Singlet Oxygen Ene Reaction - David A....
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Singlet Oxygen Ene Reaction By Pavel Nagorny Evans Group Friday Seminars O 2 concerted mechanism stepwise mechanism H O O OOH O O H
Transcript of Singlet Oxygen Ene Reaction - David A....
Singlet Oxygen EneReaction
By Pavel Nagorny
Evans Group Friday Seminars
O2
concerted mechanism
stepwisemechanism
HOO
OOH
OO
H
Table of Contents:
• Discovery of singlet oxygen
• Generation and physical properties
• Overview of reactivity
• The singlet oxygen ene reaction
• Mechanism
• Cis Effect
• Steric and Electronic Effects
• Oxidation of Indoles
• Directed Ene
• Chiral Auxiliaries
• Enantioselective Ene
• Conclusion
References:
Reviews:
Clennan, E. L. Tetrahedron, 2000, 56, 9151-9179.
Orfanopoulos, M. Tetrahedron, 2000, 56, 1959-1615
Adam, W. ACIEE, 1996, 35, 477-494
Wasserman, H. H. Tetrahedron, 1981, 37, 1825-1852.
Monographs:
Frimer, A. A. Singlet O2, CRC: Boca Raton, FL,1985.
Wasserman, H. H.; Murray, R. W. In Singlet Oxygen,Wasserman, H.H., Ed.; Academic: New York, 1979;Vol. 40.
Shaap, A.P. In Singlet Molecular Oxygen,VanderWerf, C.A., Ed.; Dowden, Hutchinson & Ross:Stroudsburg, Pennsylvania, 1976; 5.
Discovery and First Use in Organic Synthesis
• The earliest description was made by Fritzsche in 1867
OOhv, O2
heat
• In 1931 Kautsky and coworkers reported first evidence for metastable, reactive state of molecular oxygen
• In 1954 Schenck and Ziegler reported the first use of singlet oxygen in organic synthesis of (±)-ascaridole
Me
Me
Me hv, O2
chlorophyllMe
Me
Me
O
O
(±)-ascaridole
Fritzsche, M. Compt. Rend. 1867, 64, 1035-1037Kautsky, H.; de Bruijn H. Naturwissenschaften 1931, 19, 1043Schenck G. O.; Ziegler K. Naturwissenschaften 1954, 32, 157
Physical Properties
• Singlet oxygen is the first exited state of O2 lying 22.4 kcal/mol above the ground triplet state
Ground State 3Σ-g
1st Singlet State 1∆g
2nd Singlet State 1Σ+g
22.4 kcal
37 kcal Lifetime=10-12sec
Lifetime=10-4sec
• The intersystem crossing 3Σ-g →
1∆g could be achieved by photosensitization with a dye
1S0 + hvk1 1S1 + 3O2
k2 3S1 + 1O2absorption energy
transfer
energytransfer
3O21S0 + 1O2
• The lifetime of the singlet oxygen is highly solvent dependent
Solvent Lifetime (x10-6s) Deuterated Solvent Lifetime (x10-6s)
Chloroform 220
Benzene 24
Ethanol 12
Chloroform 800
Benzene 700
Ethanol 230
Frimer A. A. Singlet O2, Volume I, 13-38
Singlet Oxygen Generation
• Photosensitization with Rose-Bengal, Methelene Blue or tetraphenyl porphyrine (TPP) is the preffered method. However, to avoid side-photoreactions, other methods could be used
a) Murray Method: thermal decomposition of ozone-phosphite adducts
b) Thermal decomposition of aromatic endoperoxides
P
OPhPhO
PhO
O3, DCM, -78 °C
P
OPhPhOPhO
O
O
O -78 →-25 °CPhO P
OPh
OPh
O
OO
-OP(OPh)31O2
Ph
Ph
hv, O2
Ph
Ph
OOCS2
PhH, Reflux
Substrate
Ph
Ph
+ 1O2
c) Decomposition of hydrogen peroxide with bleach
H2O2 + OCl- HO2- + H OCl HO- + HOOCl H2O + ClOO-
ClOO- Cl- + 1O2Frimer A. A. Singlet O2, Volume I, 13-38
Different Reaction Modes
• Schenck Ene Reaction
HHH
HH
OO H1O2
Hydroperoxide
• [4+2] Cycloaddition1O2
OO
Endoperoxide
• [2+2] Cycloaddition
OMe1O2
OMe
O O
1,2-Dioxetane
• Oxidation of heteroatoms
1O2
2R2S 2R2S=O
Reaction Rate Constants in CHCl3
Compound Rate (x106 M-1s-1)
25
1.0
0.16
2.2
0.002
0.83
43
3.1
0.02
233
11
40
1.5
7.0
460
1-methylcyclohexene
5-methoxyindole
α-Pinene
2-methyl-2-pentene
Cyclopentadiene
1,3-cyclohexadiene
Isoprene
2,5-dimethylfuran
Furan
Imidazole
2,5-diphenyloxazole
diethyl sulfide
NMe2
Frimer, A. A. Singlet O2 CRC: Boca Raton, FL, 1985
Ene Reaction: Introduction
• The products of the ene reaction--allylic hydroperoxides can undergo a number of different transformations
a) Hock-Cleavage
OOH H+ O
+H2O
OMe
Me
-H2O +H2O
Me
O
Me Me
O
H+
cyclobutyl > aryl > vinyl > hydrogen > cyclopentyl ≅ cyclohexyl >> alkyl
b) Fragmentation to Divinyl Ethers
O
OH
H+O
OH2+
O+
H
O
• The ene reaction with singlet oxygen was discovered in 1943 by Schenck
• Schenk ene reaction has been highly used in organic synthesis
Schenck, G. O. Naturwissenschaften 1948, 35, 28-29 Frimer, A, A. Chemical Reviews 1979, 79(5), 359-387
Ene Reaction: Hydroperoxides
d) Kornblum-DeLaMare Dehydration
MeOOH AcCl, Py
H
OAcO
Me
O
f) Reduction to an alcohol
MeOOH NaBH4
Me
OH
c) Rearrangement to epoxides
Me
OOH Me Me
O Me Me
O
MeH or O2
MeO
Me Me
O
Me
OOH
Me
O Me Me
O
Me
MeO
MeROH
OR
e) 1,5-Isomerization
Me
OOH
Me
O O
Me
O O
Me
HO O
Frimer, A, A. Chemical Reviews 1979, 79(5), 359-387
Ene Reaction: Mechanism
• Singlet oxygen ene reaction is suprafacial
DH
H3C H
Ph
H
H3C
H
Ph
DOO
D
H3C H
PhHOO
D
H3C
H
Ph
HOO
H
H3C H
PhDOO
topattack
"Re"
bottomattack
"Si"
topattack
bottomattack
ANTARAFACIALSUPRAFACIAL
OBSERVED
(R,H)
(S,D)(S,H)
(R,D)
• Benzylic position is oxidized with 86% selectivity
Organopoulos et al. Tet. Lett. 1978, 3227-3230
Ene Reaction: Mechanism
O2
concerted mechanism
stepwisemechanism
HOO
OOH
OO
OO
OO
H
perepoxide
• Absence of the Markovnikov directing effects rules out the zwitterion and diradical intermediates
• The kinetic isotope effect studies support the perepoxide intermediate showing that the hydrogen abstraction is not the rate determining step
O
H3C CD2
O
D3C HH3C
D3C CH3
CD3 D
OOH
H3CD3C
CD2
OOD
H3CD3C
CD3 CH3
1.0 : 1.4
1O2
O
H3CCD2
CD2
O
H3C D
D3C
H3C CH3
CD3
D1O2
O
D3C
O
D3C H
H
OOH
H3CD3C
CD3
CD2
OOD
H3CD3C
CH3
-H or -D
-H
-D
1:05
1.0
Song, JOC, 1987, 52, 3938-3940Song, JACS, 1990, 112, 8126-8134
Ene Reaction: Mechanism
O2
concerted mechanism
stepwisemechanism
HOO
OOH
OO
H
• The activation energy for the ene reaction is estimated to be 1.3 kcal/mol
tButBu
tBu
tBu
tButBu tButBu
OOH
OOH
tButBu tButBu
OOH
OOH
60 : 40
33 : 67
• Calculations based on cyclohexane A values would give >99:1 ratio for the products of the concerted mechanism
Kellogg, JOC, 1975, 40(17), 2575-2576
Ene Reaction: "Cis Effect"
• Singlet oxygen abstracts hydrogen from the most congested side of an olefine. It is known as the "Cis Effect"
MeMeO
1O2
MeO
HOO
Me
MeO MeMe
Me
Me
Me
Me
100%
Me Me
Me
D3C
Me
MeMe
MeMe
Me
28%
72%
48%
0%
68%52% 22%
10% 14%
86%
0%
48%
30%
22%
33%
65%<2%
78%22%
4%
43%
53%
Conia, Tet. Lett., 1977, 2517-2520Foote, Tet. Lett., 1978, 3227-3230Clennan, Tetrahedron, 2000, 56, 9151-9179Orfanopoulos,Tetrahedron, 2000, 56, 1595-1615
Ene Reaction: "Cis effect" Explaination
Stephenson/Fukui Model Houk Model
LUMO
HOMO
Overlap is maximized on themore conjested side
O
Me
OH
H
O
Me
Me
O
Hvs
1.152.25
1.851.722.07
1.11
1.112.14
2.20
I II
• CCSD calculations gave 2.8 kcal/mol energy difference
• II is a late transition state compared to I
• II involves an asynchronous attack on olefinic carbons so that II is more polar than I
Fukui, Chem. Lett. 1976, 749-752Stephenson, Tet. Lett. 1980, 1005-1008Houk, JACS, 2003, 125, 1319-1328
Ene Reaction: Steric Effect
• Singlet oxygen ene reactions are sensitive to the steric effects. Oxygen approaches the olefine from the least sterically hyndered side.
Me
OOH
H
H
OOH
66 : 1
1O2
Me
OOH
H
H
OOH
0.19 : 1
1O2
Me Me Me Me Me Me
O
Me
O
H
HMe
Me
Me
1O2
OO
H
HMeO
O
H
HMe
OOH OOH
1O21)
2) P(OEt)3Me
MeO
Me
MeMe
MeO
MeOH
53% : 22%
Only diastereomer
Clennan, Tetrahedron, 2000, 9151-9179Jefford, JACS, 1972, 94, 8904-8905Paquette, Synth. Commun. 1986, 16, 1275-1283
Ene Reaction: Steric Effect
O
Me
O
H
H Me
Me
MeMeMe O
Me
More hindered face
More hindered facePaquette, Synth. Commun. 1986, 16, 1275-1283
Ene Reaction: Geminal Group Effect
L
Me Me
Me 1O2 L
Me
MeOOH
L= -C(O)R, -COOR, -COOH, -S(O)Ph, -CH2SPh, -CH2S(O)Ph, -CH=NtBu, -CN, -C(O)NH2, -SiR3, -SnR3, -tBu, -iPr, -Ph
Me Me Me Me Me
Me
Me Me
Me
Me Me
Me
Me Me
Met-Bu
Me Me
Me3Si
Me Me
Me Bu3Sn
Me Me
MeO2C
Me Me
Me
MeO2C
Me Me
HO2C
Me Me
OHC
Me Me
MeO2C
Me
Me S
Me
Me
t-Bu t-Bu t-Bu i-Pr
F3C
MeO
Me
O
Ph
>97 <3 >99 >99 86 80
0
>99 89 11 88
120
0
00
66 3476
83 17
24
22 4526
74>99 78 55
Orfanopoulos, JACS, 1990, 112, 6417-6419Adam, Tet. Lett. 1993, 34(52), 8423-8426Foote, JACS, 1971, 93, 5162-5167
Ene Reaction: Geminal Group Effect
L
Me Me
Me 1O2 L
Me
MeOOH
• Both steric and electronic effects were envoked to explain the geminal group directing effect
• Stereoelectronic effects are working opposite to the steric effects
t-Bu
Me Me
Me3Si
Me Me
Me Me3Sn
Me Me
>99 89 11
0
66 34
Steric Effects:Me3Sn- <Me3Si- <tBu-
Electronic Effects:σ(Me3Sn-) >σ(Me3Si-) >σ(tBu-)
O O
H
H
• MO interactions could explain selectivity in some cases
a) HOMO of the perepoxide is a linear combination of the n(O) and σ(C-L)
b) HOMO is antibonding in nature
c) Any substituent that reduces the energy between n(O) and σ(C-L) would increase the antibonding interaction and favore cleavage of the adjucent C-O bond
L
Adam, JOC, 1993, 58, 3416-3420Paquette, JACS, 1979, 101, 4420-4423
Ene Reaction: Stereoelectronic Effects
MeMe
1) 1O22) DMS
Me
Me
OHHO
+Syn
Anti
76% 16%
MeMe
MeMe Me
MeMe
MeMe
Me
MeO
OMe
Cl Cl
Cl
Cl
F F
F
F
CO2Me
CO2Me
Anti/Syn
k(M-1s-1)
80/20
1.36 x 105
79/21
4.28 x 106
48/52
9.63 x 104
46/54
5.24 x 104
49/41
• Later, Houk and coworkers proposed that the effect above results from the electrostatic repulsion of singlet oxygen and π cloud of the aromatic ring
• Paquette and coworkers pointed out that the experimental results are consistent with anchimeric π-electron density donation to the developing anti-perepoxide
• Mukai proposed that π-orbital distortion arising from the mixing of the isopropylidine π-orbital with a lying σ-orbital is responsible for the effect above
Mukai, JACS, 1978, 6509-6510Paquette, JACS, 1978, 6510-6512Houk, JOC, 1993, 4625-4628
Ene Reaction: Electronic Effects
SnBu2Cl OOSnBu2Cl1O2
SnBu2OAc OOSnBu2OAc1O2
SnMe3
1O2OOSnMe3
SnMe3HOO O
OSnMe3+ +
25% 50% 25%
SnBu3
1O2OOSnBu3
SnBu3HOO O
OSnBu3+ +
18% 40% 42%
100%
100%
SnMe3
1O2
Me3Sn
O+
O-
SnMe3
OO
O
OSnMe3
Dang, Davies, Tet. Lett., 1991, 32, 1745-1784Dang, Davies, J. Chem. Soc. Perkin Trans, 2, 1992, 1095-1101Dang, Davies, J. Organomet. Chem., 1992, 430, 287-289
Ene Reaction: Oxidation of Indoles
NH
NHBoc
CO2Me
HN
NHBoc
CO2MeOO
N NHBoc
CO2MeO
O
H
NH
NBoc
CO2Me
H
OOH
• Photooxygenation of indoles is well studied in connection with the metabolism of tryptophan and its derivatives
HN
NHBoc
CO2Me
O
O
NH
NBoc
CO2Me
H
NH
NBoc
CO2Me
H
OH
OH
NHCHO
O NHBoc
CO2Me
1)O2, MeOH, Py
Rose Bengal2) DMS
17%
12% 24%
Nakagawa, Chem. Pharm. Bull., 1981, 4(29), 1013-1026
Ene Reaction: Okaramine N by E. J. Corey• The photooxygenation of indole was imployed in one of the final stages of the Okramine N synthesis
NH
N
HN
Me Me
OOH
H
N
MTAD, DCM
0 °C, 1h
N
N
HN
Me Me
OOH
H
N
N
MeN
NH
O
O(Indole Protection)
1) O2, hv, Methelene Blue, MeOH2) DMS, MeOH
N
N
N
Me Me
OOH
H
N
N
MeN
NH
O
O
MeMe Me
Me
MeMe
OH
H
HN
N
N
Me
MeO
OH
H
N
Me
Me
OH
H
(Indole Deprotection)
110 °C, 30min
70% for 3 steps
Okramine N
Corey et al, Org. Lett. 2003, 5, 1999
Ene Reaction: Hydrogen Bonding
• Adam and coworkers have investigated the possibility of directed ene reaction
>90 10
OH1O2
CCl4
OH OH
OOH + OOH
75 25
OH1O2
CCl4
OH OH
+
OOHOOH
OH
1O2 CCl41)
2)PPh3
OH OH O O
OOH OH
+ + +
34 40 16 10
1O2 CCl41)
2)PPh3
MeCO2HMe CO2HMe CO2HMe
OOH OOH
87 13
+
Adam, Acc. Chem. Res. 1999, 32, 703-710Adam, JACS, 1996, 118, 1899-1905Adam, Angew. Chem. Int. Ed. 1996, 35, 477-494
Ene Reaction: Hydrogen Bonding
• For acyclic compounds, the hydrogen bonding coupled to A1,3 strain promoted conformational bias can produce synthetically useful diastereoselectivities
Me
OH
Me
Me 1O2
Me
OH
MeMe
OH
Me
OOH OOH
+
Me
NH2
Me
Me 1O2
Me
NH2
MeMe
NH2
Me
OOH OOH
+
Me
Cl
Me
Me 1O2
Me
Cl
MeMe
Cl
Me
OOH OOH+
Me
BocHN
Me
Me 1O2
Me
BocHN
MeMe
BocHN
Me
OOH OOH+
Me
PhSO2
Me
Me 1O2
Me
PhSO2
MeMe
PhSO2
Me
OOH OOH+
93 7
95 5
CCl4
CD3COCD3
5 95
10 90
22 78
CD3COCD3
CD3COCD3
90%
95%
90%
95%
85%
CCl4
Adam, Acc. Chem. Res. 1999, 32, 703-710Adam, JACS, 1996, 118, 1899-1905Adam, Angew. Chem. Int. Ed. 1996, 35, 477-494
Ene Reaction: Hydrogen Bonding
1O2
Me
Me
X
H MeO
O
Me
Me
X
H Me
Me
Me
X
H MeMe
Me
X
H Me
O
O
Me
Me
X
H MeO
O
Me
Me
X
H Me
O
O
Me
X
Me
Me
X
Me
OOH
OOH
Atractive or Repulsive Interactions
Favored for AtractiveInteractions
Favored for RepulsiveInteractions
X= tBu, NHBoc, NBoc2, SOPh, SO2Ph, CO2Et CO2H, Br, Cl
X= OH, NH2, NH3+
threo
erythro
Adam, Angew. Chem. Int. Ed. 1996, 35, 477-494
Ene Reaction: Chiral Auxiliaries
• The first attempt to use chiral auxiliary was made by Ensley and coworkers, and was unsuccessful
O
N
Me
MeR
1O2
>90%
O
N
Me
MeR
OOH
R dr
H 1:1Me 1:1
• Adams and coworkers ivestigated similar auxiliaries for singlet oxigen and MTAD ene reactions
NO
1O2/PPh3
>90%
R dr
Bn 1:1iPr 1:1
MeMe
R
O
Me
Me
NO
MeMe
R
O
Me
OH
NO>90%
R dr
Bn >98:2iPr >98:2
MeMe
R
O
Me
Me
NO
MeMe
R
O MeMTAD
N
N
HN
O
O
Me
Ensley et al, JACS, 1980, 102, 2836-2838Adam, Eur. J. Org. Chem. 1998, 501-506
Ene Reaction: Chiral Auxiliaries
• Dussault has demonstrated that 8-arylmenthyl auxiliaries could give acceptible diastereoselectivity in singlet oxygen reaction
Me O
Me
MeO
Me
Me
Me O
Me
MeO
Me
Me 1O2
XcO
O
Me
OOH
Sensitizer/Solv. Temp. Yield dr
TPP/CH2Cl2
TPP/CCl4
RB/MeCN
RB/MeOH
TPP/CH2Cl2
TPP/CH2Cl2 -60 °C
-45 °C
-30 °C
25 °C
25 °C
25 °C
86
83
89
82
87
94
1:2.3
1:2.3
1:2.3
1:3.3
1:3.3
1:4.5Ar and
MeMe
Me
Ar
did not give any selectivity
Dussault, Tetrahedron, 1994, 50(30), 8929-8940
Ene Reaction: Chiral Auxiliaries
• Adam has attempted to contstracted an oxazole-based system with hydrogen directing ability to mimic the oxidation of allylic alcohols
1O2
X Solvent Temp. Time Mass Balance Regioselectivity dr
O N
Ph
O
X
Me
Me
Hthen PPh3 O N
Ph
O
X
Me
HO N
Ph
O
X
MeMe
O
OOH O
-OtBu
-Ph
-NHPh
-NHPh
-NHp-(NO2)Ph
-NMePh
-5
-5
-5
-10
-10
-10
CDCl3
CCl4
CDCl3
d6-acetone
CDCl3
CDCl3
20
23
4
40
28
48
75:25
86:14
93:7
96:4
96:4
70:30
25:75
45:55
94:6
85:15
>95:5
41:59
92%
86%
>95%
72%
85
90
Adam, JACS, 2000, 122, 7610-7611
Ene Reaction: Chiral Auxiliaries
• Adam has attempted to contstracted an oxazole-based system with hydrogen directing ability to mimic the oxidation of allylic alcohols
1O2
N
H
O X
Ph
Me
Me
Atractive Interactions
N
H
O X
Ph
Me
Me
O
ON
H
O X
PhMe
OOHH
min
1O2
N
H
O X
Ph
Me
MeO
O
min
Repulsive Interactions
N
H
O X
Ph
MeH
OOH
Favored
Ene Reaction: Chiral Auxiliaries
• Adam has used oxazolidinone auxiliary to perform diastereoselective 1O2 ene and [2+2] reactions
O N
O
R1
1O2R2
R3
O N
O
R1
Ph
O NO
O
R1
OOH
O N
O
R1
Ph
OOH
OR3
R2H
R1 R2 R3 [2+2]:ene 1:2 [2+2] dr
(S)-tBu
(R)-iPr
(R)-Me
(R)-iPr
(R)-Me
(R)-iPr
(S)-Ph
(S)-tBu
1 2
(R)-Ph(Me)CH
iPr
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
>95:5
>95:5
80:20
75:25
16:84
36:64
8:92
23:77
-
-
53:47
56:44
88:12
83:17
71:29
91:9
<5:95
>95:5
>95:5
>95:5
nd
nd
nd
nd
TPFPP, CDCl3
TPFPP=5,10,15,20-tetrakis(pentafluorophenyl)porphine
Adam, JOC, 2004, 69, 1704-1715
Ene Reaction: Chiral Auxiliaries
• Both the mode of reaction and diastereoselectivity of the ene reaction strongly depend on the double bond geometry
O N
O
R1
1O2Ph
Me
O N
O
R1
Ph
OOH
O N
O
R1
Ph
OOH
12
• Ene reaction is favored when the "cis effect" is operational
NO
O
R1
MePh
NO
O
R1
Me
Ph
OO
OO
Favored
Ene Reaction: Conclusion
• Singlet oxygen ene reaction is one of the highly investigated processes in organic chemistry
• There are certain trends of oxidation ("cis effect", "geminal effect", etc.) that could be used with a to predict the outcome of the ene reaction
• Ene singlet oxigen reaction could be performed diastereo- and enantioselectively although some further advancements in this area is required
O2 OOHOO
H
