synthesis of valerenic acid

Identifying Reaction Types

Total Synthesis of Valerenic Acid, a GABAA response modulator

For each step

• Assign class of transformation:

• Assign Conditions:

• Look for:

AdditionElimination

SubstitutionRearrangement

Polar BasicPolar AcidicRadical

PericyclicTransition Metal

Acidic SitesNucleophilic SitesElectrophilic Sites

Step 1: A Grignard Reaction

OH

MgBr

THFHO

OH

BrMg

-bond electrophile

-bond nucleophile

Step 2: Silyl Protection

HO

TBSClDIPEA

DCM TBSO

OSi Cl

-bond electrophile LP nucleophile

Step 3: Ene-Yne Metathesis

TBSOOTBS

Grubbs I

DCM

ethylene

22 oC

Step 4: Deprotection

OHOTBS

TBAF, THF

22 oC

Step 1’: Isopropenylation

O Li

Et2O, 0 oC

LiO

Step 2’: Acidic Workup

LiO CF3CO2H

H2O

OH

Lewis Acid Electrophile

Step 3’: Chiral Resolution

OH

OAcLipase PS

MTBE, rtOAc

+

OH

1 : 1

Step 4’: Recycling

OH OAc

SiO2, THF/H2O, rt

Step 5: Building the Ring System

OH

MgBr2*Et2ODIPEADCM, rt

O

O HO

O

Step 6: Reduction

HO

O

DIBALH

DCM

-78 oC HO

OH

Step 7: Wittig Reaction

HO

OH

Ph3P=CMeCO2EtPhH, reflux

HHO

CO2Et

HO

OH

hemiacetal

HHOO

Ph3P CCO2Et

Me

-bond nucleophile

Step 8: Hydrogenation

HHO

CO2Et

Crabtree's Cat.

H2, DCM, 22 oC

HHO

CO2Et

H

Step 9: Oxidation

HHO

CO2Et

H IBX, DMSO

22 oC

HO

CO2Et

H

Step 10: Making an Enol Triflate

HO

CO2Et

H Tf2O, pyridine

DCM, 22 oC

TfO

CO2Et

H

Step 11: Methylation

TfO

CO2Et

H Pd(PPh3)4, TF

0 oC, 15 min

then Me2Zn,

22 oC, 15 h

CO2Et

H

Step 12: Hydrolysis

CO2Et

H LiOH, H2O, THF

CH3OH, 22 oC

CO2H

H

Valerenic Acid