Photochemical Reactions as a Key Step in Natural
Product Synthesis.
Presented by:
Augusto César Hernandez-Perez
Literature Presentation
March 21th 2011
About Me.
Guatemala: Country of Mayan civilisation
San Mateo
Ixtatan
2
About Me.
Pointe-Aux-Trembles
UdM
3
Outline.
Introduction
• History
• Basics in photochemistry
• Equipment
UV-mediated reactions
• Photocyclizations
•Photochemical Rearrangement
4
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
5
Introduction.
Basic laws
• Activation of reaction is provided by the absorption of a photon
Energy conversion table
=c/
E = h
 / nm
kJmol-1
200
598
E = Nh = Nhc / 
250
479
E = 1,197×105 kJmol-1/ 
300
399
350
342
400
299
500
239
600
200
700
171
E = hc / 
h: Planck’s constant =
: frequency
6.627×1034
Js
(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
6
Introduction.
Orbital types
•n orbitals:
Non-bonding
• and * orbitals:
• and * orbitals:
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
7
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
8
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
9
Introduction.
Jablonski Diagram
E: Energy
E
A: Photon absorption
F: Fluorescence (R)
Sn
P: Phosphorescence (R)
S2
S: Singlet state
IC
S1
T: Triplet state
ISC
A
IC: Internal conversion (N-R)
F
P
T1 ISC: Intersystem crossing (N-R)
S0
Electronic ground state
10
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
11
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
12
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
13
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
14
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
15
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
16
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
17
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
18
UV mediated-reactions
• Photocyclizations
 6 Photocyclization of trienes
 6 Photocyclization of Stilbenes
 6 Photocyclization of enamide
 4 Photocyclization of pyridinum salts
• Photochemical Rearrangement
19
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
Conrotatory
Disrotatory
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
20
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
21
Photocyclization.
• Photocyclization of Trienes:
No trans
diastereoisomer formed
22
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., Tetrahedron 2000, 56, 193 – 207.
23
Photocyclization.
• Photocyclization of Stilbenes:
• Effective route to phenanthrene.
• E/Z isomerisation possible.
• Need to shift the equilibrium to the product.
24
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
25
Photocyclization.
• Photocyclization of Stilbenes:
Santiagonamie (2) extracted from branches of shrub
Berberis darwinii 1996
Exhibits wound healing properties
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.
2
26
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.
27
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.
28
Photocyclization.
• Photocyclization of Stilbenes:
Medium-pressure
Hg lamp
Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255-3257.
29
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. Heterocycles 1981, 15, 1433-1462
30
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.
31
Photocyclization.
• Photocyclization of Enamides:
Low-pressure Hg
lamp
Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 7983-7989.
32
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
33
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
34
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
35
Photocyclization.
• 4 Photocyclization :
•Others examples:
(+)-mannostatin A
(-)-allosamidine
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
(+)-castanospermine
36
UV mediated-reactions
• Photocyclizations
• Photochemical Rearrangement
Oxa-di--Methane Rearrangement (ODPM)
Photo-Fries Rearrangement
37
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.
38
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.
39
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
40
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
41
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
42
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. 1 2002, 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
43
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
44
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
45
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. 1 2000, 3, 323
Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 1 2000, 16, 2665
Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 6032-6036
46
Photochemical Rearrangements.
• Photo-Fries Rearrangement :
Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 6032-6036
47
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
48
Conclusion.
49