complex molecule synthesis enabled by...
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Complex Molecule Synthesis Enabled by Photochemistry
Joseph Badillo
March 23, 2016
MacMillan Group Meeting
OMe
MeMe
Me
O
hv
Complex Molecule Synthesis Enabled by PhotochemistryOutline
� General outline
1) Why are photochemical reactions interesting?
2) 2+2 cycloaddtions and cyclobutane ring-opening reactions
3) Norrish type I and II applications to complex architectures
7) Photoredox applications to complex molecule synthesis
4) Oxa-di-!-methane rearrangement
8) Summary
5) Paternò−Büchi reaction
6) meta-photocycloaddition reaction in total synthesis
Complex Molecule Synthesis Enabled by Photochemistrywhy photochemistry?
� Why are photochemical reactions interesting?
1) Since excited states are rich in energy, highly endothermic reactions are possible. Such as highly strained (up-hill) targets!
2) In the excited state antibonding orbitals are occupied, which allow for reactions to occur that are not possible in the ground state
3) Photochemical reactions have the potentail to be Green as they only consume photons
Complex Molecule Synthesis Enabled by PhotochemistryThermal vs photochemical topography
� Reactant (R) goes through intermediate (I) to form product (P)
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
Complex Molecule Synthesis Enabled by Photochemistrytypical absorption range of organic compounds
� Most organic molecules absorb light in the UV-region
Simple alkenes 190 - 200 nm
Acyclic diene 220 - 250 nm
Cyclic diene 250- 270 nm
Styrene 270 - 300 nm
Saturated ketones 270 - 280 nm
α,β-Unsaturated ketones 280 - 300 nm
Aromatic compounds 250 - 280 nm
Common photocatalysts 350 - 440 nm
Ultra Violet(UV)
Visible
Complex Molecule Synthesis Enabled by PhotochemistryEnergy absorbed from light
� Energy as a function of wavelength is hyperbolic
A molecule absorbing blue light, with a wavelength of400 nm, absorbs about 71 kcal of energy
Purves, W. K., G. H. Orians, H. C. Heller, and D. Sadava. 1998. Life: The Science of Biology (Fifth Edition). Sinauer Associates, Sunderland, MA.
Complex Molecule Synthesis Enabled by Photochemistry2 basic laws governing photochemical reactions
� Stark-Einstein law (Law of Photochemical Equivalence): Each reactant molecule absorbs a single photon to provide an activated species to form products
� Grotthus-Draper law (Principle of Photochemical Activation): Only the light which is absorbed by a system can bring about chemical change
one photon (hv)
A A� B
productmolecule
excitedmolecule
reactantmolecule
Complex Molecule Synthesis Enabled by Photochemistryreactivity of excited state intermediates
AB✻
+ M
physical quenching
AB + e
ionization
A + B dissociation
AE + B or ABE direct reaction
AB + E or AB + E
+ E
charge transfer
isomerization
AB + CD‡
intermolecularenergy transfer
AB†intramolecularenergy transfer
luminescenceAB + hv
+ CD
For more physics details see: Physical Organic Photochemistry - Scott Simonovich Group Meeting (2011)
AB
BA
Complex Molecule Synthesis Enabled by PhotochemistryOutline
� General outline
1) Why are photochemical reactions interesting?
2) 2+2 cycloaddtions and cyclobutane ring-opening reactions
3) Norrish type I and II applications to complex architectures
7) Photoredox applications to complex molecule synthesis
4) Oxa-di-!-methane rearrangement
8) Summary
5) Paternò−Büchi reaction
6) meta-photocycloaddition reaction in total synthesis
Complex Molecule Synthesis Enabled by Photochemistryfirst report on the [2 + 2] photocycloaddition
� In 1908 Ciamician and Silber observed carvone camphor formation from carvone when exposed to sunlight for one year
OMe
Me
carvone
Me
Me
O
carvone camphor
MeO
Me
not observed
hv
Ciamician, G.; Silber, P. Chemische Lichwirkungen. Ber. Dtsch. Chem. Ges. 1908, 41, 1928.
Complex Molecule Synthesis Enabled by Photochemistryphotoexcitation of enones
� α,β-unsaturated carbonyl compounds are often employed due to ease of excitability
Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297.
Ohv
O
••
✻ O
••
✻
singlet triplet
RO
••
✻
R
triplet exciplex
OR• •
OR• •
triplet 1,4-biradical singlet 1,4-biradical
spin inversion
OR
ISC
Complex Molecule Synthesis Enabled by Photochemistryphotoexcitation of enones
� Regioselectivity in [2 + 2] photocycloadditions
Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297.
O
hv
OR
O
+
head-to-headR
head-to-tail
R+
HN
O
hv HN
OR
HN
O
+
head-to-head
R
head-to-tail
R+
MeMe
MeMe
MeMe
A BR
OEt
CN
rr (A: B)
5:95
82:18
Complex Molecule Synthesis Enabled by PhotochemistryTotal synthesis of (−)-littoralisone
� [2 + 2] photocycloaddition enables the the total sysnthesis of (−)-littoralisone
Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696.
Me
Me
OH
Me
(−)-citronellol
12 steps
O
H
HMe O
O
OBn
OBn
OBn
O
OO
O
OBn
O
H
HMe O
O
OH
OH
OH
OO
OH
HO
O
hv (!"= 350 nm)rt, 2h, C6H6
then H2, Pd/C84% yield
(−)-littoralisone
13 steps13% yield overall
Complex Molecule Synthesis Enabled by Photochemistry[2 + 2] cycloadditions using allenes
� Optically active allenes can be employed with retention of steroechemisitry
Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.; Millward, D. B. J. Am. Chem. Soc. 1994, 116, 6622.
hv (!"≧ 300 nm)
rt, 4h, cyclohexane88% yieldO
O
•H
H
t-Bu
O
92% ee
OO
92% ee
O
H
t-Bu
Complex Molecule Synthesis Enabled by Photochemistry[2 + 2] photocycloaddition, followed by ring-opening
� Exploiting the inherent ring strain found in cyclobutanes to access medium-sized rings
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
m n
✻
mn
photoexcited olefin cyclobutanem
n
a
b
c
d
ring-opening at positions a-dgive rise to different size rings
Complex Molecule Synthesis Enabled by Photochemistry[2 + 2] photocycloaddition, followed by ring-opening
� Three common stratagies for cyclobutane ring opening
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
O
RX
O
R
Grob fragmentation
RO
O
radical fragmentation
O
RO
O
R
De Mayo reaction
O
Complex Molecule Synthesis Enabled by PhotochemistrySynthesis of (±)-epikessane
� A [2 + 2] cycloaddition followed by Grob fragmentaion enables the synthesis of (±)-epikessane
Liu, H.-J.; Lee, S. P. Tetrahedron Lett. 1977, 3699.
O
AcO
+MeO2C
AcO
O H
H
CO2Me
OAc
1) hv (! > 300 nm)C6H6
2) p-TsOH, C6H6
steps
H
H OH
OH
Me
p-TsCl
rt, 18 hpyridine
60% (2-steps)
83%Me
H
HO
Grob fragmentation
steps O
Me
H
H
Me
Me
Me
(±)-epikessane
Complex Molecule Synthesis Enabled by Photochemistry[2 + 2] photocycloaddition, followed by ring-opening
� Three common stratagies for cyclobutane ring opening
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
O
RX
O
R
Grob fragmentation
RO
O
radical fragmentation
O
RO
O
R
De Mayo reaction
O
Complex Molecule Synthesis Enabled by Photochemistryradical fragmentation
Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519.
OHC Me1)
2) MeOCH2Cl
Li CO2Et
MeOCH2OMe
EtO2C
EtO2C ZnI
CuCN, LiCl, Me3SiCl65% 60%
OCH2OMe
OCO2Et
Me
! = 365 nmhexanes
80%
OCO2Et
MeOCH2O
Me
1) 10% HCl, EtOH
2) (imid)2C=S, NEt381%
OCO2Et
O
Me
SNN
Bu3SnH, AIBN
C6H6, 80 °C76%
O
EtO2CMe
radical fragmentation
Complex Molecule Synthesis Enabled by Photochemistryradical fragmentation
Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519.
OHC Me1)
2) MeOCH2Cl
Li CO2Et
MeOCH2OMe
EtO2C
EtO2C ZnI
CuCN, LiCl, Me3SiCl65% 60%
OCH2OMe
OCO2Et
Me
! = 365 nmhexanes
80%
OCO2Et
MeOCH2O
Me
1) 10% HCl, EtOH
2) (imid)2C=S, NEt381%
OCO2Et
MeBu3SnH, AIBN
C6H6, 80 °C76%
O
EtO2CMe
radical fragmentation
Complex Molecule Synthesis Enabled by Photochemistryradical fragmentation
Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519.
OMe
Me
R
I
Bu3SnH, C6H6
AIBN, 80 °C
Bu3SnH, C6H6
AIBN, 80 °CR = CO2Me
MeMe
O
CO2Me
75% yield
O
Me
Me
H
R = H
80% yield
OMe
Me
R
•
O
Me
Me
H
•
+ H•
Complex Molecule Synthesis Enabled by Photochemistryradical fragmentation
Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519.
OMe
Me
R
I
Bu3SnH, C6H6
AIBN, 80 °C
Bu3SnH, C6H6
AIBN, 80 °CR = CO2Me
MeMe
O
CO2Me
75% yield
O
Me
Me
H
R = H
80% yield
OMe
Me
R
•
O
Me
Me
H
•
+ H•
OMe
Me
R• R
OMe
Me
•
+ H•
Complex Molecule Synthesis Enabled by Photochemistry[2 + 2] photocycloaddition, followed by ring-opening
� Three common stratagies for cyclobutane ring opening
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
O
RX
O
R
Grob fragmentation
RO
O
radical fragmentation
O
RO
O
R
De Mayo reaction
O
Complex Molecule Synthesis Enabled by PhotochemistrySynthesis of (−)-perhydrohistrionicotoxin
� De Mayo fragmentaion enables the synthesis of (−)-perhydrohistrionicotoxin
Winkler, J. D.; Hershberger, P. M. J. Am. Chem. Soc. 1989, 111, 4852.
OH OH
O
NH2
O
L-glutamic acid
steps HN
O
O
n-C5H11
Me
MeOO
hv (! > 300 nm)
0 °C, 30 minCH3CN
O
OHN
H H
n-C5H11
OOH
Me
Me
O
OHN
H H
n-C5H11
OOH
Me
Me
then NaBH4
61% (2-steps)
NaH
rt, 30 minTHF95 %
O
HN
O
n-C5H11
O
steps
HO
HNn-C5H11
n-C4H9
(−)-perhydrohistrionicotoxinDe Mayo reaction
Complex Molecule Synthesis Enabled by PhotochemistrySynthesis of (−)-perhydrohistrionicotoxin
� De Mayo fragmentaion enables the synthesis of (−)-perhydrohistrionicotoxin
Winkler, J. D.; Hershberger, P. M. J. Am. Chem. Soc. 1989, 111, 4852.
OH OH
O
NH2
O
L-glutamic acid
steps HN
O
O
n-C5H11
Me
MeOO
hv (! > 300 nm)
0 °C, 30 minCH3CN
O
OHN
H H
n-C5H11
OOH
Me
Me
O
OHN
H
n-C5H11
OO
Me
Me
then NaBH4
61% (2-steps)
O
HN
O
n-C5H11
O
steps
HO
HNn-C5H11
n-C4H9
(−)-perhydrohistrionicotoxinDe Mayo reaction
− acetone
Complex Molecule Synthesis Enabled by PhotochemistryCargill rearrangement
� Ring expansion of cyclobutanes via the Cargill rearrangement
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
O
H+
H+ OH
OH− H+
O
bicyclo [3.2.1] octan-8-one
O
bicyclo [3.3.0] octan-6-one
− H+
Me
Complex Molecule Synthesis Enabled by PhotochemistryCargill rearrangement
� Pirrung’s synthesis of (±)-isocomene using the Cargill rearrangment
Pirrung, M. C. J. Am. Chem. Soc. 1979, 101, 7130.
O
Me
Me
Me
hv (! = 350 nm)
hexane77%
O
Me p-TsOH
reflux, 2h, C6H6
O
Me
Me
MeMe
Me
O
+
90%
1:5 rr
2 steps
Me
Me
Me
Me
(±)-isocomene
tricyclo[6.3.0.0] undecanone
Me
from major
Cargill rearrangement
[3.3.0] octane [3.2.1] octane
Complex Molecule Synthesis Enabled by Photochemistrytricyclic aziridines from pyrroles
� [2 + 2] photocycloaddition/rearrangement of pyrroles to form aziridines
Maskill, K. G.; Knowles, J. P.; Elliott, L. D.; Alder, R. W.; Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2013, 52, 1499.
hv (!"= 254 nm)
rt, 6h, CH3CN59% yield
N
Me
Me CO2Et
MeO
N
O
Me
Me
Me
EtO2C
H
N
Me
Me
Me
O CO2Et
N
Me
Me
Me
O CO2Et
•• N
Me
Me
Me
O CO2Et
12 mM in [email protected] mL/min
1 h, 0.91 g, 51%(22 g/day)
Flow:
Complex Molecule Synthesis Enabled by PhotochemistryOutline
� General outline
1) Why are photochemical reactions interesting?
2) 2+2 cycloaddtions and cyclobutane ring-opening reactions
3) Norrish type I and II applications to complex architectures
7) Photoredox applications to complex molecule synthesis
4) Oxa-di-!-methane rearrangement
8) Summary
5) Paternò−Büchi reaction
6) meta-photocycloaddition reaction in total synthesis
Complex Molecule Synthesis Enabled by PhotochemistryNorrish type I reaction
� Possible products generated by Norrish type I cleavage
Ohv
O•
•
O
••
− CO ••
C−H abstraction fragmentation
O
orO● Me
n n nn n
n n
O● +
(n = 0)cyclization
O••
n
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
oxacarbene
Me
Complex Molecule Synthesis Enabled by PhotochemistryNorrish type I reaction
� Norrish type I cleavage followed by HAT for the synthesis of (±)-boschnialactone
Callant, P.; Storme, P.; Van der Eycken, E.; Vandewalle, M. Tetrahedron Lett. 1983, 24, 5797.
H H
O
HO
hv (! = 254 nm)
rt, 17 h, CH3CN90%
Me
H H
O
HO
••
Me
H
O
HO
Me
HOO
Me
O
OH
1) PCC, CH2Cl2
2) Pd/C, H2
75% (2 steps)
Me
O
O(±)-boschnialactone
Complex Molecule Synthesis Enabled by PhotochemistryNorrish type I reaction
� Norrish type I excision of carbon monoxide observed in the synthesis of the hamigerans
Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Org. Lett. 2004, 6, 645.Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613.
Me
OOMe
H
i-Pr
OMe
hv Me
O
OMe
H
i-Pr
OMe
••
••
Me
C
OO
Me
H
i-Pr
OMe
••
Me
OMe O
i-Pr
Me
H
� Norrish type I excision of carbon monoxide for the synthesis of α-cuparenone
Me
OMe
O
steps
Me
Me hv ( ! > 300 nm)
-20 °C, 12 h85%
OMe Me
O
Me
MeMe
Me O
α-cuparenone
− CO
Complex Molecule Synthesis Enabled by PhotochemistryNorrish type II reaction
� Possible products generated by Norrish type II cleavage
OR
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
A
H
!β
αhv
HOR
A!β
α•
•
pathway A
pathway B
HOR
A•
•A
+
OHR
HOR
A•
• AR
OH
Complex Molecule Synthesis Enabled by PhotochemistrySynthesis of ouabagenin
� Norrish type II cyclization in a semisynthesis of ouabagenin
Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.
O
Me
H
OH
Me
H
OOAc
OH
cortisone acetate
stepsMe
H
OH
Me
H
O
O
O
O
hv (! > 230 nm)
rt, 120 haq. SDS solution
68%
H
HOH
Me
H
O
O
O
O
••
H
H
Me
H
O
O
O
O
HO
NIS, Li2CO3
90 W sunlamprt, 20 min
85%C6H6/MeOH (30:1)
H
H
Me
H
O
O
O
O
OI
H
H
Me
OH
HOHO
OHHO
HO
O
O
ouabagenin
Norrish type II
via hypoiodite homolysis
steps
Complex Molecule Synthesis Enabled by PhotochemistryOutline
� General outline
1) Why are photochemical reactions interesting?
2) 2+2 cycloaddtions and cyclobutane ring-opening reactions
3) Norrish type I and II applications to complex architectures
7) Photoredox applications to complex molecule synthesis
4) Oxa-di-!-methane rearrangement
8) Summary
5) Paternò−Büchi reaction
6) meta-photocycloaddition reaction in total synthesis
Complex Molecule Synthesis Enabled by PhotochemistryOxa-di-!-methane rearrangement
� General reacativity of the oxa-di-!-methane rearrangement
acyclic substrates
R
O
R
O•• O
R
•
•
O
R
cyclic substrates
O O
•
•
•
• O O
H
H
O
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
hv
hv
Complex Molecule Synthesis Enabled by PhotochemistryOxa-di-!-methane rearrangement
� Use of the Oxa-di-!-methane rearrangement in the formal total synthesis of (±)-Cedrol
Stork, G.; Clarke, F. H., Jr. J. Am. Chem. Soc. 1955, 77, 1072.
O H
MeO2C
OMeO2C
MeO2C
hv
acetophenone(sensitizer)
CO2MeMe
Me
H
CO2Me
OH
CO2MeMe2CuLi
Et2O75%
76%
H
MeMe
MeMe
MeMe
MeMe Me
OH
(±)-Cedrol
steps
Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065.
Oxa-di-!-methane rearrangement
Complex Molecule Synthesis Enabled by PhotochemistryOxa-di-!-methane rearrangement
� Use of the Oxa-di-!-methane rearrangement in the total synthesis of (±)-magellanine
Yen, C.-F.; Liao, C.-C. Angew. Chem., Int. Ed. 2002, 41, 4090.
OMe
OH
PhI(OAc)2
rt, MeOH79%
O
Me
Me
O
O
OMe
OMehv ("#> 300 nm)
rt, acetone92%
O
OMe
OMeMeOH
H
H
(CH2OTMS)2TMSOTf
-78 °C, CH2Cl299%
O
Me
OMeMeOH
H
H
OO AIBNnBu3SnH
80 °C, C6H699% O
Me
OMeMeOH
H
H
OO
steps
H
H
H
OH
MeO
NMe
(±)-magellanine
Oxa-di-!-methane rearrangement
Complex Molecule Synthesis Enabled by PhotochemistryPaternò−Büchi reaction
� [2 + 2] photocycloaddition of carbonyl compounds with alkenes− the Paternò−Büchi reaction
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
O
HR+
MeMe
OMe
MeR
hv
O
HR
✻
hv
S1
O
HR
✻
T1
ISC Me Me O
H MeMeR ••
spin inversion
diastereoselectivity depends ontriplet lifetimes
Complex Molecule Synthesis Enabled by PhotochemistryPaternò−Büchi reaction
� Total synthesis of the pyrrolindinol alkaloid (+)-preussin
Bach, T.; Brummerhop, H.; Harms, K. Chem. - Eur. J. 2000, 6, 3838.
NH
OOH steps
N C9H19
CO2Me
hv ( ! = 350 nm)Ph
O
rt, MeCN, 6 h53%
NC9H19
CO2Me
O
Ph
Pd(OH)2/CH2
rt, 3 h, MeOH
81%
N
OH
CO2Me
C9H19Ph
LiAlH4
reflux, 2 h, THF91%
N
OH
Me
C9H19Ph
(+)-preussin
H
H
Paternò−Büchi reaction
Complex Molecule Synthesis Enabled by PhotochemistryPaternò−Büchi reaction
� Intramolecular Paternò−Büchi reaction of thiocarbonyl compounds
Padwa, A.; Jacquez, M. N.; Schmidt, A. J. Org. Chem. 2004, 69, 33.
N
O
S
Mehv (! = 300 nm)
rt, 1 h, C6H6
N
O
S
Me73%
N
O
S
hv (! = 300 nm)
rt, 1 h, C6H6
N
O
74%S
Raney-NiN
O
80 °C, 6 hEtOH55%
Complex Molecule Synthesis Enabled by Photochemistrymeta-photocycloaddition
� Three modes of photocycloaddition of alkenes to benzene rings
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
+ meta
ortho
para
X
hv+X
HX
H
X
- meta-photocycloadditions are most common
meta-photocycloaddtion pathway
- formation of three σ-bonds and up to six stereocenters in one step- tricyclic product can fragment in several ways
- first reported in 1966 by Wilzbach and Kaplen
Complex Molecule Synthesis Enabled by Photochemistrymeta-photocycloaddition
� Fragmentation of the meta-photocycloaddition adduct to form complex architectures
Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.
HX
H
X
1
28
[A−B]
[2/8]H
X BA
HX
B
A1
82 2
28
1
HX
82
8
B
A1
[A−B]
[1/2]
[A−B]
[1/8]
bicyclo [3.3.0] octane
bicyclo [3.2.1] octane
bicyclo [3.2.1] octane
Powerful method for generating molecular complexity in one step!
Complex Molecule Synthesis Enabled by Photochemistrymeta-photocycloaddition
� Wender’s total synthesis of (±)-α-cedrene
Wender, P. A.; Howbert, J. J. J. Am. Chem. Soc. 1981, 103, 688.
Me
MeO
MeMe
Me
hv ( ! > 220 nm)
rt, 12 h, C6H6
OMe Me
Me
MeH Me
+Me
MeH
1:165%
Me
Me
OMeH
1) Br22) nBu3SnH
CH2Cl259%
Me
MeH
Me
Me
H O
N2H4
KOH
(HOCH2CH2)2O
Me
MeH
Me
Me
H
(±)-α-cedrene
HMe
OMeH
MeMe
∠A1,3 minimized
H
Me
OMe
MeMe
Me
meta-photocycloaddition
Complex Molecule Synthesis Enabled by PhotochemistryTotal synthesis of (−)-penifulvin using the olefin meta-photocycloaddition
Gaich, T.; Mulzer, J. J. Am. Chem. Soc. 2009, 131, 452.
Me
OH
Me
Me
hv (! > 200)
rt, 2 h, pentanes70% Me
HO
MeMe
Me
HO
MeMe
• •H H
Me
HO
MeMe
H Me
HO
MeMe
H
Me
MeH
OH
Me
MeMe
HMe
H OH
+
Li, EtNH2
-78 C, 7 h, THF72%
Me
MeH
OH
Me
IBX/DMSO
then NaClO292%
Me
MeH
OH
Me
O
O3, CH2Cl2thiourea
78%
Me
MeH
OH
Me
O
O
O Me
MeH
O
Me
O
OH
O H PDC
82%
Me
MeH
O
Me
O
O
O H(−)-penifulvin
Complex Molecule Synthesis Enabled by PhotochemistryOutline
� General outline
1) Why are photochemical reactions interesting?
2) 2+2 cycloaddtions and cyclobutane ring-opening reactions
3) Norrish type I and II applications to complex architectures
7) Photoredox applications to complex molecule synthesis
4) Oxa-di-!-methane rearrangement
8) Summary
5) Paternò−Büchi reaction
6) meta-photocycloaddition reaction in total synthesis
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Use the use of visible light to enable single-electron transfer between photoexcitable catalysts and organic or organometallic molecules
Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
Ru(bpy)32+ Ru(byp)3
2+
Ru(byp)3+
Ru(byp)33+
*D
D
A
AS
reductivequenching
S
S
S
oxidativequenching
visiblelight
A = acepter, D = doner, S = substate
Ru(bpy)32+
triplet excited state
groundstate
Strong visible light absorptionHigh quantum yield (Φ ≈ 1)
Long-lived excited state (τ = 900 ns)Easy tuning of physical properties
N
NRu
N
N
N
N
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Polar radical crossover cycloaddition (PRCC) for the synthesis of protolichestrenic acid
Zeller, M. A.; Riener, M.; Nicewicz, D. A. Org. Lett. 2014, 16, 4810.
OMe
+Cl
OHO
2.5 mol% Cat.15 mol% PhSSPh
10 mol% 2,6,-lutidine
blue LEDS (! = 450 nm)rt, 96 h, CH2Cl2
69%O
Cl
OMe
O
O
CO2H
O
Me 11
1111
1) RuCl3, NaIO4, rt, 4h2) K2CO3, rt, 24h54% ( 2-steps)
(±)-protolichesterinic acid Me
Me Me
Me
BF4–
Mes-Acr+
N
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Proposed mechanism for the polar radical crossover cycloaddition
Zeller, M. A.; Riener, M.; Nicewicz, D. A. Org. Lett. 2014, 16, 4810.Me
MeMe
Me
N
Mes-Acr+✻
34W LED
B
A
B
A
•−H+
O
OHR
Me
Me
Me
Me
N
•SET
O OA
BR
•
O
B
A
O
R•
PhS •O
B
A
O
R
SET
HAT
PhSH
PhS
✻E1/2red = +2.06
✻E1/2ox = -0.49
✻E1/2red = +0.16V
BDE = 70 - 80 kcal/mol
H+
OAc
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Overman’s synthesis of (−)-aplyviolene
Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576.
Me
Me
Me
O steps
MeMe
H
H
MeO
ON
O
O
(+)-fenchone
+ Cl
O
H
MeO2C
TBSO
NH
Me Me
CO2EtEtO2C
1 mol% [Ru(bpy)3]BF4
blue LEDs, rt, 2.5 hCH2Cl2
61%
DIPEA
MeMe
H
H
MeOTBSO
MeO2C
ClH
MeMe
H
H
MeOTBSTBSO
MeO2C
Me Me
H
H
MeMe2CuCNLi2TBS-Cl
HMPA, -20 °CTHF
76%
steps O
O
O
(−)-aplyviolenestereoselectiveformation of a
quaternary center!
photoredox-conjugate addition
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Photoredox-enabled synthesis of the pyrroloindoline (+)-gliocladin
Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2011, 50, 9655.
N
NHBoc
CO2Me
CbzBoc-D-tryptophan
methyl ester
steps NCbz
NBocH
BrO
NHMe
1 mol% [Ru(bpy)3]Cl2Bu3N
blue LEDsrt, 12 h, DMF
82%
NH
CHO
NCbz
NBocH
O
NHMe
HNOHC
NCbz
NBocH
O
NHMe
NH
CHO
DPPA = diphenylphosphoryl azidedppp = 1,3-bis (diphenylphosphino) propane
20 mol% Rh(CO)PPh3)3)Cl44 mol% dppp
DPPA
140 °C, 14 hxylenes
85%
NCbz
NBocH
O
NHMe
NH
stepsNH N
H
NH
NMe
O O
O
(+)-gliocladin
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Photoredox-enabled fragmentation of (+)-catharanthine
Beatty, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2014, 136, 10270.
NH
N
CO2Me Et NH
H
CO2Me
NEt
CN
(+)-catharanthine common intermediate
2.5 mol% Pcat
visible light MeOH
TMSCNN
NIr
N
F3C F
F
N
F3CF
F
tBu
tBu
PF6–
Complex Molecule Synthesis Enabled by PhotochemistryCatalytic cycle for fragmentation
Beatty, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2014, 136, 10270.
NH
N
CO2Me Et NH
H
CO2Me
NEt
CN
Ir3+Ir3+✻
Ir2+
visible light
NH
N
CO2Me Et
NH CO2Me
NEt
•
NH CO2Me
NEt
CN
•
SETSET
+ CN
+ H+
(+)-catharanthine common intermediate
Complex Molecule Synthesis Enabled by PhotochemistryPhotoredox catalysis
� Photoredox-enabled synthesis of (−)-pseudotabersonine, (−)-pseudovincadifformine, and (+)-coronaridine via a common intermediate
Beatty, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2014, 136, 10270.
NH
H
CO2Me
NEt
CN
common intermediate
NH
N
CO2Me Et
(+)-coronaridine
NH
(−)-pseudotabersonine
N
Et
CO2Me NH
N
Et
CO2Me
(−)-pseudovincadifformine
TFAreflux 90%
toluene
NH
H
CO2Me
NEt
CN
H
Pd/C, H2
TFAreflux 48% (2 steps)
toluene
rt, MeOHNH
H
CO2Me
NEt
H1) Pd/C, H2rt, MeOH
2) NaBH4, 0 °C
1 mol% [Ru(bpy)3]Cl2(MeO2C)CBrMe (2 equiv)
visible light, 50 °C58%
flow, tR = 5 min
98%
Complex Molecule Synthesis Enabled by PhotochemistryOutline
� General outline
1) Why are photochemical reactions interesting?
2) 2+2 cycloaddtions and cyclobutane ring-opening reactions
3) Norrish type I and II applications to complex architectures
7) Photoredox applications to complex molecule synthesis
4) Oxa-di-!-methane rearrangement
8) Summary
5) Paternò−Büchi reaction
6) meta-photocycloaddition reaction in total synthesis
Complex Molecule Synthesis Enabled by PhotochemistrySummary
Why are photochemical reactions interesting?
Photochemical reactions are “green” as they only consume photons
Highly stained adducts can leveraged to form medium rings with rich functionality
Photochemical reactions enable transformations not possible by thermal conditions
Advantages:
Disadvantages:
Requirement for high energy UV-light
In general, hard to control absolute stereochemistry
Good reviews if you want to learn more:Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683.Nicholls, T. P.; Leonori, D.; Bissember, A. C. Nat. Prod. Rep. 2016, 33, 1248.
Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000.Douglas, J. J.; Sevrin, M. J.; Stephenson, C. R. J. Org. Process Res. Dev. 2016, 20, 1134.