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