Highly Enantio- and Diastereoselective One-Pot Synthesis of Acyclic - PowerPoint PPT Presentation

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 (ja051291k) OH R 3 R 6 OH R 3 R 1 R 4 R 5 R 4 O O R 2 R 1 R 2 Adam Hoye, Oct. 15, 2005 Adam Hoye @ Wipf Group 1 10/15/2005

2 Sharpless Asymmetric Epoxidation D-(-)-tartrate (unnatural) "O" R 2 R 1 R 2 R 1 O * t -BuOOH, Ti(O i -Pr) 4 OH R 3 OH CH 2 Cl 2 , -20 o C R 3 * 70-87% yields, � 90% ee "O" L-(+)-tartrate (natural) Kinetic Resolution: D-(-)-tartrate (unnatural) "O" R 2 R 1 R 2 R 1 R 2 R 1 R 4 t -BuOOH, Ti(O i -Pr) 4 O * OH R 3 OH OH CH 2 Cl 2 , -20 o C R 3 R 3 * high ee R 5 R 5 R 4 R 4 R 5 fast reacting Slow reacting "O" stereoisomer stereoisomer L-(+)-tartrate (natural) 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 Adam Hoye @ Wipf Group 2 10/15/2005

3 Epoxy Alcohols in Natural Product Synthesis slow fast OH OH H O H O O (+)-DIPT, Ti(O i -Pr) 4 , OH O O OH O O TBHP, CH 2 Cl 2, -27 0 C H H H H O O Laulimalide 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 H TMS N OMe TMS N OMe TMS N O TMS N OMe 1. LAH (+)-DET, TBHP 2. DMP 3 steps OMOM OMOM OMOM O Ti(O- i Pr) 4 3. NaClO 2 O HO HO CH 2 OH CH 2 OH O CO 2 H O N N O Et O OH Homocamptothecin Gabarda, A. E.; Du, W.; Isarno, T.; Tangirala, R. S.; Curran, D. P. Tetrahedron 2002 , 58 , 6329 Adam Hoye @ Wipf Group 3 10/15/2005

4 Potential Limitations of Sharpless Methodology OH OH H H FAST (S) <50% yield, 97:3 d.r. O (L)-(+)-DIPT + racemic + mixture Ti(O i -Pr) 4 , t- BuOOH OH OH H H SLOW (R) 45% yield, 99% ee • 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 Adam Hoye @ Wipf Group 4 10/15/2005

5 Previous Work in the Walsh Group Et 2 Zn, -23 0 C, hexane HO H PhCHO Ph Et 98-99% yield, 63-99% ee + Ti(O i -Pr) 4 O 2 S NH HN SO 2 R OH HO R R R 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

6 Walsh Cyclopropanation Strategy O ( A ) i. Zn(R 1 ) 2 ii. 2 CF 3 CH 2 ZnCH 2 I R 3 OH R 3 OZnR 1 R 2 H R 4 R 1 R 4 R 1 O iii. H 2 O R 3 R 4 R 2 R 2 N 75-91% yield, 89-99% ee OH (>20:1 dr) (-)-MIB ( B ) H H OH i. HBEt 2 iii. R 1 CHO ZnEt R 4 R 4 R 1 iv. 5 EtZnCH 2 I ii. ZnEt 2 , H v. H 2 O (-)-MIB R 4 71-84% yield, 87-99% ee (>20:1 dr) Via Method A: Via Method B: Kim, H. Y.; Lurain, A. E.; García-García, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005 , 127 , 13138 Adam Hoye @ Wipf Group 6 10/15/2005

7 Walsh Epoxidation Strategy O N OZnEt i. OH O R 1 OH ii. O 2 (1 atm) R 1 R 1 ( A ) R R (-)-MIB H + ZnR 2 O iii. Ti(O i -Pr) 4 R 2 R 3 3 equiv. R 2 R 3 R 2 R 3 (20 mol%) 4 mol% NHSO 2 CF 3 O i. OH (4 mol%) R 1 R 1 ( B ) H NHSO 2 CF 3 Me + ZnMe 2 + Ti(O t -Bu) 4 O 3 equiv. R 2 R 3 ii. O 2 (1 atm) R 2 R 3 ( 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

8 Current Paper Et O O ZnEt ZnEt 2 + O 2 t -Bu O O H t -Bu O O ZnEt + ZnEt 2 Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP Adam Hoye @ Wipf Group 8 10/15/2005

9 Epoxidation Results Adam Hoye @ Wipf Group 9 10/15/2005

10 Diastereoselectivity of Epoxidation OH R 3 R 1 R 4 R 2 Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005 ASAP Adam Hoye @ Wipf Group 10 10/15/2005

11 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

12 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

13 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

14 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