Gives an introduction to total synthesis and why we do it (which reminds me, I must add a picture of Everest, as I think the fact that 'it is there' is the main reason for most syntheses). Then to introduce the topic with a reasonably simple synthesis, we will look at an example of the synthesis of Tamiflu.

1. LECTURE SEVEN
total synthesis
gareth j rowlands ©Michael Budde@flickr

2. 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

3. potent
anti-carcinogen
©Exothermic@flickr

4. 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

5. 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

6. < 0.5%

7. how
©mag3737@flickr

8. chemistry
as a
creative ‘art’

9. retrosynthesis
syn
thinking
backwards ©_Max-B@flickr

10. disconnections
lead to...
R1 R2

11. O IPh3P
R1 R2
Wittig
alkene
O McMurry metathesis
R1 R1
O R1 R2
R2 R2
reduction
new
R1 R2
targets

12. more
reactions
you
know...

13. easier
...the
retrosynthesis is
©spackletoe@flickr

14. O
AcHN CO2Et
H2N
Tamiflu®
oseltamivir
©ALTO CONTRASTE . Edgar AVG --BUSY--@flickr

15. 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

16. 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

17. right wrong
©Capt Kodak@flickr

19. 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

20. 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®

21. 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®

22. protecting
group
manipulation
1. EtOH, SOCl2
2. 3-pentanone,
HO CO2H ....TsOH O CO2Et
3. MsCl, Et3N
HO O
80%
OH OMs
shikimic acid

23. H
Et
CO2Et Et
O TMSOTf
BH3•SMe2 CO2Et
O
O
HO
OMs
OMs
KHCO3
~72%
H
Et
Et
Tamiflu® O CO2Et
synthesis
O

24. Et
Et " H"
O CO2Et
O CO2Et
O
TMS O
OMs
TMS OMs
H
Et
Et
selective O CO2Et
reduction HO
OMs

25. 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

26. 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

27. 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

28. Na N N N
azide-free route developed
©SiamEye@flickr

29. limited
supply of
shikimic acid
©Whirling Phoenix@flickr

30. 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

31. 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

32. 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

33. 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

34. L Pd L
L Pd L
H H
H
O
O O
O O
N SiMe3
O
asymmetric O
allylic N CO2Et
amination O

35. Tamiflu®
synthesis
1. KHMDS
....then PhSSO2Ph
O 2. mCPBA
....then DBU, heat
N CO2Et
80% PhthN CO2Et
O

36. Ph O
S
H
H
PhthN
H
EtO2C
all
diastereoisomers
undergo syn-elimination

37. 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

38. Tamiflu®
synthesis
1. 3-pentanol, Et
....BF3•OEt2
SESN 2. Ac2O, DMAP,
....pyr Ac O Et
SESN
55%
PhthN CO2Et
PhthN CO2Et

39. 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

40. OTMS
Et
O
O Et O
NH
NHAc
CO2Me
NHBoc EtO2C NH2
MeO2C
Tamiflu®
synthesis
Angew. Chem. Int. Ed., 2009, 48, 1070