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Radicals in Asymmetric Synthesis : Formation of Tertiary and Quaternary Carbon Centers Using Acyclic Radicals
Christiane Grisé
University of Ottawa
November 3, 2005
2
Radical Chemistry
(CH2-CH2)n
Polyethylene
CH2-CHPh
Polystyrene
HBr +RO-OR Br
I+ CN
Bu3SnHAIBN
CN
IS STEREOSELECTIVITY POSSIBLE WITH ACYCLIC RADICALS???
a
bc
d+
d
ab c
d
ac b
+SnBu3H
3
Outline
1. Basic concepts of radical chemistry
2. Description of asymmetric methods
ASYMMETRIC SYNTHESIS USING ACYCLIC RADICAL
Substrate-controlled Chiral auxiliary Chiral reagent
4
Radical Chain Reaction Mechanism
2. Propagation
Br +Br
+ H-BrBr
+ Br
3. Termination2 Br Br Br
+Br
Br
Br Br
Br2
Br Br
a) b)
c)
1. Initiation
Ph
O
OO
O
Ph60-80 °C
Ph
O
O2
Ph H-Br Ph H + Br
+ 2 CO22 Ph
HBr +RO-OR Br
5
Initiation Dibenzoyl peroxide (60-80 °C) AIBN (azoisobutyronitrile)
Derivative of AIBN developed for reactions at room temperature
(V-70)
Et3B : Initiator at -78 °C
Inorganic compounds : ZnCl2, SmI2 and other transition metals (Mn, Ni, Cu, Fe)
NC NN CN
CN2 + N2
66-72 °C
R3B + O2 + RR2BOO
NN CN
CN OMeMeO
6
Propagation – Types of Reactions Abstraction
Addition
Fragmentation
Rearrangement
R1 + X-R2 R1-X + R2
R1 + Non-radical R2
R1 Non-radical + R2
R1 R2
+ Br-R Bu3SnBr + R
R + H-SnBu3 R-H + Bu3Sn
Bu3Sn
R + CN CNR
R + SnBu3 R + Bu3Sn
7
Radical Stability
Can predict radical stability by looking at the bond dissociation energy
Alkyl radical : tertiary>secondary>primary Conjugating groups also stabilize radicals
Both electron-withdrawing and electron-donating groups stabilize radicals
O
N OEt
X Y X + Y G
8
Explanation by Frontier Molecular Orbitals
Radicals have Singly Occupied Molecular Orbitals (SOMO) Most radicals are uncharged and are considered soft species
Oex.
SOMOradical(p orbital)
*
Stabilizationenergy
OEt
SOMOradical(p orbital)
n orbital
9
Reactivity and Frontier Molecular Orbitals
O
OEtex.
Low energySOMO
HighenergySOMO
HOMO
LUMO
HOMO
LUMO
strong
strong
Electrophilic radical Nucleophilic radical
10
Radical Addition to α,β-Unsaturated Compounds
HighenergySOMO
HOMO
LUMO
O
OMe
O
OMe
O
OMe
• Nucleophilic radical
• Orbital interactions are important
• Size of coefficient explains the regioselectivity
O
OMe
+ O
OMe
11
Stereoselectivity and Radicals
N
SO O
CO2MeO
SnBu3
AIBN, 80 °C
93 % N
SO O
CO2MeO
Br
Cyclic radicals : The anti Rule
Acyclic radicals : substrate controlled, chiral auxiliaries and chiral reagents
a
bc
d+
d
ab c
d
ac b
+SnBu3H
12
Substrate Control : Ester Substituted Radicals
R1
OR O
OMeH Br
SnBu3DOR O
OMeR2
SnBu3D
R1
OR O
OMeR3
OR O
OMeR2 D
R2= H or alkyl
A B C
D FE
H R1
OR
CO2MeR2RO H
R1
CO2MeR2R1 OR
H
CO2MeR2
H R1
OR
R2MeO2CRO H
R1
R2MeO2CR1 OR
H
R2MeO2C
13
Important Factors for Diastereoselective Reduction
Delocalization of the radical with the adjacent ester Minimization of 1,3-allylic strain Dipole-dipole repulsions are decreased Stabilization by hyperconjugation
PhCO2Me
OMe
Me Br
HSnBu3
Initiator PhCO2Me
OMe
MePh
CO2MeOMe
Me
HSnBu3
CO2EtMe CO2Et
H
Me
Ph
MeO H
Ph
MeO H
Transition state :
90 % yield32 : 1
Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W.W.; Delorme, D.; Renaud, J.; Robinson, G.; Lavallée, J.-F.; Slassi, A.; Rancourt, J.; Durkin, K.; Liotta, D. J. Org. Chem. 1994, 59, 1166. Guindon, Y.; Slassi, A.; Rancourt, J.; Bantle, G.; Bencheqroun, M.; Murtagh, L.; Ghiro, E.; Jung, G. J. Org. Chem. 1995, 50, 288.
14
Effect of Substituents on Diastereoselectivity
RO
R1Me X
CO2MeSnBu3H
OCO2Me
Me Me
O O
Ph H
CO2tBu
Me
OMeMeO CO2Me
Me
OO
Me
CO2tBu
Me
RO
R1CO2Me
MeX= Br, I or SePh
TolueneBEt3-78°C
52:1 2:1 43:1 >100:1
Guindon, Y.; Faucher, A-M.; Bourque, E.; Caron, V.; Jung, G.; Landry, S. J. Org. Chem. 1997, 62, 9276.
15
The Exocyclic Effect
RO
R1CO2MeMe
Definition1 : Increased diastereoselectivity demonstrated by the reactions of a radical adjacent or exo to a ring formed by tethering the β-heteroatom to the R1 substituent in the
radical shown :
1 Guindon, Y.; Faucher, A-M.; Bourque, E.; Caron, V.; Jung, G.; Landry, S. J. Org. Chem. 1997, 62, 9276.
H
MeO
MeH
HCO2MeMe
HSnBu3
H
MeO
MeH
HCO2MeMe
HSnBu3
O
MeH
HCO2MeMe
HSnBu3
O
MeH
H
CO2MeMe
HSnBu3
ANTI
SYN
16
Lewis Acid Can Reverse Diastereoselectivity
O MOMe
OR1
R2
HSnBu3
R1H
OR2
Me
OMeO
M
R2
HMeOCO2MeR1
HSnBu3
HSnBu3 H
R1 CO2MeR2
HMeO
Acyclic control :
Lewis acid :
Lewis acid : MgI2, MgBr2-OEt2, AlCl3
R2 CO2MeOMe
R1
Anti
R2 CO2MeOMe
R1
Syn
H
R2
OMe
CO2Me
H
R1
Endocyclic effect
Guindon, Y.; Lavallée, J.-F.; Llinas-Brunet, M.; Horner, G.; Rancourt, J.
J. Am. Chem. Soc. 1991, 113, 9701.
17
Exocyclic vs Endocyclic Effect
O
MeH
HCO2
tBuMeM
NEt
CO2tBu
ON
Me
Et M
Me
CO2tBu
OH
SePhMe
NH
Me
Et
CO2tBu
OHNH
Me
Et
Me
AdditiveExocyclic
SnBu3H
MO
OMe
OtBu
HN
Et MeH
ONH
Me
EtO
OtBu
M
Me
CO2tBu
OHNH
Me
Et
Me
Lewis acid Endocyclic
SnBu3H
Reagent Anti:Syn
Me2SiCl2 100:1
Ph2SiCl2 85:1
Me2BBr 22:1
Bu2BOTf 32:1
MgBr2-OEt2 1:3
18
Synthesis of Proprionate Motif Using Radicals
OR
Me
OH
Me
O
OMe
OR
Me
OH
Me
O
OMe
OR
Me
OH
Me
O
OMe
OR
Me
OH
Me
O
OMe
2
3
4n n
n n
Diastereoselective Mukaiyama and Free-Radical Hydrogen Transfer
OR O
HMe
nMe
X
OSiMe3
OMe
OR
Me
OH
Me
O
OMen
X = SePh or Br
* **
*
1) Guindon, Y.; Houde, K.; Prévost, M.; Cardinal-David, B.; Landry, S.R.; Daoust, B.; Bencheqroun, M.; Guérin, B. J. Am. Chem. Soc. 2001, 123, 8496.2) Guindon, Y.; Prévost, M.; Mochirian, P.; Guérin, B. Org. Lett. 2002, 4, 1019.
19
Mukaiyama Reaction
R
O
H R3R2
R1 OSiMe3
R
OH O
R3
R1 R2+
Lewisacid
O
HMe
OP
R3R2
R1 OSiMe3
+
Bidentate L.A.
Monodentate L.A.
Me H
OPO
H Enol
L.A.OH O
R3
R1R2
OP
Me
Me
H
O
HEnol
L.A.
OP
OH O
R3
R1R2
OP
Me
Cram chelate
Felkin-Ahn
20
Tandem Mukaiyama/Hydrogen Transfer :Endocyclic Effect
O
HMe
OP
OMeX
Me OSiMe3
+
OH O
OMeMe
X
BnO
Me
OH O
OMeMe
X
TBDPSO
Me
MgBr2-OEt2
Me2AlCl
Bu3SnHEt3B
Bu3SnHEt3B
OH O
OMeMe
OBn
Me
OH O
OMeMe
TBDPSO
MeX = Br, SePh
70%Ratio 30:1
66%Ratio 11:1
2
3
4
1
2
Endocyclic effect :
O O
OMeMe
X
BnO
Me
L.A.O O
OMeMe
X
BnO
Me
L.A.
Bu3SnH H
BnO
OMe
OMe
OL.A.
Me
HSnBu3
21
Tandem Mukaiyama/Hydrogen Transfer :Exocyclic Effect
O
HMe
OP
OMePhSe
Me OSiMe3
+
OH O
OMeMe
X
BnO
Me
OH O
OMeMe
X
TBDPSO
Me
BF3-OEt2
Bu3SnHEt3B
Bu3SnHEt3BCH3COOH
OH O
OMeMe
OBn
Me
OH O
OMeMe
TBDPSO
Me
81 %Ratio 20:1
64 %Ratio 11:1
Et2BOTf2
3
4
3
4
O
Exocyclic effect :
Bu3SnH
Me CO2Me
HSnBu3O
CO2Me
MeX
TBDPSO
Me
BF3-OEt2 Et3BCH3COOH O
CO2Me
MeX
PO
Me
BEtH
PO
EtB
MeH
22
Advantages to the Mukaiyama/Hydrogen Transfer Reaction
E/Z stereochemistry of the enoxysilane is unimportant With appropriate Lewis acid selection, all 4 proprionate
units are accessible Conditions were found for one-pot procedure Iterative process was demonstrated with the synthesis of
the polyproprionate motif :
1) Mochirian, P.; Cardinal-David, B.; Guérin, B.; Prévost, M.; Guindon, Y. Tet. Lett. 2002, 43, 7067.
2) Guindon, Y.; Brazeau, J-F.; Org. Lett. 2004, 4, 2599.
OBnOBnO
HMeMe
TiCl4 OBnOBnOH
MeMeBr OMe
OSiMe3
Me
O
OMeBr
Et2BOTfSnBu3H
OBnOBnOH
MeMe
O
OMeMe
77 %, 100:1 83 %, 20:1
23
Application to the Synthesis of Zincophorin
OHO2C
HMe
HMe
MeOH OH
Me Me
OH
Me
MeMeMe
OH
Zincophorin
1) Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S.R.; Jung, G.; Bencheqroun, M.; Faucher, A.-M.; Guérin, B. J. Org. Chem. 2001, 66, 5427.2) Guindon, Y.; Mochirian, P. Unpublished results.
OH
Me
Me
Me Me
OP OP OP
CHOMeO2C
HMe
BtO2SMe
OP
Me Me
Me
+
Me Me Me
OBnOBnOBnMeO2C
Bt = benzothiazole
24
Can this Methodology be Applied to Other Free Radical Reactions?
PhCO2Me
OMe
Me I
MgBr2-OEt2
allylBu3Sn Et3B Ph
CO2MeOMe
MeO H
PhMe
Me
MeOO
Mg
Bu3Sn
ENDOCYCLIC :
PhCO2Me
OMe
Me IallylBu3Sn Et3B
R1 = H, Me
Ph
H OMeMeMeO2C
Bu3Sn
ACYCLIC STEREOCONTROL :
PhCO2Me
OMe
Me
76 %>100:1
75 %1:16
25
Synthesis of Tertiary and Quaternary Centers
O
HMe
OP
OMeX
R OSiMe3
+
Bidentate L.A.
OH O
OMeR X
OP
Me
R = H or MeX = Br or SePh
SnBu3
Endocyclic
Exocyclic
OH O
OMeR
OP
Me
OH O
OMeR
OP
Me
5
6
Monodentate L.A. OH O
OMeR X
OP
MeR = H or MeX = Br or SePh Exocyclic
Endocyclic
SnBu3
OH O
OMeR
OP
Me
OH O
OMeR
OP
Me
7
8
OMeX
R OSiMe3O
HMe
OP O
HMe
OP
Cardinal-David, B.; Guérin, B.; Guindon, Y. J. Org. Chem. 2005, 70, 776.
26
Tandem Mukaiyama and Allylation Reactions (Endocyclic Effect)
O
HMe
BnO
OMePhSe
R OSiR'+
HO O
OMeR
BnO
Me
11, R=H, R'=Et312, R=Me, R'=Me3
1. MgBr2-OEt22. CH3COOH Me2AlCl3. AllylSnBu3Et3B, O2, CH2Cl2 13, R=H 85 % (>20:1)
14, R=Me 52 % (>20:1)
O
HMe
TBDPSO
OMePhSe
R OSiR'+
11, R=H, R'=Et312, R=Me, R'=Me3
1. Me2AlCl2. AllylSnBu3Et3B, O2, CH2Cl2
15, R=H 40 % (10:1)16, R=Me 55 % (14:1)
OH O
OMeR
TBDPSO
Me
1. Cram chelate
2. Felkin-Ahn
27
Future Work : 2,3-syn Products
O
HMe
OP
Bidentate L.A.
OH O
OMeR X
OP
Me
R = H or MeX = Br or SePh
SnBu3
Endocyclic
Exocyclic
OH O
OMeR
OP
Me
OH O
OMeR
OP
Me
OMeX
R OSiMe3
Monodentate L.A. OH O
OMeR X
OP
MeExocyclic
Endocyclic
SnBu3
OH O
OMeR
OP
Me
OH O
OMeR
OP
Me
+
5
6
7
8
28
Summary – Substrate Control
Important factors for stereoselective radical reactions: allylic strain, dipole-dipole interactions, hyperconjugation, exocyclic effect and endocyclic effect
Combination of stereoselective Mukaiyama and radical reduction or allylation produced a powerful method to generate polyproprionates, tertiary and quaternary centers
SnBu3HO O
Ph H
CO2tBu
MeX= Br, I or SePh
TolueneBEt3-78°C 43:1
O O
Ph H
CO2tBu
MeX
PhCO2Me
OMe
Bri-Pr
MgBr2-OEt2Bu3SnHEt3BCH2Cl2
PhCO2Me
OMe
i-Pr84:171 % yield
OR O
HMe
nMe
X
OSiMe3
OMe
OR
Me
OH
Me
O
OMen
X = SePh or Br
* **
*
OR O
HMe
nR
X
OSiMe3
OMe
OR
Me
OH
R
O
OMen
X = SePh or BrR = Me or H
* ** *
29
Chiral Auxiliaries
O
N
O
N
N
ON
Ot-BuHgBrNaBH4
O
N
O
N
t-Bu H
[98.8 : 1.2]
2,5-dimethylpyrrolidine : Porter and Giese (1991)
O
N
MeO2C
MeO2C
ON
O
NO
O
N O
MeO2C
MeO2C
R
Other auxiliaries :
40-70 %
30
Oxazolidinone Chiral Auxiliary
Yamamoto and co-workers (1994)
Sibi and co-workers (1995)
O N
OO
Ph
Ph
R i-PrI, Bu3SnHLewis acidEt3B/O2, -78°C
O N
OO
Ph
Ph
R
Lewis acid Yield Ratio
ZnCl2 70 9:1
MgBr2 90 20:1
Yb(OTf)3 89 45:1
O N NH
OO SnBu3
ZnCl2-OEt2 O N NH
OO85 %[87:13]
CO2Me
Br
CO2Me
31
Selectivity with N-Enoyloxazolidinone
O N
OO
Ph
Ph
R
O N
OO
Ph
Ph
R
O N
OO
PhPh
O N O
O
Ph
Ph
R
A B C
Lewis acid
O N
OO
Ph
Ph
R
LA
NO
O
OLA
H
H
RTop face addition
i-PrISnBu3H
R O N O
O
Ph
Ph
R
D
32
Application to the Synthesis of (-)-Enterolactone
O N
O
CO2Et
O
PhPh
Sm(OTf)3
BrMeO
CH2Cl2/THFBu3SnH, Et3B/O2-78 C°
O N
O
CO2Et
O
PhPh
OMe
71 %
1. NaHMDS, THF3-OMeC6H4-CH2I, 50 %2. LiOH/H2O2, 88 % HO
O
CO2Me
OMe
OMe
1. BH3/THF2. PPTS78 % (2 steps)3. BBr388 %
O
O
OH
OH
(-)-EnterolactoneNO
O
O
H
CO2MeR
Na
IR
R= CH2-(3-OMe)C6H4Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-x. J. Org. Chem. 2002, 67, 1738.
33
Camphorsultam Auxiliary and Radical-Ionic Reactions
SO2
N
ONOBn
i-PrIPhCHOMe3Al, Et3BCH2Cl2, reflux
OO
i-Pr
Ph
NOBn
O
BnHNNHOBn
Ph OH
Et
OO
Et
Ph
NOBn
1. BnNH2, 2-pyridinol2. NaBH3CN, HCl
61 %, 2:1
Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem. Int. Ed. 2005, 44, 2.
γ amino acid
34
Mechanism
SN
ONOBn
O
O
BEt
Et Et
NBEt2O
PhH
AlMe3OBnH
H
i-Pr
O
X
Et
i-PrI
+ EtI
SO2
N
ONOBn
PhCHO
O Ph
Et2B
H
SO2
N
ONOBnBEt2
OO
i-Pr
Ph
NOBn
35
Summary : Chiral Auxiliaries
Chiral oxazolidinone are very useful for diastereoselective conjugate addition
Camphorsultam auxiliary used for radical addition/aldol type reaction
Importance of the Lewis acid
O N
OO
Ph
Ph
R O N
OO
Ph
Ph
RLewis acid
NO
O
OLA
H
H
R
i-PrISnBu3H
36
Enantioselective Free Radical Reactions
Wu, J.H.; Radinov, R.; Porter, N.A. J. Am. Chem. Soc. 1995, 117, 11029.
R-I +O
N O
O+
SnBu3 Zn(OTf)2
Et3B-78 °C
ON N
O
Ph Ph
R N
92 %ee : 90 %
O
O O
Porter and co-workers (1995)
37
Mechanism-Propagation
R O
N O
O
L2Zn
SnBu3
R NO
O O+ SnBu3
RX
R + XSnBu3
O
N O
O
ON N
O
Ph PhZn
R
38
Enantioselective Conjugate Addition
O
N O
O MgI2
-78 °C
ON N
O
iBu iBu88 %ee : 82 %
Ph+ i-PrI Bu3SnH
O
N O
O
Ph
Ligand 11
Sibi and Porter (1996)
Sibi, M.P.; Ji, J.; Wu, J.H.; Gürtler, S.; Porter, N.A. J. Am. Chem. Soc. 1996, 118, 9200.
O
N O
OMgI2
-78 °C
Ph+ i-PrI
Bu3SnH
O
N O
O
PhEt3B/O2
Ligand 294 %ee : 97 %
ON N
O
2
Sibi, M.P.; Ji, J. J. Org. Chem. 1997, 62, 3800.
Sibi (1997)
39
Application : Synthesis of (+)-Ricciocarpin A
O
NO
O
OBn
BrCl
MgI2, Bu3SnHEt3B/O2
O
NO
O
OBn
Cl
84 %, (97 % ee)O
N N
O
1. Sm(OTf)3 CH3OH (95%)2. NaI, acetone (98 %)
O
MeO OBn
I LHMDS-78 to RT(97 %)
OMe
H
HO
OBn
1. Pd(OH)2/H2, Hex/EtOAc2. TEMPO, KBr, NaOCl, std. NaHCO3 (76 % over two steps)
OMe
H
HO
OH
O
H
HO
O
O
Ti(OiPr)3
85 %[5.7:1]
Sibi, M.P.; He, L. Org. Lett. 2004, 6, 1749.
O
H
HO
O
40
Scope of the Conjugate Addition
ON N
O
O
NO
O cat. MgI2
-78 °C
Ph + i-PrIAllylSnBu3
O
NO
O
PhEt3B/O2
93 %dr : [37:1]ee : 93 % 1
Ligand 1
ON N
OO
NO
O MgI2
-78 °C
OCOPh+ i-PrI O
NO
O
OEt3B/O2
90 %ee : 93 % 2
Ligand 2
Bu3SnH
Ph
O
Sibi, M.P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472.Sibi, M.P.; Zimmerman, J.; Rheault, T. Angew, Chem. Int. Ed. 2003, 42, 4521.
41
Limitation of the Oxazolidinone Template
ON N
O
O
NO
O cat. MgI2
-78 °C
Ph + i-PrIAllylSnBu3
O
NO
O
PhEt3B/O2
93 %dr : [37:1]ee : 93 % 1
Ligand 1
No substituent
O N
OO
R2 O N
OO
A B
R1
R1
R2
LA LA
42
New Imide Template for Conjugate Addition
O
NH
Ocat. MgI2
-78 °C
Me Bu3SnH
O
NH
O
Et3B/O2
Ligand 1
+ i-PrI
Me
Me
Me
ON N
O
79 %dr : [99:1]ee : 92 % 1
X MgN
OO
X
N
O
NHMe
Me
OO
NH
O Me
Me
HMeMe
O
NO
Mg2+
HHSnBu3
Mg2+
Sibi, M.P.; Petrovic, G.; Zimmerman, J. J. Am. Chem. Soc. 2005, 127, 2390.
79 %dr : [99:1]ee : 92 %
43
Acyclic Radicals and Asymmetric Synthesis
Substrate control
Chiral auxiliary
Chiral lewis acids
O O
Ph H
CO2tBu
Me
PhCO2Me
OMe
i-Pr
OR
Me
OH
Me
O
OMen*
* *
OR
Me
OH
R
O
OMen*
* *
R= H or Me
O N
OO
Ph
Ph
R
OO
iPr
Ph
NOBn
O
NO
O
Ph
O
NO
O
O
Ph
O
O
NH
O Me
Me
O
NO
O
Ph
44
Acknowledgements Prof. Louis Barriault Nathalie Goulet Guillaume Tessier Steve Arns Effie Sauer Maxime Riou Rachel Beingessner Roch Lavigne Patrick Ang Louis Morency Mélina Girardin Maude Boulanger Jeff Warrington Lise-Anne Prescott Josée-Lyne Ethier Tushar Tangri
Dr. Irina Denissova and Philippe MochirianFrom Professor Yvan Guindon’s group
45
46
Ester substituted radicals and allylic strain
H
X R1
CO2Et
R2X
R2
HCO2EtR1
O
OEtR1
R2
X
Minimize allylic strain
Side of attack
depends on
R1, R2 and XH
MeH H
HMe
MeMe
H H
HMe
Me
Allylic strain : Control of a conformation by a cis substituent
In alkenes :
Eclipsed form is lowest in energy
Giese, B.; Bulliard, M.; Zeitz, H.-G. Synlett 1991, 425.
47
Dipole-dipole interactions are also important
PhBr
CO2EtX
Bu3SnPh
CO2EtX
Bu3SnHPh
CO2EtX
H
HSnBu3
CO2EtMe
PhCO2Et
X
H
Me CO2Et
HSnBu3
CO2Et
Me CO2Et
H
PhCO2Et
X
Me
anti syn
Ph
X H Ph
XH
Ph
X HPh
XH
A B
X
F
MeOMe
anti:syn66 : 3497 : 395 : 5
48
Hyperconjugation and selectivity
OYX
Me I
CO2Me
R
SnBu3H
OHN
CO2Me
Me Me
O
OO
CO2Me
Me Me
O
OYX CO2Me
R Me
OCO2Me
Me Me9:1 2:1 52:1
ANTI SYN
N
O
O
HMe
H
H
CO2MeMe
N
O
O
H MeH
HCO2MeMe
49
Diastereoselective Radical Addition/Allylation
RX Lewis acid Yield Ratio
MeI MgBr2 82 >100:1
i-PrI MgBr2 85 >100:1
C6H11I MgBr2 93 >100:1
MeOCH2Br Yb(OTf)3 70 58:1
PhCOBr MgBr2 90 50:1
O N
OO
Ph
Ph
O N
OO
PhPh
R
MgBr2 or Yb(OTf)3RX, AllylSnBu3CH2Cl2, Et3B/O2-78 °C
Sibi, M.P.; Ji, J. J. Org. Chem. 1996, 61, 6090.
50
Mechanism
NO
O
OLA
H
HR
Syn
SnBu3
O N
OO
Ph
Ph
Et3B + O2 Et
Et + RX R + EtX
RO N
OO
Ph
Ph
R
SnBu3
O N
OO
PhPh
R + SnBu3
RX
1)
2)
3) R2x R-R
51
Sequential Mukaiyama and Allylation Reactions – Endocyclic Effect
Low yield for allylation with MgBr2-OEt2 (62 %) compared to Me2AlCl (90 %) or AlMe3 (80 %)
Formation of both tertiary and quarternary carbon centers
O
HMe
OP
OMeX
R OSiMe3+
OH O
OMeR
X
BnO
Me
OH O
OMeR
X
TBDPSO
Me
MgBr2-OEt2or TiCl4
Me2AlCl or
AllylSnBu3Et3B
Bu3SnHEt3B
OH O
OMeR
OBn
Me
OH O
OMeR
TBDPSO
MeX = Br, SePhR= H or Me
MgBr2-OEt2,Me2AlCl orAlMe3
BF3-OEt2
Me2AlCl
9
10
73-97 %>20:1
62-90 %>20:1
76-97 %11:1
85 %>20:1
52
Ligand Modification and Enantioselectivity
ON
R2 R3
N
OR1
R1O
N
R2 R3
N
O ON N
O
1
O
N O
OMgI2
-78 °C
Ph+ iPrI
Bu3SnH
O
N O
O
Ph
iPr
Et3B/O2
Ligand 194 %ee : 97 %
Sibi, M.P.; Ji, J. J. Org. Chem. 1997, 62, 3800.
53
Ligand and enantioselectivity
ON
R2 R3
N
OR1 R1
ON
R2 R3
N
O
A B
Iodine TransFlexible PhenylGives S product
Iodine CisRigid ligandGives R product
O
NO
O
Ph
O
N O
O
Ph
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