organocatalytic oxidation catalytic asymmetric epoxidation of olefins with chiral ketones and...

Organocatalytic OxidationOrganocatalytic OxidationCatalytic Asymmetric Epoxidation of Olefins Catalytic Asymmetric Epoxidation of Olefins with Chiral Ketones and Synthetic Applicationswith Chiral Ketones and Synthetic Applications

Frédéric ValléeProf. Charette’s laboratoriesLiterature Meeting 20th January 2009

2

Outline

-Introduction

-Chiral Ketone-Catalyzed Epoxidation

-Carbohydrate-Based and Related Ketones

-Synthetic Applications

3

Introduction Optically active epoxides are highly useful intermediates and building blocks for the total synthesis of biologically active compounds.

OH

OO

Leukotriene A

O

O

O

O

OH

O

H

Fumagilin

NNH

HN

NH

O

O

OOH

O

O

O

Epoxomicin

4

Introduction Various effective systems have been developed over the years for enantioselective epoxidations.

-Sharpless (epoxidation of allylic alcohols with chiral titanium catalyst)

-VO(acac)2 (epoxidation of allylic and homoallylic alcohols)

-Jacobsen (epoxidation of unfunctionalized, cis and terminal olefins)

Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 2000; Chapter 6A.Hoshino, Y.;Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 10452. Zhang, W.;Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem.,Int. Ed. 2005, 44, 4389. Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 941. Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286.Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.Ed.; VCH: New York, 1993; Chapter 4.2. Collman, J. P.; Zhang, X.; Lee, V. J.; Uffelman, E. S.; Brauman, J. I. Science 1993, 261, 1404.

5

Introduction Among the many powerful methods for the epoxidation of olefins, three-membered ring compounds containing two heteroatoms are very versatile oxidation reagents.

Murray, R. W. Chem. Rev. 1989, 89, 1187. Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205.Adam, W.; Saha-Moller,C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499.

N+

Me

Me

O

Ph

BF4-

ON

H

R1R2 O

O

DioxiranesOxaziridines

Oxaziridinium Salts

6

Introduction

More rencently asymmetric epoxidations catalyzed by chiral ketones have received much attention.

Significant progress has been made in this field towards the epoxidation of various types of olefins such as

R

R'

RR'

Unfunctionalyzed

R3 R1

R2

cis

trans

Trisubstituted

7

Introduction

R R'

O

OHO

R R'O

SO3-

O-O

R R'O

SO3-

OH-

R R'

OO

HSO5-

SO42-

R3R2

R1

OR3

R3

R1

Ketone-Catalyzed Epoxidation of Olefins

The dioxiranes are generated in situ from ketone and Oxone(2KHSO5 KHSO4 K2SO4)

Edwards, J. O.; Pater, R. H.; Curci, R.; Di Furia, F. Photochem. Photobiol. 1979, 30, 63. Curci, R.; Fiorentino, M.; Troisi, L.; Edwards, J. O.; Pater, R. H. J. Org. Chem. 1980, 45, 4758. Gallopo, A. R.; Edwards, J. O. J. Org. Chem. 1981, 46, 1684.

8

Outline

-Introduction




9

Early Ketones

OMe Me

Me

1

Ph

Me O

Me

H

2

Biphasic

Me Me

O

CF3

O

Me

3

F3C OCH3

Me

O

4

Curci, R.; Fiorentino, M.; Serio, M. R. Chem. Commun. 1984, 155.Curci, R.; D’Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995, 36, 5831.

1984 Curci and co-workers

Yields from 60-92% Up to 12% ee (2, 50 mol%)

1995 Curci and co-workers

Yields from 80-82% Up to 20% ee (4, 1 equiv.)

R

R'

RR'

Unfunctionalyzed

R3 R1

R2

Cis

trans

Trisubstituted

10

C2-Symmetric Binap-Based Ketones

O

O

O

O

X

O

X

8a, X = H8b, X = Cl8c, X = Br

8d, X =O

O

R

R'

RR'

Unfunctionalyzed

R3 R1

R2

cis

trans

Trisubstituted

RTerminal

R

R'1,1'-DIsubstituted

Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491. Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem.Soc. 1996, 118, 11311. Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J.-H. J. Am. Chem. Soc. 1998, 120, 5943.

Yields from 70-95%Up to 95% ee

Best resultsCatalyst 8d, 10 mol%Substrate (E)-Stilbene

Note : As the X going larger from H (47% ee), to Cl (76% ee), to Br (75% ee), to I (32%ee).

1996 Yang and co-workers

11

Other C2-Symmetric Ketones

RR'

R3 R1

R2

trans

Trisubstituted

O

OO

OO

O

5 6

RR'trans

1997 Song and co-workers

1997 Adam and co-workers

Yields from 61-95%Up to 59% ee (6, 1 equiv)

O

O

O

OO

OO

7

O

O

PhPh

Ph Ph

Me

MeO

8

Yields from 67-80%Up to 81% ee (8, 1 equiv)

Song, E. C.; Kim, Y. H.; Lee, K. C.; Lee, S.-g.; Jin, B. W. Tetrahedron: Asymmetry 1997, 8, 2921. Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry 1997, 8, 3995.

12

Other C2-Symmetric Ketones

OMeMe

9a

OMeMe

9b

F

OMeMe

9c

F

F

OMeMe

9d

FF

1998 Denmark and co-workers

Conversion from 6-100% Enantioselectivity up to 94% ee (9c, 30 mol%)

And many others….

RR'

R3 R1

R2

trans

Trisubstituted

RTerminal

Unfunctionalyzed

Denmark, S. E.; Wu, Z. Synlett 1999, 847.Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479.

13

Bicyclo3.2.1octan-3-ones

N

CO2Et

O

X

O

O

XAcO OR

OAcO

10a, X = F10b, X = OAc

11a, X = F11b, X = OAc

12a, R = Ac12b, R = Piv12c, R = Bz

O

O

13

F

OAc

O

O

14a, R = CO2Et14b, R = CH2OC(O)Me

F

R

O

O

X

15a, X = SO2Me15b, X = OAc15c, X = F

1998 Armstrong and co-workers

Conversion from 47-100% Up to 98% ee

Best resultsCatalyst 11b, 20 mol%Substrate

RR'

R3 R1

R2

trans

Trisubstituted

RTerminal

Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621. Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67, 8610.Sartori, G.; Armstrong, A.; Maggi, R.; Mazzacani, A.; Sartorio, R.; Bigi, F. J. Org. Chem. 2003, 68, 3232.

14

Outline

-Introduction


-Carbohydrate-Based and Related Ketones (The Work of Shi)


15

Carbohydrate-Based Ketones

Yian Shi was born in Jiangsu, China, in 1963 and obtained his B.Sc. degree in chemistry from Nanjing University in 1983. Upon receiving his M.Sc. degree from University of Toronto with Professor Ian W. J. Still in 1987, he pursued his doctoral studies at Stanford University with Professor Barry M. Trost and obtained his Ph.D. degree in 1992. Subsequently, he carried out his postdoctoral studies at Harvard Medical School withProfessor Christopher Walsh from 1992 to 1995. He joined Colorado State University as assistant professor in 1995 and was promoted to associate professor in 2000 and professor in 2003.

16


1996 Shi and co-workers

OOH

OH

HO

OH

OH

OO

O

O

OHHClO4

OO

O

O

O

O

OO

D-Fructose

16

L-Sorbose Ent-16

PCC

Overall Yield = 49%

Overall Yield = 41-60%

CH2Cl2, rt

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

17


Selectivity and Reactivity; Basic General Considerations

(Catalyst Developement)

1) Stereogenic center must be close to the reacting center which favor the ‘’chiral communication’’ between substrates and catalyst.

2) Fused ring and/or a quaternary center to the carbonyl minimizes the epimerization of de stereogenic centers.

3) C2- or pseudo C2 symmetric element inducing steric discrimination as olefin approaches to the

reacting dioxirane.

4) Inductive activation of the carbonyl with the presence of many closed oxygen atoms.


O

O

O

O

OO

1

3

3

2

18

Catalyst DevelopmentWhy use carbohydrate-derived ketone ?

Y

X

O

Y

X

Y

X

O

R1

R2nO

O

O

O

OO

(a) Carbohydrates are chiral, readily available and inexpensive.

(b) They are highly substituted with oxygen groups, (inductive effect of oxygen).

(c) Carbohydrate-derived ketones can have rigid conformations due to the anomeric effect, which is desirable for selectivity.


19

Catalyst DevelopmentImpact of the pH on the epoxidation with in situ generated dioxiranes

- At high pH, Oxone autodecomposes rapidly- At pH 7-8, 16 give high enantioselectivity but… need an excess!- Raising the pH, to avoid B-V favoring 19 formation and hoping that the reaction of the ketone with Oxone will be faster than its decomposition

OH-

HSO5-

SO42-

R3R2

R1

OR3

R3

R1 O

O

O

O

OO

16

O

O

OO

OO

17O SO3

-

Baeyer-V illiger (pH 7-8) 20

O

O

OO

O

OO

21

O

O

O

O

OO

O

O

O

OO

OO

18

O SO3-

OH

O-

O

O

OO

OO

19

O

not been isolated


20

Catalyst DevelopmentA dramatic pH effect led to a catalytic asymmetric process

Plot of the conversion of trans--methylstyrene against pH using ketone 16 (0.2 equiv) as catalyst in two solvent systems, H2O-CH3CN (1:1.5 v/v) (A) and H2O-CH3CN-DMM (2:1:2 v/v) (B)

Plot of the conversion of trans--methylstyrene against pH using acetone (3 equiv) as catalyst in H2O-CH3CN (1:1.5 v/v). Samples were taken at different reaction times for the determination of conversion: 0.5 (A), 1.0 (B), 1.5 (C), and 2.0 h (D)


DMM : Dimethoxymethane

21

Reaction OptimizationSolvent effects


Temperature effects

22

Scope and Substrates

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

O

OO

O

OO

30 mol%

Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), MeCN-DMM-0.05 M, Na2B4O7 10 H2O of Na2EDTA

R'R

O

(1:2:2 v/v)

R'R

PhPh Ph Ph Cl OTBS

n-C6H13n-C6H13

OO PhOMe

O

PhPh Ph

PhC10H21

Ph

Ph

PhC10H21

C10H21

COOEt

OO

83%95% ee

89%95% ee

92%92% ee

85%98% ee

94%96% ee

49%96% ee 78%

96% ee

68%92% ee

89%96% ee

94%98% ee

98%95% ee

92%79% ee

83%95% ee

97%87% ee

94%89% ee

89%94% ee

41%97% ee

trans and Trisubstituted olefins

23


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

O

OO

O

OO

65 mol%


R'R

O

(1:2:2 v/v)

R'R

PhTMS

PhTMS TMSPh

TMS

TBDMSO TMS TMSHO

TMS

74%94% ee

82%94% ee

66%93% ee

51%90% ee

67%84% ee

67%92% ee

71%93% ee

TBDPSO

(30 mol% of theketone was used)

2,2-Disubstituted Vinylsilanes

24


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

O

OO

O

OO

30 mol%


R'R

O

(1:2:2 v/v)

R'R

85%94% ee

45%91% ee

68%91% ee

87%94% ee

93%94% ee

85%92% ee

75%74% ee

Ph OH PhOH OH

Ph OH

Ph

OHOH OHPh OH

82%90% ee

Hydroxyalkenes

25

Scope and Epoxides

O

OO

O

OO

20-30 mol%

Oxone (1.12-1.38 equiv.), K2CO3 (5.0-6.2 equiv.), MeCN-DMM-0.05 M, Na2B4O7 10 H2O of Na2EDTA

R'R

O

(1:2:2 v/v)

R'R

77%97% ee

54%95% ee

41%96% ee

68%96% ee

68%95% ee

82%95% ee

61%94% ee

Ph

89%94% ee

O Ph

O

O COOEt OOTBS

O

OH

68%90% ee

O

COOEt

O COOEt O COOEtO COOEt

O

TMS

60%92% ee

Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.

Conjugated Dienes

26


Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64, 7646.

O

OO

O

OO

30 mol%

Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), MeCN-DMM-aq K2CO3/AcOH

R'R

O

(1:2:2 v/v)

R'R

78%93% ee

71%93% ee

97%77% ee

98%96% ee

59%96% ee

71%89% ee 84%

95% ee

60%93% ee

COOEt

OTBS

OTBS

Ph

TMS TMS TMS

Conjugated Enynes

27


Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 4080. Feng, X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999,121, 11002. Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.

O

OO

O

OO

30 mol%

Oxone (1.38 equiv.), K2CO3 (5.8 equiv.), org solv/aq buffer-aq (3:2 v/v), 0oC

R'R

OR'

R

82%93% ee

79%80% ee

87%91% ee

82%95% ee

92%88% ee

66%91% ee

46%91% ee

OBz OBz OBz

OBz

Ph

OAc

PhPh

OAc

OBz

Method Limitation : cis and terminal olefins

Enol Esters

28

Understanding

3D

29

Understanding

Two mechanistic extremes for disubstituted olefins

O

O

R

R'

Spiro

O

O

R

R'

Planar

Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311-3314. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437-3439.

R1

H HR2

O

O

Me

Me

Spiro-trans

O

O

Me

Me

HR2

H R1

Planar-trans

H

R1H

R2

O

O

Me

Me

Spiro-cis

O

O

Me

Me

HH

R2 R1

Planar-cis

30

Understanding

Mechanistic studies of disubstituted olefins

Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311-3314. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437-3439.

R1

H HR2

O

O

Me

Me

Spiro-trans

O

O

Me

Me

HR2

H R1

Planar-trans

H

R1H

R2

O

O

Me

Me

Spiro-cis

O

O

Me

Me

HH

R2 R1

Planar-cis

- The cis-hexenes is more reactive- The reactivity is dependent on the size of the alkyl groups of the olefin

cis-hexenes vs. trans-hexenes

31

Understanding

Mechanistic studies disubstituted olefins

Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett. 1987, 28, 3311. Baumstark, A. L.; Vasquez, P. C. J. Org. Chem. 1988, 53, 3437.Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.

R1

H HR2

O

O

Me

Me

Spiro-trans

O

O

Me

Me

HR2

H R1

Planar-trans

H

R1H

R2

O

O

Me

Me

Spiro-cis

O

O

Me

Me

HH

R2 R1

Planar-cis

vs.

vs.

- The trans-isomers is slightly more reactive (Ph is planar)- Calculation show that the Spiro TS is favored for the epoxidation on ethylene

32

Understanding

Mechanistic studies disubstituted olefins

Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.

-The spiro orientation could benefits from a stabilizing interaction of an oxygen lone pair with the * orbital of the alkene

OO

RR'

Spiro

OO

RR'

Planar

O

O

R

R'non-bondingorbital

orbital

O

O

R


orbital

33

Stereochemical analysis

OOO

O O

R3

OO

R2

R3

FavoredSpiro (A)

OOO

O O

R3

OO

R2

R1

Favored

OOO

O O

R1

OO

R3

R2

Disfavored

R3R1

R2

O

OOO

O O OO

R2

R3

Disfavored

R1

OOO

O O

R2

OO

R1

Disfavored

R3

R3R1

R2

O

Spiro (A) Spiro (B) Spiro (C) Spiro (D)

OOO

O O OO

DisfavoredPlanar (E)

R2

R1

R3O

OO

O O OO

R3

R1

R2

OOO

O O OO

R2

R1

R3

Disfavored DisfavoredPlanar (G)Planar (F)

OOO

O O OO

R3

R1

R2

FavoredPlanar (H)

Major ( I) Minor (J)

OOO

O O OO

R1

R1

R1

FavoredPlanar (H)

Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.

No benef itf rom secondarystabilizing interactions

34

Stereochemical analysis

Bach, R. D.; Andres, J. L.; Owensby, A. L.; Schlegel, H. B. J. Am. Chem. Soc. 1992, 114, 7207.Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224.

-Due to steric repulsion B-C-D-F-G are disfavored (for disubstituted, where R2=H, B is similar to A and G to H

-Favored spiro A and planar H TS result in the opposite stereochemistry

-For trans-disubstituted and trisub-stituted olefin the spiro TS is favored since the epoxide I is formed predominately

General TS analysis OO

O

O O

R3

OO

R2

R1

Favored

OOO

O O

R1

OO

R3

R2

Disfavored

R3R1

R2

O

OOO

O O OO

R2

R3

Disfavored

R1

R3R1

R2

O

Spiro (A)

Spiro (B)

Spiro (C)

OOO

O O OO

DisfavoredPlanar (E)

R2

R1

R3

OOO

O O OO

R3

R1

R2

FavoredPlanar (H)

Major (I)

Minor (J)

OOO

O O OO

R3

R1

R2

DisfavoredPlanar (F)

OOO

O O OO

R2

R1

R3

DisfavoredPlanar (G)

OOO

O O

R2

OO

R1

Disfavored

R3

Spiro (D)

35

Stereoelectronic Effect

B

G

Reaction Coordinate


98% ee0oCO

2.5 kcal mol-1

~2.5 kcal mol-1 beetweenthe two different TS

(Ph are planar)

OO

O

O O

Ph

OO

HPh

Spiro (A)

OOO

O O OO

Ph

Ph

H

Planar (H)

+~2.5 kcal mol-1

O

O

R


orbital

The energy difference between the two TS will vary with the substituents, since the energy level of the * is affected by those…

36

Steric Effect…


OO

O

O O

R3

OO

R2

R1

Spiro (A)

OOO

O O OO

R3

R1

R2

Planar (H)

vs.

-Decreasing the size R1 → high ee (spiro A favored)-Increasing the size of R3 → high ee (spiro A favored)

The case of the trisubstituted olefin

37

Steric Effect…

OO

O

O O

R3

OO

R2

R1

Spiro (A)

OOO

O O OO

R3

R1

R2

Planar (H)

vs.

Ph

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

Ef fect of the size of R1 (decreasing)

Ef fect of the size of R3 ( increasing)

Ph C10H21

76% ee 87% ee 91% ee

Ef fect of the size of R1 and R3 (decreasing R1 and increasing R3 )

PhPh

76% ee 97% ee


Major competitingpathway

38

What about cis and Terminal Olefins?


For cis, electronic and steric factors should favor the spiro TS

OO

O

O O

R3

OO

R2

Spiro (A)

OO

O

O O

R2

OO

R3

Spiro (D)

a b

- a and b are the main interaction and furthermore, the ee depends on the energy difference between them.

- The greater the size difference between R2 and R3 the higher the ee is.

39

What about cis and Terminals olefins?

OOO

O O OO

R3

Spiro (A)

OO

O

O O

R3

OO

Spiro (D)

OOO

O O OO

R3

Planar (F)

OOO

O O OO

R3

Planar (G)

O

OO

O

NO SO2Me


Terminals olefins

-The energy difference between these TS seems too small

ON

O

O O OO

Spiro (Z)Favored

O

R

SO2Me

ON

O

O O OO

SO2Me

O

R

Spiro (AA)

-ee’s up to 97% with great conversions

Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293.Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115.Wong, O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973.

40

Ketone Structures

O

OO

O

OO O

OO

O

OO

Et Et

EtEt

O

OO

O

OO O

OO

O

OHO

ClO

OO

O

MeO

OO

O

OO

16 22 23 24 25 26

Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.

- The catalytic properties are dependant on the precise nature of the ketone.

- The pyranose oxygen is beneficial for catalysis (16 vs. 26).

-16 is still the best ketone for the epoxidation and for the enantioselectivity compared to all (TS issues).

41

Ketones StudiesO

OO

O

OO O

OO

O

OO

Et Et

EtEt

O

OO

O

OO O

OO

O

OHO

ClO

OO

O

MeO

OO

O

OO

16 22 23 24 25 26


-The rigid 5-6 spiro ring of 16, is superior in controlling the enantioselectivity.

- 16 is also superior with regard to the yield.

- 16 is more stable under the optimal epoxidation conditions.

OO

O

O O

R2R1

R3R4

R

OO

R

Spiro (A)

OO

O

O O

R2R1

R3R4

OO

R

Spiro (B)

RO

OO

O O

R3R4

OO

R

R

Planar (C)

R2R1

42

Pyranose Oxygen EffectO

OO

O

OO

OO

O

OO

16 26

Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 2001, 66, 521.

Entry Substrate Catalyst Yield (%) ee (%)

1

2

3

4

5

6

7

8

Ph 16 93 92

26 61 87

16 75 97

26 10 88

16 100 15

26 88 15

16 53 51

26 17 61

PhPh

Ph

O

O

43

Pyranose Oxygen Effect

O

O

O

O

OO

16

O

O

O

OO

26

mCPBA

O

O

OO

16a

OO

O O

O

OO

16b

O

OO

major

mCPBA

O

O

OO

26a

O

O O

O

OO

26b

O

O

43% 57%

trace


44

Outline

-Introduction



-Examples of Synthetic Applications Using 16 as Catalyst

45

First Synthesis of (+)-Aurilol

O

OSEMO

O

OHHHO H

16

Oxone

83%

O

OSEMO

O

OHHHO H

O

(15:1)

OHHO H

(10:1)

OO

O

OHH

ent-16

Oxone67%

OHHO H

OO

O

OHH

O

OH H

OOH

OH

OHHO

Br

H

(+)-Aurilol

Morimoto, Y.; Nishikawa, Y.; Takashi, M. J. Am. Chem. Soc. 2005, 127, 5806.

O

OO

O

OO

16 =

46

Enantioselective Total Synthesis of (+)-Nigellamine A2

OH

OH

H

O

Ph

16Oxone

51% two steps

1)

2) Nicotinic acid DCC, DMAP

O

O

H

O

Ph

O

ON

ON

(+)-Nigellamines A2

(7:1 favoring C7-8)

3

4

7

8

Macrocyclic epoxydation

Same diast. with ent-16

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

O

OO

O

OO

16 =

47

Total Syntheses of Nakorone, and Abudinol B via Biomimetic Oxa- and Carbacyclizations

TMS

SO2Tol

16

Oxone76% TMS

SO2Tol

O O

(20:1)

O

OH

H

HOH

ent-Nakorone

OH

H

HOH

ent-Abudinol

O

OH

H

H

Tong, R.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X.; Hardcastle, K. I. J. Am. Chem. Soc. 2007, 129, 1050.

O

OO

O

OO

16 =

48

Biomimetic

Nakanishi, K. Toxicon 1985, 23, 473.Shimizu, Y.; Chou, H.-N.; Bando, H.; Van Duyne, F.; Clardy, J. C. J. Am. Chem. Soc. 1986, 108, 514. Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 588.

O

O

O

O

O

O

O

OO

OO

O

H

H H H H H HH

H

H

HO

H H

H

H H

O-O

R

HO

O O OO O O O

O

O

O

H

O

H+

O-

R

O

HO

Biosynthetic Pathway of Brevitoxin B

Proposed all-fused epoxide-opening cascade

49

Epoxide-Opening Cascades Promoted by Water

MeO

TBSOH

16Oxone

50% (two steps)

MeO

TBSOH

O

O

O

H

1) TBAF/THF2) H2O 70oC, 72h

(71%)

O

O

O

O

HHHHMe

HHO

H H H

O

TBSOH

H

Lio, NH3

(3:1 dr)

Stereoselective Epoxidation of a Skipped-Triene

Me

H

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

O

OO

O

OO

16 =

50

Conclusion

The Shi’s epoxidation is a powerful selective and efficient way to make enantioselective epoxides and it is a wonderful tool for the synthesis of building blocks involved in modern total synthesis.

51

Thank you!

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