Enantioselective Radical
Reactions
Justin Potnick
March 12, 2004
Outline
•
•
•
•
•
•
•
Introduction to Radical Reactions
Atom Transfers
Reductive Alkylations
Fragmentations
Tandem Addition-Trapping Reactions
Oxidations
Summary
Introduction
Initiation
Precursor
Propagation
Radical-1
Termination
Radical-2
Neutral Product
Chain transfer
•
Typical radical reactions go through 3 steps
1.
Generation of radical from non-radical species
2.
Propagation/Chain transfer process
3.
Termination
Radical Properties
• Short lived, highly reactive species; difficult to use
• Proceed under mild, neutral conditions
– Radical reactions have been performed in aqueous media
• Compatible with many functional groups, inert toward
-OH or -NH
• Early, reactant-like TS‡ allows for prediction of product
stereochemistry from ground state structure
C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem Rev. 1991, 91, 1237
Creating Selectivity
•
Chiral source must be present during reaction
1.
Chiral source bound to achiral substrate (complex-controlled)
*
*
*
SUB +
2.
LA
SUB
LA
*
LA
A•
PROD*
PROD* +
LA
Chiral source bound to the reagent (reagent-controlled)
*
*
SUB +
H M
*
SUB
R
H
M
*
SUB-H* +
R
•M
R
Outline
• Introduction to Radical Reactions
• Atom Transfers
•
•
•
•
•
Reductive Alkylations
Fragmentations
Tandem Addition-Trapping Reactions
Oxidations
Summary
Atom Transfer Reactions
R1
R2
Z•
R1
R2
•
•
•
R1
+
R2
A-Z
+ Z•
A
Typically involve transfer of a hydrogen or halogen
atom
Transfer of atom from a chain-transfer agent to a
radical species to generate another radical
1.
*
Chiral Lewis Acid
LA
2.
Chiral Reagent
*
R
SnH
Enantioselective Atom Transfer
• Lewis acids have been used to enhance and catalyze radical
reactions
O
Cl Al
O
O
O
O
Al O
O
BuI
Bu3SnH
Et3B/O2
toluene
O
*
*
O
Bu
O
47%, 28% ee
• Conjugate addition followed by selective H-atom transfer
Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, F. J. Org. Chem. 1995, 60, 3576
•
Bu
Radical Initiator
Et3B/O2
•
•
•
•
Trialkylboranes give free alkyl radicals upon treatment with oxygen
Et3B/O2 works as a radical initiator even at -78 °C
Advantageous for stereoselective reactions: improved selectivities at lower
temperatures
Alternate methods of radical generation typically involve high temperatures
Initiation:
Propagation:
Et 3B + O 2
R-I + Et •
Et 2BOO • + Et •
R•
Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415-3434
+ Et-I
Enantioselective Atom Transfer
Entry
R
Yield (%)
ee (%)
1
-CH2 OMe
88
62 (R)
R
2
-CH2 OEt
84
65 (R)
O
3
-CH2 OBn
89
58 (R)
4
-Me
78
30 (R)
OBn
N
I
O
N
R
O
H
BnO
MgI2/Et2O
Bu3 SnH, CH2Cl 2
-78° C
O
• Selectivity was dependent on concentration of reactants
– Low ee at low concentration
– Suggests uncomplexed radical reacting to give racemic product in
competing background reaction
Murakata, M.; Tsutsui, H.; Takeuchi, N.; Hoshino, O. Tetrahedron 1999, 55, 10295
Acyclic Systems
•
•
With previous cyclic system, selectivity is easier to control
Acyclic systems require more control
1.
2.
3.
The complexing chiral group must be fixed relative to the prochiral
center
The chiral group must shield one face of the radical or alkene
Reactivity of the complex must exceed reactivity of the free substrate
H•
O
R2
I
OR
R1
R2
O
R1
OR
LA*
R2
• O LA*
R1
OR
•
H
Murakata, M.; Tsutsui, H.; Takeuchi, N.; Hoshino, O. Tetrahedron 1999, 55, 10295
Rotamer Control
•
•
Rotamer control in radical transformations is important for selectivity
Achiral auxiliaries can provide a handle to control rotamers of acyclic
substrates
– Oxazolidinone templates were chosen based on success of chiral auxiliaries in
Lewis acid promoted free radical transformations
– S-cis favored due to A1,3 strain
No rotamer control
H • R3
O
R1
3
• R
R2
Rotamer control
R1
H
O
R2
O
• H
R
2
O
H
O
M*
O
M*
N
3
R
• R
H
s-cis
R1
O
O
R • H
O
R1
• R
N
3
M*
O
O
R2
Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163
O
O
N
• H
R
H
s-trans
Acyclic Rotamer Control
O
O
N
N
1
O
H
N
2-naph
OMe
Mg(ClO4)2 , ligand 1
RX, Bu3 SnH, Et3 B/O2
2-naph
CH2Cl2 , -78 °C, 3h
O
H H
N
O
Entry
RX
Yield (%)
ee (%)
1
AcBr
76
80
2
MeOCH2Br
71
65
3
EtI
72
85 (R)
4
iBuI
76
79
5
iPrI
62
83 (R)
6
cHexI
62
55 (R)
7
tBuI
54
27 (R)
Sibi, M. P.; Asano, Y.; Sausker, J.B. Agnew. Chem., Int. Ed. 2001, 40, 1293
O
OMe
R
O
O
N
N
M
O
2-naph
O
OMe
N
H
Conjugate Additions to α-Methacrylates
O
O
O
O
MgBr2• Et2O, Ligand 1
O
N
O
i-PrX, Bu 3SnH, Et3 B/O2
CH2Cl2 , -78 °C
O
MgBr2• Et2 O,
N
O
O S
N
O
N
acetyl-X, Bu3 SnH, Et3B/O2
O
CH2 Cl2, -78 °C
75% yield, 75% ee
MgBr2•Et2O, Ligand 1
N
O
O S
O
N
R
R-X, Bu 3SnH, Et3 B/O2
CH2Cl2 , -78 °C
O
O
N
MgBr2•Et2 O, Ligand 1
acetyl-X, Bu3SnH, Et3B/O2
CH2Cl2 , -78 °C
N
1
Ligand 1
O
O
N
80% yield, 65% ee
O
O
O
25-96% yield, 18-90% ee
O
O
N
O
55% yield, 22% ee
Sibi, M. P.; Sausker, J. B., J. Am. Chem. Soc. 2002, 124, 984-991.
Achiral Napthosultam Template
O
O
O S
N
MgBr 2•Et 2O, Ligand 1
O
O
O S
N
R
O
N
N
R-X, Bu3SnH, Et3B/O 2
CH 2Cl2
1
Entry
R
Temp (°C)
LA (equiv.)
Yield (%)
ee (%)
1
i-Pr
-78
none
<5
0
2
i-Pr
-78
(1.0)
90
78
3
i-Pr
-78
(0.3)
80
80
4
i-Pr
-40
(0.3)
71
59
5
i-Pr
0
(0.3)
52
5
6a
i-Pr
-78
(0.3)
55
80
7
t-Bu
-78
(0.3)
84
89
8
c-Hex
-78
(0.3)
71
82
9
MeOCH2
-78
(0.3)
89
90
aPh SnH
3
O
was used as H-atom donor
Sibi, M. P.; Sausker, J. B., J. Am. Chem. Soc. 2002, 124, 984-991.
Predicted Transition State to Account
for Selectivity
O
O
O S
N
MgBr2•Et 2O, Ligand 1
O
O S
O
O
N
O
R-X, Bu3SnH, Et 3B/O2
CH2Cl 2, -78 °C
O
N
N
1
25-96% yield, 18-90% ee
Attack from re face
S-trans rotamer
Attack occurs before any rotamer
interconversion: precursor geometry
imparts on product stereochemistry
Sibi, M. P.; Sausker, J. B., J. Am. Chem. Soc. 2002, 124, 984-991.
α-Substituted ß-Amino Acids
R
MgI2 /3
R1 X, Et3B/O2
O
O
O
R
N
1a R 1 = Me
1b R 1 = t-Bu
Bu3SnH
CH 2Cl2 , -78 °C
O
O
O
*
O
N
R1
O
O
N
2a-b
Entry
RX
Compd
1
Isopropyl-I
2
O
N
3
LA mol %
Yield (%)
ee (%)
1a
No LA
99
—
Isopropyl-I
1a
100
91
40
3
Cyclohexyl-I
1a
100
71
79
4
Cyclohexyl-I
1a
30
76
40
5
CH3CH2-I
1b
100
85
68
6
CH3CH2-I
1b
30
78
36
7
Cl(CH2)3(CH3)2C-Br
1b
100
72
98
8
Cyclopentyl-I
1b
100
86
94
9
Cyclohexyl-I
1b
100
95
88
10
Cyclohexyl-I
1b
30
86
90
11
1-adamantyl-I
1b
100
71
97
Sibi, M. P.; Patil, K. Agnew. Chem., Int. Ed. 2004, 43, 1235
Reasons for selectivity
• Radical reactions proceed through an early transition
state ? resembles starting complex
• H-atom transfer occurs rapidly on rotamer conformation
timescale
– Atom transfer or radical addition to a neutral molecule proceed at
high rates: approximately 104-108 dm3M-1s-1
– Geometry of starting material affects product stereochemistry
• Exploitation of relatively slow conformation changes is
possible
Sibi, M. P.; Manyem, S.; Zimmerman, J., Chemical Reviews 2003, 103, 3263-3295.
Memory of Chirality
O
Ph
>97% ee
CO2H
N
OH
•
•
1. DIPDI, DMAP,
S
2. hν , 1 M PhSH, -78 °C
PhSH
O •
O
Ph
Atom transfer occurs at a high rate
Dependent on temperature and concentration
of H-atom donor
Ph
H
93
7
PhSH
Ph
Entry
•
O
86% ee
O
Ph
O
CN
>97% ee
Li/NH3
O
Ph
THF
-78 °C
e , H+
Ph
Ph
H
H
[PhSH] (M)
O
% yield
% ee
Entry
[Li] (M)
% ee
1
1.0
92
86
1
0.8
30
2
0.5
75
70
2
3.5
30
3
0.05
58
23
3
5.4
54
4
0.01
67
4.3
4
6.4
90
Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D., J. Am. Chem. Soc. 2000, 122, 9386-9390.
Chiral Reagents
Reduction of α-bromoketones
Me
Sn
H
+
Ph
Br
Ph
Et3B/O2
Ph
Ph
H
O
PhMe, -78 °C
O
30% yield, 41% ee
Reduction of α-bromoesters
O
Sn
t-Bu
+
H
Br
Ph
O
Et3B/O2
OMe
t-Bu
H *
OMe
Ph t-Bu
Et2O, -78 °C
52% ee
Hydrometallation of methyl methacrylate
R
CH3
S
Ge
S
R
aR=H
b R = TMS
c Tin-Hydride
t-Bu
CO2Me
H AIBN, hν or Et3B/O2
R
R
S
Ge
t-Bu
S
R
S
Ge
+
CO2Me
S
t-Bu
CO 2Me
R
a 61% yield, 3/1 dr
b 55% yield, 25/1 dr
c 60% yield, 1.3/1 dr
Nanni, D.; Curran, D. P. Tetrahedron: Asymmetry 1996, 7, 2417.
Blumenstein, M.; Schwarzkopf, K.; Metzger, J. O., Angew. Chem., Int. Ed. Eng. 1997, 36, 235-236.
Curran, D. P.; Gualtieri, G., Synlett 2001, 1038-1041.
Hydrosilylation of Alkenes
OAc
Ph
Ph
O
O
1 (0.05 eq.), 60 °C
AcO
AcO
Ph
Ph
Ph3SiH, TBHN (0.05 eq.)
Ph 3Si
* O
O
SH AcO
AcO
1a OAc
O
Entry
Thiol
Solvent
Yield (%)
ee (%)
1
1a
Dioxane
88
80
2
1a
Benzene
92
86
3
1a
Hexane/Dioxane (5:1)
93
87
4
1b
Hexane/Dioxane (5:1)
90
95
5
1c
Hexane/Dioxane (4:1)
73
85
6
1d
Hexane/Dioxane (4:1)
87
94
R'O
R'O
R'O
OAc
OAc
O
SH
1b
O
SH
OR'
R' = 2-BrC6H4C(O)1c
AcO
AcO
AcO
OMesitylcarbonyl
O
SH
1d
t-BuON=NOt-Bu
(TBHN)
R3SiCH2C(H)R1R2
XS•
R3SiH
XSH
XSH
•
R3SiCH2CR1R2
R3Si •
R1
R2
Cai, Y.; Roberts, B. P.; Tocher, D. A., J. Chem. Soc. Perkin Trans. 1 2002, 1376-1386.
Haque, M. B.; Roberts, B. P., Tetrahedron Lett. 1996, 37, 9123-9126.
Haque, M. B.; Roberts, B. P.; Tocher, D. A., J. Chem. Soc., Perkin Trans. 1 1998, 2881-2890.
Halogen Atom Transfer
initiatior
R-X
•
•
•
•
R
R • + R'
X
R-X
•
R
R'
R'
+
R•
Addition of R-X to C-C double bond
Good atom economy
Product has halide group, allowing for further functionalization
Reaction can be slow for R ? EWG
O
O
I
O
N
N
O
O
+
Ph
N
O
Ph
*
Zn(OTf)2
0.5 equiv. Et3B/O2
N
I
O
O
Yield: 5-15%
best ee approx. 40%
Mero, C. L.; Porter, N. A., J. Am. Chem. Soc. 1999, 121, 5155-5160.
Atom Transfer Radical Cyclizations
R''
R''
•
X
•R +
+ RX
R'
R'
R''
R''
•
R'
X
R''
•
R'
R''
R''
R' +
R'
•
R'
X
• Transfer of halogen atom from one C to another followed
by ring formation
• Halogen atom is retained in the product
• Can be promoted or catalyzed by Lewis acids
Radical Cyclizations
O
O
2
N
O
O
N
O
t-Bu
OEt
Br
n
O
N
t-Bu
Mg(ClO4)2
Et3B/O2, -78 °C
n
R1
Entry
Substr
Catalyst
(equiv.)
Solvent
Time (h)
1
1a
1.1
CH2Cl2
2
1a
1.1
3a
1a
4a
2a
2b
2c
2d
n = 1, R1 = R2 = Me
n = 2, R1 = Et, R2 = H
n = 2, R1 = H, R2 = Et
n = 2, R1 = R2 = Me
ee (%)
7.5
68
71
toluene
5
67
94
0.3
toluene
7
68
92
1b
0.3
toluene
12
58 (1/1)b
74/87c
5a
1c
0.3
toluene
9.5
81 (1/1.4)b 74/95c
6
1d
1.1
toluene
7.5
62
93
7a
1d
0.5
toluene
7.5
53
94
b
ratio of 2b:2c;
c
O
•
EtO
Yield (%)
4Å added;
O
R1
Br R2
R
n = 1, R1 = R2 = Me
n = 2, R1 = Et, R2 = H
n = 2, R1 = H, R2 = Et
n = 2, R1 = R2 = Me
N
Mg
CO2Et
1a
1b
1c
1d
a MS
O
O
O
N
N
Mg
O
O
•
EtO
O
CO2 Et
ee for 2b/2c
Br
Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K., J. Am. Chem. Soc. 2001, 123, 8612-8613.
Tandem Atom Transfer Cyclizations
O
O
O
Br
OEt
CH3
1a
O
CO 2Et
Me
H
O
N
N
t-Bu
t-Bu
Mg(ClO4 )2
O
O
Br
OEt
CH3
Me
Br
1b
O
Et3B/O2, solvent
CO2Et
Me
H
Me
2b
2a
Br
•
Entry
Substrate
T (°C)
Solvent
Product
Yield (%)
ee (%)
1
1a
-78
CH2Cl2
2a
41
13
2
1a
-78
CH2Cl2
2a
24
33
3
2a
-40
toluene
2b
23
82
4
2a
-20
toluene
2b
16
84
Sets four stereocenters in one step with a single diastereomer observed
Yang, D.; Gu, S.; Yan, Y.-L.; Zhao, H.-W.; Zhu, N.-Y., Angew. Chem. Int. Ed. 2002, 41, 3014-3017.
Outline
• Introduction to Radical Reactions
• Atom Transfers
• Reductive Alkylations
•
•
•
•
Fragmentations
Tandem Addition-Trapping Reactions
Oxidations
Summary
Reductive Alkylations
• Addition to carbon-carbon or carbon-heteroatom multiple
bonds, followed by trapping with an H-atom source
– Conjugate additions
– Addition to imines
– Cyclizations
• Catalysis is possible with the use of Lewis acids
O
R''
H
Y
R'''
Y = C or N
R'-X
H-atom source
Initiator
O
R''
R'
Y
•
O
•H
R'''
R''
R'
Y
H
R'''
Conjugate Additions
O
O
O
N
O
Ph
O
i-PrI, Bu 3SnH, Et3 B/O2
O
N
Ph
O
O
N
LA, Chiral Ligand 1,
CH2Cl2, -78 °C
N
R
Entry
LA
Ligand (eq)
Temp (°C)
Yield (%)
ee (%)
1
MgI2
1a (1.0)
-78
88
82 (R)
2
MgI2
1a (0.5)
-78
86
79 (R)
3
MgI2
1b (1.0)
-78
88
47 (S)
4
Zn(OTf)2
1b (1.0)
-78
88
61 (S)
5
MgI2
1c (1.0)
-78
88
93 (R)
6
MgI2
1c (0.3)
-78
91
97 (R)
7
MgI2
1c (0.3)
-20
93
95 (R)
8
MgI2
1c (0.3)
25
87
93 (R)
9
Zn(OTf)2
1c (1.0)
-78
-
53 (R)
R
1a R = i-Bu
1b R = Ph
O
O
N
N
1c
Sibi, M. P.; Ji, J., J. Am. Chem. Soc. 1996, 118, 9200.
Sibi, M. P.; Ji, J., J. Org. Chem. 1997, 62, 3800.
Conjugate Additions
O
O
O
N
O
Ph
O
i-PrI, Bu 3SnH, Et3 B/O2
O
N
Ph
O
O
N
LA, Chiral Ligand 1,
CH2Cl2, -78 °C
N
R
Entry
LA
Ligand (eq)
Temp (°C)
Yield (%)
ee (%)
1
MgI2
1a (1.0)
-78
88
82 (R)
2
MgI2
1a (0.5)
-78
86
79 (R)
3
MgI2
1b (1.0)
-78
88
47 (S)
4
Zn(OTf)2
1b (1.0)
-78
88
61 (S)
5
MgI2
1c (1.0)
-78
88
93 (R)
6
MgI2
1c (0.3)
-78
91
97 (R)
7
MgI2
1c (0.3)
-20
93
95 (R)
8
MgI2
1c (0.3)
25
87
93 (R)
9
Zn(OTf)2
1c (1.0)
-78
-
53 (R)
R
1a R = i-Bu
1b R = Ph
O
O
N
N
1c
Sibi, M. P.; Ji, J., J. Am. Chem. Soc. 1996, 118, 9200.
Sibi, M. P.; Ji, J., J. Org. Chem. 1997, 62, 3800.
Achiral Additives
•
Achiral additives were used in an attempt to increase selectivity
O
O
Ph
N
R1
R
O
O
O
R-I, Bu3SnH, Et3B/O2
Ph
Zn(OTf)2
N
O
Ph
R1
Ph
Et
Entry
R1
1 (equiv)
Additive
R
Yield (%)
ee (%)
Et
O
O
N
1
H
1.0
none
t-Bu
88
9 (S)
2
H
1.0
2b
t-Bu
78
52 (S)
3
Ph
1.0
none
t-Bu
80
3 (S)
4
Ph
1.0
2b
t-Bu
96
88 (R)
5
Ph
1.0
2b
i-Pr
86
82 (R)
6
Ph
1.0
2c
i-Pr
98
29 (S)
7
Ph
0.25
2b
i-Pr
92
80 (R)
Murakata, M.; Tsutsui, H.; Hoshino, O., Org. Lett. 2001, 3, 299-302.
Ph
N
1
Ph
O
R3 N
O
2
R
R2
2
2a R = R3 = H
2b R2 = Ph; R3 = H
2c R2 = Ph; R 3 = Me
Pyrazole Template
O
O
N
N
1
O
Me
O
N N
R-I, Bu 3SnH, Et3B/O2
Ph
Me
Zn(OTf)2/1
Me
Entry
R
N N
Ph
Me
Ligand
(equiv)
Yield (%)
ee (%)
1
i-Pr
1.0
76
51 (S)
2
i-Pr
0.3
84
39 (S)
3
Et
1.0
80
39 (R)
4
cyclohexyl
1.0
81
81
5
cyclohexyl
0.3
76
39
Sibi, M. P.; Shay, J. J.; Ji, J., Tetrahedron Lett. 1997, 38, 5955-5958.
R
Other Lewis Acids
O
O
Sm(OTf)3 , i-PrI, 1, additive
Bu3 SnH, Et3 B/O2
O
N
Ph
O
O
O
N
Ph
CH2 Cl 2, -78 °C
EtO
O
Additive: O
•
N
O
N
Ph
O
63% yield, 92% ee
No additive: 84% y, 79% ee
Ph
Ph
OH
1
Lanthanide Lewis acids can be used
Sibi, M. P.; Manyem, S., Org. Lett. 2002, 4, 2929-2932.
O
Z
Ph
30 mol% Mg(NTf2)2 , 2
i-PrI, Bu3SnH, Et3B/O2
O
O
N
Z
2
O
O
N
99% yield, 98% ee
O
Z=
N
Ph
CH 2 Cl2 , -78 °C
Z=
O
N
95% yield, 98% ee
Sibi, M. P.; Petrovic, G. Tetrahedron: Asymmetry 2003, 14, 2879.
Aldol-Type Products
O
•R
X
•
•
R1
O
1
OR
X
H•
X
OR
•
R1
O
OR
ß-Alkoxy groups prone to elimination with ionic nucleophiles
Nucleophilic radical addition avoids this
O
O
N
O
O
t-Bu
O
N
N
1
t-Bu
O
O
1
OCOPh
MgI2, Ligand 1, R X, Bu3 SnH
O
N
R1
OCOPh
Et 3B/O2 , CH2 Cl2/THF, -78 °C
R1I
i-PrI
t-BuI
Yield (%)
90
91
Sibi, M.P.; Zimmerman, J.; Rheault, T. Angew. Chem. Int. Ed. 2003, 42, 4521.
ee (%)
93
89
Addition to Imines
MeO2C
NOBn
MgBr2, 1, i-PrI, Bu 3SnH
H
MeO2C
NOBn
O
CH2Cl2, Et3B, -78 °C
H
O
N
97% Yield, 52% ee (R)
Ph
N
1
Ph
Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T., J. Org. Chem. 2000, 65, 176-185.
EtO2C
NOBn
H
i-PrI, 2, Et 3B/O2
EtO2C
Tol
P Tol
CuPF4
NHOBn
CH2Cl2, r.t.
P Tol
Tol
56% Yield, 15% ee
Halland, N.; Anker Jorgensen, K., J. Chem. Soc. Perkin Trans. 1 2001, 1290-1295.
O
N
R1
N
O
i-PrI, Et3B/O 2
Cu(1)(H2O) 2(OTf)2
CH2Cl2, 25 °C
HN
R1
N
i-Pr
66% Yield, 95% ee (R)
Friestad, G. K.; Shen, Y. H.; Ruggles, E. L., Angew. Chem. Int. Ed. 2003, 42, 5061-5063.
2
Enantioselective 5-Exo Cyclization
O
Me
O
Ti(Oi-Pr)4 (1 eq.), 1 (1 eq.)
tosyl Et3 B/O, Bu3 SnH
N
Br
OH
H
Me
N tosyl
Me
CH2 Cl 2, -78 °C
H
OH
Ph
Ph
OH
Ph
Ph
HO
1
53% Yield, 77% ee
Hiroi, K.; Ishii, M., Tetrahedron Lett. 2000, 41, 7071-7074.
•
Cyclization using “memory of chirality”
RZ
O
RE
N
O
RN
Me
Bu3SnH
Et3B/O2
I
RZ
R
C 6H 6, 25 °C
Me
E
RZ
Up to 93% Yield, 94% ee
O
RE
N
RN
I
Me
O
Bu3 SnH
Et3 B/O2
C 6H 6, 25 °C
Me
O
RE
Me
Me
RZ
RN
N
N
RN
Me
•
RN
N
RZ
Me
RE
Me
Curran, D. P.; Liu, W.; Chen, C. H.-T., J. Am. Chem. Soc. 1999, 121, 11012-11013.
Me
Outline
• Introduction to Radical Reactions
• Atom Transfers
• Reductive Alkylations
• Fragmentations
• Tandem Addition-Trapping Reactions
• Oxidations
• Summary
Fragmentation Reactions
1.
Addition of radical to a neutral molecule
2.
ß-elimination of resultant radical to generate terminal olefin
R1
R
R1 *
Z
+
X
+
X-Z
R
Z•
Z
1
R
R
•
+
R1 *
R
+
Z•
Z-X
X = halide; Z = Sn(Bu)3, Si(Me)3, Si(Si(Me)3)3
Fragmentation Reactions
O
R1
O
O
N
O
+
Z
Br
MX2, 1, Et3B/O2
O
R1
N
O
O
+ Z-Br
O
N
CH2Cl2, -78 °C
Ph
Entry
MX 2
Z
Yield (%)
ee (%)
1
Zn(OTf)2
SnBu3
84
42
2
Zn(OTf)2
SiMe3
88
90
3
MgI2
SiMe3
86
68
Porter, N. A.; Wu, J. H.; Zhang, G.; Reed, A. D., J. Org. Chem. 1997, 62, 6702-6703.
O
O
N
I
R
O
SnBu3
O
*
1-nap
O
N
1-nap
OH
O
O
O
OH
1-nap 1-nap
Me3Al/2, Et3B/O 2
-78 °C
2
Entry
R
Yield (%)
ee (%)
1
Me
93
34
2
H
90
32
Fhal, A.-R.; Renaud, P., Tetrahedron Lett. 1997, 38, 2661-2664.
N
1
Ph
Fragmentation Reactions
O
Br
N
N
R
+
SiMe 3
O
MX2 , Et3 B/O2
O
N
N
Ligand, CH2 Cl2
O
N
R
1
Ph
Entry
R
Ligand
MX2 (eq.)
T(°C)
Yield (%)
ee (%)
1
H
1
Zn(OTf)2 (1.0)
-78
70
59
2
H
2
Zn(OTf)2 (1.0)
-78
75
96
3
H
3
Zn(OTf)2 (1.0)
-78
42
75
4
H
2
MgBr2
-78
54
84
H
2
Zn(OTf)2 (2.0)
-78
83
>99
6
H
2
Zn(OTf)2 (2.0)
-20
94
95
7
H
2
Zn(OTf)2 (1.0)
-20
93
91
8
4-Me
2
Zn(OTf)2 (1.0)
-20
85
70
9
5-Cl
2
Zn(OTf)2 (1.0)
-20
88
67
10
5-CO2Me
2
Zn(OTf)2 (1.0)
-20
91
80
11
H
2
Zn(OTf)2 (0.2)
-20
69
81
Porter, N. A.; Feng, H.; Kavrakova, I. K., Tetrahedron Lett. 1999, 40, 6713-6716.
Ph
O
O
N
N
2
O
O
N
N
i-Pr
5
N
N
3
i-Pr
Fragmentation Reactions
O
Br
N
N
R
+
SiMe 3
O
MX2 , Et3 B/O2
O
N
N
Ligand, CH2 Cl2
O
N
R
1
Ph
Entry
R
Ligand
MX2 (eq.)
T(°C)
Yield (%)
ee (%)
1
H
1
Zn(OTf)2 (1.0)
-78
70
59
2
H
2
Zn(OTf)2 (1.0)
-78
75
96
3
H
3
Zn(OTf)2 (1.0)
-78
42
75
4
H
2
MgBr2
-78
54
84
H
2
Zn(OTf)2 (2.0)
-78
83
>99
6
H
2
Zn(OTf)2 (2.0)
-20
94
95
7
H
2
Zn(OTf)2 (1.0)
-20
93
91
8
4-Me
2
Zn(OTf)2 (1.0)
-20
85
70
9
5-Cl
2
Zn(OTf)2 (1.0)
-20
88
67
10
5-CO2Me
2
Zn(OTf)2 (1.0)
-20
91
80
11
H
2
Zn(OTf)2 (0.2)
-20
69
81
Porter, N. A.; Feng, H.; Kavrakova, I. K., Tetrahedron Lett. 1999, 40, 6713-6716.
Ph
O
O
N
N
2
O
O
N
N
i-Pr
5
N
N
3
i-Pr
Fragmentation Reactions of αIodolactones
• Single point binding chiral Lewis acid
SiPh3
I
OH
Me3Al, additive, 1
R
O
O
R
SnBu3
O
OH
O
SiPh3
Entry
R
Additive
Yield (%)
ee (%)
1
Me
None
72
27
2
Me
Et2O
84
81
3
CH2OEt
Et2O
85
85
4
CH2OBn
Et2O
76
91
I
OBn
O
O
1
Ph
SnBu3
LA, PhMe, 2
OBn
O
Et3B/O2, -78 C
RO2SHN
O
Entry
2 (eq.)
LA (eq.)
Yield (%)
ee (%)
1
1
Me3Al (2)
76
51
2
1
i-Bu3Al (2)
75
43
3
0.5
Me3Al (2)
72
54
4
0.5
i-Bu3Al (2)
72
37
Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O., J. Am. Chem. Soc. 1997, 119, 11713-11714.
Murakata, M.; Jono, T.; Hoshino, O., Tetrahedron: Asymmetry 1998, 9, 2087-2092.
Ph
NHSO2R
2 R = C6F5
Allylation Using an Acyclic Template
Me
SnBu3
Ts
Br
N
Bn
NHTs
Ph
NHTs
TsHN
LA, *Ligand, Et3 B/O2
CH2Cl2, -78 °C
Me H
Ts
N
Bn
1
Entry
Ligand
LA
Yield (%)
ee (%)
1
1
Et3Al
68
60
2
2
Et3Al
80
64
O
3
3
Mg(OTf)2
65
52
4
4
Mg(OTf)2
41
83
5
Ph
HO
Mg(OTf)2
64
50
S p-Tol
4
O
O
p-Tol S
S
••
NHTs
2
Ph
5
Ph
O
3
••
O
S
p-Tol
p-Tol
••
O
OH
••
5
Ph
O
O
O
p-Tol S O
S p-Tol
M
••
N Bn
O
• H
Hiroi, K.; Ishii, M., Tetrahedron Lett. 2000, 41, 7071-7074.
SnBu3
Outline
•
•
•
•
Introduction to Radical Reactions
Atom Transfers
Reductive Alkylations
Fragmentations
• Tandem Addition-Trapping Reactions
• Oxidations
• Summary
Tandem Radical Reactions
• Addition of a radical to a neutral molecule followed by trapping of the
resultant radical
• Potential of forming two stereogenic centers
R-I
+
R1
R1 *
Z
+
+ I-Z
R *
Z•
R•
R1 •
R *
Z
R1 *
+ Z•
R *
Z = Sn(Bu)3, Si(Me)3, Si(Si(Me)3)3
• Downside is possibility of reactive byproduct formed
Enantioselective Tandem Addition
O
O
N
Ph
+
2
Ph
N
O +
SnBu3
Zn(OTf)2 , Ligand 2
O
O
O
O
R-I
N
R
N
O
+
Bu3Sn-I
CH2Cl2 , Et3B/O2 , -78 C
Entry
R (equiv.)
Acrylate:M:L*
Solvent
Yield (%)
ee (%)
1
c-hexyl (10)
1:1:1
CH2Cl2
62
50
2
c-hexyl (10)
1:1:1
Et2O
90
64
3
c-hexyl (10)
1:2:2
Et2O
61
80
4
c-hexyl (1.5)
1:1:1.2
CH2Cl2/pent 6:4
62
68
5
c-hexyl (1.5)
1:2:2.4
CH2Cl2/pent 6:4
92
72
6
t-Bu (5)
1:1:1.2
CH2Cl2/pent 6:4
78
88
7
t-Bu (5)
1:1:1.2
CH2Cl2/pent 6:4
92
90
8
t-Bu (5)
1:2:2.1
Et2O
55
88
Wu, J. H.; Radinov, R.; Porter, N. A., J. Am. Chem. Soc. 1995, 117, 11029-30.
Tandem Reaction vs. Fragmentation
LA*
O
O
N
1
O
Zn(OTf)2
LA*
O
O
N
R
•
Br
LA*
R 1-I
O
LA*
O
O
N
•
R
H
3
Bu3 Sn •
2
O
N
R
3a
3b
3c
3d
O
O
allyl
stannane
R
t-Bu
cyclohexyl
ethyl
methyl
O
*
ee of product
Entry
Precursor
LA eq.
3a
3b
3c
3d
1
1
0.6
84
76
62
56
2
1
1.0
90
78
69
61
3
1
2.0
90
80
75
67
4
2
0.6
64
43
36
25
5
2
1.0
74
58
50
42
6
2
2.0
76
64
53
46
Higher selectivity of tandem reaction pathway may be due to catalysis of
background reaction by tin bromide byproduct
Wu, J. H.; Zhang, G.; Porter, N. A., Tetrahedron Lett. 1997, 38, 2067-2070.
Lanthanide Lewis Acids
•
•
•
Lanthanide triflates are generally air and moisture stable
Strong Lewis acidity
Ionic radii of lanthanide metals increase in a small and regular manner:
easy to modify chiral environment
O
O
R-I
+
N
SnBu3
O +
Y(OTf)3 (30 mol%)
Chiral Ligand 1
O
O
R
N
O
CH2Cl2, Et 3B/O2, -78 °C
Ph
Entry
R
Yield (%)
ee (%)
1
ClCH2-
56
42
2
Et
61
70
3
n-Pr
57
60
4
n-Bu
41
38
5
i-Pr
50
56
6
t-Bu
40
24
7
c-Hex
53
31
Sibi, M. P.; Manyem, S.; Subramaniam, R. Tetrahedron 2003, 59, 10575
N
EtO
Ph
OH
O
1
Allylation of an α-Sulfonyl Radical
O
O
S
Ar
Zn(OTf)2 , 1
allyltin, t-BuI, Et3B/O 2
O
O
S
O
Ar
N
CH2Cl2, -78 °C
t-Bu
Ph
Ar = 2-(1-benzylbenzimidazolyl)
Entry
Allylstannane
Time
(min)
1
AllylBu3Sn
120
Yield
(%)
ee
(%)
35
80
2
AllylPh3Sn
180
49
16
3
Allyl2Bu2Sn
120
74
50
4
Allyl2Bu2Sn (5 eq.)
50
86
78
5
Allyl2Bu2Sn (10 eq.)
O
20
80
84
Br
Zn Br
O O
S
N
•
N
Bn
s-cis
0 kcal/mol
Watanabe, Y.; Mase, N.; Furue, R.; Toru, T. Tetrahedron Lett. 2001, 42, 2981
N
1
Ph
O O
• S
Br
Zn Br
N
N
Bn
s-trans
2.5 kcal/mol
Control of α and ß carbon selectivity
O
O
N
N
1
O
X
Lewis Acid, 1, R1X
Et 3B/O2, CH2Cl 2, -78 °C
O
N
R
O
X
O
R1
N
R
Yield (%)
dr
ee (%)
Sn(R2)3
R2 = Bu or Ph
X = O, R = Ph 2
X = O, R = CH3 3
X = CH2, R = CH3 4
R1X
Entry
Sub.
LA (0.3 eq.)
1
2
EtI
MgI2
79
32:1
77
2
2
c-HexI
MgI2
80
60:1
92
3
2
t-BuI
MgI2
84
99:1
97
4
2
t-BuI
Cu(OTf)2
90
99:1
-96
5
3
c-HexI
Mg(ClO4)2
83
4:1
62
6
4
EtI
Mg(ClO4)2
83
7:1
66
7
4
t-BuI
Mg(ClO4)2
85
19:1
92
8
4
t-BuI
Cu(OTf)2
66
50:1
-83
Sibi, M. P.; Chen, J., J. Am. Chem. Soc. 2001, 123, 9472-9473.
Control of α and ß carbon selectivity
O
O
N
N
1
O
X
Lewis Acid, 1, R1X
Et 3B/O2, CH2Cl 2, -78 °C
O
N
R
Sub.
X
O
R1
N
R
Yield (%)
dr
ee (%)
Sn(R2)3
R2 = Bu or Ph
X = O, R = Ph 2
X = O, R = CH3 3
X = CH2, R = CH3 4
Entry
O
R1X
LA (0.3 eq.)
1
2
EtI
MgI2
79
32:1
77
2
2
c-HexI
MgI2
80
60:1
92
3
2
t-BuI
MgI2
84
99:1
97
4
2
t-BuI
Cu(OTf)2
90
99:1
-96
5
3
c-HexI
Mg(ClO4)2
83
4:1
62
6
4
EtI
Mg(ClO4)2
83
7:1
66
7
4
t-BuI
Mg(ClO4)2
85
19:1
92
8
4
t-BuI
Cu(OTf)2
66
50:1
-83
Sibi, M. P.; Chen, J., J. Am. Chem. Soc. 2001, 123, 9472-9473.
Control of α and ß Carbon Selectivity
O
O
N
N
1
O
X
Lewis Acid, 1, R1X
Et3B/O2, CH2Cl 2, -78 °C
O
N
R
O
O
N
Ph
Br
Mg(ClO 4)2, AllylSnBu3
Et3B/O2
O
N
R1
R
R2 = Bu or Ph
O
O
CH2Cl2, -78 °C
Yield %, (dr)
Ligand 1
83 (12:1)
No ligand
87 (5:1)
Enantiomer of 1
87 (8:1)
•
X
Sn(R2)3
X = O, R = Ph 2
X = O, R = CH3 3
X = CH2, R = CH3 4
O
O
O
N
Ph
Mg(ClO4 )2 , AllylSnBu 3
Et3B/O2
CH2 Cl2 , -78 °C
Yield %, (dr)
82 (7:1)
84 (6:1)
84 (13:1)
O
O
O
N
Ph
Br
Ligand 1
No ligand
Enantiomer of 1
Following addition, trapping occurs in an anti manner
•
•
R1 blocks syn trapping
Results suggest the stereochemistry at the ß-carbon is primary determinant of
α-stereochemistry
Sibi, M. P.; Chen, J., J. Am. Chem. Soc. 2001, 123, 9472-9473.
Outline
•
•
•
•
•
Introduction to Radical Reactions
Atom Transfers
Reductive Alkylations
Fragmentations
Tandem Addition-Trapping Reactions
• Oxidations
• Summary
Enantioselective Radical Oxidations
• Examples shown to this point involved reductive generation of
radical species
• Oxidative generation of cationic radical species is also possible
– Can undergo coupling reactions
– Oxidation of activated C-H bonds
– Oxidation of alcohols and amines
Cross-Coupling Reactions
OTMS
R
O
VO(OEt)Cl2, 1
-e-TMS+
•
O
-e
-TMS+
Ph
R
∗
OTMS
-
OH
O
1
58% yield, 85% ee
Kurihara, M.; Hayashi, T.; Miyata, N., Chem. Lett. 2001, 1324-1325.
O
O
O
N
O
O
TiCl 4, 2, Et3 N
Ph
O
∗ Ph
N
Fe(Cp)2 BF4
∗
N
O
Ph
91%
O
O
dl : meso = 25:75
76% ee
Ph
HO
Ph
O
HO
O
Ph
2
Ph
Nguyen, P. Q.; Schaefer, H. J., Org. Lett. 2001, 3, 2993-2995.
Y
Y
OH
H
N
10 mol% CuCl/3
O2 , solvent,
OH
OH
NH
Y
Yield (%)
Y=H
89
Y = CO 2 Me 81
ee (%)
17
93
Li, X.; Yang, J.; Kozlowski, M. C., Org. Lett. 2001, 3, 1137-1140.
3
Activated C-H Bond Oxidation
•
•
Benzylic hydrogens are activated towards oxidation
Several groups have used porphyrin complexes to effect this transformation enantioselectively
1 (catalytic)
Cl2PyNO
X
X
OH
N O N
Ru
N O N
Yields: 28-72%
ee's: 62-76%
(Ketone accounts for remainder of yield)
X = H, Me, Cl, OMe
1
2 (2 mol%), PhIO
+
R
C6H5 Cl
OH
2a 25% yield, 90% ee
2b 17% yield, 81% ee
O
R
N
N
Mn+
O
O
Ar Ar
O
N
i-Pr
Ph
O
N
N
3
2 mol% CuOTf/3
t-BuOOH
MeCN, -18 °C
12 d
PF6-
i-Pr
Ph OOt-Bu
70% yield, 4% ee
2
2a Ar = 4-[t-Bu(C6H5) 2]SiC6H4
R = 3,5-(CH3)2C6H3
2b Ar = 4-[t-Bu(C6H5)2]SiC6 H4
R = (CH2) 4
Zhang, R.; Yu, W.-Y.; Lai, T.-S.; Che, C.-M., Chem. Commun. 1999, 1791-1792.
Hamada, T.; Irie, R.; Mihara, J.; Hamachi, K.; Katsuki, T., Tetrahedron 1998, 54, 10017-10028.
Hamachi, K.; Irie, R.; Katsuki, T., Tetrahedron Lett. 1996, 37, 4979-4982.
Insight into Mechanism
•
Known to proceed by radical mechanism
H H
O
Mn V
Path b:
SET
•
H
O
MnV
H OH
•
OH
Mn IV
Path a: H-atom
abstraction
H
H
O
MnIV
•+
Kinetic isotope effect result supports path a
H
H
D
D
kH
= 4.6
kD
Hamada, T.; Irie, R.; Mihara, J.; Hamachi, K.; Katsuki, T., Tetrahedron 1998, 54, 10017-10028
Oxidation of Alcohols: Kinetic
Resolution
1 (catalytic)
OH
R
Me
O
R
solvent
OH
Me
+
R
Me
Entry
R1
solvent
Conversion (%)
ee (%)
1
Ph-CH=CH-
C6H6
76
97
2
Ph-
C6H5Cl
65
95
3
Ph-C=C-
C6H5Cl
65
>99
4
PhCH2-
C6H5CH3
58
82
N NO N
Ru
O Cl O
PhPh
Masutani, K.; Uchida, T.; Irie, R.; Katsuki, T., Tetrahedron Lett. 2000, 41, 5119-5123.
1
Conclusion
• Much development concerning enantioselective radical reactions
has occurred over the last ten years
– Formation of C-H, C-X, and C-C bonds is possible
– Asymmetric catalysis is now possible in many systems
– Reactions proceed under mild conditions and are tolerant of functional
groups
• Many areas left to explore
– Enantioselective group transfer has not been developed
– Use of alternate reaction conditions (aqueous media, polymer support)
– Introduction of more functional groups
– Use in a total synthesis
Acknowledgements
Advisor:
Jeff Johnson
Johnson Group:
Cory Bausch
Ashley Berman
Roy Bowman
Jody Karol
Xin Linghu
Mary Robert Nahm
David Nicewicz
Patrick Pohlhaus
Application of Tandem Radical
Reaction
R4
O
O
O
N
R
R1 +
I
2
R
3
O
SnBu3
Ln(OTf)2 (0.3-1.0 eq.)
CH2Cl2/THF 2:1
Et3 B/O2, -78 °C
O
R2
O
R1
N
R4
R3
47-72%
1
O R
O
RCM
O
R2
N
R3
R4
•
•
Example is not enantioselective
Possibility for enantioselective reaction exists and is current focus
Sibi, M. P.; Aasmul, M.; Hasegawa, H.; Subramanian, T., Org. Lett. 2003, 5, 2883-2886.
Up to 88%