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

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

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

4. UV-mediated reactions
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 / 
 / nm
kJmol-1
200
598
250
479
300
399
350
342
400
299
500
239
600
700
171
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. Not involve in most reaction
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. Electronic transition
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. Photochemical reaction
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. Electronic ground state
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. Electronic transition
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
Antiparrallel Spin
Paired Spin S1
Parrallel Spin
Unpaired Spin T1
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. Spectral emission form Hg arc lamps
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)
 of cut-off / nm
Chemical composition
Below 250
Na2WO4
Below 305
SnCl2 in HCl (0,1M)
Below 330
Na3VO4 (2M)
Below 355
BiCl3 in HCl
Above 450
CoSO4 + CuSO4
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,

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,

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 Mainz, Germany

18. Natural product synthesis
Introduction.
Natural product synthesis
UV light: High energy absorption of light facilitates
reaction pathways that cannot be accessed by
conventional methods
Access to various natural 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
Electrons
Photochemical
Thermic 4n
Disrotatory
Conrotatory
4n+2
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 , 37,
Sharma, P.; Griffiths, N.; Moses, J. E. Org. Lett. 2008, 10,
Sharma, P.; Griffiths, N.; Moses, J. E. Synlett. 2010, 525 – 528

22. No trans diastereoisomer formed
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,
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., Tetrahedron 2000, 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,

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,

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,

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

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,
Ninomiya, I.; Naito, T. Heterocycles 1981, 15,

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,

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

33. Photocyclization. 4 Photocyclization: Based on pyridinium salts
Initial contribution from Kaplan, Pavlik and Wilzbach
Azabenzvalene
Formation of azabenzvalene: * excitation K L M
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,
Zou, J.; Mariano, P. S. Photochem. Photobiol. Sci. 2008, 7,
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. Tetrahedron Lett., 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,
Zimmerman, H.E. Armesto, D. Chem. Rev. 1996, 96,
Hoffmann, N. Chem. Rev. 2008, 108,

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,
Zimmerman, H.E. Armesto, D. Chem. Rev. 1996, 96,

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,

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,

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,

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

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 , 3, 323
Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans , 16, 2665
Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48,

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

48. Photochemical reaction
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