315-22-0

Basic information

• Product Name: MONOCROTALINE
• Synonyms: MONOCROTALIN;MONOCROTALINE;CROTALIN;CROTALINE;(13-alpha,14-alpha)-14,19-dihydro-12,13-dihydroxy-20-norcrotalanan-11,15-dio;(13-alpha,14-alpha)-14,19-Dihydro-12,13-dihydroxy-20-norcrotalanan-11,15-dione;(2,3,4-gh)pyrrolizine-2,6(3h)-dione,(4,5,8,10,12,13,13a,13b-octahydro-4,5-dihy;(2,3,4-gh)pyrrolizine-2,6(3H)-dione,(4,5,8,10,12,13,13a,13b-octahydro-4,5-dihydroxy-3,4,5-trimethyl-2H-(1,6)dioxacycloundecino-
• CAS NO: 315-22-0
• Molecular Formula: C₁₆H₂₃NO₆
• Molecular Weight: 325.36
• EINECS: 2017-001-1
• Product Categories: Miscellaneous Natural Products;Amines;Heterocycles;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;Inhibitors
• Mol File: 315-22-0.mol
• Article Data: 4

Chemical Properties

• Melting Point: 204 °C (dec.)(lit.)
• Boiling Point: 463.55°C (rough estimate)
• Flash Point: 278.7 °C
• Appearance: white to light tan powder
• Density: 1.1512 (rough estimate)
• Vapor Pressure: 8.74E-14mmHg at 25°C
• Refractive Index: 1.5500 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Soluble in DMSO (up to 50 mg/ml with warming), in Ethanol (up to 10 mg/ml with warming) or in organic solvents such as Chloroform (up to 50 mg/ml)
• PKA: 12.21±0.60(Predicted)
• Water Solubility: 11.86g/L(temperature not stated)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.
• Merck: 13,6274
• BRN: 48732
• CAS DataBase Reference: MONOCROTALINE(CAS DataBase Reference)
• NIST Chemistry Reference: MONOCROTALINE(315-22-0)
• EPA Substance Registry System: MONOCROTALINE(315-22-0)

Safety Data

• Hazard Codes: T
• Statements: 25-40-35
• Safety Statements: 36/37/39-45
• RIDADR: UN 1544 6.1/PG 3
• WGK Germany: 3
• RTECS: QB3140000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 315-22-0(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 315-22-0 differently. You can refer to the following data:
1. Monocrotaline (MCT) is a toxic 11-membered macrocyclic pyrrolizidine alkaloid (PA) derived from the seeds of the Crotalaria spectabilis plant. It poisons livestock and humans through the ingestion of contaminated grains and other foods. Pyrrolizidine alkaloid is activated by cytochrome P450 to the reactive pyrrole metabolite dehydromonocrotaline (MCTP) in the liver. The alkaloid causes pulmonary artery hypertension, right ventricular hypertrophy, and pathological changes in the pulmonary vasculature. Monocrotaline is produced for research use. It is used in rat model to investigate human pulmonary hypertension as it offers technical simplicity, reproducibility, and low cost compared with other models of pulmonary hypertension.
2. A hepatotoxic alkaloid of the pyrrolizidine group obtained from Crotalaria retusa and C. spectabilis, the base is laevorotatory with [α]26D - 55.7° (CHCI3). It may be characterized as the hydrochloride, m.p. 184°C ldec.); [α]28D - 38.4° (H20) and the methiodide which crystallizes from MeOH with 3 moles of solvent, m.p. 205°C (dry, dec.); [α]28D + 23.4° (MeOH). Hydrolysis with boiling Ba(OHh furnishes retronecine and monocrotic acid, C7H120 3, b.p. 145-6°C/ 18 mm which is optically inactive. This acid yields a methyl ester, b.p. 94-6°Cj 18 mm, a p-bromophenacyl ester, m.p. 78°C and a 2:4-dinitrophenylhydrazone, m.p. 95-6°C. Hydrogenation in the presence of Pt02 as catalyst yields retro_x0002_necanol and monocrotalic acid, CSH120S' m.p. 181-2°C; [α]28D - 5.33° (H20) which gives a methyl ester, m.p. 79-800 C; [α]30D - 16.2° (EtOH) and a pbromophenacyl ester, m.p. 162-3°C.

References

Different sources of media describe the References of 315-22-0 differently. You can refer to the following data:
1. [1] Jose G. Gomez-Arroyo, Laszlo Farkas, Aysar A. Alhussaini, Daniela Farkas, Donatas Kraskauskas, Norbert F. Voelkel, Harm J. Bogaard (2012) The monocrotaline model of pulmonary hypertension in perspective, Am J Physio Lung Cell Mol Phyisol, 302, L363-L369 [2] https://pubchem.ncbi.nlm.nih.gov/compound/monocrotaline#section=Top
2. Adams, Rogers., J. Amer. Chern. Soc., 61,2815 (1939)

Physical properties

Appearance: white prism crystal. Solubility: soluble in methanol, ethanol, and chloroform; slightly soluble in benzene, water, ether, and acetone; insoluble in petroleum ether. Melting point: 197–198 °C. Specific optical rotation: ?54.7 ° (in chloroform).

History

In 1935, W.?M. Neil and L.?L. Russoff isolated monocrotaline from Crotalaria sessiliflora L.?Monocrotaline showed anticancer activity in?vivo, especially for treating squamous cell carcinoma, cervical cancer, and leukemia. However, since many pyrrolizidine alkaloid compounds have hepatotoxicity, further development of these compounds is restricted.China began the research of monocrotaline, as early as 1943. Crotalaria sessiliflora L. was also recorded in the 1977 edition of the Pharmacopoeia of the People’s Republic of China. But monocrotaline was reported for its liver toxicity; teratogenic, allergic reactions; and other side effects, limiting its further clinical applications. In 1992, the Ministry of Health stopped the clinical application of monocrotaline injection. Further pharmacology study is essential for monocrotaline .

Uses

Different sources of media describe the Uses of 315-22-0 differently. You can refer to the following data:
1. Crotaline has been used in hydrochloric acid (HCl) and injected into experimental animals to induce-pulmonary hypertension.
2. A toxic pyrrolizidine alkaloid isolated from Crotalaria spp. It is used for inducing pulmonary diseases in rats.
3. antineoplastic, insect sterilant

Indications

This product is available in the Pharmacopoeia of the People’s Republic of China (1977).Clinical available formulations include gel and liposome transdermal preparations. It is effective in treating skin cancer, basal cell carcinoma, acute leukemia, and cervical and penile cancer.

General Description

This substance is a primary reference substance with assigned absolute purity (considering chromatographic purity, water, residual solvents, inorganic impurities). The exact value can be found on the certificate. Produced by PhytoLab GmbH & Co. KG

Biochem/physiol Actions

Crotaline induces pulmonary vascular syndrome in rats. It is considered toxic and results in hepatic cirrhosis, enlarged liver, sinusoidal obstruction syndrome and right ventricular hypertrophy.

Pharmacology

Monocrotaline is a pyrrolizidine alkaloid which has anticancer and anti-choline effects. In vitro study suggested that monocrotaline has significant cytotoxicity in human BEL-7402, KB cancer cells through inducing DNA alkylation . Monocrotaline’s toxicity is low, but its metabolites in the liver have high liver toxicity. The metabolites are highly electrophilic and can bind to enzymes, proteins, DNA, and RNA, thus causing several side effects. Monocrotaline can reduce blood pressure and inhibit cardiac contractility and heart rate and also shows mild inhibition of respiratory rate and depth.

Clinical Use

Monocrotaline injection shows well therapeutic effect for treating squamous cell carcinoma and basal cell carcinoma. In folk, the fresh pulp or dry powder of the herb has been also used for treating squamous cell carcinoma and basal cell carcinoma .

Safety Profile

Suspected carcinogen with experimental carcinogenic data. Poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Purification Methods

Crotaline forms prisms from absolute EtOH and recrystallises also from CHCl3. UV in 96% EtOH has max 217nm (log  3.32). [Adams et al. J Am Chem Soc 74 5612 1952, Culvenor & Smith Aust J Chem 10 474 1957.] The hydrochloride has m 212-214o (from MeOH/Et2O) and [] D28 -38.4o (c 5, H2O) [Adams & Gianturco J Am Chem Soc 78 1922 1956]. The picrate has m 230-231.5o(dec) [Adams et al. J Am Chem Soc 74 5614 1952]. [Beilstein 27 III/IV 6660.]

InChI:InChI=1/C16H23NO6/c1-9-13(18)23-11-5-7-17-6-4-10(12(11)17)8-22-14(19)16(3,21)15(9,2)20/h4,9,11-12,20-21H,5-8H2,1-3H3/p+1/t9-,11+,12+,15+,16-/m0/s1

Synthetic route

monocrotaline methylene acetal (110121-56-7, 121719-98-0, 121720-00-1) → monocrotaline (315-22-0)

Conditions	Yield
With trityl tetrafluoroborate In dichloromethane for 48h; Heating;	86%
With hydrogenchloride; trityl tetrafluoroborate 1.) CH2Cl2, reflux, 48 h, 2.) room temperature, 17.5 h; Yield given. Multistep reaction;

C17H23NO6 (110121-56-7, 121719-98-0, 121720-00-1) → monocrotaline (315-22-0)

Conditions	Yield
With hydrogenchloride In ethylene glycol at 110℃; for 2h;	75%

Monocrotaline N-oxide (35337-98-5) → monocrotaline (315-22-0)

Conditions	Yield
With intestinal gut bacteria in a human fecal suspension at 37℃; for 5h; Enzymatic reaction;	38%

grahamine (24583-56-0) → monocrotaline (315-22-0)

Conditions	Yield
With hydrogenchloride

(2R,3R,4R)-2,3,4-trimethyl-2,3-methylenedioxypentanedioic anhydride (109391-24-4, 121787-06-2) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 2: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 3: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 2: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 3: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(2R,3R,4R)-2,3,4-Trimethyl-2,3-(methylenedioxy)pentanedioic acid (109494-78-2, 121787-04-0) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: Ac2O / CH2Cl2 / 3.5 h / Heating 2: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 3: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 4: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 4 steps 1: Ac2O / CH2Cl2 / 3.5 h / Heating 2: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 3: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 4: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(2'R,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxy-2-pentene (121719-94-6) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 8 steps 1: 1) BH3*THF, 2) 3 M NaOH, 30percent H2O2 / 1) THF, 0 deg C, 20 h, 2) THF, r.t., 3 h 2: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 2 min, 2) CH2Cl2, -78 deg C, 1 h 3: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 4: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 5: Ac2O / CH2Cl2 / 3.5 h / Heating 6: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 7: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 8: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 8 steps 1: 1) BH3*THF, 2) 3 M NaOH, 30percent H2O2 / 1) THF, 0 deg C, 20 h, 2) THF, r.t., 3 h 2: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 2 min, 2) CH2Cl2, -78 deg C, 1 h 3: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 4: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 5: Ac2O / CH2Cl2 / 3.5 h / Heating 6: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 7: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 8: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid (4S,5R)-4,5-dimethyl-5-((R)-1-methyl-2-oxo-ethyl)-[1,3]dioxolan-4-ylmethyl ester (146070-68-0) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 2: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 3: Ac2O / CH2Cl2 / 3.5 h / Heating 4: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 5: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 6: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 6 steps 1: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 2: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 3: Ac2O / CH2Cl2 / 3.5 h / Heating 4: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 5: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 6: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(2'R,2S,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxypentanoic acid (121719-96-8) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 2: Ac2O / CH2Cl2 / 3.5 h / Heating 3: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 4: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 5: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 2: Ac2O / CH2Cl2 / 3.5 h / Heating 3: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 4: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 5: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(2'R,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxy-2-pentanol (121719-93-5, 121787-08-4) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 9 steps 1: 83 percent / POCl3, pyridine / 17 h / 85 °C 2: 1) BH3*THF, 2) 3 M NaOH, 30percent H2O2 / 1) THF, 0 deg C, 20 h, 2) THF, r.t., 3 h 3: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 2 min, 2) CH2Cl2, -78 deg C, 1 h 4: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 5: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 6: Ac2O / CH2Cl2 / 3.5 h / Heating 7: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 8: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 9: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 9 steps 1: 83 percent / POCl3, pyridine / 17 h / 85 °C 2: 1) BH3*THF, 2) 3 M NaOH, 30percent H2O2 / 1) THF, 0 deg C, 20 h, 2) THF, r.t., 3 h 3: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 2 min, 2) CH2Cl2, -78 deg C, 1 h 4: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 5: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 6: Ac2O / CH2Cl2 / 3.5 h / Heating 7: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 8: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 9: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(2'R,2S,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxy-1-pentanol (121719-95-7, 121787-09-5) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 2 min, 2) CH2Cl2, -78 deg C, 1 h 2: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 3: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 4: Ac2O / CH2Cl2 / 3.5 h / Heating 5: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 6: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 7: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 7 steps 1: 1) (COCl)2, DMSO, 2) Et3N / 1) CH2Cl2, -78 deg C, 2 min, 2) CH2Cl2, -78 deg C, 1 h 2: 1 M KMnO4 / 2-methyl-propan-2-ol / 0.08 h / pH 7 phosphate buffer 3: 86 percent / 1 M NaOH, Na2RuO4 / 0.5 h / Ambient temperature 4: Ac2O / CH2Cl2 / 3.5 h / Heating 5: 1) Bu2SnO / 1) benzene, reflux, 24 h, 2) toluene, a) -40 deg C, 2 h, b) to r.t. 6: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 7: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(4R,5R)-5-((R)-1-Carboxy-ethyl)-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid (7R,7aR)-7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester (121719-97-9) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) Et3N, 2,4,6-trichlorobenzoyl chloride, 2) 4-(dimethylamino)pyridine / 1) THF, r.t., 3.5 h, 2) THF, toluene, reflux, 10 min 2: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme
Multi-step reaction with 2 steps 1: 64 percent / 4-(dimethylamino)pyridine, 4-(dimethylamino)pyridine hydrochloride, dicyclohexylcarbodiimide / CHCl3 / 85 h 2: 86 percent / Ph3C*BF4 / CH2Cl2 / 48 h / Heating View Scheme

(4R,5S)-5-[(R)-2-(Diethoxy-phosphoryloxy)-1-methyl-2-oxo-ethyl]-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrahydrofuran / Ambient temperature 2: 96 percent / 5percent aqueous HF / tetrahydrofuran 3: Et3N / CH2Cl2 4: 71 percent / Bu4N(1+)F(1-)*3H2O / acetonitrile / 34 °C 5: 75 percent / 38percent HCl / ethane-1,2-diol / 2 h / 110 °C View Scheme

(4R,5S)-5-[(R)-1-((1R,7aR)-7-Hydroxymethyl-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yloxycarbonyl)-ethyl]-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester (109391-29-9) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 2: 71 percent / Bu4N(1+)F(1-)*3H2O / acetonitrile / 34 °C 3: 75 percent / 38percent HCl / ethane-1,2-diol / 2 h / 110 °C View Scheme

(4R,5S)-5-{(R)-1-[(1R,7aR)-7-(tert-Butyl-dimethyl-silanyloxymethyl)-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yloxycarbonyl]-ethyl}-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester (109432-25-9) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 96 percent / 5percent aqueous HF / tetrahydrofuran 2: Et3N / CH2Cl2 3: 71 percent / Bu4N(1+)F(1-)*3H2O / acetonitrile / 34 °C 4: 75 percent / 38percent HCl / ethane-1,2-diol / 2 h / 110 °C View Scheme

(4R,5S)-5-[(R)-1-((1R,7aR)-7-Methanesulfonyloxymethyl-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yloxycarbonyl)-ethyl]-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 71 percent / Bu4N(1+)F(1-)*3H2O / acetonitrile / 34 °C 2: 75 percent / 38percent HCl / ethane-1,2-diol / 2 h / 110 °C View Scheme

Lithium; (1R,7aR)-7-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-olate (89710-47-4) → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrahydrofuran / Ambient temperature 2: 96 percent / 5percent aqueous HF / tetrahydrofuran 3: Et3N / CH2Cl2 4: 71 percent / Bu4N(1+)F(1-)*3H2O / acetonitrile / 34 °C 5: 75 percent / 38percent HCl / ethane-1,2-diol / 2 h / 110 °C View Scheme

(4R,5R)-5-((R)-1-Carboxy-ethyl)-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid (7R,7aS)-7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-yl ester → monocrotaline (315-22-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) 2,4,6-trichlorobenzoyl chloride, 2.) 4-dimethylaminopyridine / 1.) THF, room temperature, 3.5 h, 2.) toluene, reflux, 10 min 2: 1.) Ph3CBF4, 2.) 1M HCl / 1.) CH2Cl2, reflux, 48 h, 2.) room temperature, 17.5 h View Scheme

monocrotaline (315-22-0) → retronecine (480-85-3)

Conditions	Yield
With methanol; potassium hydroxide at 100℃; for 0.0833333h; Microwave irradiation;	99%
With barium dihydroxide In water 1.) from 40 deg C to 50 deg C, 2 h, 2.) reflux, 2 h;	91%
With barium dihydroxide for 2h; heating;	81%

monocrotaline (315-22-0) → retronecanol (567-39-5)

Conditions	Yield
With platinum(IV) oxide; hydrogen In water; isopropyl alcohol at 80℃; under 750.075 Torr; Solvent; Pressure; Temperature; Flow reactor;	61%

monocrotaline (315-22-0) → Monocrotalic acid (26543-09-9)

Conditions	Yield
With ethanol; acetic acid; platinum Hydrogenation;
With ethanol; nickel Hydrogenation;

monocrotaline (315-22-0) → 1,2-didehydro-7β-hydroxy-1-methyl-8α-pyrrolizidine (6029-72-7)

Conditions	Yield
With quinoline; Pd/SrCO3; ethanol Hydrogenation;

monocrotaline (315-22-0) → Monocrotaline N-oxide (35337-98-5)

Conditions	Yield
With ethanol; dihydrogen peroxide
With dihydrogen peroxide

monocrotaline (315-22-0) → spectabiline (520-55-8) + 12,13-diacetoxy-(13βH,14βH)-14,19-dihydro-20-nor-crotalanane-11,15-dione (25490-68-0)

Conditions	Yield
With acetyl chloride

monocrotaline (315-22-0) → 12,13-[(Ξ)-sulfinyldioxy-(13βH,14βH)-14,19-dihydro-20-nor-crotalanan-11,15-dione (77057-77-3)

Conditions	Yield
With thionyl chloride

monocrotaline (315-22-0) → (7aR)-7t-methyl-(7ar)-hexahydro-pyrrolizin-1t-ol; salt with monocrotalic acid

Conditions	Yield
With ethanol; acetic acid; platinum under 2206.5 Torr; Hydration;
With ethanol; nickel under 2206.5 Torr; Hydration;

monocrotaline (315-22-0) → 2,3-dimethyl-4-oxo-valeric acid (526-79-4) + retronecine (480-85-3)

Conditions	Yield
With barium dihydroxide; water

acetic anhydride (108-24-7) + monocrotaline (315-22-0) → 12,13-diacetoxy-(13βH,14βH)-14,19-dihydro-20-nor-crotalanane-11,15-dione (25490-68-0)

Conditions	Yield
With acetyl chloride

monocrotaline (315-22-0) → 2,3,4-trimethyl-L-2-deoxy-arabinitol

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran

monocrotaline (315-22-0) → (2R,3R,4R)-2,3,4-Trimethyl-2,3-(methylenedioxy)pentanedioic acid (109494-78-2, 121787-04-0)

Conditions	Yield
Multistep reaction;

monocrotaline (315-22-0) → spectabiline (520-55-8) + O,O'-diacetyl-monocrotaline

Conditions	Yield
With acetyl chloride

Ketene (463-51-4) + monocrotaline (315-22-0) → 12,13-carbonyldioxy-(13βH,14βH)-14,19-dihydro-20-nor-crotalanan-11,15-dione (76971-16-9) + spectabiline

Conditions	Yield
With chloroform

monocrotaline (315-22-0) → Dehydroretronecine (23107-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 81 percent / Ba(OH)2*8H2O / 2 h / heating 2: 40 percent / o-bromanil / CHCl3 / 0.03 h View Scheme

monocrotaline (315-22-0) → 5'-monophosphate of 7-(deoxyguanosin-N2-yl)dehydrosupinidine (103958-13-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / Ba(OH)2*8H2O / 2 h / heating 2: 40 percent / o-bromanil / CHCl3 / 0.03 h 3: 0.9 percent / aq. K2CO3 / 6 h / 60 °C / pH 7.4 View Scheme

monocrotaline (315-22-0) → hydroquinone

Conditions	Yield
Multi-step reaction with 2 steps 1: 81 percent / Ba(OH)2*8H2O / 2 h / heating 2: o-bromanil / CHCl3 / 0.03 h View Scheme

monocrotaline (315-22-0) → 3'-monophosphate of 7-(deoxyadenosine-N6-yl)dehydrosupinidine

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / Ba(OH)2*8H2O / 2 h / heating 2: 40 percent / o-bromanil / CHCl3 / 0.03 h 3: aq. K2CO3 / 40 h / 60 °C / pH 8.0 View Scheme

monocrotaline (315-22-0) → 3'-monophosphate of 7-(deoxyguanosin-N2-yl)dehydrosupinidine (612490-81-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / Ba(OH)2*8H2O / 2 h / heating 2: 40 percent / o-bromanil / CHCl3 / 0.03 h 3: 2.5 percent / aq. K2CO3 / 6 h / 60 °C / pH 8.0 / stirred anaerobically View Scheme

monocrotaline (315-22-0) → 3',5'-bisphosphate of 7-(deoxyguanosin-N2-yl)dehydrosupinidine

Conditions	Yield
Multi-step reaction with 4 steps 1: 81 percent / Ba(OH)2*8H2O / 2 h / heating 2: 40 percent / o-bromanil / CHCl3 / 0.03 h 3: 2.5 percent / aq. K2CO3 / 6 h / 60 °C / pH 8.0 / stirred anaerobically 4: dithiotreitol; ATP; MgCl2 / cloned T4 polynucleotide kinase / H2O / 0.67 h / 37 °C / pH 9.5 View Scheme

monocrotaline (315-22-0) → platynecine (520-62-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: Ba(OH)2 / H2O / 1 h / Heating 2: 20 mg / hydrogen / Pd/C / ethanol / 2 h View Scheme
Multi-step reaction with 2 steps 1: potassium hydroxide; methanol / 0.08 h / 100 °C / Microwave irradiation 2: hydrogen / ethanol / 50 °C / 750.08 Torr / Flow reactor View Scheme

monocrotaline (315-22-0) → (7R,7aR)-7-Hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizine-1-carbaldehyde (154922-76-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / Ba(OH)2*8H2O / H2O / 1.) from 40 deg C to 50 deg C, 2 h, 2.) reflux, 2 h 2: Dess-Martin periodinane, CF3COOH / CH2Cl2 / 1 h View Scheme

monocrotaline (315-22-0) → <9-2H>-retronecine

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / Ba(OH)2*8H2O / H2O / 1.) from 40 deg C to 50 deg C, 2 h, 2.) reflux, 2 h 2: Dess-Martin periodinane, CF3COOH / CH2Cl2 / 1 h 3: NaB(2)H4 / methanol / 0.5 h / 0 °C View Scheme

Upstream product

• 110121-56-7 monocrotaline methylene acetal 
• 35337-98-5 Monocrotaline N-oxide 
• 89710-47-4 Lithium; (1R,7aR)-7-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-olate 
• 109432-25-9 (4R,5S)-5-{(R)-1-[(1R,7aR)-7-(tert-Butyl-dimethyl-silanyloxymethyl)-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yloxycarbonyl]-ethyl}-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester 
• 109391-29-9 (4R,5S)-5-[(R)-1-((1R,7aR)-7-Hydroxymethyl-2,3,5,7a-tetrahydro-1H-pyrrolizin-1-yloxycarbonyl)-ethyl]-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester 
• 121719-97-9 (4R,5R)-5-((R)-1-Carboxy-ethyl)-4,5-dimethyl-[1,3]dioxolane-4-carboxylic acid (7R,7aR)-7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester 
• 121719-95-7 (2'R,2S,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxy-1-pentanol 
• 121719-93-5 (2'R,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxy-2-pentanol 
• 121719-96-8 (2'R,2S,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxypentanoic acid 
• 146070-68-0 (R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid (4S,5R)-4,5-dimethyl-5-((R)-1-methyl-2-oxo-ethyl)-[1,3]dioxolan-4-ylmethyl ester 
• 121719-94-6 (2'R,3R,4S)-5-<2'-methoxy-2'-(trifluoromethyl)phenylacetoxy>-2,3,4-trimethyl-3,4-methylenedioxy-2-pentene 
• 109494-78-2 (2R,3R,4R)-2,3,4-Trimethyl-2,3-(methylenedioxy)pentanedioic acid 
• 109391-24-4 (2R,3R,4R)-2,3,4-trimethyl-2,3-methylenedioxypentanedioic anhydride 
• 110121-56-7 C₁₇H₂₃NO₆ 

Downstream Products

• 26543-09-9 Monocrotalic acid 
• 35337-98-5 Monocrotaline N-oxide 
• 520-55-8 spectabiline 
• 25490-68-0 12,13-diacetoxy-(13βH,14βH)-14,19-dihydro-20-nor-crotalanane-11,15-dione 
• 23291-96-5 monocrotaline pyrrole 
• 23107-12-2 Dehydroretronecine 
• 608-40-2 meso 2,3-dimethylsuccinic acid 
• 76040-28-3 (7aR)-1t-hydroxy-7-hydroxymethyl-4-methyl-(4ξ,7ar)-2,3,5,7a-tetrahydro-1H-pyrrolizinium; iodide 
• 95363-37-4 9-O-Benzoylretronecine 
• 49679-23-4 (4aR,8S,9R,12bR)-9-Hydroxy-8,9-dimethyl-2,3,4,4a,8,9,12,12b-octahydro-7H-5,11-dioxa-2a-aza-cycloundeca[cd]pentalene-6,10-dione 
• 76405-16-8 (2R,3S)-2,3-Dimethyl-5-oxo-tetrahydro-furan-2-carboxylic acid (7R,7aR)-7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester 
• 154922-76-6 (7R,7aR)-7-Hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizine-1-carbaldehyde 
• 26625-83-2 1,2-Dihydro-1α,2α-epoxymonocrotalin 
• 26625-83-2 1,2-Dihydro-1β,2β-epoxy-monocrotalin 

Relevant articles and documents

Human intestinal bacteria mediate reduction of the N-oxides of isoline and monocrotaline to the corresponding parent alkaloids

The role of human intestinal bacteria in the biotransformation of pyrrolizidine alkaloid N-oxides was investigated. Two naturally-occurring hepatotoxic pyrrolizidine alkaloids, isoline and monocrotaline and their N-oxides were incubated with a human fecal suspension in an in vitro model, respectively. The metabolites were isolated and purified by chromatographic techniques and identified by the spectral analyses and the metabolic profiles were further analyzed by a specific TLC method. Human intestinal bacteria showed high reduction effects on the pyrrolizidine alkaloid N-oxides but not on the resultant tertiary alkaloids, suggesting that IB may play a partial role in the cyclic conversion between each pyrrolizidine alkaloid and its N-oxide in vivo. This evidence implied the potential risk of the pyrrolizidine alkaloid-containing Chinese medicinal herbs to human health when used in decoctions.

TOTAL SYNTHESIS OF OPTICALLY ACTIVE MONOCROTALINE, A CARCINOGENIC PYRROLIZIDINE ALKALOID HAVING AN 11-MEMBERED DILACTONE

Monocrotaline (1), a representative of carcinogenic pyrrolizidine alkaloids with an 11-membered dilactone has been synthesized in optically active form by virtue of regioselective coupling of (+)-retronecine (2) and the protected necic acid 3, the latter being synthesized enantioselectively from the meso-diester 4.