Lecture2: 123.702
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©fensterbme@flickr LECTURE TWO substrate control gareth j rowlands
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More substrate control, including allylic strain and directed reactions.
Transcript of Lecture2: 123.702
©fensterbme@flickr
LECTURE TWO
substrate control
gareth j rowlands
control
Me SiMe2Ph
Me
Me SiMe2Ph
MeO
Me SiMe2Ph
MeO
m-CPBA
>95% <5%
Me m-CPBA
61% 39%
MeO
MeOMe Me Me
SiMe2Ph SiMe2Ph SiMe2Ph
acyclicsubstrate
epoxidation
©e-magic@flickr stereocentrechange in
no
MeH H
HMe
MeMeH H
MeMe
H
strain(A1,3)allylic
Me
MeMeH
disfavoured
strain(A1,3)allylic
H HMe
HH
Me
MeMe
H Me
HMe
Me
MeMeH
disfavoured
strain(A1,3)allylic
little difference
HH H
HMe
MeHH H
MeMe
H
Me
MeH
H HH
HH
Me
MeH
H Me
HMe
strain(A1,3)allylic
little difference
Me
MeH
MeH H
HSi
Me
MeMe
Ph
"O "
MeH H
HSi
Me
MeMe
PhO
controlacyclicsubstrate
Me SiMe2Ph
Me
Me SiMe2Ph
MeO
m-CPBA
>95%
X
controlacyclicsubstrate
HHMe
HH
Si
Me
MeMe
Ph
"O "
MeH
HSi
Me
MeMe
PhO
Me SiMe2Ph
Me
Me SiMe2Ph
MeO
m-CPBA
>95%
X
MeH H
HSi
Me
MeMe
Ph
"O "
MeH H
HSi
Me
MeMe
Ph
O
controlacyclicsubstrate
Me SiMe2Ph
Me
Me SiMe2Ph
MeO
m-CPBA
>95%
acyclicsubstrate
Me m-CPBA
61% 39%
MeO
MeOMe Me Me
SiMe2Ph SiMe2Ph SiMe2Ph
control
Me
H SiMe2Ph
Me
HMe H
HSi
Me
MePh Me
m-CPBA attacks least hindered
face
HMe H
MeH
SiPh
MeMe
HMe H
HSi
Me
MePh Me
O
HMe H
MeH
SiPh
MeMe
O
controlacyclic substrate
R
R1
HS
L
preferred approach
L R1
RS H
R
R1
SL
HR
R1
LH
S
destabilised by repulsion between C-1 & C-3 substituents
known as A(1,3) strainfavoured
1 13 3
Bu OEt
Me O
i. LDAii. MeI
Bu OEt
Me O
Bu OEt
Me O
Me
Me
83%
27%
other examples of substratecontrol
strain(A1,3)allylic
HOOEtH
HMe
Bu Li
MeI
OOEt
HMe
Bu
Me
conformationfavoured
Bu OEt
Me O
i. LDAii. MeI Bu OEt
Me O
Me
L OEt
OS H LDA
L OLi
OEtS H
L OEt
OLiS H
OEt
OLi
HS
L
preferred approach
OLi
OEt
HS
L
preferred approach
≡ ≡
EL OEt
OS H
E H
strain(A1,3)allylic
other examples of substratecontrol
H2B
Me
OBn
H Me
O
H CH2OBnMeH
Me
O
H2B H
BH3
H CH2OBnMeH
Me
O
H
OBn
H Me
O
H Me
H2B
H2O2NaOH
OBn
H Me
O
H Me
OH74% de
strain(A1,3)allylic
HMe
HMe
O
OBn
H2B H
Me
H
HMe
BnO
BH2H O
strain(A1,3)allylic
favoured
©AJC1@flickr
OO
O
OO
OHOH
H
H
HEt
H
HO
H
O
O OH
monensinJ. Am. Chem. Soc, 1979, 101, 260&262
control
Me
OBn
H Me
O
i. BH3ii. H2O2NaOH
74% deOBn
H Me
O
H Me
OH
H Me
O
H Me
OMeMe
OHi. BH3ii. H2O2NaOH
85% de
H Me
O
H Me
OMe
OH
OH
MeH
acyclicsubstrate
O
OO
OO
HO
OH
HHH
Et
HHO
H
O O
OH
directedreactions
epoxidation
OAcmCPBA
OAc
OAc
O
O
63%
37%
normal
reason...
OAc
H
"O "
epoxidationdirected
OHmCPBA
OH
OH
O
O
8%
92%
reason...
H
OO
HO
OH
Ar
epoxidationacyclic
directed
Me Me
Me OHHm-CPBA
Me Me
Me OHH
O
Me Me
Me OHH
O
95
5
(A1,3)allylic
epoxidation
acyclicdirected
Me Me
Me OHHm-CPBA Me Me
Me OHH
O
MeMe H
HO
Me
HOO
OH
Ar
MeMe H
H
OH
Me
O
strain
(A1,3)allylic
epoxidation
acyclicdirected
Me Me
Me OHHm-CPBA Me Me
Me OHH
O
strain
HMeMe
OH
H Me
120°
favoured
(A1,3)allylic
epoxidation
acyclicdirected
Me Me
Me OHHm-CPBA Me Me
Me OHH
O
strain
O
MeMe H H
OH
HO
O
Me
Ar
disfavoured
MeMe
OHH
t-BuO2HVO(acac)2
MeMe
MeMe
O
O
OH
OH
19
1
epoxidation
acyclicdirected
howwhy
no C3 substituent
RRR
50°R
HO
HR
RR
H
R
HO
50°
(A1,2)strain
(A1,2)strain
H O Me
H
O
OV
t-Bu
H Me
LLH O H
Me
O
OV
t-Bu
H Me
LL
favoured
OH
O
OO
O
OO
O
NMe2OH
H
O
OHO
H
©Microbiology 148, 405 (2002)
oleandomycinJ. Am. Chem. Soc, 1996, 118, 11323
MeNO
BnMe
O
Me
O OH
Me
OH OTIPS
MeMe
Ph
O O
MeNO
BnMe
O
Me
O OH
Me
OH OTIPS
MeMe
Ph
O O
O
VO(acac)2t-BuOOH
91%100% de
OH
O
OO
O
OO
O
NMe2
OHH
O
OHO
H
favoured
H O H
R2
O
OV
t-Bu
H R1
LLH O R2
H
O
OV
t-Bu
H R1
LL
versus
(A1,2)strain
HOCO2H
OO
OH O
EtH Et
H
OHEt
lasalocid AJ. Am. Chem. Soc, 1978, 100, 2933
MeO
OH
Et
Et
t-BuO2HVO(acac)2
dr = 8:1
MeO
OH
Et
EtO AcOH
75%OAr
EtOH
H
Et
epoxidationlong range directed
HOCO2H
OO
OH O
EtH Et
H
OHEt
HH
EtR
Ar
O V OO t-Bu
L
L
cyclic
transition state
other
reactionsdirected
IrO
N
O
N
H H
Py PCy3
PF6
H2dr = 99:1
