LECTURE SEVEN

total synthesis
gareth j rowlands ©Michael Budde@flickr
 O
HO
OAc OMe

O O
O O

AcO HO

O O
HO
OH O

O OH
OH
Cl OH

(+)-spongistatin 1
altohyrtin A
©Saad.Akhtar@flickr
 potent
anti-carcinogen

©Exothermic@flickr
 O
HO

400kg
OAc OMe

O O
O O

AcO HO

O O
HO
OH O

O OH
OH
Cl OH

13mg

©Saad.Akhtar@flickr
 O
HO
O OMe

O O
O O

AcO HO
O
need
O OH

PPh3I
total synthesis OH
HO
OH O

O OH
OH
Cl OH
< 0.5%
how
©mag3737@flickr
chemistry
as a
creative ‘art’
retros nthesis
syyn
thinking
backwards ©_Max-B@flickr
disconnections
lead to...

R1 R2
 O IPh3P
R1 R2

Wittig
alkene
O McMurry metathesis
R1 R1
O R1 R2
R2 R2

reduction
new
R1 R2
targets
 more
reactions
you
know...
 easier
...the

retrosynthesis is
©spackletoe@flickr
 O

AcHN CO2Et

H2N

Tamiflu®
oseltamivir
©ALTO CONTRASTE . Edgar AVG --BUSY--@flickr
retrosynthesis of Tamiflu®

TMSO
O CO2Et
RO CO2Et

aziridine AcHN CO2Me

Asymmetric
HN opening NH2 Diels-Alder MeO2C
substrate aziridine
control opening

HO CO2H CO2Et
PGN O
HO
Asymmetric
O
OH NHPG allylic
shikimic acid alkylation
retrosynthesis of Tamiflu®

TMSO
O CO2Et
RO CO2Et

aziridine AcHN CO2Me

Asymmetric
HN opening NH2 Diels-Alder MeO2C
substrate aziridine
control opening

HO CO2H CO2Et
PGN O
HO
Asymmetric
O
OH NHPG allylic
shikimic acid alkylation
right wrong

©Capt Kodak@flickr
 O CO2Et aziridine
RO CO2Et
opening

AcHN C–N
formation HN
NH2
C–N epoxide opening /
formation aziridine formation
selective
reduction
O CO2Et epoxide RO CO2Et
formation
O

OMs O

protection

retrosynthesis of
HO CO2H

Tamiflu®
HO
OH
shikimic acid
J. Org. Chem., 1998, 63, 4550
 O CO2Et aziridine
RO CO2Et
opening

AcHN C–N
formation HN
NH2
C–N epoxide opening /
formation aziridine formation
selective
reduction
O CO2Et epoxide RO CO2Et
formation
O

OMs O

protection

HO CO2H

HO retrosynthesis of
OH
shikimic acid Tamiflu®
 O CO2Et aziridine
RO CO2Et
opening

AcHN C–N
formation HN
NH2
C–N epoxide opening /
formation aziridine formation
selective
reduction
O CO2Et epoxide RO CO2Et
formation
O

OMs O

protection

HO CO2H

HO retrosynthesis of
OH
shikimic acid Tamiflu®
protecting
group
manipulation

1. EtOH, SOCl2
2. 3-pentanone,
HO CO2H ....TsOH O CO2Et
3. MsCl, Et3N
HO O
80%
OH OMs
shikimic acid
 H
Et
CO2Et Et
O TMSOTf
BH3•SMe2 CO2Et
O
O
HO
OMs
OMs

KHCO3
~72%
H
Et
Et
Tamiflu® O CO2Et

synthesis
O
 Et
Et " H"
O CO2Et
O CO2Et
O
TMS O
OMs
TMS OMs

H
Et
Et
selective O CO2Et

reduction HO

OMs
 Et Et Et Et
Et Et
O CO2Et O CO2Et
O CO2Et NaN3
86%
HO N3
O N3 OH

Me3P
97%
Et Et

Tamiflu®
O CO2Et

synthesis HN
aziridine formation
OH
OH OH
R1
R1 R2 R1
R2 R2
N
N N N
N Me3P N
N :PMe3 N N
Me3P
N N

H
R1 R2 R1 R2 O
R1 R2
R1
HN O HN O R2
N P P
H N
Me3 Me3
Me3P
Tamiflu® synthesis

1. NaN3 Et Et
Et Et 2. Ac2O
3. Ra-Ni, H2
4. H3PO4 O CO2Et
O CO2Et
Ac
N
H
HN NH2•H3PO4
 Na N N N

azide-free route developed

©SiamEye@flickr
 limited
supply of

shikimic acid

©Whirling Phoenix@flickr
 Et retrosynthesis
of
AcHN
O Et
Tamiflu®
Angew. Chem. Int. Ed., 2008,
aziridine 47, 3759
opening
C–O H2N CO2Et

PGN aziridine
formation

C–N PG2N CO2Et

PG2N CO2Et
functional group
interconversion
asymmetric C=C
allylic amination

O C–N PG2N CO2Et

O
 Et retrosynthesis
of
AcHN
O Et
Tamiflu®
Angew. Chem. Int. Ed., 2008,
aziridine 47, 3759
opening
C–O H2N CO2Et

PGN aziridine
formation

C–N PG2N CO2Et

PG2N CO2Et
functional group
interconversion
asymmetric C=C
allylic amination

O C–N PG2N CO2Et

O
 Et retrosynthesis
of
AcHN
O Et
Tamiflu®
Angew. Chem. Int. Ed., 2008,
aziridine 47, 3759
opening
C–O H2N CO2Et

PGN aziridine
formation

C–N PG2N CO2Et

PG2N CO2Et
functional group
interconversion
asymmetric C=C
allylic amination

O C–N PG2N CO2Et

O
 asymmetric
allylic
O
Cl
Pd Pd N SiMe3
amination
Cl
O
1.
O O
NH HN
Ph Ph
P P
O
Ph Ph
N CO2Et
O 2. EtOH, TsOH
O 84%
98%ee O
 L Pd L
L Pd L
H H
H
O
O O
O O

N SiMe3

asymmetric O

allylic N CO2Et

amination O
Tamiflu®
synthesis

1. KHMDS
....then PhSSO2Ph
O 2. mCPBA
....then DBU, heat
N CO2Et
80% PhthN CO2Et
O
 Ph O
S
H
H
PhthN
H
EtO2C
all
diastereoisomers
undergo syn-elimination
 aziridine
synthesis
cat (2mol%),
SESNH2,
PhI(O2Ct-Bu)2, SESN
MgO

PhthN CO2Et 86%

PhthN CO2Et

O
O
O Rh O
O Rh O
O
O

nitrene chemistry
 Tamiflu®
synthesis
1. 3-pentanol, Et
....BF3•OEt2
SESN 2. Ac2O, DMAP,
....pyr Ac O Et
SESN
55%
PhthN CO2Et
PhthN CO2Et
 Tamiflu®
synthesis
Et
O Et
Me3Si
S O O Et
1. TBAF
N 2. NH2NH2 O Et
Ac H
O N
95% Ac
N CO2Et
H2N CO2Et
O

end-game
 OTMS
Et
O
O Et O
NH
NHAc
CO2Me
NHBoc EtO2C NH2
MeO2C

Tamiflu®
synthesis
Angew. Chem. Int. Ed., 2009, 48, 1070