Baran Lab Mo r phine and Codeine KE LI HO MeO MeO For excellent reviews on Morphine and Codeine, see 1. Hudlicky, T. et al Studies in Natural Products O O O Chemistry, 1996, 18, 43 H N H N H N H H 2. Taber, D.F. et al Strategies and Tactics in Organic synthesis, 2004, 5, 353 HO HO MeO Morphine Codeine Thebaine 3. Maier, M. Organic Synthesis Highlights II, 1995, 357 4.Novak, B.H. et al Curr. Org. Chem. 2000, 4, 343 OMe 5. Blakemore, P.R. et al, Chem. Comm. 2002, 1159 MeO O O 6. Zezula, J. et al, Synlett, 2005, 388 O HO OH MeO OH N O MeO The following work will be included in this talk due to the time limitation. Papaverine Meconic Acid Gates 1952 (-)-Morphine Rice 1980 (-)-Dihydrocodeinone Evans 1982 O-Me-thebainone-A O Fuchs 1988 Codeine N Tius 1992 Thebainone-A Parker 1992 Dihydrocodeinone MeO Overman 1993 (-)-Dihydrocodeinone O Mulzer 1996 (-)-Dihydrocodeinone Parsons 1996 Morphine White 1997 (+)-Morphine MeO O Hudlicky 1998 10-hydroxy-ent-epi-dihydrocodeinone OMe Cheng 2000 Desoxycodeine-D Noscapine Ogasawara 2001 (-)-Dihydrocodeinone ethylene ketal Taber 2002 (-)-Morphine Trost 2002 (-)-Codeine Raw opium contains approximately 25 different alkaloids by weight, Michels 2005 14-Hydroxycodeinone depending on the variety. The chief alkaloids are Morphine (4-21%), Codeine (0.8-2.5%), Thebaine (0.5-2%), Papaverine (0.5-2.5%), Noscapine (4-8%), Meconic Acid (3-5%). 0 Baran Lab Morphine and Codeine KE LI 2 HO 3 1 Morphine and codeine are the principal ingredients from opium poppy latex OH extract. The legal medicinal use of morphine in the US is more than 80 tons/year 4 11 and the world wide illicit market for narcotics is probably more than $760 billion. 10 12 (-)-Morphine OH O 15 Biosynthesis: O 5 14 HO MeO H 13 9 N H MeN 8 NH2 NH HO 6 CO2H HO 7 HO dopamine H NH2 MeO MeO OMe HO + L-tyrosine MeO CHO (S)-reticuline O O O O HO H N H N H H MeN MeO MeO HO O MeO N (-)-Codeine Codeinone Dihydrocodeinone HO O HO HO H MeO NMe NMe MeO HO MeO MeO MeO O O (R)-reticuline O O OH H N salutaridine H N H N OH OH O MeO MeO O Codeinone Thebaine Noroxymorphone Hydoxycodeinone Thebaine O HO HO HO H NMe Codeine O O O O N neopinone H N H N H H OH OH HO O O Morphine Nalorphine Naltrexone Naloxone Chem. Comm. 2002, 1159 1 Baran Lab Morphine and Codeine KE LI MeO MeO HO VOCO VOCO 2 eq. HBr TPP, O2, TFA, light O O Ethanol/ether O O O H N H N OH H N H NVOC H NH H H H MeO HO HO VOCO VOCO Thebaine VOCO HO Tetrahedron Lett. 1994, 31, 5727 Allyl bromide HCl Na2CO3 O O MeO MeO MeO H N H N H tBuOK, 18-crown-6, mCPBA H H2SO4 VOCO HO Me2SO4 O O O Overall 77% from morphine H N H N H N H OH Tetrahedron Lett.. 1977, 1571 O MeO O Heterocycles, 1998, 49, 43 J. Org. Chem., 1996, 61, 6774 O HO MeO MeO AcO AcO MeO O Cl O Ac2O O O O O O N H N H N H H N H N OH H NVOC H H OAc OAc OH O HO O O O O Oxymorphone HO HO (-) Codeine 1. HCl J. Am. Chem. Soc. 2005, ASAP allyl bromide, EtOH 2. MeOH,∆ O O 3. H SO , reflux H NH H N 2 4 OH OH O O Tetrahedron Lett. , 1977, 1567 Naloxone 2 Baran Lab Morphine and Codeine KE LI RO MeO MeO MeO MeO Br MeO Br O HO MeO O CN HO HO HO H N N OH H H H N NCHO NCHO HO O H H O O O HO MeO MeO MeO NH2 1. a) NaHSO3 MeO MeO MeO O O b) KCN, H2SO4 HO MeO MeO CN H AcOH/∆ (50%) H 2. SnCl /H O/HCl 1. 200°C HO 2 2 HO OH O OH HOAc 2. a) POCl3 NH CN O CO2H b) NaCNBH4 MeO MeO MeO MeO Br MeO Br 1. Li/NH MeO 3 NH4F/HF H2 1. N2H4/KOH 2. PhOCHO O 1. H2SO4 TfOH CuCrO3 2. a) MeI, NaH 2. KOH HO 50% MeO b) LAH MeO HO HO 3.MeSO3H H 3. 1. HCl/H2O NH NMe (HOCH2)2 NCHO KOtBu NH 2. H , Pd/C NMe H H 4. NBA H 2 H O /Ph2CO 5. HCO H/H O HCHO 2 2 MeO O O MeO MeO BBr3/CHCl3 Gates' 1. a) Br2 rt 1. Br , AcOH Codeine Morphine Rice introduced BBr3 for b) 2,4-DNPH 2 the O-demethylation in intermediate HO 2. HCl 2. 2,4-DNPH HO 88% morphine synthesis 3. HCl NMe3. H2/PtO2 NMe Rapaport procedure H H O O MeO MeO MeO Br 1. Br2/AcOH 1. HC(OMe)3/MeOH/H2SO4 2. CHCl3/1N NaOH MeO Br MeO Br 2.TsOH/CHCl3/120°C O 3. HBr/H2O/CHCl3 O HO 3. H2, Pd/C, HCHO LAH NMe HO H NMe 4.NBA/MeOH H O NCHO H H Br H 5.KOtBu/DMSO NMe NMe O O O 6.HOAc/H2O H H 79% 67% ArHNN O Rice modified procedure MeO HO MeO MeO MeO 1.PhSeCl pyr•HCl 2.NaIO4 O O ClCO2Et O O O NMe 34% NMe 3. LAH H H NMe H NCO2Et H NMe H H H H HO HO O O HO Gates, JACS, 1952, 74, 1109 Rice, K.C. Heterocycles 1977, 6, 1157 Rapaport, H. J. Med. Chem. 1976, 19,1171 3 JOC, 1980, 45, 592 Baran Lab Morphine and Codeine KE LI MeO MeO MeO MeO MeO MeO O O Br Br O Br O O O SPh H NMeTEOC H NMeTs NMe H NMeTs SO2Ph H H SO2Ph H H O HO H HO HO HO HO 1. Br /AcOH 2 1. a) (Sia)2BH/THF 1. Li/NH3 1. mCPBA 2. MOMCl/NaH MeO NMeTs MeO MeO b) H2O2/NaOH NH2 2.a)TsCl NMeTs 2. Ti(OiP)4/PhH 3.Ph3PCH2/NaOH 2. TsOH/MeOH b) 1N HCl 3. TBDMSOTf HO H HO HO MOMO 3. CBr4, Ph3P 3. MeI, K CO Br 2 3 HO TBDMSO O Br Br MeO 4. NaBH /CeCl 1. allylic bromide/KOH 4 3 O 2.(COCl)2/CHCl3 OH 3. PhSO Na/PhH 2 TBDMSO MeO MeO OH 4. a) TBSOTf/Et3N H HO 1. Br2/Fe/AcOH HO SPh b)mCPBA SO2Ph NMeTs O 2. PhSCH2P(O)(OEt)2/ Br 5. CeCl3/NaBH4 HO NaH/(CH2OMe)2 MeO MeO TBDMSO 1. nBu3P/DEAD/THF 1. LiH/THF 2. HF/CH3CN 2. nBuLi/THF MeO Br MeO MeO O Br O 3. Jones/acetone nBu3SnH 4. DIBAL/THF H Li/NH3 SO Ph SO2Ph O AIBN Br H 2 O O SPh HO NMeTs NMe H NMeTs H H HO H H HO HO MeO MeO HO 1. TFA Swern oxidation 2. NaHCO3/H2O/CHCl3 O O NMeTEOC MeO MeO H H NMeTEOC 3. a) HCl/Et2O/CH2Cl2 SO Ph 2 b) NaOH/H2O/CHCl3 Rapaport procedure Rice procedure O O 4. NaBH4/MeOH O O Morphine NMe H H NMe H H (-)-Codeine O O Fuchs, P.L. JOC, 1987, 52, 473 Parker, K.A. JACS, 1992, 114, 9688 4 Baran Lab Morphine and Codeine KE LI OMe MeO OMe O -CH MeO 2 OMe O O X OMe 1. PhSeCl O H2C O NMe 2. H2O2 H N + H N 3. H Me NHCO2Me X Me H Br NHCO Me O MeO CN 2 2 O H O H OMe MeO O MeO O OMe OMe OMe 1. KN(TMS) MeO O 2 O O OMe OMe Li HO OMe NTos Ph NMe OMe 2. H2/Pd NMe NMe MeO 1. Swern oxiat. MeO O 2. BF3•OEt2 A,BuLi NMe 3. K CO , MeI H CH Br ZnBr , C H Br 2 3 2 2 6 6 A then NaI O HO CH Br Br O 2 MeN Br MeO CN MeO CN 2 H 2 O OMe OMe OMe MeO O H HClO CH2N2 4 MeO O MeO O OMe OMe OMe H2C H2C H2C Zn, EtOH N N N H Me H Me Me MeO MeO MeO 1. DIBAL DMSO 2. H+ AcOH, 100°C HO HO HO NMe NMe NMe OMe MeO MeO H H H 1. MesCl MeO O O O OMe MeO OH 2. LiEt3BH MeO H2C NMe 3. OsO4, NMe BF3•OEt2 H N H NaIO4 H Me O CHO MeO CHO MeO NMe H Evans, D.A. et al, Tetrahedron Lett. 1982, 23, 285 Tius, M. et al, JACS, 1992, 114, 5959 5 Baran Lab Morphine and Codeine KE LI MeO MeO MeO O MeO Cl O O H 4 steps O O H MeO a H N H H H H MeO CHN2 MOMO COOH H O MOMO O MeO O CO2H MeO (CH2CO2Et)2 MeO CO2Me H MeO HO HO MeO Cl Cl OMe MeO Cl OH O Cl OMe O CO2H b N MeO Br 2 H O H Br OMe O O CO2Me CO Me O 2 O H Br H O O MeO MeO MeO H H H OH O O Br H H OMOM OMe OMe O OH 4 steps c d O O O O MeO MeO O O Rh2(OAc)2 O O O (+)-Morphine H N H H H OMe OMe MOMO O O e (-)-morphine O O O O O N N MeO MeO BsO O N O O NH a) (H2C=CH)2CuMgCl, THF, - 78 °C to 0 °C; ii) TMSCl, Et3N, 0 °C to 25 °C; H H H H iii) NBS, THF (63-80%).