Lecture7: 123.702
40
LECTURE SEVEN total synthesis gareth j rowlands ©Michael Budde@flickr
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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.
Transcript of Lecture7: 123.702
LECTURE SEVEN
total synthesis gareth j rowlands
©Michael Budde@flickr
OO
OAc
O
OO
O
O
OOHO
OH
Cl
AcO
OHOH
OH
HO
OMeHO
(+)-spongistatin 1 altohyrtin A
©Saad.Akhtar@flickr
©Exothermic@flickr
potentanti-carcinogen
400kg 13mg
©Saad.Akhtar@flickr
OO
OAc
O
OO
O
O
OOHO
OH
Cl
AcO
OHOH
OH
HO
OMeHO
PPh3I
O
O
OHHO
OH
Cl OHOH
OH
OO
OHO
AcO
HO O
O
OO
OHO
OMe
needtotal synthesis
0.5%<
©mag3737@flickr
how
chemistryas a creative ‘art’
©_Max-B@flickr
retrosynthesisnys
backwardsthinking
R1 R2
lead to...disconnections
R1 R2R1
R2
R1 R2
OR1
IPh3PR2
OR1
OR2
Wittigalkene
metathesis
reduction
McMurry
targetsnew
morereactions
you know...
©spackletoe@flickr
...the easier
retrosynthesis is
©ALTO CONTRASTE . Edgar AVG --BUSY--@flickr
AcHN
O
H2N
CO2Et
Tamiflu®oseltamivir
O
NH2
AcHN
CO2EtRO CO2Et
HN
CO2H
OHHO
HO
shikimic acidNHPG
CO2EtPGN
MeO2CCO2Me
TMSO
O
O
aziridine opening
aziridine opening
Asymmetric Diels-Alder
Asymmetric allylic
alkylation
substrate control
retrosynthesis of Tamiflu®
O
NH2
AcHN
CO2EtRO CO2Et
HN
CO2H
OHHO
HO
shikimic acidNHPG
CO2EtPGN
MeO2CCO2Me
TMSO
O
O
aziridine opening
aziridine opening
Asymmetric Diels-Alder
Asymmetric allylic
alkylation
substrate control
retrosynthesis of Tamiflu®
©Capt Kodak@flickr
right wrong
O
NH2
AcHN
CO2Et RO CO2Et
HN
aziridine opening
C–N formation
RO CO2Et
O
epoxide opening /aziridine formation
C–N formation
O
O
OMs
CO2Et
selective reductionepoxide
formation
CO2H
OHHO
HO
shikimic acid
protection
retrosynthesis of
Tamiflu®J. Org. Chem., 1998, 63, 4550
O
NH2
AcHN
CO2Et RO CO2Et
HN
aziridine opening
C–N formation
RO CO2Et
O
epoxide opening /aziridine formation
C–N formation
O
O
OMs
CO2Et
selective reductionepoxide
formation
CO2H
OHHO
HO
shikimic acid
protection
retrosynthesis of
Tamiflu®
O
NH2
AcHN
CO2Et RO CO2Et
HN
aziridine opening
C–N formation
RO CO2Et
O
epoxide opening /aziridine formation
C–N formation
O
O
OMs
CO2Et
selective reductionepoxide
formation
CO2H
OHHO
HO
shikimic acid
protection
retrosynthesis of
Tamiflu®
CO2H
OHHO
HO
shikimic acid
1. EtOH, SOCl22. 3-pentanone, ....TsOH3. MsCl, Et3N
80%
O
O
OMs
CO2Et
protectinggroup
manipulation
O
O
OMs
CO2Et TMSOTfBH3•SMe2 O
HO
OMs
CO2Et
EtEtH
KHCO3~72%
O CO2Et
EtEtH
Osynthesis
Tamiflu®
O
O
OMs
CO2Et
TMS
O
O
OMs
CO2Et
TMS
EtEt H" "
O
HO
OMs
CO2Et
EtEtH
reduction
selective
NaN3
86%
O
O
CO2Et
EtEt
O CO2Et
EtEt
HON3
O CO2Et
EtEt
N3OH
Me3P97%
O
HN
CO2Et
EtEt
synthesis
Tamiflu®
NR2
R1OH
NN :PMe3
NR2
R1OH
NN
Me3P
NR2
R1OH
Me3PNN
NR2
R1O
Me3P
N N
H
HNPMe3
O
R1 R2
HNPMe3
O
R1 R2R1 R2
NH
formationaziridine
O
HN
CO2Et
EtEt1. NaN32. Ac2O3. Ra-Ni, H24. H3PO4
O CO2Et
EtEt
NH
NH2•H3PO4
Ac
synthesisTamiflu®
N NNNa
developedrouteazide-free©SiamEye@flickr
©Whirling Phoenix@flickr
supply of
limited
shikimic acid
OAcHN
H2N CO2Et
Et
Et
PG2N CO2Et
PGN
PG2N CO2Et
PG2N CO2EtOO
aziridine opening
C–O
aziridine formation
C–Nfunctional group interconversion
C=Casymmetric allylic amination
C–N
retrosynthesis of
of Tamiflu®Angew. Chem. Int. Ed., 2008,
47, 3759
OAcHN
H2N CO2Et
Et
Et
PG2N CO2Et
PGN
PG2N CO2Et
PG2N CO2EtOO
aziridine opening
C–O
aziridine formation
C–Nfunctional group interconversion
C=Casymmetric allylic amination
C–N
retrosynthesis of
of Tamiflu®Angew. Chem. Int. Ed., 2008,
47, 3759
OAcHN
H2N CO2Et
Et
Et
PG2N CO2Et
PGN
PG2N CO2Et
PG2N CO2EtOO
aziridine opening
C–O
aziridine formation
C–Nfunctional group interconversion
C=Casymmetric allylic amination
C–N
retrosynthesis of
of Tamiflu®Angew. Chem. Int. Ed., 2008,
47, 3759
OO
N CO2Et
O
O
1.
2. EtOH, TsOH84%
98%ee
PdClPd
ClN
O
O
SiMe3
HNNHO O
P PPh
Ph Ph
Ph
asymmetricallylic
amination
asymmetricallylic
amination
L
O
HH
O
Pd L
H
O O
L Pd L
N
O
O
SiMe3
N CO2Et
O
O
N CO2Et
O
O
1. KHMDS....then PhSSO2Ph2. mCPBA....then DBU, heat
80% PhthN CO2Et
synthesis
Tamiflu®
H
PhthN
S
H
H
Ph O
EtO2C
syn-eliminationundergodiastereoisomers
all
PhthN CO2Et
cat (2mol%), SESNH2,
PhI(O2Ct-Bu)2, MgO
86%PhthN CO2Et
SESN
synthesis
aziridine
Rh
O
OO
Rh
O
OO
OO
nitrene chemistry
PhthN CO2Et
SESN
1. 3-pentanol, ....BF3•OEt22. Ac2O, DMAP, ....pyr
55%
OSESN
PhthN CO2Et
Et
Et
Ac
synthesis
Tamiflu®
ON
N CO2Et
Et
Et
S
Ac
O
O
OOMe3Si
1. TBAF2. NH2NH2
95%
OHN
H2N CO2Et
Et
Et
Ac
synthesis
Tamiflu®
end-game
synthesisTamiflu®
Angew. Chem. Int. Ed., 2009, 48, 1070
OTMS
CO2Me
MeO2C
NHO
O
NHBoc EtO2C NH2
NHAcO
Et
Et
OTMS
CO2Me
MeO2C
NHO
O
NHBoc EtO2C NH2
NHAcO
Et
Et
