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HO O NMe H HO
Molecule in Review
Trevor Sherwood (Snyder Group) Synthesis Literacy Group 7/17/09
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 morphine
2 codeine
Introduction
Total Syntheses examined
Gates (1952) 1st total synthesis of morphine, includes resolution
M. Gates, G. Tschudi. JACS, 1956, 78, 1380
Other Sources
Hudlicky, Tomas; Josephine Reed. The Way of Synthesis. WILEY-VCH: Weinheim, 2007.
Gates Synthesis
HO MeO
1 morphine
Diels Alder
HO
2,6-dihydroxynaphthalene
Gates Synthesis
HO
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
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
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
O NMe H HO
14
13
1 morphine
Rice Synthesis
MeO NH2
CO 2H MeO OH OH
dihydrocodeinone
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
Overman Synthesis
SiMe2Ph
dihydrocodeinone
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
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
Overman Synthesis
SiMe2Ph
NHDBS
25
CHO
PhMe2Si
Ar
Ar
H N DBS
H N DBS H
MeO OBn
dihydrothebainone
2 codeine
1 morphine
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
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