Synthesis of Morphine Alkaloids

HO
Synthesis of Morphine Alkaloids
NH 2
CO 2H
N
B
A
D
C
MeO
HO
MeO
O
E
OH
OH
NMe
MeN
OH
O OH

Cultivation:
Fig 1: Lanced Poppy with
raw opium exturding
Introduction
• Opium is harvested from the immature poppy seed capsule
MeN
O OH
• 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
OH
(-)-morphine
10 -15 %
MeN
OMe
O OH
MeO
MeO
(-)-codeine
(-)-thebaine
3-4% 1-2 %
H
O
N Me

Introduction
History of Morphine as a Pharmaceutical
• Laudanum (16th Century):
• Heroin (1898):
-Developed by Swiss alchemist Paracelus
-alcoholic tincture of alcohol, opium, and other herbs
-Eased suffering from the plague
-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
N
B
A
D
C
Morphine
O
E
Synthesis
OH
HO
Introduction
O
H
HO
3
4
5
6
12
2
13
14
7
1
11
15
10
16
• Landmark synthesis was in 1952 by Gates
8
9
H
N
Me
Key Features: 5 rings, 5
contiguous stereocenters,
compact array of functionality
• Since then at least 18 more total and formal synthesis
of Morphine have appeared
• This overview will encompass 6 unique routes

HO
MeO
HO
MeO
MeO
L-Tyrosine
OH
salutaridinol
S N2'
NH 2
CO 2H
NMe
Biosynthesis of Morphine
?
HO
HO
dopamine
HO
MeO
O
MeO
salutaridine
MeO
O
NH 2
CHO
NMe
HO
HO
HO
NH
H
(S)-norcoclaurine
MeO
O
MeO
O
Phenolic coupling
MeO
NMe
O
O
O
H
NMe
H
NMe
H
H
NMe
MeO
O
O
thebaine neopinone
codeinone
?
MeO
HO
HO
MeO
MeO
HO
MeO
HO
(S)-reticuline
OH
(R)-reticuline
O
H
HO
H
morphine
NMe
H
NMe
NMe

Retrosynthesis
MeO
HO
O
Morphine
MeO
MeO
NC
H
N
O
O
[Ox]
[Red]
Gates Synthesis
[4 + 2]
MeO
HO
O
MeO
MeO
H
N
O
OH
CN
Epimerization
Reductive
Amidation
MeO
HO
O
MeO
MeO
14
H
H
[Red]
O
N
O
NH

Forward Synthesis: Diene
HO
OH
Gates Synthesis
1. BzCl BzO
2. NaNO2 3. Pd/C
4. FeCl3 O
(56 %)
O
NC
O
OMe
OMe
O
1.
5. SO 2
6. (MeO) 2SO 2
(78 %)
NC CO 2Et
NEt 3
2. K3FeCN6 3. KOH,EtOH
(82 %)
BzO
O
O
OMe
OMe
7. KOH
8. NaNO2 9. Pd/C
10. FeCl3 (69 %)
OMe
OMe

Forward Synthesis: Morphine
MeO
HO
O
MeO
MeO
CN
14
H
N
O
O
AcOH/Δ
(50 %)
1. (a) Br 2
(b) 2,4-DNP
2. HCl
3. H 2/ PtO 2
(7 %)
Gates Synthesis
MeO
MeO
MeO
HO
O
14
O
OH
CN
H
N
27 atm H 2
CuO/Cr 2O
EtOH
150 °C
(50 %)
1. H 2SO 4
2. KOH,
(HOCH2CH2) 2O
3. KOt-Bu/Ph2CO (14 %)
MeO
MeO
MeO
MeO
H
O
O
NH
1. N2H4/KOH 2. MeI/NaH
3. LAH
(76 %)
H
N

Forward Synthesis: Morphine
MeO
HO
O
H
N
Analysis: Gates Method
• 29 Steps
1. (a) Br 2
(b) 2,4-DNP
2. HCl
(8 %)
• Overall Yield: 0.0014%
Gates Synthesis
MeO
O
• Key Disconnections: Diels-Alder & Reductive Amidation
O
Br
H
N
1-Bromo-Codeinone
1. LAH (44 %)
2. Pyr-HCl, 220 °C
(34%)
MeO
HO
O
MeO
H
HO
N
O
H
Morphine
N

Retrosynthesis
HO
O
HO
OMe
N
CO 2H H 2N
OH
OMe
Rice Synthesis
MeO
O
O
MeO
HO
MeO
N
H
NH
MeO
HO
O
MeO
HO
O
Br
Br
NCHO
H
NCHO

Rice Synthesis
Forward Synthesis: Grewe cyclization
MeO
CHO
OMe
HO
O
OH
Br
1. a) NaHSO 3
b) KCN, H 2SO 4
2. SnCl2, HCl
HOAc
(67 %)
NCHO
NH 4F/HF
TfOH
(60 %)
MeO
HO
OMe
O
CO 2H
OH
1.
Br
NH 2
OMe
MeO
200 °C
2. a) POCl3 b) NaCNBH4 HO
MeO
H
NH
(86 %) 1. Li/NH3 2. PhOCHO,
EtOAc
(85 %)
H
NCHO
1. a) MeSO3H b) (CH2OH) 2
c) NBS
d) HCO2H (aq)
(90 %)
MeO
HO
MeO
H
NH

Forward Synthesis: End Game
MeO
HO
O
Br
Analysis: Rice Method
• 16 steps
NCHO
• Overall yield 12 %
Rice Synthesis
MeO
1. ClCO2Et 1. Br2, AcOH
2. PhSeCl
2. CHCl3, NaOH
3. NaIO4 O
3. H2, Pd(C),
4. NaBH4 CH2O, NaOAc
N 5. BBr3, CHCl3 (79 %)
O
(42 %)
Dihydrocodeinone
• Grewe cyclization was key disconnection
• Practical method for conversion of dihydrocodeinone to morphine
HO
O
HO
HO
O
HO
N
Morphine
N

Retrosynthesis
HO
N
Me
O
OMe
OMe
OH
H
N
Me
Br
Br
Evans Synthesis
O
MeO
OMe
H
N
Me
Gates Intermediate
Br
OMe
OMe
N
Me
H 2C
MeO
H
H
N
Me
- [CH 2]
OMe
OMe
OMe
N Me
ClO 4

Evans Synthesis
Forward Synthesis: Immonium Perchlorate
O
N
Me
H
1.
OMe
OMe
Li
2. TsOH, 110 °C
OMe
OMe
N Me
Thermodynamic
Product
(43 %)
ClO 4
N
Me
MeOH
50 °C
60 % overall,
95:5 cis:trans
OMe
OMe
1. n-BuLi
2.
Br
Br
H
OMe
OMe
N Me
Kinetic
Product
ClO 4
OMe
OMe
N
Me
HClO 4
Br
OMe
OMe
N
Me
3. NaI
OMe
OMe
N Me

Forward Synthesis:
OMe
Evans Synthesis
OMe
OMe
CH2N2 DCM
OMe
H
N
Me
ClO4 (95 %)
H
N Me
Stereochemical Analysis:
H
Me N Ar
Nu
MeN H
Nu
H
Ar
DMSO
(95 %)
?
H
MeO
?
OMe
OMe
N
CHO
Me
BF 3-Et 2O
OMe
OH
H
N
Me

Forward Synthesis:
OMe
Evans Synthesis
OMe
OMe
CH2N2 DCM
OMe
H
N
Me
ClO4 (95 %)
H
N Me
Stereochemical Analysis:
H
Me N Ar Nu
MeN H
Nu
H
Ar
DMSO
(95 %)
H
MeO
OMe
OMe
N
CHO
Me
BF 3-Et 2O
OMe
OH
H
N
Me

Forward Synthesis: End Game
MeO
OMe
OH
H
N
Me
Evans Synthesis
1. MsCl, TEA
2. LiEt3BH 3. OsO4, NaIO4 (80 %)
Analysis: Evans Synthesis
O
MeO
OMe
H
N
Me
Gates Intermediate
• Short sequence to achieve the gates intermediate (10 steps)
• Cleaver and original disconnect
• Major limitation is having to go through gates intermediate
HO
O
H
N
Me
OMe

Retrosynthesis
MeN
(-)-morphine
OH
O OH
Overman Synthesis
Rice
SiMe 2Ph
MeN
HN DBS
OHC
OMe
O O
OMe
I
OBn
Epoxide
Opening
Mannich
DBS
DBS
N
N
I
OMe
OBn
Heck
Cyclization
OBn
OMe

Overman Synthesis
Forward Synthesis: amine component
OCH 3
CO 2H
1.a) NH 3 (l)
b.) Li wire
c.)
d.) HCl aq
(27 %)
Stereochemical Analysis:
Cu
R 1
R 2
O
N O
Ph
Cl
Syn Facial
Oxidative
Addition
O
?
H
R Cu 1 (III)
N
Ph
2.
3.
H Ph
Ph
O
N
BH
catechol borane
PhN C P
4. OsO4/NMO, Acetone
(90 % ee, 68 %)
R 2
,
Reductive
Elimination
OCONHPh
H
R 1
O
O
R 2
5. n-BuLi,
CuI(Ph 3P) 2
PhMe 2SiLi
(81 %)
DBS =
SiMe 2Ph
O
6. a) TsOH,
NaIO 4
SiMe 2Ph
O
b) DBS-NH 2,
NaCNBH 3
(83 %)
HN DBS

Overman Synthesis
Forward Synthesis: amine component
OCH 3
CO 2H
1.a) NH 3 (l)
b.) Li wire
c.)
d.) HCl aq
(27 %)
Stereochemical Analysis:
Cu
R 1
R 2
O
N O
Ph
Cl
Syn Facial
Oxidative
Addition
O
H
R Cu 1 (III)
N
Ph
2.
3.
H Ph
Ph
O
N
BH
catechol borane
PhN C P
4. OsO4/NMO, Acetone
(90 % ee, 68 %)
R 2
,
Reductive
Elimination
OCONHPh
H
R 1
O
O
R 2
5. n-BuLi,
CuI(Ph 3P) 2
PhMe 2SiLi
(81 %)
DBS =
SiMe 2Ph
O
6. a) TsOH,
NaIO 4
SiMe 2Ph
O
b) DBS-NH 2,
NaCNBH 3
(83 %)
HN DBS

Overman Synthesis
Forward Synthesis: aldehyde component
HO
CHO
OMe
1. HC(OMe) 3, H
MeO OMe
n-BuLi; I 2; HCl
2. NaH, ClCH2OMe MOMO
BnBr, K2CO 2. BF
3
3 -THF
BnO
(96 %)
OMe (78 %)
(84 %)
OMe
Forward Synthesis: mannich reaction
SiMe 2Ph
HN DBS
OHC
OMe
I
OBn
ZnI 2
EtOH
60 °C
PhMe 2Si
Me 3Si
N
R 2
N
DBS
R 1
H
H
Stereochemical Analysis:
Ar
CHO
I 1. CH2SMe2 I
Vs.
80 %
dr > 20:1
Me 3Si
N
R 2
H
DBS
R 1
Favored for large R 1 Favored for small R 1
N
BnO
I
OMe
CHO
OBn
OMe

Overman Synthesis
Forward Synthesis: Heck Cyclization and End Game
DBS
N
I
(1)
OBn
OMe
Pd(TFA) 2(PPh 3) 2
PMP, 120 °C
(60 %)
DBS
N
MeN
OMe
OBn
(-)-morphine
OH
O OH
1. BF 3-OEt
2. ArCO3H, CSA
(60 %)
1. ClCO 2Et
2. PhSeCl
3. NaIO 4
4. LAH
5. BBr 3
(36 %)
DBS
N
MeN
HO
OMe
O
1. TPAP/NMO
2. H 2, Pd/C,
CH 2O
(69 %)
OMe
O O

Overman Synthesis
Forward Synthesis: Bis-Heck Cyclizations
1
MeO 2C
1. a) CH 2O, Δ
b) ClCO 2Me
2. a) EtSH, BF 3
b) TMDSOTf
3. CrO 3, 3-5-dimethyl
pyrazole
OMe
O O
OsO 4
NaIO 4
(70 %)
MeO 2C
N
MeO 2CN
I
O
OTBDMS
OMe
OMe
O
1. H2C PPh3 N
MeO2C 2. TBAF, THF
(47 %)
MeO 2CN
OMe
OH
PdL n
I
OH
OMe
Pd(TFA) 2(PPh 3) 2
PMP, 120 °C
(58 %)

Analysis: Overman Approach
Overman Synthesis
• 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
MeN
OH
O OH

Retrosynthesis
MeO
O
H H
HO
MeO
HO
NMe
MeO
HO
HO2C CHO
MeO
O
H H
O
White Synthesis
O
NMe
MeO
Rice Beckman C-H
CO 2Me
1. Stobbe
2. Hydrogenation
MeO
MeO
O
O
S EAr
MeO
HO
MOMO
O
O
O
H H
CO 2H
O
Insertion
Robinson
MeO
H
MOMO
MeO
HO
O
O
H
H
H
O
N 2
OH
O

Forward Synthesis:
MeO
HO
MeO
O
O
Br
CHO
O
OMe
(CH 2CO 2Me) 2
1.
2. H 2, [RhCl(COD)] 2,
(-)-MOD-DIOP
MeO
HO
Br
O
White Synthesis
Br
MeO
HO
HO2C O
OMe
DBU
70 °C
(80 %)
CO 2Me
MeO
HO
Br
O
1. P 2O 5, MeOH
2. H2, Pd(OH) 2
3. LiOH (aq), THF
H
Br
O
OMe
MeO
HO
O
MeO
1. CH2N2 HO
2. Br2, NaHCO3 O
CO 2H
1. KH, HCO 2Me
2. MVK, NEt 3
3. NaOH, THF
H
OH
O

Forward Synthesis:
MeO
O
MeO
O
O
Br
O
OMe
MeO
O
1. NaBH 4
2. H 2, Pd/C
(77 %)
H
MOMO
H
NH H
O MOMO
H N
H
11 1
White Synthesis
O
MeO
H
HO
O
H
H
22:1
MeO
MOMO
O
O
OMe
H H
AcO
1. CH2(OMe) 2
2. LiOH
3.( COCl) 2
4. CH2N2 (50 %)
OBs
NH
MeO
H
MOMO
O
H
MeO
H
1. NH2OH-HCl O
2. p-BrPhSO2Cl, NaOAc H H
(63 %)
MOMO
O
N 2
Rh 2(OAc) 4
(50 %)
O

End Game:
MeO
MOMO
O
H H
O
NH
Analysis: White Approach
• 29 steps
1. NaH/MeI
2. HBr, MeCN
3. D-Mperiodinane
(90 %)
• Overall yield of 1.73 %
White Synthesis
MeO
O
H H
O
O
NMe
1. PhSeCl/MsOH
2. NaIO 4
3. LiAlH 4
4. BBr 3
(52 %)
MeO
O
H H
• Asymmetry was introduced early via enantioselective hydrogenation
• Key disconnect was the Rhodium (II) catalyzed C-H insertion
MeO
O
H H
HO
HO
NMe
NMe

Retrosynthesis:
HO
H
O
HO morphine
N Me
Rice
PhS
MeO
H
O
O
Br
Parker Synthesis
OMe
OH
N Me
TBDMSO
[Ox]
MeO
H
HO
O
NTs
HO Me
N Me
Mitusunobo
MeO
H
HO
MeO
H
HO
O
O
X
S
R
Me
N
Ts
Radical
Cyclization
Me
N
Ts

Forward Synthesis:
MeO
1
• Racemic Route:
NH 2
1. Br 2, TEA
2. catechol
borane
(76 %, 80 % ee)
1. Li, NH 3
2. a) TsCl, TEA
b) 1N HCl
3. MeI, K2CO3 (75 %)
•Asymmetric Route:
Br
HO
Parker Synthesis
NTs
Me
O
NTs
Me
1. NaBH4, CeCl3 2. MCPBA
3. Ti(Oi-Pr) 4
HO
NTs
Me
4. TBDMSCl TBDMSO
(1) (63 %)
racemic
Na(Hg)
(90 %)
Failed routes included direct CBS reduction of 1 (35 % ee) and
Sharpless kinetic resolution of the allylic alcohol (44 %ee)
HO
NTs
Me
1. MCPBA
2. Ti(Oi-Pr) 4
3. TBDMSCl
(52 %)
TBDMSO
NTs
HO Me
enantiomerically
enriched
(S)-B-Me =
H Ph
Ph
O
N
BMe

Parker Synthesis
Forward Synthesis: Mitsunobu Coupling
PhS
MeO
HO CHO
Br
Br
OMe
OH
PhS
TBDMSO
O
P
(OEt) 2
n-BuLi
HO
NTs
Me 1. PBu3, DEAD
MeO
THF HO
SPh
(82 %)
Br
2. 10 % HF
MeO
O Br
H
HO
SPh
Me
N
Ts

Parker Synthesis
Forward Synthesis: Radical Cyclization
MeO
O Br
H
HO
MeO
O
H
HO
SPh
SPh
Me
N
Ts
-[ SPh]
Me
N
Ts
Bu 3SnH
AIBN
Bond
Rotation
MeO
H
HO
MeO
O
O
HO
N
Me
N
Ts
Ts
N
Me
(35 %) (11 %)
Me
Ts
H
SPh
O
OH
Ts
N
Me

Parker Synthesis
Forward Synthesis: Radical Cyclization
MeO
O Br
H
HO
MeO
O
H
HO
SPh
Me
N
Ts
-[ SPh]
Bu 3SnH
AIBN
MeO
H
HO
MeO
Bond
O
Draw a mechanism that HO H accounts
Me
SPh
N Rotation
SPh for formation of the side product
Ts
O
N
Me
N
Ts
Ts
N
Me
(35 %) (11 %)
Me
Ts
O
OH
Ts
N
Me

Parker Synthesis
Forward Synthesis: Radical Cyclization
MeO
O Br
H
HO
MeO
O
H
HO
SPh
SPh
Me
N
Ts
-[ SPh]
Me
N
Ts
Bu 3SnH
AIBN
Bond
Rotation
MeO
H
HO
MeO
O
O
HO
N
Me
N
Ts
Ts
N
Me
(35 %) (11 %)
Me
Ts
H
SPh
O
OH
Ts
N
Me

End Game
MeO
H
HO
O
Me
N
Ts
Li/NH 3
t -BuOH
(85 %)
MeO
H
HO
Parker Synthesis
O
MeO
Me O
N
H
HO
HO
H
O
HO
morphine
DMSO
Me
N
(COCl) 2
(83 %)
N Me
MeO
H
O
O
dihydrocodeinone
Rice
Method
N Me

Analysis: Parker Method
(+/-) Morphine:
• 22 steps
• Overall yield of 2.07 %
Parker Synthesis
• Radical cyclization was the key disconnect
• First published in August, 1992
(-) Morphine:
• 24 steps
• Overall yield of 1.7 %
• CBS reduction of α-bromoenone was key step
• Published in January, 2006
MeO
H
O
HO morphine
Br
HO
N Me
NTs
Me

Conclusions
Disconnection approaches have evolved with the
methods of synthetic chemistry
N
B
A
D
C
Morphine
O
E
OH
Gates (1952): Diels-Alder
Rice (1980): Grewe Cyclization
Evans (1982): Iminium Salts
Overman (1993): Heck chemistry
White (1997): C-H insertion
Parker (2006): Radical Cyclization
Morphine approaches will continue to grow
(Only Rice has come close to synthetically viable route)
Racemic
Asymmetric
Continued need for developing morphine derivatives
which can attenuate addictive properties

Review:
References
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