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The Current State of Synthetic Organic Photochemistry Frontiers in Chemistry Series Stephen Lynch 1/24/04 Steve Lynch @ Wipf Group 1 1/25/2004
The Current State of Synthetic Organic Photochemistry
Frontiers in Chemistry Series
Stephen Lynch
1/24/04
Steve Lynch @ Wipf Group 1 1/25/2004
► Introduction to Photochemistry
► Some Historical Aspects
► Recent Applications of Photochemistry in Organic Synthesis- Isomerizations- Cycloadditions- Rearrangements- Cyclizations
► New Directions in Organic Photochemistry- Photoactivated Scavengers- Photolabile Protecting Groups- Photochirogenesis
► Summary
The Current State of Synthetic Organic Photochemistry
Steve Lynch @ Wipf Group 2 1/25/2004
Overview of Photochemistry
• Molecules absorb radiation which results in excited electronic states.→ usually C=C and C=O
• Chemically useful light is generally in the range of 200-400 nm.• Often employ filters to regulate the wavelength of the radiation.
π
n
π∗
π
n
π∗
π
n
π∗
π
n
π∗
π
n
π∗
groundstate
n→π*singlet
n→π*triplet
π→π*singlet
π→π*triplet
• Triplet state lower in energy than singlet state (due to Hund’s rule)Steve Lynch @ Wipf Group 3 1/25/2004
S0
S2
S1
T1
IC
ISC
vc
vc
vc
vc
ISC
IC
hν
hνhνf
hνp
hν = light excitationhνf = fluorescencehνp = phosphorescencevc = vibrational quenchingIC = internal conversionISC = intersystem crossing
What is the Fate of an Excited Molecule?
Jablonski Diagram
Ener
gy(k
cal/m
ol)
0
75-80
80-75
Steve Lynch @ Wipf Group 4 1/25/2004
Physical Processes Undergone by Excited Molecules
S0 + hν → S1v Excitation
S1v → S1 + heat Vibrational Relaxation
S1 → S0 + hν FluorescenceS1 → S0 + heat Internal ConversionS1 → T1
v Intersystem CrossingT1
v → T1 + heat Vibrational RelaxationT1 → S0 + hν PhosphorescenceT1 → S0 + heat Intersystem CrossingS1 + A(S0) → S0 + A(S1) Singlet-Singlet TransferT1 + A(S0) → S0 + A(T1) Triplet-Triplet Transfer
photosensitization
Steve Lynch @ Wipf Group 5 1/25/2004
Chemical Processes Undergone by Excited Molecules
1. (A-B-C) → A-B• + C• Simple Cleavage into Radicals2. (A-B-C) → E + F Decomposition into Molecules3. (A-B-C) → A-C-B Intramolecular Rearrangement4. (A-B-C) → A-B-C’ Photoisomerization5. (A-B-C) → A-B-C-H + R• Hydrogen-atom Abstraction6. (A-B-C) → (ABC)2 Photodimerization7. (A-B-C) → ABC + A* PhotosensitizationA
RH
R R'
O
R
OhνR'
R
OH R'
R
OH R'
R
OHR'
R
OH R'
OHR
R'hν Yang
cyclization
fragmentation
Norrish Type I
Norrish Type II
Steve Lynch @ Wipf Group 6 1/25/2004
Some Common Photosensitizers
O
Me
Me
O
O
O O
O
acetone p-xylene acetophenone acetonaphthone
xanthone benzophenone triphenylene
A good sensitizer must:- absorb light entirely in order to avoid concurrent reactions- not undergo chemical alteration until reaction is complete- be easily eliminated from the reaction mixture upon completion
Review: Albini, A. Synthesis 1981 249.Steve Lynch @ Wipf Group 7 1/25/2004
Woodward-Hoffman Rules and Orbital Symmetry
Number ofπelectrons Thermal Photochemical
2 disrotatory conrotatory4 conrotatory disrotatory6 disrotatory conrotatory8 conrotatory disrotatory
∆ hνconrotatory disrotatory
ψ2 is HOMO ψ3 is HOMO
Stereochemical outcome will be impacted!
Steve Lynch @ Wipf Group 8 1/25/2004
Why Use Photochemistry?
√ Overcome large kinetic barriers in a short amount of time
√ Produce immense molecular complexity in a single step
√ Form thermodynamically disfavored products
√ Allows reactivity that would otherwise be inaccessible by almostany other synthetic method
√ The reagent (light) is cheap, easily accessible, and renewable
Drawbacks?
X Reactivity is often unpredictable
X Many substrates are not compatible
X Selectivity and conversion are sometimes low
Steve Lynch @ Wipf Group 9 1/25/2004
Emergence of Photochemistry in Natural Product Synthesis
Quinkert, G.; Eis, K. In Essays in Contemporary Chemistry; Quinkert, G.; Kisakurek, M. V., Eds.; Wiley-VCH: Weinheim, 2001, pp 189-282.
Me
H OH
Me
H
RH
Me
H
RH Me
H
RH
Me Me
HHHO HO
H H
Me
H
RH
Me
Me
H
RH
CH2OH
H HOH
∆
Previtamin D
Provitamin D Lumisterol
Tachysterol Vitamin D
hνhν
hν
X
X
XX
Steve Lynch @ Wipf Group 10 1/25/2004
Recent Applications of Traditional Photochemical Methodology
■ [2+2] Cycloadditions■ [4+2] Cycloadditions■ Photoisomerizations■ Photoenolizations■ Photorearrangements■ Electrocyclizations
Steve Lynch @ Wipf Group 11 1/25/2004
N
OMe O
Cl
N
O
O
N
O
O
N
O
O
SmI2
N
O
O
N
OH
1.
2. i-PrMgCl3. H3O+
75%
hν
acetone
90%
1. PhSeCl2. H2O2
3. H2, Pd/C THF/DMPU
single diastereomer
(±)-Plumerinine
Highly Facial Selective Intramolecular [2+2] Photocyclization
Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett. 2002, 4, 1611.Steve Lynch @ Wipf Group 12 1/25/2004
Highly Diastereoselective Intramolecular Photocycloaddition
O CO2Me
O
O
O CO2Me
O
O
H
O CO2Me
O
O
O CO2Me
O
O
H
O CO2Me
O
O
H
EtO
O OH
O
O
CO2Me OEt
OTMS
O CO2Me
O
O
OO
OR
H
H O
OO
RH
H
hν
97%
hν
95%
83 : 17
single diastereomer
4 steps
ZnCl2, Et2OCuBr•SMe2
83%
∆∆G = 1.5 kcal/mol
vs.
Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J. Am. Chem. Soc. 1998, 120, 1747.Steve Lynch @ Wipf Group 13 1/25/2004
Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J. Am. Chem. Soc. 1998, 120, 1747.
Elaboration of the Photocycloadduct
O CO2Me
O
O
HTHF
O CO2Me
OH
OH
HDMAP
O CO2Me
OH
O
H
N
S
N
Bu3SnH, AIBN
O CO2Me
OH
H
O CO2Me
OH
CO2Me
OH
OO
HO
CO2Me
OH
OH
p-TsOH (imid)2C=S
87%
C6H6, 80°C
92%
3:2 (β:α)
(±)-Lubiminol
Dowd-Beckwith Rearrangement
Steve Lynch @ Wipf Group 14 1/25/2004
H
O
H
OO
H
OO
Cl
H
OO
O
ClH
H
OMeO
O
ClH
K2CO3
MeOHH
OMeO
O
ClH
O
H
Cl
H CO2Me
O
H
HOHOHO OH
H
H
1. LDA, MeO2CCN
2. PMB-OH3. TFAA/TFA/Ac2O Me2CO
80% (3 steps)
1. SeO2, TBHP
2. triphosgene PPh3
66% (2 steps)
hν
CH3CN, 0°C
60%
5:2 (β:α)
retro-
aldol
De Mayo Reaction
(±)-Ingenol
30 steps
Photocycloaddition/Fragmentation Sequence
Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726.Steve Lynch @ Wipf Group 15 1/25/2004
Paterno-Büchi Type Photocycloaddition/Fragmentation
Reddy, T. J.; Rawal, V. H. Org. Lett. 2000, 2, 2711.
Me
Me
Me
Me
Me
Me Me
MeMe
O O Me
Me Me
O Me
LiDBB
Me
Me
HMe
Me
HO
Me Me
OHMe
Me Me
OHMe
Me
Me
HMe
Me
OPDC
1. O3
2. base
77%
10% Eu(FOD)3toluene, 80°C
84%
hν
Corex filter19h
79%
-78°C to 10°C
57%
84%
(±)-5-Oxosilphiperfol-6-ene
radical fragmentation
Steve Lynch @ Wipf Group 16 1/25/2004
Dorr, H.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121, 10229.
O O H
H
O
hν
O H
H
O H
HH
H
HH
O H
HH
H
O
hν
O H
H
O H
HH
H
HH
O H
HH
H
O O
O
uranium filter
88%
25°C, 30 min
140°C
xylenes, 24 h
45%
3 : 2 : 1
uranium filter
77%
-75°C, 3 h
10 : -- : 1
Additional Substrates:
Photoisomerization Diels-Alder Reactions
Steve Lynch @ Wipf Group 17 1/25/2004
Application of Photoenolization Diels-Alder Reaction
Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613.
O
H
Me
OH
OHR
R'
OHR
R'
OR
R'
R = electron withdrawing group
Ox
tetralones
[4+2]
hν
hν
fast
orthoquinodimethane
O
H R
OH
R
OHR OH
OH
Me
BrO
HMeCO2Me
hν [4+2]
fast
(±)-Hamigeran A
Steve Lynch @ Wipf Group 18 1/25/2004
OMe
Me
NHtBu
O
t-BuLi
O
OMe
Me
O
O OMe
Me
OTBS
HO
MOMCl
OMe
Me
OTBS
MOMO
Pd(OAc)2Cu(OAc)2
OMe
Me
OTBS
MOMO
O(MeO)2P
OCH2CO2Me
NaH
OMe
Me
OTBS
MOMO
CO2MeOMe
Me
O
MOMO
CO2Me
then p-TsOH, C6H6
91%
1. LAH
2. TBSCl
89%
DMA/H2O, O2
83% 81% 94%
E/Z = 3.5:1
2. SO3•py
1. HF•py
84% (2 steps)
Application of Photoenolization Diels-Alder Reaction
Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613.Steve Lynch @ Wipf Group 19 1/25/2004
Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613.
Application of Photoenolization Diels-Alder Reaction
OMe
Me
O
MOMO
CO2Me CO2MeOMe
Me
MOMO
Me
H
CO2MeOMe
Me
HO
Me
H
OH
OMe
Me
OH
MOMOMe
CO2MeH
OHOH
Me
BrO
HMeCO2Me
hν, Pyrex 1% HCl/MeOH
85% (2 steps)
25 min
upon irradiation theolefin readily undergoes E/Z isomerization
observed product arisesfrom endo cycloadditionof the E olefin
(±)-Hamigeran A
bulky MOM ether also contributes to good selectivity
avoids unfavorable interactionwith methyl group
Steve Lynch @ Wipf Group 20 1/25/2004
Photochemical Isomerization/Diels-Alder CycloadditionApplied to Biomimetic Synthesis
Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Claridge, T. D. W.; Odell, B. Org. Lett. 2003, 5, 661.
O2N
CHO CO2Et
PPh3 O2N
CO2Et
O2N
CHO
O2N
CHO PPh3CHCO2Et
O2N
CO2Et
toluene
reflux
95%
1. DIBAL-H
2. Swern Ox.
repeat sequence
2 times
94%
25% (6 steps)
toluene, reflux
very strained due to steric interactionsbetween the methyl substituents
98%
Steve Lynch @ Wipf Group 21 1/25/2004
Photochemical Isomerization/Diels-Alder CycloadditionApplied to Biomimetic Synthesis
Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Claridge, T. D. W.; Odell, B. Org. Lett. 2003, 5, 661.
O2NMe Me Me
CO2Et Me Me
HH Me
CO2Et
O2N
Me Me Me
CO2Et
NO2 Me
NO2
MeMe
CO2Et
Me Me
HH MeMe
O
MeMe
O
OMeMe
OMe
600W
tungsten bulb
60%
hν
hν
Z, Z, E, E
E, E, E, E
Z, E, E, E
Crispatene
Steve Lynch @ Wipf Group 22 1/25/2004
O
O
HOOH
TsOH
O
O
OO
HOBn
O
O
OHO
OBn
O
O
OOBn
O
O
OHN3 TiCl4O
N
O
H
enantiomericallypure
LDA1. MsCl
2. DBU
64% (4 steps)
1. H2, Pd/C, Pd(OH)2
2. Zn(N3)2•2pyr, DEAD, PPh3
78% 62%
Smith, B. T.; Wendt, J. A.; Aubé, J. Org. Lett. 2002, 4, 2577.
Photochemistry Completes First Asymmetric Total Synthesis of (+)-Sparteine
Steve Lynch @ Wipf Group 23 1/25/2004
ON
O
H ONH O
NH
N3
1. Lawesson's reagent
2. Raney Ni
1. LDA, I(CH2)4Cl
2. NaI, acetone
76% (5 steps)
Schmidt does not work!
3. NaN3
Smith, B. T.; Wendt, J. A.; Aubé, J. Org. Lett. 2002, 4, 2577.
Photochemistry as a Key Step in (+)-Sparteine Total Synthesis
ONH
I
OBocHN Boc
K2CO3 ONH
NBoc
OBocN
NH
O
NNH O
NH
N
ONH
N
95%
TFA, 4Å MS
then NaHCO3
74%
hν
benzene
76%
LAH
95%(+)-Sparteine
photo-Beckmann rearrangement
Steve Lynch @ Wipf Group 24 1/25/2004
Clayden, J.; Knowles, F. E.; Menet, C. J. J. Am. Chem. Soc. 2003, 125, 9278.
Photochemically Induced Ring Expansion
Nt-Bu
O
Ph
t-BuLi Nt-Bu
O
PhLiNt-Bu
Ph
OLi
H
NH4ClNt-Bu
Ph
O
H
H
Ph
NHt-Bu
O
HMPA, -78°C-78°C
16 h
80%
hν
72%
Nt-Bu
O
Ph
1. t-BuLi
R
CONHt-Bu
H
PhRPh
CONHt-BuR
RCONHt-Bu
R
Ph
H
H
CONHt-Bu
Ph
HMPA, -78°C
2. hν
or
or
3. NH4Cl or HCl
product isolated depends onsubstrate and reaction conditions
24 - 80 % yield
Steve Lynch @ Wipf Group 25 1/25/2004
Photochemically Induced Ring Expansion
Clayden, J.; Knowles, F. E.; Menet, C. J. J. Am. Chem. Soc. 2003, 125, 9278.
Nt-Bu
O
PhR
CONHt-Bu
H
PhRPh
CONHt-BuR
RCONHt-Bu
R
Ph
H
H
CONHt-Bu
Ph
Nt-Bu
Ph
OLi
H
R
X
hν[1,3]
hν[1,5]
6e-
6e-
[1,7]hν
suprafacial & retentive
invertive suprafacial migration
disrotatory opening
N
O
Ph
1. t-BuLiNH
O
Ph
HMPA, -78°C
2. hν3. NH4Cl
80%
99% eeStereospecificity persiststhrough deprotonation, cyclization, and rearrangement!
Steve Lynch @ Wipf Group 26 1/25/2004
New Directions in Organic Photochemical Methodology
■ Photoactivated Reagent Scavengers■ Photolabile Protecting Groups■ Photoreleasable “Caged” Molecules■ Photochirogenesis (Asymmetric Photochemistry)
Steve Lynch @ Wipf Group 27 1/25/2004
Photoactivated Reagent Scavangers (Precipitons)
Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194.
NH2N
CO
THF/Et2ONH
NH
O
NH2
1.1 - 1.2 equiv 1.0 equiv excess
NC
O
NHNH
ONH
NH
O
NHNH
ONH
NH
O
hν
350 nm, 15 min
95% yield>95% pure
insoluble:precipitatesfrom solution!
Steve Lynch @ Wipf Group 28 1/25/2004
Photolabile Protecting Groups
Review: Bochet, C. G. J. Chem. Soc., Perkin Trans. 1, 2002, 125.
NO2
O X
O
N
O X
O
O
O
N
O X
O
O
OH N
O X
O
OH
O
ONOH
O
X
O
NO
CHO
HO X
O
NO2
OH
NO2
OH
MeO
MeO
X = NR1R2, R, OR
hν
Norrish Type II
320nm
350nm
Steve Lynch @ Wipf Group 29 1/25/2004
Photochemical Release of “Caged” MoleculesInositol Triphosphate (InsP3)
O
OO
OO
O
PO
(OPM)2
OMe
PPO
(PMO)2
O(PMO)2
NO2
OMeMeO
O
O
O
OO
OO
O
PO
(O-)2
OMe
PPO
(-O)2
O(-O)2
NO2
OMeMeO
O
OHO
OO
O
PO
(O-)2
OMe
PPO
(-O)2
O(-O)2
PM =
cmIP3/PM
diffusion
plasma membrane
cmIP3
esterases
hν
mIP3
regulation of Ca2+ levels and gene expression
350 nm
Li, W.-H.; Liopis, J.; Whitney, M.; Zlokarnik, G.; Tsien, R. Y. Nature, 1998, 392, 936.Steve Lynch @ Wipf Group 30 1/25/2004
Photochemical Release of “Caged” Molecules
Lu, M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003, 5, 2119.
O OHO
Br
HOOH
PPTS, MgSO4
R R'
O
O OHO
Br
OO
R'R
O OHO
Br
HOOH
R R'
O
NHOBr
O
ONHO
Br
OH HO
O
toluene
hν365 nm
pH 7.2 KMOPSbuffer
Bhc-diol
hν370 nm
pH 7.2 KMOPSbuffer
BHQ-OAc
Fedoryak, O. D.; Dore, T. M. Org. Lett. 2002, 4, 3419.
Steve Lynch @ Wipf Group 31 1/25/2004
Attempts at Asymmetric Photochemistry
• Stoichiometric chirality transfer from pre-existing stereocenters present in the substrate
• Use of chiral auxiliaries
• Solid state photochemical transformations in clays and chirallymodified zeolites
• Chiral solvents, liquid crystalline phases and polymer matrices
• Chiral molecular receptors
• Circularly polarized light
• Chiral photosensitizers
Review: Inoue, Y.; Wada, T.; Asaoka, S.; Sato, H.; Pete, J.-P. J. Chem. Soc., Chem. Commun. 2000, 251.Steve Lynch @ Wipf Group 32 1/25/2004
HO2C CO2HCO2H
NHOCO2H
SOCl2
OHC
OH
NHO OO
H
O
NHO OO
H
O
NH
ONHO O
O
O
NH
O
NHO OO
O
NH
O
Kemp's triacid
hν
toluene, -10°C
56%
95 : 5
Bach, T.; Bergmann, H.; Harms, K. J. Am. Chem. Soc. 1999, 121, 10650.
Chiral Auxiliary
Steve Lynch @ Wipf Group 33 1/25/2004
NH NO
O
B
NH
O
O
NH
O
O
NH
O
O
HH
NH
O
O
H
H
B (2.6 eq)hν
-60°C, toluene
77%
B (2.6 eq)hν
-60°C, toluene
87%
93% ee
>90% ee
Chiral Molecular Receptors(Host-Guest Systems)
Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124, 7982.Steve Lynch @ Wipf Group 34 1/25/2004
Chiral Molecular Receptors(Host-Guest Systems)
Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124, 7982.
HN NO
A
O
NH
OMe
OOH
NH
O
MeO
H
HO H
NH
OMe
OOAc
NH
O
MeO
H
AcO H
HN
O
O CO2MeNH NO
O
B
HN
O
OHCO2Me
hν
toluene, -60°C
hν
toluene, -60°C
80%
80%
81% ee
92% ee
hν
toluene, -60°C73%
A (2.6 eq)
A (2.6 eq)
B (1.2 eq)
94% ee
Grosch, B.; Orlebar, C. N.; Herdtweck, E.; Masa, W.; Bach, T. Angew. Chem. Int. Ed. 2003, 42, 3693.Steve Lynch @ Wipf Group 35 1/25/2004
OOMe
O
OOMe
OMe
hν
'In'
'Out'
50% ee(-)-norephedrine
NaY, -20°C
Joy, A.; Scheffer, J. R.; Corbin, D. R.; Ramamurthy, V. J. Chem. Soc. Chem. Commun. 1998, 1379.
Ellison, M. E.; Ng, D.; Dang, H.; Garcia-Garibay, M. A. Org. Lett. 2003, 5, 2531.
100% transfer of ee
Solid State or Crystalline Reactions Can Induce Asymmetry
Steve Lynch @ Wipf Group 36 1/25/2004
O
Ph
Ph
O
Ph
Ph
O
Ph
Ph
CO2R*
CO2R*
*RO2C
*RO2C
Ph
hν / Sens*
-80°C, hexane
(R)-1E (S)-1E1Z
-70°C
(S,S)
(R,R)
(-)-bornyl (-)-menthyl (-)-8-phenylmenthylSensitizer*
77% ee
Hoffmann, R.; Inoue, Y. J. Am. Chem. Soc. 1999, 121, 10702.
Sensitization by Chiral Aromatic Esters
Steve Lynch @ Wipf Group 37 1/25/2004
Designing a Catalytic Asymmetric Sensitizing Receptor
Cauble, D. F.; Lynch, V.; Krische, M. J. J. Org. Chem. 2003, 68, 15.
Requirements for such an endeavor:
1. The substrate must be placed in a well-defined chiral micro-environment upon binding to a template
- Host-guest system where hydrogen bonding dictatesorientation in predictable fashion
2. Substrate-template binding confers a kinetic advantage to thetransformation of interest
- Sensitizer which contains a highly localized sphere ofenergy transfer (exciplex)
If the lifetime of the exciplex is comparable to the rate of desiredreaction, the exciplex formation can be enantiodiscriminating!
Steve Lynch @ Wipf Group 38 1/25/2004
Designing a Catalytic Asymmetric Sensitizing Receptor
Cauble, D. F.; Lynch, V.; Krische, M. J. J. Org. Chem. 2003, 68, 15.
HN
O
OHN
O
O
NH
O
O
hν, Sens*
-70°C, 70 h
100%
100 mol%; 22% ee 25 mol%; 19% ee
Steve Lynch @ Wipf Group 39 1/25/2004
Summary
► Traditional photochemistry will continue to occupy a uniqueniche in the realm of organic synthesis.
- New and creative applications of established reactions will continue to solve important synthetic problems
- Photochemistry allows access to reactive intermediates that would prove difficult to achieve by almost any other synthetic method.
► The field of photochirogenesis will continue to be developed withhopes of unlocking its full potential, especially in applicationstoward total synthesis.
► New directions in organic photochemistry will likely focuson more contemporary biological and analytical applications.
Steve Lynch @ Wipf Group 40 1/25/2004
