lecture tw o - massey universitygjrowlan/chem312/lct2.pdf · phnh!! oph o phnh2 br route c part ii...
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lecture twoC–X bonds continued
guideline !
-
consider alternative disconnections; avoid
chemoselectivity issues - disconnect reactive groups first
!
OOMe
MeO
OH
NH
bisoprolol(hypertension)
?O PhOHNPh ICI-D7114 intermediate(anti-obesity) abcdwhichdisconnection
Why no groovy picture? Well I could find one with a fat person that wasn’t either offensive or just plain wrong! I guess I could have used the fatboy slim album cover but then we’re into a world of copyright issues (not that I care as we shall see).
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!guideline 1
Route AO Ph
O
HNPh
a
C–O
O
O
HNPh
Ph
! !
OH
O
HNPh
base
PhCl
"Route A
OH
O
HNPh
PhCl
chemoselectivity
Be careful with amines. They are not always our friend, with a nasty habit of interfering when we least expect them to.
-
!guideline 1
Route BO Ph
O
HNPh
b
C–O
O Ph
O
HNPh
! !
O Ph
HO
baseHNPh
Br
"chemoselectivity
Route B
O Ph
HO
HNPh
Br
I told you that you had to keep a sharp eye on these amines...
-
ClN
Cl
Me
mustine mechlorethamine
HN2 nitrogen mustard gasprotoype chemotherapy drug
The mustards used in the World Wars were actually based on sulfides.
!guideline 1
Route CO Ph
O
HNPh
c
C–O
O Ph
O
NHPh
! !
O Ph
O
NH2Ph
Br
-
!guideline 1
Route DO Ph
O
HNPh
d
C–O
! !O Ph
OHN
Ph
O Ph
OH2N
Ph Cl
but what is the next disconnection?
-
Route D part IIO Ph
OH2N
d2
d3
O
Ph
OH2N
O Ph
O
H2N
C–OC–O Only two steps into the retrosynthesis and we’re in trouble...
"chemoselectivity
Route D part II
R NH2I told you amines were bad news!
-
plan ahead!
introduce reactive groups late in synthesis
-
!guideline 1
Route CO Ph
O
HNPh
c
C–O
O Ph
O
NHPh
! !
O Ph
O
NH2Ph
Br
Route C part IIO Ph
OBr
d2
d3
d2
C–O
d3
C–O
O
Ph
OBr
O Ph
O
Br
Nope, not a mistake...I’m trying to emphasise that these are the same disconnections as before...
-
"Disconnection d2
chemoselectivity
OPh
OBr
! !
OH
Ph
OBr
Br
O Ph
OBr
d2
d2
C–ODON’T leave reactive functionality in the molecule...
!Disconnection d3
O Ph
OBr
d3
d3
C–O
O Ph
O
Br
! !
O Ph
HO
baseBrBr
Remove the reactive group.
-
!Disconnection d2
O Ph
HO
d2
d2
C–O
OPh
HO ! !
PhBr
OH
HO
synthesis
OH
HO
PhClO
HO
BrBr
base
O
O
NH2PhO
O
PhPh
HN
Ph
Br
Ph
Selectivity could be an issue in these two reactions but by careful control of the reaction conditions this can be overcome...
-
OH
HO
BrBr
problems
experiment(use an excess)
?HO
HN Me
O
C–N
HO
NH Me
O
! !
HO
NH2 Me
O
Cl
HO
NH2
C–N
-
not all retrosynthesis is about disconnections
functional group interconversion (FGI)
HO
NH2 FGI
HO
NO2
aids disconnection
you should be able to disconnect this molecule
-
HO
HN Me
O
C–N
amide
! !
HO
NH2Me
O
Cl
HO
FGI
NO2
HON
O
O
HO
HNO3+
H2SO4
C—N
nitration
retrosynthesis
synthesis of paracetamol
HO
HNO3H2SO4
HO
NO2
HO
NH2Ac2O
79%
H2 / Pd
HO
HN Me
O
Remember directing effects
acetylation only occurs once; why?
-
© 2002 National Geographic Society
N
Me t-Bu
terbinafine
C–X disconnection
N
Me t-BuC–N
-
but...
"R NH2 R2 Br R NH R2 R2 Br R N R2
R2
R2Br
R NR2
R2R2
product more reactive
-
but...
(a quick aside)
H2N
CO2Et
R Br
NH
CO2Et
R X
steric hindrance prevents further reaction
not always...
-
functional group interconversion offers a solution
retrosynthesis 1
R1HN R2
FGI
reduction
R1HN R2
O
C–N
amide
R1 NH2
R2
O
Cl
-
synthesis
R1 NH2
R2
O
Cl R1HN R2
O
LiAlH4
or BH3
R1HN R2
retrosynthesis 2
R1HN R2
FGI
reduction
R1 N R2C–N
imine
R1 NH2
R2
O
H
-
synthesis
R1 NH2
R2
O
HR1 N R2
NaBH4
or
NaCNBH3or
H2 / cat.
R1HN R2
H
Often we try to avoid isolating the imine as they can be unstable and prone to hydrolysis (return to starting materials)
NaCNBH3 is a mild and selective reagent. It reduces imines / iminium ions but not carbonyls
N
N
Ph
OOMe
F
ocfentanilpain-killer
-
retrosynthesis
N
N
Ph
OOMe
F
C–N
amide
N
HN
Ph F
OOMe
Cl
FGI
imine
N
N
Ph F
C–N
imineN
O
Ph
H2N
F
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