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…!