Morphine and Codeine

Baran Lab

HO

MeO

MeO

For excellent reviews on Morphine and Codeine, see

HO

2. Taber, D.F. et al Strategies and Tactics in Organic

synthesis, 2004, 5, 353

H
MeO

HO

3. Maier, M. Organic Synthesis Highlights II, 1995, 357

Thebaine

Codeine

Morphine

1. Hudlicky, T. et al Studies in Natural Products

Chemistry, 1996, 18, 43

KE LI

4.Novak, B.H. et al Curr. Org. Chem. 2000, 4, 343

5. Blakemore, P.R. et al, Chem. Comm. 2002, 1159

OMe
MeO

O
O

HO
MeO

6. Zezula, J. et al, Synlett, 2005, 388

OH

OH

MeO

Meconic Acid

Papaverine

N
MeO
O
MeO

O
OMe

Noscapine

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%).

The following work will be included in this talk due to the time limitation.
Gates
Rice
Evans
Fuchs
Tius
Parker
Overman
Mulzer
Parsons
White
Hudlicky
Cheng
Ogasawara
Taber
Trost
Michels

1952
1980
1982
1988
1992
1992
1993
1996
1996
1997
1998
2000
2001
2002
2002
2005

(-)-Morphine
(-)-Dihydrocodeinone
O-Me-thebainone-A
Codeine
Thebainone-A
Dihydrocodeinone
(-)-Dihydrocodeinone
(-)-Dihydrocodeinone
Morphine
(+)-Morphine
10-hydroxy-ent-epi-dihydrocodeinone
Desoxycodeine-D
(-)-Dihydrocodeinone ethylene ketal
(-)-Morphine
(-)-Codeine
14-Hydroxycodeinone

Morphine and Codeine

Baran Lab

HO

OH

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/year
and the world wide illicit market for narcotics is probably more than $760 billion.

11
10
12
15
O
5
14
N
9
H
13
4

O OH
MeN

HO

MeO

KE LI

(-)-Morphine

Biosynthesis:

HO

MeO

CO2H

MeO

OMe

O
N

H
HO

Dihydrocodeinone

Codeinone

MeO

MeO

MeO

HO

O
N

H
MeO

N
OH

H
O

Thebaine

Noroxymorphone

N
OH

MeO

HO

Nalorphine

N
OH

MeO

Hydoxycodeinone

Codeinone
Thebaine
O
NMe

Naltrexone

Codeine

neopinone

N
OH

Morphine

(R)-reticuline

OH

salutaridine

O
N

NMe

H
O

HO

MeO

HO

HO

HO

MeO

NMe
MeO

(S)-reticuline

HO

MeO

HO

MeO

HO

MeN

(-)-Codeine

CHO

+
L-tyrosine

NH

HO

dopamine

NH2

HO

NH2

HO

Naloxone
Chem. Comm. 2002, 1159

Morphine and Codeine

Baran Lab

MeO

MeO

KE LI

VOCO

HO

VOCO
2 eq. HBr

TPP, O2, TFA, light

O
H

O
H

MeO

O
H

N
OH

HO

tBuOK, 18-crown-6,
Me2SO4

O
H

Ac2O

O
H

1. HCl
2. MeOH,

O
H

allyl bromide, EtOH

NVOC
OAc

O
HO

HO

3. H2SO4, reflux H

O
H

HO
Overall 77% from morphine

N
OH

Tetrahedron Lett.. 1977, 1571

MeO

AcO
Cl

N
OAc

Oxymorphone

HCl

VOCO

AcO

N
OH

VOCO

J. Org. Chem., 1996, 61, 6774

Heterocycles, 1998, 49, 43

O
H

NH

MeO

HO

HO

O
H

MeO

O
H

O
H

NVOC

VOCO

Allyl bromide
Na2CO3

mCPBA
H2SO4

O
H

VOCO

Tetrahedron Lett. 1994, 31, 5727

MeO

HO

Thebaine

MeO

Ethanol/ether

O
H

NH
OH

Tetrahedron Lett. , 1977, 1567

O
H
HO

MeO

O
H

MeO

O
H

N
OH

(-) Codeine

J. Am. Chem. Soc. 2005, ASAP

O
H

N
OH

Naloxone

Morphine and Codeine

Baran Lab

RO

MeO

MeO

HO

O
H

MeO

HO

O
CN
OH

MeO

MeO

HO

HO
H

MeO

O
CN
OH

MeO

AcOH/ (50%)

OH

MeO
HO

H 2. SnCl2/H2O/HCl
HOAc

MeO

MeO

H2
CuCrO3
MeO
50%

1. N2H4/KOH
2. a) MeI, NaH
MeO
b) LAH

1. H2SO4
2. KOH

NMe 3.
KOtBu
H
/Ph2CO

NH
O

MeO
HO
H

NMe 3. H2/PtO2

O
MeO
HO

Br
H

NMe

NCHO

HO

1. HCl/H2O
2. H2, Pd/C
HCHO

NMe

Gates'
intermediate

Rice introduced BBr3 for

the O-demethylation in
morphine synthesis

Morphine

MeO
1. HC(OMe)3/MeOH/H2SO4
2.TsOH/CHCl3/120C
3. HBr/H2O/CHCl3

O
H

NCHO

79%

ArHNN

MeO

HO

3. H2, Pd/C, HCHO

HO
H

NMe

MeO

Br

MeO
1. Br2/AcOH
2. CHCl3/1N NaOH

Br

Br
LAH

MeO

H
NH

Rapaport procedure
MeO

MeO

Br

HO

88%

NMe 3. HCl

HO

1. 200C
2. a) POCl3
b) NaCNBH4
CO2H

H
NH

BBr3/CHCl3
rt

MeO

MeO

MeO

Codeine

1. Br2, AcOH
2. 2,4-DNPH

MeO

NH4F/HF
TfOH

HO

3.MeSO3H
(HOCH2)2
4. NBA
5. HCO2H/H2O

MeO
1. a) Br2
b) 2,4-DNPH
2. HCl
HO

Br

MeO

1. Li/NH3
2. PhOCHO

H
NCHO

NCHO

NH2

1. a) NaHSO3
b) KCN, H2SO4

CN

Br

HO

MeO

MeO

MeO

Br

O
HO

KE LI

O
H

NMe 4.NBA/MeOH
H
5.KOtBu/DMSO
6.HOAc/H2O

NMe

O
67%

Rice modified procedure

MeO

HO

pyrHCl

O
H

NMe

34%

HO

Gates, JACS, 1952, 74, 1109

MeO

H
HO

NMe

MeO
ClCO2Et

O
H
O

NMe

1.PhSeCl
2.NaIO4

O
H
O

Rice, K.C. Heterocycles 1977, 6, 1157

JOC, 1980, 45, 592

NCO2Et

3. LAH

MeO
O
H

NMe

HO

Rapaport, H. J. Med. Chem. 1976, 19,1171

Morphine and Codeine

Baran Lab

MeO

MeO

MeO

O
NMeTEOC

MeO

KE LI

SO2Ph

Br

MeO

Br

SO2Ph

HO

MeO

NMe

HO
MeO
H

HO

1. Br2/AcOH
2. MOMCl/NaH
MeO
3.Ph3PCH2/NaOH

1. allylic bromide/KOH
2.(COCl)2/CHCl3
3. PhSO2Na/PhH

HO

1. a) (Sia)2BH/THF
MeO
b) H2O2/NaOH
2. TsOH/MeOH
HO
3. CBr4, Ph3P

MOMO

Br

1. Li/NH3

b)mCPBA
5. CeCl3/NaBH4

1. mCPBA

NH2 2.a)TsCl
Br

OH

TBDMSO

MeO

MeO
H 1. Br /Fe/AcOH
2

HO

SO2Ph

HO

3. TBDMSOTf

3. MeI, K2CO3
4. NaBH4/CeCl3HO

Br MeO

NMeTs

NMeTs 2. Ti(OiP)4/PhH

b) 1N HCl

TBDMSO

OH 4. a) TBSOTf/Et3N

SPh
NMeTs

HO

HO

Br

NMeTs

HO

2. PhSCH2P(O)(OEt)2/
NaH/(CH2OMe)2

SPh
Br

NMeTs
HO

MeO

3. Jones/acetone
4. DIBAL/THF

TBDMSO

MeO

1. nBu3P/DEAD/THF
2. HF/CH3CN
O
H

1. LiH/THF
2. nBuLi/THF

Br

Br
SO2Ph

SO2Ph

HO

HO

Li/NH3
O

NMe

MeO

O
H
O

NMeTEOC
SO2Ph

O
H
O

b) NaOH/H2O/CHCl3
4. NaBH4/MeOH

MeO

Fuchs, P.L. JOC, 1987, 52, 473

SPh
NMeTs

HO

MeO

Br

Rice procedure

Rapaport procedure
H

(-)-Codeine

NMeTs

Swern oxidation

1. TFA
2. NaHCO3/H2O/CHCl3
NMeTEOC 3. a) HCl/Et2O/CH2Cl2

nBu3SnH
AIBN

HO

HO
MeO

MeO

MeO

MeO

NMe

Morphine

O
H

NMe

Parker, K.A. JACS, 1992, 114, 9688

Morphine and Codeine

Baran Lab

OMe

MeO
-CH2

MeO
H

OMe

OMe

OMe

H 2C

NMe

Li

HO

NMe

CH2Br ZnBr2, C6H6

CH2Br

Me

Me

OMe

OMe

OMe

OMe

OMe

NMe

NMe

OMe

OMe

OMe

NMe

HClO4

OMe

H 2C

Me

H 2C

OMe

H 2C

OMe

MeO

N
H

CHO

Me

BF3OEt2

Me

NMe 3. OsO4,
NaIO4

NTos
Ph
2. H2/Pd
O

MeO2CN

MeO2CN

H
O

MeO

HO

MeO

MeO
1. MesCl
OH 2. LiEt3BH

1. Swern oxiat.
2. BF3OEt2
3. K2CO3, MeI

MeO

MeO

H
O

H
MeO

MeO
H

MeO

MeO
1. DIBAL
2. H+

HO
MeO

H
O

Zn, EtOH

DMSO
OMe

MeO
1. KN(TMS)2
O

MeO

MeO

MeO2CN

H
O

OMe
N

Me

1. PhSeCl
2. H2O2
+
NHCO2Me 3. H

MeO

MeN

Br

CH2N2

NHCO2Me

MeO

A,BuLi
then NaI

Br
A
Br

OMe

O
OMe

H 2C

O
O
O

Br
OMe

KE LI

AcOH, 100C
HO

HO

NMe

H
O

NMe

NMe

NMe

MeO
MeO

CHO

NMe

Evans, D.A. et al, Tetrahedron Lett. 1982, 23, 285

Tius, M. et al, JACS, 1992, 114, 5959

Morphine and Codeine

Baran Lab

MeO

Cl

MeO

COOH

MeO

MeO
Br

Cl

Cl

MeO

OMe

(CH2CO2Et)2

MeO

Cl
b

OMe O
Br

CO2Me
MeO

H
OH

MeO

MeO

OMe

O
H

H
O

MOMO

(+)-Morphine

(-)-morphine

MeO

MeO
BsO
N

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 %).

Mulzer, J. ACIE, 1996, 35, 2835

Synthesis, 1998, 653

OMOM

O
O

Rh2(OAc)2

MeO

O
O

CO2Me
H

MeO

O
N2

OMe

OMe

OH

CO2H

OH
Br

MeO

HO

4 steps

CO2H

Br

OMe

CHN2

CO2Me

OMe

MOMO

MeO

HO

Cl

MOMO

MeO

MeO

MeO

MeO

MeO

4 steps

KE LI

MOMO

White, J. JOC, 1997, 62, 5250

O
O
H

NH
H

MOMO

Morphine and Codeine

Baran Lab

MeO

MeO

MeO

BnO

BnO

MeO

O
NDBS

HO

I
NDBS

KE LI

MeO

MeO

BnO

BnO

NDBS

NDBS

NDBS

MeO

MeO

HO

CHO

MOMO

1. nBuLi, I2
2. 6 N HCl
3. BnBr, K2CO3

MeO

4. CH2SMe2

BnO

MeO

CH(OCH3)2 5. BF OEt
3
2
O

MeO

CHO
O

OCONHPh

OMe
O

HO
MeO

MeO

SiMe2Ph
NDBS

PhMe2SiLi

BnO

HO
H

Proposed transition state:

NDBS

BnO
CHO

SiMe2Ph

NCO2Et

MeO

Ar
H

H
NCO2Et

MeO

PhMe2Si

MeO

I
NDBS

SiMe2Ph

MeO

nBuLi
CuI(Ph3P)2

COOH

(-) Morphine

NDBS

DBS

ZnI2, EtOH

Overman, L.E. JACS 1993, 115, 11028 and Tetrahedron Lett. 1994, 35, 3543

O
H

NCO2Et

NMe
H

HO

Morphine and Codeine

Baran Lab

MeO

MeO

NHMe

MeO

HO

CHO

O
H

CN

CN

HO

Br

Br

HO

CHO

MeO

O
H

CN

BBr3

HO

CHO

CHO
O

CO2Me

Photoinduced SET cyclization

Br
CO2Me

OMe

TrocO

MeO

O
OH

CHO
CN

O
H

Trost, B.M. JACS, 2002, 124, 14542

CN

O
H

MeN
Li

Br
CN

MeN

OH

OMe
H-abstraction

Br
CHO

O
OH

OMe

MeO

OMe
SET

MeO

OMe
LDA

MeHN

Br

(-)-Morphine

MeO

Br

NMe

HO

(-)-Codeine

Br

CN

HO

HO

MeO

LDA/THF
Tungsten bulb

TrocO

MeO

CN

CHO
CO2Me

CN

For the first step, palladium-catalyzed

tin debromination, only yielded (Z)-vinyl
bromide as the product.
MeO

CHO

MeO

MeO

O
H

MeO

MeO

1. 5% Pd(PPh3)4/n-Bu3SnH
2. 15% Pd(OAc)2/15% dppp
/Ag2CO3

KE LI

O
MeN

OH

from solvent

MeN

OH

(-)-Codeine

Morphine and Codeine

Baran Lab
MeO

MeO

MeO

MeO

MeO
N

OHC

SO2Ph

MeO

MeO

SO2Ph

SO2Ph

O
Br

Br
Ph

Br
Ph

MeO

4 steps
Br

MeO

MeO

MeO

MeO

Br

O
O

Br

MeO

Ph

1. KHMDS
2. AcOH/H2O

3. BrCH2CH2Br
4. O3/PPh3

alkylidene carbene C-H insertion

Taber, D.F. JACS, 2002, 124, 12416

SO2Ph

3. (PhSe)2/NaBH4/EtOH
4. a) NaIO4/THF/H2O
b) Na2CO3/Toluene/H2O

SO2Ph

SO2Ph

HO
MeO

MeO

1. MnO2
2. LAH
O

O
H
HO

NCO2Et

NMe
H

HO

O
Br

Ph

O
Ph

1. L-Selectride
2.a) (PhO)2P(O)N3 MeO
/DEAD/Ph3P
b) LAH
MeO
c) PhSO2Cl/Et3N
H

HO

+ MeO

Ph
MeO

MeO

MeO

3. a) alkylation
b) LiCl/DMSO Br
/H2O/reflux

BBr3

MeO

1. (MeO)2CO
NaOMe
2. 2 eq LDA MeO

MeO

desired
alkylation
position

MeO

MeO

1. a) Red-Al/Toluene
b)ClCO2Et/Et3N
2. H2O2/MTPT/DCE

MeO
O

MeO

MeO

MeO

MeO

MeO

Br

KE LI

O
H

NMe
H

HO

(-)-Morphine
SO2Ph
N

OHC

Br

K2CO3/TBAB
/Toluene
/Reflux
9

Morphine and Codeine

Baran Lab

OPiv

MeO

MeO

MeO

MeO

O
O
O

NMeSO2Ph

OMe

vinylMgCl,
CuBr-Me2S
O TM-Cl, HMPA

PCC

MeO
O
OH

OMOM

MeO

O
O

MeO

MeO

Li/NH3/t-BuOH

MOMO
OMe

OMe

OH

OPiv
OH

O
O

OPiv
H

MOMO

OPiv

O
H

DMF, reflux

OMe

OMOM

OH

O
Br

Ar

OPiv

H
O

OMOM

NBS

O
H

Me
N
SO2Ph

H+

O
HO

OH

H
O

Ar

OMOM

OPiv

MeO

MeO

OTMS

O
OPiv

OH

HO

OH
O

OPiv

KE LI

MeO

O
OMe

O
H

OMe

O
H

NMe
H

O
O

Ogasawara, K. Chem. Comm. 2001, 1094

10

Morphine and Codeine

Baran Lab

KE LI

MeO

O
N

X
NH

N
OH

OH

Desoxycodeine-D

1. NaBH4/CeCl3
2.DMFDMA

OH

OAc

OAc

1. OsO4/NaIO4
2. MeNHOH

NCO2Et

NCH3

NMe2
O
OBn

OBn

O
O

NMe2
N Me
O

O
O

NMe2

1. CuBr2, MeCN
then KOtBu

CH2Cl

CH2OH

Br

NCO2Et

NCO2Et

MeO

4. O3, Ph3P

MeO

MeO

MeO

Pd

NCO2Et

N I

O
O

NMe 2. LAH
O

CH2OH

NCO2Et

HO

MeO

Br

1. H2, PdCl2
2. HCl, heat in vacuo

N Me 3. p-NO2C6H4SeCN,
Bu3P, then H2O2
O
OBn

OBn

CHO
O

MeO

NMe
HO
Pd
R

Parsons, P.J. Chem. Rev. 1996, 96, 195

L O
Cl

R
PdL

Cheng, C. Tetrahedron Lett. 2000, 41, 915

PdL

11

Morphine and Codeine

Baran Lab

MeO

OH

Br

Br

Br

MeO

OH

potassium
azodicarboxylate HO

HO

Br

KE LI

TfOH

AcOH

Br

Br

OH
O

N
H

2,2-dimethoxypropane
pTSA
O

2-oxazolone
NaH, DMSO

Br

Br

Br

N
O

AIBN, Bu3SnH, benzene reflux

OH

N
H

Cl

MsCl, Et3N, LiCl

MeO

MeO
OH

RO

+
N

MeO

HO

N
H

AlCl3

N
H

RO

N
H

RO

MeO
MeO
O AIBN, Bu3SnH,
O

Br

benzene reflux

O
O

Hudlicky, T. Synthesis, 1998, 665

N
H

H
TBSO

1. DIBAL
2. swern

TBSO

12