Photoinduced Electron Transfer: Strategies for Organic Synthesis
MacMillan Group Meeting Alex Warkentin 2.12.08
D* + Acc = D- + Acc+
Contents
• History of photoinduced electron transfer • Basics of electron transfer versus energy transfer • Oxidative PET bond cleavage • Reductive PET bond cleavage • Enabling of macrocyclic ring closures • Intramolecular alpha-amino radical additions • Intermolecular alpha-amino radical additions and applications • Catalytic asymmetric? • Mechanistic verification via spectroscopic analysis
Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005.
Griesbeck, A. G.; et. al. Acc. Chem. Res. 2007, 40, 128.
Roth, H. D. Photoinduced Electron Transfer I Springer-Verlag, Heidelberg, 1990. 5.
Joseph Priestley, 1733 - 1804 British chemist
The First Understandings of Photochemistry Priestley was the first to discover photosynthesis, albeit fortuitously
H2O + CO2 O2 + C6H12O6hν
Discovered accidentally while Priestly was studying the “influence Of light in the production of ‘dephlogisticated air’ [O2] in water by Means of a ‘green substance’.” Priestley, J. Phil. Trans. Roy. Soc. (London) 1772, 62, 147
Jan Ingenhousz, 1730 - 1799 Dutch chemist, physicist and physician
Ingenhousz developed photosynthesis more rigorously
Ingenhousz, along with Saussure, established the requirement of light in macroscopic photosynthesis.
But, despite work by Liebig, Baeyer and Willstatter, electron transfer remained unsolved untill the 20th century when J. J. Thompson (1897) and Milikan (1913) convinced the community of the presence
of the electron.
J. W. Dobereiner, 1780 - 1849 German Chemist
Designed the first actinometer that measures the power of electromagnetic radiation
Fe2O3 +
(Fe3+)
FeO + CO2 + CO2
(Fe2+)O
OO
O
hν
Electron Transfer and Actinometry Dobereiner foreshadowed photo-redox chemistry with actinometry
The place and usefulness of actinometry was fiercely debated and no other photo-redox chemistry was studied in-depth in the 19th century
Furthermore, prior to the advent of NMR, ESR, and CIDNP the presence of ionic radicals remained highly speculative and their identity often erroneously presumed.
20th Century PET contributions were made by Bauer and Weiss. The latter enunciated the basic form of modern PET theory:
“Fluorescence quenching in solution can be considered as a simple electron transfer process.”
D* + Acc = D- + Acc+
Weiss, J.; Fischgold, H. Z. Physik. Chem. 1936, B32, 135.
Photoinduced Electron Transfer: A Representative Mechanism
Understanding α-amino radical formation is important for utlizing its reactivity
1 or 3Sens 1 or 3Sens*hν
RNR
R
E
1 or 3Sens* + RNR
R
E
1 or 3Sens +
PET
RNR
R
E
Nu + Nu ER
NR
R+R
NR
R
RNR
R Further chemistry
Basics of Photoinduced Electron Transfer
Efficiency dependent on redox potential
+
+
+
+
1Sens + D 1Sens + D
1Sens + A 1Sens + A
More efficient as distance decreases
Singlet-excited sensitizer is both a better oxidant AND reductant. Both processes quench fluorescence
Triplet fluorescence quenching is known
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry University Science Books, Sausalito, CA. 2005, 955 - 958.
Energy Transfer Mechanisms do not Occur Via Polar Intermediates
Energy Transfer I: Dexter Mechanism
+ +
3Sens* + A Sens + 3A*
+ +
1Sens* + A 1Sens + A*
Energy Transfer II: Forster Mechanism
Both Energy Transfer Mechanisms Require that E(excited state D) > E(excited state A)
kee = KJe^(-2rDA/L), so rDA ~ 5 - 10 A
Primarily triplet sensitization
Can operate at over 50 A via a dipole- dipole (Coulombic) mechanism (transition dipole coupling) Basis for FRET
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry University Science Books, Sausalito, CA. 2005. 955 - 958.
Kornblum, N; et. al. J. Am. Chem. Soc. 1955, 77, 6269; Angew. Chim. Int. Ed. 1975, 14, 734
Reductive PET Bond Cleavage
O2N
Cl+
Me NO2
Me Na PET
Me
Me
NO2
NO2
Cl
O2N
Me
Me
NO2
O2NMe Me
NO2
N
Cl
OO
+
ambient light
O2N
NO2
Me MeNaN3
O2N
N3
Me MeConditions
Dark
ambient
fluorescentlight (20 W)
Yield
0%
63%
100%
Reductive cleavage proceeds by electron transfer to benzyl halide or pseudo-halide
Reductive PET Reactions and Non-Halide Examples
NBoc substituents stabilize benzylic radical formation
OBocHN
Ph
OMeO
OMe
OMe
OO
OBocHN
OOMe
O
OMe
OMe
H
94%, 10 : 1 dr
hν, NMQPF6
O2, Na2S2O3NaOAc, 4 A MS
DCE, PhMe
PhOMe
O OEtO O hν, NMQPF6
O2, Na2S2O3NaOAc, 4 A MS
DCE, PhMe
O OMeO OH
OEtHH H
NMQNMe
OMeOO OEt
MeOH
OMe groups stabilize benzylic nucleofuges toward tandem epoxide ring openings
79%
Floreancig, P. E. Synlett 2007, 191.
Cristol, S. J.; et. al. J. Am. Chem. Soc. 1987, 109, 830 Zimmerman, H.; et. al. J. Am. Chem. Soc. 1963, 85, 913; J. org. Chem. 1986, 51, 4681.
Wagner-Meerwein rearrangement
Reductive PET Bond Cleavage
Homobenzylic chlorides also participate in reductive PET chemistry
ClCl
MeO
MeOPET
AgOAc, HOAc
OAcCl
ClCl
MeO
MeO
MeO
MeO
Besides anti/syn considerations, differences occur between homopara vs. homometa C-X bonds
ClPET
AgOAc, HOAc
OAcMeO
Cl Cl
ClMeO MeO
70%
plus 18% RCl
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1982, 104, 617
Oxidative PET Bond Cleavage
NMe
PhClO4SiMe3
PET
NMe
Ph + SiMe3+
SiMe3 + Nu + NuSiMe3
NMe
Ph +NMe
Ph
A representative and early example of oxidative PET bond cleavage
Oxidative Intramolecular PET Bond Cleavage
N MeClO4
Me3SiPET N Me
ClO4
Me3SiNu
N
Me
90% indolizidine
O
NBn
Me3Si
PET
CN
CN
O
NBn
Intramolecular C-C bond formation to form indolizidines
Intramolecular organocatalytic Hiyama-type coupling
Difficult to perform this chemistry as efficiently with a non-PET approach (polar reagents)Mariano, P. S.; et. al. J. Am. Chem. Soc. 1984, 106, 6439.
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1994, 116, 4211.
Oxidative PET Bond Cleavage
Me
O
NMe
Me3SiPET
MeOH/MeCNDCA
Me
O
NMe
Me3SiMe
O
NMe
Me
O
NMe
90%
Me
O
NMe3Si
Less polar and aprotic solvents (MeCN alone) afford product retaining silyl group
Me
O
NMe
SiOMe
H
Me
O
NMe
SiNMe
vs
Hu, S.; Neckers, D. C. Tetrahedron 1997, 53, 2751
Application to Macrocyclic RIng Closures
O
O
ONR2
R1
N
O
OHO
Ph
R1
R2
PET
O
O
OS R1
R2
PET
S
O
OHO
PhR1
R2
38 - 76%
35 - 65%
N NH
NH
SO
O
HO
O 36%
Hasegawa, T. Tetrahedron, 1998, 54, 12223
Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005. 276.
Application to Poison Frog Therapeutics
NMe
Me
HOH
NN
OH
OH
HO H
OH
O
O
O
HOOH
Carbohydrate-mimetic hydroxylated indolizidines
(+)-Pumiliotoxin
Antidiabetics, antiviral, anticancer, immunosuppressant, transplantation medicine
Pyrrolizidines also offer opportunities for synthetic application
alexine riddelliine
Potent glycosidase inhibitor, antiviral, anti HIV, anticancer
Insect defense agent
Griesbeck, A. G.; et. al. Acc. Chem. Res. 2007, 40, 128.
Dendrobates spp.
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1991, 113, 8847
Intermolecular Non-Silylated, Simple Amino-Alkyl Additions
Triplet sensitizers have very specific transition energies and can markedly improve reaction efficiency
O OMenthO
OMenth
OR
Me
Me
Me
NMe
+PET
O ORO
O ORO
H H
NMe NMeH H+
2 : 1
60%
1 : 1.2
94%
Ph Ph
O
O
MeO OMe
N N
H HOHOH
(-)-Isoretronecanol (+)-Laburnine
Proposed Mechanism for Pyrrolidine Addition
The catalytic cycle may provide more than one opportunity for a product forming step
O ORO
NMe
O
MeO OMe
OH
MeO OMe
OOOR
MeN
NMe
O
O
ORNMe
NMe
productPET
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1991, 113, 8847
77 - 94% 5 examples
Further Development of Amine Coupling Partners
Triethyl amine, piperidone and other amines are a viable coupling partner in PET C-C bond construction
O O+
PETO O
NEt2
TEA350 nm
sensitizer85%, 1:1 dr
O ONMe
+PET O O
H H
H H+
1 : 1
60%
1 : ~0
48%
MenthORO RO
EtO
S
SMe
EtO
S
SMe
No
With
350 nmsensitizer NMe NMe
N 2.5 : 1 constitutionalisomeric products
favoring tertiary radical
Org. Biomol. Chem. 2006, 4, 1202; Zard Angew. Chim. Int. Ed. 1997, 36, 672.
Bertrand, S.; et. al. J. Org. Chem.2000, 65, 8690; Marinkovic, S.; et. al. J. Org. Chem. 2004, 69, 1646.
Intramolecular Trapping of Presumed Oxy-allyl Radical
When trapping oxy-allyl radical acetone was necessary to act as benign oxidant
O O+
PET O O
H H+
38% : 2% : 18%
74% : 3% : 0%
MenthORO RO
With acetone
Without acetone
350 nmMichler'sketone
O
Me2N NMe2Michler's ketone
NMeMe
N NMe Me
H H + O
O
RO
N
OO OR
N
OO OR
71%, 1 : 1 dr 74%, 2 : 1 dr
NO
O
OR
56%, 20 : 1 dr
Me
Demuth, M. J.; et. al. J. Am. Chem. Soc. 1999, 121, 4894; Griesbeck, A. G.; et. al. Angew. Chem. 2001, 113, 586
Non-Direct Methods for Enantioinduction in PET Reactions
Cascade cyclization of terpene polyolefins via photoinduced electron transfer
MeMe
Me
O O
OMe
Me 1) PET, DCTMB
BP, MeCN/H2O-25 oC
2) removal of (-)-menthone HO
Me
Me Me
Me
MeH
H H
OHCO2Me Perfect diastereoinduction
Only 2 of 256 possible isomers formed and 8
stereocenters set
Shortest steroid route
Remarkably far reachingasymmetric induction
N
N
O
O
O
CO2K
PET, acetone/H2O
X N
N
O
O
OH
X
X = H, 45%, 86% eeX = Cl, 50%, 79% ee
With ethylene di-ortho linker: 0% ee
Memory of chirality PET study explained by rigidity of amide and aniline bonds toward rotation
12%
NH
NH
O
O
N N
N
O
N
OH
O
N
H
N
O
Hhν (λ > 300 nm)
30% catalystToluene
64% yield, 70% eesingle diastereomer
Recent Precedent for Catalytic Asymmetric PET Carbon-Carbon Bond Formation
The Bach example is the only method thus far for a direct, catalytic, asymmetric reaction with chemical yields above 1%
Bauer, A.; Westkamper, F.; Grimme, S.; Bach, T. Nature 2005, 436, 1139
Evidence Supporting the Occurence of Charge Separation
NNN
N
N
N O
RN H
H
NMe
Me
Rib
O Rib
NHH
hνET
Rib =O
ORORHOR
R = SiMe2tBu
1 2
Why should we trust that charge separation is occuring?
2 Fluoresces upon irradiation and is quenched upon increasing concentration of 1 in solution. This levels off at 1 molar equivalent of 1.
Quenching of simple anthracene* fluorescence by adition of aniline only occurs at 2%.
If masked donor (R = COCHMe2) is used, little quenching occurs.
Thus, diffusion controlled collisional quenching cannot be responsible for electron transfer.
Ka = 38,000 +/- 1300 M-1 ΔGo
CS = -0.41 eV; ΔGoCR = -2.5 eV
Sessler, J. L.; et. al. J. Am. Chem. Soc. 2001, 123, 3655.
PET Projects in Total Synthesis
Selected natural products formed by PET bond-constructive key steps
O
O
MeMe N
Bn
SiMe3
O
O
MeMe N
Bn
PET
NH
HO
HO
OH
60%
N
O
O
HOMeO
MeO
berberine analog
NH
OH
(+/-)-epilupinine
(+)-isofagomine
HN
O
O
OHHO
HO
O
(+)-2.7-dideoxypancratistatin
O Me
OOHO
Me Me
H
H
Me
Me Me
(+/-)-stypoldionepolyterpene cyclization
HOMe
H
MeMe
Me(+/-)-isoafricanol
O
HO OH
HO CO2Me
C-furanoside
Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005. 292.
Conclusions
• Photoinduced electron transfer (PET) utilizing alpha-amino radicals was shown to be applicable to problem solving in organic synthesis.
• Alpha oxo- and alpha thio-radicals are also useful. • Advantages - unique and/or expedited carbon-carbon
bond construction; vastly underexploited asymmetric potential for interesting reactivity.
• Disadvantages - Limited substrate scope and/or specific wavelength for some methods.