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Gareth
Rowlands
sources
sources
http://www.massey.ac.nz/~gjrowlan/teaching.html
Organic synthesis is
a creative science
PhS Me
the difficulty in this synthesis is producing the syn relationship between the 3 & 4 substituents
3
radical H H Me CO2H N H CO2H ()-!-kainic acid Me OTBS EtS CN CO2t-Bu Pure Appl. Chem. 1998, 70, 259
Me
PausonKhand
different approaches
retrosynthesis
retrosynthesis methodology
Strategy
Experiment Knowledge
understanding reagents protecting groups
terminology
target molecule
Me
O Me S Me N O
HO Me Me O
UCLA in the LA Times 05/12/07
Me
Me
OH O epothilone B
retrosynthetic analysis
O Me HO Me Me O OH O Me Me O S Me N
Me HO Me Me O OTBS O Me Me OH OH
S Me N
retrosynthetic arrow
H HO Me Me O OTBS Me Me CO2H Me O OTBS O Me Me CO2H
Me
retrosynthetic arrow
HO Me Me O
Me
Me
CO2H OTBS
.
...could be made from...
Me
H O
Me
Me Me CO2H O OTBS
disconnection
Me O HO O O Me OH Me Me Me O HO O O Me Me OH Me Me Me
S Me
Me epothilone C
synthons
HO N H O Ph
HO N H
O Ph
synthon
O
reagent
O HO O Cl Ph O O O H Ph (and oxidation) Ph Ph
Ph O Ph
retrosynthesis
Me HO Me Me O Me Me O OH O epothilone C S Me N
Me HO Me Me O Me Me O OH O epothilone C
S Me N
R1
R2
R1
R2
R1
R2
R1
R2
R1
R2
Br R1 R1 R2 reduction elimination R2 R1
O Ph P 3 R2 Wittig
O O R1 McMurry R2
R1
R2
alkene metathesis
guidelines
CX bonds only
guideline !
reliable reactions
Cl O CO2H CO O
Cl
CO2H Cl
Cl
SN2
Cl Cl OH CO2H NaOH O CO2H Cl Cl Cl
guideline "
Cl
CO2H Cl
Cl
"
Cl S Cl
chlorbenside
Cl
CS route A
Cl
possibilities
S Cl
2
S Cl
Cl
CS route B S Cl
Cl
HS
Cl
! "
Route A
Cl CS S S Cl
Cl
guideline 2
Route A
NaOEt
Cl
Cl
Cl
Cl
guideline 1
Cl
"
Route A
Cl Cl S
guideline 1
overcome limitations
Br MeO Me HS Si Me Me Me Me Me Pd(OAc)2, PPh3, Cs2CO3 MeO S Si(iPr)3
chemical research
Adv. Synth. Catal. 2005, 47, 313
Cl
!
Route B
Cl Cl CS S
! !
Cl
Br
SH
Cl
Cl
guidelines 1 & 2
Route B
Cl SH Cl Br Cl Cl NaOEt S
OMe
Me Me OH Me OMe O Me Me O OH Me O O HO OH O OH O
Me OH
Me Me MeO
Me OH Me Me OH
OMe
swinholide A
Picture Yoichi Nakao, University of Tokyo
OMe
Me Me OH Me OMe O Me Me OH OH O OH O HO
Me
Me
Me O OH HO
OH
O HO
Me Me
Me
OMe
!
O
MeO Me
OH
OH
OH
the problem