memory of chirality in cascade rearrangements of enediynes ...€¦ · 10/11/2011 · bertrand, m....
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Memory of Chirality in Cascade Rearrangements of EnediynesNechab, M.; Campolo, D.; Maury, J.; Perfetti, P.; Vanthuyne, N.; Siri, D.;
Bertrand, M. JACS, 2010, ASAP.
A Flexible, Stereoselective Dimethylzinc-Mediated Radical-Anionic Cascade: Dramatic Influence of Additional Lewis Acids
Maury, J.; Feray, L.; Perfetti, P.; Bertrand, M. Org. Lett., 2010, 12, 3590-3593.
Roxanne AtienzaShort Literature Presentation
October 25, 2010
Michèle Bertrand
(Teacher-Researchers)
Memory of Chirality (MOC)
“an asymmetric transformation in which the chirality of the starting material is preserved in the conformationally labile intermediate during the transformation”
as defined by Fuji and Kawabata
Fuji, K. and Kawabata, T. Chem. Eur. J., 1998, 4, 373-376.Seebach, D.; Sting, A. R.; Hoffmann, M. 1996, 35, 2708-2748
To produce a nonracemic product, a chiral environment is required: -chiral electrophiles-chiral ligands-chiral auxiliaries-chiral solvents
Or is it? Consider information concerning the chirality of organic molecules to be not simply about the three-dimensional structures but to include the fourth dimension of a timescale.
Saito-Myers and Bergman Cyclizations
H
H
H H
H
H H
C R
R R
H
Saito-Myers:Bergman:
Initial Reaction
Ts
XEtO2C XEtO2C
C Ts
Ts
XH
CO2Et
Ts
X
CO2Et
H
H
X
Ts
CO2Et
Al2O3
MeCN65 °C
A B C
step aenynealleneformation
step bSaito-Myerscyclization
step c1,5hydrogen shift
step drecombination
82%
“Investigation of the MOC in the reaction was by far the most exciting purpose”
Access to dihydrobenzoisochromenesandtetrahydrobenzoisoquinolines
Ts
NEtO2C NEtO2C
C Ts
Ts
NEtO2C
Me
Ts
N
Me
Me Me
EtO2C
Ts Ts
Ts Ts
Conformation of “Native” Biradical
Ts
NTs
CO2Me
Me
vs
step a step b step c
Ts
NMeO2C NMeO2C
C Ts
Ts
NMeO2C
Me
Ts
N
Me
Me Me
MeO2C
Ts Ts
Ts Ts
Investigation of MOC
H
N
Ts
CO2MeMe
Ts
H
N
Ts
Ts
CO2Me
+
Al2O3
benzene80 °C6.5 h
(S)- 97.5% ee
20% (3S, 4S) - 29% (81.5% ee)(3S, 4R) - 34% (78.5% ee)
dismutation side product
Dismutation Process Mitigated
Ts
N
H
N
Ts
O
Ph O
O
Ph
OH
N
Ts
O
Ph
O
+Base
Benzene80 °C24 h
(S)- >99% ee
(11R, 11aS)-cis (11S, 11aS)-trans
1111a
1111a
50% (93.5% ee) 29% (80% ee)
75% (86% ee)
Al2O3
K2CO3
(11R, 11aS)-cis
Biradical Intermediate
Ts
N
O
OPh
Ts
N
N
Ts
MeO2C O
O
CO2Me
O
N
Ts
O
CO2Me
O
+
Retention
Al2O3
Benzene80 °C3 h
(S)- 97% ee
cis trans
30% (94.5% ee) 45% (87% ee)
Biradical Intermediate
Ts
NOMeO2C
Ts
N
N
Ts
MeO2C O
O
CO2Me
O
N
Ts
O
CO2Me
O
+Al2O3
Benzene80 °C3 h
(S)- 97% ee
cis trans
30% (94.5% ee) 45% (87% ee)
To produce a nonracemic product, a chiral environment is required: -chiral electrophiles-chiral ligands-chiral auxiliaries-chiral solvents
Or is it? Consider information concerning the chirality of organic molecules to be not simply about the three-dimensional structures but to include the fourth dimension of a timescale.
Memory of Chirality - not such a fanciful ideaif the timescale dimension is considered
Memory of Chirality in Cascade Rearrangements of EnediynesNechab, M.; Campolo, D.; Maury, J.; Perfetti, P.; Vanthuyne, N.; Siri, D.;
Bertrand, M. JACS, 2010, ASAP.
A Flexible, Stereoselective Dimethylzinc-Mediated Radical-Anionic Cascade: Dramatic Influence of Additional Lewis Acids
Nechab, M.; Campolo, D.; Maury, J.; Perfetti, P.; Vanthuyne, N.; Siri, D.; Bertrand, M. Org. Lett., 2010, 12, 3590-3593.
Roxanne AtienzaShort Literature Presentation
October 25, 2010
Dialkylzincs
Dialkylzincs can generate nucleophilic species from an initial radical elementary step
Potential to perform tandem radical-anionic reactions
O2
ZnR2 R
Diethylzinc vs Dimethylzinc
-oxidation fast-competitive addition
of ethyl radical
-oxidation slow-methyl radical
less reactive
Initial Reaction
EtO2C
CO2Et O
ROI+
O
O
CO2Et
R
O
98%
1) ZnMe2 (3 eqv.)CH2Cl2,
air, 23 °C, 18h
2) NH4Cl
O
O
CO2EtO
O
O
CO2EtO
O
O
CO2EtO
F
63%
72%
O
O
CO2EtO
OMe
O
O
CO2EtO
Me
42%
36%
5 equiv.
Proposed Reaction Mechanism
EtO2C
CO2EtO
ROI
O
O
CO2Et
O
R
O
RO
EtO
O
O
EtO
O
Zn Me
EtO
O
O
EtO
O
R
O
ZnMe
Me
RO
H
EtO
O
O
O
OEt
R
O
ZnMe
O
O
EtO
Zn Me
O
R
OEt
O
O
R
OEt
OO
OOEt
ZnMe
MeZnMe2
O2
MeI
1 2
3
4 5
iodine atomtransfer
addition todouble bond
homolytic substitution
intramolecular acyl transfer
intramolecular nucleophilicsubstituion
Mechanism Support
EtO
O
O
EtO
Zn Me
OMeO
EtO
O
O
EtO
O
Zn Me
RO
1) ZnMe2 (3 eqv.)CH2Cl2,
air, 23 °C, 18h
2) NH4Cl
compare toproposed mechanism
EtO2C
CO2Et O
OMeI+
O
CO2Et
CO2Et
5 equiv.
45%
O
O
OEt
n-Bu
O
ZnMe
EtO
O
O
EtO
O
Zn Me
n-BuO
O
O
n-Bu
Zn Me
O
EtO
OEt
O
H
EtO2C
EtO2C
CO2Et O
n-BuOI+ O
EtO2C
EtO2C
n-BuOH
Lewis Acid Modification BF3•OEt2
1) ZnMe2 (3 eqv.)BF3•OEt2 (1.2 eqv.) CH2Cl2, 23 °C, 18h
2) NH4Cl
85%
BF3 inhibits the chelation of the carbonyl
nucleophilic attack of ketoneinstead of ester
Lewis Acid Modification BF3•OEt2
1) ZnMe2 (3 eqv.)BF3•OEt2 (1.2 eqv.) CH2Cl2, 23 °C, 18h
2) silica / oxalic acid
68%
EtO2C
CO2Et O
PhOI+ O
Ph
EtO2C
EtO2C
O
O
OEt
Ph
O
ZnMe
EtO
O
O
EtO
O
Zn Me
PhO
O
O
Ph
Zn Me
O
EtO
OEt
O
H
EtO2C
Formation of lactol, followed by elimination results in dihydrofuran
product
Lewis Acid Modification Yb(OTf)3
EtO2C
CO2Et O
n-BuOI+
CO2Et
CO2Et
O
n-Bu
O1) ZnMe2 (3 eqv.)Yb(OTf)3 (1.2 eqv.) CH2Cl2, 23 °C, 18h
2) NH4Cl
O
O
OEt
Ph
O
ZnMe
EtO
O
O
EtO
O
Zn Me
H
EtO2C O
n-Bu
Ytterbium triflate suppresses acyl group transfer
72%
4 Different Products Accessible