Epoxidation with Peroxy AcidsR

morereactive

OH

OCO O

‡

RCO3H

Freccero, M.; Gandolfi, R.; Sarzi-Amadè, M.; Rastelli, A. J. Org. Chem. 2000, 65, 2030.Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 3385.

more likely

Epoxidation under Basic ConditionsM O

t-Bu

O

MeOt-BuOOHTriton® B

O

MeO

O

O

OO

H THFO

OH

t d li h lf h i

Triton® B = benzyltrimethylammonium hydroxide in H2O

trans-decalin half-chair

O

MeO

OO

OO

H

1,3-diaxial interaction

Grieco, P. A. et al. J. Am. Chem. Soc. 1977, 99, 5773.

transition metal-catalyzedHenbest epoxidationEpoxidation of Allyl Alcohols

transition metal catalyzed epoxidation

relative rateVO(acac)2

Henbest epoxidation

O

VO(acac)2t-BuOOH

1.00

OH OH

O >200

O

t-Bu

V O

OO

RO

Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.Henbest, H. B.; Wilson, R. A. I. J. Chem. Soc. 1957, 1958.Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.

O

Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.

Early Examples of Asymmetric Epoxidationof Allyl Alcohols

Yamada, S. et al. J. Am. Chem. Soc. 1977, 99, 1988.

Sharpless, K. B. et al. J. Am. Chem. Soc. 1977, 99, 1990.

Essence of Sharpless Asymmetric EpoxidationOHEtO C

[O]slow

CO2Et

OHEtO2C

HO

R2 R1

R3 OH2 1

D-(–)-diethyl tartrate(unnatural)

[O]R3

R

HR2 R1

R2 R1

R3 OHO

Ti(Oi-Pr)4t B OOH

[O]fast

R R

R3 OH

R

R2 R1

O

t-BuOOH

CH2Cl2

R2 R1

R3 OHH

R3 OHO

[O]R H

R

CO2Et

OHEtO2C

HO

Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York; 2000.

CO2EtHO

L-(+)-diethyl tartrate(natural)

Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.pSharpless, K. B., et al. J. Am. Chem. Soc. 1987, 109, 5765.

Katsuki, T. In Comprehensive Asymmetric Synthesis, Vol II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:Berlin; 1999.

(+) DETBnO OH

OBnO

BnO OH

OBn

Sharplessepoxidation

L-(+)-DET OBnClCH2SO2O

OB

single isomer

OBnClCH2SO2Oepoxidation

D-(–)-DETBnO OH

OBn

OBn

ClCH2SO2O

O

OBnClCH2SO2O

single isomer

Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1995, 36, 8247.

Kinetic Resolution of Racemic Allylic Alcohols

OH

H

OH

H

OH

H

O O

+

(+)-DIPTTi(Oi-Pr)4

CH2Cl2–20 ºC20 C

erythro threo98 : 2(S)

kfast/kslow = 104OH

H

OH

H

OH

H

O O

+

(+)-DIPTTi(Oi-Pr)4

CH2Cl2

fast slow

H H HCH2Cl2–20 ºC

erythro threo38 : 62(R)

Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.

Combination of asymmetric synthesis and kinetic resolution can deliver products with very high ee.p y g

OH

OHTi(Oi-Pr)4 (1.1 equiv)t-BuOOH (2.0 equiv)(–)-DIPT (1.3 equiv)

O major

CH2Cl2–25 ºC

80–85% yieldOH

iy

Ominor

0.5 h: 88% ee

1 h : 94% ee

1.5 h: >99.3% ee

Schreiber, S. L., et al. J. Am. Chem. Soc. 1987, 109, 1525.

OH

k1k1 k2 k3 k4

OH OH OH OH

O O O O

OH OH OH OHOH OH OH OH

O O O OO O O OO O O OO O O O

Catalyst Structure and Proposed “Loaded” Catalyst

O ORO

ORE OR

TiO

TiO OR

O

OO

E

OR

ROHO

t-BuOOH

TiO ORO

OR

E

E O

TiO

TiO O

OO

E E

t-BuRO

Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 113.Katsuki, T. In Comprehensive Asymmetric Synthesis, Vol II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:Berlin; 1999.

Asymmetric Epoxidation of Unfunctionalized Olefins

O OO

OO

O

O

O(30 mol %)

OXONE®, K2CO3

Ph Ph

OOXONE , K2CO3

CH3CN/dimethoxymethane0.05 M Na2B4O7 10H2O of aqueous 94% yield0.05 M Na2B4O7 10H2O of aqueous

Na2(EDTA) (4x10-4 M) solution

OXONE® = 2KHSO5 · KHSO4 · K2SO4

94% yield95.5% ee

Shi, Y. et al. J. Am. Chem. Soc. 1997, 119, 11224.

Na2(EDTA) is used to prevent trace-metal-catalyzed peroxide decomposition.

OO O

O

HSO5Ph OO

O5

O

PhO

O OO

OOO

Ph

‡

OO

OO

SO3O

O

OO

O O

Ph

SO3O O

O

OO

OO

Ph

dioxirane

Mn–Salen-Catalyzed Asymmetric Epoxidation

N NMn

H H

Ph

O O

t-Bu t-Bu

t-But-Bu Cl

(5 mol %)Ph Ph

O

(5 mol %)NaOCl (aq.)

CH2Cl2

81% yield92% ee

Jacobsen, E. N. et al. J. Am. Chem. Soc. 1991, 113, 7063. Jacobsen, E. N. et al. J. Am. Chem. Soc. 1990, 112, 2081. Katsuki, T. et al. Tetrahedron Lett. 1990, 31, 7345.

Dihydroxylation with Osmium Tetroxide

catalytic reaction

Milas, N. A.; Sussman, S. J. Am. Chem. Soc. 1936, 58, 1302.

acceleration by tertiary aminesy y

Criegee, R.; Marchand, B.; Wannowius, H. Liebigs Ann. Chem. 1942, 550, 99.

OMe

Asymmetric Dihydroxylation (AD)

N

OAc

OMe

Sharpless, K. B., et al. J. Am. Chem. Soc. 1980, 102, 4263.

PhPh

PhPh

OHN (1.1 equiv)

OsO4 (1.1 equiv)

toluene

LiAlH4

OHtoluene

90% yield83.2% ee

NNO O

N

H

N

H

(1 mol%)K OsO (OH) (0 2 mol%)

N N

MeO OMeSharpless, K. B., et al. J. Org. Chem.

1992, 57, 2768..

PhPh

PhPh

OHK2OsO2(OH)4 (0.2 mol%)

K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv)CH3SO2NH2 (1 equiv)

t-BuOH/H2OOH

2

>80% yield>99.5% ee

RR

Catalytic Cycle

+ L

R

OOs

O

O

OOs O

OO

O

R

HO

R

OH

R

+ L OOO

L

HO OH + L

organic

aqueous

2 HO2 H2O

Os

OHO OH

2–

Os

OHO O

2– 2 HO

aqueous

Os

OHO OH

Os

OHO O

2 HO 2 H2O2 Fe(CN)6

3–2

2 Fe(CN)64–

Two Proposed Mechanisms

Hoffmann, R., et al. J. Am. Chem. Soc. 1986, 108, 1867.Corey, E. J., et al. J. Am. Chem. Soc. 1996, 118, 11038.

Sharpless, K. B., et al. J. Am. Chem. Soc. 1997, 119, 1840.Houk, K. N.; Sharpless, K. B.; Singleton, D. A., et al. J. Am. Chem. Soc. 1997, 119, 9907.

Click Chemistry: Diverse Chemical Function from a Few Good ReactionsFunction from a Few Good Reactions

H h C K lb M G Fi d K B Sh l *

Angew Chem Int Ed 2001 40 2004

Hartmuth C. Kolb, M. G. Finn, and K. Barry Sharpless*

Angew. Chem. Int. Ed. 2001, 40, 2004.

“Nature is a matchless creator of C‐C linkages and we propose leaving the tough job of C‐C bond synthesis as much as possible to her.”