UNIVERSITY OF IOWA

Abstracted by:

SYNTHETIC PATHWAYS

ABSTRACT No:

James D. White, Peter Hrnciar, and
Frank Stappenbeck

(+)-morphine

J. Org. Chem. 1997, 62, 5250.

Horacio F. Olivo

Department of Chemistry,
Oregon State University
Corvallis, OR 97331

OH

O

H

NMe

MeO

OH

CO

2

Me

CO

2

H

H

2

, [Rh(COD)Cl]

2

(4R,5R)-(-)-MOD-DIOP

100%, 94%ee

MeO

OH

CO

2

Me

CO

2

H

H

Br

2

, HOAc

93%

MeO

OH

CO

2

Me

CO

2

H

H

Br

Ms-OH, P

2

O

5

75%

MeO

OH

CO

2

Me

H

Br

O

H

2

, Pd/C, NaHCO

3

DME, 0 °C

85%

MeO

OH

CO

2

Me

H

O

KH, HCO

2

Me

DME, 0 °C

85%

LiOH
THF-H

2

O

100 %

MeO

OH

CO

2

H

H

O

MeO

OH

CO

2

H

H

O

O

H

MVK, Et

3

N

CH

2

Cl

2

, 95%

MeO

OH

H

O

O

O

O

OH

6

5

4

NaOH,
H

2

O-THF

95%

MeO

OH

H

OH

O

O

H

CH

2

N

2

Et

2

O-CH

2

Cl

2

95%

7

7a

HO

Treatment of severe pain
(+)-morphine, unnatural isomer

isovanillin + dimethyl succinate
Stobbe condensation
Org. react. 1951, 6, 1

Friedel-Crafts

92Perkin1, 1415

Robinson
annulation

MeO

OH

H

OMe

O

O

H

Br

2

, NaHCO

3

CH

2

Cl

2

, 80%

MeO

OH

H

OMe

O

O

H

Br

DBU, C

6

H

6

50°C, 90%

8

synthetic pathways, morphine, page 2

Br

MeO

H

OMe

O

O

H

Br

O

9

NaBH

4

, i-PrOH-CH

2

Cl

2

99%

MeO

H

OMe

O

OH

H

Br

O

H

2

, Pd/C

MeOH, 78%

MeO

H

OMe

O

OH

H

O

CH

2

(OMe)

2

P

2

O

5

, CHCl

3

80%

MeO

H

OMe

O

OMOM

H

O

10

LiOH,

THF-H

2

O,

99%

MeO

H

OH

O

OMOM

H

O

(COCl)

2

C

6

H

6

MeO

H

Cl

O

OMOM

H

O

CH

2

N

2

63%

MeO

H

CHN

2

O

OMOM

H

O

11

Rh

2

(OAc)

4

CH

2

Cl

2

, 50%

H

H

H

H

H

MeO

OMOM

H

O

O

12

H

2

NOH·HCl

NaOAc, MeOH

90%

MeO

OMOM

H

O

NOH

p-BrC

6

H

4

SO

2

Cl

Et

3

N

MeO

OMOM

H

O

NOSO

2

C

6

H

4

Br

13

14

AcOH, rt

62% from 13

15

MeO

OMOM

H

O

NH

O

Beckmann rearrangement

1.2:1 mixture
syn/anti isomers

11:1 mixture
regioisomers

MeO

OMOM

H

O

NH

O

NaH, MeI

C

6

H

6

, heat

95%

MeO

OMOM

H

O

NMe

O

15

HBr,

MeCN,
96%

synthetic pathways, page 3, synthesis of (+)-morphine

MeO

OH

H

O

NMe

O

Dess-Martin
periodinane,
CHCl

3

, 99%

MeO

O

H

O

NMe

O

PhSeCl, MsOH

CH

2

Cl

2

MeO

O

H

O

NMe

O

SePh

NaIO

4

65% from 16

MeO

O

H

O

NMe

O

17

LiAlH

4

THF, heat
90%

MeO

OH

H

O

NMe

18

KC Rice
JMedChem 1977, 20, 164

HO

OH

H

O

NMe

(+)-morphine

16

(+)-codeine