1. Tandem Reactions in Organic Synthesis Townsend Group Meeting Dorothy Ackerman February 24, 2015

2. Common Terms used to Describe Tandem Reactions Tandem: “one after another” Sequential: “one pot” Domino: “two or more tranformations forming bonds, taking place under the same reaction conditions” Cascade: “describes how reactions happen-each subsequent change happens under structural change provided by the previous step” L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, Wiley- VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006 Ho, Tse-Lok. Tandem Organic Reactions, Wiley, New York, 1992.

3. Characteristics of Tandem Reactions Occur in succession locally, one after another Can have independent reaction sites Composed of ordinary reactions Sometimes in situ generation of reactive species L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, Wiley- VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006 Ho, Tse-Lok. Tandem Organic Reactions, Wiley, New York, 1992.

4. Benefits of Tandem Reactions Minimizes steps to build complex molecules Cost factor: less waste reduces materials used Often reduces natural resources used L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, Wiley- VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006 Ho, Tse-Lok. Tandem Organic Reactions, Wiley, New York, 1992. D. A. Barrera-Adame, J. M. Alvarez-Caballero, E. D. Coy-Barrera. Revista Facultad de Ciencias Basicas. 2012, 2, 292-309.

5. Categories of Tandem Reactions Nature of the first step: 1.Cationic 2.Anionic 3.Radical 4.Pericyclic 5.Photochemical 6.Transition Metal-Catalyzed 7.Oxidation or Reduction Initiated 8.Enzyme Assisted

6. Cationic Reactions Kumausallene via Prins/Pinacol: Overman, 1991 Triterpene Sophoradiol: Fish and Johnson, 1994 T.A. Grese, K.D. Hutchinson, L.E. Overman, J. Org. Chem. 1993, 53, 2468-2477. Fish, P. V.; Johnson, W. S. J. Org. Chem. 1994, 59, 2324

7. Cationic Reactions G. Dyker, W. Stirner, G. Henkel, M. Kockerling, Tetrahedron Lett. 1999, 40, 7457-7458 Benzil Domino Cyclization: Dyker, 1999

8. Cationic Reactions X. Li, B. Wu, X. Z. Zhao, T. X. Jia, T. Q. Tu, D. R. Li, Synlett 2003, 623-626 Double Reactivity of THF-inactivated AlEt 3 : Tu, 2003

9. Anionic Reactions Several well-known tandem reactions that proceed via an anionic process: – Robinson annulation – Michael reaction – Pictet-Spengler cylcization – Reductive amination

10. Anionic Reactions Robinson Annulation leads to Weiland-Miescher Ketone: 1950 P. Wieland. K. Miescher, Helv. Chim. Acta 1950, 33, 2215 L. B. Barkley, W. S. Knowles, H. Raffelson, Q. E. Tompson, J. Am. Chem. Soc. 1956, 78, 4111 Cortisone: Barkley, 1956

11. Anionic Reactions Zimmerman-Traxler Model: Z-enolates lead syn product E-enolates lead trans product Michael-Aldol: Oshima, 2001 Z. Han, S. Uehira, H. Shinokubo, K. Oshima, J. Org. Chem. 2001, 66, 7854-7857

12. Anionic Reactions Y. L. Lin, H. S. Kuo, Y. W. Wang, S. T. Huang, Tetrahedron, 2003, 59, 1277-1281 J. K. Gallos, A. E. Koumbis, Arkivoc, 2003, 6, 135-144 Knoevenagel and hetero Diels-Alder: Gallos, 2003 S N 2 and Wittig Olefination: Huang, 2003

13. Radical Reactions Ideal for sequencing Useful for building ring systems Able to add to inactivated double or triple bonds L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, Wiley- VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006

14. Radical Reactions Azadirachtin: Nicolaou, 2003 K. C. Nicolaou, A. J. Roecker, H. Monenschein, P. Guntupalli, M. Follmann, Ange. Chem. Int. Ed. 2003, 42, 3637-3642

15. Radical Reactions Sevenfold 6-endo-trig Cyclization: Pattenden, 1999 S. Handa, G. Pattenden, J. Chem. Soc. Perkin Trans. 1 1999, 843-845

16. Pericyclic Reactions Pagodane: Prinzbach, 1987 W. D. Fessner, G. Sedelmeier, P R. Spurr, G. Rihs, H. Prinzbach. J. Am. Chem. Soc. 1987, 109, 4626-4642

17. Pericyclic Reactions Steroid Skeleton from D-Galactose: Sherburn, 2003 Cyclopentenones: Jung, 2001 C. I. Turner, R. M. Williamson, P. Turner, M. S. Sherburn, Chem. Comm. 2003, 1610-1611 M. E. Jung, P. Davidov, Org. Lett. 2001, 3, 3025-3027

18. Photochemically Induced Reactions 1,2-disubstitued Cyclopentanes: Tietze, 1992 Tetra-substituted Furans: Agosta, 1996 L. F. Tietze, J. R. Wunsch, M. Noltemeyer, Tetrahedron, 1992, 48, 2081-2099 A. K. Mukherjee, P. Margaretha, W. C. Agosta, J. Org Chem. 1996, 61, 3388-3391

19. Photochemically Induced Reactions Cyclic γ-Keto Esters: Komatsu, 2002 I. Ryu, S. Kreimerman, R. Araki, S. Nishitani, Y. Oderaotoshi, S. Minakata, M. Komatsu, J. Am. Chem. Soc. 2002, 124, 3812-3813

20. Transition Metal-Catalyzed Reactions Estradiol: Tietze, 1996 L. F. Tietze, T. Nobel, M. Spescha, Angew. Chem. Int. Ed. Engl. 1996, 35, 2259-2261 L. F. Tietze, T. Nobel, M. Spescha, J. Am. Chem. Soc. 1998, 35, 8971-8977 T. Sugihara, C. Coperet, Z. Owczwarczyk, L. S. Harring, E. Negishi, J. Am. Chem. Soc. 1994, 116, 6923-7924 Enetetraynes Cyclization: Negishi, 1994

21. Transition Metal-Catalyzed Reactions H. Nemeto, M. Yoshida, K. Fukumoto, M. Ihara, Tetrahedrom Lett. 1999, 40, 907-910 M. Yoshida, Yakugaku Zasshi, 2004, 124, 425-435 Equilenin: Nemoto, 1999

22. Transition Metal-Catalyzed Reactions Tropane nucleus: Davies, 1997 Spiro and Dioxa-Triquinane: Nandurdikar, 2004 H. M. L. Davies, J. J. Matasi, L. M. Hodges, N. J. S. Huby, C. Thornley, N. Kong, J. H. Houser, J. Org Chem. 1997, 62, 1095-1105 H. M. L. Davies, Curr. Org. Chem. 1998, 2, 463-488. K. P. Kaliappan, R. S. Nandurdikar, Chem. Comm. 2004, 2506-2507.

23. Transition Metal-Catalyzed Reactions Hydrozirconation lead to biscyclopronanes: Wipf, 2003 Pauson-Khand and Diels-Alder lead to tetracycles: Chung, 2000 S. U. Son, Y. K. Chung, S. G. Lee, J. Org. Chem. 2000, 65, 6142-6144 P. Wipf, C. Kendall, C. R. J. Stephenson, J. Am. Chem. Soc. 2003, 125, 761-768.

24. Oxidation/Reduction Initiated Reactions Chiral Cyclobutanones: Katzenellenbogen, 1997 G. M. Anstead, K. E. Carlson, J. A. Katzenellenbogen, Steroids 1997, 62, 268-303

25. Oxidation/Reduction Initiated Reactions P. J. Black, M. C. Edwards, J. M. J. Williams, Tetrahedron, 2005, 61, 1363-1374. L. Finet, J. I. Candela Lena, T. Kaoudi, N. Birlirakis, S. Arseniyadis, Chem. Sur. J. 2003, 9, 3813-3820. Bridged-ring systems: Arsenivadis, 2003 Substituted alcohols: Williams, 2005

26. Oxidation/Reduction Initiated Reactions J. Y. Cha, J. T. S. Yeoman, S. E. Reisman, J. Am. Chem. Soc., 2011, 133, 4964–14967 Maoecrystal : Reisman, 2011

27. Use of Enzymes Rerrangement of Paclitaxel precursor: Vyas, 1995 Epoxide Opening: Williams, 1987 Taxane Anticancer Agents: Basic Science and Current Status (Eds.: G. I. Gerog, T. T. Chem, I. Ojima, D. M. Vyas), American Chemical Society, Washington, DC, 1995, ACS Symposium Series 538 S. T. Russel, J. A. Robinson, D. J. Williams, J. Chem. Soc. Chem. Commun. 1987, 351-352.

28. Multicomponent Reactions Type I: all reactions are reversible – Amines, carbonyl compounds, and weak acids Type II: majority of reactions are reversible – Final irreversible step pushed equilibrium forward Type III: practically all reactions are irreversible – Majority of biochemical compounds fromed this way

29. Multicomponent Reactions Acylcarboxamide: Passerini, 1921 Peptide-like structures: Ugi, 1960 M. Passerini, Gazz. Chim. Ital. 1921 51, 126; M. Passerini, Gazz. Chim. Ital. 1921 51, 181. I. Ugi, R. Meyr, U. Fetzer, C. Steinbrukner, Angew. Chem. 1959, 71, 386 I. Ugi, C. Steinbruckner, Angew. Chem. 1960, 72, 267-268.

30. Multicomponent Reactions Tropinone: Robinson, 1917 Thiazolines: Assinger, 1956 F. Assinger, Angew. Chem. 1956, 68, 413. R. Robinson, J. Chem. Soc. 1917, 111, 762-768