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Alkoxyallenes : Chemical Versatility and Application

Alkoxyallenes : Chemical Versatility and Application

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Alkoxyallenes : Chemical Versatility and Application

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  1. Alkoxyallenes: Chemical Versatility and Application Anna Chkrebtii November 19, 2009

  2. Alkoxyallenes: Chemical Versatility and Application • Introduction • Geometry and reactivity • Umplong synthons • Synthesis of alkoxyallenes • Substituted Pyridine Synthesis • Palladium catalysis of alkoxyallenes • 2,5-disubstitued dihydropyran • Quinolizidine Amino Acid • Deoxysugar synthesis • Benzannulated Spiroketals

  3. Alkoxyallenes: the Basics - C-C-C bond 180° - substituents at 90° - β-C nucleophilic - γ-C electrophilic - lithiated α-C nucleophilic General reactivity pattern: Carbonyl reactivity pattern: General Geometry: γ β α

  4. Alkoxyallenes: Umpolung Synthons “[synthons] are defined as structural units within a molecule which are related to possible synthetic operations” E. J. Corey. Pure Appl. Chem. 1967, 14, 19-37 "Umpolung or polarity inversion in organic chemistry is the chemical modification of a functional group with the aim of the reversal of polarity of that group" D. Seebach. Angew. Chem. Int. 1979, 239-258

  5. Synthesis of Alkoxyallenes: Alkyne Isomerization Pourcelot, G.; Cadiot, P. Bull. Soc. Chim. Fr. 1966, 3016-3024. Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1968, 87, 916-924. Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1968, 87, 1179-1184. Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas1969,88, 609-619.

  6. Synthesis of Alkoxyallenes: Substituents • Kuwajima, I.; Kato, M. Tetrahedron Lett.1980, 21, 623-626. • Verkruijsse, H. D.; Verboom, W.; van Rijn, P. E.; Brandsma, L. J. Organomet. Chem. 1982, 232, C1-C4. • Hausherr, A.; Orschel, B.; Scherer, S.; Reissig, H.-U. Synthesis2001, 1377-1385. • Leroux, Y.; Jaquelin, C. Synth. Commun.1976, 6, 597-600.

  7. Synthesis of Alkoxyallenes: Regio- and Enantioselective Synthesis Hoppe, D.; Reimenschneider, C. Angew. Chem.1983, 95, 64-65 Hoppe, D.; Reimenschneider, C. Angew. Chem. Int. Ed. Engl.1983, 22, 54. Hoppe, D.; Genschorrek, C.; Schmidt, D.; Egert, E. Tetrahedron 1987, 43, 2457-2466. Schultz-Fademrecht, C.; Wibbeling, B.; Frohlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221-1224.

  8. Alkoxyallenes: Chemical Versatility and Application • Introduction • Geometry and reactivity • Umplong synthons • Synthesis of alkoxyallenes • Substituted Pyridine Synthesis • Palladium catalysis of alkoxyallenes • 2,5-disubstitued dihydropyran • Quinolizidine Amino Acid • Deoxysugar synthesis • Benzannulated Spiroketals

  9. Functionalized Pyridines: Valerian 9 • Herb extract used in the treatment of: • sleeping disorders, restlessness, anxiety, and • as a muscle relaxant and a sedative • Was popular during WWI to treat shell-shock • In medieval Sweden, it was sometimes placed in the wedding clothes of the groom to ward off the "envy" of the elves

  10. Functionalized Pyridines Synthesis Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett.2007, 9, 5541-5544. Eidamshaus, C.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351, 1162-1166.

  11. Functionalized Pyridines Synthesis Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett.2007, 9, 5541-5544. Eidamshaus, C.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351, 1162-1166.

  12. Functionalized Pyridines Lechel, T.; Dash, J.; Brudgam, I.; Reissig, H.-U. Eur. J. Org. Chem.2008, 3647-3655.

  13. Alkoxyallenes: Chemical Versatility and Application • Introduction • Geometry and reactivity • Umplong synthons • Synthesis of alkoxyallenes • Substituted Pyridine Synthesis • Palladium catalysis of alkoxyallenes • 2,5-disubstitued dihydropyran • Quinolizidine Amino Acid • Deoxysugar synthesis • Benzannulated Spiroketals

  14. Alkoxyallenes in Natural Product Synthesis chromenes oxepines furans pipercolic acids azepines quinolizidines

  15. Alkoxyallenes in Natural Product Synthesis chromenes oxepines furans pipercolic acids azepines quinolizidines

  16. 2,5-disubstitued dihydropyrans Rutjes, F. P. J. T., et al. Adv. Synth. Catal. 2002, 344, 736-748. δ+ δ+

  17. Pd-catalyzed Hydroalkoxylation: Scope Rutjes, F. P. J. T., et al. Adv. Synth. Catal. 2002, 344, 736-748.

  18. 2,5-disubstitued dihydropyrans Rutjes, F. P. J. T., et al. Adv. Synth. Catal. 2002, 344, 736-748. δ+ δ+

  19. Quinolizidine Amino Acid Rutjes, F. P. J. T., et al. Adv. Synth. Catal. 2002, 344, 736-748.

  20. Pd-catalyzed Hydroalkoxylation: Scope Rutjes, F. P. J. T., et al. Adv. Synth. Catal. 2002, 344, 736-748.

  21. Quinolizidine Amino Acid Rutjes, F. P. J. T., et al. Adv. Synth. Catal. 2002, 344, 736-748.

  22. Alkoxyallenes: Chemical Versatility and Application • Introduction • Geometry and reactivity • Umplong synthons • Synthesis of alkoxyallenes • Substituted Pyridine Synthesis • Palladium catalysis of alkoxyallenes • 2,5-disubstitued dihydropyran • Quinolizidine Amino Acid • Deoxysugar synthesis • Benzannulated Spiroketals

  23. L-cymarose and other Deoxysugars • 2,6-dideoxy sugars or deoxysugars include: L-cymarose L-sarmentose L-diginose Kennedy, J. F.; White, C. A. Bioactive Carbohydrates in Chemistry, Biochemistry and Biology. Ellis Horwood Publisher, Chichester, 1983. Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr. Chem. 1997, 188 1-84.

  24. L-cymarose and other Deoxysugars • Occur as subunits in antitumor antibiotics: • A well documented example is Heliquinomycin, a DNA helicase inhibitor • These sugars are an important synthetic target

  25. Deoxysugar Synthesis Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007, 46, 1634-1637. Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem.2009, 3595-3604. αβ

  26. Au Catalytic Cycle Cui, D.-M.; Zheng, Z.-L.; Zhang, C. J. Org. Chem.2009, 74, 1426-1427.

  27. Deoxysugar Synthesis Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007, 46, 1634-1637. Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem.2009, 3595-3604. αβ

  28. Oxidative Ring Cleavage: Part I Flogel, O.; Reiβig, H.-U. Eur. J. Org. Chem.2004, 2797-2804.

  29. Oxidative Ring Cleavage: Part II Flogel, O.; Reiβig, H.-U. Eur. J. Org. Chem.2004, 2797-2804.

  30. Oxidative Ring Cleavage: Part II Flogel, O.; Reiβig, H.-U. Eur. J. Org. Chem.2004, 2797-2804.

  31. Deoxysugar Synthesis Achmatowicz, O. Jr.; Bukowski, P; Szechner, Z.; Zwierzchowska, Z., Zamojski, A. Tetrahedron1971, 27, 1973-1996. Wahlstrom, J. L.; Ronald, R. C. J. Org. Chem. 1997, 63, 6021-6022. αβ

  32. Deoxysugars: L-cymarose and L-sarmentose Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem.2009, 3595-3604.

  33. Deoxysugars: L-diginose Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007, 46, 1634-1637. Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem.2009, 3595-3604.

  34. Alkoxyallenes: Chemical Versatility and Application • Introduction • Geometry and reactivity • Umplong synthons • Synthesis of alkoxyallenes • Substituted Pyridine Synthesis • Palladium catalysis of alkoxyallenes • 2,5-disubstitued dihydropyran • Quinolizidine Amino Acid • Deoxysugar synthesis • Benzannulated Spiroketals

  35. Rubromycin • Isolated from Streptomyces collinus in 1953 • The rubromycins are a group of structurally related pigments with antitumor antibiotic activity • α- and β-rubromycins inhibit the growth of some bacteria and fungi • Heliquinomycin is both an antitumor and antimicrobial agent

  36. Rubromycin • Basic structure combines a naphthoquinone moiety with a 5,6-spiroketal fused to an isocoumarin unit • To date, several model studies have been investigated, all give racemic heliquinomycinone

  37. Benzannulated Spiroketals: Model Study for Rubromycin Sorgel, S.; Azap, C.; Reissig, H.-U. Org. Lett.2006, 8, 4875-4878.

  38. Benzannulated Spiroketals: Model Study for Rubromycin Sorgel, S.; Azap, C.; Reissig, H.-U. Org. Lett.2006, 8, 4875-4878.

  39. Benzannulated Spiroketals: Model Study for Rubromycin • This model study gives the 5,6-spiroketal subunit in 4 steps

  40. Alkoxyallenes: Summary • Alkoxyallenes are umpolungsynthons of conjugated carbonyl groups • They can be lithiated at the α-C to yield a wide range of synthons • Alkoxyallenes can be used as reagents in the synthesis of complex natural product intermediates • This includes substituted pyridines, 2,5-disubstituted dihydropurans, quinolizidine amino acids, deoxysugars and benxannulatedspiroketals

  41. Acknowledgements Dr. Tony Durst Asim Muhammad Ana Francis Carballo Christine Choueiri Linda “Skippy” Jewell DariaKlonowska Lina Chan David Nguyen DariaMuharemagic Ana Gargaun Devin Tonelli Margaret Taylor Keith Lam

  42. Hydroalkoxylation of alkoxyallenes Rutjues, F.; Kooistra, T. M.; Heimstra, H. H.; Schoemaker, H. E. Synlett Lett.1997, 192-194.

  43. Deoxysugars: L-oleandrose Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007, 46, 1634-1637. Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem.2009, 3595-3604.