Retrosynthetic analysis 123.312 Organic Chemistry Gareth Rowlands sources
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Retrosynthetic analysis123.312 Organic Chemistry
Gareth Rowlands
sources
sources
http://www.massey.ac.nz/~gjrowlan/teaching.html
Organic synthesis is a creative science
3NH
Me CO2H
CO2H
H H
(–)-!-kainic acid
NP1
Me
PhS
OP2 NP1
OP2
Me
EtS CN
Me OTBS
CO2t-Bu
radicalPauson-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
Knowledgeunderstanding
Strategyretrosynthesismethodology
Experimentreagents
protecting groups
terminology
Me
O
HO
Me
O
Me Me
OH O
Me
OMe
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
OTBSO
OH
Me
N
S
Me
retrosynthetic analysis
retrosynthetic arrow
Me
CO2H
HO
Me
O
Me Me
OTBS
H
O
Me
CO2HMe
O OTBS
Me Me
.”“
retrosynthetic arrow
...could be made from...
Me
CO2H
HO
Me
O
Me Me
OTBS
H
O
Me
CO2HMe
O OTBS
Me Me
disconnection
Me
O
OHMe
O Me
MeHO
O
Me
N S
Me
epothilone C
Me
O
OHMe
O Me
MeHO
O
Me
N S
Me
synthons
HO
NH
O
Ph
HO
NH
Ph
O
synthons are not real
synthon reagent
O
Ph
O
PhH(and oxidation)
O
PhOPh
O
O
PhCl
O
PhHO
retrosynthesisMe
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
R1Ph3P
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
guideline !
disconnections must correspond to known,
reliable reactions
Cl
Cl
O CO2H
Cl
Cl
O
CO2H
C–O
!
SN2Cl
Cl
OHCO2H
Cl
NaOH
Cl
Cl
O CO2H
guideline "
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
Clchlorbenside
2possibilities
S
Cl
Cl
ClS
Cl S
Cl
Cl
C–S
route A
C–S
route B
!SCl
Cl
Cl
S
Cl
C–S
Route A
guideline 2
"Route A
guideline 1
S
Cl
Cl
Cl
HS
Cl
Cl
NaOEt
"Route A
guideline 1
Cl
Cl
S
Cl
chemical researchAdv. Synth. Catal. 2005, 47, 313
MeO
BrMe
Si
Me
Me
Me
MeMe
HS
Pd(OAc)2, PPh3,
Cs2CO3
MeO
SSi(iPr)3
overcome limitations
!Route B
guidelines 1 & 2
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
MeOH
MeO
OMe
Me
Me
OHO
O
O
MeO
Me
OHOH
Me
MeHO
MeO
OMe
Me
Me
OH O
swinholide A
2works for allmolecules
Picture ©Yoichi Nakao, University of Tokyo
O
O
OMe
Me
OH OH
Me
MeOH
MeO
OMe
Me
Me
OHO
O
O
MeO
Me
OHOH
Me
MeHO
MeO
OMe
Me
Me
OH O
O
OH
OMe
Me
OH OH
Me
MeOH
MeO
OMe
Me
Me
OH O
OH
Me
OHO
O
HO
MeO
Me
OHOH
Me
MeHO
MeO
OMe
Me
HO
!the problem
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