7/27/2019 lct1

1/19

Retrosynthetic analysis123.312 Organic Chemistry

GarethRowlands

sources

7/27/2019 lct1

2/19

7/27/2019 lct1

3/19

3NHMe CO2H

CO2H

H H

()-!-kainic acid

NP1

Me

PhS

OP2 NP1

OP2

Me

EtS CN

Me OTBS

CO2t-Bu

radicalPauson-Khand

Synlett1997, 275 J. Org. Chem.1994, 59, 6968

Pure Appl. Chem.1998, 70, 259

differentapproaches

which one is best?

7/27/2019 lct1

4/19

how do you plana synthesis?

retrosynthesis

7/27/2019 lct1

5/19

Knowledgeunderstanding

Strategyretrosynthesis

methodology

Experimentreagents

protecting groups

terminology

7/27/2019 lct1

6/19

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

7/27/2019 lct1

7/19

7/27/2019 lct1

8/19

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

7/27/2019 lct1

9/19

synthons are not real

synthon reagent

O

Ph

O

PhH(and oxidation)

O

PhOPh

O

O

PhCl

O

PhHO

7/27/2019 lct1

10/19

retrosynthesisMe

O

HO

Me

O

Me Me

OH O

Me

N

S

Me

epothilone C

knowyour reactions

7/27/2019 lct1

11/19

Me

O

HO

Me

O

Me Me

OH O

Me

N

S

Me

epothilone C

R1 R2

O

R1Ph3P

R2

R1 R2

O

R1O

R2

R1 R2

R1 R2

R1 R2

R1 R2

Br

elimination Wittig McMurry alkene metathesis

R1 R2

R1 R2

reduction

guidelines

7/27/2019 lct1

12/19

CXbonds only

guideline!

7/27/2019 lct1

13/19

disconnections must correspondto known,

reliable reactions

Cl

Cl

O CO2H

Cl

Cl

O

CO2H

CO

!

Cl

Cl

OHCO2H

Cl

NaOH

Cl

Cl

O CO2H

7/27/2019 lct1

14/19

guideline"

for compounds consisting oftwopartsjoined by a heteroatom,disconnect next to

heteroatom

Cl

Cl

O CO2

H

Cl

Cl

O

CO2H

CO

"

7/27/2019 lct1

15/19

S

Cl

Cl

chlorbenside

S

Cl

Cl

ClS

Cl S

Cl

Cl

CS

route A

CS

route B

7/27/2019 lct1

16/19

S

Cl

Cl

Cl

S

Cl

CS

Route A

guideline 2

Route A

guideline 1

S

Cl

Cl

Cl

HS

Cl

Cl

NaOEt

7/27/2019 lct1

17/19

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

7/27/2019 lct1

18/19

Route B

guidelines 1 & 2

S

Cl

Cl

S

Cl

Cl

CS

Cl

Br

SH

Cl

!

!

Route B

Cl

Br

SH

Cl

NaOEt S

Cl

Cl

7/27/2019 lct1

19/19