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
CH3OH, Δ, 10 h N CO2CH3 N CO2CH3 3. CH2N2 H (75% yield) CH OH/Et O CO CH 3 2 2 3 (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
N CO CH 2. NaSBn N CO CH 3. KOH(aq) 2 3 MeOH, rt 2 3 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. HBr, red P KOH OH AcOH, Δ, 2.5 h H EtOH N N 2. H2SO4, H2O, Δ N H H H (13% yield) H H 100 °C, 5 h H HO (88% yield) O O O O H (±)-strychnine Woodward et al. J. Am. Chem. Soc. 1954, 76, 4749-4751. 0.00006% yield Woodward et al. Tetrahedron 1963, 19, 247-288. 28 steps H H N N
H H Retrosynthetic Analysis of Magnus's N N H H H H H O O (±)-Synthesis (1992) HO O H
H N H N H N
H H H OH N N H H H N H H H H O O O Mbs H HO O (±)-strychnine Wieland−Gumlich aldehyde relay compound
N H N
N O O N H H N O N O H3CO2C H H H H CO2CH3 CO2CH3 H H N N
H H Magnus's (±)-Total Synthesis (1992) N N H H H H H O O HO O H
O N Troc N Troc
Cl O CCl3 NaOCH3 N Cl N CH Cl H 2 2 CH3OH/H2O 25 °C, 40 h N 25 °C, 30 min N H3CO2C H H (40% yield) CO CH (98% yield) CO CH (+ 27% yield 2 3 2 3 α,β-unsaturated) O O 1. Cl OCH3 SPh Et3NBnCl 1. HO O NaOH(aq)/CH2Cl2 NH Et N, CH Cl N 3 2 2 O 0 °C, 3 h 0 °C, 1.5 h S 2. Zn, AcOH N 2. m-CPBA, NaHCO3 N Ph THF, 25 °C, 10 h CH2Cl2, 0 °C, 30 min (71% yield) CH3O2C CO2CH3 (67% yield) CH3O2C CO2CH3
O N O TFAA N O NaH (3.0 equiv) 2,6-t-Bu-4-CH -pyr H 3 O CF3 H Ph H THF, 0 °C, 1 h S CH Cl , 0 °C, 15 min S N 2 2 N (98% yield) H O H Ph CH3O2C CO2CH3 CH3O2C CO2CH3 Magnus et al. J. Am. Chem. Soc. 1992, 114, 4403-4405. Magnus et al. J. Am. Chem. Soc. 1993, 115, 8116-8129. H H N N
H H Magnus's (±)-Total Synthesis (1992) N N H H H H H O O HO O H O N O N O 1. HgO, CaCO3 1. BH3•THF THF/H O, 25 °C, 12 h THF, 25 °C, 1 h O CF3 2 O H H S 2. BrCH CH OH, DBU 2. Na CO N 2 2 N O 2 3 H Ph PhCH3, 25 °C, 1 h H CH3OH, Δ, 16 h CH3O2C CO2CH3 (84% yield) CH3O2C CO2CH3 (72% yield)
N N N Hg(OAc) 2 O O O H H H AcOH N O N O N O 25 °C, 60 h H H H H H H CO2CH3 CO2CH3 CO2CH3
O H N H N N R O O O H N O N N O H H H H H H CO CH CO CH CO2CH3 2 3 2 3 (3% yield) R = H (46% yield) R = HgOAc (6% yield) Magnus et al. J. Am. Chem. Soc. 1992, 114, 4403-4405. Magnus et al. J. Am. Chem. Soc. 1993, 115, 8116-8129. H H N N
H H Magnus's (±)-Total Synthesis (1992) N N H H H H H O O HO O H
H N H N NaBH R = HgOAc R 4 O Zn, H2SO4 O CH3OH H (>95% yield) CH OH, Δ, 30 min R = H N O 3 N O H H (88% yield) H H H CO2CH3 CO2CH3
H H N N 1. NaOCH3 LiBH4 THF, 50 °C, 19 h CH3OH, Δ, 2 h O O H H then diethanolamine 2. 4-OCH3-C6H4-SO2Cl N O N O (67% yield) H i-Pr2NEt, DMAP H H H CH Cl , 25 °C, 24 h Mbs CO CH Mbs 2 2 2 3 OH (81% yield) HClO4 neat, 25 °C, 24 h (55% yield)
H 1. MbsCl, i-Pr2NEt H N N H DMAP, CH2Cl2 1. LiBH4 N 25 °C, 2 h OH THF, Δ, 16 h H H H OH N 2. OsO4, NMO N 2. HIO4, TFA H H THF/t-BuOH H H N H CH3OH/H2O H O 25 °C, 2 h Mbs H HO O HO O OH Mbs Magnus et al. J. Am. Chem. Soc. 1992, 114, 4403-4405. Relay Compound Magnus et al. J. Am. Chem. Soc. 1993, 115, 8116-8129. (40% yield - four steps) H H N N
H H Magnus's (±)-Total Synthesis (1992) N N H H H H H O O HO O H O
H3CO P CN H H N N TIPSOTf (1.2 equiv) H3CO DBU (1.3 equiv) KHMDS H H OH O CH2Cl2, 25 °C, 30 min N THF, 25 °C, 42 h N H H H O (69% yield) H (72% yield) Mbs Mbs OTIPS
H N H N 1. DIBAL, CH2Cl2 1. TBSOTf, DBU 2. NaBH4, CH3OH CH2Cl2, −20 °C H H N 3. 2N HCl/CH3OH N 2. SO3•pyr, Et3N H H CN (25% yield) H H DMSO, 25 °C, 4 h Mbs Mbs OH (42% yield) OTIPS OH 3:2 E:Z
O O H H H N N 1. HF•pyr, pyr N HO OH 0 °C, 2 h NaOAc, Ac2O H H H 2. Na•anthracene N N N AcOH, Δ, 2 h H H H DME, 25 °C, 14 h H H H (70% yield) H Mbs OTBS (42% yield) O O O H HO O H (±)-strychnine Magnus et al. J. Am. Chem. Soc. 1992, 114, 4403-4405. 0.03% yield Magnus et al. J. Am. Chem. Soc. 1993, 115, 8116-8129. 27 steps H H N N
H H Retrosynthetic Analysis of Stork's N N H H H H H O O (±)-Synthesis (1992) HO O H
H N H N H N
H H I N N H H H N H H H TBSO O O CH3O2C CO2CH3 H HO O (±)-strychnine Wieland−Gumlich aldehyde
H O NBn NBn CO CH N 2 3 H NHBn N H H N CO2CH3 H CO2CH3 CH3O2C CO2CH3 H H N N
H H Stork's (±)-Total Synthesis (1992) N N H H H H H O O HO O H
O NBn t-BuOCl CO CH N Et3N 2 3 H NHBn N H Pictet−Spengler condensation H CO2CH3
CH3O2C CO2CH3
Cl Cl H NBn NBn NaH N NBn N H CH3O2C N CH3O2C CH3O2C CO2CH3 CH3O2C CO2CH3
H NBn H NBn H NH NaBH3CN 1. ClCO2CH3
or 2. Pd/C, H2 N Zn, HCl N N H H H H CH OH CO2CH3 3 CO2CH3 CH3O2C CO2CH3
Stork, Disclosed at the Ischia Advanced School of Organic Chemistry, Ischia Porto, Italy, Sept. 21, 1992. H H N N
H H Stork's (±)-Total Synthesis (1992) N N H H H H H O O HO O H
H NH H NH H N 1. LDA, OTBS PhSeBr TsO I 2. m-CPBA I N N N H H H TBSO CH3O2C CO2CH3 CH3O2C CO2CH3 CH3O2C CO2CH3
O H H N N N N N N 1. t-BuLi, −78 °C LiBH4 O H H 2. MnCl2, CuCl2 N 30 °C N H − H H H H (~35% yield) CH O C CO CH OTBS OTBS 3 2 2 3 HO
O O H N H N H N HO OH NaOAc, Ac O HF 2 H H H AcOH N N N H H H H H H H H OTBS O O O H HO O H (±)-strychnine 15 steps Stork, Disclosed at the Ischia Advanced School of Organic Chemistry, Ischia Porto, Italy, Sept. 21, 1992. H H N N
H H Retrosynthetic Analysis of N N H H H H H O O Overman's (−)-Synthesis (1993) HO O H
O
H N H N H3CN NCH3
H N H H N N H N H H H H O O HO O O H H (−)-strychnine Wieland−Gumlich aldehyde t-BuO
F3COC N OEt H OAc Ot-Bu O O O EtO Ot-Bu O Ot-Bu OAc NCH3 OAc N O NCH3 H H N N
H H Overman's (−)-Total Synthesis (1993) N N H H H H H O O HO O H
O O O OAc OH OCO2CH3 Ot-Bu electric eel Cl OCH3 EtO acetylcholinesterase pyridine NaH
CH2Cl2, 23 °C Pd2dba3, (1 mol %) Ph3P (15 mol %) OAc OAc OAc THF, 23 °C >99% ee (88% yield - two steps) t-Bu t-Bu
O O Cl4Ti O Cl4Ti O H NaCNBH O O 3 H H EtO TiCl4 H Ot-Bu EtO O EtO O THF, −78 °C H H (98% yield)
1:1 dr OAc OAc OAc
O OH O OH H H EtO EtO H H Ot-Bu Ot-Bu
OAc >20:1 anti OAc 1:1 dr Overman et al. J. Am. Chem. Soc. 1993, 115, 9293-9294. Overman et al. J. Am. Chem. Soc. 1995, 117, 5776-5788. H H N N
H H Overman's (−)-Total Synthesis (1993) N N H H H H H O O HO O H
Cy Cy HN HN O OH O OH H H Cy Cy N O N O EtO EtO DCC, CuCl H H H H Ot-Bu Ot-Bu PhH, 80 °C CH3O2C H CH3O2C H (91% yield) Ot-Bu Ot-Bu
OAc >20:1 anti OAc 1:1 dr OAc OAc
1. DIBAL OEt CH2Cl2, −78 °C 2. TIPSCl, tetramethylguandine TIPSO TIPSO O L-selectride NMP, −10 °C Ot-Bu PhNTf2 Ot-Bu Ot-Bu 3. H2CrO4 THF, −78 -> 0 °C acetone, −5 °C (80% yield) (63% yield) O OTf OAc
Overman et al. J. Am. Chem. Soc. 1993, 115, 9293-9294. Overman et al. J. Am. Chem. Soc. 1995, 117, 5776-5788. H H N N
H H Overman's (−)-Total Synthesis (1993) N N H H H H H O O HO O H
I NCH3 N O TIPSO NCH3 Pd(PPh3)4 Ot-Bu TIPSO TIPSO (10 mol %) Pd2dba3 (2.5 mol %) Ot-Bu (CH3)6Sn2 Ot-Bu Ph3As (22 mol %) LiCl, THF, 60 °C CO (50 psi), LiCl O (79% yield) NMP, 70 °C NCH3 OTf Sn(CH ) 3 3 (80% yield) N O
NCH3
F3COC HO 1. MsCl, i-Pr NEt N 2 H Ot-Bu CH2Cl2, −23 °C; Ot-Bu 1. t-BuO2H, Triton-B then LiCl THF, −15 °C DMF, 23 °C O 2. Ph3P=CH2, 2. H2NCOCF3, NaH O THF, −78 → 0 °C; NCH DMF, 23 °C 3 NCH3 then TBAF (83% yield) N O N O THF, −15 °C NCH (84% yield) 3 NCH3
Overman et al. J. Am. Chem. Soc. 1993, 115, 9293-9294. Overman et al. J. Am. Chem. Soc. 1995, 117, 5776-5788. H H N N
H H Overman's (−)-Total Synthesis (1993) N N H H H H H O O HO O H
t-BuO t-BuO F3COC N H Ot-Bu HN NaH N O PhH, 100 °C; H COCF3 O then KOH HO NCH EtOH/H2O, 60 °C 3 NCH3 (62% yield) NCH3 N O N O N O NCH 3 NCH3 NCH3
t-BuO t-BuO t-BuO
+ + (CH2O)n N N N NaSO4 O CH CN, 80 °C HO aza-Cope HO Mannich 3 (98% yield) NCH3 NCH3 NCH3 N O N O N O
NCH3 NCH3 NCH3
Overman et al. J. Am. Chem. Soc. 1993, 115, 9293-9294. Overman et al. J. Am. Chem. Soc. 1995, 117, 5776-5788. H H N N
H H Overman's (−)-Total Synthesis (1993) N N H H H H H t-BuO O O O HO O H
H3CN NCH3 H N N 1. LDA, NCCO2CH3 N THF, −78 °C H N O 2. 5% HCl-CH OH, Δ 3 N (70% yield) H H NCH3 CO2CH3 OH N O O H NCH3 t-BuO
OH H Zn H OH N N N 10 % H2SO4 H NaOCH3 H CO2CH3 CH OH, CH OH, 23 °C 3 Δ N 3 NH H H H (68% yield - H CO2CH3 NH CO2CH3 OH two steps)
O O H H N H N N HO OH NaOAc, Ac O DIBAL 2 H H H CH2Cl2, −78 °C N AcOH, 110 °C N N H H H H H H (76% yield) H H (64% yield) CO2CH3 OH O O HO O H (±)-strychnine Overman et al. J. Am. Chem. Soc. 1993, 115, 9293-9294. 3% yield Overman et al. J. Am. Chem. Soc. 1995, 117, 5776-5788. 25 steps H H N N H Retrosynthetic Analysis of Kuehne's N N H H H H HO O O (±)-Synthesis (1993) O H
H N H N H N H N H H H N OH H H N H O O HO H H O CO2CH3 O CH (±)-strychnine Isostrychnine 3
O Bn H N H H HN NH 2 N Bn OCH O N H 3 H N CO2CH3 H H OCH3 CO2CH3 H H N N H Kuehne's (±)-Total Synthesis (1993) N N H H H H HO O O O H
Tl Bn O O 1. BnBr, K2CO3 Cl CH OH, Δ, 70 h N 3 H3CO OCH3 Bn NH2 2. t-BuOCl, Et N THF, CO2CH3 N 3 N N H THF, −78 °C, 2 h N Bn Bn −78 °C → rt, 12 h H (74% yield - CO2CH3 O three steps)
H
OCH3 Bn OCH N 1. Pd/C, H2 3 AcOH BF3•OEt2 HN N Bn PhCH OCH 2. LiCl, Et3N•HCl H 3 3 110 °C, 18 h N DMA, 130 °C, 3 h CO2CH3 H (71% yield) CH3O2C OCH3
Bn Bn Bn H N N H N OCH H 3
OCH3 OCH3 OCH3 N N N H H H H H CH3O2C OCH3 CH3O2C OCH3 CO2CH3 Kuehne & Xu, J. Org. Chem. 1993, 58, 7490-7497. Kuehne & Xu, J. Org. Chem. 1998, 63, 9427-9433. H H N N H Kuehne's (±)-Total Synthesis (1993) N N H H H H O HO O O O H H OCH 3 Bn H Bn H OCH3 N N OCH3 H BF3•OEt2 HClO4 HN N Bn OCH O H PhCH3 3 THF/H2O N rt, 5 h N CO2CH3 110 °C, 18 h H H H H (51% yield - CO2CH3 CO2CH3 two steps)
Bn Bn H N H N (CH3)3SI n-BuLi O OH then DBU THF Δ, 10 h N N −20 → 45 °C; H H H H CO2CH3 CO2CH3 kinetic product
Bn 1. NaBH CN H H 3 H N N N AcOH, rt Pd/C, H2 2. Ac O, pyr 2 H CH OH OH OH 3 OH 3. NaOCH N N (67% yield - N 3 H H H H H CH3OH, 0 °C H two steps) CO2CH3 CO2CH3 CO2CH3 (83% yield) O CH3 Kuehne & Xu, J. Org. Chem. 1993, 58, 7490-7497. Kuehne & Xu, J. Org. Chem. 1998, 63, 9427-9433. H H N N H Kuehne's (±)-Total Synthesis (1993) N N H H H H HO O O O H
H N H N H N 1. NaBH4 LiHMDS CH OH H 3 OH OAc OAc N THF, Δ, 30 min N 2. Ac2O, pyr N H H H H (64% yield - H H CO2CH3 three steps) O CH3 O O O OAc 3:10 α-OAc:β-OAc
O H CO P CO CH H N H N 3 2 3 H3CO DBU (COCl)2, DMSO KHMDS dioxane/H O OH O 2 N Et3N, CH2Cl2 N THF, 25 °C, 2 h 100 °C H H (91% yield) H H (81% yield) (65% yield) O O
H H H N N DIBAL N BF3•OEt2 KOH H CH Cl N 2 2 N EtOH, 85 °C N −78 °C, 4 h (28% yield) H H H H CO2CH3 H H (87% yield) HO O O O O 1:1 E:Z H (±)-strychnine Kuehne & Xu, J. Org. Chem. 1993, 58, 7490-7497. 1.4% yield Kuehne & Xu, J. Org. Chem. 1998, 63, 9427-9433. 17 steps H H N N H Retrosynthetic Analysis of Rawal's N N H H H H HO O O (±)-Synthesis (1994) O H
H N H N H N
H I N H N N H H H H TBSO O O HO H O O (±)-strychnine Isostrychnine
CO2CH3 N H CH3 N Bn CN O N NO2 NO 2 CH3O2C CO2CH3
CO2CH3 H H N N H Rawal's (±)-Total Synthesis (1994) N N H H H H Br HO Br O O O H 1. 50% NaOH n-Bu4NBr CN CH3CN, rt O BnNH , MgSO N 2 4 Bn
2. DIBAL Et2O NO2 H H PhCH3, −78 °C; NO2 NO2 + then H3O (96% yield)
I I TMS NH4Cl (cat.) TMS CH3CN, 120 °C N Bn N Bn or (89-96% yield) H TMSCl (cat.), NaI (cat.) NO DMF, 60 °C 2 NO2
H CH3
O H 9:1 CO2CH3 Z:E N
1. ClCO2CH3 CO2CH3 N Bn acetone, rt N CO2CH3 neat, rt;
2. 10% Pd-C then ClCO2CH3 N NO HCO2NH4 NH Et NPh 2 2 2 CH3O2C CH3OH (85% yield) (86% yield) CO2CH3 Rawal & Iwasa, J. Org. Chem. 1994, 59, 2685-2686. H H N N H Rawal's (±)-Total Synthesis (1994) N N H H H H HO O O O H
CO2CH3 N H N CO CH 2 3 H OTBS TMSI (10 equiv) NH Br I CHCl3, Δ, 5 h; K2CO3 PhH N acetone/DMF N 185 °C, 4 h H then CH3OH N (99% yield) Δ, 6 h (83% yield) CH O C CH3O2C H 3 2 (90% yield) O CO2CH3 CO2CH3
1. Pd(OAc) (30 mol %) H H N 2 H N N n-Bu4NCl, K2CO3 DMF, 70 °C, 3 h KOH H I 2. 2 N HCl EtOH N N N H H TBSO THF H H H (74% yield) HO O O O O H (±)-strychnine 10% yield 15 steps Rawal & Iwasa, J. Org. Chem. 1994, 59, 2685-2686. H H N N
H H Retrosynthetic Analysis of Bonjoch− N N H H H H H O O Bosch's (−)-Synthesis (1999) HO O H
H N H NO2 N H N
H H N H N O H H H H H O O CO2CH3 OTBS H HO O (−)-strychnine Wieland−Gumlich aldehyde
O Ph NO2 NO2 NO2 O H N I CH3 H
HO O O H H N N
H H Bonjoch−Bosch's (−)-Synthesis (1999) N N H H H H H O O HO O H
NO O 2 1. K2CO3 NO O DMSO, 90 °C 2 I O 2. allyl bromide sealed tube HO K2CO3 PhCH3, 190 °C acetone, Δ O2N (80% yield) O (61% yield) O
O CH3
1. C l O C l 135 °C Ph 2. HMDS, TMSI O NO2 CH Cl /pentane NO2 H N 2 2 H O3, CH2Cl2, −78 °C; −20 °C N CH3 CH3 H O then P h . 3. PhSeCl, (PhSe)2 Cl THF H2N O O CH3 4. O , CH Cl , −78 °C; H 3 2 2 97:3 cis-isomers then i-Pr2NEt NaCNBH3, i-PrOH (36% yield) (37% yield-cis: 8% yield-trans (3:1))
Bonjoch, Bosch et al. Angew. Chem. Int. Ed. 1999, 38, 395-397. Bonjoch, Bosch et al. Chem. Euro. J. 2000, 6, 655-665. H H N N
H H Bonjoch−Bosch's (−)-Synthesis (1999) N N H H H H H O O HO O H
Pd(OAc)2 (30 mol %) O NO2 NO2 H N Ph3P (60 mol %) H N CH 1. CH OH, 3 3 Δ Et3N O 2. Br Cl I 90 °C, 1 h I OTBS O (53% yield) O K2CO3, LiI TBSO CH3CN, 50 °C (74% yield)
NO NO2 2 H H N LiHMDS N 1. Zn dust HMPA, THF, −78 °C; 10% H2SO4/CH3OH, Δ
then NCCO2CH3 2. NaOCH , CH OH, Δ O O 3 3 H (67% yield) H (26% yield) OTBS CO2CH3 OTBS
O O H H N H N N HO OH DIBAL NaOAc, Ac2O H H H PhCH3, −40 °C N AcOH, 120 °C, 2 h N N (65% yield) H H H H H H H H (49% yield) CO2CH3 OH O O HO O H (−)-strychnine Bonjoch, Bosch et al. Angew. Chem. Int. Ed. 1999, 38, 395-397. 0.15% yield Bonjoch, Bosch et al. Chem. Euro. J. 2000, 6, 655-665. 15 steps H H N N
H H Retrosynthetic Analysis of Martin's N N H H H H H O O (±)-Synthesis (1996-2001) HO O H
H N H H N N N H H N H H N H H H O O CO2CH3 OH H H3CO2C OTBS (±)-strychnine formal synthetic intermediate of Overman
H H N O N O N N H H H N OBn N H H O OBn O O H H N N
H H Martin's (±)-Formal Synthesis (1996-2001) N N H H H H H O O HO O H O OBn H Cl N O N (1.1 equiv) H N N mesitylene H OTMS sealed tube then (6.0 equiv) OBn 160 °C, 72 h THF, −78 °C → rt, 2 h (85% yield) (79% yield) O
O H N H 1. aq. HClO N O O N O 4 N OBn N OBn THF H H H H H H H 2. (Ph P) RuCl NH BnO 3 3 2 H H Et3N, O O O H C Ph 3 O (79% yield)
1. Pd/C, H (CH3)3OBF4 2 H 2,6-t-Bu-pyridine H 2. NaOCH3, MeOH; O N then TsOH N CH2Cl2, rt, 24 h; N H H 3. TBSCl, pyr, DMAP then NaBH4 (36% yield) H CH3OH, 0 °C, 15 min H (83% yield) H3CO2C OTBS H3CO2C OTBS Martin et al. J. Am. Chem. Soc. 1996, 118, 9804-9805. Martin et al. J. Am. Chem. Soc. 2001, 123, 8003-8010. H H N N
H H Martin's (±)-Formal Synthesis (1996-2001) N N H H H H H O O HO O H
1. SnCl (1.0 equiv) -Cl H 4 β CO2CH3 N PhCH3 OTBS N −15 °C, 30 min; H N N then t-BuOCl H H (2.0 equiv) 30 min α-Cl H H3CO2C OTBS
Cl Cl
H 2. LiHMDS N N N CO2CH3 (4.0 equiv) − CO2CH3 N THF N N −15 °C → rt, 3 h H minor CO2CH3 OTBS TBSO TBSO H N H N H N HCl H
(26% yield) CH3OH N N N H H H H rt, 12 h H H CO2CH3 OTBS (83% yield) CO2CH3 OH O O H (±)-strychnine Martin et al. J. Am. Chem. Soc. 1996, 118, 9804-9805. 3.4% yield Martin et al. J. Am. Chem. Soc. 2001, 123, 8003-8010. 11(+4) steps H H N N H Retrosynthetic Analysis of Eichberg− N N H H H H HO O O Vollhardt's (±)-Synthesis (2000) O H
H N H N H N
H I N H N N H H H H TBSO O O HO H O O (±)-strychnine Isostrychnine
NHAc NHAc
NH2 N N N H H Co(Cp) O O H H N N H Eichberg−Vollhardt's (±)-Synthesis (2000) N N H H H H HO O O O H
NHAc NHAc (Cp)Co(C2H4)2 1. Ac2O C2H4 NH2 N O THF, 0 °C 2. Cl N H (46% yield) N H Co(Cp) TMS O O NaOH, n-Bu4NCl H2O/CH2Cl2, 0 °C (78% yield)
OTBS Br I H H 1. 30% KOH NH N 1. Li2CO3 H2O/CH3OH, Δ DMF, 40 °C I 2. Fe(NO3)3•9H2O N 2. NaOi-Pr, i-PrOH N CH3CN/THF/H2O, 0 °C H (67% yield) H TBSO (72% yield) O O
Eichberg, Vollhardt et al. Org. Lett. 2000, 2, 2479-2481. H H N N H Eichberg−Vollhardt's (±)-Synthesis (2000) N N H H H H HO O O O H
H N H N H N n-Bu3SnH OTBS AIBN I PhH, 80 °C N N N H TBSO (71% yield) H H H H 1:1 Z:E TBSO O O O
H N H N Pd(OAc)2 (30 mol %) Ph P (58 mol %) 3 LiAlH4 Et N, 85 °C, 5 h 3 N Et2O/THF, 0 °C N (46% yield) H (54% yield) H H TBSO TBSO O O
H H N H N N
HCl KOH H THF EtOH N N N H H H (99% yield) H H (20% yield) H TBSO HO O O O O H (±)-strychnine 0.6% yield Eichberg, Vollhardt et al. Org. Lett. 2000, 2, 2479-2481. 16 steps H H N N H Retrosynthetic Analysis of Bodwell's N N H H H H HO O O (±)-Synthesis (2002) O H
H N CO2CH3 H NH N H N H H N N H H O O H O (±)-strychnine formal synthetic intermediate of Rawal
NH CO CH N 2 3 I N N N N NH2 N N N H I N N I H H N N H Bodwell's (±)-Formal Synthesis (2002) N N H H H H HO O O O H
1. 9-BBN, THF N N 0 °C → rt, 12 h; I I NH then Pd(PPH ) CO CH 3 4 N 2 3 1. Cs2CO3, THF s-BuOH, Δ, 4 d N Δ, 2 d N NH2 N 2. KOH, DMF, rt, 1 h; N N 2. NaHMDS N N H then allyl bromide THF, −78 °C, 1 h; rt, 2 h I then ClCO2CH3 (91% yield) −78 °C → rt, 3 h (62% yield)
1. NaBH4, TFA CO CH H 2 3 PhH, rt, 12 h H NH N N 2. PDC, celite CH2Cl2, rt, 3d H 3. TMSI N N,N-Et2-aniline N N H H Δ, 1 h H CHCl3, Δ, 6 h H (28% yield - (>99% yield) O O O three steps) H (±)-strychnine 2.6% yield 8(+4) steps Bodwell & Li, Angew. Chem. Int. Ed. 2002, 41, 3261-3262. H H N N H Retrosynthetic Analysis of Mori's N N H H H H HO O O (−)-Synthesis (2002) O H
H N H N Boc H N
H I N H H N N H Br H TBSO O O H O O (−)-strychnine
CN Boc OTBS N H
NH O N Br Ts N (EtO)2PO H Br Ts Ts H H N N H Mori's (−)-Total Synthesis (2002) N N H H H H HO O O O H
PPh2 O O PPh2
OTBS OTBS (S)-BINAPO (5.6 mol %) O pyr, DMAP Pd2dba3•CHCl3 (2.8 mol %) EtO P Cl O NH EtO CH2Cl2, rt, 3 h DMF, 36 h (88% yield) HO (EtO)2PO Br Ts (80 % yield)
1. 4N HCl, THF OTBS rt, 1 h CN CN Pd(OAc) (2 mol %) 2. PBr3, THF 2 0 °C, 30 min PhP(CH3)2 (4 mol %)
3. NaCN, DMSO Ag2CO3 (1 equiv) N N rt, 1 h DMSO, 90 °C, 17 h N (87% yield) H Br Ts (86% yield) Br Ts Ts 84% ee recrystallized to 99% ee (73% recovery) Nakanishi & Mori, Angew. Chem. Int. Ed. 2002, 41, 1934-1936. Mori et al. J. Am. Chem. Soc. 2003, 125, 9801-9807. H H N N H Mori's (−)-Total Synthesis (2002) N N H H H H HO O O O H CN Boc N Pd(OAc)2 (5 mol %) H N Boc 1. LiAlH4, THF H benzoquinone (20 mol %) rt, 1.5 h MnO2 (2.0 equiv)
2. Boc2O, DMF AcOH, 50 °C, 20 h N rt, 1 h N (77% yield) N H H H Ts (66% yield) Ts Ts
H H 9-BBN (5.0 equiv) N Boc N Boc PhNTf2 THF, 50 °C, 9 h; (COCl)2, DMSO KHMDS then Et N then H2O2, NaOH 3 THF N OH (87% yield) N O −35 °C, 15 min rt, 4 h H H (80% yield) Ts Ts (63% yield)
1. Na•C10H8, THF Pd(OAc)2 (10 mol %) H H 0 °C,, 15 min; H N Boc N Boc Ph3P (20 mol %) N Boc then TFA, CH2Cl2 HCO2H (4.0 equiv) 0 °C, 15 min i-Pr NEt Cl 2 2. Br N N OTf 60 °C, 1 h N O H Br H (>99% yield) H Ts Ts K2CO3, n-Bu4NCl O DMF, 0 °C, 2 h (49% yield) Nakanishi & Mori, Angew. Chem. Int. Ed. 2002, 41, 1934-1936. Mori et al. J. Am. Chem. Soc. 2003, 125, 9801-9807. H H N N H Mori's (−)-Total Synthesis (2002) N N H H H H HO O O O H
H N Boc H N Boc Pd(OAc)2 (10 mol %) 1. NaOi-Pr, i-PrOH Ph3P (20 mol %) 2. CF3CO2H, CH2Cl2
N i-Pr2NEt, DMSO N 3. Li2CO3, H Br 80 °C, 1.5 h H OTBS (46% yield) Br I O O DMF, 40 °C, 14 h (53% yield)
H N H N Pd(OAc)2 (20 mol %) Ph3P (40 mol %) LiAlH4 I N K2CO3, n-Bu4NCl N Et2O/THF H TBSO DMF, 70 °C, 30 min H 0 °C, 1.5 h (48% yield) TBSO O O
H H N H N N
HCl KOH H THF/H O EtOH N N 2 N H H H rt, 3 h H H 85 °C, 6 h H TBSO (44% yield - HO (16% yield) O O O two steps) O H (−)-strychnine Nakanishi & Mori, Angew. Chem. Int. Ed. 2002, 41, 1934-1936. 1.3% yield Mori et al. J. Am. Chem. Soc. 2003, 125, 9801-9807. 22 steps H H N N
H H Retrosynthetic Analysis of N N H H H H H O O Shibasaki's (−)-Synthesis (2002) HO O H
SEt H N H N EtS H N H H N H N H H H H N O O HO O H H H PMBO (−)-strychnine Wieland−Gumlich aldehyde SEMO
OTIPS O O CO2CH3 O2N O O O H3CO OCH3 H H CO2CH3 HO OPMB H H N N
H H Shibasaki's (−)-Total Synthesis (2002) N N H H H H H O O HO O H
O O Al O O Li
(R)-ALB (0.10 mol %) O O KOt-Bu (0.09 mol %) + CO2CH3 >99% ee O O H3CO OCH3 4A MS, THF (49 M) H (91% yield) CO2CH3
O O Et LDA; CH PMBO OCH3 1. O 3 N TsOH (cat.) then .CH CO CH O 3 2 3 CO CH O 2 3 THF, 78 °C H 2. LiCl, H2O/DMSO − O H (72% yield) CO2CH3 140 °C (97% yield) 1. DIBAL, CH2Cl2 −78 °C O 1. NaBH3CN, TiCl4 O 2. TIPSOTf, Et3N OTIPS CO CH CO CH 2 3 THF/CH2Cl2, −55 °C 2 3 CH2Cl2, −78°C O H O H O 2. DCC, CuCl 3. CSA (cat.) H O PhH, Δ H acetone PMBO OPMB (70% yield) OPMB (61% yield) Shibasaki et al. J. Am. Chem. Soc. 2002, 124, 14546-14247. H H N N
H H Shibasaki's (−)-Total Synthesis (2002) N N H H H H H O O HO O H O O Al O O Li
LiAlH4 228 mg (6 mmol) (R)-BINOL 3.44 g (12 mmol) O O KOt-Bu 606 mg (5.1 mmol) + CO2CH3 1.243 kg 150 g O H3CO OCH3 4A MS H >99% ee O 123 mL THF CO2CH3 581 mL 686 mL 20 °C, 24 h (6.0 mol) (6.0 mol) O O Et LDA; CH PMBO OCH3 1. O 3 N TsOH (cat.) then .CH CO CH O 3 2 3 CO CH O 2 3 THF, 78 °C H 2. LiCl, H2O/DMSO − O H (72% yield) CO2CH3 140 °C (97% yield) 1. DIBAL, CH2Cl2 −78 °C O 1. NaBH CN, TiCl O 2. TIPSOTf, Et3N OTIPS CO CH 3 4 CO CH 2 3 THF/CH2Cl2, −55 °C 2 3 CH2Cl2, −78°C O H O H O 2. DCC, CuCl 3. CSA (cat.) H O PhH, Δ H acetone PMBO OPMB (70% yield) OPMB (61% yield) Shibasaki et al. J. Am. Chem. Soc. 2002, 124, 14546-14247. H H N N
H H Shibasaki's (−)-Total Synthesis (2002) N N H H H H H O O HO O H N OTIPS 1. TMSCl, Li OTIPS 1. LDA, TMSCl THF, −78 °C THF, −78 °C O O H 2. Pd2(dba)3•CHCl3 H 2. HCHO (aq), THF PMBO PMBO (5 mol %) Yb(OTf)3 (20 mol %) diallyl carbonate, CH3CN (3:1 α:β) (90% yield-two steps) 3. DBU, CH Cl Sn(CH3)3 2 2 (57% yield)
NO2 Pd (dba) •CHCl I 2 3 3 OTIPS OTIPS (5 mol %) Ph3As (20 mol %) I2 1. SEMCl, i-Pr2NEt DMAP CuI (10 mol %) O O OTIPS CH2Cl2 H H O N CH2Cl2 DMF 2 2. 3HF•NEt , THF HO HO O 3 (>99% yield) (>99% yield) H (>99% yield) OPMB OPMB HO SEt OPMB SEt
OH EtS EtS H Tf2O, i-Pr2NEt NH Zn N
O2N then S E t . O CH3OH/NH4Cl (aq) H O2N 77% yield EtS O N PMBO H H SEMO NH2 H PMBO PMBO CH2Cl2, −78 °C SEMO SEMO Shibasaki et al. J. Am. Chem. Soc. 2002, 124, 14546-14247. H H N N
H H Shibasaki's (−)-Total Synthesis (2002) N N H H H H H O O SEt HO O H EtS EtS H N NaBH CN H 3 N DMTSF (5.0 equiv) TiCl4
4A MS, CH2Cl2 (0.005 M) N THF/CH2Cl2, −78 °C (86% yield) H (68% yield) N PMBO H H SEMO PMBO SEMO
EtS EtS H N H N 1. 1M HCl, CH3OH NiCl2 2. Ac2O, pyridine NaBH4 H N 3. NaOCH3, CH3OH N EtOH/CH3OH (4:1) H H H 4. TIPSCl, imidazole Ac H H (61% yield PMBO DMF/CH2Cl2, 4 °C TIPSO after 3x process) SEMO (51% yield) HO
H H H N N N 1. SO3•pyridine 1. NaOCH3 Et N, DMSO CH3OH, 40 °C H 3 H H O O 2. 3HF•NEt , THF N 2. N N 3 Ac H H H H Ac H H (83% yield) HO OH TIPSO NaOAc, Ac O HO HO O 2 O O AcOH, 110 °C H (42% yield) (−)-strychnine 0.7% yield Shibasaki et al. J. Am. Chem. Soc. 2002, 124, 14546-14247. 31 steps H H N N
H H Retrosynthetic Analysis of N N H H H H H O O Fukuyama's (−)-Synthesis (2004) HO O H
H NNs N H N
H CO2CH3 H H N CHO H H N N H H H Boc O O CO2CH3 H HO O (−)-strychnine Wieland−Gumlich aldehyde
OTBS CH3O2C O HO OH
H OMOM OTBS N Boc CO2CH3 CO2CH3 N N H CO2CH3 H H N N
H H Fukuyama's (−)-Total Synthesis (2004) N N H H H H H O O HO O H
CH3O2C 1. Na/NH3 CH3O2C CH3O2C OH Lipase AYS EtOH, −78 °C NBS vinyl acetate
Br 2. AcCl, MeOH H2O/DMSO, rt 40 °C rt; then NaOCH3 (62% yield - three steps) racemic
OH OTBS 1. NaOCH CH3O2C OH CH3O2C OAc 3 DIBAL OH CH3OH O Br Br CH Cl , 0 °C 2 2 Br 2. TBSCl (73% yield) imidazole 99% ee 99% ee CH2Cl2, rt (50% yield) (46% yield) (61% yield)
1. TBSCl TBSO TBSO 1. CSCl2 n-Bu3SnH imidazole Na2CO3(aq) HO BEt3 THF, 0 °C; CH2Cl2, rt PhCH3, rt 2. NaH, O O N 2. NaBH NH (52% yield) CO2CH3 4 N CH OH, 0 °C 3 NCS H3CO OCH3 CO CH H 2 3 CO CH (56% yield) THF, rt S 2 3 (70% yield) CO2CH3 Fukuyama et al. J. Am. Chem. Soc. 2002, 126, 10246-10247. H H N N
H H Fukuyama's (−)-Total Synthesis (2004) N N H H H H H O O HO O H TBSO TBSO OTBS OTBS Pd2(dba)3 (5 mol %) P(2-furyl)3 (25 mol %) O + H PhCH , rt CO2CH3 3 OH N (86% yield) N H H CO2CH3 H3CO2C CO2CH3
TBSO HO OTBS OH 1. MOMCl, i-Pr2NEt 1. Boc2O, DMAP CH2Cl2, rt CH3CN, rt H H 2. LiI, collidine OMOM 2. NH4F•HF OMOM 80 °C N DMF/NMP, rt N H Boc CO CH (72% yield - CO CH 2 3 four steps) 2 3
Ns Ns N N NsNH2 1. DBU, PhCH3, 100 °C PPh3, DEAD OMOM 2. aq. HCl, THF, 50 °C O H H PhCH3, rt 3. DMP, CH2Cl2, 0 °C (95% yield) N (69% yield) N Boc Boc CO2CH3 CO2CH3
Fukuyama et al. J. Am. Chem. Soc. 2002, 126, 10246-10247. H H N N
H H Fukuyama's (−)-Total Synthesis (2004) N N H H H H H O O HO O H NNs NNs NNs 1. TMSOTf, Et3N O CH2Cl2, 0 °C O Pb(OAc)4 CO2CH3 H H H 2. m-CPBA CH3OH/PhH CHO N NaHCO N OH 0 °C N Boc 3(aq) Boc Boc CO CH CH2Cl2, 0 °C; CO CH CO CH 2 3 then HCl 2 3 2 3 MeOH/H2O, rt (66% yield)
N H N PhSH, Cs2CO3 DIBAL, CH3CN; BF3•OEt2
then TFA, (CH3)2S CH2Cl2, −78 °C CH Cl , 50 °C N N (95% yield) 2 2 H H CO2CH3 H H CO2CH3 (84% yield - two steps) CO2CH3 CO2CH3
1. NaBH3CN O O AcOH, 10 °C H H N H N N HO OH 2. NaOCH3 CH3OH/THF, rt NaOAc, Ac O H 2 H 3. DIBAL N AcOH, 110 °C N N H H H H H CH2Cl2, −98 °C H H (42% yield - CO2CH3 OH four steps) O O HO O H (−)-strychnine 1.1% yield Fukuyama et al. J. Am. Chem. Soc. 2002, 126, 10246-10247. 25 steps H H N N
H H Retrosynthetic Analysis of Padwa's N N H H H H H O O (±)-Synthesis (2007) HO O H
H N H N H N
H H I N N H H H N H H H MOMO O O DMB O H HO O (±)-strychnine Wieland−Gumlich aldehyde
H3C
O O O N OH N CH N N 3 H Ac O N Ac H O H H N N
H H Padwa's (±)-Total Synthesis (2007) N N H H H H H O O HO O H
1. i-BuO2CCl, N-CH3-morpholine; THF, 0 °C, 5 min; 1. MgClO4, CH3CN, 50 °C, 2h O then Li Boc O N 2. NaH, DMF, 0 °C, 2 h; then O N OH 0 °C, 20 min Boc Br N N Ac 0 °C, 3 h CH3 H 2. AcCl, n-Bu4NHSO4, NaOH O (65% yield) CH2Cl2, rt, 1 h (60% yield) H3C H3C O O O MgI2 (20 mol %) N N N µwave (200 W) N CH3 PhCH3, 150 °C, 3 h Ac O O N N Ac H H Ac H OH H3C
O H3C N 1. NaBH , EtOH/THF, 0 °C, 30 min 4 H 2. NaOCH3, THF/CH3OH, 15 min N
(95% yield) 3. LiAlH4, THF, Δ, 3 h 4. NaBH(OAc) , DCE, −20 °C, 3 h N 3 N Ac H (65% yield) H H O OH Padwa et al. Org. Lett. 2007, 9, 279-282. H H N N
H H Padwa's (±)-Total Synthesis (2007) N N H H H H H O O HO O H CHO H3C H N 1. Pd(OH)2/C, H2 (60 psi) H H3CO OCH3 N CH3OH, rt, 2 d 1. NaBH(OAc)3 I AcOH/DCE, rt, 12 h 2. K2CO3, OMOM N H H MOMO 2. TPAP, NMO N Br I OH H H 4Å MS, CH3CN, rt, 2 h OH DMF/H2O, 0 °C, 12 h (56% yield) (69% yield) O H H Ph P OCH3 N Pd(PPh3)4 (19 mol %) N Ph KOPh (1.3 equiv) LDA
I THF, Δ, 2 h THF, rt, 24 h N N (72% yield) H MOMO (56% yield) H H DMB O DMB O OMOM
O O H H H N N N HO OH 3N HCl NaOAc, Ac O 2 H THF, 55°C, 10 h H AcOH, 120 °C, 2 h N N (54% yield) N H H H H H H (80% yield) H DMB OMOM OCH O O 3 HO O H (±)-strychnine 1.7% yield Padwa et al. Org. Lett. 2007, 9, 279-282. 17 steps H N N Conclusions on 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 14 total syntheses 8 racemic syntheses 6 asymmetric syntheses 2 utilize the chiral pool, 2 utilize enzymatic transformations, 2 utilize an asymmetric method • R. B. Woodward - 1954
QuickTime™ and a TIFF (Uncompressed) decompressor • Philip Magnus - 1992 are needed to see this picture. • Gilbert Stork - 1992 • Larry E. Overman - 1993 • Martin E. Kuehne - 1993 • Viresh H. Rawal - 1994 • Josep Bonjoch & Joan Bosch - 1999 • Stephen F. Martin - 1996-2001 • Michael Eichberg & Peter Vollhardt - 2000 • Graham J. Bodwell - 2002 • Miwako Mori - 2002 • Masakatsu Shibasaki - 2002 • Tohru Fukuyama - 2004 • Albert Padwa - 2007 $273 / Kg (Shanghai FWD Chemicals Limited) approximately 1.4¢ / lethal human dose (~50 mg)