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NOOH
A
B
CD
E
Synthesis of Morphine Alkaloids
MeN
O
OH
OHHO
MeO
MeOOH
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(-)-thebaine
3-4% 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
HHO
HO
NHMe
12
34
5
67
8
9
1011
12
1314
15 16
NO
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 synthesis of Morphine have appeared
• This overview will encompass 6 unique routes
Biosynthesis of Morphine
CO2H
NH2HOL-Tyrosine
NH2HO
CHO
HO
dopamine
HO
NHH
HO
HO
HO
NMeH
MeO
HO
MeO
HO
(S)-reticuline
HO
MeO
MeOOH
NMe
(R)-reticulinePhenolic couplingsalutaridinesalutaridinol
thebaine codeinoneneopinone
(S)-norcoclaurine
O
MeO
MeOO
NMe
O
MeO
MeOO
NMe
HO
MeO
MeOOH
NMe
O
MeO
MeO
NMeHO
MeO
O
NMeH
O
MeO
O
NMeHH
O
HO
HO
NMeHH
morphine
SN2'
??
Gates Synthesis
Retrosynthesis
MeO
NH
O
HO
Morphine
HO
MeO
N
OH
HO
MeO
N
OH14
MeO
MeO
O
NH
OH
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. BzCl2. NaNO23. Pd/C4. FeCl3 O
O
5. SO2
6. (MeO)2SO2
BzO
OMeOMe
BzO
7. KOH8. NaNO29. Pd/C10. FeCl3
OMeOMe
OONC CO2Et1.
NEt32. K3FeCN63. KOH,EtOHOMe
OMe
OO
NC
(56 %)(78 %)
(69 %)
(82 %)
Gates Synthesis Forward Synthesis: Morphine
MeO
MeO
O
O
CN
AcOH/ΔMeO
MeO
OH
O
CN(50 %)
27 atm H2CuO/Cr2O
EtOH150 °C
MeO
MeO
O
NH(50 %)
1. N2H4/KOH2. MeI/NaH3. LAH
MeO
MeO
N
1. H2SO4
2. KOH,(HOCH2CH2)2O3. KOt-Bu/Ph2CO
(76 %)
O
HO
MeO
N
O
H
HH14
HO
MeO
N
OH14
1. (a) Br2 (b) 2,4-DNP2. 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
NH
O
HO
HO
MeO
N
OH
1. (a) Br2 (b) 2,4-DNP2. HCl
MeO
NH
O
O
Br1. 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
OHOMe
CO2H H2N
OMe
Rice Synthesis Forward Synthesis: Grewe cyclization
CHO
OHOMe
1. a) NaHSO3 b) KCN, H2SO4
2. SnCl2, HCl HOAc OH
OMe
NH2
OMe1.
200 °C2. 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/HFTfOH(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, NaOH3. H2, Pd(C), CH2O, NaOAc
1. ClCO2Et2. PhSeCl3. NaIO44. NaBH45. BBr3, CHCl3
O
HO
N
HODihydrocodeinone Morphine
(79 %) (42 %)
Evans Synthesis Retrosynthesis
O
OH
NMe
H
HOMeO
OMe
NMe
H
H2C
N Me
OMe
OMe
ClO4H
MeOOMe
NMe
H
O
Gates Intermediate
- [CH2]
N
OMe
OMe
MeBrN
OMe
OMe
Me
BrBr
Evans Synthesis Forward Synthesis: Immonium Perchlorate
N
O
Me
OMeOMe
Li1.
2. TsOH, 110 °CN
OMe
OMe
Me(43 %)
BrBr
1. n-BuLi2.
N
OMe
OMe
Me N
OMe
OMe
MeBr
N Me
3. NaI
OMe
OMeHClO4
N Me
OMe
OMe
ClO4H
MeOH
50 °CN Me
OMe
OMe
ClO4H
60 % overall, 95:5 cis:trans
Kinetic Product
Thermodynamic Product
Evans Synthesis Forward Synthesis:
CH2N2
DCM(95 %) N
OMe
OMe
Me
MeNH
ArNH
ArMe NuH
Nu
DMSO(95 %)
N Me
OMe
OMe
ClO4H H
N
OMe
OMe
CHOMe
H
MeOOMe
NMe
HOH
BF3-Et2OStereochemical Analysis:
?
?
Evans Synthesis Forward Synthesis:
CH2N2
DCM(95 %) N
OMe
OMe
Me
MeNH
ArNH
ArMe NuH
Nu
DMSO(95 %)
N Me
OMe
OMe
ClO4H H
N
OMe
OMe
CHOMe
H
MeOOMe
NMe
HOH
BF3-Et2OStereochemical Analysis:
Evans Synthesis Forward Synthesis: End Game
1. MsCl, TEA2. LiEt3BH3. OsO4, NaIO4
MeOOMe
NMe
HOH
MeOOMe
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 ON
OMe
DBS
OBn
N
OBn
OMe
DBSI
OMeOBn
OHC
SiMe2Ph
HN DBS
I
RiceEpoxideOpening
HeckCyclization
Mannich
Overman Synthesis Forward Synthesis: amine component
DBS =
OCH3CO2H
1.a) NH3 (l)b.) Li wire
c.) Cld.) HCl aq
O
(27 %)
N BH
O
H PhPh
2.
PhN C P3.4. OsO4/NMO, Acetone
OCONHPh
OO
OO
5. n-BuLi, CuI(Ph3P)2
PhMe2SiLi
SiMe2Ph
R2
O
N OPh
CuR1
R2
CuR1N(III)
Ph
R2
R1
HHSyn FacialOxidativeAddition
ReductiveElimination
(81 %)
6. a) TsOH, NaIO4
b) DBS-NH2, NaCNBH3
SiMe2Ph
HN DBS
catechol borane
,
Stereochemical Analysis:
(90 % ee, 68 %)
(83 %)
?
Overman Synthesis Forward Synthesis: amine component
DBS =
OCH3CO2H
1.a) NH3 (l)b.) Li wire
c.) Cld.) HCl aq
O
(27 %)
N BH
O
H PhPh
2.
PhN C P3.4. OsO4/NMO, Acetone
OCONHPh
OO
OO
5. n-BuLi, CuI(Ph3P)2
PhMe2SiLi
SiMe2Ph
R2
O
N OPh
CuR1
R2
CuR1N(III)
Ph
R2
R1
HHSyn FacialOxidativeAddition
ReductiveElimination
(81 %)
6. a) TsOH, NaIO4
b) DBS-NH2, NaCNBH3
SiMe2Ph
HN DBS
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, ClCH2OMe MOMOOMe
n-BuLi; I2; HCl
BnBr, K2CO3
CHO
HOOMe
CHO
OMeBnO
OMeBnO
CHOMeO OMe
1. CH2SMe2
2. BF3 -THF(78 %)(96 %) (84 %)
I I
N
R2
R1
H
Me3SiN
R2
Me3Si
R1
H
Favored for large R1 Favored for small R1
OMeOBn
OHC
SiMe2Ph
HN DBS
ZnI2EtOH N
DBS
Ar
HPhMe2Si
60 °C
NI
I
OBn
OMe
Vs.
80 %dr > 20:1 DBS
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)2PMP, 120 °C
(60 %)2. ArCO3H, CSA1. BF3-OEt
1. TPAP/NMO2. H2, Pd/C, CH2O
MeN
OMe
O O
(69 %)
MeN
O
OH
OH
(-)-morphine
1. ClCO2Et2. PhSeCl3. NaIO44. LAH5. BBr3
(36 %)
(60 %)
(1)
I
Overman Synthesis Forward Synthesis: Bis-Heck Cyclizations
1. a) CH2O, Δ b) ClCO2Me2. a) EtSH, BF3 b) TMDSOTf3. CrO3, 3-5-dimethyl pyrazole
NI
OTBDMS
OMe
MeO2C
O
1 PPh3H2C2. TBAF, THF1. N
IOH
OMe
MeO2C
MeO2CN
OMe
OH
PdLn
Pd(TFA)2(PPh3)2PMP, 120 °C
(58 %)
MeO2CN
OMe
O
MeO2C
OMe
O OOsO4NaIO4(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
OH H NMe
HO
MeO
OH H
ONMe
O
MeO
O
MOMOH H
O
O
O
OHH
HO
MeO
HO
MeO
CO2HO
O
O
MeO
O
MOMOH
H
HN2
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, MeOH2. H2, Pd(OH)2 HO
MeO
CO2HO3. LiOH(aq), THF
1. KH, HCO2Me2. 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 °CDBU
(80 %)
White Synthesis Forward Synthesis:
1. NaBH4
2. H2, Pd/C O
OMe
MeO
O
HOH
H
H
1. CH2(OMe)2
22:1
O
MeO
O
MOMOH
H
HN2
MeO
O
MOMOH H
O
Rh2(OAc)4(50 %)
O
O
OMe
MeO Br
O 3.( COCl)24. CH2N2
MeO
O
MOMOH H NH
AcO
OBs
1. NH2OH-HCl
2. p-BrPhSO2Cl, NaOAc
MeO
O
MOMOH H
ONH
MeO
O
MOMOH H N
H O
11 1
(63 %)
(77 %)
2. LiOH
(50 %)
White Synthesis End Game:
Analysis: White Approach
MeO
O
MOMOH H
ONH
MeO
OH H
ONMe
O
1. NaH/MeI2. HBr, MeCN3. D-Mperiodinane
MeO
OH H NMe
HO
1. PhSeCl/MsOH2. NaIO43. 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
OH H NMe
HO
Parker Synthesis Retrosynthesis:
O
HO
HNMe
HOmorphine
O
MeO
HNMe
O
O
MeO
HHO
NMe O
MeO
HHO
NMe
Ts
Rice [Ox]
O
MeO
HHO
NMe
TsSR
X
RadicalCyclization
MitusunoboOMe
OHBr
PhS
NTs
TBDMSO
HO Me
Parker Synthesis Forward Synthesis:
MeO
NH2 1. Li, NH32. a) TsCl, TEA b) 1N HCl
O
NTs
3. MeI, K2CO3
NTs
TBDMSO
HO1. NaBH4, CeCl32. MCPBA3. Ti(Oi-Pr)44. TBDMSCl
Me Me
(1) racemic(75 %) (63 %)
1. Br2, TEA NTsMeBr
HO
2. catechol borane
Na(Hg) NTsMe
HO
1. MCPBA2. Ti(Oi-Pr)43. TBDMSCl
NTs
TBDMSO
HO Me1
(76 %, 80 % ee)enantiomerically enriched
(90 %)
(52 %)
• Racemic Route:
•Asymmetric Route:
N BMe
O
H PhPh
(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
HOBrBr
PO
PhS (OEt)2
n-BuLi
THF SPh(82 %)
OMe
OHBr
PhS
NTs
TBDMSO
HO Me 1. PBu3, DEAD2. 10 % HF SPh
O BrN
Ts
Me
H
HO
MeO
Parker Synthesis Forward Synthesis: Radical Cyclization
SPhO Br
NTs
Me
H
HO
MeO
Bu3SnHAIBN
O
MeO
HHO
NMe
Ts
SPhO
NTs
Me
H
HO
MeO
SPhO
MeO
HHO
NMe
Ts
Bond
Rotation
OH
NMe
Ts
-[ SPh]
O
NMe
Ts
(35 %) (11 %)
Parker Synthesis Forward Synthesis: Radical Cyclization
SPhO Br
NTs
Me
H
HO
MeO
Bu3SnHAIBN
O
MeO
HHO
NMe
Ts
SPhO
NTs
Me
H
HO
MeO
SPhO
MeO
HHO
NMe
Ts
Bond
Rotation
OH
NMe
Ts
-[ SPh]
O
NMe
Ts
(35 %) (11 %)
Draw a mechanism that accountsfor formation of the side product
Parker Synthesis Forward Synthesis: Radical Cyclization
SPhO Br
NTs
Me
H
HO
MeO
Bu3SnHAIBN
O
MeO
HHO
NMe
Ts
SPhO
NTs
Me
H
HO
MeO
SPhO
MeO
HHO
NMe
Ts
Bond
Rotation
OH
NMe
Ts
-[ SPh]
O
NMe
Ts
(35 %) (11 %)
Parker Synthesis End Game
O
MeO
HHO
NMe
Ts
Li/NH3t -BuOH O
MeO
HHO
NMe O
MeO
HHO
NMe DMSO
(COCl)2O
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
NTsMeBr
HO
O
MeO
HNMe
HOmorphine
Conclusions Disconnection approaches have evolved with the
methods of synthetic chemistry
Morphine approaches will continue to grow
(Only Rice has come close to synthetically viable route)
Continued need for developing morphine derivativeswhich can attenuate addictive properties
NO
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
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