64285-06-9

Basic information

• Product Name: (+/-)-2-ACETYL-9-AZA BICYCLO[4.2.1]NON-2-ENE FUMARATE
• Synonyms: (1r)-ethanon;anatoxini;(+/-)-ANATOXIN A;(+/-)-ANATOXIN A FUMARATE;(+/-)-ANATOXIN A FUMERATE;(+/-)-2-ACETYL-9-AZA BICYCLO[4.2.1]NON-2-ENE FUMARATE;(-)-Anatoxin;(1β,6β)-5-Acetyl-9-azabicyclo[4.2.1]non-4-ene
• CAS NO: 64285-06-9
• Molecular Formula: C₁₀H₁₅NO
• Molecular Weight: 165.23
• Product Categories: Acetylcholine receptor;Nicotinic;Amines;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 64285-06-9.mol
• Article Data: 11

Chemical Properties

• Boiling Point: 293.09°C (rough estimate)
• Flash Point: 124.7 °C
• Appearance: Lyophilized Solid
• Density: 1.0203 (rough estimate)
• Vapor Pressure: 0.002mmHg at 25°C
• Refractive Index: 1.5200 (estimate)
• Storage Temp.: Desiccate at +4°C
• PKA: 9.4(at 25℃)
• CAS DataBase Reference: (+/-)-2-ACETYL-9-AZA BICYCLO[4.2.1]NON-2-ENE FUMARATE(CAS DataBase Reference)
• NIST Chemistry Reference: (+/-)-2-ACETYL-9-AZA BICYCLO[4.2.1]NON-2-ENE FUMARATE(64285-06-9)
• EPA Substance Registry System: (+/-)-2-ACETYL-9-AZA BICYCLO[4.2.1]NON-2-ENE FUMARATE(64285-06-9)

Safety Data

• Hazardous Substances Data: 64285-06-9(Hazardous Substances Data)

Usage

Acute toxicity

Intraperitoneal-mouse LDL0: 0.25 mg/kg

Occurrence

An oily alkaloid, anatoxin-a has been isolated from Anabaena jfos-aquae.

Uses

(+)-Anatoxin-a is a secondary, bicyclic amine alkaloid and cyanotoxin with acute neurotoxicity. The toxin is produced by at least four different genera of cyanobacteria and has been reported in North America, Europe, Africa, Asia, and New Zealand. Symptoms of anatoxin exposure are loss of coordination, muscular fasciculations, convulsions and death by respiratory paralysis.

Synthesis Reference(s)

Journal of the American Chemical Society, 106, p. 4539, 1984 DOI: 10.1021/ja00328a040

Biological Activity

A potent nicotinic agonist (K i values are 1.25 and 1840 nM for α 4 β 2 and α 7 nicotinic receptors respectively). Stimulates [ 3 H]-dopamine release from rat striatal synaptosomes (EC 50 = 136 nM).

Safety Profile

Poison by intraperitoneal route.An experimental teratogen. When heated todecomposition it emits toxic fumes of NOx.

InChI:InChI=1/C10H15NO/c1-7(12)9-4-2-3-8-5-6-10(9)11-8/h4,8,10-11H,2-3,5-6H2,1H3

Synthetic route

(+)-(1R)-2-acetyl-9-benzyloxycarbonyl-9-azabicyclo[4.2.1]-2-nonene (120692-41-3) → anatoxin-a (64285-06-9)

Conditions	Yield
With trimethylsilyl iodide In acetonitrile at -10℃; for 0.333333h;	99%

(-)-N-tosylanatoxin-a (143264-77-1) → anatoxin-a (64285-06-9)

Conditions	Yield
With disodium hydrogenphosphate; sodium amalgam In methanol at -40℃; for 0.166667h;	76%

(1R,6R)-2-Acetyl-9-aza-bicyclo[4.2.1]non-2-ene-9-carboxylic acid vinyl ester (216166-93-7) → anatoxin-a (64285-06-9)

Conditions	Yield
With hydrochloric acid diethyl ether In ethanol at 50℃;

methyl (2R)-pyroglutamate (64700-65-8) → anatoxin-a (64285-06-9)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 100 percent / LiHMDS / tetrahydrofuran / -78 - 20 °C 2.1: Mg / tetrahydrofuran / 0.83 h / 20 °C 2.2: 73 percent / TMEDA / tetrahydrofuran / 1.5 h / -78 °C 3.1: BF3*OEt2; Ph3SiH / CH2Cl2 / 2.5 h / -78 - 20 °C 3.2: DIBAL-H / toluene / 3 h / -78 °C 3.3: 826 mg / Cs2CO3 / toluene; propan-2-ol / 17 h / 20 °C 4.1: 97 percent / NaHMDS / tetrahydrofuran / 2 h / -78 °C 5.1: 84 percent / second generation Grubbs catalyst / CH2Cl2 / 16 h 6.1: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 7.1: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 8.1: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

1-benzyl 2-methyl (R)-5-oxopyrrolidine-1,2-dicarboxylate (690211-34-8) → anatoxin-a (64285-06-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: Mg / tetrahydrofuran / 0.83 h / 20 °C 1.2: 73 percent / TMEDA / tetrahydrofuran / 1.5 h / -78 °C 2.1: BF3*OEt2; Ph3SiH / CH2Cl2 / 2.5 h / -78 - 20 °C 2.2: DIBAL-H / toluene / 3 h / -78 °C 2.3: 826 mg / Cs2CO3 / toluene; propan-2-ol / 17 h / 20 °C 3.1: 97 percent / NaHMDS / tetrahydrofuran / 2 h / -78 °C 4.1: 84 percent / second generation Grubbs catalyst / CH2Cl2 / 16 h 5.1: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 6.1: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 7.1: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(2R,5R)-5-but-3-enyl-2-ethynylpyrrolidine-1-carboxylic acid 1-benzyl ester (690211-37-1) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: 97 percent / NaHMDS / tetrahydrofuran / 2 h / -78 °C 2: 84 percent / second generation Grubbs catalyst / CH2Cl2 / 16 h 3: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 4: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 5: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(2R)-but-3-enyl-(5R)-prop-1-ynylpyrrolidine-1-carboxylic acid 1-benzyl ester (690211-38-2) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 84 percent / second generation Grubbs catalyst / CH2Cl2 / 16 h 2: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 3: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 4: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(+)-(1R)-2-isopropenyl-9-benzyloxycarbonyl-9-azabicyclo[4.2.1]-2-nonene (690211-39-3) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 2: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 3: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(2R)-benzyloxycarbonylamino-5-oxonon-8-enoic acid methyl ester (690211-35-9) → anatoxin-a (64285-06-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: BF3*OEt2; Ph3SiH / CH2Cl2 / 2.5 h / -78 - 20 °C 1.2: DIBAL-H / toluene / 3 h / -78 °C 1.3: 826 mg / Cs2CO3 / toluene; propan-2-ol / 17 h / 20 °C 2.1: 97 percent / NaHMDS / tetrahydrofuran / 2 h / -78 °C 3.1: 84 percent / second generation Grubbs catalyst / CH2Cl2 / 16 h 4.1: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 5.1: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 6.1: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(+)-(1R)-2-(1,2-dihydroxy-1-methylethyl)-9-benzyloxycarbonyl-9-azabicyclo[4.2.1]-2-nonene (690211-40-6) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 2: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(2R)-but-3-enyl-(5R)-2-(1-methylsiletan-1-ylethynyl)pyrrolidine-1-carboxylic acid benzyl ester (760968-59-0) → anatoxin-a (64285-06-9)

Conditions

Yield

Multi-step reaction with 6 steps 1: 9 percent / second generation Grubbs catalyst / CH2Cl2 / 80 °C 2: 97 percent / NaHMDS / tetrahydrofuran / 2 h / -78 °C 3: 84 percent / second generation Grubbs catalyst / CH2Cl2 / 16 h 4: 76 percent / Et3N; OsO4 / tetrahydrofuran / 22 h / -78 - 20 °C 5: 95 percent / NaIO4 / tetrahydrofuran; H2O / 1.5 h / 20 °C 6: 99 percent / TMSI / acetonitrile / 0.33 h / -10 °C View Scheme

(1R)-9-methyl-9-azabicyclo[4.2.1]nonan-2-one (126811-06-1) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: LiN(SiMe3)2 / tetrahydrofuran / -40 °C 2: 95 percent / K2CO3 / CH2Cl2 / Heating 3: AlCl3 / 1,2-dichloro-ethane / -10 °C 4: 65 percent / LiBr, Li2CO3 / dimethylformamide / 150 °C 5: HCl*Et2O / ethanol / 50 °C View Scheme

C12H18N2O → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 95 percent / K2CO3 / CH2Cl2 / Heating 2: AlCl3 / 1,2-dichloro-ethane / -10 °C 3: 65 percent / LiBr, Li2CO3 / dimethylformamide / 150 °C 4: HCl*Et2O / ethanol / 50 °C View Scheme

(1R,2S,6R)-2-Acetyl-2-chloro-9-aza-bicyclo[4.2.1]nonane-9-carboxylic acid vinyl ester → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / LiBr, Li2CO3 / dimethylformamide / 150 °C 2: HCl*Et2O / ethanol / 50 °C View Scheme

C14H18N2O3 → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: AlCl3 / 1,2-dichloro-ethane / -10 °C 2: 65 percent / LiBr, Li2CO3 / dimethylformamide / 150 °C 3: HCl*Et2O / ethanol / 50 °C View Scheme

(-)-(5S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-1-tosylpyrrolidin-2-one (132974-84-6) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 9 steps 1: 92 percent / DIBAL / CH2Cl2 / -78 °C 2: 87 percent / PPTS / methanol 3: 96 percent / Bu4NF / tetrahydrofuran 4: 1.) BuLi / 1.) THF, -78 deg C 5: toluene / Irradiation 6: 1.) O3, 2.) Me2S / 1.) CH2Cl2, -78 deg C 7: 79 percent / NaH / tetrahydrofuran 8: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 9: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme
Multi-step reaction with 12 steps 1: 92 percent / DIBAL / CH2Cl2 / -78 °C 2: 87 percent / PPTS / methanol 3: 96 percent / Bu4NF / tetrahydrofuran 4: 1.) BuLi / 1.) THF, -78 deg C 5: toluene / Irradiation 6: 1.) BH3*DMS, 2.) H2O2, 6M NaOH / 1.) THF 7: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 8: tetrahydrofuran 9: 76 percent / TiCl4 / CH2Cl2 / -78 °C 10: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 11: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 12: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

[(2S,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol (143264-74-8) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1.) BuLi / 1.) THF, -78 deg C 2: toluene / Irradiation 3: 1.) O3, 2.) Me2S / 1.) CH2Cl2, -78 deg C 4: 79 percent / NaH / tetrahydrofuran 5: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 6: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme
Multi-step reaction with 9 steps 1: 1.) BuLi / 1.) THF, -78 deg C 2: toluene / Irradiation 3: 1.) BH3*DMS, 2.) H2O2, 6M NaOH / 1.) THF 4: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 5: tetrahydrofuran 6: 76 percent / TiCl4 / CH2Cl2 / -78 °C 7: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 8: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 9: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

(2R,5R)-2-But-3-enyl-5-methoxy-1-(toluene-4-sulfonyl)-pyrrolidine (143264-75-9) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) O3, 2.) Me2S / 1.) CH2Cl2, -78 deg C 2: 79 percent / NaH / tetrahydrofuran 3: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 4: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme
Multi-step reaction with 7 steps 1: 1.) BH3*DMS, 2.) H2O2, 6M NaOH / 1.) THF 2: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 3: tetrahydrofuran 4: 76 percent / TiCl4 / CH2Cl2 / -78 °C 5: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 6: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 7: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

(1R,6R)-9-(Toluene-4-sulfonyl)-2-vinyl-9-aza-bicyclo[4.2.1]nonane (143264-80-6) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 2: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 3: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

3-[(2S,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionaldehyde → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 79 percent / NaH / tetrahydrofuran 2: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 3: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

4-[(2R,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol (143264-78-2) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 2: tetrahydrofuran 3: 76 percent / TiCl4 / CH2Cl2 / -78 °C 4: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 5: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 6: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

1-[(1R,6R)-9-(Toluene-4-sulfonyl)-9-aza-bicyclo[4.2.1]non-2-yl]-ethanone → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 2: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

4-[(2R,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyraldehyde → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrahydrofuran 2: 76 percent / TiCl4 / CH2Cl2 / -78 °C 3: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 4: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 5: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

(E)-6-[(2R,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-hex-3-en-2-one (143264-76-0, 143292-29-9) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 2: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

(2R,5R)-2-Methoxy-1-(toluene-4-sulfonyl)-5-((E)-5-trimethylsilanyl-pent-4-enyl)-pyrrolidine (143264-79-3, 143292-31-3) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 76 percent / TiCl4 / CH2Cl2 / -78 °C 2: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 3: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 4: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

Thiocarbonic acid O-[(2S,5R)-5-methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl] ester O-phenyl ester → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene / Irradiation 2: 1.) O3, 2.) Me2S / 1.) CH2Cl2, -78 deg C 3: 79 percent / NaH / tetrahydrofuran 4: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 5: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme
Multi-step reaction with 8 steps 1: toluene / Irradiation 2: 1.) BH3*DMS, 2.) H2O2, 6M NaOH / 1.) THF 3: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 4: tetrahydrofuran 5: 76 percent / TiCl4 / CH2Cl2 / -78 °C 6: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 7: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 8: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

N-p-toluenesulphonyl(5-diphenyl-tert-butylsilyloxymethyl)-2-hydroxypyrrolidine (143264-72-6, 143292-32-4) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 8 steps 1: 87 percent / PPTS / methanol 2: 96 percent / Bu4NF / tetrahydrofuran 3: 1.) BuLi / 1.) THF, -78 deg C 4: toluene / Irradiation 5: 1.) O3, 2.) Me2S / 1.) CH2Cl2, -78 deg C 6: 79 percent / NaH / tetrahydrofuran 7: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 8: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme
Multi-step reaction with 11 steps 1: 87 percent / PPTS / methanol 2: 96 percent / Bu4NF / tetrahydrofuran 3: 1.) BuLi / 1.) THF, -78 deg C 4: toluene / Irradiation 5: 1.) BH3*DMS, 2.) H2O2, 6M NaOH / 1.) THF 6: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 7: tetrahydrofuran 8: 76 percent / TiCl4 / CH2Cl2 / -78 °C 9: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 10: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 11: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

N-p-toluenesulphonyl(5-diphenyl-tert-butylsilyloxymethyl)-2-methoxypyrrolidine (143264-73-7, 143292-30-2) → anatoxin-a (64285-06-9)

Conditions	Yield
Multi-step reaction with 7 steps 1: 96 percent / Bu4NF / tetrahydrofuran 2: 1.) BuLi / 1.) THF, -78 deg C 3: toluene / Irradiation 4: 1.) O3, 2.) Me2S / 1.) CH2Cl2, -78 deg C 5: 79 percent / NaH / tetrahydrofuran 6: 1.) HCl, 2.) DBU / 1.) CH2Cl2, MeOH, 2.) toluene, reflux 7: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme
Multi-step reaction with 10 steps 1: 96 percent / Bu4NF / tetrahydrofuran 2: 1.) BuLi / 1.) THF, -78 deg C 3: toluene / Irradiation 4: 1.) BH3*DMS, 2.) H2O2, 6M NaOH / 1.) THF 5: 1.) (COCl)2, 2.) Et3N / 1.) DMSO, 2.) CH2Cl2, -78 deg C 6: tetrahydrofuran 7: 76 percent / TiCl4 / CH2Cl2 / -78 °C 8: 71 percent / O2 / PdCl2, CuCl / dimethylformamide; H2O 9: 1.) KH, TMSCl, 2.) Et3N / 2.) Pd(OAc)2 / 2.) CH3CN 10: 76 percent / Na(Hg), Na2HPO4 / methanol / 0.17 h / -40 °C View Scheme

anatoxin-a (64285-06-9) + L-N-Boc-Ala (15761-38-3) → (S)-Ala-(1R)-anatoxin

Upstream product

• 51693-17-5 (S)-toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester 
• 1552-12-1 1,5-cis,cis-cyclooctadiene 
• 4946-37-6 3-azabicyclo<6.2.0>dec-7-ene-2-one 
• 85514-42-7 anatoxin-a 
• 101347-86-8 (racemic)-5-(2'-butenyl)-2-pyrrolidinone 
• 120692-41-3 (+)-(1R)-2-acetyl-9-benzyloxycarbonyl-9-azabicyclo[4.2.1]-2-nonene 
• 126811-06-1 (1R)-9-methyl-9-azabicyclo[4.2.1]nonan-2-one 
• 132974-84-6 (-)-(5S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-1-tosylpyrrolidin-2-one 
• 143264-73-7 N-p-toluenesulphonyl(5-diphenyl-tert-butylsilyloxymethyl)-2-methoxypyrrolidine 
• 143264-72-6 N-p-toluenesulphonyl(5-diphenyl-tert-butylsilyloxymethyl)-2-hydroxypyrrolidine 
• 143264-79-3 (2R,5R)-2-Methoxy-1-(toluene-4-sulfonyl)-5-((E)-5-trimethylsilanyl-pent-4-enyl)-pyrrolidine 
• 143264-76-0 (E)-6-[(2R,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-hex-3-en-2-one 
• 143264-78-2 4-[(2R,5R)-5-Methoxy-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol 
• 143264-80-6 (1R,6R)-9-(Toluene-4-sulfonyl)-2-vinyl-9-aza-bicyclo[4.2.1]nonane 

Downstream Products

• 64314-16-5 (+/-)-anatoxin-a 
• 90741-53-0 t-butyl-1-(9-azabicyclo<4.2.1>-non-2-ene-2-yl)ethanone carbamate 

Relevant articles and documents

Efficient new syntheses of (+)and (-)-anatoxin-a. Revised configuration of resolved 9-methyl-9-azabicyclo[4.2.1]nonan-2-one

The bicyclic ketone 2, as either enantiomer, was converted in high yield to the glycidonitrile 4 by successive base-catalysed condensation with 2-chloropropionitrile and N-dealkylation. Opening of the epoxide followed by elimination of HCl from the resulting α-chloroketone gave the enone 7 which was converted to anatoxin-a 1 by mild acidolysis. Maintenance of chiral homogeneity from both (+)- and (-)2 was demonstrated by diastereomeric amide formation from (+)- and (-)-1. However, the prior correlation of (+)- 2 with (+)- 1 was found to be incorrect; in fact (-)- 2 gives (+)- 1.

Investigation of a unified strategy for the synthesis of anatoxin analogues: Scope and limitations

Syntheses of the potent neurotoxins and biochemical probes anatoxin-a and homoanatoxin and several analogues by a combined two-directional synthesis-tandem reaction strategy are presented. Key steps include an oxidative desymmetrisation and a tandem Micha

Enantioselective synthesis of (+)-anatoxin-a via enyne metathesis

A concise synthesis of the potent nAChR agonist (+)-anatoxin-a (1) has been completed by a series of nine chemical operations and in 27% overall yield from commercially available D-methyl pyroglutamate (12). The strategy featured the application of a new protocol for the diastereoselective synthesis of cis-2,5-disubstituted pyrrolidines bearing unsaturated side chains and an intramolecular enyne metathesis to provide the bridged bicyclic framework of 1. Thus, D-methyl pyroglutamate (12) was converted in five steps to 32, which underwent facile enyne metathesis to deliver the bicyclic diene 33. Selective oxidative cleavage of the less substituted carbon-carbon double bond in 33 followed by deprotection furnished (+)-anatoxin-a (1).

Tandem reactions of anions: A short and efficient route to ±anatoxin-a

A new route to anatoxin-a (1) is reported which involves an anionically induced small ring opening/ring closure/ring opening cascade. The azabicyclo [4.2.1]nonane ring system of anatoxin-α is hence formed in one synthetic operation.