Morphine Topic Review!Guillaume Povie

May 31st, 2012

> na!

Opium

1!

Extracted from Papaverum Somniferum !Known since 3000 AC (Sumerians)!!

!

!

!

! !!!

Traditional drug for its sedative and analgesic effects!!

XVIe, Paracelsius used it as a medicine in alcoholic! solution: Laudanum !!

Widely prescript in the XIXe century for a simple cold, a meningite or even cardiovascular deseases, to adults as to babies (they sleep better…)!!

40 000 tons of opium produced in 1906, 8000 in 2008!

MeN

OOH

OH

Morphine

2!

Named after Morpheus, the greek god of the dreams!!

Isolated by A. Seguin, B. Courtois, in the 1804!But first F. W. Sertürner showed it was a “vegetal alkali”: the first alkaloid.!

! !!

Extraction from poppy is still by far cheaper than synthetic morphine!France and Australia are the main producer of legal morphine!

Many famous morphine addicts: Baudelaire, Bismarck, Alphonse Daudet.!!

1874: A. Wright prepared diacetylmorphine: heroin, quickly a success.!

MeN

OOH

OH

Effects

3!

Morphine and its derivative are important analgesic and anaesthetic.!!

µ-opioid receptor agonist in the CNS. !!

Cough medecine, induces constipation, nausea, dependence and tolerance.!!

!

!

!

!

! !!

ONMe

HO

MeO

ONMe

HO

HO

HH

morphine codeine

ON

O

HO

OHH

naxoloneantagonist

ONMe

O

HO

H

ethorphine1000 times more potent

HO

H

Structure Elucidation

4!J. M. Gulland R. Robinson, J. Chem. Soc. 1923, 980 – 998.!J. M. Gulland R. Robinson, J. Chem. Soc. 1923, 998 – 1011.!!!

extensive Hoffmandegradation

HO

+HO NMe2O

NMe

HO

MeO

codeine

O

MeO

+ NMe

C18H21NO3

O

+ OH + 2 insaturations

melted KOH

HO

HOHO

codeineC18H21NO3

ONMe

MeO

RO

thebaineC18H18NO3

ONMe

O

MeO

codeinone

HCl [Ox]

ether bridge less stable towards reducing agent O

MeO

+ NMe

+ 2 insaturations

HO

MeN

OOH

OH

Structure Elucidation

5!

ONMe

MeO

MeO

ONMe

MeO

OHCMeO2C

O3

ONMe

HO

MeO

1) MeI, NaOH2) RONa O

HO

MeO

NMe2

ONMe

HO

MeO

KMnO4O

NMe

O

MeO

ONMe

O

MeO

OH+

acetone

O

MeO

HO

NMe

+ 1 insaturations

C19H23NO3

No double bond?thebaine

codeine codeinone

O NMe

HO

MeO

?

codeineC18H21NO3

J. M. Gulland R. Robinson, J. Chem. Soc. 1923, 980 – 998.!J. M. Gulland R. Robinson, J. Chem. Soc. 1923, 998 – 1011.!!!

MeN

OOH

OH

Biosynthetic Hypothesis

6!

HO

MeO

HO

NMe

OMe

HO

MeO

O

NMe

OMe

HO

MeO

MeO

NMe

HOHO

MeO

MeO

NMe

HO

MeO

MeO

NMe

O

thebaine

protosinomenine

O

MeO

NH2

HO

HO

MeO+

“It is strongly held that the only promising route to an ultimate synthesis of morphine and its congeners is by a path already laid down by Nature.” R. Robinson!

O

MeO

HO

NMe

codeine revised structure

double bond Eventually accepted MeO

HO

MeO

N MeHO

laudanosine derivative

R. Robinson, S. Sugasawa, J. Chem. Soc. 1931, 3163 – 3172.!!!

MeN

OOH

OH

Oxidative Coupling

7!R. Robinson, S. Sugasawa, J. Chem. Soc. 1932, 785 – 789.!R. Robinson, S. Sugasawa, J. Chem. Soc. 1932, 789 – 805.!!!

HO

HO

HO

N MeHO

HCl

laudanosoline

o-chloranilAcOK, EtOH OH

HO

N MeHO

60 - 70%

Cl

O

O

ClCl

ClCl

O

O

HO

N MeHO

o-chloranil

OH

Modern Biogenesis!

8!

NH2

HO

HO

HO

O

NH

HO

HO

HO

(S)-norcauclorine

Pictet-Spenglerasedopamine

4-HPAA

[Ox]methylation NMe

MeO

MeO

HO

(S)-reticuline

HO

NMe

MeO

MeO

HO

(R)-reticuline

HO

[Ox][Red]

NMe

MeO

MeO

HO

(R)-reticuline

HONMe

MeO

MeO

HO

OH

SalSynOx. coupling NMe

MeO

MeO

HO

Osalutaridine

W. Brandt et al., Phytochemistry 2009, 70, 1696 – 1707.!T. Kutchan et al., J. Biol. Chem. 2009, 284, 24432 – 24442. !

MeN

OOH

OH

Morphine Biosynthesis

9!

NMe

MeO

MeO

HO

OH

NMe

MeO

MeO

HO

Osalutaridine 7(S)-salutaridinol

[Red] [Ac]NMe

MeO

MeO

HO

OAc7(S)-salutaridinol-7-O-acetate

spontaneous[SN2']

ONMe

MeO

RO

H

R = Me, thebaineR = H, oripavine[–Me]

ONMe

MeO

RO

H

R = Me, thebaineR = H, oripavine

ONMe

O

RO

R = Me, codeinoneR = H, morphinone

R = Me, codeineR = H, morphine

ONMe

HO

RO

HH

[–Me]

[Red][–Me]

H H

W. Brandt et al., Phytochemistry 2009, 70, 1696 – 1707.!T. Kutchan et al., J. Biol. Chem. 2009, 284, 24432 – 24442. !

MeN

OOH

OH

Dopamine

J. F. Carpenter J. Org. Chem. 1993, 58, 1607 – 1609.!!

10!

NH2HO

CO2H Tyr. hydroxylaseNH2HO

CO2HHO

tyrosine L-DOPA

decarboxylasePLP dependent NH2

HO

HOdopamine

NHMe

OHHO

HONMe

OHO

O

Ag2O

epinephrine (adrenaline) adrenochrome

NH2

O

O NH

HO

HO

[Ox]NH2HO

CO2HHO

L-DOPA

CO2HCO2H melanine polymer

[Ox]

NHMe

HO

HOepinine

1) MnO2

2) Ac2O DMAP NMe

AcO

AcO80%

examples!P. M. Dewick in Medicinal Natural Products: A Biosynthetic Approach. 2nd Ed. John Wiley & Sons, Inc., New. York, 2002!

Pictet Spengler

11!

!

NH2HO

CO2H aminotransferaseOHO

CO2H

tyrosine 4-hydroxyphenylpyruvic acid

decarboxylaseOHO

4-hydroxyphenylacetaldehyde4-HPAA

PLP dependent

OHO NH2

HO

HO–H2O

+N

O

HO

HO

H

NH

HO

HO

HON

O

HO

HO(S)-norcauclorine

NH

O

HO

HO

HH+

–H+

In Aqueous Media

12!

K. D. McMurtrey, L. R. Meyerson, J. L. Cashaw, V. E. Davis, J. Org. Chem. 1984, 49, 948 – 950.!!

NHMe

OHHO

HOepinephrine

MeCHO

Me

NMe

HO

HO

OH

Me

NMeHO

OH

OH

+H2O

pH 0.4, t1/2 = 1 day > 99 : 1 (dr 1:1, 95% isolated)pH 9, t1/2 = 6 min 66 : 34 (dr 1.5:1)

with CH2O aq., reaction complete in less than a minute (pH 7)

NH

HO

HO

HO Same trends in rates and ratio of products depending on the pH of the reaction

CH2OH2OHO

N

HO

OH

HOOH

tetrahydropapaverine tetrahydroprotoberberine

H. A. Bates, J. Org. Chem. 1981, 46, 4931 – 4935. H. A. Bates, J. Org. Chem. 1983, 48, 1932– 1934!!

C. Schöpf, W. Salzer, Justus Liebigs Ann. Chem. 1940, 544, 1 – 30.!!

O NH2

BnO

BnO+

O

O

NH

BnO

BnOH2O, 20 °C

O

O

pH 7, t1/3 = 13 minpH 3, t1/3 = 5 dayspH 6

84%

Pummererʼs Ketone:a Model for Morphine Biosynthesis!

13!

Pummerer proposed a p-O coupled intermediate!

Bartonʼs revision!

OH

Me

crystalline dimerup to 25%

K3Fe(CN)6

Radical pairing

Me

O OH

Me+

O

Me

Me

OH

O

Me O

Me

H

Me

O

O

Me

Me

O

O

Me O

Me

proposed structure Pummerer 1923

unlikely forBarton

radical substitution

O

Me+

unprobablerather Ox.

O

Me

O

Me

Phenolic coupling ortho-para

+

OH

MeO

Me

O

Me

O

Me

Revised structure Barton 1955

Radical coupling preferred but substitution not discarded.!

D. H. R. Barton, A. M. Deflorin, O. E. Edwards, J. Chem. Soc. 1956, 530 – 534.!

Bartonʼs Hypothesis

14!

N

MeO

HO

MeO

HO

p'

o'

p

o

N

OOMe

OMe

N

OOMe

OOMe

NMeNMe

NMe

O

NMe

O

HO

MeO MeOOH

OHMeO

MeO

HO

MeO

HO

MeO

HO

MeO

MeO

o-p'o-o'

p-p'p-o'

O

N

OOMe

OOMe

N

OOMe

OMeO

salutaridine

corytuberine

H H

H H

isoboldine

pallidine

(R)-reticuline

D. H. R. Barton, T. Cohen, Festschrift Arthur Stoll 1957, 177 – 142.!

Revision of the biogenesis of morphine and aporphines, and proposal of a key phenolic coupling also for amaryllidaceae and erythrina alkaloids as well as fungal metabolites (usnic acid). !

MeN

OOH

OH

!

15!

Ox. Phenolic Coupling

D. H. R. Barton, D. S. Bhakuni, R. James, G. W. Kirby,, J. Chem. Soc. C 1967, 128 – 132.!

HO

NMe

MeO

MeO

HO

(±)-reticuline

3H2O, SOCl2 100 °C, 96 h HO

NMe

MeO

MeO

HO

[3H]-(±)-reticuline

3H

3H

K3Fe(CN)6

CHCl3/H2O (1:1), 10-3 MHO

NMe

MeO

MeO

[3H]-salutaridine0.03% (by scintillation)

O

3H

3H

HO

NR

MeO

MeO

HO

R = Me, COR

[Ox.]

[Ox.] = K3Fe(CN)6[Ox.] = AgCO3 celite[Ox.] = VOCl3[Ox.] = MnO2 silica gel

NR

MeO

MeO

O

OH

isosalutaridine 0.3 - 4% +

NR

MeO

MeO

HO

OH

isoboldine0.4 - 53%

T. Kametani, A. Kozuka, K. Fukumoto, J. Chem. Soc. C 1971, 1021 – 1023.!

!

16!

Oxidative Coupling

M. A. Schwartz, I. S. Mami, J. Am. Chem. Soc. 1975, 97, 1239 – 1240.!

HO

NCO2Et

MeO

MeO

HO HO

NCO2Et

MeO

MeO

O

Tl(CF3CO2)3

CH2Cl2, –78 °Cethoxycarbonyl-norsalutaridine

23%

!See also: C. Szàntay, et al., J. Org. Chem. 1982, 47, 594 – 596. M. A. Schwartz, et al. J. Org. Chem. 1985, 50, 743 – 747. D. A. Burnett, D. J. Hart, J. Org. Chem. 1987, 52, 5662 – 5667. H. Hara, S. Komoriya, T. Miyashita, O. Hoshino, Tetrahedron asym. 1995, 6, 1683 – 1692.!

!

N

MeO

MeO

MeO

BnO

Pt anode, 1.1 VNMe

BnO

MeO

O

OMe

44%

!For electrochemical approaches see also: Ronlàn et al., J. Org. Chem. 1979, 44, 196 – 203. S. M .Kupchan et al. J. Am. Chem. Soc. 1975, 97, 5622 – 5623.!

!

L. L .Miller, F. Stermitz, J. R. Falck, J. Am. Chem. Soc. 1973, 95, 2651 – 2656.!!

Schwartz Codeine Synthesis! !

17!M. A. Schwartz, P. T. K. Pham, J. Org. Chem. 1988, 53, 2318 – 2322.!!

BnO

NH2

MeO

MeO

HO

CO2CH3

CO2HOH

HN

MeO

OMe

HO

CO2CH3

O1) CDI2) H2, Pd/C

79%

99% ee1) ClCO2Me, Et3N2) POCl3, then NaBH43) ClCO2Me, Et3N

HO

NCO2Me

MeO

MeO

HO

CO2CH3

90% 52% ee

HO

NCO2Me

MeO

MeO

HO

CO2CH3 Tl(CF3CO2)3CH2Cl2, –78 °C

orPhI(OAc)2, CF3CO2HCH2Cl2 (5. 10–4 M), rt

HO

NCO2Me

MeO

MeO

O 25%

CO2CH3 1) NaBH42)

NMe2NpO

NpO

HO

NCO2Me

MeO

MeO

O

CO2CH3

ONp

NMe2

ONCO2Me

MeO

MeO

CO2CH3

76%

Schwartz Codeine Synthesis! !

18!

M. A: Schwartz, P. T. K. Pham, J. org. Chem. 1988, 53, 2318 – 2322.!!

ONCO2Me

MeO

MeO

CO2CH3

1) MeOH, NaOH aq.2) PivCl, NMM2) then

NS

ONa

3) t-BuSH, 3) AIBN, h!

ONCO2Me

MeO

MeO

70%

1) HBr2) LiAlH4

ONMe

MeO

codeine62%

HO

Noyoriʼs synthesis of (R)-reticuline in high optical purity ([Ru] cat. Hydrogenation of enamides): access to a rapid asymmetric version.!

R. Noyori, M. Otha, Y. Hsiao, M. Kitamura, T. Otha, H. Takaya, J. Am. Chem. Soc. 1986, 108, 7117 – 7119. !!

NMe

MeO

OMe

OHHO NMe

MeO

OMe

OHHO 92% yield

95% ee

PPh2Ru(OAc)2

PPh2

H2 (4 bars)EtOH, CH2Cl2

(R)-reticuline

Grewe Cyclisation

19!R. Grewe, A. Mondon, E. Nolte, justus Liebigs Ann. Chem. 1949, 564, 12 – 161 – 198.!!

N

MeO

MeO

CHO

Br1) n-BuLi, Et2O

N

OH

MeO

MeO

54%

1) HBr, AcOH2) Zn powder N

MeO

MeO

54%

N

MeO

MeO

Br

1) MeI2) H2 (2 equiv), Pt2) MeOH, NaOH aq. N

MeO

MeO

87%

NMe

MeO

HOHCl aq.120°C, 10 h

if longer timehigher temperatureor HBr is usedmixed with methoxy isomers

MeN

OOH

OH

Rice Synthesis

20!

HO

NCHO

MeO Br

O

minor product formed in the Grewe cyclisation

14% NH4F.HFin dry TfOH0 °C, 96 h

NCHO

MeO

HO

O

Br

only traces

HO

NCHO

MeO

MeO

1) (CH2OH)2 (3 equiv) THF, MeSO3H (1% v/v)then NBA O

NH

BrHO

NCHO

MeO

O

O

Br

HCO2H, H2OHO

NCHO

MeO Br

O14% NH4F.HFin dry TfOH0 °C, 96 h

NCHO

MeO

HO

90% (3 steps)O

Br

60%

K. C. Rice, J. Org. Chem. 1980, 45, 3137 – 3139.!!

MeN

OOH

OH

HO

NH2

MeO

MeO

CO2H

HN

MeO

MeO

Oneat, 200 °C

95%

1) POCl3, 2) NaBH3CN, H2O

HO

NH

MeO

MeO86% (0.35 mol)

HO1) Li, NH3/t-BuOH2) PhOCHO, EtOAc HO

NCHO

MeO

MeO85% (85 mmol)

Rice Synthesis

21!

NCHO

MeO

HO

O

Br

1) MeOH, HCl aq.2) H2, Pd/C, CH2O aq. AcONa/AcOH in H2O NMe

MeO

HO

Odihydrothebainone

quant.

NCHO

MeO

HO

O

BrH2, Pd/C, CH2O aq.AcONa/AcOH in H2O

2) Br2, AcOH3) CHCl3, aq. NaOH 1M

1) MeOH, HCl aq.

NH

MeO

O

O

Br

NMe

MeO

O

Odihydrocodeinone

79% (4 steps)

37% overall

29% overall

NCHO

MeO

HO

O

BrH2, Pd/C, AcONa/AcOH in H2O

2) Br2, AcOH3) CHCl3, aq. NaOH 1M

1) MeOH, HCl aq.

NH

MeO

O

O

Br

NH

MeO

O

Odihydronorcodeinone

80% (4 steps)

30% overall

K. C. Rice, J. Org. Chem. 1980, 45, 3137 – 3139.!!

MeN

OOH

OH

End Game to Morphine

22!

NMe

MeO

O

O

1) (MeO)3CH, H2SO4

2) PTSA, CHCl3 NMe

MeO

O

MeO

1) NBA, MeOH

NMe

MeO

O

MeOMeO

Br

1) t-BuOK, DMSO2) 3N aq. AcOH NMe

MeO

O

Ocodeinone

> 80%

NMe

MeO

O

O

BBr3 (6 equiv)CHCl3NaBH4, MeOH

NMe

MeO

O

HO

NMe

HO

O

HOcodeine

84%morphine

91%codeinone

D. D. Weller, H. Rapoport, J. Med. Chem. 1976, 19, 1171 – 1175.!!

M. Gates J. Am. Chem. Soc. 1953, 75, 4340 – 4341.!!

K. C: Rice, J. Med. Chem. 1977, 20, 164 – 165.!!

MeN

OOH

OH

Overman Synthesis

23!Allylic substitution of lithiated carbamate: C. Gallina, P. G. Ciattini, J. Am. Chem. Soc. 1979, 101, 1035 – 1036. !!

C. Y. Hong, N. Kado, L. E. Overman, J. Am. Chem. Soc. 1993, 115, 11028 – 11029.!!

MeN

OOH

OH

O 1) CBS, CatBH

2) PhNCO3) OsO4, NMO4) Me2CO, H+

OCONHPh

67% > 96% ee

OO then CuI(Ph3P)2

PhMe2SiLi

n-BuLiO

OO

NPh

OLi

Cu(SiMe2Ph)2.LiI

SN2' synSiMe2Ph

OO

81 %

SiMe2Ph

OO

1) PTSA, MeOH

2) NaIO43) DBS-NH2, NaBH3CN

SiMe2Ph HN

DBS = dibenzosuberyl 82% (3 steps)

CHO

IOBn

MeO

ZnI2, EtOHN

DBS

ArPhMe2Si

chair-like TS

NH

IOBn

MeO

DBS

82% (d.r. > 20:1, 91% ee)

Pd(CF3CO2)2(PPh3)2PMP, toluene, 120 °C

NH

MeO

BnO

NDBSH

1) BF3.OEt2, EtSH

60%

2) ArCO3H

MeO

ONBSHH

HO47%

The First Synthesis of Morphine!

24!M. Gates, J. Am. Chem. Soc. 1950, 72, 228 – 234.!M. Gates, G. Tschudi, J. Am. Chem. Soc. 1952, 74, 1109 – 1110.!!!!

HO

OH

1) PhCOCl, pyr2) NaNO2, AcOH3) H2/PdC

HO

OBz

H2NFeCl3aq. work up

O

O

OBz

1) SO22) Me2SO43) KOH

MeO

OH

MeO

MeO

MeO O

O

CNEtO2C1)

then K3Fe(CN)6

MeO

MeO O

OEtO2C

CN

KOH

MeO

MeO O

OCN

as before

30% overall83% (2 steps)

Et3N

80 °C, 48 h

MeO

MeO O

OHNC

50%

Cr-CuH2 (27 bar)130 °C

MeO

MeO O

O

NH

MeO

MeO O

O

NH

MeO

MeO O

NH

O

50%

Gates Synthesis

25!

MeO

MeO O

NH

O1) NH2NH2, KOH, 150 °C2) NaH, MeI3) LiAlH4

MeO

MeO

NMe

80%

benzoyl tartric acid resolution

MeO

MeO

NMe

(+) and (–) (around 80%)

MeO

MeO

NMe

H2SO4

MeO

MeO

NMe

HO28%

1) Ph3NMe.OEt2) t-BuOK benzophenone

MeO

HO

NMe

O 48%

M. Gates, G. Tschudi, J. Am. Chem. Soc. 1956, 78, 1380 – 1393.!!!!

Definitely proved the structure proposed by Robinson!

MeO

HO

NMe

O

same strategy as seen before but less efficient

HO

ONMe

HO(–)-morphine

The Phenanthrene Route

26!

J. D. White, P. Hrnciar, J. Org. Chem. 1999, 64, 7871 – 7884.!!

MeN

OOH

OH

MeO

O

H O

N2

HH

Rh(OAc)2

CH2Cl2

MeO

O

H

O

H

50%MOMO MOMO

1) NH2OH2) BsCl

MeO

O

H

NOBs

HMOMO

AcOH

MeO

O

HHMOMO

NH

O

62% (regio 92:8)

White’s C-H insertion

Ginsburg unexpected cyclisation

MeO

MeO

H

OHO

O

C5H11ONONaOEtthen aq. AcOH

MeO

MeO

H

OH

NO

O

1) H2, Pd/C2) AcOCH2COCl CHCl3, pyr.

MeO

MeO

H

OH

NHO

OOAc

76% 76%

MeO

HO

HNHO

OO

O

(CH2OH)2

TsOH, C6H6

> 80%

D. Ginsburg, R. Pappo, J. Chem. Soc. 1953, 1524.!!

Mulzer Approach

27!J. Mulzer, G. Dürner, D. Trauner, Angew. Chem. Int. Ed. 1996, 35, 2830 – 2832. !!

MeN

OOH

OH

MeO

MeO

O

Cl HCO2Me NaOMe

MeO

MeO

OHCO

Cl 1) MVK, Et3N MeOH2) KOH dioxane/H2O

MeO

MeO

Cl

O73% ( 2 steps)

1) (C2H3)2CuMgCl THF, –78 °C then TMSCl2) NBS

MeO

MeO

Cl

O

Br

84% cis/trans 3:1

H

MeO

O

NMeSO2PhO

O

H

NBS, (PhCOO)2CCl4, reflux

MeO

O

NMeSO2PhO

O

H

Li, NH3MeOH/THF

MeO

O

NMeO

O

H

MeO

ONMe

O

O65% 79%

H

HHH

MeO

MeO

Cl

O

Br

DMF, 140 °C

MeO

O

Cl

Oquant.

1) (CH2OH)2, TMSCl, CH2Cl22) BH3.Me2S then HO2Na

MeO

O

Cl

OHO

O

H H

64%

1) Ni Raney MeOH, KOH

2) PhSO2NHMe ADDP, PBu3

MeO

O

NMeSO2PhO

O

H

80%

H H H H

Radical Cyclisation

28!K. A. Parker, D. Fokas, J. Am. Chem. Soc. 1992, 114, 9688 – 9689.!!

MeN

OOH

OH

MeO

O NMeTsH

HO

OMe

O

TsMeN OH

PhS

BrSPh

Bu3SnH, AIBN

MeO

O NMeTsH

HOSPh

C6H6, 130 °C, 35 h

MeO

O NMeTsH

HOSPh

MeO

O NMeTsH

HO

–PhS Li, NH3THF, t-BuOH –78 ° C

MeO

ONMeHH

HO

Swerndihydrocodeinone

35% 85%

Parker’s formal synthesis

Evans Route

29!D. A. Evans, C. H. Mitch, Tetrahedron Let. 1982, 23, 285 – 288.!!

MeN

OOH

OH

NMe

OMe

OMe n-BuLi

NMe

OMe

OMeBr

Br

NMe

OMe

OMe

Br

NaI

NMe

OMe

OMe

NMe

OMe

OMe

ClO4

HClO4MeOH

60%

CH2N2

NMe

OMe

OMe

HH

CH2Cl2DMSO– Me2S

NMe

OMe

OMe

H CHO

BF3.OEt2

MeO

MeO

NMeH

OH

Fuchs Double Cyclisations

30!J. E. Toth, P. R. Hamann, P. L. Fuchs, J. Org. Chem. 1988, 53, 4694 – 4708.!!

MeN

OOH

OH

HOO

SO2t-Bu

Br

Br

n-BuLi (2 equiv)THF, –78 °C LiO

O

SO2t-Bu

Li

Br

LiO

O

SO2t-Bu

Br

Li

MeO

O

SO2t-BuH

HO63%

LiOO

SO2t-Bu

H

Br

LiOO

SO2t-Bu

H

Br

10 - 20%

TBDMSOO

SO2t-Bu

Li

Br

TBDMSOO

SO2t-Bu

H

Br

H –OTBDMS O

SO2t-Bu

H

Br

Heck Cyclisations

31!

B. M. Trost, W. Tang, J. Am. Chem. Soc. 2005, 127, 14785 – 14803.!!

MeN

OOH

OH

Trost

O Br

CHOMeO

CN

Pd(OAc)2, dpppAg2CO3, toluene, reflux

MeO

O

H

91%

CHOCN

MeO

O

HCN

Br

Pd(OAc)2, dpppAg2CO3, toluene, reflux

MeO

O CN

HH

MeO

O

HH

65%

NHMe

HO

LDAtungsten lamp

MeO

O

HH NMe

HO(–)-codeine

overall 7%57%

O OMe

OMeMeO

I

OTBS

Pd2(dba)3P(o-tolyl)3

Et3N, MeCN, refluxthen TBAF

OOMe

MeOMeO

O

H

87%

NHCO2MeNHCO2Me

HCl, MeOHreflux O

NCO2Me

MeO

OH H

94%

Fukuyama

K. Ushida, S. Yokoshima, T. Kan, T. Fukuyama, Org. Lett. 2006, 8, 5311 – 5313.!!

Miscellanous

32!

D. F. Taber, T. D. Neubert, A. L. Rheingold, J. Am. Chem. Soc. 2002, 124, 12416 – 12417.!

MeN

OOH

OH

Taber

Storck’s [4+2]

O

OBr Ph

Ph

MeO

MeO

KHMDS, Et2O

O

OPh

Ph

MeO

MeO

H

H

MeO

MeO

OHC N SO2Ph

BrO

77%

K2CO3, TBABtoluene, reflux

MeO

MeO

HNSO2Ph

O

MeO

HO

OHC HNSO2Ph

O

via

92%

O

CHOCO2Me 1) Cp2ZrCl, AgOTf

2) TESCl, Imid.O

CO2Me

OTES

decalin, Et3N230 °C

OMe OMe

MeO

O CO2Me

HH OTES

92 % endo product89%

G. Stork, A. Yamashita, J. Adams, G. R. Schulte, R. Chesworth, Y. Miyazaki, J. J. Farmer, J. Am. Chem. Soc. 2009, !131, 11402 – 11406. !!

And many others…

33!

MeN

OOH

OH

390 J. Zezula, T. Hudlicky ACCOUNT

Synlett 2005, No. 3, 388–405 © Thieme Stuttgart · New York

Note: Key transformations in the Schemes are depicted inblue.

2.1 Taber

In 2002 Taber23 published a total synthesis of (–)-mor-phine starting from tetralone 9, which provided the AB-ring system and the carbon atoms needed for the construc-tion of the C-ring. Compound 9 had been prepared from

1,6-dibromo-2-naphthol (7) in 7 steps utilizing modifiedliterature procedures.25

Several issues deserve mention from strategic as well astactical viewpoints. First, the incorporation of asymmetrywas accomplished by resolution of racemic 9 via dia-stereomeric ketals derived from (S,S)-(–)-hydrobenzoin togive 10 and 11, which were separated by column chroma-tography (Scheme 1).

The undesired diastereomer 11 was easily recycled to ra-cemic 9 by reflux in aqueous acetic acid. Second, the cy-clization of ketal 10 via alkylidene carbene C–Hinsertion26 followed by hydrolysis gave the enantiomeri-cally pure ketone 12, which, unlike tetralone 9, cannot ra-cemize because of the large energy difference betweencis- and trans-fused hydrindanones (Scheme 2).

Taber introduced the nitrogen atom along with the re-maining two carbons necessary for the construction of theD-ring to provide the key intermediate, keto aldehyde 14as shown in Scheme 2. Third, both C- and D-rings wereclosed in a single operation, as shown in Scheme 3.

The introduction of the nitrogen atom required the stereo-selective reduction of ketone 12 with L-Selectride to thea-alcohol, which was converted, with inversion of config-uration, to the corresponding azide by Mitsunobu cou-pling.27 Reduction and protection gave sulfonamide 13.The key intermediate in Taber’s synthesis, the keto alde-

Figure 3 Key design considerations for morphine and noroxymor-phone

O

N

HO

HO

O

NH

HO

OOH

C-10/C-11 bond

C-9/C-14 stereocenters

13

14

9

C-13 quarternary center

14

C-14 alcoholcis-1,2-aminoalcohol

1 6

Table 1 Total and Formal Syntheses of Morphine and its Deriva-tives

Principle author

Date Product (no. of steps) Yield (%)

Gates 1952 (–)-Morphine (23) 0.016

Ginsberg 1954 rac-Dihydrothebainone (21) 8.86a,7

Grewe 1967 rac-Dihydrothebainone (9) 0.818

Rice 1980 (–)-Dihydrocodeinone (10) 29.009

Evans 1982 rac-O-Me-thebainone-A (12) 16.6710

Rapoport 1983 rac-Codeine (26) 1.1511

Fuchs 1988 rac-Codeine (22) 1.5312

Tius 1992 rac-Thebainone-A (28) 0.9713

Parker 1992 rac-Dihydrocodeinone (12) 9.4214

Overman 1993 (–)-Dihydrocodeinone (14) 4.4315

Mulzer 1996 (–)-Dihydrocodeinone (15) 11.5016

Parsons 1996 Morphine 0.88b,17

White 1997 (+)-Morphine (28) 3.0018

Hudlicky 1998 10-Hydroxy-ent-epi-dihydro-codeinone (14)

2.7019

Cheng 2000 rac-Desoxycodeine-D (15) 13.2620

Ogasawara 2000 rac-3,4-Dimethoxy-6-mor-phinanone (29)

0.2521

Ogasawara 2001 (–)-Dihydrocodeinone ethyl-ene ketal (24)

0.3722

Taber 2002 (–)-Morphine (27) 0.5123

Trost 2002 (–)-Codeine (15) 6.7824

a First 16 steps.b Last 5 steps.

Scheme 1 Reagents and conditions: (a) MeI, K2CO3, DMF (97%);(b) MeONa, collidine, CuI, MeOH, D (89%); (c) Na, EtOH, D; (d)HCl, H2O, D (76%, 2 steps); (e) (MeO)2CO, MeONa, D (76%); (f)LDA (2 equiv), THF, 0 °C; (g) LiCl, DMSO, H2O, D (80%, 2 steps);(h) p-TsOH, (S,S)-(–)-hydrobenzoin, HC(OEt)3, CH2Cl2 (86%).

HO

Br

Br

O

MeO

OMe Br

MeO

OMe Br

O

O

Ph

Ph

MeO

OMe Br

O

O

Ph

Ph

O

MeO

OMe

a–d

e–g

h

+

9

7 8

10 11

Dow

nloa

ded

by: U

nive

rsitä

tssp

ital-B

iblio

thek

USB

. Cop

yrig

hted

mat

eria

l.

Guillou synthesis of rac-codeine!M. Varin, E. Barré, B. Lorga, C. Guillou, Chem. Eur. J., 2008, 14 , 6606-6608!

Metz synthesis of rac-codeine!T. Erhard, G. Ehrlich, P. Metz, angew. Chem. Int. Ed. 2011, 50, 3892 – 3894.!

Reviews on Morphine syntheses!J. Zezula, T. Hudlicky, synlett 2005, 388 – 405.!P. R. Blakemore, J. D. White, Chem. Commun. 2002, 1159 – 1168.!

Conclusions

34!

MeN

OOH

OH

“It is strongly held that the only promising route to an ultimate synthesis of morphine and its congeners is by a path already laid down by Nature.” R. Robinson!

The most efficient synthesis does not always require the most sophisticated tools.!!!Still a long way untill the ultimate synthesis…!