tandem reactions in organic synthesis townsend group meeting dorothy ackerman february 24, 2015

Tandem Reactions in Organic Synthesis

Townsend Group MeetingDorothy AckermanFebruary 24, 2015

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.

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.

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.

Categories of Tandem Reactions

• Nature of the first step:1. Cationic2. Anionic3. Radical4. Pericyclic5. Photochemical6. Transition Metal-Catalyzed7. Oxidation or Reduction Initiated8. Enzyme Assisted

Cationic ReactionsKumausallene 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

Cationic Reactions

G. Dyker, W. Stirner, G. Henkel, M. Kockerling, Tetrahedron Lett. 1999, 40, 7457-7458

Benzil Domino Cyclization: Dyker, 1999

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 AlEt3: Tu, 2003

Anionic Reactions

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

Anionic Reactions

Robinson Annulation leads to Weiland-Miescher Ketone: 1950

P. Wieland. K. Miescher, Helv. Chim. Acta 1950, 33, 2215L. B. Barkley, W. S. Knowles, H. Raffelson, Q. E. Tompson, J. Am. Chem. Soc. 1956, 78, 4111

Cortisone: Barkley, 1956

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

Anionic Reactions

Y. L. Lin, H. S. Kuo, Y. W. Wang, S. T. Huang, Tetrahedron, 2003, 59, 1277-1281J. K. Gallos, A. E. Koumbis, Arkivoc, 2003, 6, 135-144

Knoevenagel and hetero Diels-Alder: Gallos, 2003

SN2 and Wittig Olefination: Huang, 2003

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

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

Radical Reactions

Sevenfold 6-endo-trig Cyclization: Pattenden, 1999

S. Handa, G. Pattenden, J. Chem. Soc. Perkin Trans. 1 1999, 843-845

Pericyclic ReactionsPagodane: Prinzbach, 1987

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

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, 1610-1611M. E. Jung, P. Davidov, Org. Lett. 2001, 3, 3025-3027

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, 2081-2099A. K. Mukherjee, P. Margaretha, W. C. Agosta, J. Org Chem. 1996, 61, 3388-3391

Photochemically Induced ReactionsCyclic 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

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

Transition Metal-Catalyzed Reactions

H. Nemeto, M. Yoshida, K. Fukumoto, M. Ihara, Tetrahedrom Lett. 1999, 40, 907-910M. Yoshida, Yakugaku Zasshi, 2004, 124, 425-435

Equilenin: Nemoto, 1999

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, 1095-1105H. M. L. Davies, Curr. Org. Chem. 1998, 2, 463-488.

K. P. Kaliappan, R. S. Nandurdikar, Chem. Comm. 2004, 2506-2507.

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, 6142-6144P. Wipf, C. Kendall, C. R. J. Stephenson, J. Am. Chem. Soc. 2003, 125, 761-768.

Oxidation/Reduction Initiated Reactions

Chiral Cyclobutanones: Katzenellenbogen, 1997

G. M. Anstead, K. E. Carlson, J. A. Katzenellenbogen, Steroids 1997, 62, 268-303

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

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

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.

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

Multicomponent ReactionsAcylcarboxamide: 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.

Multicomponent Reactions

Tropinone: Robinson, 1917

Thiazolines: Assinger, 1956

F. Assinger, Angew. Chem. 1956, 68, 413.R. Robinson, J. Chem. Soc. 1917, 111, 762-768