trevor sherwood- morphine: molecule in review

8/3/2019 Trevor Sherwood- Morphine: Molecule in Review

1/15

Molecule in Review

Trevor Sherwood (Snyder Group)Synthesis Literacy Group

7/17/09 Columbia University Chemistry

Morphine

O

HO

NMe

H

HO


2/15

Introduction

The opium alkaloids are among the oldest known natural products,with recorded use by ancient Sumerians

Isolation of morphine (Serturner, 1805) predates Wohlers urea

synthesis Morphine is exclusively isolated from the poppy plant for medicinal

purposes

Morphine and other members of the opioid class of alkaloids cause

their affects via the opioid receptors Morphine and codeine differ only by a methyl group and are easily

interconverted(1)

(1) J Med Chem, 1977, 20(1), 164

Sherwood 2 - CU Synthesis Lit Group - Morphine

O

HO

NMeH

HO

1 morphine

O

HO

NMeH

MeO

2 c

odeine


3/15

Introduction

Total Syntheses examined

Gates (1952) 1st total synthesis of morphine, includes resolution

M. Gates, G. Tschudi. JACS, 1956, 78, 1380

Rice (1982) shortest formal synthesis when published Rice, . JOC, 1980, 45, 3135

Overman (1993) enantioselective

L. Overman, C. Hong, N. Kado. JACS, 1993, 115, 11028

Other Sources Hudlicky, Tomas; Josephine Reed. The Way of Synthesis.

WILEY-VCH: Weinheim, 2007.



4/15

Gates Synthesis


O

H O

NMeH

H O

1 morphine

HO

O

N MeH

MeO

MeO

O

MeO

O

CN

OH

HO

Halogen displacement*

Diels Alder

Cu-Cr reductive coupling

C onjugate addition2,6-dihydroxynaphthalene


5/15

Gates Synthesis


MeO

NMeH

MeO

MeO

NHH

MeO

OO

MeO

OH

CN

MeO

O

MeO

O

MeO

O

CN

MeO

O

MeO

O

OCOPh

O

O

OH

HO

1. PhCOCl, py2. NaNO2, AcOH

3. H2, Pd/C4. FeCl3

1.SO22.Me2SO4, K2CO33. KOH

4. NaNO2, AcOH5. H2, Pd/C6. FeCl3

1. NCCH2CO2Et

2. K 3Fe(CN)63. KOH

Heat

Cu-Cr,H2 (27 atm.),130 C

1.NH2NH2, KOH2. MeI3. LiAlH4

3 45 6

78

9


6/15

Gates Synthesis


MeO

OH

CN

MeO

O

MeO

O

MeO

ONH

MeO

O

MeO

ONH

MeO

NH

MeO

OO

7

8

H

HH


7/15

Gates Synthesis


O

HO

NMeH

HO

O

O

NMeH

MeO

Br

O

ArNHN

NMeH

MeO

Br

HO

O

NMeH

MeO

Br

HO

ArNHN

NMeH

MeO

Br

HO

O

NMeH

MeO

MeO

NMeH

MeO

1 morphine

1. dibenzoyl

tartaric acid2. H

2SO

4, H

2O

3. PhN+Me3 Et O-

4. t BuOK, Ph2CO

1. Br2, AcOH

2. ArNHNH2

1. aq HCl, acetone

2. H2, Pt

1.Br2 ( 2 eq)2. ArNHNH2

aq HCl, acetone

1. H2 Pd/C2. LiAlH4 , THF3. Py, HCl

1211109

1314


8/15

Rice Synthesis

Sherwood 8 - CU Synthesis Lit Group Morphine

O

O

NMeH

MeO

dihydrocodeinone

NCHO

OH

MeO

O

O

Br

MeO

NH2

CO2H

MeO

OH

Halogen displacement

Beyerman-Grewe Cycl izationBischler-Napieralski

Thermal amidation


9/15

Rice Synthesis


MeO

16

NH2

MeO

18

NH

17

CO2H

MeO

OH OH

MeO

MeO

19

NCHO

OH

MeO

20

NCHO

OH

MeO

O

O

Br

HO

O

NCHOH

MeO

21

Br

O

O

NMeH

MeO

15 dihydrocodeinone

1. 200 C, 2h2. POCl3, MeCN3. NaCNBH4 , MeOH

1. Li,NH32. PhOCHO, heat

1. ( CH2OH)2MeSO3H

2. CH3CONHBr

1. HCO2H-H2O 5-12.NH4F HF, TfOH

0 C 3-4 days

1. MeOH, HClthen NH3/H 2O/iPrOH

2. H2 , Pd/C, HOAc, HCHO

3. Br2 , HOAc4. NaOH, CHCl35. H2 , HOAc-HCHO


10/15

Overman Synthesis


O

O

N Me

H

M eO

dihydrocodeinone

Epoxide opening

Intramolecular Heck

NDBS

HI

OBn

OM e

SiMe2Ph

NHD BS

MeO

OB n

I

CH Oallylsilane-iminium cyclization

Iminium formation


11/15

Overman Synthesis


DBS=

O OCONHPh

O

O

SiMe2Ph

O

O

SiMe2Ph

NHDBS

1. cat echol borane

(R)-oxazaborolidine

2. PhNCO3. OsO4, R3NO

4. acetone, H+

nBuLi, THF, -30 CCuI(Ph3P)2 , 0 CPhMe2 SiLi, 0 C

1. MeOH, TsOHNaIO4

2. DBS-NH2NaCNBH3

2223 24 25

>96% ee

CHO

MeO

OH

MeO

OMOM

OMe

OMe

CHO

MeO

OBn

I MeO

OBn

I

CHO1. MOM protection2. acetal formation

1. nBuLi, I22. 6N HCl3. BnBr, K 2CO3

1. CH2SMe22. BF3-OEt2

26 2728 29


12/15

Overman Synthesis


SiMe2Ph

NHDBS

MeO

OBn

I

CHO

NDBS

H

20:1 cis:trans

IOBn

OMe

BnO

NDBSH

MeO

31

O

HO

NDBSH

MeO

32

O

O

NMe

H

MeO

15 dihydrocodeinone

ZnI2

, EtOHPd(TFA3)2(PPh3)2

PMP, toluene, 120 C

1. BF3-OEt 2, EtSH

2. 3,5-(NO2)2PhCO3H,CSA

1. TPAP, NMO2. H2, Pd(OH)2 , HCHO

25

29

30

91% ee


13/15

Overman Synthesis


SiMe2Ph

NHDBS

MeO

OBn

I

CHO

25

29

NDBS

Ar

H

PhMe2Si

NDBS

Ar

H

H

E/Z > 20:1


14/15

Formal syntheses of morphine


Rice formal synthesis extension(1,2)

Overman formal synthesis extension(3)

(1) J Med Chem, 1977, 20(1), 164

(2) J Med Chem, 1976, 19(10), 1171

(3) Proc Jpn Acad, 1960, 36, 145

HO

O

NMeH

MeO

O

HO

NMeH

MeO

2 codeinedihydrothebainone

O

HO

NMeH

HO

1 morphine

several steps

BBr3

O

O

NMeH

MeO

15 dihydrocodeinone

O

HO

NMeH

HO

1 morphine

5 steps


15/15

Final Comments


Gates synthesis

First reported

Cu-Cr method creatively forges bridged heterocycle

31 steps Requires resolution to obtain enantiopure material

Rice Synthesis

Beyerman-Grewe cyclization to form last ring

14 steps to dihydrocodeinone Requires resolution at end to obtain enantiopure material

Overman Synthesis

Allylsilane-Iminium cyclization and Heck reaction to close core

14 steps to dihydrocodeinone following longest linear sequence

No resolution necessary to achieve enantiopure material

trevor sherwood- morphine: molecule in review

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