Lysergic acid

Lysergic acid
Names
	IUPAC name 6-Methyl-9,10-didehydroergoline-8β-carboxylic acid
	Systematic IUPAC name (5R,8R)-7-Methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylic acid
Identifiers
CAS Number	82-58-6 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:6604 ;
ChemSpider	6461 ;
ECHA InfoCard	100.001.302
IUPHAR/BPS	139;
PubChem CID	6717;
UNII	ITO20DAO7J ;
CompTox Dashboard (EPA)	DTXSID60904515 ;
	InChI InChI=1S/C16H16N2O2/c1-18-8-10(16(19)20)5-12-11-3-2-4-13-15(11)9(7-17-13)6-14(12)18/h2-5,7,10,14,17H,6,8H2,1H3,(H,19,20)/t10-,14-/m1/s1 Key: ZAGRKAFMISFKIO-QMTHXVAHSA-N ; InChI=1/C16H16N2O2/c1-18-8-10(16(19)20)5-12-11-3-2-4-13-15(11)9(7-17-13)6-14(12)18/h2-5,7,10,14,17H,6,8H2,1H3,(H,19,20)/t10-,14-/m1/s1 Key: ZAGRKAFMISFKIO-QMTHXVAHBD;
	SMILES CN1C[C@@H](C=C2[C@H]1CC3=CNC4=CC=CC2=C34)C(=O)O;
Properties
Chemical formula	C16H16N2O2
Molar mass	268.316 g·mol−1
Melting point	238 to 240 °C (460 to 464 °F; 511 to 513 K)
Acidity (pKa)	pKa1 = 7.80, pKa2 = 3.30
Legal status	BR: Class D1 (Drug precursors);
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

Lysergic acid, also known as D-lysergic acid and (+)-lysergic acid, is a precursor for a wide range of ergoline alkaloids that are produced by the ergot fungus and found in the seeds of Turbina corymbosa (ololiuhqui), Argyreia nervosa (Hawaiian baby woodrose), and Ipomoea tricolor (morning glories, tlitliltzin).

Amides of lysergic acid, lysergamides, are widely used as pharmaceuticals and as psychedelic drugs, e.g. lysergic acid diethylamide (LSD). Lysergic acid is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.^[3]

Lysergic acid received its name as it was a product of the lysis of various ergot alkaloids.^[4]

Synthesis

Laboratory

Lysergic acid is generally produced by hydrolysis^[5] of natural lysergamides, but can also be synthesized in the laboratory by a complex total synthesis, for example by Robert Burns Woodward's team in 1956.^[6] An enantioselective total synthesis based on a palladium-catalyzed domino cyclization reaction has been described in 2011 by Fujii and Ohno.^[7] Lysergic acid monohydrate crystallizes in very thin hexagonal leaflets when recrystallized from water. Lysergic acid monohydrate, when dried (140 °C at 2 mmHg or 270 Pa) forms anhydrous lysergic acid.

Biosynthesis

The biosynthetic route is based on the alkylation of the amino acid tryptophan with dimethylallyl diphosphate (isoprene derived from 3R-mevalonic acid) giving 4-dimethylallyl-L-tryptophan which is N-methylated with S-adenosyl-L-methionine. Oxidative ring closure followed by decarboxylation, reduction, cyclization, oxidation, and allylic isomerization yields D-(+)-lysergic acid.^[4] The biosynthetic pathway has been reconsituted in transgenic baker's yeast.^[8]

Isomers

Lysergic acid is a chiral compound with two stereocenters. The isomer with inverted configuration at carbon atom 8 close to the carboxyl group is called isolysergic acid. Inversion at carbon 5 close to the nitrogen atom leads to L-lysergic acid and L-isolysergic acid, respectively.

Legality

In the United States, Lysergic acid and Lysergic acid amide are Schedule III substances.^[9]

References

^ Brown, H. C.; et al. (1955). Braude, E. A.; Nachod, F. C. (eds.). Determination of Organic Structures by Physical Methods. New York, NY: Academic Press.
^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-15.
^ "List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control" (PDF). International Narcotics Control Board. Archived from the original (PDF) on 2008-02-27.
^ ^a ^b Schiff, P. L. (Oct 15, 2006). "Ergot and its alkaloids". Am. J. Pharm. Educ. 70 (5): 98. doi:10.5688/aj700598. PMC 1637017. PMID 17149427.
^ Martínková, L.; Kren, V.; Cvak, L.; Ovesná, M.; Prepechalová, I. (Nov 17, 2001). "Hydrolysis of lysergamide to lysergic acid by Rhodococcus equi A4". J. Biotechnol. 84 (1): 63–6. doi:10.1016/s0168-1656(00)00332-1. PMID 11035188.
^ Kornfeld, Edmund C.; Fornefeld, E. J.; Kline, G. Bruce; Mann, Marjorie J.; Morrison, Dwight E.; Jones, Reuben G.; Woodward, R. B. (1956). "The Total Synthesis of Lysergic Acid". J. Am. Chem. Soc. 78 (13): 3087–3114. doi:10.1021/ja01594a039.
^ Inuki, S.; Iwata, A.; Oishi, S.; Fujii, N.; Ohno, H. (2011). "Enantioselective Total Synthesis of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol by Palladium-Catalyzed Domino Cyclization of Allenes Bearing Amino and Bromoindolyl Groups". J. Org. Chem. 76 (7): 2072–2083. doi:10.1021/jo102388e. PMID 21361331.
^ Wong, Garrett; Lim, Li Rong; Tan, Yong Quan; Go, Maybelle Kho; Bell, David J.; Freemont, Paul S.; Yew, Wen Shan (2022). "Reconstituting the complete biosynthesis of D-lysergic acid in yeast". Nature Communications. 13 (1): 712. Bibcode:2022NatCo..13..712W. doi:10.1038/s41467-022-28386-6. PMC 8821704. PMID 35132076.
^ https://www.ecfr.gov/current/title-21/chapter-II/part-1308/subject-group-ECFRf62f8e189108c4d/section-1308.13

[1] Brown, H. C.; et al. (1955). Braude, E. A.; Nachod, F. C. (eds.). Determination of Organic Structures by Physical Methods. New York, NY: Academic Press.

[2] Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-15.

[3] "List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control" (PDF). International Narcotics Control Board. Archived from the original (PDF) on 2008-02-27.

[Schiff-4] Schiff, P. L. (Oct 15, 2006). "Ergot and its alkaloids". Am. J. Pharm. Educ. 70 (5): 98. doi:10.5688/aj700598. PMC 1637017. PMID 17149427.

[5] Martínková, L.; Kren, V.; Cvak, L.; Ovesná, M.; Prepechalová, I. (Nov 17, 2001). "Hydrolysis of lysergamide to lysergic acid by Rhodococcus equi A4". J. Biotechnol. 84 (1): 63–6. doi:10.1016/s0168-1656(00)00332-1. PMID 11035188.

[6] Kornfeld, Edmund C.; Fornefeld, E. J.; Kline, G. Bruce; Mann, Marjorie J.; Morrison, Dwight E.; Jones, Reuben G.; Woodward, R. B. (1956). "The Total Synthesis of Lysergic Acid". J. Am. Chem. Soc. 78 (13): 3087–3114. doi:10.1021/ja01594a039.

[ohno1-7] Inuki, S.; Iwata, A.; Oishi, S.; Fujii, N.; Ohno, H. (2011). "Enantioselective Total Synthesis of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol by Palladium-Catalyzed Domino Cyclization of Allenes Bearing Amino and Bromoindolyl Groups". J. Org. Chem. 76 (7): 2072–2083. doi:10.1021/jo102388e. PMID 21361331.

[Wong2022-8] Wong, Garrett; Lim, Li Rong; Tan, Yong Quan; Go, Maybelle Kho; Bell, David J.; Freemont, Paul S.; Yew, Wen Shan (2022). "Reconstituting the complete biosynthesis of D-lysergic acid in yeast". Nature Communications. 13 (1): 712. Bibcode:2022NatCo..13..712W. doi:10.1038/s41467-022-28386-6. PMC 8821704. PMID 35132076.

[9] ttps://www.ecfr.gov/current/title-21/chapter-II/part-1308/subject-group-ECFRf62f8e189108c4d/section-1308.13

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v t e Ergolines
Lysergic acid derivatives	2-Bromo-LSD (BOL-148) Amesergide Bromerguride (2-bromolisuride) Bromocriptine Cabergoline Dihydroergocornine Dihydroergocristine Dihydroergocryptine Dihydroergometrine (Dihydroergonovine, Dihydroergobasine) Dihydroergosine Dihydroergotamine Epicriptine Ergine (LSA; LA-111; Lysergamide) Ergocornine Ergocristine Ergocryptine Ergoloid (Dihydroergotoxine) Ergometrine (Ergonovine, Ergobasine) Ergometrinine Ergostine Ergotamine Ergotoxine Ergovaline Fludihydroergotamine Lisuride LY-215,840 LSH Lysergic acid Lysergic acid methyl ester Lysergine Lysergol Mergocriptine Mesulergine Metergoline Metergotamine MIPLA Methysergide Propisergide Sergolexole
Psychedelic lysergamides	1B-LSD 1cP-LSD 1P-ETH-LAD 1P-LSD AL-LAD ALD-52 BU-LAD CYP-LAD Diallyllysergamide (DAL) Dimethyllysergamide (DAM-57) ECPLA Ergonovine ETFELA ETH-LAD IP-LAD LAMPA LAE-32 LSD (lysergide) LPD-824 LSM-775 LSH LSD-Pip Lysergic Acid 2-Butylamide Lysergic Acid 2,4-Dimethylazetidide Lysergic Acid 3-Pentylamide Lysergic acid cyclobutylamide Lysergic acid cyclopentylamide Methylergometrine (Methylergonovine, Methylergobasine) MIPLA MLD-41 PARGY-LAD PRO-LAD
Clavines	9-Deacetoxyfumigaclavine C Agroclavine Chanoclavine Chanoclavine II Costaclavin Cycloclavine Elymoclavine Epoxyagroclavine Festuclavine Fumigaclavine A Fumigaclavine B Fumigaclavine C Paliclavine Penniclavine Setoclavine
Other ergolines	Acetergamine Brazergoline Cianergoline CY-208,243 Delergotrile Disulergine Dosergoside Ergoline Etisulergine Lergotrile Nicergoline Pergolide Proterguride Romergoline Terguride Tiomergine Voxergolide
Related compounds	Adrogolide Naxagolide Quinagolide
Natural sources	Achnatherum robustum (Sleepy Grass) Claviceps spp. (Ergot) Morning glory: Argyreia nervosa (Hawaiian Baby Woodrose), Ipomoea spp.(Morning Glory, Tlitliltzin, Badoh Negro), Rivea corymbosa (Coaxihuitl, Ololiúqui)