Synthesis of morphine

• Heroin 1898:-Developed by Heinrich Dreser at Fredich Bayer and Company -Diacetyl derivative of morphine -Marketed to the German people as a cough remedy • Morphine Present day -One of

O OH

A B

C D

 Cultivation:

Fig 1: Lanced Poppy with

raw opium exturding

• Opium is harvested from the immature poppy seed capsule

• Primary areas of cultivation are south east and west asia and latin america

• An average Indian acreage of P somniferum yields 25-30 kg of opium

OMeO

H N

Me

MeO(-)-thebaine3-4% 1-2 %

• Heroin (1898):

-Developed by Heinrich Dreser at Fredich Bayer and Company -Diacetyl derivative of morphine

-Marketed to the German people as a cough remedy

• Morphine (Present day)

-One of the most widely used drugs for treatment of severe pain

 Structure

OHHO

HO

N

H Me

1 2 3 4 5

6 7 8 9

10 11 12 13 14

15 16

N

OOH

A

B

C D

E

Morphine

Key Features: 5 rings, 5 contiguous stereocenters, compact array of functionality

 Synthesis

• Landmark synthesis was in 1952 by Gates

• Since then at least 18 more total and formal synthesis

of Morphine have appeared

• This overview will encompass 6 unique routes

Biosynthesis of Morphine

CO2H

NH2HO

L-Tyrosine

NH2HO

CHOHO

dopamine

HO

NHH

HOHO

salutaridinesalutaridinol

Gates Synthesis

 Retrosynthesis

MeO

NHO

HO

Morphine

HOMeO

N

O

H

HOMeO

HMeO

OO

Epimerization[Ox]

[Red]

[Red]

ReductiveAmidation[4 + 2]

NC

O

O

NC CO2Et1

NEt3

2 K3FeCN6

3 KOH,EtOHOMe

OMe

OO

NC

(69 %)

(82 %)

27 atm H2CuO/Cr2OEtOH

1 N2H4/KOH

2 MeI/NaH

3 LAH

MeOMeO

N

1 H2SO4

2 KOH,(HOCH2CH2)2O

3 KOt-Bu/Ph2CO

(76 %)O

HOMeO

NO

H

HH

2 HCl

3 H2/ PtO2(7 %)

(14 %)

Gates Synthesis

HO

HO

MeO

NO

H

1 (a) Br2 (b) 2,4-DNP

2 HCl

MeO

NHO

O

Br

1 LAH (44 %)

2 Pyr-HCl, 220 °C (34%)

MeO

NHO

HO

(8 %)

Rice Synthesis

 Retrosynthesis

OHO

NHO

OMeO

NO

HOMeO

NCHOBr

O

NCHOHO

MeO

O

HBr

NHHO

MeO

MeO

H

OHOMe

CO2H H2N

OMe

Rice Synthesis

CHO

OHOMe

200 °C

2 a) POCl3 b) NaCNBH4

NHHO

NHHO

MeO

MeO

H

1 a) MeSO3H b) (CH2OH)2c) NBSd) HCO2H(aq)NCHO

HOMeO

O

NH4F/HFTfOH(60 %)

CO2H

Rice Synthesis

OHO

NHO

• 16 steps

• Overall yield 12 %

• Grewe cyclization was key disconnection

• Practical method for conversion of dihydrocodeinone to morphine

HO

MeO

NCHOBr

O

OMeO

NO

NHO

Dihydrocodeinone Morphine

H2C

NMe

OMe

OMe

ClO4H

MeO

OMe

NMe

NMe

3 NaI

OMe

OMeHClO4

NMe

OMe

OMe

ClO4H

MeOH

50 °CN

Me

OMe

OMe

ClO4H

60 % overall, 95:5 cis:trans

Kinetic ProductThermodynamic

Product

Evans Synthesis

CH2N2DCM

HArMe

Nu

H

Nu

DMSO(95 %)N

MeO

OMe

NMe

BF3-Et2OStereochemical Analysis:

?

?

Evans Synthesis

CH2N2DCM

HArMe

Nu

H

Nu

DMSO(95 %)N

MeO

OMe

NMe

BF3-Et2OStereochemical Analysis:

OMe

NMe

H

HO

(80 %)

• Short sequence to achieve the gates intermediate (10 steps)

• Cleaver and original disconnect

• Major limitation is having to go through gates intermediate

HNDBS

I

HeckCyclization

Mannich

(27 %)

N BHO

H PhPh2

PhN C P3

4 OsO4/NMO, Acetone

OCONHPh

OO

OO

5 n-BuLi, CuI(Ph3P)2PhMe2SiLi

SiMe2Ph

R2O

N OPh

Cu

R1

R2Cu

R1N(III)

OxidativeAddition

ReductiveElimination

(81 %)

6 a) TsOH, NaIO4b) DBS-NH2, NaCNBH3

SiMe2Ph

HNDBS

(27 %)

N BHO

H PhPh2

PhN C P3

4 OsO4/NMO, Acetone

OCONHPh

OO

OO

5 n-BuLi, CuI(Ph3P)2PhMe2SiLi

SiMe2Ph

R2O

N OPh

Cu

R1

R2Cu

R1N(III)

OxidativeAddition

ReductiveElimination

(81 %)

6 a) TsOH, NaIO4b) DBS-NH2, NaCNBH3

SiMe2Ph

HNDBS

Overman Synthesis

CHOMeO OMe

1 CH2SMe2

2 BF3 -THF(78 %)

Favored for large R1 Favored for small R1

OMeOBn

OHC

SiMe2Ph

HNDBS

(60 %)

(1)

I

(47 %)

• 1st enantioselective synthesis that did not contain a resolution

• Natural and unnatural morphine available

• 23 steps with an overall yield of 0.56 % (single heck)

• 26 steps with an overall yield of 0.184 % (bis-cyclization)

• Key disconnections were the Heck and Mannich

HOMeO

HOMeO

CO2HO

HH

N2

HOMeO

CO2Me

HO2C

CHOHO

MeO

OMeO

White Synthesis

(CH2CO2Me)21

2 H2, [RhCl(COD)]2, (-)-MOD-DIOP

HOMeO

OOMeH

HO

O

OOHH

HOMeO

Br

O

OOMeHO

Br

O

OOMe

O

HO2CCHO

HO

MeO

70 °CDBU

(80 %)

HH

O

OOMe

OBs

1 NH2OH-HCl

2 p-BrPhSO2Cl, NaOAc

• 29 steps

• Overall yield of 1.73 %

• Asymmetry was introduced early via enantioselective hydrogenation

• Key disconnect was the Rhodium (II) catalyzed C-H insertion

MeO

O

H H NMeHO

O

OMeO

HHO

NMe

OMeO

HHO

NMeTs

OMeO

HHO

NMe

TsSRX

RadicalCyclization

MitusunoboOMe

OHBr

PhS

NTs

TBDMSO

H PhPh(S)-B-Me =

Failed routes included direct CBS reduction of 1 (35 % ee) and

Sharpless kinetic resolution of the allylic alcohol (44 %ee)

OPhS

Me

HHOMeO

HHO

NMe

Ts

SPh

O

NTs

Me

HHO

MeO

SPhO

MeO

HHO

NMeTs

Bond

Rotation

OH

NMeTs-[ SPh]

O

NMeTs

HHO

NMe

Ts

SPh

O

NTs

Me

HHO

MeO

SPhO

MeO

HHO

NMeTs

Bond

Rotation

OH

NMeTs-[ SPh]

O

NMeTs

Draw a mechanism that accounts for formation of the side product

HHO

NMe

Ts

SPh

O

NTs

Me

HHO

MeO

SPhO

MeO

HHO

NMeTs

Bond

Rotation

OH

NMeTs-[ SPh]

O

NMeTs

t -BuOH O

MeO

HHO

MeO

HHO

NMe

DMSO(COCl)2

OMeO

morphine

• Radical cyclization was the key disconnect

• First published in August, 1992

HO

OMeO

Me

HOmorphine

methods of synthetic chemisty

(Only Rice has come close to synthetically viable route)

with which can attenuate addictive properties

N

OOH

A B

C D

E

Morphine

Gates (1952): Diels-AlderRice (1980): Grewe CyclizationEvans (1982): Iminium SaltsOverman (1993): Heck chemistryWhite (1997): C-H insertionParker (2006): Radical Cyclization

Racemic

Asymmetric

Gates, M.J J Am Chem Soc 1953, 75, 4340

Rice, C.; Brossi, A J Org Chem 1980, 45, 592

Evans, D.A.; Mitch, C.H Tetrahedron Lett 1982, 23, 285

Overman, L.E Pure and Appl Chem 1994, 66, 1423

White, J.D J Org Chem 1999, 64, 7871

Parker, K.A J Org Chem 2006, 71, 449

Lead References for Syntheses:

Review:

Taber, D.F The Enantioselective Synthesis of Morphine: Strategies and

Tactics in Organic Synthesis 2004, 5, 353