Synthesis of Morphine Alkaloids

MeO OH

CO2H HO
O OH
NH2 NMe
HO
MeN
MeO
OH

D C

N OH
B O
A
E
 Introduction
Cultivation:
Opium is harvested from the immature poppy seed capsule

OH OMe MeO

O OH O OH O Me
N
MeN H
MeN
MeO
(-)-morphine (-)-codeine (-)-thebaine
10 -15 % 3-4% 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
N OH 4
11
10 Key Features: 5 rings, 5
B 12 15
O 16
O
5 contiguous stereocenters,
N Me
13 9
A H
E
14 H compact array of functionality
HO 6 8
7
Morphine

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
HO MeO
CO2H NH2
HO NMe
dopamine NH
HO HO
NH2 H H
HO HO
L-Tyrosine CHO
HO MeO
HO
(S)-norcoclaurine (S)-reticuline

MeO MeO MeO MeO

HO O O HO

NMe NMe NMe NMe

MeO MeO MeO MeO

OH O O OH
salutaridinol salutaridine Phenolic coupling (R)-reticuline

SN2'

MeO MeO MeO HO

O ? O O ? O
H NMe NMe H NMe H NMe
H
H H
MeO O O HO
thebaine neopinone codeinone morphine
 Gates Synthesis
Retrosynthesis

MeO MeO MeO

[Ox] Epimerization
O HO HO
N [Red] N
H 14 N
H H
HO O O
Morphine

[Red]

MeO MeO MeO

[4 + 2] Reductive
O O Amidation
MeO O
MeO MeO
NC
O OH NH
CN H
O
 Gates Synthesis
Forward Synthesis: Diene

HO 1. BzCl BzO BzO

2. NaNO2 5. SO2
3. Pd/C O 6. (MeO)2SO2
OH OMe
4. FeCl3 O (78 %) OMe
(56 %)
7. KOH
8. NaNO2
9. Pd/C
10. FeCl3
(69 %)
O O
O 1. NC CO2Et
O
NEt3
OMe 2. K3FeCN6 OMe
OMe 3. KOH,EtOH OMe
NC
(82 %)
 Gates Synthesis
Forward Synthesis: Morphine

MeO MeO MeO

27 atm H2
O O CuO/Cr2O O
MeO MeO MeO
AcOH/ EtOH
O (50 %) OH 150 C NH
CN (50 %) H
CN
O

1. N2H4/KOH
2. MeI/NaH
3. LAH
(76 %)
MeO
1. (a) Br2 MeO MeO
(b) 2,4-DNP 1. H2SO4
HO
2. HCl HO 2. KOH, MeO
14
N 3. H2/ PtO2 (HOCH2CH2)2O
H N N
(7 %) 14 3. KOt-Bu/Ph2CO
O H H
O (14 %)
 Gates Synthesis
Forward Synthesis: Morphine

MeO
MeO MeO Br
1. (a) Br2
(b) 2,4-DNP 1. LAH (44 %)
HO O
2. HCl O 2. Pyr-HCl, 220 C
N
N (8 %) N (34%) H
H H
HO
O O
1-Bromo-Codeinone Morphine

Analysis: Gates Method MeO

29 Steps O
N
H
Overall Yield: 0.0014% HO

Key Disconnections: Diels-Alder & Reductive Amidation

 Rice Synthesis
Retrosynthesis

HO MeO MeO Br

O HO
O
N N NCHO
HO O O

MeO MeO Br
CO2H H2N
HO HO
H H
NH NCHO
OH
OMe OMe MeO O
 Rice Synthesis
Forward Synthesis: Grewe cyclization

CO2H MeO
OMe
CHO 1.
1. a) NaHSO3
b) KCN, H2SO4 NH2 HO
H
2. SnCl2, HCl 200 C NH
OH HOAc OH
2. a) POCl3
OMe (67 %) OMe b) NaCNBH4 MeO
(86 %) 1. Li/NH3
2. PhOCHO,
EtOAc
(85 %)
MeO Br MeO Br MeO
1. a) MeSO3H
HO NH4F/HF HO b) (CH2OH)2 HO
H H
TfOH c) NBS
NCHO NCHO NH
(60 %) d) HCO2H(aq)
O O (90 %) MeO
 Rice Synthesis
Forward Synthesis: End Game

MeO Br MeO 1. ClCO2Et HO

1. Br2, AcOH 2. PhSeCl
HO 2. CHCl3, NaOH 3. NaIO4
O O
3. H2, Pd(C), 4. NaBH4
NCHO CH2O, NaOAc N 5. BBr3, CHCl3 N
(79 %) (42 %)
O O HO
Dihydrocodeinone Morphine

Analysis: Rice Method HO

16 steps O
N
Overall yield 12 % HO

Grewe cyclization was key disconnection

Practical method for conversion of dihydrocodeinone to morphine
 Evans Synthesis
Retrosynthesis
OMe
OH
MeO OMe
O MeO
O
HO
H2C

H
H N
N Me H
Me N
Gates Intermediate Me

- [CH2]
OMe
OMe OMe
OMe
Br
Br OMe OMe

N N N
Me Br Me Me ClO4
H
 Evans Synthesis
Forward Synthesis: Immonium Perchlorate
OMe
OMe
O OMe
OMe OMe
1. OMe
Li 1. n-BuLi
OMe OMe
N 2. TsOH, 110 C 2.
Me Br
(43 %) N N N
Br Me Br Me
Me
3. NaI

OMe OMe OMe

OMe MeOH HClO4

OMe OMe
50 C
N 60 % overall, N
Me ClO4 95:5 cis:trans
N
Me
ClO4 Me
H
H
Thermodynamic Kinetic
Product Product
 Evans Synthesis
Forward Synthesis:

OMe OMe OMe

OMe

N
CH2N2
DCM
(95 %)
OMe DMSO
(95 %) ? OMe

N Me
Me ClO4 N Me
H H H
CHO

Stereochemical Analysis: BF3-Et2O

H H
Me N MeN
Ar Nu Nu Ar OMe
MeO
H

? H
OH
N
Me
 Evans Synthesis
Forward Synthesis:

OMe OMe OMe

OMe CH2N2 OMe DMSO OMe

DCM (95 %)
N (95 %) N Me
Me ClO4 N Me
H H H
CHO

Stereochemical Analysis: BF3-Et2O

H H
Me N MeN
Ar Nu Nu Ar OMe
MeO
H

OH
H
N
Me
 Evans Synthesis
Forward Synthesis: End Game

OMe OMe
OMe
MeO MeO
1. MsCl, TEA O
O
HO
2. LiEt3BH
OH 3. OsO4, NaIO4
H H
N (80 %) N H
Me 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
 Overman Synthesis
Retrosynthesis

OH OMe OMe
Epoxide
Rice Opening OBn
O OH O O
MeN MeN DBS N
(-)-morphine
Heck
Cyclization
OHC

I Mannich
HN N
DBS DBS
OBn I
SiMe2Ph OBn
OMe

OMe
 Overman Synthesis
Forward Synthesis: amine component
Ph
H
Ph
2. O,
N B OCONHPh 5. n-BuLi,
OCH3 1.a) NH3 (l) O
H CuI(Ph3P)2
CO2H b.) Li wire catechol borane O O

c.) Cl ? 3. PhN C P O PhMe2SiLi O

d.) HCl aq 4. OsO4/NMO, (81 %)

SiMe2Ph
Acetone
(27 %) (90 % ee, 68 %)
6. a) TsOH,
NaIO4
Stereochemical Analysis: b) DBS-NH2,
R2 H Reductive H NaCNBH3
Syn Facial R2 Elimination
R2 (83 %)
O Oxidative
Cu Addition R1 Cu (III) R1
R1 N O N
Ph Ph HN
DBS
SiMe2Ph

DBS =
 Overman Synthesis
Forward Synthesis: amine component
Ph
H
Ph
2. O,
N B OCONHPh 5. n-BuLi,
OCH3 1.a) NH3 (l) O
H CuI(Ph3P)2
CO2H b.) Li wire catechol borane O O
Cl 3. PhN C P O PhMe2SiLi O
c.)
d.) HCl aq 4. OsO4/NMO, (81 %)
SiMe2Ph
Acetone
(27 %) (90 % ee, 68 %)
6. a) TsOH,
NaIO4
Stereochemical Analysis: b) DBS-NH2,
R2 H Reductive H NaCNBH3
Syn Facial R2 Elimination
R2 (83 %)
O Oxidative
Cu Addition R1 Cu (III) R1
R1 N O N
Ph Ph HN
DBS
SiMe2Ph

DBS =
 Overman Synthesis
Forward Synthesis: aldehyde component
CHO MeO OMe CHO
CHO
1. HC(OMe)3, H n-BuLi; I2; HCl I 1. CH2SMe2 I
2. NaH, ClCH2OMe BnBr, K2CO3 2. BF3 -THF
HO MOMO BnO BnO
OMe (96 %) (78 %) (84 %)
OMe OMe OMe

Forward Synthesis: mannich reaction

OHC
Ar
ZnI2 PhMe2Si 80 % N
I
HN N H DBS
DBS EtOH dr > 20:1 I
60 C OBn
SiMe2Ph OBn DBS
OMe
OMe
Stereochemical Analysis:
R1 Me3Si H
Me3Si
N Vs. N
H
R1
R2 R2
Favored for large R1 Favored for small R1
 Overman Synthesis
Forward Synthesis: Heck Cyclization and End Game

OMe
OMe
N Pd(TFA)2(PPh3)2
DBS 1. BF3-OEt
I OBn O
OBn PMP, 120 C 2. ArCO3H, CSA
(60 %) (60 %) DBS N
OMe DBS N
HO
(1)
1. TPAP/NMO
2. H2, Pd/C,
CH2O
(69 %)
OH OMe
1. ClCO2Et
2. PhSeCl
3. NaIO4
O OH O O
4. LAH
MeN 5. BBr3 MeN
(36 %)
(-)-morphine
 Overman Synthesis
Forward Synthesis: Bis-Heck Cyclizations

O
1. a) CH2O,
b) ClCO2Me N 1. H2C PPh3 N
1 2. a) EtSH, BF3
MeO2C
I
MeO2C
I
2. TBAF, THF
b) TMDSOTf OTBDMS OH
(47 %)
3. CrO3, 3-5-dimethyl
pyrazole OMe OMe

OMe
OMe OMe Pd(TFA)2(PPh3)2
PMP, 120 C
OsO4 OH (58 %)
O O NaIO4 O
(70 %) MeO2CN PdLn
MeO2C MeO2CN
 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 MeO MeO

Rice Beckman C-H

O O O O H
Insertion O
H NMe H NMe H H H
H H H
HO O O MOMO O MOMO N2

MeO
MeO MeO
SEAr Robinson
HO
HO HO
O
HO2C O CO2H H
CO2Me OH
O

1. Stobbe O
2. Hydrogenation

O
MeO
MeO
HO CHO MeO

O
 White Synthesis
Forward Synthesis:

MeO MeO
MeO
1. (CH2CO2Me)2 1. P2O5, MeOH
HO 2. H2, Pd(OH)2 HO
HO CHO 2. H2, [RhCl(COD)]2,
(-)-MOD-DIOP HO2C 3. LiOH(aq), THF
CO2Me O CO2H

1. KH, HCO2Me
2. MVK, NEt3
3. NaOH, THF

MeO Br MeO Br MeO Br MeO

DBU 1. CH2N2
HO HO HO
O 70 C 2. Br2,
O Br O Br O O
(80 %) NaHCO3
H H
OMe OMe OMe OH
O O O O
 White Synthesis
Forward Synthesis:

MeO Br MeO MeO

1. CH2(OMe)2
1. NaBH4 2. LiOH
O O H H
O 2. H2, Pd/C O 3.( COCl)2 O
O
H H 4. CH2N2 H
(77 %) H
OMe OMe
O HO (50 %)
MOMO N2
22:1

Rh2(OAc)4
(50 %)

MeO MeO MeO MeO

1. NH2OH-HCl
O O O O
2. p-BrPhSO2Cl,
H OBs NaOAc H
H H NH H H N O H H
H NH (63 %)
O MOMO MOMO O
MOMO MOMO AcO
11 1
 White Synthesis
End Game:
MeO MeO MeO
1. PhSeCl/MsOH
1. NaH/MeI
O 2. HBr, MeCN 2. NaIO4
O O
3. D-Mperiodinane 3. LiAlH4
H H NH H H NMe H NMe
(90 %) 4. BBr3 H
MOMO O O O (52 %) HO

Analysis: White Approach MeO

O
29 steps H H
NMe
HO
Overall yield of 1.73 %
Asymmetry was introduced early via enantioselective hydrogenation
Key disconnect was the Rhodium (II) catalyzed C-H insertion
 Parker Synthesis
Retrosynthesis:

HO MeO MeO MeO

Rice [Ox]
O Me O O Me
O Me Me
N N N
H N
H H H Ts
HO O HO HO
morphine

Radical
Cyclization

MeO

OMe NTs Mitusunobo

O X Me
HO Me N
PhS OH H S Ts
Br TBDMSO HO R
 Parker Synthesis
Forward Synthesis:
Racemic Route:

NH2 NTs 1. NaBH4, CeCl3 NTs

1. Li, NH3 HO
Me 2. MCPBA Me
2. a) TsCl, TEA 3. Ti(Oi-Pr)4
b) 1N HCl
MeO O 4. TBDMSCl TBDMSO
3. MeI, K2CO3
(75 %) (1) (63 %) racemic

Asymmetric Route:

1. Br2, TEA NTs NTs NTs

Na(Hg) 1. MCPBA HO
1 Br Me Me Me
2. catechol (90 %) 2. Ti(Oi-Pr)4
borane 3. TBDMSCl
(76 %, 80 % ee) HO HO (52 %) TBDMSO
enantiomerically
enriched

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

Ph
Ph
Sharpless kinetic resolution of the allylic alcohol (44 %ee) (S)-B-Me = O
N B
Me
 Parker Synthesis
Forward Synthesis: Mitsunobu Coupling

MeO MeO
O n-BuLi
PhS P
HO CHO (OEt)2 THF HO SPh
Br (82 %)
Br

MeO

OMe NTs
HO Me 1. PBu3, DEAD O Me
Br
PhS OH 2. 10 % HF N
H SPh Ts
Br TBDMSO
HO
 Parker Synthesis
Forward Synthesis: Radical Cyclization

MeO MeO O

Bu3SnH
O Br Me O Me
N AIBN N
SPh H Ts
H Ts Ts N
HO Me
HO
(35 %) (11 %)

-[ SPh]
MeO
OH
MeO

Bond O
HO H
O Me SPh
N Rotation Ts
H SPh Ts N
Me
HO Ts
N
Me
 Parker Synthesis
Forward Synthesis: Radical Cyclization

MeO MeO O

Bu3SnH
O Br Me O Me
N AIBN N
SPh H Ts
H Ts Ts N
HO Me
HO
(35 %) (11 %)

-[ SPh]
MeO
OH
MeO

Bond
O
Draw Me
a mechanism O
that
HO H accounts
SPh

H
for Tsformation of the side product
SPh
N Rotation
N
Ts

Me
HO Ts
N
Me
 Parker Synthesis
Forward Synthesis: Radical Cyclization

MeO MeO O

Bu3SnH
O Br Me O Me
N AIBN N
SPh H Ts
H Ts Ts N
HO Me
HO
(35 %) (11 %)

-[ SPh]
MeO
OH
MeO

Bond O
HO H
O Me SPh
N Rotation Ts
H SPh Ts N
Me
HO Ts
N
Me
 Parker Synthesis
End Game

MeO MeO MeO

MeO

O Me Li/NH3 DMSO
N O Me O Me O Me
t -BuOH N N (COCl)2 N
H Ts H H
(85 %) H
(83 %)
HO HO O
HO
dihydrocodeinone
HO
Rice
Method
O Me
N
H
HO
morphine
 Parker Synthesis
Analysis: Parker Method
MeO
(+/-) Morphine:
O Me
22 steps H
N

Overall yield of 2.07 % HO

morphine

Radical cyclization was the key disconnect

First published in August, 1992

(-) Morphine:
NTs
24 steps Br Me

Overall yield of 1.7 % HO

CBS reduction of -bromoenone was key step

Published in January, 2006
 Conclusions
Disconnection approaches have evolved with the
methods of synthetic chemistry

D C

Gates (1952): Diels-Alder

N OH Rice (1980): Grewe Cyclization Racemic
B O Evans (1982): Iminium Salts
Overman (1993): Heck chemistry
A White (1997): C-H insertion Asymmetric
E Parker (2006): Radical Cyclization
Morphine

Morphine approaches will continue to grow

(Only Rice has come close to synthetically viable route)

Continued need for developing morphine derivatives

which can attenuate addictive properties
 References
Review:
Taber, D.F. The Enantioselective Synthesis of Morphine: Strategies and
Tactics in Organic Synthesis 2004, 5, 353
Lead References for Syntheses:
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