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1 Highly Enantio- and Diastereoselective One-Pot Synthesis of Acyclic Epoxy Alcohols and Allylic Epoxy Alcohols Ann Rowley Kelly, Alice E. Lurain, and Patrick J. Walsh* University of Pennsylvania, Philadelphia, PA J. Am. Chem. Soc., ASAP

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Highly Enantio- and Diastereoselective One-Pot Synthesis of Acyclic 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 O R4 R2 OH R3 O R1 R6 R5

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

Adam Hoye @ Wipf Group 1 10/15/2005

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Sharpless 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 R3 OH 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 R3 OH O *

*

fast reacting stereoisomer R4 R5 R2 R1 R3 OH R5 R4 Slow reacting stereoisomer high ee OH R4 R5 Adam Hoye @ Wipf Group 2 10/15/2005

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Epoxy Alcohols in Natural Product Synthesis

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

N TMS OMe OMOM CH2OH O N TMS OMe OMOM CH2OH (+)-DET, TBHP Ti(O-iPr)4 H N TMS O O O HO N N O O O OH Et

Homocamptothecin

  • 1. LAH
  • 2. DMP
  • 3. NaClO2

N TMS OMe OMOM CO2H HO 3 steps OH O O O O H H H OH (+)-DIPT, Ti(Oi-Pr)4, TBHP, CH2Cl2, -27 0C OH O O O O H H H OH O fast slow

Laulimalide

Adam Hoye @ Wipf Group 3 10/15/2005

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Potential Limitations of Sharpless Methodology

  • If epoxy alcohol is the desired product, kinetic

resolution must be quenched at low conversion to ensure high ee (i.e. quenching early to inhibit ‘mismatched’ enantiomer from reacting)

  • Alternatively, the resolved allylic alcohol is often

isolated and epoxidized in an additional step

  • Inherent to the KR of a racemic substrate, the maximum

yield 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 racemic mixture (L)-(+)-DIPT Ti(Oi-Pr)4, t-BuOOH + FAST SLOW H OH H H O OH H

(S) (R)

+ 45% yield, 99% ee <50% yield, 97:3 d.r.

Adam Hoye @ Wipf Group 4 10/15/2005

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Previous Work in the Walsh Group

PhCHO Et2Zn, -23 0C, hexane HO R R SO2 HN NH O2S 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

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Walsh 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 H

  • i. Zn(R1)2

(-)-MIB R4 R3 R2 OZnR1 R1

  • ii. 2 CF3CH2ZnCH2I
  • iii. H2O

R4 R3 R2 OH R1 H R4

  • i. HBEt2
  • ii. ZnEt2,

(-)-MIB OH N O R4 ZnEt

  • iii. R1CHO
  • iv. 5 EtZnCH2I
  • v. 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

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Walsh Epoxidation Strategy

R2 R3 R1 O H (-)-MIB OH N O

(A)

+ ZnR2 4 mol% R2 R3 R1 OZnEt R i.

  • ii. O2 (1 atm)
  • iii. Ti(Oi-Pr)4

(20 mol%) R3 R2 R1 OH R O 3 equiv. R2 R3 R1 O H

(B)

+ ZnMe2 Ti(Ot-Bu)4 3 equiv. + NHSO2CF3 NHSO2CF3 i.

  • ii. O2 (1 atm)

(4 mol%) R3 R2 R1 OH Me O

(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

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Current Paper

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

ZnEt2 O2 + Et O O ZnEt ZnEt2 + t-Bu O O ZnEt t-Bu O O H

Adam Hoye @ Wipf Group 8 10/15/2005

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Epoxidation Results

Adam Hoye @ Wipf Group 9 10/15/2005

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Diastereoselectivity 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

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Determination 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

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Allylic Epoxy Alcohol Synthesis - in Situ Vinylzinc Reagents

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

Adam Hoye @ Wipf Group 12 10/15/2005

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Allylic 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

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Conclusion

  • Convenient one-pot method for the synthesis of epoxy

alcohols and allylic epoxy alcohols, involving an initial asymmetric C-C bond formation followed by diastereoselective epoxidation in high yields and stereoselectivities.

  • Circumvents the need to prepare and isolate allylic or

bis(allylic) alcohol intermediates, and offers a choice of both stoichiometric oxidant and ligand environment to be used.

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

Adam Hoye @ Wipf Group 14 10/15/2005