Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method

Michael CaputoDr. Paul Blakemore

Department of Chemistry

O

H

NMe

OMe

MeO

What is Thebaine?

Found naturally occurring in the opium poppy, Papaver somniferum, as a minor component

It only makes up 0.1% to 2.0% of all of the alkaloidal extracts from the poppy

What Makes Thebaine so Special?

A biogenetic precursor of morphine, codeine, etorphine, heroine, naltrexone, naloxone, etc.

It can be used to synthesize a wide array of medicinally relevant compounds

No practical synthesis of thebaine has been reported

OH

NMe

OMe

MeO

OH

NMe

OH

HOO

H

NMe

OMe

HO

thebaine morphinecodeine

O

H

NMe

OAc

AcO

heroin

Background of Opiates Use of Opiates date back to 3000

B.C. Legal Production

Regulated by the United Nations India, Turkey, and Tasmania

(Australia) Main Consumer: USA

Legal use exceeds 80,000 kg/year in US

Illicit Production More than $760 Billion USD

annually Afghanistan

Facts About Opiates

Used for/as: Chronic pain relief Cough suppressant Analgesic Epidural anesthesia Anti-diarrhea Respiratory suppression

The Objective

Create an efficient multi-step synthesis of thebaine Do it in the least number of steps Do it with the highest yields Join the A and B rings via a [4+2]

intramolecular cycloaddition reaction

The Ring System

O

H

NMe

OMe

MeOAB

C

D

E

The Starting Materials

N

N

Cl

Cl

3,6-dichloropyridazine 3-hydroxy-4-methoxybenzaldehyde

OMe

OH

O

isovanillin

Cost: $1.84 g-1Cost: $1.02 g-1

Research Strategy

The use of dichloropyridazine and isovanillin as the starting materials for the synthesis will lead to the desired thebaine product

Me : Methyl group (CH3)

Et : Ethyl group (CH2CH3) Ac : Acetyl Group Ph : Phenyl Group -ane : Refers to a single bond -ene : Refers to a double

bond -yne : Refers to a triple bond

Helpful Information

O

R

Helpful Information

Reaction Arrows:

Reagents

Solvents

ProductsStarting Materials

The Procedure The proposed procedure involves the creation of

two sub-products

N

N

OMe

I

6-iodo-3-methoxypyridazine 3-(acetaldehyde diethyl acetal)-4-methoxybenzaldehyde

OMe

O

O

EtO OEt

The Procedure Synthesis of sub-product 1:

(pyridazine)

N

N

Cl

Cl

N

N

I

I

N

N

OMe

I

NaIcat. HI

AcetoneΔ (56 °C)

NaOMe

MeOH

54% *46%

(*Hadduck)

The Procedure Synthesis of sub-product 2:

(isovanillin)

OMe

OH

O

OMe

O

O

EtO OEtBr

OEtEtO

KOH

DMSOΔ (80 °C)90%

The Procedure Tandem Linge-Pin Wittig Coupling:

P

Ph

Ph

Ph

CH3 THF

n-Buli

(rt)

I

(-20 oC)

NN

MeO I

-LiI

P

Ph

Ph

Ph

CH2

Ylide 1

N

N

MeO

PPh3

IH H

N

N

MeO

PPh3

H

Ylide2

OMe

O

O

EtO OEt

(rt)

OMe

O

EtO

OEt

N

N

MeO

4%

The Procedure Hydrogenation of Alkene:

OMe

O

EtO

OEt

N

N

MeO

OMe

O

EtO

OEt

N

N

MeO

H2Pd(C)

EtOH(rt)

The Procedure Cylclization of Benzofuran:

OMe

O

EtO

OEt

N

N

MeO

OMe

O

N

N

MeO

PPAToluene(80 oC)

Proposed Cycloaddition

OMe

O

N

NOMe

Diels-Alder

[4+2]

OMe

O

NN

H

H±

RetroDiels-Alder

-N2O

OMe

OMe

H

H

±

(5 steps from isovanillin)

The Model System It represents the basic structure of the desired

molecule without specific substituents It acts as a major checkpoint for the completion of a

synthesis

Thebaine model Thebaine

O

H

NMe

OMe

MeOAB

C

D

E

O

HOMe

MeOAB

C D

Thanks

Dr. Paul Blakemore Chris Emerson Heath Giesbrecht J Gunderson Dr. Kevin Ahern Howard Hughes Medical Institute