deactivated towards epoxidation (attributed to sterics and inductive deactivation, respectively).

Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948–2953.

Epoxidation of enynes occurs selectively at the C–C double bond.

Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425–4428.Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646–7650.

1,1-Disubstituted epoxides can be synthesized enantioselectively by Shi epoxidation of trisubstituted vinyl silanes followed by TBAF-mediated desilyation.

TBAF

82%

94% ee

Warren, J.D.; Shi, Y. J. Org. Chem. 1999, 64, 7675–7677.

R = HR = CH3

Ratio1:114:1

Yield31%77%

ee95%92%

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.

25 mol % 1, Oxone, K2CO3

CH3CN, DMM

81%, 96% ee

1, Oxone, K2CO3,

CH3CN, DMM

1, Oxone, K2CO3,

CH3CN, DMM

64%, 94% ee

1, Oxone, K2CO3

CH3CN, DMM

74%, 94% ee

+

20 mol % 1, Oxone, K2CO3

CH3CN, DMM

65%, 89% ee

Ph Ph

Ph Cl

Ph O

O

n-C10H21 CH3

CH3

Ph PhO

Ph ClO

Ph OO O

n-C10H21 CH3

CH3

O

Examples of Shi Epoxidations:

Substrate Product Yield ee (%)

95%

93%

93%

89%

73%

61%

41%

94%

Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806–9807and Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224–11235.

Chem 115Shi Asymmetric Epoxidation ReactionMyers

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OTMSPh

OTMSPh

OTMS

OPh

Ph

OTBS

Ph

OTBS

Ph

OTBS

O

Soojin Kwon

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

35 mol % 1

49% conversion96% ee trans:cis >20:1

95% ee trans

Frohn, M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 7718–7719.

35 mol % 1

70% conversion99% ee trans:cis 4:1

81% ee trans

Ph CH3

O

Ph CH3

O

OAc

Ph CH3

O

OH

Ph CH3

O

OH

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

91% ee

K2CO3, MeOH

90%

94% ee

195 °C, 0.5 h

92%

K2CO3, MeOH

88% ee

Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819–7822.

66%, 91% eeO

CH3

Ph CH3

O O

CH3

O

Ph CH3

O

OOO

NBocO

CH3H3C

O

ONBocO

OO

OO

O

CH3CH3

R"R1

O

Ph CH3

OH

H

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

Oxone, K2CO3, DME, DMM

82%, 91% ee

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

Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551–11552.

Oxone, K2CO3, DME, DMM

100%, 81% ee

Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929–1931.Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435–2446.

2

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

O

OOO

NBocO

CH3H3C

O

2

Chem 115Shi Asymmetric Epoxidation ReactionMyers• •

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Ph CO2Et

O

O

OO

AcOOAc

CH3H3C

O O O HCH3HH H CH3O O CH3H CH3 HH3C CH3

OHCH3H3C

OH

Ph CO2EtO

H3C CH3

CH3CH3CH3

CH3CH3

OH

CH3HO

O O

O O O

Soojin Kwon

1, Oxone, DMM, CH3CN, H2O,

pH 10.5, 0 °C, 1.5 h

73%, 96% ee

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

Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792–8793.

CSA, toluene, 0 °C, 1 h31% (2 steps)

originally proposed structure of Glabrescol

Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 4831–4832.

H3C CH3

CH3CH3CH3

CH3CH3

OH

CH3HO

Applications in Synthesis:

88% ee

Glabrescol:

squaleneasymmetric

dihydroxylation

73%

H3C O NHFmoc

H3C O OHO

H3C CH3

O

HN

OO

CCl3

CH3

OH Cl

OCH3

O

HN

ONH

CH3

Cl

OCH3H3C O

H3CO O

O

H3C CH3

O

HN

OO

CCl3

CH3

O Cl

OCH3H3C O

H3CO

O

CH3

CH3

NHFmoc

O

HN

OO

CCl3

CH3

OH R

O

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

6.5:11.5:1

Conditions

Ketone 1m-CPBA

",! ratio

DMAP, DCC, CH2Cl271% (2 steps)

Conditions

Hoard, D. W.; Moher, E. D.; Martinelli, M. J.; Norman, B. H. Org. Lett. 2002, 4, 1813–1815.

Cryptophycin 52:

piperidine, DMF79%

Cryptophycin 52

O

O

Chem 115Shi Asymmetric Epoxidation ReactionMyers•

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TBSO

CO2CH3

TBSO CO2CH3O

TBSO CO2CH3

CH3

OAc

CH3

H3C

H3C

OOH OAc

CH3

H3CCH3

H

H3C

BrH

OOAc OH

CH3

H3CCH3

H

H3C

BrH

O

TBSO CO2CH3

OTBS

CH3

OHO

CH3CH3

O

CH3

OHCH3

CH3

O

O

OOAc OH

CH3

H3CCH3

H

H3C

BrH

CH3

OAc

CH3

H3CO

BrH3CHO

H

OOH3C

CH3

H

H3C

BrH

OH3C

H

H

HO CH3

OHO H

CH3

HO CH3

H3C H

TBSO

OTBS

CH3

H

O

Soojin Kwon

Octalactin A:

Ph3P, AcOH

80 °C, 8 h

85%

30 mol % 1, OxoneK2CO3, 0 °C, 6 h

45 %

1. Me3Al; H2O, –30 °C, 2 h, 82%

2. TBDMSCl, Im, 23 °C, 2 d, 84%

Octalactin A

Bluet, G.; Campagne, J.-M. Synlett 2000, 1, 221–222.

90–96% ee

Thyrsiferol:

1. NBS, THF, H2O, 67%

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

farnesyl acetate

cat. CSAEt2O50%

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

(+)-diethyl tartrate, CH2Cl299%

Thyrsiferol

McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593–595.

(proposed)

(proposed)

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

>95% de

Chem 115Shi Asymmetric Epoxidation ReactionMyers

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myers sharpless asymmetric epoxidation reaction chem...

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