1. Enantioselective Formation of Quaternary Carbon Centers Cory C. Bausch November 18, 2004

2. Outline Introduction Types of Reactions –Alkylations –Diels-Alder –Cyclopropanation –Pd Catalyzed Reactions –Chiral Transfer Reactions Summary

3. Introduction Chiral quaternary center: Carbon with four different non-hydrogen substituents Quaternary Center in this context: Carbon with four non-equivalent carbon substituents

4. Synthetic Targets

5. Outline Introduction Types of Reactions –Alkylations –Diels-Alder –Cyclopropanation –Pd Catalyzed Reactions –Chiral Transfer Reactions Summary

6. ,  -Alkylated Ketones Shun-ichi Hashimoto and Kenji Koga Tetrahedron Lett. 1978, 6, 573 R’Isolated YieldOptical Yield a Me62%94 (S) a) Based on optical rotation of pure enantiomer

7. Tandem Michael Addition/Aldol Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron Lett. 1980, 21, 4005

8. Scope of Addition/Alkylation EntryMethodRTrans (yield)Cis (yield)%ee 1AC6H5C6H5 55082 2ACH 2 =CH62092 3BC6H5C6H5 06582 4BCH 2 =CH06192 Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron Lett. 1980, 21, 4005 Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron 1981, 37, 3951

9. Alkylation of  -Keto Esters Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. J. Am. Chem. Soc. 1984, 106, 2718 Achieve both enantiomers with the same chiral species Binding properties of ligand affect orientation of enamine

10. Orientation of Addition Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. Tetrahedron Lett. 1984, 25, 5677 THF is poor coordinating ligand HMPA is strong coordinating ligand

11. Scope of Alkylation EntryR 1,R 2 R3R3 R4XR4XLigand (equiv)ProductYield (%)% ee 1(CH 2 ) 4 MeMeIHMPA (1.0)A57>99 (R) 2(CH 2 ) 4 MeMeITHF (2.0)B6392 (S) 3(CH 2 ) 4 MeCH 2 =CHCH 2 BrHMPA (1.0)A7176 (S) 4(CH 2 ) 4 MeCH 2 =CHCH 2 BrDioxolane (1.2)B5656 (R) 5MeEtCH 2 =CHCH 2 BrHMPA (1.0)A6894 (S) 6MeEtCH 2 =CHCH 2 BrDioxolane (2.0)B2047 (R) 7MeEtPhCH 2 BrHMPA (1.0)A9092 (S) 8MeEtPhCH 2 BrDioxolane (2.0)B8390 (R) Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. J. Am. Chem. Soc. 1984, 106, 2718

12. Chiral Phase Transfer Catalysis Hermann, K. and Wynberg, H. J. Org. Chem. 1979, 44, 2238 EntryCatalystSolventReaction Time Yield (%)% Optical Purity 1ADioxane67 h995 (R) 2ACH 2 Cl 2 43 h898 (R) 3ABenzene74 h9910 (R) 4AToluene18 h9010 (R) 5ACCl 4 1 h9817 (R) 6BCCl 4 1 h999 (S)

13. PTC, cont. Reaction gives up to 95% yield, 92% ee Dolling, U.H.; Davis, P.; Grabowski, E.J. J. Am. Chem. Soc. 1984, 106, 446

14. PTC, cont. Convenient, efficient Robinson annulation. Product can be obtained in 78% ee and 99% yield. Dolling, U.H., et al. Angew. Chem. Int. Ed. Engl. 1986, 25, 476

15. Nucleophilic Chiral Pd Enolates Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240 Works for  -keto esters as well Reaction scope gives 69-92% yield and 89-93% ee

16. Salen-Al Catalyzed Michael Additions EntryRR’TimeYield (%)%eed.r. 1n-PrPh19 hr989714:1 2n-Prm-CF 3 C 6 H 4 15 hr969835:1 3n-Prp-MeOC 6 H 4 38 hr94956:1 4n-Pr2-thienyl4 d769114:1 5MePh24 hr95865:1 6i-BuPh24 hr96 16:1 Taylor, M.S. and Jacobsen, E.N. J. Am. Chem. Soc. 2003, 125, 11204

17. Outline Introduction Types of Reactions –Alkylations –Diels-Alder –Cyclopropanation –Pd Catalyzed Reactions –Chiral Transfer Reactions Summary

18. Enantioselective Diels Alder Cycloadditions Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamota, H. J. Org. Chem. 1989, 54, 1481 Reaction scope gives 40-91% yield and 82-96% ee

19. Cr(III)-Salen Catalyzed Enantioselective Diels-Alder Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843

20. Cr(III)-Salen Catalyzed, cont. EntryRCatalystTemp (°C)TimeYield (%)% ee 1Allyl1b-402 d9390 2Me1b-402 d8978 3Benzyl1b-402 d95 4Benzyl1c-402 d9397 5Benzyl1brt8 hr8093 6Benzyl1crt16 hr9291 Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843

21. Cr(III)-Salen Catalyzed, cont. EntryRTemp (°C)TimeYield (%)% ee 1Me-402 d9397 2Et-402 d9197 3Isopropyl-405 d92>97 4TBSO(CH 2 ) 2 -402 d9395 5TBSO-402 d86>97 Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843

22. Advances of Cr(III)-Salen Catalyzed Diels-Alder Huang, Y.; Iwama, T.; Rawal, V.H. Org. Lett. 2002, 4, 1163 Preserves second stereocenter Possesses more functionality General reaction scope Mild and convenient conditions

23. Rare-Earth Metal Catalyzed Quinone Diels-Alder Evans, D.A. and Wu, J. J. Am. Chem. Soc. 2003, 125, 10162 New effective chiral lewis acid in quinone Diels-Alder reactions Sm, Gd are optimal metals from lanthanide metal screen

24. Quinone Diels-Alder Reaction EntryQuinoneCatalystR1R1 R2R2 ProductYield (%)% ee 11a-(Sm)MeH8797 21a-(Gd)MeH9998 31a-(Gd)HH9998 41a-(Gd)HMe9997 51a-(Gd)n-PrH9698 61a-(Sm)MeH91>99 71a-(Gd)HH88>99 81a-(Sm)HMe8498 91b-(Gd)MeH>9991 101b-(Gd)HH91 Evans, D.A. and Wu, J. J. Am. Chem. Soc. 2003, 125, 10162

25. Application of Enantioselective Diels-Alder Key step in the synthesis of Aspidosperma alkaloids Generates two key stereocenters in one step Synthesis gives >95% ee in 12 overall steps Can be completed on >1 g scale Kozmin, S.A.; Iwama, T.; Huang, Y.; Rawal, V.H. J. Am. Chem Soc. 2002, 124, 4628

26. Further Applications Corey, E.J.; Guzman-Perez, A.; Teck-Peng, L. J. Am. Chem. Soc. 1994, 116, 3611 Diels-Alder sets stereocenter in high ee Efficient synthesis of 6-membered ring backbone

27. Outline Introduction Types of Reactions –Alkylations –Diels-Alder –Cyclopropanation –Pd Catalyzed Reactions –Chiral Transfer Reactions Summary

28. Enantioselective Cyclopropanation Asymmetric Modified Simmons-Smith Reaction –Reported in 1985 by Yamamoto, et al. and Mash, et al. Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254 Mash, E.A. and Nelson, K.A. J. Am. Chem. Soc. 1985, 107, 8256

29. Cyclopropanation, cont. EntryAcetal Temp (°C), Time (hr) ProductYield (%)% de 1-20, 18189 2-20, 76188 3-20, 75085 430, 46395 530, 47593 Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254 Mash, E.A. and Nelson, K.A. J. Am. Chem. Soc. 1985, 107, 8256

30. Cyclopropanation in Total Synthesis Cyclopropanation in 84% yield, 89% ee 15% overall yield in 14 Steps Mash, E.A.; Math, S.K.; Flann, C.J. Tetrahedron Lett. 1988, 29, 2147

31. Cyclopropanation of Allylic Alcohols General substrate scope No stoichiometric chiral source necessary Order of addition of reagents is important Denmark, S.E. and O’Connor, S.P. J. Org. Chem. 1997, 62, 584

32. Outline Introduction Types of Reactions –Alkylations –Diels-Alder –Cyclopropanation –Pd Catalyzed Reactions –Chiral Transfer Reactions Summary

33. Pd-Catalyzed Heck Reactions Thoroughly explored pathway to quaternary carbons Reaction is enantioselective and catalytic Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738

34. Heck Reactions Cis-decalin derivatives among first systems studied EntryRLigandTemp (°C)Time (hr)Yield (%)% ee 1CO 2 Me(DIPHOS)60568-- 2CO 2 Me(R)-BINAP6037.57446 3CH 2 OTBDMS(R)-BINAP40447044 4CH 2 OAc(R)-BINAP40886636 Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738

35. Heck Reactions Improvements using vinyl triflates –No silver salt needed –Higher enantiomeric excess obtained EntryRLigandTemp (°C)Time (hr)Yield (%)% ee 1CO 2 Me(R)-BINAP60315491 2CH 2 OTBDMS(R)-BINAP60303592 3CH 2 OAc(R)-BINAP60304489 4CH 2 OPv(R)-BINAP60276091 Sato, Y.; Watanabe, S.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2589

36. Heck Reactions Synthesis of hydrindans Sato, Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2593

37. Heck-Type Reactions Palladium catalyzed polyene cyclizations of trienyl triflates Carpenter, N.E.; Kucera, D.J.; Overman, L.E. J. Org. Chem. 1989, 54, 5846

38. Application of Polyene Cyclization Enantioselective total synthesis Heck reaction unsuccessful, polyene cyclization works well Maddaford, S.P.; Anderson, N.G.; Cristofoli, W.A.; Keay, B.A. J. Am. Chem. Soc. 1996, 118, 10766

39. Heck Reaction, cont. Form enantioenriched spirocycles Achieve either enantiomer with same catalyst Ashimori, A.; Bachand, B.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6477

40. Enantioenriched Spirocycles Silver salt works better than amine base Scope is fairly general Ashimori, A.; Bachand, B.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6477

41. Enantioenriched Natural Products Heck cyclization can obtain either enantiomer Matsuura, T.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6500

42. Synthesis of Vicinal Stereogenic Quaternary Carbon Centers Overman, L.E.; Paone, D.V.; Stearns, B.A. J. Am. Chem. Soc. 1999, 121, 7702

43. Vicinal Quaternary Centers, cont. Overman, L.E.; Paone, D.V.; Stearns, B.A. J. Am. Chem. Soc. 1999, 121, 7702 Both products formed with complete stereocontrol Variation in protecting group allows access to both stereogenic products

44. Further Expansion of Heck Coupling Lebsack, A.D.; Link, J.T.; Overman, L.E.; Stearns, B.A. J. Am. Chem. Soc. 2002, 124, 9008

45. Pd-Catalyzed Allylation Chiral ferrocenylphosphine ligands among first used Works for wide array of  -diketones Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113

46. Pd-Catalyzed Allylation Trost, B.M.; Radinov, R.; Grenzer, E.M. J. Am. Chem. Soc. 1997, 119, 7879 Trost, B.M.; Schroeder, G.M. J. Am. Chem. Soc. 1999, 121, 6759

47. Enantioselective Tsuji Allylation Behenna, D.C. and Stoltz, B.M. J. Am. Chem. Soc. ASAP

48. Tsuji Allylation, cont. Catalytic cycle of racemic allylation Behenna, D.C. and Stoltz, B.M. J. Am. Chem. Soc. ASAP Tsuji, J. and Minami, I. Acc. Chem. Res. 1987, 20, 140

49. Outline Introduction Types of Reactions –Alkylations –Diels-Alder –Cyclopropanation –Pd Catalyzed Reactions –Chiral Transfer Reactions Summary

50. Chiral Transfer Reactions Chirality transfer based on thermodynamic stability Hiroi, K.; Nakamura, H.; Anzai, T. J. Am. Chem. Soc. 1987, 109, 1249

51. Pinacol-Type Rearrangement Lewis acid promoted migration forms quaternary carbon center Larger group migrates 87-100% Yield, 95-100% retension of stereochemistry Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 5891

52. Lewis Acid Cat. Rearrangement Form  -siloxy aldehydes from epoxy silyl ethers Can use catalytic L.A., but decreases yields Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamota, H. Tetrahedron 1991, 47, 6983

53. Summary

54. Acknowledgements Advisor: Jeff Johnson Johnson Group