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Photochemical Reactions as a Key Step in Natural Product Synthesis.

Photochemical Reactions as a Key Step in Natural Product Synthesis. Presented by: Augusto César Hernandez-Perez Literature Presentation March 21 th 2011. About Me. Guatemala: Country of Mayan civilisation . San Mateo Ixtatan. About Me. Pointe-Aux-Trembles. I ’ m not Mexican.

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Photochemical Reactions as a Key Step in Natural Product Synthesis.

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  1. Photochemical Reactions as a Key Step in Natural Product Synthesis. Presented by: Augusto César Hernandez-Perez Literature Presentation March 21th 2011

  2. About Me. Guatemala: Country of Mayan civilisation San Mateo Ixtatan

  3. About Me. Pointe-Aux-Trembles I’m not Mexican UdM

  4. Outline. Introduction • History • Basics in photochemistry • Equipment UV-mediated reactions • Photocyclizations • Photochemical Rearrangement

  5. Introduction. Brief history • Photochemical reactions have been known for almost as long as chemistry • Most observations remained uninterpreted until the 19th century • Important work done in Italy by Ciamician, Silber and Paterno • After World War I, it became the province of the physical chemistry for 35 years • In the 50’s: general interest in photochemistry by the organic chemist due in part by • natural product synthesis • In the 60’s: emergence of mechanistic organic photochemistry and merging of the organic • and physical viewpoints. Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  6. Introduction. Basic laws • Activation of reaction is provided by the absorption of a photon Energy conversion table E = h  = c /  E = hc /  E = Nh = Nhc /  E = 1,197×105 kJmol-1/  h: Planck’s constant = 6.627×1034 Js : frequency (s-1) c: speed of light = 2,998 ×108 ms-1 N: Avagadro’s number = 6,023 ×1023 mol-1 Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  7. Introduction. Orbital types • n orbitals: •  and * orbitals: •  and * orbitals: Non-bonding Overlap of p orbitals Not involve in most reaction Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  8. Introduction. Electronic transition • Photochemical excitation: • Involves the transfer of a electron from a lower orbital to a higher one E antibonding bonding Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  9. Introduction. Photochemical reaction • Photochemically excited molecule: • Non-radiative (deactivation) processes between states • Radiative processes between states • Intermolecular energy transfer • Chemical reaction A + h’ (emission) A + heat (radiationless decay) A + h A* C* (change excited state) B B* + A (energy transfer) (i.e.: sensititzer) chemical reaction Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  10. Introduction. Jablonski Diagram E: Energy A: Photon absorption F: Fluorescence (R) P: Phosphorescence (R) S: Singlet state T: Triplet state IC: Internal conversion (N-R) ISC: Intersystem crossing (N-R) E Sn S2 IC S1 ISC A F T1 P S0 Electronic ground state

  11. Introduction. Electronic transition • Multiplicity: Singlet VS Triplet • Sum of the angular quantum number S in (2S+1) • Each electron has a value of 1/2 • Paired spin: ½ - ½ =0  S = 0, multiplicty is 1 (singlet) • Unpaired spin: ½ + ½ =1  S = 1, multiplicity is 3 (triplet) LUMO HOMO Parrallel Spin Unpaired Spin T1 Antiparrallel Spin Paired Spin S1 Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  12. Equipment. Light sources • Sun: • Free • Not practical • Example: 30 days in • Cairo sunlight • Mercury lamp: • Most popular • Versatile • Laser: • Monochromatic, • coherent • Possibility of extremely • high light intensities • Surface area low • Use to solve special • problems Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976

  13. Equipment. Hg lamps • Low pressure lamp: • 4,010-6 atm • 90% at 254nm • intensity per area is low • Medium pressure lamp: • 4,610-2 atm • broader spectral distribution • (265nm, 310nm, 635nm) • high temperature • High pressure lamp: • 100 atm • Emission below 280nm is very weak • high temperature Spectral emission form Hg arc lamps Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976

  14. Equipment. Filter and glassware • Choice of lamp: • Irradiation between 250 nm – 450 nm • For greater degree of selectivity • Use of cut-off filters (glass or solution) Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976

  15. Equipment. Setup Immersion well batch photochemical reactor: • Limited application for large-scale • reaction occurs within a short radius of • the lamp • Efficiency is scale dependant • Others solutions • Use various lamps • Concentrated reaction mixture Hook, B.D.A.; Dohle, W.; Hirst, P.R.; Pickworth, M.; Berry, M.B.; Booker-Milburn, K.I. J. Org. Chem. 2005, 70, 7558-7564

  16. Equipment. Reactor • Single pass continuous flow reactor: • Use of traditional water-cooled immersion well • FEP: Fluorinated ethylenepropylene • Solvent resistant • Polymeric material • Excellent UV-transmission properties Hook, B.D.A.; Dohle, W.; Hirst, P.R.; Pickworth, M.; Berry, M.B.; Booker-Milburn, K.I. J. Org. Chem. 2005, 70, 7558-7564

  17. Equipment. Micro-Reactor • Adopted for photochemical application: • Serpentine reactor: • long path length (1,15m = 20 turns) • Heat-exchanging channel on top • Reagents pre-mixed or not Mikroglas chemtech GmbH, Galileo-Galilei-Str. 28 55129 Mainz, Germany http://www.mikroglas.de

  18. Introduction. Natural product synthesis • UV light: High energy absorption of light facilitates • reaction pathways that cannot be accessed by • conventional methods • Access to variousnatural products

  19. UV mediated-reactions • Photocyclizations • 6 Photocyclization of trienes • 6 Photocyclization of Stilbenes • 6 Photocyclization of enamide • 4 Photocyclization of pyridinum salts • Photochemical Rearrangement

  20. Photocyclization. • Photocyclizations: light-induced pericylic ring closing reactions • 6 Photocyclizations • Photocyclization of Trienes • Photocyclization of Enamides • 4 Photocyclizations A: Carbocycles B: Heterocyclic products C: X = NR: pyrrolines, dihydroindoles, hexahydrocarbazoles X=O: vinyl aryl ether Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

  21. Photocyclization. • Photocyclization of Trienes: • Tridachiahydropyrone (1), marine-derived natural • product isolated in 1996 • Original structure assigned to 1 • Unsual fused bicyclic pyrone-contaning ring system 1 Proposed Biosynthetic Origin of 1 Gavagnin, M.; Mollo, E.; Cimino, G.; Ortea, J. Tetrahedron Lett. 1996, 37, 4259-4262 Sharma, P.; Griffiths, N.; Moses, J. E. Org. Lett.2008, 10, 4025-4027. Sharma, P.; Griffiths, N.; Moses, J. E.Synlett.2010, 525 – 528

  22. Photocyclization. • Photocyclization of Trienes: No trans diastereoisomer formed

  23. Photocyclization. • Photocyclization of Trienes: • Others examples: Photodeoxytridachione Dictyodendrins B Ellipticine • Oxidation of intermediate cyclohexadiene: O2 in air, I2, (PhSe)2 Eade, S. J. ; Walter, M.W.; Byrne, C.; Odell, B.; Rodriguez, R.; Baldwin, J. E.; Adlington, R. M.; Moses, J. E. J. Org. Chem.2008, 73, 4830-4839. Frstner, A.; Domostoj, M.M.; Scheiper, B. J. Am. Chem. Soc.2006, 128, 8087 – 8094. Ishikura, M .; Hino, A.; Yaginuma, T.; Agata, I.; Katagiri, N., Tetrahedron2000, 56, 193 – 207.

  24. Photocyclization. • Photocyclization of Stilbenes: • Effective route to phenanthrene. • E/Z isomerisation possible. • Need to shift the equilibrium to the product.

  25. Photocyclization. • Photocyclization of Stilbenes: • Problem of regioselectivity if X and Z are different: • If Z = H atom or if Z is smaller than X; formation of undesired regioisomers • Solution: Tether the ring if R is in meta or use a vinylbenzene

  26. Photocyclization. • Photocyclization of Stilbenes: • Santiagonamie (2) extracted from branches of shrub Berberis darwinii 1996 • Exhibits wound healing properties 2 Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 3163. Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett.2007, 9, 3255-3257.

  27. Photocyclization. • Photocyclization of Stilbenes: 2 • Benzofquinoline instead of Benzohisoquinoline Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 3163. Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett.2007, 9, 3255-3257.

  28. Photocyclization. • Photocyclization of Stilbenes: • Failure due to repulsive steric interaction between OMOM and PhNHCO • Backup plan: formation of lactone before photocyclization Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 3163. Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett.2007, 9, 3255-3257.

  29. Photocyclization. • Photocyclization of Stilbenes: Medium-pressure Hg lamp Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett.2007, 9, 3255-3257.

  30. Photocyclization. • Photocyclization of Enamides: • 3 possible reaction products generated from zwitterion G • H: Formed under oxidative conditions • I: Formed by a suprafacial 1,5-H shift (absence of oxidative conditions) • J: Formed under reductive conditions (NaBH4, MeOH) Ninomiya, I. J. Nat. Prod.1992, 55, 541-564 Ninomiya, I.; Naito, T. Heterocycles1981, 15, 1433-1462

  31. Photocyclization. • Photocyclization of Enamides: • Mappicine ketone (MPK) (3) : antiviral lead compound • against herpes viruses 3 Pendrak, I .; Barney, S. Wittrock, R.; Lambert, D.M.; Kingsbury, W.D.; J. Org. Chem.1994, 59, 2623 Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem.2003, 68, 7983-7989.

  32. Photocyclization. • Photocyclization of Enamides: Low-pressure Hg lamp Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem.2003, 68, 7983-7989.

  33. Photocyclization. • 4 Photocyclization: • Based on pyridinium salts • Initial contribution from Kaplan, Pavlik and Wilzbach Azabenzvalene • Formation of azabenzvalene: * excitation M K L • K: Direct traping of initially formed allylic cation • L and M: Trapping of rearragement product Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E.; J. Am. Chem. Soc., 1972, 94, 3283 King, R.A. ; Lüthi, H.P.; Schaefer, F.; Glarner, F.; Burger, U. Chem.-Eur. J.2001, 7, 1734

  34. Photocyclization. • 4 Photocyclization: • Generates bicyclic aziridine which can undergo nucleophilic ring opening • Common nucleophiles: H2O, MeOH, KOH, etc. • Others nucleophiles can be used: Organocuprate reagents • High yields with polar solvent • Bicyclic aziridine: neutralisation prior concentration • Aminocyclopentene: concentration prior neutralisation Damiano, T.; Morton, D.; Nelson, A. Org. Biomol. Chem.2007, 5, 2735-2752 Zou, J.; Mariano, P. S. Photochem. Photobiol. Sci.2008, 7, 393-404 Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E.; J. Am. Chem. Soc., 1972, 94, 3283

  35. Photocyclization. • 4 Photocyclization : • (-)-swainsonine (4), potent glycosidase inhibitor product isolated from • different plant species such as Asclepiadaceae, • Convulaceae, Moraceae and Orchidaceae • Polyhydroxylated Indozilidne alkaloid 4 Acetylcholine esterease Gellert, E. J. Nat. Prod. 1982,45,50 Pearson, W. H.; Ren, Y.; Powers J. D. Heterocycles 2002,58,421 Song, L.; Duesler, E. N.; Mariano, P. S. J. Org. Chem.2004, 69, 7284 – 7293

  36. Photocyclization. • 4 Photocyclization : • Others examples: (+)-mannostatin A (-)-allosamidine (+)-castanospermine Ling, R.; Mariano, P.S. J. Org. Chem., 1998, 63, 6072. Li, J.; Lang, F.; Ganem, B. J. Org. Chem., 1998, 63, 3403 Zhao, Z.; Song, L.; Mariano, P.S. TetrahedronLett., 2005, 61, 8888

  37. UV mediated-reactions • Photocyclizations • Photochemical Rearrangement • Oxa-di--Methane Rearrangement (ODPM) • Photo-Fries Rearrangement

  38. Photochemical Rearrangements. • Oxa-di--Methane Rearrangement (ODPM): • ,-unsaturated ketones undergo a rearrangement involving a formal 1,2-acyl migration and cyclopropane formation • First example in 1966: • 2 possibles processes upon irradiation: 1,3-acyl migration or ODPM • ODPM proceeds via a triplet state to yield the corresponding cyclopropyl ketone • Use of a sensitizer (i.e. acetophenone) to generate the triplet state Hixson, S.S.; Mariano, P.S.; Zimmerman, H.E. Chem. Rev.1973, 73, 531-551. Zimmerman, H.E. Armesto, D. Chem. Rev.1996, 96, 3065-3112. Hoffmann, N. Chem. Rev.2008, 108, 1052-1103.

  39. Photochemical Rearrangements. • Oxa-di--Methane Rearrangement (ODPM): • Cleavage of bond in  position to the photoexcited carbonyl group; • acyl group migrates onto the neighbouring C=C bond • High chemical yield • High degree of stereoselectivity • Very general for many cyclic ,-unsaturated ketones Givens, R. S.; Oettle, W. F. J. Chem. Soc., Chem. Commun. 1969, 1164-1165. Zimmerman, H.E. Armesto, D. Chem. Rev.1996, 96, 3065-3112.

  40. Photochemical Rearrangements. • Oxa-di--Methane Rearrangement : • (-)-phellodonic acid (5) isolated from fermentation of fungus in • Tasmania in 1993 • Exhibits strong inhibitory activities towards various bacteria and • cancer cells 5 Medium-pressure Hg lamp M. Stadler, T. Anke, J. Dasenbrock, W. Steglich, Z. Naturforsch. C: J. Biosci. 1993, 48, 545. Reekie, T. A. ; Austin, K. A. B.; Banwell, M. G. ; Willis, A. C. Aust. J. Chem.2008, 61, 94-106

  41. Photochemical Rearrangements. • Oxa-di--Methane Rearrangement : M. Stadler, T. Anke, J. Dasenbrock, W. Steglich, Z. Naturforsch. C: J. Biosci. 1993, 48, 545. Reekie, T. A. ; Austin, K. A. B.; Banwell, M. G. ; Willis, A. C. Aust. J. Chem.2008, 61, 94-106

  42. Photochemical Rearrangements. • Oxa-di--Methane Rearrangement : • Relief of steric compressions between Me and Bz group by photoenolization or -cleavage • process M. Stadler, T. Anke, J. Dasenbrock, W. Steglich, Z. Naturforsch. C: J. Biosci. 1993, 48, 545. Reekie, T. A. ; Austin, K. A. B.; Banwell, M. G. ; Willis, A. C. Aust. J. Chem.2008, 61, 94-106

  43. Photochemical Rearrangements. • Oxa-di--Methane Rearrangement : • Others examples: (-)-hirsutene (-)-complicatic acid ()-Magellanine ()-capnellene Banwell, M.G.; Edwards, A.J.; Harfoot, G.J.; Jolliffe, K.A. J. Chem. Soc. Perkin Trans. 12002, 22, 2439-2441 Singh, V.; Prathap, S.; Porinchu, M. J. Org. Chem. 1998, 63, 4011-4017 Yen, C.-F.; Liao, C.-C. Angew. Chem. Int. Ed.2002, 41, 4090-4093

  44. Photochemical Rearrangements. • Fries Rearrangement: • Require strong Lewis acid • Recombination can occur in ortho or para position Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976

  45. Photochemical Rearrangements. • Photo-Fries Rearrangement: • First observed in 1960 • Does not involve carbonium ions • Cleavage of C-O bond proceeds via a triplet state • Formation of phenol if aryloxy radical escapes from solvent cage • Does not require strong Lewis acid • Mild synthetic pathway Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976

  46. Photochemical Rearrangements. • Photo-Fries Rearrangement : • Kendomycin (6) is a potent endothelin receptor antagonist compound with remarkable antibacterial and cytostatic activity • Isolated from different Streptomyces species 6 Medium-pressure Hg lamp Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 12000, 3, 323 Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 12000, 16, 2665 Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed.2009, 48, 6032-6036

  47. Photochemical Rearrangements. • Photo-Fries Rearrangement : Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed.2009, 48, 6032-6036

  48. Conclusion. Equipment • Use of continuous flow reactor • Possibilities to scale-up reaction Photochemical reaction • Light as the only reactant • Control in the product generated • Access to important fragment from simple molecules

  49. Conclusion. I’m not Mexican

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