Baran Lab

Morphine and Codeine

MeO MeO

KE LI

HO

For excellent reviews on Morphine and Codeine, see

O N H MeO H N

O H HO N H

O H HO

1. Hudlicky, T. et al Studies in Natural Products Chemistry, 1996, 18, 43 2. Taber, D.F. et al Strategies and Tactics in Organic synthesis, 2004, 5, 353 3. Maier, M. Organic Synthesis Highlights II, 1995, 357 4.Novak, B.H. et al Curr. Org. Chem. 2000, 4, 343

Morphine

Codeine

Thebaine

OMe MeO HO MeO N O O O OH OH O

5. Blakemore, P.R. et al, Chem. Comm. 2002, 1159 6. Zezula, J. et al, Synlett, 2005, 388

MeO

Papaverine

Meconic Acid

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

O 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%).

Baran Lab
2

Morphine and Codeine

HO

KE LI

OH

1 (-)-Morphine

O OH MeN

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

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. Biosynthesis:
CO2H OMe HO NH2 HO NH2 MeO NH H

8 7

HO

HO

dopamine +
MeO

MeO

L-tyrosine
O H HO N H O H O N H MeN MeO MeO O O HO

CHO

(S)-reticuline

MeO N H

(-)-Codeine

Codeinone

Dihydrocodeinone
MeO

O NMe MeO

HO NMe MeO

HO HO

MeO

HO

MeO OH

O H MeO N

O H O N OH

O H O N OH

salutaridine
MeO

(R)-reticuline

Thebaine
HO

Noroxymorphone
HO

Hydoxycodeinone
HO

Codeinone Thebaine
O H NMe

Codeine neopinone Morphine

O H HO N H

O H O N OH

O H O N OH

Nalorphine

Naltrexone

Naloxone Chem. Comm. 2002, 1159 1

Baran Lab

Morphine and Codeine

MeO
TPP, O2, TFA, light

KE LI

MeO

HO

VOCO

VOCO
2 eq. HBr Ethanol/ether

O H MeO
Thebaine

O H HO

N OH

O H HO

O H VOCO

NVOC

O H VOCO

NH

Tetrahedron Lett. 1994, 31, 5727

VOCO
Allyl bromide Na2CO3

HO

HCl
H N O H HO
Overall 77% from morphine

MeO

MeO

O H O

tBuOK, 18-crown-6, Me2SO4

H N

mCPBA H2SO4
N

MeO

O H

VOCO O H O N OH

O H MeO

Tetrahedron Lett.. 1977, 1571

Heterocycles, 1998, 49, 43

HO

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

O O AcO Cl O H O HO
allyl bromide, EtOH

AcO

MeO

MeO

MeO

O H O

Ac2O
N OH HO

O H O

N OAc

NVOC OAc

O H HO
(-) Codeine

O H O

O H O

N OH

Oxymorphone 1. HCl 2. MeOH,

J. Am. Chem. Soc. 2005, ASAP

O H O N OH

O NH OH O

3. H2SO4, reflux H

Tetrahedron Lett. , 1977, 1567

Naloxone

Baran Lab

Morphine and Codeine

MeO HO MeO MeO H O O MeO MeO O O CN MeO O NH O MeO
1. a) Br2 b) 2,4-DNPH 2. HCl HO 1. Br2, AcOH 2. 2,4-DNPH Codeine 1. N2H4/KOH 2. a) MeI, NaH MeO b) LAH 1. H2SO4 2. KOH

KE LI

RO

O H HO HO

O CN OH

MeO HO H N

MeO HO

Br

MeO HO

Br

H O

NCHO O NH2

H NCHO

MeO MeO O CN OH MeO HO O 1. Li/NH3 2. PhOCHO 3.MeSO3H (HOCH2)2 4. NBA 5. HCO2H/H2O

MeO HO

1. a) NaHSO3 b) KCN, H2SO4 H 2. SnCl2/H2O/HCl HOAc MeO HO Br

MeO HO MeO HO

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

AcOH/ (50%)

OH MeO
H2 CuCrO3 MeO 50%

H NH MeO HO H O NMe

MeO

NH4F/HF TfOH H NH

H MeO HO H O MeO HO Br H ArHNN MeO O H HO Br

NMe 3. KOtBu H /Ph2CO

H O

NCHO

MeO
BBr3/CHCl3 rt 88% Morphine

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

Rice introduced BBr3 for the O-demethylation in morphine synthesis

Gates' intermediate

NMe 3. H2/PtO2 O MeO O NMe O

H Br

NMe 3. HCl MeO HO

Rapaport procedure
Br MeO 1. Br2/AcOH 2. CHCl3/1N NaOH 3. H2, Pd/C, HCHO H O NCHO O H O
79%

MeO 1. HC(OMe)3/MeOH/H2SO4 2.TsOH/CHCl3/120C 3. HBr/H2O/CHCl3 NMe 4.NBA/MeOH H 5.KOtBu/DMSO 6.HOAc/H2O O H O

67%

LAH

NMe

NMe

Rice modified procedure

HO MeO O H O H MeO ClCO2Et NMe O H O H NCO2Et 1.PhSeCl 2.NaIO4 3. LAH MeO O H HO H NMe

pyrHCl
NMe

O H HO NMe

34%

Gates, JACS, 1952, 74, 1109

Rice, K.C. Heterocycles 1977, 6, 1157 JOC, 1980, 45, 592

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

Baran Lab

Morphine and Codeine

MeO O NMeTEOC H HO SO2Ph MeO MeO O H HO Br O H HO H NMe MeO O H HO H Br MeO

KE LI

MeO O H O

Br SO2Ph

NMeTs

O H HO

SPh NMeTs

MeO HO O O H

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

MOMO Br

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

NH2 2.a)TsCl Br

1. Li/NH3 b) 1N HCl

NMeTs 2. Ti(OiP)4/PhH

1. mCPBA

NMeTs HO

3. TBDMSOTf

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

Br MeO MeO

3. MeI, K2CO3 4. NaBH4/CeCl3HO

MeO H 1. Br /Fe/AcOH 2 O HO Br SPh

TBDMSO

OH

TBDMSO SO2Ph

OH 4. a) TBSOTf/Et3N

b)mCPBA 5. CeCl3/NaBH4
MeO

HO

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

NMeTs HO

1. nBu3P/DEAD/THF 2. HF/CH3CN 3. Jones/acetone 4. DIBAL/THF

O H HO MeO O H O NMeTEOC SO2Ph

Br

1. LiH/THF 2. nBuLi/THF
Br SO2Ph

MeO O H HO SO2Ph MeO MeO

TBDMSO MeO

Li/NH3
O H HO H NMe

O H HO H

nBu3SnH AIBN
NMeTs H

Br

SPh NMeTs

MeO O H O

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

Swern oxidation

HO

MeO

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

Rapaport procedure
H NMe O H O H NMe

Rice procedure Morphine

(-)-Codeine Fuchs, P.L. JOC, 1987, 52, 473

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

Baran Lab

Morphine and Codeine

OMe -CH2 H NMe OMe H 2C N Me Br OMe OMe OMe HO OMe NMe Br A Br OMe CH2N2 OMe N H OMe OMe N Me O OMe OMe NMe A,BuLi then NaI OMe OMe N OMe OMe NMe Br HClO4 H 2C MeO O MeN MeO O Zn, EtOH MeO O NHCO2Me O MeO O O H H O O O X

KE LI

MeO MeO

1. PhSeCl 2. H2O2 + NHCO2Me 3. H

O H

MeO2CN MeO 1. KN(TMS)2 O NTos Ph 2. H2/Pd O HO H

H O

O NMe

Li

MeO O MeO2CN MeO H O

CH2Br ZnBr2, C6H6 CH2Br OMe OMe N H

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

MeO2CN MeO

H O

H 2C

H 2C

Me

Me

Me

MeO HO 1. DIBAL 2. H+ H MeO NMe O NMe

MeO AcOH, 100C HO H O NMe

MeO HO H O NMe

DMSO OMe OMe N H CHO BF3OEt2 Me MeO MeO CHO NMe MeO MeO H 1. MesCl OH 2. LiEt3BH NMe 3. OsO4, NaIO4 MeO MeO H O

H 2C

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

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

Baran Lab

Morphine and Codeine

MeO O O
a

KE LI

MeO

MeO

4 steps

MeO MeO

Cl

O H MOMO H O

O H MOMO H

O CHN2

MeO MeO COOH H

H O

MeO HO Cl OMe

(CH2CO2Et)2 H O Br

MeO HO

CO2H CO2Me MeO CO2H OH O N2

MeO MeO Br O

Cl

Cl

OMe
b

MeO

Cl

OMe O Br

H O O MeO

CO2Me H OH Br H O MeO O H H

CO2Me H MeO O H OH MeO O H

OMe
4 steps c

OMe
d

OMOM

O O

O O Rh2(OAc)2

MeO

O OMe
e

OMe
(-)-morphine

H MOMO O

H O

O H O

(+)-Morphine

O N

O O N

MeO BsO O N H

MeO O O H MOMO H NH

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 %).

H MOMO

Mulzer, J. ACIE, 1996, 35, 2835 Synthesis, 1998, 653

White, J. JOC, 1997, 62, 5250

Baran Lab

Morphine and Codeine

MeO MeO MeO MeO MeO BnO BnO NDBS H I NDBS HO NDBS O H BnO NDBS H BnO I

KE LI

MeO

O H O N H

H NDBS

MeO

MeO

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

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

MeO MeO BnO I CHO O H O HO MeO MeO NDBS H O H O MeO N H MeO

HO

CHO

MOMO

4. CH2SMe2

(-) Morphine

OMe O SiMe2Ph O O SiMe2Ph NDBS

COOH

nBuLi CuI(Ph3P)2 PhMe2SiLi

BnO I H NDBS

HO I H NCO2Et O H H NCO2Et

Proposed transition state:

PhMe2Si

MeO Ar H O H O H NCO2Et

MeO

MeO

O H HO NMe H

+
BnO I CHO SiMe2Ph

NDBS

DBS

ZnI2, EtOH

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

Baran Lab

Morphine and Codeine

MeO MeO 1. 5% Pd(PPh3)4/n-Bu3SnH 2. 15% Pd(OAc)2/15% dppp /Ag2CO3 MeO MeO O H H CN O H CHO CN

KE LI

MeO

O H HO MeO H

NHMe

O H For the first step, palladium-catalyzed tin debromination, only yielded (Z)-vinyl bromide as the product. MeO MeO H

O CN H HO H CN

MeO

CHO O Br CN

HO Br

CHO CO2Me O H HO H CN O H HO H

LDA/THF Tungsten bulb

NMe

TrocO

MeO

MeO CHO Br

(-)-Codeine
MeO CHO Br O CO2Me

BBr3

(-)-Morphine

HO

HO

CHO Br CO2Me OMe

Photoinduced SET cyclization

OMe
LDA SET

OMe O

TrocO MeHN

O OH MeN Li

O OH MeN OMe
H-abstraction from solvent

OH

MeO MeO CHO O Br CN O H CHO CN O H CN MeO Br Br MeN OMe O OH

O MeN OH

(-)-Codeine

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

Baran Lab
MeO MeO

Morphine and Codeine

MeO MeO SO2Ph N H O MeO Br H O MeO MeO MeO N H SO2Ph O MeO N H SO2Ph MeO H MeO N SO2Ph HO MeO MeO MeO N H SO2Ph

KE LI

O H

BBr3
O H N H SO2Ph

OHC

MeO

MeO

H H O

MeO O Br O Ph Ph Br MeO Br

1. a) Red-Al/Toluene b)ClCO2Et/Et3N 2. H2O2/MTPT/DCE 3. (PhSe)2/NaBH4/EtOH 4. a) NaIO4/THF/H2O b) Na2CO3/Toluene/H2O

1. MnO2 2. LAH
O H HO H NCO2Et O H HO NMe H

MeO

4 steps
Br Br

MeO

MeO O MeO

MeO

desired alkylation position

X

1. (MeO)2CO NaOMe 2. 2 eq LDA MeO 3. a) alkylation b) LiCl/DMSO Br /H2O/reflux

MeO O

MeO

MeO

MeO O Br O Ph

+ MeO
Ph O Br O Ph Ph

HO

O H HO NMe H

MeO

H H O

1. L-Selectride 2.a) (PhO)2P(O)N3 MeO /DEAD/Ph3P b) LAH MeO c) PhSO2Cl/Et3N H 3. BrCH2CH2Br 4. O3/PPh3
OHC H

(-)-Morphine
SO2Ph N Br

1. KHMDS 2. AcOH/H2O

alkylidene carbene C-H insertion Taber, D.F. JACS, 2002, 124, 12416

K2CO3/TBAB /Toluene /Reflux 9

Baran Lab
MeO

Morphine and Codeine

OPiv O O MeO OH O O HO OMe OH O H O OPiv O O H MeO O OPiv O H O O MeO PCC OH OMOM O NBS Br OMe MOMO OMe OPiv O O O HO OMe O H OPiv O OH MOMO OMe DMF, reflux O O H O O H OH O H O O H Me N SO2Ph Ar OMOM O MeO MeO vinylMgCl, CuBr-Me2S O TM-Cl, HMPA H

KE LI

MeO

O H O O H

NMeSO2Ph

OPiv

OH

MeO H O O O O H OPiv OH

MeO

MeO O OMOM

O H O O H

OPiv

OTMS

Ar OMOM

Li/NH3/t-BuOH

H+
O OMe MeO

O H O O H

NMe

Ogasawara, K. Chem. Comm. 2001, 1094

10

Baran Lab

Morphine and Codeine

MeO

KE LI

O X NH OH N OH N
Desoxycodeine-D

O O

OAc O NMe2

OAc

OH

1. NaBH4/CeCl3 2.DMFDMA

1. OsO4/NaIO4 2. MeNHOH

NCH3

NCO2Et

O OBn O O O NMe2 N Me O OBn O O O NMe2 MeO O Br NCO2Et MeO O CH2Cl MeO CHO MeO O Br NCO2Et MeO O N N I CH2OH MeO O CH2OH

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

NCO2Et

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

OBn

4. O3, Ph3P

Pd

O O O

HO

NCO2Et O

1. CuBr2, MeCN then KOtBu

O NMe HO Pd R N L O Cl N R PdL PdL O N O

NMe 2. LAH O

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

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

11

Baran Lab

Morphine and Codeine

OH HO MeO MeO O Br O H O O N

KE LI

potassium azodicarboxylate HO
Br Br

OH

TfOH
O H

OH N

Br

Br

AcOH
Br

2,2-dimethoxypropane pTSA O

2-oxazolone NaH, DMSO

Br

O O N O O MeO OH O H RO RO N H O N MeO MeO Cl N H RO

Br

Br

AIBN, Bu3SnH, benzene reflux

O O O O HO N H O OH

MsCl, Et3N, LiCl

AlCl3

O H

+
N H O O

1
MeO

MeO O AIBN, Bu3SnH, O Br

benzene reflux

O O H N

1. DIBAL 2. swern
O

H TBSO TBSO

Hudlicky, T. Synthesis, 1998, 665

12