505-75-9

Basic information

• Product Name: cicutoxin
• Synonyms: cicutoxin;8,10,12-HEPTADECATRIENE-4,6-DIYNE-1,14-DIOL;WATERHEMLOCKTOXIN
• CAS NO: 505-75-9
• Molecular Formula: C₁₇H₂₂O₂
• Molecular Weight: 258.39
• Mol File: 505-75-9.mol
• Article Data: 3

Chemical Properties

• Melting Point: 54°
• Boiling Point: 341.61°C (rough estimate)
• Flash Point: 218.3°C
• Appearance: /
• Density: 1.0756 (rough estimate)
• Vapor Pressure: 1.08E-10mmHg at 25°C
• Refractive Index: 1.4770 (estimate)
• PKA: 14.07±0.20(Predicted)
• CAS DataBase Reference: cicutoxin(CAS DataBase Reference)
• NIST Chemistry Reference: cicutoxin(505-75-9)
• EPA Substance Registry System: cicutoxin(505-75-9)

Safety Data

• Hazardous Substances Data: 505-75-9(Hazardous Substances Data)

Usage

General Description

Cicutoxin is a highly poisonous unsaturated alcohol found in Cicuta, or water hemlock, one of the most poisonous plants in North America. It affects the central nervous system, causing seizures and potentially leading to respiratory failure and death. It is categorized as a neurotoxin due to its impacts on the nervous system. Initial symptoms of cicutoxin poisoning can include nausea, dizziness, and abdominal pain, progressing into more severe symptoms such as tremors, seizures, and delirium. No known antidote for cicutoxin exists, making water hemlock ingestion greatly dangerous and often fatal.

InChI:InChI=1/C17H22O2/c1-2-14-17(19)15-12-10-8-6-4-3-5-7-9-11-13-16-18/h4,6,8,10,12,15,17-19H,2,11,13-14,16H2,1H3/b6-4+,10-8+,15-12+

Synthetic route

(4R,5E,7E,9E)‐17‐((tetrahydro‐2H‐pyran‐2‐yl)oxy)heptadeca‐5,7,9‐trien‐11,13‐diyn‐4‐ol (1150616-77-5) → Cicutotoxin (505-75-9)

Conditions	Yield
With toluene-4-sulfonic acid In methanol at 20℃; for 0.5h; Inert atmosphere;	61%
With toluene-4-sulfonic acid In methanol at 20℃; for 1.5h; Darkness;	53%

7-bromohepta-4,6-diyn-1-ol (1001587-76-3) + (4R,5E,7E,9E)-10-(tributylstannyl)deca-5,7,9-trien-4-ol (1265526-17-7) → Cicutotoxin (505-75-9)

Conditions	Yield
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium fluoride; copper(l) iodide; triphenyl-arsane; 2,6-di-tert-butyl-4-methyl-phenol In 1-methyl-pyrrolidin-2-one at 45℃; for 3.5h; Stille coupling; Inert atmosphere;

7-iodohepta-4,6-diyn-1-ol (1265526-19-9) + (4R,5E,7E,9E)-10-(tributylstannyl)deca-5,7,9-trien-4-ol (1265526-17-7) → Cicutotoxin (505-75-9)

Conditions	Yield
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; copper(l) iodide; triphenyl-arsane; 2,6-di-tert-butyl-4-methyl-phenol In tetrahydrofuran at 20 - 45℃; for 5h; Stille coupling; Inert atmosphere;

pent-1-yn-5-ol (5390-04-5) → Cicutotoxin (505-75-9)

Conditions

Yield

Multi-step reaction with 4 steps 1: iodine; potassium hydroxide / methanol; water / 7 h / 20 °C 2: piperidine; copper(l) chloride / 1 h / 0 °C / Inert atmosphere; Neat (no solvent) 3: N-Bromosuccinimide; silver nitrate / acetone / 18 h / 20 °C / Inert atmosphere; Darkness 4: copper(l) iodide; potassium fluoride; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; triphenyl-arsane; 2,6-di-tert-butyl-4-methyl-phenol / 1-methyl-pyrrolidin-2-one / 3.5 h / 45 °C / Inert atmosphere View Scheme

7-(trimethylsilyl)hepta-4,6-diyn-1-ol (83670-22-8) → Cicutotoxin (505-75-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-Bromosuccinimide; silver nitrate / acetone / 18 h / 20 °C / Inert atmosphere; Darkness 2: copper(l) iodide; potassium fluoride; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; triphenyl-arsane; 2,6-di-tert-butyl-4-methyl-phenol / 1-methyl-pyrrolidin-2-one / 3.5 h / 45 °C / Inert atmosphere View Scheme

5-iodo-4-pentyn-1-ol (94230-39-4) → Cicutotoxin (505-75-9)

Conditions

Yield

Multi-step reaction with 3 steps 1: piperidine; copper(l) chloride / 1 h / 0 °C / Inert atmosphere; Neat (no solvent) 2: N-Bromosuccinimide; silver nitrate / acetone / 18 h / 20 °C / Inert atmosphere; Darkness 3: copper(l) iodide; potassium fluoride; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; triphenyl-arsane; 2,6-di-tert-butyl-4-methyl-phenol / 1-methyl-pyrrolidin-2-one / 3.5 h / 45 °C / Inert atmosphere View Scheme

(E)-7-chlorohept-6-en-4-yn-1-ol (646534-13-6) → Cicutotoxin (505-75-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 3 h / -20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: copper(l) iodide; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; triphenyl-arsane; 2,6-di-tert-butyl-4-methyl-phenol / tetrahydrofuran / 5 h / 20 - 45 °C / Inert atmosphere View Scheme

(5E,7E,9E)‐17‐((tetrahydro‐2H‐pyran‐2‐yl)oxy)heptadeca‐5,7,9‐trien‐11,13‐diyn‐4‐one → Cicutotoxin (505-75-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 1.5 h / -50 °C 2: toluene-4-sulfonic acid / methanol / 1.5 h / 20 °C / Darkness View Scheme

C17H20O4 → Cicutotoxin (505-75-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 12 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C / Schlenk technique 2.2: 12 h 3.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Darkness; Schlenk technique 4.1: barium(II) hydroxide / tetrahydrofuran; water / 0.5 h / 20 °C / Schlenk technique; Darkness 5.1: dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 1.5 h / -50 °C 6.1: toluene-4-sulfonic acid / methanol / 1.5 h / 20 °C / Darkness View Scheme

C17H20O3 → Cicutotoxin (505-75-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: barium(II) hydroxide / tetrahydrofuran; water / 0.5 h / 20 °C / Schlenk technique; Darkness 2: dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 1.5 h / -50 °C 3: toluene-4-sulfonic acid / methanol / 1.5 h / 20 °C / Darkness View Scheme

2‐(hepta‐4,6‐diyn‐1‐yloxy)tetrahydro‐2H‐pyran (159646-46-5) → Cicutotoxin (505-75-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: methyllithium / tetrahydrofuran; diethyl ether / 0.5 h / Schlenk technique 1.2: 1 h / -78 °C 1.3: 4 h / -78 - 20 °C 2.1: 12 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C / Schlenk technique 3.2: 12 h 4.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Darkness; Schlenk technique 5.1: barium(II) hydroxide / tetrahydrofuran; water / 0.5 h / 20 °C / Schlenk technique; Darkness 6.1: dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 1.5 h / -50 °C 7.1: toluene-4-sulfonic acid / methanol / 1.5 h / 20 °C / Darkness View Scheme

(2E,4E)‐12‐((tetrahydro‐2H‐pyran‐2‐yl) oxy)dodeca‐2,4‐dien‐6,8‐diynoic acid → Cicutotoxin (505-75-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.5 h / 20 °C / Schlenk technique 1.2: 12 h 2.1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Darkness; Schlenk technique 3.1: barium(II) hydroxide / tetrahydrofuran; water / 0.5 h / 20 °C / Schlenk technique; Darkness 4.1: dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 1.5 h / -50 °C 5.1: toluene-4-sulfonic acid / methanol / 1.5 h / 20 °C / Darkness View Scheme

(2E,4E)‐N‐methoxy‐N‐methyl‐12-((tetrahydro‐2H‐pyran‐2‐yl)oxy)dodeca‐2,4‐dien‐6,8‐diyne amide → Cicutotoxin (505-75-9)

Conditions

Yield

Multi-step reaction with 4 steps 1: diisobutylaluminium hydride / dichloromethane / 1.5 h / -78 °C / Darkness; Schlenk technique 2: barium(II) hydroxide / tetrahydrofuran; water / 0.5 h / 20 °C / Schlenk technique; Darkness 3: dimethylsulfide borane complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / 1.5 h / -50 °C 4: toluene-4-sulfonic acid / methanol / 1.5 h / 20 °C / Darkness View Scheme

tert-butyldimethylsilyl chloride (18162-48-6) + Cicutotoxin (505-75-9) → (5E,7E,9E)-(R)-17-(tert-Butyl-dimethyl-silanyloxy)-heptadeca-5,7,9-triene-11,13-diyn-4-ol

Conditions	Yield
With dmap; triethylamine In dichloromethane at 0℃; for 3h; Substitution;	80%

(S)-(+)-2-methoxy-2-trifluoromethyl-2-phenylacetyl chloride (39637-99-5, 20445-33-4) + Cicutotoxin (505-75-9) → (R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid (2E,4E,6E)-(R)-1-propyl-14-((R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxy)-tetradeca-2,4,6-triene-8,10-diynyl ester

Conditions	Yield
With dmap; triethylamine In dichloromethane at 20℃; for 5h; Esterification;	76%

acetic anhydride (108-24-7) + Cicutotoxin (505-75-9) → Acetic acid (8E,10E,12E)-(R)-14-hydroxy-heptadeca-8,10,12-triene-4,6-diynyl ester + Acetic acid (2E,4E,6E)-(R)-14-acetoxy-1-propyl-tetradeca-2,4,6-triene-8,10-diynyl ester + Acetic acid (2E,4E,6E)-(R)-14-hydroxy-1-propyl-tetradeca-2,4,6-triene-8,10-diynyl ester

Conditions	Yield
With pyridine at 0℃; for 8.3h;	A 55% B 23% C 10%

Cicutotoxin (505-75-9) + methyl iodide (74-88-4) → (8E,10E,12E)-(R)-1,14-Dimethoxy-heptadeca-8,10,12-triene-4,6-diyne + (14R)-(8E,10E,12E)-14-methoxyheptadecatriene-4,6-diyn-1-ol + (5E,7E,9E)-(R)-17-Methoxy-heptadeca-5,7,9-triene-11,13-diyn-4-ol

Conditions	Yield
With potassium hydroxide In N,N-dimethyl-formamide at 0℃; for 0.166667h;	A 27% B 5% C 24%

Cicutotoxin (505-75-9) → 17-hydroxy-heptadeca-5t,7t,9t-triene-11,13-diyn-4-one (25525-18-2) + (8E,10E,12E)-14-oxoheptadecatriene-4,6-diyn-1-al + (8E,10E,12E)-(R)-14-Hydroxy-heptadeca-8,10,12-triene-4,6-diynal (321655-32-7)

Conditions	Yield
With pyridine-SO3 complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0℃; for 4h;	A 8% B 16% C 13%

(R)-methoxytrifluoromethylphenylacetyl chloride (20445-33-4, 39637-99-5) + Cicutotoxin (505-75-9) → (S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid (2E,4E,6E)-(R)-1-propyl-14-((S)-3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxy)-tetradeca-2,4,6-triene-8,10-diynyl ester

Conditions	Yield
With dmap; triethylamine In dichloromethane at 20℃; for 5h; Esterification;

Cicutotoxin (505-75-9) → (8E,10E,12E)-(R)-14-Hydroxy-heptadeca-8,10,12-triene-4,6-diynoic acid (321655-37-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 13 percent / DMSO; SO3*pyridine; Et3N / CH2Cl2 / 4 h / 0 °C 2: 71 percent / KOH; I2 / 0.25 h / 0 °C 3: 75 percent / 1 N aq. NaOH / methanol / 9 h / 20 °C View Scheme

Cicutotoxin (505-75-9) → (8E,10E,12E)-(R)-14-Hydroxy-heptadeca-8,10,12-triene-4,6-diynoic acid methyl ester (321655-36-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 13 percent / DMSO; SO3*pyridine; Et3N / CH2Cl2 / 4 h / 0 °C 2: 71 percent / KOH; I2 / 0.25 h / 0 °C View Scheme

Cicutotoxin (505-75-9) → (8E,10E,12E)-(R)-14-Hydroxy-heptadeca-8,10,12-triene-4,6-diynoic acid amide

Conditions	Yield
Multi-step reaction with 4 steps 1: 13 percent / DMSO; SO3*pyridine; Et3N / CH2Cl2 / 4 h / 0 °C 2: 71 percent / KOH; I2 / 0.25 h / 0 °C 3: 75 percent / 1 N aq. NaOH / methanol / 9 h / 20 °C 4: 63 percent / NH4Cl; DPPA; Et3N / dimethylformamide / 8.5 h / 0 °C View Scheme

Cicutotoxin (505-75-9) → (8E,10E,12E)-(R)-14-Hydroxy-heptadeca-8,10,12-triene-4,6-diynoic acid butylamide

Conditions	Yield
Multi-step reaction with 4 steps 1: 13 percent / DMSO; SO3*pyridine; Et3N / CH2Cl2 / 4 h / 0 °C 2: 71 percent / KOH; I2 / 0.25 h / 0 °C 3: 75 percent / 1 N aq. NaOH / methanol / 9 h / 20 °C 4: 70 percent / DPPA; Et3N / dimethylformamide / 9.5 h / 0 °C View Scheme

Cicutotoxin (505-75-9) → 4-Methoxy-benzoic acid (2E,4E,6E)-(R)-14-(tert-butyl-dimethyl-silanyloxy)-1-propyl-tetradeca-2,4,6-triene-8,10-diynyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / Et3N, DMAP / CH2Cl2 / 3 h / 0 °C 2: 94 percent / Et3N, DMAP / CH2Cl2 / 3 h / 0 °C View Scheme

Upstream product

• 25462-05-9 deca-2t,4t,6t-trienal 
• 6728-26-3 (E)-2-Hexenal 
• 159646-46-5 2‐(hepta‐4,6‐diyn‐1‐yloxy)tetrahydro‐2H‐pyran 
• 1150616-80-0 (5E,7E,9E)‐17‐((tetrahydro‐2H‐pyran‐2‐yl)oxy)heptadeca‐5,7,9‐trien‐11,13‐diyn‐4‐ol 
• 1150616-77-5 (4R,5E,7E,9E)‐17‐((tetrahydro‐2H‐pyran‐2‐yl)oxy)heptadeca‐5,7,9‐trien‐11,13‐diyn‐4‐ol 
• 1001587-76-3 7-bromohepta-4,6-diyn-1-ol 
• 1265526-17-7 (4R,5E,7E,9E)-10-(tributylstannyl)deca-5,7,9-trien-4-ol 
• 1265526-19-9 7-iodohepta-4,6-diyn-1-ol 
• 5390-04-5 pent-1-yn-5-ol 
• 83670-22-8 7-(trimethylsilyl)hepta-4,6-diyn-1-ol 
• 94230-39-4 5-iodo-4-pentyn-1-ol 
• 646534-13-6 (E)-7-chlorohept-6-en-4-yn-1-ol 

Relevant articles and documents

A concise synthesis of R-(-)-cicutoxin, a natural 17-carbon polyenyne

A concise synthesis of the natural polyenyne R-(-)-cicutoxin (1) is described. After several trials, the successful synthesis commenced with three key fragments, R-(-)-1-hexyn-3-ol (8), 1,4-diiodo-1,3-butadiene (9), and THP-protected 4,6-heptadiyn-1-ol (6

Sn/Li exchange reactions in 1,ω-distannylated conjugated trienes and tetraenes: An enabling step for polyene synthesis

Successive treatments of (1E,3E,5E)- or (1E,3Z,5E)-1,6-bis(tributylstannyl) hexa-1,3,5-triene with nBuLi and butanal rendered polyenyl alcohols resulting from one Sn/Li exchange reaction and exhibiting complete retention of the configuration of all C=C bonds. Mono- or dimethylated all-E-configured 1,6-distannylated conjugated trienes as well as all-E-1,8-bis(tributylstannyl) octa-1,3,5,7-tetraene and dimethylated congeners thereof reacted similarly. The respective Sn/Li exchange reactions affected the substructure Bu 3Sn-CH=CH with a 93-94:7-6 preference over Bu3Sn-CMe=CH and with a 90:10 preference over Bu3Sn-CH=CMe. all-E-1-Lithio-6- (tributylstannyl)hexa-1,3,5-triene was incorporated into navenone B after Negishi coupling and into (-)-cicutoxin after acylation. NMR spectroscopy of our navenone B specimen revealed that certain resonances were misassigned previously. Molecular tinkertoy: all-E-1,6-(Tributylstannyl)hexa-1,3,5-triene, all-E-1,8-(tributylstannyl)octa-1,3,5,7-tetraene, and related bis(tributylstannylated) polyenes undergomono-Sn/Li exchange reactions. They set the stage for terminus-differentiating functionalizations, which provide inter alianavenone B and (-)-cicutoxin.