Sparteine

Structural formula
Structural formula of (-) - Sparteine
General
Non-proprietary name	Sparteine
other names	[7 S - (7α, 7aα, 14α, 14aβ)] - dodecahydro-7,14-methano-2 H , 6 H -dipyrido [1,2- a : 1 ', 2'- e ] [1,5] diazocin
Molecular formula	C 15 H 26 N 2
External identifiers / databases
CAS number 90-39-1 (-) - Sparteine 299-39-8 (-) - Sparteine ​​sulfate anhydrous 6160-12-9 (-) - Sparteine ​​sulfate pentahydrate EC number 201-988-8 ECHA InfoCard 100.001.808 PubChem 644020 DrugBank DB06727 Wikidata Q419552
Drug information
ATC code	C01 BA04 Q C01BA04
properties
Molar mass	234.38 g · mol -1
Physical state	firmly
density	1.02 g cm −3
Melting point	30.5 ° C
boiling point	325 ° C 137-138 ° C (1.3 hPa)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302-312-332 P: 280
Toxicological data	960 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sparteine [more precisely (-) - Sparteine, L -sparteine; also lupinidine ] is a natural product from the group of lupine alkaloids . It has a stimulating effect on the heart , circulation and intestines and increases diuresis . Sparteine ​​is toxic to humans and can lead to death from circulatory collapse.

The enantiomer (+) - sparteine, also called pachycarpine , occurs only rarely. That is why “Spartein” - unless otherwise stated - always means the (-) - Spartein.

Occurrence

Greater celandine ( Chelidonium majus ) contains (-) - sparteine.

Lupine ( Lupinus pusillus ) contains (+) - sparteine

(-) - Sparteine ​​is found, for example, in broom and celandine . In the seeds of the yellow lupine ( Lupinus luteus ) the alkaloid content consists of 30–50% sparteine.

Problems with the commercial availability of (-) - sparteine ​​have been reported for some years, causing the prices to rise significantly. In connection with this, research on the chiral chemical, which used to be easily and cheaply accessible, has also declined significantly.

(+) - Sparteine ​​(pachycarpine) is much rarer, it is very toxic and occurs in various legumes , e.g. B. in the US lupine species Lupinus pusillus .

Historical

Sparteine ​​was discovered by John Stenhouse , who obtained it by acid extraction and distillation from the broom (Latin also Spartium scoparium ) and who described the discovery in 1850/1851. He described it as a volatile organic base and a colorless oil, significantly denser than water, with a faint, aniline- like odor and a bitter taste. Sparteine, in the form of sparteine ​​sulfate, has been used to treat heart disease since 1873. Since 1939 it was used as a means of labor. In the 1980s it was still considered a reliable and safe effective antiarrhythmic of first choice for emergency medicine, and a reliable contraceptive.

The first total syntheses of Sparteine ​​were announced in 1948. The first syntheses required a resolution. The first asymmetric total synthesis of the (+) - sparteine ​​isomer uses a variant of the Beckmann rearrangement and was published in 2002.

properties

Sparteine ​​is hardly soluble in cold water. The solution is clearly alkaline. It dissolves easily in ethanol , diethyl ether , dichloromethane and chloroform . Sparteine ​​is insoluble in gasoline ( petroleum ether or ligroin ) and benzene . It is unstable in light and air and turns yellowish to brown in color. Sparteine ​​smells similar to aniline and tastes intensely bitter.

The orally lethal dose for mice is 220 mg / kg body weight.

Structurally, the sparteine ​​is characterized by a bridged ring system and four chiral carbon atoms: In the center there is a symmetrical heterocycle that is bridged by a methylene group . Another ring (A and D) is fused onto two sides , so that a tetracyclic is formed. In addition to the enantiomer (+) - sparteine, there are also α-isosparteine ​​(C-11 epimer) and β ‑ isosparteine ​​(C-6 epimer) as epimers to sparteine.

Naturally occurring isomers	Structural formula	Stereochemical arrangement	Position of the rings A / BC / D
(-) - Sparteine ​​(lupinidine)		6 R , 7 S , 9 S , 11 S	cis-trans ( exo / endo )
(+) - Sparteine ​​(pachycarpine)		6 S , 7 R , 9 R , 11 R
(-) - α-isosparteine ​​( genistein )		6 R , 7 S , 9 S , 11 R	cis-cis ( endo / endo )
(-) - β ‑ isosparteine ​​( Pusillin , Spartalupine)		6 R , 7 R , 9 R , 11 R	trans-trans ( exo / exo )

Sparteine ​​biosynthesis

The tetracyclic sparteine ​​is built up from the amino acid L- lysine during biosynthesis . Initially, three molecules of cadaverine are formed from three molecules of L- lysine . In the course of further reactions, four molecules of pyruvate take up four of the amine groups; four molecules of alanine are produced . The biosynthesis takes place in chloroplasts ; then the alkaloids are transported to the other parts of the plant, especially to the ripening fruits.

use

Sparteine ​​sulfate has been used as an antiarrhythmic , i.e. H. used to treat cardiac arrhythmias . It could be given for severe symptomatic tachycardias  when the doctor judged them to be life-threatening. Class I antiarrhythmics are rarely used. Sparteine ​​was also used in obstetrics in the past. However, in some cases the labor was unusually violent, and in some cases the fetus died. This drug side effect has been explained by hereditary polymorphisms . Sparteine ​​is used in biomedical research as a model substance for studying this polymorphism, which affects the oxidation of substances by cytochrome P450 .

Similar to bispidine, sparteine ​​can serve as a bidentate ligand with its two nitrogen atoms . In contrast to bispidine, sparteine ​​is chiral . (-) - Sparteine ​​is used as an effective tool in enantioselective synthesis .

Pachycarpine is used medicinally in the CIS for the treatment of hypertensive crises, spasms of the peripheral vessels and myopathies .

Sparteine ​​sulfate

Sparteine ​​sulfate (Sparteinum sulfuricum, sulfuric acid Sparteine) forms colorless, needle-shaped crystals. In contrast to sparteine ​​itself, they are easily soluble in water and a neutral solution is formed. In addition, sparteine ​​sulfate is soluble in alcohol but not in chloroform.

Individual evidence

1. ↑ ^{a b c d e} data sheet (-) - Sparteine at Sigma-Aldrich , accessed on April 23, 2011 ( PDF ).
2. ↑ ^{a b} David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-462.
3. ↑ Michael Wink, Methods for the Detection of Lupine Alkaloids ( Memento from February 5, 2016 in the Internet Archive )
4. ↑ Stephen K. Ritter: Where has all the sparteine ​​gone? | April 24, 2017 Issue - Vol. 95 Issue 17 | Chemical & Engineering News. Retrieved July 22, 2019 . 
5. ↑ ^{a b} H. J. Roth: Symmetrical alkaloids * . In: Deutsche Apothekerzeitung . tape 18, 2010 ( deutsche-apotheker-zeitung.de ).
6. ^ Léo Marion, Stuart W. Fenton: The Papilionaceous Alkaloids. VI. Lupinus pusillus, Pursh. In: ACS (Ed.): The Journal of Organic Chemistry (JOC) . tape 13 , no. 5 , September 1948, p. 780-781 , doi : 10.1021 / jo01163a025 .
7. ^ ^{A b} John Stenhouse : On the Action of Nitric Acid on Various Vegetables, with a More Particular Examination of Spartium scoparium, Linn., Or Common Broom . In: The Royal Society (Ed.): Philosophical Transactions R. Soc. Lond. tape 141 . London January 1, 1851, p. 413-431 , doi : 10.1098 / rstl.1851.0020 , JSTOR : 108406 .
8. ↑ John Stenhouse: On the Action of Nitric Acid on Various Vegetables, with a More Particular Examination of Spartium scoparium, Linn., Or Common Broom. Abstract. In: Royal Society (Ed.): Abstracts of the Papers Communicated to the Royal Society of London . 1850-1854. Volume 6 . Taylor and Francis, London 1854, pp. 3-6 , JSTOR : 111121 ( online at Internet Archive [accessed February 2, 2016]).
9. ^ ^{A b} John Stenhouse: On the effect of nitric acid on various vegetables, together with a closer study of Spartium Scoparium. Linn. In: Friedrich Wöhler, Justus Liebig, Hermann Kopp (Hrsg.): Annalen der Chemie und Pharmacie . tape 78 , no. 1 . CF Winter, Heidelberg 1851, p. 1–30 ( online at the Internet Archive [accessed February 2, 2016]).
10. ↑ ^{a b} Peter W. Thies: Spartium and Spartein . From broom to antiarrhythmic. In: Pharmacy in our time . tape 15 , no. 6 . VCH, Weinheim November 1986, p. 172-176 , doi : 10.1002 / pauz.19860150604 .
11. ↑ Burritt W. Newton, Ralph C. Benson, Colin C. McCorriston: Sparteine ​​sulfate: a potent, capricious oxytocic . In: American Journal of Obstetrics and Gynecology . tape 94 , no. 2 , January 15, 1966, p. 234-241 .
12. ^ Nelson J. Leonard, Roger E. Beyler: The Total Synthesis of Sparteine . In: ACS (Ed.): Journal of the American Chemical Society . JACS. tape 70 , no. 6 June 1948, p. 2298–2299 , doi : 10.1021 / ja01186a522 .
13. ↑ Nelson J. Leonard, Roger E. Beyler: The Total Synthesis of Sparteine ​​and an Isosparteine ​​by Reductive Cyclization . In: ACS (Ed.): Journal of the American Chemical Society . JACS. tape 72 , no. 3 , March 1950, p. 1316-1323 , doi : 10.1021 / ja01159a067 .
14. ↑ Raissa M. Trend: Sparteine ​​- A lupine alkaloid ( Memento from April 4, 2015 in the Internet Archive ) (English, with an overview of the syntheses)
15. ^ Brenton T. Smith, John A. Wendt, Jeffrey Aubé: First Asymmetric Total Synthesis of (+) - Sparteine . Letter. In: ACS (Ed.): Organic Letters . tape 4 , no. 15 , July 2002, p. 2577-2579 , doi : 10.1021 / ol026230v .
16. ↑ Biochemisches Handlexikon: Volume 5: Alkaloids, Animal Poisons, Products of Internal Secretion, Antigens, Ferments, edited by H. Altenburg et al., Pages 114–117 in the Google book search
17. ↑ Hans Günther Boit: Results de Alkaloid-Chemie up to 1960, with special consideration of the progress since 1950 . Akademie-Verlag, 1961, p. 194 .
18. ↑ External identifiers of or database links to (+) - Spartein : CAS number: 492-08-0, EC number: 805-899-0, ECHA InfoCard: 100.232.882 , PubChem : 7014 , ChemSpider : 10254876 , Wikidata : Q66604441 .
19. ↑ Gerhard Richter Metabolic Physiology of Plants: Physiology and Biochemistry of Primary and Secondary Metabolism. Georg Thieme Verlag, 1998 in the Google book search.
20. ↑ Description of the application and its restrictions at arznei-telegramm.de
21. ↑ Clinical pharmacology: drug therapy, edited by N. Rietbrock, AH Staib, D. Loew, page 66, right column in the Google book search
22. ↑ Clinical Pharmacology: Medicinal therapy, edited by N. Rietbrock, AH Staib, D. Loew, page 68 in the Google book search
23. Jump up ↑ SV Otton, T. Inaba, W. Kalow: Competitive Inhibition Of Sparteine ​​Oxidation In Human Liver By β-Adrenoceptor Antagonists And Other Cardiovascular Drugs . In: Life Sciences . tape 34 , no. 1 , January 1984, pp. 73-80 , doi : 10.1016 / 0024-3205 (84) 90332-1 .
24. ↑ Dieter Hoppe , Thomas Hense: Enantioselective synthesis with lithium / ( -) - sparteine-carbanion pairs . In: Angewandte Chemie . tape 109 , no. 21 , February 1, 2006, p. 2376-2410 , doi : 10.1002 / anie.19971092105 .
25. ↑ E. Teuscher: Biogenic Medicines. 5th edition. Wissenschaftliche Verlagsgesellschaft, 1997. ISBN 3-8047-1482-X . P. 356.