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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