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Retrosynthetic analysis

123.312 Organic Chemistry

Gareth
Rowlands

sources

sources

http://www.massey.ac.nz/~gjrowlan/teaching.html

Organic synthesis is

a creative science

PhS Me

N OP2 P1 Synlett 1997, 275

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

N OP2 P1 J. Org. Chem. 1994, 59, 6968

different approaches

which one is best?

how do you plan a synthesis?

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

synthons are not real

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

know your reactions

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 !

disconnections must correspond to known,

reliable reactions
Cl O CO2H CO O

Cl

CO2H Cl

Cl

SN2
Cl Cl OH CO2H NaOH O CO2H Cl Cl Cl

guideline "

for compounds consisting of two parts joined by a heteroatom,

disconnect next to heteroatom


Cl O CO2H CO O

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

works for all molecules

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