Retrosynthetic analysis
123.312 Organic Chemistry
Gareth
Rowlands
sources
sources
http://www.massey.ac.nz/~gjrowlan/teaching.html
Organic synthesis is
a creative science
3
Me(–)-!-kainic acidH HNH COCO2H2H NP1 Me
PhS
OP2 N
P1
OP2 Me
EtS CN
Me OTBS
CO2t-Bu radical
Pauson- Khand
Synlett 1997, 275 J. Org. Chem.
1994, 59, 6968
Pure Appl. Chem.
1998, 70, 259
different approaches
the difficulty in this synthesis is producing the syn relationship between the 3 & 4 substituents
which one is best?
how do you plan
a synthesis?
retrosynthesis
Knowledge
understanding
Strategy
retrosynthesis methodology
Experiment
reagents
protecting groups
terminology
Me
O HO
Me
O
Me Me
OH O
Me MeO
N S
Me
epothilone B
target molecule
© UCLA in the LA Times 05/12/07
Me
O HO
Me O
Me Me
OH O
Me O
N S
Me
Me
OH HO
Me O
Me Me
OTBS O
OH Me
N S
Me
retrosynthetic analysis
retrosynthetic arrow
Me
CO2H HO
Me
O
Me Me
OTBS
H O
Me
CO2H Me
O OTBS Me Me
“ .”
retrosynthetic arrow
...could be made from...
Me
CO2H HO
Me
O
Me Me
OTBS
H O
Me
CO2H Me
O OTBS Me Me
disconnection
Me
O
OH Me
O Me
HO Me
O
Me
N S
Me epothilone C
Me
O
OH Me
O Me
HO Me
O
Me
N S
Me
synthons
HO
NH
O Ph HO
NH Ph O
synthons are not real
synthon reagent
O Ph
O Ph H
(and oxidation) O
Ph O
Ph O
O Ph Cl
O Ph HO
retrosynthesis
Me
O HO
Me
O
Me Me
OH O
Me
N S
Me
epothilone C
know your reactions
Me
O HO
Me O
Me Me
OH O
Me
N S
Me
epothilone C
R1 R2
O R1 Ph3P
R2
R1 R2
O R1
O R2
R1 R2
R1 R2
R1 R2
R1 R2 Br
elimination Wittig McMurry alkene metathesis
R1 R2
R1 R2 reduction
guidelines
C–X bonds only
guide line !
disconnections must correspond to known,
reliable reactions
Cl
Cl
O CO2H
Cl
Cl
O
CO2H C–O
!
S
Cl Cl OH Cl CON
2H NaOH Cl2
Cl O CO2Hguide line "
for compounds consisting of two parts joined by a heteroatom,
disconnect next to heteroatom
Cl
Cl
O CO2H
Cl
Cl
O
CO2H C–O
"
S
Cl
Cl chlorbenside
possibilities 2
S
Cl
Cl
Cl S
Cl S
Cl
Cl C–S
route A
C–S route B
!
S ClCl
Cl S
Cl C–S
Route A
guideline 2
" Route A
guideline 1S
Cl
Cl Cl
HS
Cl
Cl
NaOEt
" Route A
guideline 1Cl
Cl
S
Cl
chemical researchAdv. Synth. Catal. 2005, 47, 313 MeO
Br Me
Si Me
Me Me
Me Me
HS
Pd(OAc)2, PPh3, Cs2CO3
MeO
S Si(iPr)3
overcome limitations
!
guidelines 1 & 2Route B
S
Cl
Cl
S
Cl
Cl
C–S
Cl Br
SH
Cl
!
!
Route B
Cl Br
SH
Cl
NaOEt S
Cl
Cl
O
O OMe Me
OH OH
Me
Me OH
Me O
OMe
Me
Me O OH
O
O
MeO
Me OH OH Me
HO Me O Me
OMe Me
Me
OH O
swinholide A
2
works for all moleculesPicture ©Yoichi Nakao, University of Tokyo
O
O OMe
Me
OH OH
Me
Me OH
Me O
OMe
Me
Me O OH
O
O
MeO
Me OH OH Me
HO Me O Me
OMe Me
Me
OH O
O
OH OMe
Me
OH OH
Me
Me OH
Me O
OMe
Me
Me
OH O
OH Me O OH
O
HO
MeO
Me OH OH Me
HO Me O Me
OMe Me
HO
