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Molecule in Review
Trevor Sherwood (Snyder Group)Synthesis Literacy Group
7/17/09 Columbia University Chemistry
Morphine
O
HO
NMe
H
HO
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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
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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
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Gates Synthesis
Sherwood 4 - CU Synthesis Lit Group - Morphine
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
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Gates Synthesis
Sherwood 5 - CU Synthesis Lit Group - Morphine
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
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Gates Synthesis
Sherwood 6 - CU Synthesis Lit Group - Morphine
MeO
OH
CN
MeO
O
MeO
O
MeO
ONH
MeO
O
MeO
ONH
MeO
NH
MeO
OO
7
8
H
HH
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Gates Synthesis
Sherwood 7 - CU Synthesis Lit Group - Morphine
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
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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
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Rice Synthesis
Sherwood 9 - CU Synthesis Lit Group Morphine
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
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Overman Synthesis
Sherwood 10 - CU Synthesis Lit Group Morphine
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
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Overman Synthesis
Sherwood 11 - CU Synthesis Lit Group Morphine
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
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Overman Synthesis
Sherwood 12 - CU Synthesis Lit Group Morphine
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
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Overman Synthesis
Sherwood 13 - CU Synthesis Lit Group Morphine
SiMe2Ph
NHDBS
MeO
OBn
I
CHO
25
29
NDBS
Ar
H
PhMe2Si
NDBS
Ar
H
H
E/Z > 20:1
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Formal syntheses of morphine
Sherwood 14 - CU Synthesis Lit Group 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
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Final Comments
Sherwood 15 - CU Synthesis Lit Group Morphine
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