ke li- morphine and codeine
TRANSCRIPT
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Morphine and CodeineBaran Lab KE LI
0
MeO
O
HO
HH
N
HO
O
HO
HH
N
MeO
O
MeO
H N
NMeO
MeO
OMe
MeO
Papaverine
O
O
OH
OO
OHHO
Meconic Acid
N
O
OOMe
MeO
MeO
O
Noscapine
Morphine Codeine Thebaine
Raw opium contains approximately 25 different alkaloids by weight,depending on the variety. The chief alkaloids are Morphine (4-21%),Codeine (0.8-2.5%), Thebaine (0.5-2%), Papaverine (0.5-2.5%), Noscapine (4-8%),Meconic Acid (3-5%).
For excellent reviews on Morphine and Codeine, see
1. Hudlicky, T. et al Studies in Natural ProductsChemistry, 1996, 18, 43
2. Taber, D.F. et al Strategies and Tactics in Organicsynthesis, 2004, 5, 353
3. Maier, M. Organic Synthesis Highlights II, 1995, 357
4.Novak, B.H. et alCurr. Org. Chem. 2000, 4, 343
5. Blakemore, P.R. et al, Chem. Comm. 2002, 1159
6. Zezula, J. et al, Synlett, 2005, 388
Gates 1952 (-)-MorphineRice 1980 (-)-DihydrocodeinoneEvans 1982 O-Me-thebainone-AFuchs 1988 CodeineTius 1992 Thebainone-AParker 1992 DihydrocodeinoneOverman 1993 (-)-DihydrocodeinoneMulzer 1996 (-)-DihydrocodeinoneParsons 1996 MorphineWhite 1997 (+)-MorphineHudlicky 1998 10-hydroxy-ent-epi-dihydrocodeinoneCheng 2000 Desoxycodeine-DOgasawara 2001 (-)-Dihydrocodeinone ethylene ketalTaber 2002 (-)-MorphineTrost 2002 (-)-CodeineMichels 2005 14-Hydroxycodeinone
The following work will be included in this talk due to the time limitation.
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Morphine and CodeineBaran Lab KE LI
1
HO
O
HO
HH
N
12
3
4
5
67
8
9
1012
1314
15
MeO
O
HO
HH
N
(-)-Codeine
MeO
O
HH
N
Codeinone
O
MeO
O
HOH
N
O
Hydoxycodeinone
MeO
O
MeO
H N
Thebaine
HO
O
HOH
N
O
Naltrexone
HO
O
HOH
N
O
Naloxone
(-)-Morphine
Morphine and codeine are the principal ingredients from opium poppy latex
extract. The legal medicinal use of morphine in the US is more than 80 tons/yearand the world wide illicit market for narcotics is probably more than $760 billion.
HO
CO2H
NH2
L-tyrosine
HONH2
HO
HO
CHO
+
HONH
MeO
MeO
HON
MeO
MeO
H
HO
MeO
HO
OH
MeO
NMe
MeO
O
O
MeO
NMe
Thebaine
MeO
O
O
NMeH
neopinone
Codeinone
Codeine
Morphine
MeN
O
OMe
O
MeN
O
OH
OH
HO
O
HO
H
H
N
Nalorphine
Dihydrocodeinone
11
HO
O
O
HOH
N
Noroxymorphone
H
dopamine
(S)-reticuline
(R)-reticulinesalutaridine
Chem. Comm. 2002, 1159
Biosynthesis:
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CHO
O
Morphine and CodeineBaran Lab KE LI
5
MeO
X
HNMe
-CH2MeO
OMe
OMe
N
X
Me
OMe
OMe
N
H2C
MeBr
CH2Br
CH2Br
ZnBr2, C6H6
Br
Br
NMe
O
OMe
OMe
Li
NMe
HO
OMe
OMe
NMe
OMe
OMe
OMe
OMe
N
H2C
Me
OMe
OMe
N
H2C
MeH
OMe
OMe
N
H2C
MeH
OMe
OMe
N
H2C
MeHCHO
MeO
HNMe
MeO OH
MeO
O
HNMe
MeO
O
O
O
OMeO
NHCO2MeO
OMeO
NHCO2Me
OO
H
H
OMeO
MeO2CN H
H
O
O
OMeO
MeO2CN H
H
O
HO
OMeO
MeO2CN H
MeO
O
OMeO
MeN
MeO
O
OMeO
NMe
MeO
HO
H
O
NMe
MeO
HO
H
O
NMe
MeO
HO
H
NMe
OMe
OMe
Br
HClO4CH2N
2
DMSO
BF3OEt2
1. MesCl2. LiEt3BH
3. OsO4,NaIO4
MeO
MeO
HNMe
1. PhSeCl2. H2O23. H+
1. KN(TMS)2O
NTosPh
2. H2/Pd1. Swern oxiat.2. BF3OEt23. K2CO3, MeI
Zn, EtOH
1. DIBAL2. H+ AcOH, 100C
Evans, D.A. et al, Tetrahedron Lett. 1982, 23, 285 Tius, M. et al, JACS, 1992, 114, 5959
AA,BuLithen NaI
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Br
Morphine and CodeineBaran Lab KE LI
6
a) (H2C=CH)2CuMgCl, THF, - 78 C to 0 C; ii) TMSCl, Et3N, 0 C to 25 C;iii) NBS, THF (63-80%). b) DMF, 140 C (99%). c) NBS, (PhCOO)2, CCl4, rflx
(68 - 81%). d) Li, NH3, THF, t-BuOH (79 %). e) 3 N HCl, 90 C (95 %).
MeO
O
HH
N
O
O
MeO
O
HH
MOMO O
MeO
O
HH
MOMO
O
CHN2
H
MeO
HO
O
H
MeO
HO
CO2Me
CO2H
MeOOH O
CO2H
MeO
OH
CO2Me
Br
O
Br
HMeO
O
CO2Me
OH
H
H
H
MeO
O
OMOM
H
H
HO
N2
MeO
O
MOMO
HH
O
MeO
O
HH
N
O
O
MeO
O
MOMO
HH
N
BsO
MeO
O
MOMO
HH
NH
O
(CH2CO2Et)2
(+)-Morphine
Rh2(OAc)2
Mulzer, J.ACIE, 1996, 35, 2835 Synthesis, 1998, 653
White, J. JOC, 1997, 62, 5250
MeO
MeO
COOH
4 steps
O
MeO
MeO
Cl
H
a
O
MeO
MeO
Cl
HBr
OMe
OMe
Cl
O
O
MeO
O
Cl
H
OMe
O
Cl
O
b
4 steps
OMe
O O
c
O
OMe
O O
O
d
OMe
O
N
e
OMe
O
N
OO
O
(-)-morphine
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Morphine and CodeineBaran Lab KE LI
7
MeO
O
HH
N
O
MeO
BnO
HNDBS
NDBS
HI
BnO
MeO
NDBS
IBnO
MeO
HO
MeO
CHO MOMO
MeO
CH(OCH3)2
I
BnO
MeO
CHO
NDBS
HIBnO
MeOMeO
BnO
HNDBS
MeO
HO
HNDBS
O
MeO
O
HH
NDBS
HO
MeO
O
HH
N
O
(-) Morphine
NCO2Et
HI
HO
MeO MeO
O
HH
NCO2Et
MeO
O
HH
NCO2Et
O
MeO
O
HH
NMe
HO
OMe
COOH
O OCONHPh
O
O
SiMe2Ph
O
O
NDBS
SiMe2Ph
Overman, L.E. JACS1993, 115, 11028 and Tetrahedron Lett. 1994, 35, 3543
1. nBuLi, I22. 6 NHCl
3. BnBr, K2CO3
4. CH2SMe25. BF3OEt2
PhMe2Si
N
Ar
H
DBS
I
BnO
MeO
CHO
NDBS
SiMe2Ph
+
ZnI2, EtOH
nBuLiCuI(Ph3P)2
PhMe2SiLi
Proposed transition state:
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Morphine and CodeineBaran Lab KE LI
8
MeO
O
HH
NHMe
HO
MeO
O
HH CN
MeO
CHOO
H CN
MeO
CHO
OCN
Br
HO
MeO
CHO
Br
TrocO
CO2Me
HO
MeO
CHO
Br
HO
MeO
CHO
Br
O O TrocO
CO2Me
MeO
CHO
OCO2MeBr
MeO
CHO
OBr
CN
MeO
CHOO
H CN
MeO
O
H CN
Br
Br
MeO
O
H
H CN
MeO
O
HH CN
HO
MeO
O
HH CN
HO
MeO
O
HH
HO
NMe
Trost, B.M. JACS, 2002, 124, 14542
LDA/THFTungsten bulb
(-)-CodeineBBr3
(-)-Morphine
O
MeHNOH
OMe
LDA
O
MeNOH
OMe
Li
O
MeNOH
OMe
SET
O
MeNOH
OMe
(-)-Codeine
O
MeNOH
OMe
H-abstraction
from solvent
Photoinduced SET cyclization
1. 5% Pd(PPh3)4/n-Bu3SnH2. 15% Pd(OAc)2/15% dppp
/Ag2CO3
For the first step, palladium-catalyzedtin debromination, only yielded (Z)-vinyl
bromide as the product.
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Morphine and CodeineBaran Lab KE LI
9
MeO
O
HH
N
SO2Ph
MeO
MeO
HN
SO2Ph
O
MeO
OHC
MeO
HN
SO2Ph
O
H
Br
MeO
MeO
H
H
O
MeO
MeO
BrO
O
Ph
Ph
MeO
Br
Br
MeO
Br
Br
MeO
MeO
O
MeO
MeO
XMeO
MeO
OBr
MeO
MeO
BrO
O
Ph
Ph
MeO
MeO
BrO
O
Ph
Ph
+
MeO
MeO
H
H
O
MeO
OHC
MeO
HN
SO2Ph
O
H
Br
MeO
MeO
HN
SO2Ph
O
MeO
MeO
HN
SO2Ph
HO
MeO
O
HH
N
SO2Ph
MeO
O
HH
NCO2Et
HO
Taber, D.F. JACS, 2002, 124, 12416
4 steps
1. (MeO)2CONaOMe
2. 2 eq LDA
3. a) alkylationb) LiCl/DMSO
/H2O/reflux
1. L-Selectride2.a) (PhO)2P(O)N3
/DEAD/Ph3Pb) LAHc) PhSO2Cl/Et3N
3. BrCH2CH2Br
4. O3/PPh3 K2CO3/TBAB/Toluene/Reflux
BBr3
1. a) Red-Al/Toluene
b)ClCO2Et/Et3N2. H2O2/MTPT/DCE
3. (PhSe)2/NaBH4/EtOH4. a) NaIO4/THF/H2O
b) Na2CO3/Toluene/H2O
MeO
O
HH
NMe
HO
1. MnO22. LAH
HO
O
HH
NMe
HO
(-)-Morphine
1. KHMDS2. AcOH/H
2O
alkylidene carbene C-H insertion
desiredalkylation
position
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Morphine and CodeineBaran Lab KE LI
10
MeO
O
HH
NMeSO2Ph
O
O
MeO
O
HH
OPiv
O
O
O
O
OPiv
O
OMe
HO
OMOM
O
OMOM
OH
MeO
MeO
OMOM
Ar
O
OMOM
Ar
OTMS
O
OMe
MOMO
O
OMe
OMe
MOMO
O
Br
O
OPiv
O
OMeO
H
OHO
O
OPiv
O
OMeHO
MeO
O
H
OPivOH
O
OH
MeO
O
H
OPiv
O
O
O
OH
MeO
O
H
OPiv
O
O
HO
OH
MeO
O
HH
OPiv
O
O
MeO
O
HH
OH
O
O
MeO
O
HH
MeN
O
O
SO2Ph
Li/NH3/t-BuOH
MeO
O
HH
NMe
O
O
Ogasawara, K. Chem. Comm. 2001, 1094
PCC
vinylMgCl,CuBr-Me2STM-Cl, HMPA
NBS DMF, reflux
H+
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Morphine and CodeineBaran Lab KE LI
11
N
OH
X
NH
OH
O
OBn
O
O
OBn
O
OO
NMe2
N
OBn
O
OO
NMe2
O
Me N
OBn
O
OO
NMe2
O
Me
NMe
O
OO
O
Parsons, P.J. Chem. Rev. 1996, 96, 195
MeO
ON
Desoxycodeine-D
N
OAc
NCH3
OAc
NCO2Et
OH
NCO2Et
OBr
CHOMeO
NCO2Et
OBr
CH2OHMeO
NCO2Et
O CH2Cl
MeO
NCO2Et
O CH2OH
MeO
N
O
MeO
N
O
MeO
I
N
OPd
R
L
Cl
NO
R
PdL
NO
PdL
Cheng, C. Tetrahedron Lett. 2000, 41, 915
1. NaBH4/CeCl32.DMFDMA
1. OsO4/NaIO42. MeNHOH
1. H2, PdCl22. HCl, heat in vacuo
3. p-NO2C6H4SeCN,Bu3P, then H2O24. O3, Ph3P
NMe
HO
OO
1. CuBr2, MeCNthen KOtBu
2. LAH
HO
Pd
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Morphine and CodeineBaran Lab KE LI
12
BrBr
BrBr
HO
OH
BrBr
HO
OH
BrBr
O
O
BrN
O
O
O
O
N
O O
O
OH
N
OO
O
OH
+
21
N
HO
OH
O
OH
N
TBSO
OO
O
H
Br
MeO
TBSO
O
MeO
N
H
OO
RO
O
MeO
NH
OH
O
MeO
N
H
O
O
O
MeO
N
H
OH
O
RO
O
MeO
NH
Cl
RO
O
MeO
N
H
Hudlicky, T. Synthesis, 1998, 665
potassiumazodicarboxylate
AcOH
2,2-dimethoxypropanepTSA
2-oxazolone
NaH, DMSO
AIBN, Bu3SnH, benzene reflux
AIBN, Bu3SnH,benzene reflux
1. DIBAL2. swern
TfOH
MsCl, Et3N, LiCl AlCl3