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N
O
OH
A
B
CD
E
Synthesis of Morphine Alkaloids
MeN
O
OH
OHHO
MeO
MeO
OH
NMe
CO2H
NH2HO
Introduction Cultivation:
Fig 1: Lanced Poppy withraw 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
MeN
O
OH
OH
10 -15 %
MeN
O
OMe
OH
(-)-codeine(-)-morphine
O
MeO
HN
Me
MeO
(-)-thebaine3-4% 1-2 %
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
O
H
HO
HO
NH
Me
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1516
N
O
OH
A
B
CD
E
Morphine
Key Features: 5 rings, 5contiguous stereocenters,compact array of functionality
Synthesis
• Landmark synthesis was in 1952 by Gates
• Since then at least 18 more total and formal synthesisof Morphine have appeared
• This overview will encompass 6 unique routes
Biosynthesis of Morphine
CO2H
NH2HO
L-Tyrosine
NH2HO
CHO
HO
dopamine
HO
NH
H
HO
HO
HO
NMe
H
MeO
HO
MeO
HO
(S)-reticuline
HO
MeO
MeO
OH
NMe
(R)-reticulinePhenolic couplingsalutaridinesalutaridinol
thebaine codeinoneneopinone
(S)-norcoclaurine
O
MeO
MeO
O
NMe
O
MeO
MeO
O
NMe
HO
MeO
MeO
OH
NMe
O
MeO
MeO
NMeH
O
MeO
O
NMeH
O
MeO
O
NMeHH
O
HO
HO
NMeHH
morphine
SN2'
??
Gates Synthesis
Retrosynthesis
MeO
NH
O
HO
Morphine
HO
MeO
N
O
H
HO
MeO
N
O
H14
MeO
MeO
O
NH
O
H
MeO
MeO
OH
O
CN
MeO
MeO
O
O
Epimerization[Ox]
[Red]
[Red]
ReductiveAmidation
[4 + 2]
NC
Gates Synthesis Forward Synthesis: Diene
OH
HO 1. BzCl
2. NaNO2
3. Pd/C
4. FeCl3 O
O
5. SO2
6. (MeO)2SO2
BzO
OMe
OMe
BzO
7. KOH
8. NaNO2
9. Pd/C
10. FeCl3
OMe
OMe
O
ONC CO2Et1.
NEt32. K3FeCN6
3. KOH,EtOHOMe
OMe
O
O
NC
(56 %)(78 %)
(69 %)
(82 %)
Gates Synthesis Forward Synthesis: Morphine
MeO
MeO
O
O
CN
AcOH/!MeO
MeO
OH
O
CN(50 %)
27 atm H2
CuO/Cr2O
EtOH150 °C
MeO
MeO
O
NH(50 %)
1. N2H4/KOH
2. MeI/NaH
3. LAH
MeO
MeO
N
1. H2SO4
2. KOH,(HOCH2CH2)2O
3. KOt-Bu/Ph2CO
(76 %)
O
HO
MeO
N
O
H
HH14
HO
MeO
N
O
H14
1. (a) Br2 (b) 2,4-DNP
2. HCl3. H2/ PtO2
(7 %)(14 %)
Gates Synthesis Forward Synthesis: Morphine
Analysis: Gates Method
• 29 Steps
• Overall Yield: 0.0014%
• Key Disconnections: Diels-Alder & Reductive Amidation
MeO
N
H
O
HO
HO
MeO
N
O
H
1. (a) Br2 (b) 2,4-DNP
2. HCl
MeO
NH
O
O
Br
1. LAH (44 %)
2. Pyr-HCl, 220 °C (34%)
MeO
NH
O
HO
1-Bromo-Codeinone Morphine
(8 %)
Rice Synthesis Retrosynthesis
O
HO
N
HO
O
MeO
N
O
HO
MeO
NCHO
Br
O
NCHO
HO
MeO
O
H
Br
NH
HO
MeO
MeO
H
OH
OMe
CO2H H2N
OMe
Rice Synthesis Forward Synthesis: Grewe cyclization
CHO
OH
OMe
1. a) NaHSO3
b) KCN, H2SO4
2. SnCl2, HCl HOAc OH
OMe
NH2
OMe1.
200 °C
2. a) POCl3 b) NaCNBH4
NH
HO
MeO
MeO
H
(67 %)
(86 %) 1. Li/NH3
2. PhOCHO, EtOAc
NH
HO
MeO
MeO
H
1. a) MeSO3H b) (CH2OH)2
c) NBSd) HCO2H(aq)
NCHO
HO
MeO
O
H
Br
(85 %)
(90 %)
HO
MeO
NCHO
Br
O
NH4F/HF
TfOH
(60 %)
CO2H
Rice Synthesis Forward Synthesis: End Game
Analysis: Rice Method
O
HO
N
HO
• 16 steps
• Overall yield 12 %
• Grewe cyclization was key disconnection
• Practical method for conversion of dihydrocodeinone to morphine
HO
MeO
NCHO
Br
O
O
MeO
N
O
1. Br2, AcOH2. CHCl3, NaOH
3. H2, Pd(C), CH2O, NaOAc
1. ClCO2Et2. PhSeCl3. NaIO4
4. NaBH45. BBr3, CHCl3
O
HO
N
HO
Dihydrocodeinone Morphine
(79 %) (42 %)
Evans Synthesis Retrosynthesis
O
OH
NMe
H
HO
MeO
OMe
NMe
H
H2C
NMe
OMe
OMe
ClO4
H
MeO
OMe
NMe
H
O
Gates Intermediate
- [CH2]
N
OMe
OMe
MeBr
N
OMe
OMe
Me
Br
Br
Evans Synthesis Forward Synthesis: Immonium Perchlorate
N
O
Me
OMe
OMe
Li1.
2. TsOH, 110 °C
N
OMe
OMe
Me
(43 %)Br
Br
1. n-BuLi
2.
N
OMe
OMe
MeN
OMe
OMe
MeBr
NMe
3. NaI
OMe
OMeHClO4
NMe
OMe
OMe
ClO4
H
MeOH
50 °CN
Me
OMe
OMe
ClO4
H
60 % overall, 95:5 cis:trans
Kinetic Product
Thermodynamic Product
Evans Synthesis Forward Synthesis:
CH2N2
DCM
(95 %) N
OMe
OMe
Me
MeNH
ArN
H
ArMeNu
H
Nu
DMSO
(95 %)
NMe
OMe
OMe
ClO4
H HN
OMe
OMe
CHO
MeH
MeO
OMe
NMe
HOH
BF3-Et2OStereochemical Analysis:
?
?
Evans Synthesis Forward Synthesis:
CH2N2
DCM
(95 %) N
OMe
OMe
Me
MeNH
ArN
H
ArMeNu
H
Nu
DMSO
(95 %)
NMe
OMe
OMe
ClO4
H HN
OMe
OMe
CHO
MeH
MeO
OMe
NMe
HOH
BF3-Et2OStereochemical Analysis:
Evans Synthesis Forward Synthesis: End Game
1. MsCl, TEA
2. LiEt3BH
3. OsO4, NaIO4
MeO
OMe
NMe
HOH
MeO
OMe
NMe
H
O
Gates Intermediate
O
OMe
NMe
H
HO
(80 %)
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
MeN
O
OH
OH
(-)-morphine
MeN
OMe
O O
N
OMe
DBS
OBn
N
OBn
OMe
DBSI
OMe
OBn
OHC
SiMe2Ph
HNDBS
I
RiceEpoxideOpening
HeckCyclization
Mannich
Overman Synthesis Forward Synthesis: amine component
DBS =
OCH3
CO2H
1.a) NH3 (l)
b.) Li wire
c.) Cl
d.) HCl aq
O
(27 %)
N BH
O
HPh
Ph
2.
PhN C P3.
4. OsO4/NMO, Acetone
OCONHPh
O
O
O
O
5. n-BuLi, CuI(Ph3P)2
PhMe2SiLi
SiMe2Ph
R2
O
N O
Ph
CuR1
R2
CuR1
N
(III)
Ph
R2
R1
HHSyn Facial
OxidativeAddition
ReductiveElimination
(81 %)
6. a) TsOH, NaIO4
b) DBS-NH2, NaCNBH3
SiMe2Ph
HNDBS
catechol borane
,
Stereochemical Analysis:
(90 % ee, 68 %)
(83 %)
?
Overman Synthesis Forward Synthesis: amine component
DBS =
OCH3
CO2H
1.a) NH3 (l)
b.) Li wire
c.) Cl
d.) HCl aq
O
(27 %)
N BH
O
HPh
Ph
2.
PhN C P3.
4. OsO4/NMO, Acetone
OCONHPh
O
O
O
O
5. n-BuLi, CuI(Ph3P)2
PhMe2SiLi
SiMe2Ph
R2
O
N O
Ph
CuR1
R2
CuR1
N
(III)
Ph
R2
R1
HHSyn Facial
OxidativeAddition
ReductiveElimination
(81 %)
6. a) TsOH, NaIO4
b) DBS-NH2, NaCNBH3
SiMe2Ph
HNDBS
catechol borane
,
Stereochemical Analysis:
(90 % ee, 68 %)
(83 %)
Overman Synthesis Forward Synthesis: aldehyde component
Forward Synthesis: mannich reaction
1. HC(OMe)3, H
2. NaH, ClCH2OMeMOMO
OMe
n-BuLi; I2; HCl
BnBr, K2CO3
CHO
HO
OMe
CHO
OMe
BnO
OMe
BnO
CHOMeO OMe
1. CH2SMe2
2. BF3 -THF
(78 %)(96 %) (84 %)
I I
N
R2
R1
H
Me3Si
N
R2
Me3Si
R1
H
Favored for large R1 Favored for small R1
OMe
OBn
OHC
SiMe2Ph
HNDBS
ZnI2
EtOHN
DBS
Ar
H
PhMe2Si
60 °C
N
I
I
OBn
OMe
Vs.
80 %
dr > 20:1DBS
Stereochemical Analysis:
Overman Synthesis Forward Synthesis: Heck Cyclization and End Game
N
OMe
DBS
OBn
N
OMe
DBS
O
HO
N
OBn
OMe
DBS Pd(TFA)2(PPh3)2
PMP, 120 °C
(60 %)2. ArCO3H, CSA
1. BF3-OEt
1. TPAP/NMO2. H2, Pd/C, CH2O
MeN
OMe
O O
(69 %)
MeN
O
OH
OH
(-)-morphine
1. ClCO2Et2. PhSeCl3. NaIO4
4. LAH5. BBr3
(36 %)
(60 %)
(1)
I
Overman Synthesis Forward Synthesis: Bis-Heck Cyclizations
1. a) CH2O, ! b) ClCO2Me
2. a) EtSH, BF3 b) TMDSOTf
3. CrO3, 3-5-dimethyl pyrazole
N
I
OTBDMS
OMe
MeO2C
O
1PPh3H2C
2. TBAF, THF
1. N
I
OH
OMe
MeO2C
MeO2CN
OMe
OH
PdLn
Pd(TFA)2(PPh3)2
PMP, 120 °C(58 %)
MeO2CN
OMe
O
MeO2C
OMe
O O
OsO4
NaIO4(70 %)
(47 %)
Overman Synthesis Analysis: Overman Approach
MeN
O
OH
OH
• 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
White Synthesis Retrosynthesis
MeO
O
H HNMe
HO
MeO
O
H H
O
NMe
O
MeO
O
MOMO
H HO
O
O
OHH
HO
MeO
HO
MeO
CO2HO
O
O
MeO
O
MOMO
H
H
H
N2
HO
MeO
CO2MeHO2C
CHOHO
MeOO
MeO
O
MeO
Rice Beckman C-H
Insertion
RobinsonSEAr
1. Stobbe 2. Hydrogenation
White Synthesis Forward Synthesis:
(CH2CO2Me)21.
2. H2, [RhCl(COD)]2, (-)-MOD-DIOP
HO
MeO
CO2Me
1. P2O5, MeOH
2. H2, Pd(OH)2 HO
MeO
CO2HO3. LiOH(aq), THF
1. KH, HCO2Me
2. MVK, NEt33. NaOH, THF
1. CH2N2
2. Br2, NaHCO3
O
O
OMeH
HO
MeO Br
O
O
OHH
HO
MeO
Br
O
O
OMe
HO
MeO Br
Br
O
O
OMe
MeO Br
O
HO2CCHOHO
MeO
70 °C
DBU
(80 %)
White Synthesis Forward Synthesis:
1. NaBH4
2. H2, Pd/C O
OMe
MeO
O
HO
H
H
H
1. CH2(OMe)2
22:1
O
MeO
O
MOMO
H
H
H
N2
MeO
O
MOMO
H HO
Rh2(OAc)4(50 %)
O
O
OMe
MeO Br
O 3.( COCl)24. CH2N2
MeO
O
MOMO
H HNH
AcO
OBs
1. NH2OH-HCl
2. p-BrPhSO2Cl, NaOAc
MeO
O
MOMO
H H
O
NH
MeO
O
MOMO
H H NH
O
11 1
(63 %)
(77 %)
2. LiOH
(50 %)
White Synthesis End Game:
Analysis: White Approach
MeO
O
MOMO
H H
O
NH
MeO
O
H H
O
NMe
O
1. NaH/MeI2. HBr, MeCN
3. D-Mperiodinane
MeO
O
H HNMe
HO
1. PhSeCl/MsOH2. NaIO4
3. LiAlH44. BBr3
(52 %)(90 %)
• 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 HNMe
HO
Parker Synthesis Retrosynthesis:
O
HO
HNMe
HOmorphine
O
MeO
HNMe
O
O
MeO
H
HO
NMe O
MeO
H
HO
NMe
Ts
Rice [Ox]
O
MeO
H
HO
NMe
TsS
R
X
RadicalCyclization
MitusunoboOMe
OH
Br
PhS
NTs
TBDMSO
HO Me
Parker Synthesis Forward Synthesis:
MeO
NH21. Li, NH3
2. a) TsCl, TEA b) 1N HCl
O
NTs
3. MeI, K2CO3
NTs
TBDMSO
HO1. NaBH4, CeCl32. MCPBA
3. Ti(Oi-Pr)44. TBDMSCl
Me Me
(1) racemic(75 %) (63 %)
1. Br2, TEA NTs
MeBr
HO
2. catechol borane
Na(Hg)NTs
Me
HO
1. MCPBA
2. Ti(Oi-Pr)43. TBDMSCl
NTs
TBDMSO
HO Me1
(76 %, 80 % ee)
enantiomerically enriched
(90 %)
(52 %)
• Racemic Route:
•Asymmetric Route:
N BMe
O
HPh
Ph
(S)-B-Me =
Failed routes included direct CBS reduction of 1 (35 % ee) andSharpless kinetic resolution of the allylic alcohol (44 %ee)
Parker Synthesis Forward Synthesis: Mitsunobu Coupling
MeO
HO CHO
MeO
HO
BrBr
P
O
PhS(OEt)2
n-BuLi
THF SPh(82 %)
OMe
OH
Br
PhS
NTs
TBDMSO
HO Me 1. PBu3, DEAD
2. 10 % HF SPh
O BrN
Ts
Me
H
HO
MeO
Parker Synthesis Forward Synthesis: Radical Cyclization
SPh
O BrN
Ts
Me
H
HO
MeO
Bu3SnH
AIBNO
MeO
H
HO
NMe
Ts
SPh
ON
Ts
Me
H
HO
MeO
SPh
O
MeO
HHO
N
Me
Ts
Bond
Rotation
OH
N
Me
Ts
-[ SPh]
O
N
Me
Ts
(35 %) (11 %)
Parker Synthesis Forward Synthesis: Radical Cyclization
SPh
O BrN
Ts
Me
H
HO
MeO
Bu3SnH
AIBNO
MeO
H
HO
NMe
Ts
SPh
ON
Ts
Me
H
HO
MeO
SPh
O
MeO
HHO
N
Me
Ts
Bond
Rotation
OH
N
Me
Ts
-[ SPh]
O
N
Me
Ts
(35 %) (11 %)
Draw a mechanism that accountsfor formation of the side product
Parker Synthesis Forward Synthesis: Radical Cyclization
SPh
O BrN
Ts
Me
H
HO
MeO
Bu3SnH
AIBNO
MeO
H
HO
NMe
Ts
SPh
ON
Ts
Me
H
HO
MeO
SPh
O
MeO
HHO
N
Me
Ts
Bond
Rotation
OH
N
Me
Ts
-[ SPh]
O
N
Me
Ts
(35 %) (11 %)
Parker Synthesis End Game
O
MeO
H
HO
NMe
Ts
Li/NH3
t -BuOHO
MeO
H
HO
NMe O
MeO
H
HO
NMe
DMSO
(COCl)2
O
MeO
HN
Me
O
(85 %)(83 %)
O
HO
HN
Me
dihydrocodeinone
HO
RiceMethod
morphine
Parker Synthesis Analysis: Parker Method
(+/-) Morphine:
• 22 steps
• Overall yield of 2.07 %
• 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
NTs
MeBr
HO
O
MeO
HNMe
HOmorphine
Conclusions Disconnection approaches have evolved with the
methods of synthetic chemisty
Morphine appoaches will contiune to grow
(Only Rice has come close to synthetically viable route)
Continued need for developing morphine derivatieswith which can attenuate addictive properties
N
O
OH
A
B
CD
E
Morphine
Gates (1952): Diels-AlderRice (1980): Grewe CyclizationEvans (1982): Iminium SaltsOverman (1993): Heck chemistryWhite (1997): C-H insertionParker (2006): Radical Cyclization
Racemic
Asymmetric
References
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 andTactics in Organic Synthesis 2004, 5, 353
