Synthesis of morphine

Synthesis of Morphine Alkaloids MeO CO2H HO OH HO O OH NH2 NMe MeN MeO OH D N B C OH O A E Introduction  Cultivation: • Opium is harvested from the immature poppy seed capsule OH OMe O OH O OH MeN O N H MeN (-)-morphine 10 -15 % MeO (-)-codeine 3-4% Me MeO (-)-thebaine 1-2 % Fig 1: Lanced Poppy with raw opium exturding • Primary areas of cultivation are south east and west asia and latin america • An average Indian acreage of P somniferum yields 25-30 kg of opium Introduction  History of Morphine as a Pharmaceutical • Laudanum (16th Century): -Developed by Swiss alchemist Paracelus -alcoholic tincture of alcohol, opium, and other herbs -Eased suffering from the plague • Heroin (1898): -Developed by Heinrich Dreser at Fredich Bayer and Company -Diacetyl derivative of morphine -Marketed to the German people as a cough remedy • Morphine (Present day) -One of the most widely used drugs for treatment of severe pain Introduction  Structure D C HO OH N B O A E O  12 H HO Morphine 11 15 13 16 14 10 H N Me Key Features: rings, contiguous stereocenters, compact array of functionality Synthesis • Landmark synthesis was in 1952 by Gates • Since then at least 18 more total and formal synthesis of Morphine have appeared • This overview will encompass unique routes Biosynthesis of Morphine HO CO2H HO NH2 dopamine NH H HO NH2 HO MeO HO NMe H HO HO CHO L-Tyrosine MeO HO HO (S)-norcoclaurine (S)-reticuline MeO MeO MeO MeO HO O O HO NMe NMe NMe MeO MeO MeO OH MeO O O salutaridinol NMe salutaridine OH (R)-reticuline Phenolic coupling SN2' MeO ? O NMe H MeO thebaine MeO MeO O O H O neopinone NMe H HO ? NMe H O O H NMe H HO codeinone morphine Gates Synthesis  Retrosynthesis MeO MeO [Ox] O H MeO Epimerization HO [Red] N H HO HO N 14 O H N O Morphine [Red] MeO MeO NC MeO O [4 + 2] O MeO O CN OH Reductive Amidation MeO O MeO NH H O Gates Synthesis  Forward Synthesis: Diene BzCl NaNO2 HO OH BzO SO2 Pd/C FeCl3 (56 %) O BzO (MeO)2SO2 O OMe (78 %) OMe KOH NaNO2 Pd/C 10 FeCl3 (69 %) O NC O OMe NC OMe CO2Et NEt3 K3FeCN6 KOH,EtOH (82 %) O O OMe OMe Gates Synthesis  Forward Synthesis: Morphine MeO MeO O MeO O AcOH/! (50 %) MeO 27 atm H2 CuO/Cr2O O MeO CN CN OH EtOH 150 °C (50 %) O MeO NH H O N2H4/KOH MeI/NaH LAH (76 %) MeO (a) Br2 (b) 2,4-DNP HO 14 O H N HCl H2/ PtO2 (7 %) MeO H2SO4 HO 14 O H N MeO KOH, MeO (HOCH2CH2)2O KOt-Bu/Ph2CO (14 %) H N Gates Synthesis  Forward Synthesis: Morphine MeO (a) Br2 (b) 2,4-DNP HO H N HCl (8 %) O MeO MeO Br LAH (44 %) O H N O Pyr-HCl, 220 °C (34%) H HO O Morphine 1-Bromo-Codeinone  Analysis: Gates Method • 29 Steps • Overall Yield: 0.0014% MeO O N H HO • Key Disconnections: Diels-Alder & Reductive Amidation N Rice Synthesis  Retrosynthesis HO MeO O O MeO HO N N HO NCHO O CO2H O MeO H2N HO OH OMe Br OMe MeO MeO H NH HO O Br H NCHO Overman Synthesis  Analysis: Overman Approach • 1st enantioselective synthesis that did not contain a resolution • Natural and unnatural morphine available • 23 steps with an overall yield of 0.56 % (single heck) • 26 steps with an overall yield of 0.184 % (bis-cyclization) • Key disconnections were the Heck and Mannich OH O OH MeN White Synthesis  Retrosynthesis MeO MeO Beckman Rice O H C-H O H NMe H HO O NMe H O H O MOMO Insertion O Stobbe Hydrogenation O MeO CHO MeO MeO O H MOMO N2 Robinson HO HO CO2Me O MeO SEAr HO HO2C H O H H MeO MeO HO MeO MeO O O H CO2H O O OH White Synthesis  Forward Synthesis: MeO MeO HO MeO (CH2CO2Me)2 CHO P2O5, MeOH H2, [RhCl(COD)]2, (-)-MOD-DIOP HO HO2C CO2Me H2, Pd(OH)2 LiOH(aq), THF HO O CO2H KH, HCO2Me MVK, NEt3 NaOH, THF MeO O O Br MeO O OMe HO Br O Br MeO Br DBU O OMe 70 °C (80 %) CH2N2 HO Br O H O MeO OMe Br2, NaHCO3 HO O H O OH White Synthesis  Forward Synthesis: Br MeO MeO NaBH4 O OMe O H O H2, Pd/C (77 %) O H H O OMe HO CH2(OMe)2 LiOH 3.( COCl)2 CH2N2 (50 %) 22:1 MeO H O H O H MOMO N2 Rh2(OAc)4 (50 %) MeO O H NH H O MOMO 11 MeO MeO O O H H MOMO N H O H MOMO MeO NH2OH-HCl OBs NH H AcO O p-BrPhSO2Cl, NaOAc H (63 %) MOMO H O White Synthesis  End Game: MeO MeO O H MOMO  NH H O NaH/MeI HBr, MeCN D-Mperiodinane (90 %) MeO PhSeCl/MsOH NaIO4 O H O Analysis: White Approach NMe H O O LiAlH4 BBr3 (52 %) H H NMe HO MeO O • 29 steps • Overall yield of 1.73 % H H NMe HO • Asymmetry was introduced early via enantioselective hydrogenation • Key disconnect was the Rhodium (II) catalyzed C-H insertion Parker Synthesis Retrosynthesis:  HO N H HO [Ox] Rice O Me O N H O Me H N Me N Ts O Me H HO HO O morphine MeO MeO MeO Radical Cyclization MeO OMe HO PhS Mitusunobo O H OH Br NTs Me TBDMSO HO Me X N S R Ts Parker Synthesis  Forward Synthesis: • Racemic Route: NH2 a) TsCl, TEA b) 1N HCl MeI, K2CO3 (75 %) MeO NTs Me Li, NH3 O NaBH4, CeCl3 MCPBA Ti(Oi-Pr)4 TBDMSCl (1) (63 %) Na(Hg) NTs Me NTs Me HO TBDMSO racemic •Asymmetric Route: 1 Br2, TEA catechol borane (76 %, 80 % ee) Br HO NTs Me (90 %) HO MCPBA Ti(Oi-Pr)4 TBDMSCl (52 %) HO NTs Me TBDMSO enantiomerically enriched Failed routes included direct CBS reduction of (35 % ee) and Sharpless kinetic resolution of the allylic alcohol (44 %ee) H (S)-B-Me = Ph Ph O N B Me Parker Synthesis  Forward Synthesis: Mitsunobu Coupling MeO HO CHO PhS O P n-BuLi (OEt)2 Br THF (82 %) MeO HO SPh Br MeO OMe HO PhS OH Br NTs Me PBu3, DEAD 10 % HF TBDMSO O H HO Me Br SPh N Ts Parker Synthesis  Forward Synthesis: Radical Cyclization MeO O MeO O Me Br SPh H N Bu3SnH AIBN Me N Ts O H Ts HO HO (35 %) Ts N Me (11 %) -[ SPh] MeO OH MeO Bond Me O H HO SPh N O HO H Rotation Ts Ts N Me SPh Ts N Me Parker Synthesis  Forward Synthesis: Radical Cyclization MeO O MeO O Me Br SPh H N Bu3SnH AIBN Me N Ts O H Ts HO HO (35 %) Ts N Me (11 %) -[ SPh] MeO OH MeO O H HO Bond O Draw a mechanism that HO H accounts Me SPh N Rotation for Tsformation of the side product SPh Ts N Me Ts N Me Parker Synthesis  Forward Synthesis: Radical Cyclization MeO O MeO O Me Br SPh H N Bu3SnH AIBN Me N Ts O H Ts HO HO (35 %) Ts N Me (11 %) -[ SPh] MeO OH MeO Bond Me O H HO SPh N O HO H Rotation Ts Ts N Me SPh Ts N Me Parker Synthesis  End Game MeO O H HO MeO MeO Me Li/NH3 N t -BuOH Ts (85 %) O Me N MeO O H H HO HO N Me DMSO (COCl)2 (83 %) O H N O dihydrocodeinone HO Rice Method O N H HO morphine Me Me Parker Synthesis  Analysis: Parker Method MeO (+/-) Morphine: • 22 steps • Overall yield of 2.07 % O N H HO Me morphine • Radical cyclization was the key disconnect • First published in August, 1992 (-) Morphine: • 24 steps • Overall yield of 1.7 % • CBS reduction of α-bromoenone was key step • Published in January, 2006 Br HO NTs Me Conclusions  Disconnection approaches have evolved with the methods of synthetic chemisty D C OH N B O A E Gates (1952): Diels-Alder Rice (1980): Grewe Cyclization Evans (1982): Iminium Salts Overman (1993): Heck chemistry White (1997): C-H insertion Parker (2006): Radical Cyclization Racemic Asymmetric Morphine  Morphine appoaches will contiune to grow (Only Rice has come close to synthetically viable route)  with Continued need for developing morphine derivaties which can attenuate addictive properties References Review: Taber, D.F The Enantioselective Synthesis of Morphine: Strategies and Tactics in Organic Synthesis 2004, 5, 353 Lead References for Syntheses: Gates, M.J J Am Chem Soc 1953, 75, 4340 Rice, C.; Brossi, A J Org Chem 1980, 45, 592 Evans, D.A.; Mitch, C.H Tetrahedron Lett 1982, 23, 285 Overman, L.E Pure and Appl Chem 1994, 66, 1423 White, J.D J Org Chem 1999, 64, 7871 Parker, K.A J Org Chem 2006, 71, 449 ... • Since then at least 18 more total and formal synthesis of Morphine have appeared • This overview will encompass unique routes Biosynthesis of Morphine HO CO2H HO NH2 dopamine NH H HO NH2 HO... Company -Diacetyl derivative of morphine -Marketed to the German people as a cough remedy • Morphine (Present day) -One of the most widely used drugs for treatment of severe pain Introduction... acreage of P somniferum yields 25-30 kg of opium Introduction  History of Morphine as a Pharmaceutical • Laudanum (16th Century): -Developed by Swiss alchemist Paracelus -alcoholic tincture of alcohol,