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    Organometallics

     

    THE DESIGN AND DEVELOPMENT OF NEW METAL-CATALYZED REACTIONS represents one of the most important endeavors in chemistry if we are to realize the full potential of the field.  The ability to make target molecules with step economy, efficiency, selectivity, and in an environmentally safe and operationally simple fashion is an objective of great importance.  The design or discovery of new reactions is key to realizing this aim. New reactions provide fundamentally new ways to think about synthesis, thereby allowing us to realize practical syntheses of important targets (see earlier discussion in this handout). Our research group has pioneered the invention of many new transition metal-catalyzed reactions, some of which are illustrated below or described in the accompanying references. Complexity-generating cycloadditions such as these have application in the expedient syntheses of novel ligand scaffolds, therapeutic leads, and molecules of biological and theoretical interest.

    First Intramolecular Metal-Catalyzed [4+4] Cycloadditions

    First Intramolecular Metal-Catalyzed [4+2] Cycloadditions


    First Metal-Catalyzed Intramolecular [5+2] Cycloadditions

    First Metal-Catalyzed Intermolecular [5+2] Cycloadditions

    Serial [5+2]/[4+2] Cycloadditions to Achieve High Molecular Complexity

    The First Transition Metal-Catalyzed [6+2] Cycloaddition

    The First Transition Metal-Catalyzed [5+2+1] Three Component Cycloaddition

    The First Transition Metal-Catalyzed [5+1+2+1] Four Component Cycloaddition

    New Intra- and Intermolecular Dienyl Pauson-Khand Reactions


    New [2+2+1] Reactions of Dienes, Alkenes or Allenes, and CO

    New [4+2+2] Reactions of Dienes, Alkenes and Alkynes

    Novel [3+2] Cycloadditions of Cyclopropenones & Alkynes

    New Carbonylative Rearrangements and [6+1] Ring Expansions of Allenyl Ethers


    Novel [2 + 2 + 2 + 2] Cycloadditions of Terminal Diynes for the Synthesis of Cyclooctatetraenes

    Theoretical Calculations Explain Experimental Trends with Mechanistic Insight

     

    Lead references:

  1. Liu, P.; Cheong, P. H.; Yu, Z.-X.; Wender, P. A.; Houk, K. N. "Substituent Effects, Reactant Preorganization, and Ligand Exchange Control the Reactivity in Rh(I)-Catalyzed (5+2) Cycloadditions between Vinylcyclopropanes and Alkynes"; Angew. Chem. Int. Ed. 2008, 47, 3939-3941.
  2. Z.-X. Yu, P. Ha-Yeon Cheong, P. Liu, C. Legault, P. Wender, K. Houk “Origins of Differences in Reactivities of Alkenes, Alkynes, & Allenes in [Rh(CO)2Cl]2-Catalyzed (5+2) Cycloaddition Reactions with Vinylcyclopropanes” J. Am. Chem. Soc. 2008, 130, 2378-2379.
  3. Wender, P.; Christy, J. “Nickel(0)-Catalyzed [2+2+2+2] Cycloadditions of Terminal Diynes for the Synthesis of Substituted Cyclooctatetraenes” J. Am. Chem. Soc. 2007, 13402.
  4. Wender, P.; Paxton, T.; Williams, T. "Cyclopentadienone Synthesis by Rhodium(I)-Catalyzed [3+2] Cycloaddition Reactions of Cyclopropenones and Alkynes" J. Am. Chem. Soc. 2006, 14814.
  5. Wender, P.; Croatt, M.; Witulski, B. "New Reactions and Step Economy: Total Synthesis of Salsolene Oxide Based on the Type II Transition Metal-Catalyzed Intramolecular [4+4] Cycloaddition" Tetrahedron 2006, 7505.
  6. Wender, P.; Haustedt, L.; Lim, J.; Love, J.; Williams, T.; Yoon, J. "Asymmetric Catalysis of the [5+2] Cycloaddition Reaction of Vinylcyclopropanes and Pi-Systems" J. Am. Chem. Soc. 2006, 6302.
  7. Wender, P.; Christy, J. “Rh (I)-Catalyzed [4+2+2] Cycloadditions of 1,3-Dienes, Alkenes, & Alkynes for the Synthesis of Cyclooctadienes” J. Am. Chem. Soc. 2006, 5354.
  8. Wender, P.; Croatt, M.; Deschamps, N. “Metal-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Allenes, & CO” Angew. Chem. Int. Ed. 2006, 2459.
  9. Wender, P.; Deschamps, N.; Sun, R. "Rh-Catalyzed C-C Bond Activation; Seven-membered Ring Synthesis by a [6+1] Carbonylative Ring-expansion Reaction of Allenylcyclobutanes" Angew. Chem. Int. Ed. 2006, 3957.
  10. Wender, P.; Deschamps, N.; Sun R. "Rh(I)-catalyzed cleavage of unactivated C-O bonds - Carbonylative rearrangement reactions of allenyl ethers to 2-carboalkoxy-1,3-dienes" Can. J. Chem. 2005, 838. 
  11. Wegner, H.; de Meijere, A.; Wender, P. "Transition Metal-catalyzed Intermolecular [5+2] and [5+2+1] Cycloadditions of Allenes & Vinylcyclopropanes" J. Am. Chem. Soc. 2005, 6530.
  12. Wender, P.; Gamber, G.; Hubbard, R.; Pham, S.; Zhang, L.; “Multicomponent Cycloadditions: The Four-Component [5+1+2+1] Cycloaddition of Vinylcyclopropanes, Alkynes, & CO” J. Am. Chem. Soc. 2005, 2836.
  13. Wender, P., Deschamps, N., Williams, T. “The Intermolecular Dienyl Pauson–Khand Reaction” Angew. Chem. Int. Ed. 2004, 3076-3079. 
  14. Wender, P., Croatt, M Deschamps, N. M. “Rhodium(I)-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Alkenes, & CO” J. Am. Chem. Soc. 2004, 5948;
  15. Wender, P.; Love, J.; Williams, T. “Rhodium-catalyzed [5+2] cycloaddition reactions in water”, Synlett, 2003, 1295.
  16. Wender, P.; Deschamps, N.; Gamber, G. “The dienyl Pauson-Khand reaction”, Angew. Chem. Int. Ed. 2003, 1853.
  17. Wender, P.; Bi, F.; Gamber, G.; Gosselin, F.; Hubbard, R.; Scanio, M.; Sun, R.; Williams, T. J.; Zhang, L."Toward the Ideal Synthesis. New Transition Metal-catalyzed Reactions Inspired by Novel Medicinal Leads," Pure Appl. Chem. 2002, 25.
  18. Wender, P.; Williams, T. "[(Arene)Rh(COD)]+ Complexes as Catalysts for [5+2] Cycloadditions” Angewandte Chemie Int. Ed., 2002, 4550.
  19. Wender, P.; Gamber, G.; Hubbard, R.; Zhang, L. "Three Component Cycloadditions: The First Transition Metal-Catalyzed [5+2+1] Cycloaddition Reactions", J. Am. Chem. Soc, 2002, 2876.
  20. Wender, P.; Correa, A.; Sato, Y.; Sun R. "Transition Metal-Catalyzed [6+2] Cycloadditions of 2-Vinylcyclobutanones & Alkenes: A new Reaction for the Synthesis of 8-Membered Rings" J. Am. Chem. Soc. 2000, 7815.
  21. Wender, P.; Fuji, M.; Husfeld, C.; Love, J. "Rhodium-Catalyzed [5+2] Cycloadditions of Allenes and Vinylcyclopropanes: Asymmetric Total Synthesis of (+)-Dictamnol" Org. Lett. 1999, 137.
  22. Wender, P.; Glorius, F.; Husfeld, C.; Langkopf, E.; Love, J. "Transition Metal-Catalyzed [5+2] Cycloadditions of Allenes & Vinylcyclopropanes: First Studies of Endo-Exo Selectivity, Chemoselectivity, Relative Stereochemistry, & Chirality Transfer" J. Am. Chem. Soc. 1999, 5348. 
  23. Wender, P.; Rieck, H.; Fuji, M. “The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition: The Homologous Diels-Alder Reaction, J. Am. Chem. Soc. 1998, 10976.
  24. Wender, P.; Smith, T. J. Org. Chem. 1996, 824; Tetrahedron 1998, 1255 (steroids).
  25. Wender; Takahashi, Witulski, "Transition-Metal-Catalyzed [5+2] Cycloadditions of Vinylcyclopropanes and Alkynes: A Homolog of the Diels-Alder Reaction for the Synthesis of 7-Membered Rings" J. Am. Chem. Soc. 1995, 4720.
  26. Wender; Ihle; Correia,“Nickel-Catalyzed Intramolecular [4+4] Cyclo-Additions. 4. Enantioselective Total Synthesis of (+)-Asteriscanolide”  J. Am. Chem. Soc. 1988, 5904.


    The Arene-Alkene meta-Photocycloaddition Reaction

     

    Introduction:

    Our research program focuses on developing methods to make organic synthesis practical and efficient. Our ultimate objective is the ideal synthesis: making complex molecules from simple starting materials in one step and 100% yield in a manner that is operationally simple, fast, safe, environmentally acceptable, and resource efficacious. To achieve this formidable goal we are working on developing reactions that rapidly build complexity in a synthesis.

    The arene-alkene photocycloaddition has the potential to meet the criteria for the ideal synthesis (Figure 1). It uses simple, readily available starting materials and in one operation can create up to 3 new rings and 6 new stereocenters with the added benefit that one can easily convert the products to synthetically significant targets. Because the reactant is light, there are no toxic reagents to store and no toxic waste materials to dispose of making the reaction environmentally friendly. The three-step synthesis of silphinene (Figure 2) illustrates the remarkable power of this reaction and serves as a measure to determine how close we are to the ideal synthesis. In addition to silphinene, many other complex molecules have been synthesized using this method (Figure 3).

    Figure 1
    Figure 2

    Mechanism of the Photocycloaddition [17]:

    Figure 3
    Figure 4

     

    Selectivity Issues [18]:

    Figure 5

    Projects:

    A number of triquinanes have been synthesized using the intramolecular arene-alkene photocycloaddition reaction, but the utility of the reaction has never been expanded to include a tetraquinanyl structure.

    In 1978 Steglich and coworkers isolated from the basidiomycetous fungus Crinipellis stipitaria a group of natural products showing activity against Gram-positive bacteria, yeasts, and filamentous fungi [20]. Several years later they elucidated the structures of three biologically active crinipellins: crinipellin A, O-acetylcrinipellin A, and crinipellin B [21] (Figure 6). Early in 1993 Piers reported the first synthesis of a crinipellin; starting from 2-methylcyclopent-2-enone crinipellin B was synthesized in 22 steps [22].

    Our synthetic efforts focus on synthesizing Crinipellin A using the arene-alkene meta-photocycloaddition reaction.

    Figure 6

    Lead References:

  1. Wender, P. A.; Siggel, L.; Nuss, J. M. [3+2] and [5+2] Arene-Alkene Photocycloadditions, In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Elmsford, NY, 1991, Vol. 5, p. 645. Cornelisse, J. Chem. Rev. 1993, 93, 615. Wender, P. A.; Dore T. M. "Intra- and Intermolecular Cycloadditions of Benzene Derivatives." In Handbook of Organic Photochemistry and Photobiology; Horspool, W. S.; Song, P. -S., Eds.; CRC Press Inc: Boca Raton, FL. 1995, pp. 277-86. In Press.
  2. Wender, P. A.; Ternansky, R. J. Tetrahedron Lett. 1985, 26, 2625.
  3. Wender, P. A.; Howbert, J. J. J. Am. Chem. Soc. 1981, 103, 688. Wender, P. A.; Howbert, J. J.; Dore, T. M. "The Total Synthesis of ±-œ-Cedrene." In Photochemical Key Steps in Organic Synthesis ; Mattay, J.; Griesbeck, A. G., Eds.; VCH Verlagsgesellschaft: Weinheim, Germany, 1994, pp. 181-185.
  4. Howbert, J. J. Ph.D. Dissertation, Harvard University, 1983.
  5. Wender, P. A.; Dreyer, G. Tetrahedron 1981, 37, 4445.
  6. Wender, P. A.; Howbert, J. J. Tetrahedron Lett. 1982, 23, 3983.
  7. Wender, P. A.; Howbert, J. J. Tetrahedron Lett. 1983, 24, 5325.
  8. Wender, P. A.; Fisher, K. Tetrahedron Lett. 1986, 27, 1857.
  9. Wender, P. A.; Dreyer, G. J. Am. Chem. Soc. 1982, 104, 5805.
  10. Wender, P. A.; Dreyer, G. Tetrahedron Lett. 1983, 24, 4543.
  11. Wender, P. A.; Singh, S. Tetrahedron Lett. 1985, 26, 5987.
  12. Wolanin, D. Ph.D. Dissertation, Harvard University, 1982.
  13. Wender, P. A.; Singh, S. Tetrahedron Lett. 1990, 31, 2517.
  14. Wender, P. A.; von Geldern, T. W.; Levine, B. H. J. Am. Chem. Soc. 1988, 110, 4858.
  15. Wender, P. A.; deLong, M. A. Tetrahedron Lett. 1990, 31, 5429.
  16. Mani, J.; Sch��ttel, S.; Zhang, C.; Bigler, P.; M��ller, C.; Keese, R. Helv. Chim. Acta 1989, 72, 487. Mani, J.; Keese, R. Tetrahedron 1985, 41, 5697. deLong, M. A. Ph.D. Dissertation, Stanford University, 1992.
  17. See reference 1 and references cited therein.
  18. See reference 1 and references cited therein.
  19. Sugimura, T.; Nishiyama, N.; Tai, A. Tetrahedron: Asymmetry 1994, 5, 1163.
  20. Kupka, J.; Anke, T.; Oberwinkler, F.; Schramm, G.; Steglich, W. J. Antibiotics 1979, 32, 130.
  21. Anke, T.; Heim, J.; Knoch, F.; Mocek, U.; Steffen, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1985, 24, 709.
  22. Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11.

 

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