Singlet oxygen : From discovery to natural and biologically active product synthesis
48
Singlet oxygen : From discovery to natural and biologically active product synthesis November, 8-15-22-28 th 2005 By Isabelle Bonnaventure Literature Meeting
description
Singlet oxygen : From discovery to natural and biologically active product synthesis. Literature Meeting. By Isabelle Bonnaventure. November, 8-15-22-28 th 2005. Presentation Outlook. Discovery of 1 O 2 and use as a reagent. Properties of 1 O 2. Generation of 1 O 2. - PowerPoint PPT Presentation
Transcript of Singlet oxygen : From discovery to natural and biologically active product synthesis
Singlet oxygen:From discovery to
natural and biologically active product synthesis
November, 8-15-22-28th 2005
By Isabelle Bonnaventure
Literature Meeting
Presentation OutlookPresentation Outlook
I. IntroductionI.1. Discovery of 1O2
I.2. Properties of 1O2
I.3. Sources of 1O2
II. ReactivityII.1. Reaction overview
II.2. Ene reaction
II.2.1. Introduction
II.2.2. Mechanism
II.2.3. Various effects
II.2.4. Diastereoselectivity
II.3. [4+2] cycloaddition
II.4. [2+2] cycloaddition
II.5. Competition between 3 modes
IV. Applications
IV.1. Ene reaction
IV.2. [4+2] cycloaddition
V. Conclusion
IV.3. [2+2] cycloaddition
Discovery of Discovery of 11OO22 and use as a reagent and use as a reagent
Ranby, B. The History of Singlet Oxygen-An Introduction. In Singlet Oxygen, Reactions with Organic Compounds and Polymers, Ranby, R., Rabek, J. F., Ed. John Wiley & Sons Ltd.: 1978; pp. 1-12.
° °
-1811: Avogadro, O2 is a diatomic molecule-1848: Faraday, O2 is paramagnetic
-1867: Fritzsche, reaction occured with light and oxygen
-1931: Kautsky, discovery of photo-oxygenation of unsaturated molecules (1O2 as "active oxygen")
-1954: Schenk and Ziegler, first use in organic synthesis
O Oh, O2
heat
naphthacene
h, O2
chlorophyllO
O
( )-ascaridole-terpinene
Properties of Properties of 11OO22
2 outer e in the degenerate antibonding x* and y*
3 g
1 +g
1 g
_
22.5 kcal/mol
37.5 kcal/mol
Ground state
1st Singlet state
2nd Singlet state Lifetime = 10-12 s
Lifetime = 10-3-10-6 s
Mulliken, 1928
Childe/Mecke, 1931
Herzberg, 1934
Kearns, D. R.; Merkel, P. B. J. Am. Chem. Soc. 1972, 94, 7244.Young, R. H.et al J. Am. Chem. Soc. 1973, 95, 375.Kearns, D. R.; Long, C. A. J. Am. Chem. Soc. 1975, 97, 2018.
Lifetime highly dependent on solvent No significant effect of temperature
Lifetime (.10-6 s)H2O (2)
MeOH (9)
EtOH (12)
n-BuOH (19)
C6H12 (17)
C6H6 (25)
t-BuOH (34)
Acetone (26)
C5H5N (33)
C6F6 (600)
CHCl3 CCl4
CS2 (200)
n-PrBr Freon(CF3Cl)
C6D6 (36)
D2O CDCl310 20 30 40 50 60 100 300 500 700 900 1000
Generation of Generation of 11OO22
H2O2/NaOCl
ClO + H2O2_
1O2 Cl+_
- MeOH (production of up to 80% of 1O2)
But versatility of H2O2
Khan, A. U.; Kasha, M. J. Am. Chem. Soc. 1970, 92, 3293.
H2O+
Thermolysis of triaryl phosphite ozonides
T> -20 °C
Trialkylphosphites: problem of stability
(ArO)3P + O3
O(ArO)3P
OO (ArO)3P O + 1O2
Murray, R. W.; Kaplan, M. J. Am. Chem. Soc. 1968, 90, 537.
Production of ~ 90% of 1O2
Generation of Generation of 11OO22
Dye-sensytized photochemical excitation
+ h 1S* + 3O2
absorption intersystemcrossing 3S* 1O2+
energytransfer
S = Rose Bengal, methylene blue, tetraphenylene porphyrine (TPP)
ET >> 22.5 kcal/mol
S S
spin allowed
Small size of O2: rapid diffusion in media N
NH N
HN
Ph
Ph
Ph
Ph
Kearns, D. R. et al Chem. Rev. 1971, 71, 395.
Decomposition of 9,10-phenylanthracene peroxide
Ph
Ph
Ph
Ph
O Obenzene, reflux
+1O2
Production of ~ 96% of 1O2Long process: up to 4 days Wasserman, H. H. et al J. Am. Chem. Soc. 1972, 94, 4991.
Reaction OverviewReaction Overview
1O2
heteroatomoxidation
organosulfurorganophosphorus
organometallic complexes
amines
heterocyclicphoto-oxygenation
furans, benzofurans
pyrroles, indoles
oxazoles
reaction withdouble bonds
ene reaction:hydroperoxide
[2+2] cycloadditions:1,2-dioxetane
[4+2] cycloadditions:endoperoxide
O O
HOO
OO
H
XR
XR
Discovered by Schenck in 1943
Formation of allylic hydroperoxides: access to diverse functionalities
R2
R1 1O2
R2
OOHR1
Ene reaction: IntroductionEne reaction: Introduction
Reduction
Rearrangement to epoxide
Kornblum-DeLaMare Dehydration
NaBH4
R2
OHR1
R2
OR1
R2
R1
OR2
R1
O
R3
R3
R2
OHOAcAcCl, Py
R1
R2
OR1
Frimer, A. A. Chem. Rev. 1979, 79, 359.
Ene reaction: IntroductionEne reaction: Introduction
Fragmentation to divinyl ethers (cyclic cases)
OOH H+O
OH2+
O+
H
O
Frimer, A. A. Chem. Rev. 1979, 79, 359.
1,3-allylic isomerisation
R2
OR1O
O O
R2
R1 O
R2
R1
HO
Hock cleavage
R2
OR1
OH2+
R1
O+
R2
-H2O + H2O
O
R1
O
R2
+H
Ene reaction: MechanismEne reaction: Mechanism
Foote, C. S.; Houk, K. N. et al J. Am. Chem. Soc. 2003, 125, 1319.
1O2 O2
O+ O_
H
H
HOO
exciplexintermediate
perepoxideintermediate
OOH
stepwisemechanism
concertedmechanism
OO
+O
O
Concerted process
Stepwise process
versus no significant intermolecular KIE suggests the presence of an intermediate
Ene reaction: MechanismEne reaction: Mechanism
Stephenson, L. M.; Grdina, M. J.; Orfanopoulos, M. Acc. Chem. Res. 1980, 13, 419.
Perepoxide intermediate: Stephenson inter/intramolecular isotope effect test
D3C
H3C CD3
CH3
D3C
H3C CH3
CD3
H3CD3C
O+ O
D
H
D3CD3C
O+ O
H
H
H3CH3C
O+ O
D
D
E
Z
- H
- D
- H or - D CD2
CH3D3C
DOO
H3C
CH2
CD3D3C
HOO
H3C
CD2
CH3D3C
DOO
H3C
CH2
CD3D3C
HOO
H3C
1.0
1.0
1.05
1.4
kanti
ksyn
Exciplex intermediate
- G ~ 0- S << 0
characteristics of singlet oxygen reactionand reactions involving rapid and reversibly formed exciplexes
Zwitterionic/biradical intermediates ruled out
- reaction not subjected to Markovnikov regioselectivity(control experiments on trisubstituted olefins)
- radical scavengers are ineffective
- cis-trans isomerisation does not occur
O2
OO
+O
O
+
Ene reaction: MechanismEne reaction: Mechanism
Orfanopoulos, M.; Stephenson, L. M. J. Am. Chem. Soc. 1980, 102, 1417.
HH3C
HPh
D
H
H3CD
PhHOO
HH3C
H
Ph
H
H3CH
PhDOO
OOD
HH3C
D
Ph
OOH
ANTARAfacial SUPRAfacialobserved
"Re" face (top)
"Si" face (bottom)
Interaction * (1O2) - (ene)
1O2
+
Ene reaction: “Ene reaction: “ciscis effect” effect”
X
R1
R2 X
R1
R2
HOO1O2
X = Alkyl, ethers
10%
22% 68% 48% 52%
0%
48%
22%30%
65%33%
<2% 43%4%
53%
MeO 72%
28%
"cis effect" = Hydrogen abstraction syn to X (most congested side of olefin)
Conia, J. M. et al Tetrahedron Lett. 1977, 2517. Foote, C. S. et al Tetrahedron Lett. 1978, 3227.Orfanopoulos, M. et al J. Am. Chem. Soc. 1979, 101, 275. Schulte-Elte K. H. et al J. Am. Chem. Soc. 1980, 102, 1738.
Ene reaction: “Ene reaction: “ciscis effect” effect”
Stephenson/Fukui model
H
H
LUMO (*-like)
HOMO ()
H
HH
R
H
R
H
H
eclipsed cis: 1.06 kcal/moltrans: 2.06 kcal/mol
Houk
Stephenson, L. M. Tetrahedron Lett. 1980, 21, 1005.
Houk, K. N. et al J. Am. Chem. Soc. 1981, 103, 949.
Foote, C. S.; Houk, K. N. et al J. Am. Chem. Soc. 2003, 125, 1319.
TS: 2.8 kcal/mol higher
1O2
O+ O
HH
Stratakis, M.; Orfanopoulos, M.; Foote, C. S. J. Org. Chem. 1998, 63, 1315.
Ene reaction: “Ene reaction: “ciscis effect” in styrene derivatives effect” in styrene derivatives
CD3
Styrene derivatives: solvent-dependent syn selectivity
CD3 CD21O2
+
syn anti
MeCN
MeOH
56
71
82
44
29
18
H
D
OO
H
D
O
syn anti
O
more stabilised
CCl4
HOO DOO
Orfanopoulos, M. Tetrahedron Lett. 1989, 30, 4755.
Ene reaction: large group non-bonded effectEne reaction: large group non-bonded effect
L s
O
O
L s
O
O
L s
O
O
H
minor
major
1,3-non bonded interactionH
L s
1O2
L s L s+
major minor
OOH HOO
Ph
PhPh
Ph
Ph70% 30%
70% 30%
73% 27%
95% 5%
56% 44%Ph 11% 89%
Orfanopoulos, M. et al J. Am. Chem. Soc. 1990, 112, 6417.Clennan, E. L. et al J. Am. Chem. Soc. 1990, 112, 5193.
Orfanopoulos, M. et al Synth. Comm. 1993, 23, 425.
Ene reaction: bulky subtituentsEne reaction: bulky subtituents
L
1O2
OOHL L+
major minor
HOO
>97% 82% 18%
>97%29%
71% 96%4%
- Allylic bulk
- Vinylic bulk
66% 34%
77%
23%>97%
O
O
L OL
O
O
O
L
O
O
L
H
H
minor
major
OL
OH
not observed
Thomas, A. F.; Pawlak, W. Helv. Chim. Acta 1971, 54, 1822.
Rautenstrauch, V.; Thommen, W.; Schulte-Elte, K. H. Helv. Chim. Acta 1986, 69, 1638.
Ene reaction: gem dimethyl/diethyl trisubstituted olefinsEne reaction: gem dimethyl/diethyl trisubstituted olefins
L R
1O2
L R L R+
major minor
HOOR HOO R R
Ph
Ph68%
32%
91%
9%
Ph
PhPh
92%
8%
94%
6%
53%
47%
47%
53%
Geminal dimethyl, diethyl trisubstituted olefins: reaction at the most congested side of olefin
L R
O
O
Hminor
1,3-non bonded interactionR
A1,3 in the newly formed double bond
Ene reaction: hydroxyl group directing effectEne reaction: hydroxyl group directing effect
Adam, W.; Nestler, B. J. Am. Chem. Soc. 1993, 115, 5041.
OH1O2 HOO
OH
HOO
OH
OOH
OH
OOH
OH
93 7
96%
:E Z
4%
H
H H
O
H MeMe H
O
O
H
HH
O
HMeMe H
O
O H
HH
H
MeHOMe H
O
O H
HH
Me
HHOMe H
O
O
threo erythro
H
H
++ +
CCl4
OAc1O2 HOO
OAc
HOO
OAc
OOH
OAc
OOH
OAc
:E Z
39 61 38 62
82% 18%
:
H
H H
H
Me OAcMe H H
HH
H
MeAcOMe H
O
O
O
OA1,3 smaller
cis effect ++ +
threo erythro
Adam, W.; Nestler, B. Tetrahedron Lett. 1973, 34, 611.
Ene reaction: hydroxyl group directing effectEne reaction: hydroxyl group directing effectAllylic strain
OH
Ha1O2
OH
HOO
OH
HOO
O
HOO
+ +
93 : 7
>97% <3%
OH
Ha 54 : 46
>96% <4%
H
H H
O
H MeH Ha
O
O
threo
H
Z: highly threo diastereoselectivity
1O2
OH OH
HOO
OH
HOO+
93 : 7
A1,2 strain: no significant effect
1O2
Ene reaction: hydroxyl group directing effectEne reaction: hydroxyl group directing effect
Stratakis, M.; Orfanopoulos, M.; Foote, C. S. Tetrahedron Lett. 1996, 37, 7159.Vassilikogiannakis, G.; Orfanopoulos, M.; Foote, C. S. J. Org. Chem. 1999, 64, 4130.
Solvent effect
H
D
O+ O
OH
destabilised in polar protic solvents
CD3HO
syn
anti
syn:anti
75:25
Benzene 73:27
MeCN 41:59
MeOH 33:67
CCl4
CH3
CD2HO
DOO
CH2
CD3HO
HOO
anti
syn
Adam, W. et al J. Am. Chem. Soc. 1995, 117, 3976.Adam, W. et al J. Am. Chem. Soc. 1996, 118, 1899.
Ene reaction: hydroxyl group directing effectEne reaction: hydroxyl group directing effect
X
H
X
MeHMe
Me
H
X
MeHMe
Me
1O2
H
X
MeHMe
Me
H
X
MeHMe
Me
O
O
O
O
_
erythro:threoX
NH2
NH3+Cl
NHAc
NHBocaNBoc2
ClaSO2Ph
8:92
6:94
64:36
65:35
95:5
85:15
>95:5
aOH 7:93
66:34aOOH
a: CCl4 used as solvent
erythro
threo
attractive interactions: OH, NH2, NH3+
repulsive interactions: NHAc, NHBoc, NBoc2, NHPhth, Cl, SO2Ph, OOH
threo selectivity
erythro selectivity
Ene reaction: EWG at vinylic and allylic positionEne reaction: EWG at vinylic and allylic position
- Allylic substitution
bad selectivities
OMe
O62%
38%P
Ph
OSOPhPh
52%
48%
38%
62%
electronic repulsion with highly polarised X-O bonds
Stratakis, M.; Orfanopoulos, M. Tetrahedron Lett. 1997, 38, 1067.
EWG 1O2 HOO EWG EWG+ OOH
majorX = CHO, COMe, COOH, COOEt, CN, CNR, SOPh
driving force: double-bond-carbonyl conjugation
- Vinylic substitution
solvent effect: non polar solvents: >95polar solvents: 80:20 (higher dipole moments, stabilisation of perepoxide TS)
O+
EWG
O
O+
EWG
O
majorAdam, W.; Richter, M. J. Tetrahedron Lett. 1993, 34, 8423.
minor
1O2
OOH
OOH
H
H
H
OOH
OOH
H
98.5 1.5
16 84
+
+
Steric effect
exo endo
1O2
Jefford, C. W. et al Helv. Chim. Acta 1974, 57, 2242.Jefford, C. W. et al J. Am. Chem. Soc. 1972, 94, 8904.
Ene reaction: cyclic moleculesEne reaction: cyclic molecules
Ene reaction: cyclic moleculesEne reaction: cyclic molecules
Paquette, L. et al Synth. Commun. 1986, 16, 1275.
O
H
H
OO
H
H
OO
H
H
O+
OOHOOH
71 (53%) 29 (22%)
O O
1. 1O22. P(OEt)3
OH
single diastereoisomer
1O2
less hindered face
less hindered face
O
O
O
Steric effect
Ene reaction: cyclic moleculesEne reaction: cyclic molecules
Okada, K.; Mukai, T. J. Am. Chem. Soc. 1978, 100, 6509. Paquette, L. A. et al J. Am. Chem. Soc. 1978, 100, 6510.Houk, K. N. et al J. Org. Chem. 1993, 58, 4625.
1. 1O22. Me2S
+OH HO
17:83
CO2Me
CO2Me
OMe
MeO
F
F F
F
Cl
Cl
Cl
Cl
syn/anti 46:54 24:76 21:79 56:44 59:41
anti
syn
Stereoelectronic effect
major
Mukai: distortion of exo orbital to the anti side by mixing orbital due to perturbation induced by orbital
Paquette: electron density donation to the developping anti perepoxide
Houk: syn attack disfavored by electrostatic repulsion between 1O2 and cloud of aromatic ring
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
Oxazoline
N
O
N
O
OOH
1O2
>95%
d.r 1:1
Adam, W. et al Tetrahedron Lett. 1991, 32, 1957.
Menthol derivatives
Dussault, P. H. et al Tetrahedron 1994, 50, 8929.
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
O
O
O
O
Si attackRe attack
O
OXc
Me
OOH
Xc =no selectivityAr
Me Me
Me
Ar
Sensitiser/solvent T (°C) Yield (%) d.r
TPP/DCM rt 82
TPP/CCl4 rt 87
RB/MeCN rt 94
RB/MeOH - 30 89
TPP/DCM - 45 83
TPP/DCM - 60 86 82:18
77:23
77:23
70:30
70:30
70:30
or
Adam, W. et al Eur. J. Org. Chem. 1998, 501.
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
ON
O
Me
MeR
MeMe
1. 1O22. PPh3 O
NO
R
MeMe
OH
Me
R = Bn, iPr d.r = 1:1
R
HO
MeMe
O
Me
Me H
no facial selectivity
Oxazolidine
Adam, W. et al J. Am. Chem. Soc. 2000, 122, 7610.
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
Oxazolidine
NO
Ph
Xc
OH
O2, h
NO
Ph
Xc
OH
NO
Ph
Xc
O+
OH OO
Xc solvent T (°C) time (h) crude yield (%) regio d.r
OtBu
Ph
NHPh
NHPh
NHp-NO2Ph
NMePh
d6-acetone
- 5
- 5
- 5
- 10
- 10
- 10
20
23
4
40
28
48
92
86
>95
72
85
90
75:25
86:14
93:7
96:4
96:4
70:30
25:75
45:55
94:6
85:15
>95:5
41:59
CCl4
CDCl3
CDCl3
CDCl3
CDCl3
TPP
steric model: failedhydrogen bonding model: successful (mimic of allylic alcohols)
O
NPh
OXc
H
H
HH
N
OMeH
PhXc
O
H
H
HH
N
OMeH
Ph Xc
O
H
1O2
1O2
O
N HH
OOH
Me
CH2
O Xc
Ph
O
N H
O Xc
Ph
OOH
H Me
CH2
NO
Ph
Xc
OH
OOH
NO
Ph
Xc
OH
OOH
Diastereoselectivity
Me
OOHH
HH
N
O
Ph
OXc
H
HHN
O
MeHPh
XcO1O2
NO
Ph
Xc
OO
O
Regioselectivity
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
major
S
N
O O
O
R
S
N
O O
O
S
N
O O
R
O
R
C-C rotation
C-N rotation
O O
Re attack favored
S
N
O O
O
R H
HH
O O
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
Adam, W. et al J. Am. Chem. Soc. 2002, 124, 12938.
Bornane-derived sultam
S
N
O O
O
R
1O2
S
N
O O
O
OOHR
R
MeiPr
time (d)
1
3
conversion (%)
>95
90
yield (%)
90
78
d.r
83:17
>95:5
Ene reaction: diastereoselectivity?Ene reaction: diastereoselectivity?
Adam, W. et al J. Org. Chem. 2004, 69, 1704.
Enecarbamates
NO O
PhHR
NO O
PhH
R
R d.r
MeiPr
R d.r
PhtBu
88:12
83:17
71:29
91:9
N
Me
Ph
O
O
R
N
Me
Ph
O
O
R
N Ph
O
O
R
OO HOO
+
1O2CDCl3
Z olefin: [2+2] mode
E olefin: ene mode
NPh
O O
R
cis-effect: orbital directing effect of the vinylic nitrogen (HOMO)
H
less accessible
NPh
O O
RH
favored
R4
R3
R2
R1
R4
R3
R2
R1OOHConditions
Comparison with other Comparison with other -oxidation methods-oxidation methods
Denny, R. W.; Nickon, A. Org. React. 1973, 20, 133.
1O2
convenient
few side products
disubstituted-olefins react slowly
Auto-oxidation
hydroperoxide cleavage under reaction conditions
SeO2
toxic
functional group not tolerated
complementary (different isomers) to 1O2
Dehydrohalogenation of -Halohydroperoxides
functional group not tolerated
limited to tetraalkylated olefins
AcNHCl, H2O2Et2O
N
NBr
O
O
Brhydantoin
or
OOH
X NaOHMeOH
OOH
(O2, air)
by-products
Adam, W.; Prein, M. Acc. Chem. Res. 1996, 29, 275.
[4+2] cycloaddition[4+2] cycloaddition
R2
R1
O
O+
R2
R1
O
O
exciplex
O
O
R1
R2
endoperoxide
cyclic dienes: high anti/syn diastereoselectivities (cyclopentadiene)moderate diastereoselectivity for endo/exo
acyclic dienes: low diastereoselectivitydependent on A1,3 allylic strain
steric and electronic factors which depend on type of substrate and reaction conditions
OO
X
anti
exo
endo
more recent (1969) than [4+2] cycloaddition and ene reaction
Clennan, E. L. Tetrahedron 1991, 47, 1343.
[2+2] cycloaddition[2+2] cycloaddition
electron rich olefin
1,3-diene: cis-geometry: trans dioxetane
trans-geometry: cis dioxetane
H
ORO
OR
O
+H
H
OOR OR+
H
O
OR
RO
OR
OR
OR
RO
OR
OO
OO
RO
RX RX1O2
1O2
exciplex
RX+ OO
RX OO
1,2-dioxetane
?
1,3-diene s-cis/s-trans ratio
Alignment of allylic hydrogens
C1-C4 distance in diene
Steric factors
Ionisation potential of diene
[4+2], [2+2] cycloaddition or ene reaction ?[4+2], [2+2] cycloaddition or ene reaction ?
ene reaction:hydroperoxide
[2+2] cycloaddition:1,2-dioxetane
[4+2] cycloaddition:endoperoxide
O OHOO
OO
XR
XRH
1O2
XR
RX
[4+2], [2+2] cycloaddition or ene reaction ?[4+2], [2+2] cycloaddition or ene reaction ?
Matsumoto, M.; Kuroda, K.; Suzuki, Y. Tetrahedron Lett. 1981, 22, 3253.
Matsumoto, M.; Kondo, K. Tetrahedron Lett. 1975, 3935.
1,3-diene s-cis/s-trans ratio
OMe
OMeOMe
CHO
+1O2
4753
O
O
OMe
OMe
86%cis
trans 98% >99 1
HH
1O2
H OOH
O
O
H
Me
Alignment of allylic hydrogens
1O2
55%90%
Clennan, E. Tetrahedron 1991, 47, 1343.
[4+2], [2+2] cycloaddition or ene reaction ?[4+2], [2+2] cycloaddition or ene reaction ?
[4+2] rate constants (M-1s-1):
1x108 7.1x106 1.1x106 6.5x104
C1-C4 distance in diene
Ionisation potential of diene: IP (eV)
1O2 OO
8.639.13
+
OOH HOO8.48 8.68
1O2
39 61
79%
92%
Kondo, K.; Matsumoto, M. J. Org. Chem. 1975, 40, 2259.
[4+2], [2+2] cycloaddition or ene reaction ?[4+2], [2+2] cycloaddition or ene reaction ?
Paquette, L. A. et al Tetrahedron Lett. 1976, 2681.
H H
+
+
1O2 OO
HOO
HOO HOO
10-15% 85-90%
1O2
OO
Me
[4+2], [2+2] cycloaddition or ene reaction ?[4+2], [2+2] cycloaddition or ene reaction ?
Barrett, H. C.; Buchi, G. J. Am. Chem. Soc. 1967, 89, 5665.
Sasson, I.; Labovitz, J. J. Org. Chem. 1975, 40, 3670.
Steric factors
Paquette, L. A. et al J. Am. Chem. Soc. 2000, 122, 2742.
Ene reaction: applicationEne reaction: application
OOBr S
O O
TolO
O CO2Me
H
SOTol
O
O CO2Me
H
HH
O
TfO CO2Me
H
HH
O
CO2Me
H
HH
1. n-BuLi2. (-)-menthyl p-toluenesulfinate, CSA, acetone
77%
CO2MeHO
K2CO3, THF
38%
H2, RaNi(150 psi),
MeOH
88%
KHMDS, PhNTf2,THF, -78 °C
98%
SnBu3
Pd2(dba)2·CHCl3LiCl, THF
95%
O O
O
H
H
HH
(+)-Asteriscanolide
Ene reaction: applicationEne reaction: application
Paquette, L. A. et al J. Am. Chem. Soc. 2000, 122, 2742.
O
CO2Me
H
HH
OH
HH I
OH
HH
O
H
H
H
O
H
H
H
HO
O
H
H
H
O
O O
O
H
H
HH
1. LAH2. MsCl, Et3N3. NaI
74%
MgCl
CuI, THF, 0 °C98%
RuPy
PCy3
PCy3Cl
Cl
DCM, 93%
1. O2, TPP, DCM, h2. LAH
61%
1. Dess-Martin2. H2, 10% Pd/C EtOH, 300 psi
67%
RuCl3, NaIO4CCl4, MeCN, H2O
63%
4%, 13 steps
H
O
P2O
OH
O
OP1
OH O
P2O
O
O
OP1
OP3
OH
P2O
OH
O
OP1
HO
ORX
O
OP1
O
HO
OSiR'3
XHO
CH(OR)2
O
OSiR'3
XHO
[4+2] cycloaddition: application[4+2] cycloaddition: application
Kusama, H. et al J. Am. Chem. Soc. 2000, 122, 3811.
O
O
O
O
NHPh
O
OH
OAcHO
Ph
AcOBzO
H
OH
( )Taxol
[4+2] cycloaddition: application[4+2] cycloaddition: application
Kusama, H. et al J. Am. Chem. Soc. 2000, 122, 3811.
O
OTIPS
SPhHO
HO
OTIPS
SPhHO
CH(OBn)2CH(OBn)2
Br
1. tBuMgCl, THF, -78 °C, 30min2. tBuLi, -78 °C, 1h
68%+
(MeBO)3,Py, rt, 30min
77%
O
OTIPS
SPhO
CH(OBn)2
B
TiCl2(OiPr)2,DCM,
-78 °C to 0 °C,1.5h
pinacol, DMAP,rt, benzene
59%
OBn
O
O
OB SPh
OBn
O
HO
HOSPh
1. PhCH(OMe)2, PPTS, 1h2. DIBAL3. TBSOTf, 2,6-lutidine
80%
OBn
TBSO
O
OSPhPh
OBn
TBSO
O
OPh
HO
OH
1. h, O2, TPP2. Bu3SnH, AIBN
85%
O
TBSO
O
OPh
HO
O Ph
1. Pd/C, HCO2NH42. PhCH(OMe)2, CSA
87%
NH
NH2
CO2MeH
N
NHFmoc
CO2HH
MeMe
+
NH
NH2
CO2MeH
NaBH3CN, AcOH
60%
NH
NHBoc
CO2MeH1. CuCl, iPr2NEt, THF, reflux
2. DDQ3. H2, quinoline, Pd/C
Me
Me OAc
83%
N
NHBoc
CO2MeH
MeMe
1. SOCl2, MeOH2. LiOH3. Fmoc-Cl
81%
[2+2] cycloaddition: application[2+2] cycloaddition: application
Corey, E. J. et al J. Am. Chem. Soc. 2003, 125, 5628.
NH
N
N
NMe Me
OO
Me Me
H
HH
OH
Okaramine N
8%, 10 steps
[2+2] cycloaddition: application[2+2] cycloaddition: application
Corey, E. J. et al J. Am. Chem. Soc. 2003, 125, 5628.
NH
NH2
CO2MeH CHO
Me
MeN
NHFmoc
CO2HH
MeMe
DCM
1.
2. NaBH4, MeOHNH
NH
CO2MeH
Me Me
BOPCl
NH
N
FmocHNMeO2C
NMe Me
OH
H
70%
Pd(OAc)2 (1 equiv),AcOH:dioxane:H2O
1 atm O2, rt, 16h
NH
N
FmocHNMeO2C
NMe Me
O
Me Me
H
H
44%
Et2NH/THF
95%
NH
N
HN
NMe Me
OO
Me Me
H
H
1. MTAD, DCM, -5 °C2. -DCM3. O2, sunlamp, 7.5h MeOH, MB, -28 °C4. DMS
N
N
N
NMe Me
OO
Me Me
H
HH
OH
H-MTAD
, 110 °C,30min
70%
Me
Me
ConclusionConclusion
1O2
Discovery of reactionwith organic molecules
1867 (Fritzche)
Generation: dye-photosensitisation
Choice of solventimportant (lifetime)
Diverse modes of reactivity- heteroatom oxidation- heterocyclic oxygenation- reaction with double bonds
- ene reaction- [2+2], [4+2] cycloadditions
Diastereoselectivity:essentially based on
steric factors and/or hydrogen bonding
Application to biologically activeand natural product synthesis
