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Morphine

HO O NMe H HO

Molecule in Review
Trevor Sherwood (Snyder Group) Synthesis Literacy Group 7/17/09

Columbia University Chemistry

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) HO MeO
O NMe H H HO HO O NMe

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

1 morphine

2 codeine

Sherwood 2 - CU Synthesis Lit Group - Morphine

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.

Sherwood 3 - CU Synthesis Lit Group - Morphine

Gates Synthesis
HO MeO

O Halogen displacement HO * H NMe

HO N Me H O Cu-C r reductive coupling

1 morphine
Diels Alder

HO

MeO O MeO OH O CN C onjugate addition

2,6-dihydroxynaphthalene

Sherwood 4 - CU Synthesis Lit Group - Morphine

Gates Synthesis

HO

O 1. PhCOCl, py 2. NaNO2, AcOH O 3. H2, Pd/C OH 4. FeCl3

MeO 1. SO2 2. Me2 SO4 , K2 CO3 3. KOH 4. NaNO2, AcOH 5. H2 , Pd/C OCOPh 6. FeCl 3 MeO 1. NCCH2CO2 Et O 2. K 3Fe(CN)6 3. KOH O

MeO O MeO O CN

Heat MeO MeO 1. NH2NH2 , KOH 2. MeI 3. LiAlH4 MeO NMe H H O O Cu-Cr, H2 (27 atm.), 130 C MeO NH MeO O CN OH

MeO

Sherwood 5 - CU Synthesis Lit Group - Morphine

Gates Synthesis
MeO O MeO CN OH MeO O H MeO O NH

MeO O O MeO NH H

MeO O NH MeO O H

Sherwood 6 - CU Synthesis Lit Group - Morphine

Gates Synthesis
MeO 1. dibenzoyl tartaric acid 2. H 2SO4, H2O MeO H HO 3. PhN+Me3 EtONMe 4. tBuOK, Ph2 CO H NMe H O MeO 1. Br2, AcOH 2. ArNHNH2 HO NMe H O ArNHN MeO Br 1. aq HCl, acetone 2. H2 , Pt HO NMe MeO Br

10

11

12
1. Br2 ( 2 eq) 2. ArNHNH2

HO

MeO 1. H 2 Pd/C 2. LiAlH4 , THF 3. Py, HCl Br

MeO Br aq HCl, acetone O NMe H H NMe ArNHN

O NMe H HO

14

13

1 morphine

Sherwood 7 - CU Synthesis Lit Group - Morphine

Rice Synthesis

MeO Beyer man-Gr ewe Cyclization O O Halogen displacement H O MeO NMe

O Bischler-N apieralski NCH O Br T hermal amidation

MeO NH2

CO 2H MeO OH OH

dihydrocodeinone

Sherwood 8 - CU Synthesis Lit Group Morphine

Rice Synthesis
MeO O MeO 1. 200 C, 2h 2. POCl3, MeCN NH2 3. NaCNBH , MeOH 4 MeO 1. Li, NH3 NH 2. PhOCHO, heat 1. (CH 2OH)2 O MeSO3 H NCHO 2. CH3 CONHBr Br CO2H NCHO

16 18
MeO OH17 MeO OH MeO OH

19
MeO OH

20

1. HCO2H-H2O 5-1 2. NH4F HF, TfOH 0 C 3-4 days MeO 1. MeOH, HCl then NH3/H 2O/iPrOH 2. H2 , Pd/C, HOAc, HCHO O NMe H O 3. Br2 , HOAc 4. NaOH, CHCl3 5. H2 , HOAc-HCHO HO NCHO H O MeO Br

21

15 dihydrocodeinone

Sherwood 9 - CU Synthesis Lit Group Morphine

Overman Synthesis

M eO Intramolecular Heck N DBS I H Epoxide opening H O OMe MeO N Me allylsilane-iminium cyclization

SiMe2Ph

NHD BS Iminium formation OBn CH O I OBn

dihydrocodeinone

Sherwood 10 - CU Synthesis Lit Group Morphine

Overman Synthesis
O 1. catechol borane (R)-oxazaborolidine 2. PhNCO 3. OsO4 , R3NO 4. acetone, H+ O OCONHPh nBuLi, THF, -30 C CuI(Ph3 P)2 , 0 C PhMe2 SiLi, 0 C O SiMe2Ph 1. MeOH, TsOH NaIO4 2. DBS-NH2 O NaCNBH3 O SiMe2Ph

22

23
>96% ee

NHDBS

24

25

D BS =

OMe CHO 1. MOM protection 2. acetal formation MeO 1. nBuLi, I 2 OMe 2. 6N HCl 3. BnBr, K 2CO3 CHO 1. CH2 SMe2 2. BF3-OEt2 MeO OBn I CHO MeO OBn I

26
OH

MeO OMOM

27

28

29

Sherwood 11 - CU Synthesis Lit Group Morphine

Overman Synthesis
SiMe2Ph MeO NHDBS NDBS I H CHO MeO OBn MeO MeO 1. TPAP, NMO 2. H2, Pd(OH)2 , HCHO NMe H O H O NDBS HO I 29 Pd(TFA3 )2(PPh3 )2 PMP, toluene, 120 C OBn
20:1 cis:trans
91% ee

25

ZnI 2, EtOH

30

BnO NDBS H

OMe

31
1. BF3 -OEt 2, EtSH 2. 3,5-(NO2 )2 PhCO3 H, CSA

15 dihydrocodeinone

32

Sherwood 12 - CU Synthesis Lit Group Morphine

Overman Synthesis

SiMe2Ph

NHDBS

25
CHO

PhMe2Si

Ar

Ar

H N DBS

H N DBS H

MeO OBn

I 29 E/Z > 20:1

Sherwood 13 - CU Synthesis Lit Group Morphine

Formal syntheses of morphine


Rice formal synthesis extension(1,2)
MeO MeO HO

several steps HO NMe H O HO H HO O NMe H BBr3 O NMe

dihydrothebainone

2 codeine

1 morphine

Overman formal synthesis extension(3)


MeO HO

5 steps
O NMe H O HO H O NMe

15 dihydrocodeinone

1 morphine

(1) J Med Chem, 1977, 20(1), 164 (2) J Med Chem, 1976, 19(10), 1171 (3) Proc Jpn Acad, 1960, 36, 145

Sherwood 14 - CU Synthesis Lit Group Morphine

Final Comments
Gates synthesis
First reported Cu-Cr method creatively forges bridged heterocycle 31 steps Requires resolution to obtain enantiopure material Beyerman-Grewe cyclization to form last ring 14 steps to dihydrocodeinone Requires resolution at end to obtain enantiopure material Allylsilane-Iminium cyclization and Heck reaction to close core 14 steps to dihydrocodeinone following longest linear sequence No resolution necessary to achieve enantiopure material

Rice Synthesis

Overman Synthesis

Sherwood 15 - CU Synthesis Lit Group Morphine

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