morphine - renaudresearchgrouprenaud.dcb.unibe.ch/topic-review/topic-review-2012/... · me...
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Morphine Topic Review!Guillaume Povie
May 31st, 2012
> na!
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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!
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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+
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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%
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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.!
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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
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!
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.!
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!
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.!!
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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%
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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
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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
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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)
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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
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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
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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%
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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%
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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
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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.!!
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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
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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
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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
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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
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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.!!
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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. !!
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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.!
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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…!