1

Highly Enantio- and Diastereoselective One-Pot Synthesis ofAcyclic Epoxy Alcohols and Allylic Epoxy Alcohols

Ann Rowley Kelly, Alice E. Lurain, and Patrick J. Walsh*University of Pennsylvania, Philadelphia, PA

Adam Hoye, Oct. 15, 2005

R4

R2

OH

R1

R3

OR4

R2

OH R3

OR1

R6

R5

J. Am. Chem. Soc., ASAP (ja051291k)

Adam Hoye @ Wipf Group 1 10/15/2005

2Sharpless Asymmetric Epoxidation

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

Kinetic Resolution:

R2 R1

R3

D-(-)-tartrate (unnatural)

L-(+)-tartrate (natural)

"O"

"O"

t-BuOOH, Ti(Oi-Pr)4

CH2Cl2, -20oC

R2 R1

R3OH

O*

*70-87% yields,! 90% ee

OH

R2 R1

R3

D-(-)-tartrate (unnatural)

L-(+)-tartrate (natural)

"O"

"O"

t-BuOOH, Ti(Oi-Pr)4

CH2Cl2, -20oC

R2 R1

R3OH

O*

*

fast reactingstereoisomer

R4 R5

R2 R1

R3OH

R5 R4

Slow reactingstereoisomer

high ee

OHR4

R5

Adam Hoye @ Wipf Group 2 10/15/2005

3Epoxy Alcohols in Natural Product Synthesis

Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149Wender, P. A;, Hedge, S. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 4956Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A. J. Am. Chem. Soc., 2002, 124, 13654

Gabarda, A. E.; Du, W.; Isarno, T.; Tangirala, R. S.; Curran, D. P. Tetrahedron 2002, 58, 6329

NTMS OMe

OMOM

CH2OH

O

NTMS OMe

OMOM

CH2OH

(+)-DET, TBHP

Ti(O-iPr)4

HNTMS O

O

OHO

N

NO

O

OOH

Et

Homocamptothecin

1. LAH2. DMP

3. NaClO2

NTMS OMe

OMOM

CO2HHO

3 steps

OH

O

O O

O

H

H

H

OH

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

TBHP, CH2Cl2, -27 0COH

O

O O

O

H

H

H

OHO

fastslow

Laulimalide

Adam Hoye @ Wipf Group 3 10/15/2005

4Potential Limitations of Sharpless Methodology

• If epoxy alcohol is the desired product, kineticresolution must be quenched at low conversion to ensurehigh ee (i.e. quenching early to inhibit ‘mismatched’enantiomer from reacting)• Alternatively, the resolved allylic alcohol is oftenisolated and epoxidized in an additional step• Inherent to the KR of a racemic substrate, the maximumyield is 50%

Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237

OH

OH

racemicmixture

(L)-(+)-DIPT

Ti(Oi-Pr)4, t-BuOOH

+

FAST

SLOW

H OHH

H

O

OHH

(S)

(R)

+

45% yield, 99% ee

<50% yield, 97:3 d.r.

Adam Hoye @ Wipf Group 4 10/15/2005

5Previous Work in the Walsh Group

PhCHO

Et2Zn, -23 0C, hexane

HO

R

R

SO2HNNHO2S

OH

R

R

+ Ti(Oi-Pr)4

Ph Et

HO H

98-99% yield, 63-99% ee

Guo, C.; Qui, J. Zhang, X.; Verdugo, D.; Larter, M. L.; Christie, R.; Kenney, P.; Walsh, P. J. Tetrahedron 1997, 53, 4145

Adam Hoye @ Wipf Group 5 10/15/2005

6Walsh Cyclopropanation Strategy

Kim, H. Y.; Lurain, A. E.; García-García, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138

Via Method A:

Via Method B:

R3 R4

R2

O

Hi. Zn(R1)2

(-)-MIB

R4

R3

R2

OZnR1

R1

ii. 2 CF3CH2ZnCH2I

iii. H2OR4

R3

R2

OH

R1

H

R4

i. HBEt2

ii. ZnEt2, (-)-MIB

OH

N

O

R4ZnEt

iii. R1CHO

iv. 5 EtZnCH2Iv. H2O

R4

H

H

OH

R1

75-91% yield, 89-99% ee(>20:1 dr)

71-84% yield, 87-99% ee(>20:1 dr)

(A)

(B)

Adam Hoye @ Wipf Group 6 10/15/2005

7Walsh Epoxidation Strategy

R2 R3

R1

O

H (-)-MIBOH

N

O

(A)+ ZnR2

4 mol%R2 R3

R1

OZnEt

R

i.

ii. O2 (1 atm)

iii. Ti(Oi-Pr)4(20 mol%) R3R2

R1

OH

RO

3 equiv.

R2 R3

R1

O

H(B) + ZnMe2 Ti(Ot-Bu)4

3 equiv.

+ NHSO2CF3

NHSO2CF3i.

ii. O2 (1 atm)

(4 mol%)

R3R2

R1

OH

MeO

(C)

Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 13608

Adam Hoye @ Wipf Group 7 10/15/2005

8Current Paper

Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP

ZnEt2 O2+Et

OOZnEt

ZnEt2 +t-Bu

OOZnEt

t-BuOOH

Adam Hoye @ Wipf Group 8 10/15/2005

9Epoxidation Results

Adam Hoye @ Wipf Group 9 10/15/2005

10Diastereoselectivity of Epoxidation

R4

R2

OH

R1

R3

Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP

Adam Hoye @ Wipf Group 10 10/15/2005

11Determination of Predominant Steric Interaction in Epoxidation

Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP

Adam Hoye @ Wipf Group 11 10/15/2005

12Allylic Epoxy Alcohol Synthesis - in Situ Vinylzinc Reagents

Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAPOppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 10677

Adam Hoye @ Wipf Group 12 10/15/2005

13Allylic Epoxy Alcohol Synthesis - Isolated Divinylzinc Reagents

Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP

Adam Hoye @ Wipf Group 13 10/15/2005

14Conclusion

• Convenient one-pot method for the synthesis of epoxyalcohols and allylic epoxy alcohols, involving an initialasymmetric C-C bond formation followed bydiastereoselective epoxidation in high yields andstereoselectivities.

• Circumvents the need to prepare and isolate allylic orbis(allylic) alcohol intermediates, and offers a choice ofboth stoichiometric oxidant and ligand environment tobe used.

Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP

Adam Hoye @ Wipf Group 14 10/15/2005