1. Samarium(II) Iodide Mediated Sequential Reactions Roy Bowman January 16, 2004

2. Sequential Reactions Multiple bonds formed in a one pot process No need to collect and purify intermediates Access to elaborate products Although conceptually attractive, design of sequential reactions can be overwhelming Cationic, anionic, radical, pericyclic, carbenoid, and transition metal catalyzed sequential processes have been realized Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321-3354.

3. Samarium(II) Iodide Totleben, M. J.; Curran, D. P.; Wipf, P. Journal of Organic Chemistry 1992, 57, 1740-4. Concellon, J. M.; Rodriguez-Solla, H.; Bardales, E.; Huerta, M. European Journal of Organic Chemistry 2003, 1775-1778 Typically generated and utilized in situ Most stable as Sm(III)

4. Samarium(II) Iodide Girard, P.; Namy, J. L.; Kagan, H. B. Journal of the American Chemical Society 1980, 102, 2693-8.

5. Samarium(II) Iodide Promotes several individual reactions important in synthesis: - Radical Cyclizations - Ketyl-Olefin Coupling - Pinacolic Coupling - Barbier Type Reactions - Aldol Type Reactions - Reformatsky Type Reactions - Conjugate Additions - Nucleophilic Acyl Substitutions -Cycloadditions

6. Samarium(II) Iodide Ability to promote both one and two electron processes Radical/Anionic Anionic/Radical Anionic/Anionic Radical/Radical

7. Reactivity Reactivity can be manipulated using: Co-solvents: HMPA, TMG, DBU Additives: Ni(II), Fe(III) Irradiation of the reaction mixture Allows for highly selective and efficient sequential reactions to be effective Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9. Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron Letters 1995, 36, 949-52. Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.; Hirao, T. Journal of the American Chemical Society 1997, 119, 2745-2746. Machrouhi, F.; Hamann, B.; Namy, J. L.; Kagan, H. B. Synlett 1996, 633-634.

8. Radical Cyclization/Carbonyl Addition Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8. Unclear how carbonyl addition proceeded Barbier or Grignard type reaction?

9. Formation of Organosamarium Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.

10. Formation of Organosamarium Samarium-Barbier Conditions: Addition of O-Allyl-iodobenzene and acetophenone to a THF solution containing Samarium diiodide and HMPA Samarium-Grignard Conditions: Iodobenzene was added to a solution of SmI 2 /HMPA after; 5 minutes acetophenone was added Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.

11. Radical Cyclization/Carbonyl Addition Ketone% Yield 3-pentanone69 4-heptanone81 cyclopentanone68 cyclohexanone65 2-methylcyclohexanone70 4-t-butylcyclohexanone67 Molander, G. A.; Harring, L. S. Journal of Organic Chemistry 1990, 55, 6171-6.

12. Radical Cyclization/Carbonyl Addition ElectrophileProductYieldElectrophileProductYield Curran, D. P.; Totleben, M. J. Journal of the American Chemical Society 1992, 114, 6050-8.

13. Radical Cyclization/Carbonyl Addition Molander, G. A.; Kenny, C. Journal of Organic Chemistry 1991, 56, 1439-45. Pendent ester activates ketone Control of three stereocenters Forming radical is trans to ketyl oxygen

14. Radical Cyclization/Carbonyl Addition EntryKetone% Yieldd.r. 1Acetone7931:1 23-Pentanone7365:1 3Diisopropyl ketone32>200:1 4Cyclohexanone58200:1 5Cyclopentanone6560:1 62-Methylcyclohexanone751:1 74-t-Butylcyclohexanone6110:1 Molander, G. A.; Kenny, C. Journal of Organic Chemistry 1991, 56, 1439-45.

15. Radical Cyclization/Nucleophilic Addition Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9. Facile cyclization was achieved with unactivated ketones

16. Radical Cyclization/ Nucleophilic Addition Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.

17. Radical Cyclization/ Nucleophilic Addition ElectrophileProduct% YieldElectrophileProduct% Yield Molander, G. A.; McKie, J. A. Journal of Organic Chemistry 1992, 57, 3132-9.

18. Intramolecular Nucleophilic Acyl Substitution/Intramolecular Barbier Cyclization Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16. Provides access to a variety of bi- and tri-cyclic ring systems

19. Intramolecular Nucleophilic Acyl Substitution/Intramolecular Barbier Cyclization Ability to sequence formation of the organosamarium species so carbon-carbon bonds may be directed Alkyl halides are reduced in the order I > Br > Cl Sequences where order is unimportant are performed with diiodides Sequenced reactions in which side chain reaction order is significant are performed with alkyl iodide/alkyl chloride substrates Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16.

20. Intramolecular Nucleophilic Acyl Substitution/Intramolecular Barbier Cyclization Molander, G. A.; Harris, C. R. Journal of the American Chemical Society 1995, 117, 3705-16.

21. Nucleophilic Acyl Substitution/Ketyl Olefin Coupling for Preparation of Oxygen Heterocycles Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956. Provides access to bi- and tricyclic furans an pyrans

22. Nucleophilic Acyl Substitution/Ketyl Olefin Coupling Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.

23. Nucleophilic Acyl Substitution/Ketyl Olefin Coupling Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.

24. Ketyl-Olefin Coupling/β-Elimination Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 812-816. Result is net addition of an alkenyl moiety to a carbonyl group Complementary to traditional alkylation techniques

25. Ketyl-Olefin Coupling/β-Elimination Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.

26. Nucleophilic Acyl Substitution/Alkenyl Transfer Reactions Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380. Provides cyclic products from acyclic starting materials

27. Nucleophilic Acyl Transfer/Alkenyl Transfer Reactions EntryR1R1 R2R2 R3R3 X%Yield A%Yield B 1MeMe/HH/MeCl73- 2MeEt/HH/EtCl71<5 3MeEt/HH/EtI77<5 4t-Bui-PrHI7023 5t-BuHi-PrI6925 6Mei-PrHCl6214-23 7MeHi-PrCl60-7014-23 Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.

28. Nucleophilic Acyl Transfer/Alkenyl Transfer Reactions EntryR1R1 R2R2 R3R3 X%Yield A%Yield B 1MeMe/HH/MeCl73- 2MeEt/HH/EtCl71<5 3MeEt/HH/EtI77<5 4t-Bui-PrHI7023 5t-BuHi-PrI6925 6Mei-PrHCl6214-23 7MeHi-PrCl60-7014-23 Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.

29. Nucleophilic Acyl Transfer/Alkenyl Transfer Reactions Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1998, 63, 4374-4380.

30. Epoxide Ring Opening/Ketyl Olefin Coupling Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956. Complete selectivity was achieved through chelation of the ketyl oxygen and the hydroxyl group

31. Domino Epoxide Ring Opening/Ketyl Olefin Coupling Reactions EntryR%Yield 2 + 3 (Ratio 2:3) %Yield 4%Yield 5Reaction Time (min) 1Me88 (12:1)--15 2Et86 (10:1)--20 3i-Pr72 (10:1)--20 4t-Bu10 (7:1)-4760 5Ph-164520 Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.

32. Domino Epoxide Ring Opening/Ketyl Olefin Coupling Reactions EntryR%Yield 7+8 (ratio 7:8) %Yield 9%Yield 10Time (min) 1Me61 (>100:1)--10 2Et65 (100:1)--15 3i-Pr66 (50:1)--20 4t-Bu81 (2:1)--30 5Ph-532415 Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.

33. Domino Epoxide Ring Opening/Ketyl Olefin Coupling Reactions EntryR1R1 R2R2 T(°C)%Yield 12+13 (ratio 12:13) 1CO 2 EtMe-7885 (>50:1) 2PhMe-7882 (2.6:1) 3PhMe23 °C79 (1:1.6) 4PhMe076 (1:1) 5PhMe-2078 (1.5:1) Molander, G. A.; Harris, C. R. Journal of Organic Chemistry 1997, 62, 2944-2956.

34. Epoxide Fragmentation/Tandem Radical Cyclizations Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.

35. Epoxide Fragmentation/Tandem Radical Cyclizations EntrymnT (°C)Cis/trans Ratio 3 %Yield 2 % Yield 3 12105/1-72 221-204/1-70 311018/1-61 411-2037/1-60 51203/14322 612rt3/14027 72202/16714 822rt2/15626 Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.

36. Epoxide Fragmentation/Tandem Radical Cyclizations EntrymnT (°C)Cis/trans Ratio 3 %Yield 2 % Yield 3 12105/1-72 221-204/1-70 311018/1-61 411-2037/1-60 51203/14322 612rt3/14027 72202/16714 822rt2/15626 Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.

37. Epoxide Fragmentation/Tandem Radical Cyclizations Molander, G. A.; Del Pozo Losada, C. Tetrahedron 1998, 54, 5819-5832.

38. Intramolecular Barbier Cyclization/Grob Fragmentation Molander, G. A.; Le Huerou, Y.; Brown, G. A. Journal of Organic Chemistry 2001, 66, 4511-4516. Stereospecific with regard to the leaving group Stereochemistry of the alkoxide plays no role in the stereochemistry of the fragmentation Fragmentation proceeds under mild conditions

39. Ring Expansion by Grob Fragmentation Mediated by SmI 2 EntryXnmRing SizeYield 1Cl208- 2I11869 3I12942 4I21986 5I221051 6I2412- Molander, G. A.; Le Huerou, Y.; Brown, G. A. Journal of Organic Chemistry 2001, 66, 4511-4516.

40. Ring Expansion by Grob Fragmentation Mediated by SmI 2 Molander, G. A.; Le Huerou, Y.; Brown, G. A. Journal of Organic Chemistry 2001, 66, 4511-4516.

41. Reformatsky/Nucleophilic Acyl Substitution Provides an efficient route to functionalized 8 and 9 membered carbocycles Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.

42. Reformatsky/Nucleophilic Acyl Substitution Diastereoselectivity of sequential process originates in the initial Reformatsky reaction Selectivity results from highly organized transition state Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.

43. Reformatsky/Nucleophilic Acyl Substitution EntrySubstrateProduct% Yield Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.

44. Reformatsky/Nucleophilic Acyl Substitution EntrySubstrateProduct% Yield Molander Gary, A.; Brown Giles, A.; Storch de Gracia, I. Journal of Organic Chemistry 2002, 67, 3459-63.

45. Transformation of Carbohydrate Derivatives into Cyclopentanols Grove, J. J. C.; Holzapfel, C. W.; Williams, D. B. G. Tetrahedron Letters 1996, 37, 5817-5820.

46. Transformation of Carbohydrate Derivatives into Cyclopentanols EntryRR’R’’Yield (%) 1AcOAcAc70 2AcOPivPiv72 3AcOBnBn76 4PhHPiv72 5PhHBn71 Grove, J. J. C.; Holzapfel, C. W.; Williams, D. B. G. Tetrahedron Letters 1996, 37, 5817-5820.

47. Insertion of Isocyanides into Organic Halides Preparation of  -Hydroxy Ketones Murakami, M.; Kawano, T.; Ito, Y. Journal of the American Chemical Society 1990, 112, 2437-9. Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65. Facile synthesis of  -hydroxy ketones by samarium mediated coupling of organic halides, 2,6-xylyl isocyanide, and carbonyl compounds  -Addition of organosamarium to isocyanide forms an (  -iminoalkyl)samarium complex which can act as an acyl anion equivalent Compatibility with a variety of functional groups under mild conditions

48. Insertion of Isocyanides into Organic Halides Preparation of  -Hydroxy Ketones EntryR-XElectrophileProductYield Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.

49. Insertion of Isocyanides into Organic Halides Preparation of  -Hydroxy Ketones EntryR-XKetoneProductYield Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.

50. Insertion of Isocyanides into Organic Halides Preparation of  -Hydroxy Ketones EntryR-XElectrophileProductYield Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.

51. Insertion of Isocyanides into Organic Halides Preparation of  -Hydroxy Ketones EntryR-XElectrophileProductYield Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.

52. Insertion of Isocyanides into Organic Halides Preparation of  -Hydroxy Ketones EntryImineMethodProductYield Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. Journal of Organic Chemistry 1993, 58, 1458-65.

53. Synthesis of Vicinal Di- and Tri-Carbonyl Compounds Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.

54. Synthesis of Vicinal Di- and Tri-Carbonyl Compounds EntryAlkyl HalideMethodProductYield Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.

55. Synthesis of Vicinal Di- and Tri-Carbonyl Compounds EntryAlkyl HalideElectrophileProductYield Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.

56. Synthesis of Vicinal Di- and Tri-Carbonyl Compounds Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. Journal of Organic Chemistry 1991, 56, 1-2.

57. Cyclizations of Indole Derivatives Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307. Indole derivatives can act as accepter units for intramolecular coupling of ketyls The intermediate organosamarium species can be trapped by electrophiles

58. Cyclizations of Indole Derivatives Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307. High degree of diastereoselectivity comes from ordered transition state

59. Cyclizations of Indole Derivatives Gross, S.; Reissig, H.-U. Organic Letters 2003, 5, 4305-4307.

60. Cascade Radical Cyclizations: Synthesis of Paeonilactone B Boffey, R. J.; Santagostino, M.; Kilburn, J. D.; Whittingham, W. G. Chemical Communications (Cambridge) 1998, 1875-1876. Initiated by ketyl radical cyclization onto a methylene cyclopropane with subsequent endo ring opening

61. Cascade Radical Cyclizations: Synthesis of Paeonilactone B Boffey, R. J.; Santagostino, M.; Kilburn, J. D.; Whittingham, W. G. Chemical Communications (Cambridge) 1998, 1875-1876. Stereochemistry set in initial cyclization which proceeds through a chair-like transition state

62. Synthesis of (±) Hypnophilin Fevig, T. L.; Elliott, R. L.; Curran, D. P. Journal of the American Chemical Society 1988, 110, 5064-7. Radical cyclizations can construct multiple five- membered rings in a controllable fashion Tandem radical cyclizations about a cyclopentene forms the triquinane core for Hypnophilin and Coriolin

63. Synthesis of (±) Hypnophilin Fevig, T. L.; Elliott, R. L.; Curran, D. P. Journal of the American Chemical Society 1988, 110, 5064-7. Product isolated as a 10:1 mixture of product and reduced aldehyde

64. Synthesis of Phomoidrides John Wood, Unpublished Results, webpage A and B isolated in 1995 at Pfizer Later the two related congeners,C and D, were isolated and found to be epimers of A and B

65. Synthesis of Phomoidrides Poses several challenges

66. Synthesis of Phomoidrides Poses several challenges Bridgehead olefin contained in a [4.3.1] bicyclic framework

67. Synthesis of Phomoidrides Poses several challenges Bridgehead olefin contained in a [4.3.1] bicyclic framework Stereogenic all carbon quaternary center

68. Synthesis of Phomoidrides Poses several challenges Bridgehead olefin contained in a [4.3.1] bicyclic framework Stereogenic all carbon quaternary center Potentially hydrolytically labile maleic anhydride moiety

69. Synthesis of Phomoidrides Poses several challenges Bridgehead olefin contained in a [4.3.1] bicyclic framework Stereogenic all carbon quaternary center Potentially hydrolytically labile maleic anhydride moiety Two olefinic side chains attached to the phomoidride core at stereogenic centers

70. Synthesis of Phomoidrides Efficient method for construction of the isotwistane core John Wood, Unpublished Results, Webpage

71. Summary Mild conditions, tolerant to functionality Reactivity can be manipulated allowing each step in the sequence to be tuned Capable of driving sequential reactions Highly diastereoselective resulting from highly organized transition states Sequential radical cyclization mediated by SmI 2 have shown utility in natural product synthesis

72. Acknowledgements Dr. Jeff Johnson Johnson Group