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Photochemical Reactions as a Key Step in Natural Product Synthesis.
Presented by: Augusto César Hernandez-Perez
Literature Presentation March 21th 2011
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About Me.
Guatemala: Country of Mayan civilisation
San Mateo Ixtatan
2
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About Me.
Pointe-Aux-Trembles
UdM
I’m not
Mexican
3
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Outline.
• Photocyclizations
•Photochemical Rearrangement
Introduction
4
UV-mediated reactions
• History
• Basics in photochemistry
• Equipment
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Introduction.
• Photochemical reactions have been known for almost as long as chemistry
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
Brief history
• 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.
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Introduction.
Basic laws
• Activation of reaction is provided by the absorption of a photon
E = h
6
E = hc /
E = 1,197×105 kJmol-1/
= c / Energy conversion table
/ nm kJmol-1
200 598
250 479
300 399
350 342
400 299
500 239
600 200
700 171
h: Planck’s constant = 6.627×1034 Js
: frequency (s-1)
c: speed of light = 2,998 ×108 ms-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
E = Nh = Nhc /
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Introduction.
Orbital types
•n orbitals:
7
C O
n
• and * orbitals:
C O
C O
• and * orbitals:
C C
C C
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
Non-bonding Overlap of p orbitals Not involve in most reaction
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Introduction.
Electronic transition
•Photochemical excitation: Involves the transfer of a electron from a lower orbital to a higher one
8Arnold, 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
E
antibonding
bonding
*
*
n
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Introduction.
Photochemical reaction
• Photochemically excited molecule:Non-radiative (deactivation) processes between statesRadiative processes between statesIntermolecular energy transferChemical reaction
9
A + h A*
A + h’ (emission)
A + heat (radiationless decay)
C* (change excited state)
B* + A (energy transfer) (i.e.: sensititzer)
chemical reaction
B
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
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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)
Electronic ground state
S2
S1
Sn
ICISC
T1
S0
E
PFA
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Introduction.
•Multiplicity: Singlet VS Triplet •Sum of the angular quantum number S in (2S+1)•Each electron has a value of 1/2Paired spin: ½ - ½ =0 S = 0, multiplicty is 1 (singlet)Unpaired spin: ½ + ½ =1 S = 1, multiplicity is 3 (triplet)
Antiparrallel SpinPaired Spin
S1
Parrallel SpinUnpaired Spin
T1
HOMO
LUMO
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
Electronic transition
h ISC
11
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Equipment.
Light sources
• Sun:FreeNot practicalExample: 30 days in Cairo sunlight
12
•Mercury lamp:Most popularVersatile
• Laser:Monochromatic, coherentPossibility of extremely high light intensitiesSurface area lowUse to solve special problems
Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976
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Equipment.
Hg lamps
• Low pressure lamp: 4,010-6 atm 90% at 254nm intensity per area is low
13
• Medium pressure lamp: 4,610-2 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
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Equipment.
• For greater degree of selectivity Use of cut-off filters (glass or solution)
14
Filter and glassware
• Choice of lamp: Irradiation between 250 nm – 450 nm
of cut-off / nm Chemical compositionBelow 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
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Equipment.
• Limited application for large-scale reaction occurs within a short radius of the lamp
Efficiency is scale dependant
15
Setup
Immersion well batch photochemical reactor:
• 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
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Equipment.
16
Reactor
•Single pass continuous flow reactor: Use of traditional water-cooled immersion well FEP: Fluorinated ethylenepropyleneSolvent resistantPolymeric materialExcellent 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
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Equipment.
17
Micro-Reactor
• Adopted for photochemical application:
Mikroglas chemtech GmbH, Galileo-Galilei-Str. 28 55129 Mainz, Germany http://www.mikroglas.de
•Serpentine reactor: long path length (1,15m = 20 turns)Heat-exchanging channel on topReagents pre-mixed or not
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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
O
O
OMe
O
HOO
HOO
OHN
OH
OH
OHH
H
HHO2C
OHO
OOO
6
18
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UV mediated-reactions• Photocyclizations
6 Photocyclization of trienes
19
6 Photocyclization of Stilbenes
6 Photocyclization of enamide
4 Photocyclization of pyridinum salts
• Photochemical Rearrangement
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• Photocyclizations: light-induced pericylic ring closing reactions•6 Photocyclizations Photocyclization of TrienesPhotocyclization of Enamides• 4 Photocyclizations
Photocyclization.
A: Carbocycles
B: Heterocyclic productsX
NR
O
A B C
C: X = NR: pyrrolines, dihydroindoles, hexahydrocarbazoles X=O: vinyl aryl ether
Electrons Photochemical Thermic
4n Disrotatory Conrotatory
4n+2 Conrotatory Disrotatory
20Arnold, 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
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• Photocyclization of Trienes:
Photocyclization.
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
O
O
OMe
Tridachiahydropyrone (1), marine-derived natural product isolated in 1996Original structure assigned to 1Unsual fused bicyclic pyrone-contaning ring system
1
O
O
OMe O
O
OMe
Con6h
Dis6
O
O
OMe
Proposed Biosynthetic Origin of 1
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• Photocyclization of Trienes:
Photocyclization.
22
O
O
OMe
h (sunlight)MeOH, 60h, r.t.
29%
O
O
OMe
H O
O
OMe
HH
OOMe
O
150Cxylene
0%
O
O
OMe O
O
OMe
No trans diastereoisomer formed
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• Photocyclization of Trienes:
Photocyclization.
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
•Others examples:
Photodeoxytridachione Dictyodendrins B
O
O
OMe
H
N
NHO
HO
OH
OH
SO3Na
HO
HO
N
NH
Ellipticine
•Oxidation of intermediate cyclohexadiene: O2 in air, I2, (PhSe)2
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• Photocyclization of Stilbenes:
Photocyclization.
24
• Effective route to phenanthrene.• E/Z isomerisation possible.• Need to shift the equilibrium to the product.
Z
YX
R
Z
YX
R
Z
YX
R
D
G
Z
YX
R
E
F
HH
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• Photocyclization of Stilbenes:
Photocyclization.
25
Z
YX
R
Z
YX
R
Z
YX
R
VS
D IH
• 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
Z
YX
R
Z
YX
R
X
YZ
R
VS
D IH
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• Photocyclization of Stilbenes:
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. 26
Santiagonamie (2) extracted from branches of shrub Berberis darwinii 1996Exhibits wound healing properties
2
N
MeO NMe2
O
O
I NCy
MeO
MOMON
IO
PhHN
1. Cu0, Pd(PPh3)4DMF, 100C
39%
1 equiv 1,6 equiv
2. K2CO3, PPh3CH3I18-c-6, DMF, 100C
79% N
MeO
MOMOPhHNOC
N
MeO
MOMOPhHNOC
h, I2, benzene, 0C
O
N
MeO
PhHNOCMOMO
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• Photocyclization of Stilbenes:
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. 27
2
N
MeO NMe2
O
O
Benzofquinoline instead of Benzohisoquinoline
h, I2, benzene, 0C 83%
O
N
OMe
OMOM
N
MeO
PhHNOCMOMO
N
MeO
MOMOPhHNOC
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• Photocyclization of Stilbenes:
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
Failure due to repulsive steric interaction between OMOM and PhNHCO
N
MeO
MOMOPhHNOC
N
OMe
OMOM
PhHNOCN
OMe
OMOM
PhHNOCH
I I I2h
h
I
N
OMe
OMOM
PhHNOCN
OMe
OMOM
Backup plan: formation of lactone before photocyclization
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• Photocyclization of Stilbenes:
Photocyclization.
29Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255-3257.
N
O
MeO
MOMOPhHNOC
N
MeO
HOPhHNOC
Br
N
MeO
O
Br
O
TFA, THF, 80C76%
h, I2, DCM, 1h -37C to -18C 89%
O
N
MeO
O
Br
O
N
MeO NMe2
O
O
Medium-pressure Hg lamp
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• Photocyclization of Enamides:
Photocyclization.
Ninomiya, I. J. Nat. Prod. 1992, 55, 541-564 Ninomiya, I.; Naito, T. Heterocycles 1981, 15, 1433-1462 30
3 possible reaction products generated from zwitterion G
H: Formed under oxidative conditionsI: Formed by a suprafacial 1,5-H shift (absence of oxidative conditions)
J: Formed under reductive conditions (NaBH4, MeOH)
NR
O
B
NR
O
H
H
G
h NR
O
NR
O
HN
R
O
H
H
H H
H I J
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• Photocyclization of Enamides:
Photocyclization.
Pendrak, I .; Barney, S. Wittrock, R.; Lambert, D.M.; Kingsbury, W.D.; J. Org. Chem. 1994, 59, 2623Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 7983-7989. 31
Mappicine ketone (MPK) (3) : antiviral lead compound against herpes viruses
NN
O
O
3
NN
O
PhS
mCPBA, DCM, 0C98%
NN
CO2Et
O
PhSO
CaCO3, PhMereflux, 13h
63%
CO2Et
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• Photocyclization of Enamides:
Photocyclization.
Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 7983-7989. 32
NN
O
O 10% Pd/C, CH3CO2H, 80C, 3h
28%
1,5-H shiftH
NN
O
O
NN
O
Oh,
MeOH, 1,5h NN
O
O
H
Low-pressure Hg lamp
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h (=254 nm)H2O, KOH
NH
Cl
N
N
N
2
34
5 6N
2
34
6N
2
34
6
OHHO
55
65
N
OH3
• 4 Photocyclization:
Photocyclization.
Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E.; J. Am. Chem. Soc., 1972, 94, 3283King, R.A. ; Lüthi, H.P.; Schaefer, F.; Glarner, F.; Burger, U. Chem.-Eur. J. 2001, 7, 1734 33
Based on pyridinium saltsInitial contribution from Kaplan, Pavlik and Wilzbach
Azabenzvalene
Formation of azabenzvalene: * excitation
K: Direct traping of initially formed allylic cationL and M: Trapping of rearragement product
K L M
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• 4 Photocyclization:
Photocyclization.
Damiano, T.; Morton, D.; Nelson, A. Org. Biomol. Chem. 2007, 5, 2735-2752Zou, J.; Mariano, P. S. Photochem. Photobiol. Sci. 2008, 7, 393-404Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E.; J. Am. Chem. Soc., 1972, 94, 3283 34
Generates bicyclic aziridine which can undergo nucleophilic ring openingCommon nucleophiles: H2O, MeOH, KOH, etc.Others nucleophiles can be used: Organocuprate reagents
h solvent
N X NH X
Nuc Nuc
NH2R
Nuc
NH
NucNuc
High yields with polar solvent Bicyclic aziridine: neutralisation prior concentrationAminocyclopentene: concentration prior neutralisation
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• 4 Photocyclization :
Photocyclization.
Gellert, E. J. Nat. Prod. 1982, 45, 50Pearson, W. H.; Ren, Y.; Powers J. D. Heterocycles 2002, 58, 421Song, L.; Duesler, E. N.; Mariano, P. S. J. Org. Chem. 2004, 69, 7284 – 7293 35
(-)-swainsonine (4), potent glycosidase inhibitor product isolated from different plant species such as Asclepiadaceae, Convulaceae, Moraceae and OrchidaceaePolyhydroxylated Indozilidne alkaloid 4
N
OH
OH
OHH
NH ClO4
1. h (254nm) HClO4, H2O2. Ac2O, DMAP pyr 42%
OAcAcO
HNAc
Acetylcholine esterease
OAcHO
HNAc
OBnTBSO
NAc
EEACE H2O, pH 6.9
68%
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• 4 Photocyclization :
Photocyclization.
Ling, R.; Mariano, P.S. J. Org. Chem., 1998, 63, 6072.Li, J.; Lang, F.; Ganem, B. J. Org. Chem., 1998, 63, 3403Zhao, Z.; Song, L.; Mariano, P.S. Tetrahedron Lett., 2005, 61, 8888 36
•Others examples:
(+)-mannostatin A (-)-allosamidine (+)-castanospermine
NH3
HO
HO OH
SMe
Cl
O
N
OH
OH
HO
Me2N
N
OH
OH
OH
H
OH
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UV mediated-reactions• Photocyclizations
• Photochemical Rearrangement
37
Oxa-di--Methane Rearrangement (ODPM)
Photo-Fries Rearrangement
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Photochemical Rearrangements.
• Oxa-di--Methane Rearrangement (ODPM):
38
2 possibles processes upon irradiation: 1,3-acyl migration or ODPMODPM proceeds via a triplet state to yield the corresponding cyclopropyl ketoneUse 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.
,-unsaturated ketones undergo a rearrangement involving a formal 1,2-acyl migration and cyclopropane formation
First example in 1966:
Ph
OPhPh
Ph hPhH, 1h30
7%
Ph
H
H
PhPh
O
Ph
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Photochemical Rearrangements.
• Oxa-di--Methane Rearrangement (ODPM):
39
Cleavage of bond in position to the photoexcited carbonyl group; acyl group migrates onto the neighbouring C=C bond
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.
O OO
O
O
O
A
B
High chemical yieldHigh degree of stereoselectivityVery general for many cyclic ,-unsaturated ketones
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• Oxa-di--Methane Rearrangement :
(-)-phellodonic acid (5) isolated from fermentation of fungus in Tasmania in 1993Exhibits strong inhibitory activities towards various bacteria and cancer cells
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
H
HHO2C
OHO
OOO
6
Photochemical Rearrangements.
Obz
O
MeO2C
O
O
6
hAcetophenone
Acetone66% H
HMeO2C
OOO
6BzO
H
HMeO2C
OOO
6BzO
8% 82%
H H
5
Medium-pressure Hg lamp
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• 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
Photochemical Rearrangements.
Obz
O
MeO2C
O
O
6
hAcetophenone
Acetone
H
HMeO2C
OOO
6BzO
Obz
O
MeO2C
O
O
6
*
T1Obz
O
MeO2C
O
O
6
Obz
O
MeO2C
O
O
6
H
HMeO2C
OOO
6BzO
H H
8% 82%
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• 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
Photochemical Rearrangements.
hAcetophenone
Acetone96% H
HMeO2C
OOO
6BzO
H
H
HMeO2C
OOO
6BzO
H
•Relief of steric compressions between Me and Bz group by photoenolization or -cleavage process
H
HMeO2C
OOO
6BzO
H
HMeO2C
OOO
6
SmI2, THF-MeOH,
-78C to 18C, 0,25h96%
H H
H
HHO2C O
OOO
6
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• Oxa-di--Methane Rearrangement :
Banwell, M.G.; Edwards, A.J.; Harfoot, G.J.; Jolliffe, K.A. J. Chem. Soc. Perkin Trans. 1 2002, 22, 2439-2441Singh, V.; Prathap, S.; Porinchu, M. J. Org. Chem. 1998, 63, 4011-4017Yen, C.-F.; Liao, C.-C. Angew. Chem. Int. Ed. 2002, 41, 4090-4093
Photochemical Rearrangements.
•Others examples:
(-)-hirsutene (-)-complicatic acid
()-capnellene
H
H
H
H
HHO2C O
O
H
H
NH
OHH
H
H
O
()-Magellanine
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Photochemical Rearrangements.
• Fries Rearrangement:
44
Require strong Lewis acidRecombination can occur in ortho or para position
O
O
RAlCl
ClCl
O
O
R
AlCl
ClCl
OAlCl
ClCl
O
R
r.t.
100COH
OH
OR
R
O
Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976
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Photochemical Rearrangements.
Formation of phenol if aryloxy radical escapes from solvent cageDoes not require strong Lewis acidMild synthetic pathway
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O
O
RO OH
hO O O
R
OR
• Photo-Fries Rearrangement:
Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976
First observed in 1960Does not involve carbonium ionsCleavage of C-O bond proceeds via a triplet state
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• Photo-Fries Rearrangement :
Kendomycin (6) is a potent endothelin receptor antagonist compound with remarkable antibacterial and cytostatic activity Isolated from different Streptomyces species
Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 1 2000, 3, 323Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 1 2000, 16, 2665Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 6032-6036
Photochemical Rearrangements.
O
HOO
HOO
OH
O
OMe
OO
O O
h (=254 nm)cyclohexane
50min75%
HOMe
OO
OO
6
Medium-pressure Hg lamp
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• Photo-Fries Rearrangement :
Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 6032-6036
Photochemical Rearrangements.
O
OMe
OO
O O
h (=254 nm)cyclohexane
50min75%
HOOMe
OO
OO
O
OMe
OO
O
O
OMe
OO
OO O
O
OMe
OO
O O
O
OMe
OO
O O
OOMe
OO
OO
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Conclusion.
• Access to important fragment from simple molecules
•Control in the product generated
Equipment
48
Photochemical reaction
• Use of continuous flow reactor
• Possibilities to scale-up reaction
• Light as the only reactant
N XR
H
HHO2C
OHO
OOO
6
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Conclusion.
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I’m not
Mexican