Post on 20-Feb-2021
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).
!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