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Comparative Total Syntheses of Strychnine

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Comparative Total Syntheses of Strychnine Comparative Total Syntheses of Strychnine NH2 N O H OCH3 N N O H H H CO2CH3 OCH3 H N H N H N H H N N H H H N H H H H HO HO O O Wieland Gumlich aldehyde O O isostrychnine − H Strychnine OH CN Nolan T. McDougal O2N O H April 20, 2009 N OPMB Br Ts OSEM 8:00 pm, 147 Noyes H N Strychnine − Isolation H N H H O O H First isolated from Strychnos ignati: Pelletier & Caventou, Ann. Chim. Phys. 1818, 8, 323. Strychnos nux vomica Stychnine Poisoning and Treatment • Biological Response - Blocks postsynaptic inhibition as an antagonist of glycine in the central nervous system, resulting in over-transmission of signals and in reflex arcs, which would normally be suppressed by the postsynaptic action of glycine. i.e. the tiniest sensory stimulus (noises, movement, or light) produces powerful muscular contraction. • Symptoms - Tightness and twitching of the muscles, agitation and hyperreflexia. Stiffness of the body and lockjaw. Nearly continuous convulsions. Cessation of respiration. Death comes from asphyxiation caused by paralysis of the neural pathways that control breathing, or by exhaustion from the convulsions. The patient never loses consciousness. • Treatment -There is no specific antidote. Oral application of an activated charcoal infusion. Anticonvulsants are administered along with muscle relaxants, and if necessary artificial respiration. Treatment in the late 19th and early 20th centuries was to administer tannic acid which precipitates the strychnine as an insoluble salt, and then to anaesthetise the patient with chloroform until the effects of the strychnine had worn off. • Dr. Pierre-Eloi Fouquier - doctor during Napoleanic Wars H N N Structure of Strychnine H O H H H "For its molecular size it is the most complex N N H H H substance known." - Robert Robinson (1952) H O O O H "Admittedly, by one whose special familiarity with the intricacies of its structure and behaviormight excuse a certain prejudice, but with six nuclear asymmetric centers and seven rings constituted from only twenty-four skeletal atoms, the case is a good one" - R. B. Woodward (1963) • First isolated in 1818 by Pelletier & Caventou − Pelletier & Caventou, Ann. Chim. Phys. 1818, 8, 323. • Elemental composition determined in 1838 by Regnault − Regnault, Ann. 1838, 26, 35. • Degradation studies (1880's-1950's) by Robinson, Leuchs, and Woodward publications (~250) (~125) • Structure defined in 1946 by Robinson and in 1947 by Woodward − Openshaw & Robinson, Nature 1946, 157, 438. − Woodward et al. J. Am. Chem. Soc. 1947, 69, 2250. − Woodward & Brehm, J. Am. Chem. Soc. 1948, 70, 2107-2115. • Relative stereochemistry defined by X-ray crystal in 1951 by Robertson & Beevers, and Bijvoet − Robertson & Beevers, Nature 1950, 165, 690-691. − Bijvoet et al. Acta Crystallogr. 1951, 4, 275-280. • Absolute stereochemistry defined by X-ray crystal in 1956 by Peerdeman − Peerdeman, Acta Crystallogr. 1956, 9, 824. • Absolute stereochemistry defined by chemical methods in 1963 by Schmid − Schmid et al. Helv. Chim. Acta. 1963, 46, 1212-1231. Biosynthesis of Strychnine OGlc OGlc NH OHC N H NH2 O H N O H H3CO2C tryptamine H3CO2C secologanin strictosidine N H H N N N H H H CH N N 3 H CH3 H H CH3 H3CO2C H3CO2C CHO CHO OH geissoschizine dehydropreakuammicine norfluorocurarine H H H N N N H H N N N H H H H H H H H HO2C OH CHO OH OH O O H H Wieland−Gumlich aldehyde prestrychnine strychnine Schmid et al. Helv. Chim. Acta. 1969, 52, 776-789. Helmberger & Scott, J. Chem. Soc., Chem. Commun. 1973, 217-218. Syntheses of Strychnine • R. B. Woodward - Harvard University (1954) • Philip Magnus - University of Texas (1992) • Gilbert Stork - Columbia University (1992) • Larry E. Overman - University of California, Irvine (1993) • Martin E. Kuehne - University of Vermont (1993) • Viresh H. Rawal - The Ohio State University (1994) • Josep Bonjoch & Joan Bosch - University of Barcelona (1999) • Stephen F. Martin - University of Texas (1996-2001) • Michael J. Eichberg & K. Peter C. Vollhardt - University of California, Berkeley (2000) • Graham J. Bodwell - Memorial University of Newfoundland (2002) • Miwako Mori - Hokkaido University (2002) • Masakatsu Shibasaki - University of Tokyo (2002) • Tohru Fukuyama - University of Tokyo (2004) • Albert Padwa - Emory University (2007) O O H N H N HO OH H N NaOAc, Ac2O KOH H H AcOH, 110 °C N EtOH, 85 °C N H N H H H H H H O O HO HO O H O Wieland−Gumlich aldehyde strychnine Isostrychnine Wieland−Gumlich aldehyde synthesis: Wieland & Gumlich, Liebigs Ann. Chem. 1932, 494, 191-200. Conversion to strychnine: Anet & Robinson, Chem. Ind. 1953, 245. Isostrychnine synthesis: Wieland & Jennen, Liebigs Ann. Chem. 1940, 545, 99-112. Conversion to strychnine: Prelog et al. Helv. Chim. Acta 1948, 31, 2244-2246. H H N N H Retrosynthetic Analysis of N N H H H H HO O O Woodward's (±)-Synthesis (1954) O H H N H N H N O H N O H N N H H H H O O HO H O O (±)-strychnine Isostrychnine 2nd relay compound H NTs H CH3 NAc CO Et OCH3 2 O NH OCH3 N N CO2H NH2 OCH3 OCH3 O 1st relay compound H H N N H Woodward's (±)-Total Synthesis (1954) N N H H H H HO O O O H CH3 CH N 3 polyphosphoric 1. CH3 acid dioxane, rt , 2 h OCH3 OCH O 3 NH N rt, 10 min H 2. CH3I NH (54% yield) PhH, 0 °C, 2h 2 OCH3 OCH 3 (92% yield) I NH2 O N(CH3)3 1. NaCN DMF, rt, 1 h H CO2Et OCH3 OCH3 N N H 2. LiAlH4 H PhH, Δ, 5 h THF , , 2 h (92% yield) Δ OCH OCH3 (82% yield) 3 Cl O2S Ar CO2Et H N H NTs N TsCl CO2Et CO2Et pyr OCH3 OCH3 OCH3 (64% yield) N rt, 18 h N N H H OCH OCH OCH3 pyr 3 3 Woodward et al. J. Am. Chem. Soc. 1954, 76, 4749-4751. Woodward et al. Tetrahedron 1963, 19, 247-288. H H N N H Woodward's (±)-Total Synthesis (1954) N N H H H H HO O O O H H NTs H NTs 1. NaBH4 CO2Et EtOH/H2O, Δ, 1h CO2Et O3 OCH3 OCH3 N 2. Ac2O, pyr N AcOH/H2O 100 °C, 1 h H rt, 22 min (84% yield) (29% yield) OCH3 O CH3 OCH3 1. HI, red P H NTs H NTs AcOH, Δ 2. Ac O, pyr HCl 2 CO2Et CO2Et rt, 1 h CH OH, Δ, 10 h N CO2CH3 3 N CO CH 3. CH N H (75% yield) 2 3 2 2 CH3OH/Et2O CO2CH3 (57 % yield) O CH3 O H H NAc NAc H O NAc CO2CH3 NaOCH3 OH OCH3 O CH3OH Dieckmann N CO2CH3 N Δ, 20 min (88% yield) N CO2CH3 OCH3 O O O Woodward et al. J. Am. Chem. Soc. 1954, 76, 4749-4751. Woodward et al. Tetrahedron 1963, 19, 247-288. H H N N H Woodward's (±)-Total Synthesis (1954) N N H H H H HO O O O H 1. Raney nickel EtOH, Δ, 3 h H NAc H NAc OH 1. TsCl, pyr SBn 2. Pd/C, H2 rt, 10 h EtOH, rt 2. NaSBn 3. KOH N CO2CH3 N CO2CH3 (aq) MeOH, rt CH3OH, Δ, 1 h (73% yield) O O (53% yield) Ac Ac H NAc H N H N H3C O H3C Ac2O, pyr O O Δ, 1 h N CO2H N N O H − CO2 O O O O O 1st relay compound pyr Ac H N H NAc H NH CH HCl 3 CH3 CH3 O N (42% yield) N AcOH/H2O N Δ, 6 h H O OAc O O O Woodward et al. J. Am. Chem. Soc. 1954, 76, 4749-4751. Woodward et al. Tetrahedron 1963, 19, 247-288. H H N N H Woodward's (−)-Relay Synthesis (1954) N N H H H H HO O O O H H N H N O 1. Na-Hg, HCl KMnO H 4 H H2O, 0 °C O N CHCl3, acetone N 2. NaOH H H H H rt, 5 h H2O, 6 h (24% yield) (89% yield) O O O O CO2H H H (−)-strychnine Strychninonic acid 1. Hg(OAc) H H 2 N O N O AcOH, Δ, 2h 1. Ac2O, pyr 100 °C, 2 h 2. NH4OH(aq) H OH OAc N 2. HCl N 3. CrO3•pyr H H Ac2O, 115 °C H H pyr, rt, 12 h (75% yield) (54% yield) O O Strychninolone a Strychninolone b H N O H NAc 1. H2O2, Ba(OH)2 2nd relay H2O, rt, 3h 1st relay O compound compound N 2. Ac2O, pyr N CO H H rt. 12 h 2 (52% yield) O O dehydrostrychninone Leuchs & Schwaebel, Ber. Dtsch. Chem. Ges. 1913, 46, 3693-3699. Leuchs & Schwaebel, Ber. Dtsch. Chem. Ges. 1914, 47, 1552-1560. Prelog et al. Helv. Chim. Acta 1949, 32, 1052-1057. Leuchs & Schwaebel, Ber. Dtsch. Chem. Ges. 1919, 52, 1443-1453. Woodward et al. J. Am. Chem. Soc. 1954, 76, 4749-4751. H H N N H Woodward's (±)-Total Synthesis (1954) N N H H H H HO O O O H O H H H O H NH N N H CH3 O SeO2 O O N EtOH (12% yield) H rt, 15 h N N O O O N H N O H N O O 1. NaC CH THF, 0 °C → rt, 1 h OH LiAlH4 H Al O N 2. Lindlar catalyst N EtOH, Δ N (30% yield) H H2, CH3OH, 3 min H (46% yield) O O R3AlO 2nd relay compound H H N H N N 1.
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