Synthesis of morphine

Synthesis of Morphine Alkaloids
MeO
CO2H
HO

OH

HO

O OH

NH2

NMe
MeN
MeO
OH

D
N
B

C
OH
O

A

E

Introduction


Cultivation:
• Opium is harvested from the immature poppy seed capsule

OH

OMe

O OH

O OH

MeN

O
N

H

MeN
(-)-morphine
10 -15 %

MeO

(-)-codeine
3-4%

Me

MeO
(-)-thebaine
1-2 %

Fig 1: Lanced Poppy with
raw opium exturding

• 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


Introduction


History of Morphine as a Pharmaceutical
• Laudanum (16th Century):
-Developed by Swiss alchemist Paracelus
-alcoholic tincture of alcohol, opium, and other herbs
-Eased suffering from the plague
• 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


Introduction



Structure
D

C

2

HO

1

3

OH

N
B

O
A

E

O



12

5

H
HO

Morphine

11

4
15

13

16
9

14
6

10

H
8

N Me

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

7

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
HO
CO2H

HO

NH2
dopamine

NH
H

HO

NH2

HO

MeO

HO

NMe
H

HO
HO

CHO

L-Tyrosine

MeO

HO

HO

(S)-norcoclaurine

(S)-reticuline

MeO

MeO

MeO

MeO

HO

O

O

HO

NMe

NMe

NMe

MeO

MeO

MeO
OH

MeO

O

O

salutaridinol

NMe

salutaridine

OH
(R)-reticuline

Phenolic coupling

SN2'
MeO

?

O
NMe

H
MeO
thebaine

MeO

MeO

O

O

H
O
neopinone

NMe

H

HO

?
NMe
H

O

O
H

NMe
H

HO
codeinone

morphine


Gates Synthesis


Retrosynthesis
MeO

MeO
[Ox]

O
H

MeO
Epimerization

HO

[Red]

N

H

HO

HO

N

14

O

H

N

O

Morphine
[Red]

MeO
MeO
NC

MeO
O

[4 + 2]

O

MeO
O
CN

OH

Reductive
Amidation

MeO
O

MeO

NH

H
O


Gates Synthesis


Forward Synthesis: Diene
1. BzCl
2. NaNO2

HO
OH

BzO
5. SO2

3. Pd/C

4. FeCl3
(56 %)

O

BzO

6. (MeO)2SO2

O

OMe

(78 %)

OMe
7. KOH
8. NaNO2
9. Pd/C
10. FeCl3
(69 %)

O
1. NC

O
OMe
NC

OMe

CO2Et

NEt3
2. K3FeCN6
3. KOH,EtOH
(82 %)

O
O
OMe
OMe


Gates Synthesis


Forward Synthesis: Morphine
MeO

MeO
O

MeO

O

AcOH/!
(50 %)

MeO
27 atm H2
CuO/Cr2O

O

MeO
CN

CN

OH

EtOH
150 °C
(50 %)

O

MeO

NH

H
O

1. N2H4/KOH
2. MeI/NaH
3. LAH
(76 %)

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

HO
14

O

H

N

2. HCl
3. H2/ PtO2
(7 %)

MeO
1. H2SO4
HO
14

O

H

N

MeO

2. KOH,
MeO
(HOCH2CH2)2O
3. KOt-Bu/Ph2CO
(14 %)

H

N


Gates Synthesis


Forward Synthesis: Morphine
MeO
1. (a) Br2
(b) 2,4-DNP

HO
H

N

2. HCl
(8 %)

O

MeO

MeO

Br
1. LAH (44 %)

O
H

N

O

2. Pyr-HCl, 220 °C
(34%)

H
HO

O

Morphine

1-Bromo-Codeinone



Analysis: Gates Method
• 29 Steps
• Overall Yield: 0.0014%

MeO

O
N
H
HO

• Key Disconnections: Diels-Alder & Reductive Amidation

N


Rice Synthesis


Retrosynthesis
HO

MeO

O

O

MeO
HO

N

N

HO

NCHO

O

CO2H

O

MeO

H2N

HO
OH
OMe

Br

OMe

MeO

MeO
H
NH

HO

O

Br

H
NCHO


Rice Synthesis


Forward Synthesis: Grewe cyclization
CO2H

CHO

1. a) NaHSO3
b) KCN, H2SO4
OH

OMe

MeO

2. SnCl2, HCl
HOAc
(67 %)

Br
NH4F/HF
NCHO

O

1.

MeO

NH2
OH
OMe

MeO

HO

OMe

HO

TfOH
(60 %)
O

HO

200 °C
2. a) POCl3

b) NaCNBH4
(86 %)

H
NH

MeO
1. Li/NH3
2. PhOCHO,
EtOAc
(85 %)
MeO

Br

H
NCHO

1. a) MeSO3H
b) (CH2OH)2
c) NBS
d) HCO2H(aq)
(90 %)

HO

MeO

H
NH

Rice Synthesis


Forward Synthesis: End Game
MeO

MeO

Br
1. Br2, AcOH
2. CHCl3, NaOH

HO
NCHO
O

3. H2, Pd(C),
CH2O, NaOAc
(79 %)

1. ClCO2Et
2. PhSeCl
3. NaIO4

O
N
O

4. NaBH4
5. BBr3, CHCl3
(42 %)

HO

O
N
HO
Morphine

Dihydrocodeinone



Analysis: Rice Method
• 16 steps

HO

O
N

• Overall yield 12 %

HO

• Grewe cyclization was key disconnection
• Practical method for conversion of dihydrocodeinone to morphine

Evans Synthesis


Retrosynthesis
OMe

OH
O

OMe

MeO
MeO

O

HO

H2C
H

H
N

Me

N

Me

Gates Intermediate

H

N

Me

- [CH2]
OMe
OMe

N
Me

Br
Br
Br

OMe

OMe

OMe

OMe

N

N

Me

H

Me ClO4


Evans Synthesis


Forward Synthesis: Immonium Perchlorate
OMe

OMe

OMe

O
1.
N
Me

OMe

Li

2. TsOH, 110 °C
(43 %)

N
Me

1. n-BuLi
2.
Br
Br

OMe

OMe

OMe

OMe

N

Me

Br

N

Me

3. NaI
OMe
OMe
N

H

Me ClO4

Thermodynamic
Product

OMe

OMe
MeOH

HClO4

OMe

50 °C
60 % overall,
95:5 cis:trans

N
H

Me

Kinetic
Product

ClO4

OMe
N

Me


Evans Synthesis


Forward Synthesis:
OMe

OMe
OMe
N
H

Me ClO4

CH2N2

OMe

DCM
(95 %)

Stereochemical Analysis:
H
Me N
Ar

Nu

OMe
DMSO
(95 %)

?

OMe

N Me
H

N Me
H

CHO
BF3-Et2O

MeN
Nu
H

H
OMe

Ar
MeO

?

H

OH
N

Me


Evans Synthesis


Forward Synthesis:
OMe

OMe
OMe
N
H

Me ClO4

CH2N2

OMe

DCM
(95 %)

Stereochemical Analysis:

H
Me N
Ar
Nu

OMe
DMSO

OMe

(95 %)
N Me
H

N Me
H

CHO
BF3-Et2O

MeN
Nu
H

H
OMe

Ar
MeO

H

OH
N

Me


Evans Synthesis


Forward Synthesis: End Game
OMe

OMe

MeO
1. MsCl, TEA

H



OMe

MeO

OH
N

O

O

HO

2. LiEt3BH
3. OsO4, NaIO4

H

(80 %)
Me

N

Me
Gates Intermediate

Analysis: Evans Synthesis
• Short sequence to achieve the gates intermediate (10 steps)
• Cleaver and original disconnect
• Major limitation is having to go through gates intermediate

H

N

Me

Overman Synthesis


Retrosynthesis
OH
O OH

OMe

OMe
Epoxide
Opening

Rice
O

MeN

OBn

O
DBS N

MeN
(-)-morphine

Heck
Cyclization
OHC

I
HN
SiMe2Ph

DBS

OBn
OMe

Mannich
DBS

N
I
OBn
OMe


Overman Synthesis


Forward Synthesis: amine component
H

Ph
Ph

O,
N B
H

catechol borane

OCONHPh

PhN C P

O

2.

OCH3
1.a) NH3 (l)
CO2H b.) Li wire
Cl
c.)
d.) HCl aq
(27 %)

O

?

3.

O

5. n-BuLi,
CuI(Ph3P)2
PhMe2SiLi
(81 %)

4. OsO4/NMO,
Acetone
(90 % ee, 68 %)

O
O
SiMe2Ph
6. a) TsOH,
NaIO4

Stereochemical Analysis:
R2
Syn Facial
O
Oxidative
Addition
Cu
N
O
R1
Ph

H
R1 Cu (III)
N
Ph

R2

Reductive
Elimination

H

b) DBS-NH2,
NaCNBH3
(83 %)

R2

R1
HN
SiMe2Ph

DBS =

DBS


Overman Synthesis


Forward Synthesis: amine component
H

Ph
Ph

O,

N B
H
catechol borane

OCONHPh

PhN C P

O

2.

OCH3
1.a) NH3 (l)
CO2H b.) Li wire

O

Cl
c.)
d.) HCl aq
(27 %)

3.

O

5. n-BuLi,
CuI(Ph3P)2
PhMe2SiLi

(81 %)

4. OsO4/NMO,
Acetone
(90 % ee, 68 %)

O
O
SiMe2Ph
6. a) TsOH,
NaIO4

Stereochemical Analysis:
R2
Syn Facial
O
Oxidative
Addition
Cu
N
O
R1
Ph

H
R1 Cu (III)
N
Ph

R2

Reductive
Elimination

H

b) DBS-NH2,
NaCNBH3
(83 %)

R2

R1
HN
SiMe2Ph

DBS =

DBS


Overman Synthesis


Forward Synthesis: aldehyde component
MeO

CHO

OMe

HO
OMe



2. NaH, ClCH2OMe
(96 %)

I

n-BuLi; I2; HCl

1. HC(OMe)3, H

BnBr, K2CO3

MOMO
OMe

CHO

CHO
1. CH2SMe2
2. BF3 -THF

BnO

(78 %)

(84 %)

OMe

I
BnO
OMe

Forward Synthesis: mannich reaction
OHC
HN

Ar
I

ZnI2

OBn

EtOH
60 °C

DBS

SiMe2Ph

PhMe2Si

80 %
N

H

DBS

dr > 20:1

DBS

OMe

H

R2
Favored for large R1

I

OBn
OMe

Stereochemical Analysis:
R1
Me3Si
N

N

Me3Si
Vs.

N
R2

H
R1

Favored for small R1


Overman Synthesis


Forward Synthesis: Heck Cyclization and End Game
OMe

OMe
DBS

N

Pd(TFA)2(PPh3)2

I
OBn
OMe

1. BF3-OEt

OBn

PMP, 120 °C
(60 %)

2. ArCO3H, CSA
(60 %)

DBS N

O
DBS N
HO

(1)

1. TPAP/NMO
2. H2, Pd/C,
CH2O
(69 %)
OH
O OH
MeN
(-)-morphine

OMe

1. ClCO2Et
2. PhSeCl
3. NaIO4
4. LAH

5. BBr3
(36 %)

O
MeN

O


Overman Synthesis


Forward Synthesis: Bis-Heck Cyclizations

1

O

1. a) CH2O, !
b) ClCO2Me
2. a) EtSH, BF3
b) TMDSOTf
3. CrO3, 3-5-dimethyl
pyrazole

MeO2C

1. H2C PPh3

N

I
OTBDMS

2. TBAF, THF
(47 %)

OMe

OMe

MeO2C

NaIO4
(70 %)

OH
OMe

OsO4
O

I

OMe

OMe
O

N

MeO2C

OH
O
MeO2CN

MeO2CN

PdLn

Pd(TFA)2(PPh3)2
PMP, 120 °C
(58 %)


Overman Synthesis


Analysis: Overman Approach
• 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

OH
O OH
MeN

White Synthesis


Retrosynthesis

MeO

MeO
Beckman

Rice
O
H

C-H

O
H

NMe

H

HO

O
NMe

H

O

H

O

MOMO

Insertion
O

1. Stobbe
2. Hydrogenation
O

MeO
CHO

MeO
MeO
O

H

MOMO

N2

Robinson
HO

HO
CO2Me

O

MeO

SEAr

HO
HO2C

H

O
H

H

MeO

MeO

HO

MeO

MeO

O
O

H

CO2H
O

O

OH