Ergot

The ergoline skeleton looks not entirely unlike a cock-n-balls.

Ergot is pronounced ur-git, not er-go. Highly toxic, it ought not be consumed. Properly modified, it has many uses, primarily due to fortuitous similarity between the ergoline skeleton and the monoamide neurotransmitters (e.g. serotonin, dopamine, adrenaline)...

Ergopeptides ergonovine and ergotamine (and their salts) are both original List I controlled precursors under the 1970 Controlled Substances Act. Ergocristine was added to List I in 2010 (see the DEA's 2010-03 Microgram Journal). Derivatives lysergic acid and its amide ("ergine") are Schedule III controlled substances under the CSA, and ergine is a Class A precursor in the United Kingdom. Subsequent derivative lysergic acid diethylamide is an original Schedule I controlled substance, and its functional analogues (any chemical "substantially similar", as if that had any kind of precise meaning) are treated as Schedule I due to the 1986 Federal Analogue Act. So there's clearly something worth knowing about ergot!

Some basic terminology

• Ergot: fungi of the genus Claviceps. All Claviceps species are ergot. The most well-known member is Claviceps purpurea (Latin purpuro, purple, "to adorn/beautify"), the rye ergot fungus, which is parasitic on grasses and cereals (especially rye, Secale cereale).
  • A Claviceps spore infects a flowering grass or cereal's floret. Upon connection to the vascular bundle, soft white sphacelia tissue develops. This hardens and dries into a sclerotium in the destroyed floret's husk.
  • Alkaloids and lipids accumulate in the sclerotium. Dry, mature claviceps purpurea sclerotium consist of about 2% ergot alkaloids by weight. Claviceps africana also contains substantial alkaloids.
  • Petri-grown Claviceps sees best results with potato dextrose or malt extract agar.
• Alkaloid: Basic (high-pH) naturally-occurring organic compounds containing nitrogen. The "true alkaloids" are biosynthesized from amino acids and contain nitrogen in a heterocycle (a cyclic structure containing more than one element).
  • Indole: The aromatic heterocycle C₈H₇N. Bicyclic pair of benzene (C₆H₆) and pyrrole (C₄H₄NH) sharing an edge. A biosynthetic precursor to the indole alkaloids, including the amino acid tryptophan and 3-indolepropionic acid (IPA).
  • Tryptophan: An essential amino acid (one which cannot be biosynthesized in humans), and a precursor in humans of serotonin, melatonin, and vitamin B3. Clostridium sporogenes in the human gut metabolizes tryptophan into indole.
  • Ergoline: the tetracyclic structural skeleton (C₁₄H₁₆N₂) shared by ergoline alkaloids. Also a tanning bed by JK Products (pronounced differently).

Ergoline path (biosynthesis of the ergot alkaloids)

The road to the ergopeptides begins with L-tryptophan and culminates in D-lysergic acid. The ergoline skeleton is complete in agroclavine (and indeed apparent in its three sibling daughters of chanoclavine). Note that if one is interested in the water-soluble lysergamides, ergopeptines are not a necessary precursor.

• L-Tryptophan C₁₁H₁₂N₂O₂ -> (prenylation via DMAPP from mevalonic acid, catalyzed by DMATS)
  • DMAT(S): dimethylallyltryptophan (synthetase)
• 4-L-DMAT -> (N-methylation via SAM, catalyzed by EasF)
• 4-DMA-L-abrine -> (decarboxylation+oxidation via EasC, catalyzed by EasE)
• Chanoclavine-I -> (oxidation via EasD)
• Chanoclavine-I-aldehyde (a D₂ dopamine receptor stimulant) ->
• Agroclavine ->
• D-Lysergic acid (DLA).

Chanoclavine-I-aldehyde branches to festuclavine, pyroclavine, and cycloclavine (in addition to agroclavine), leading to the dihydroergopeptides and fumigaclavines. In addition to DLA, agroclavine branches to emiloclavine (also seen as emyloclavine) and thus paspalic acid.

Paspalic acid

Paspalic acid is an isomer of lysergic acid, and will spontaneously convert. Efficient isomerization can be achieved using 2N sodium hydroxide or 0.5N potassium hydroxide. In 1999, Jean-Claude Gaullier reported 59.3% RRi with NaOH (6.8% iso) and 49.8% RRi with KOH (1% iso).

D-Lysergic acid

Lysergic: discovered via hydrolysis of ergotamine. A Table I precursor under the UN Convention Against Psychotropic Substances and a Schedule III controlled substance. About 15 tons of DLA (also seen as (+)-lysergic acid) are legitimately manufactured each year, primarily from submerged fermentation of special strains of Calviceps purpurea but also from field harvests.

The ergopeptides are biosynthetic derivatives of DLA, but DLA is a synthetic derivative of the ergopeptides. DLA was first isolated by hydrolysis of ergot alkaloids in the 1930s. It was first synthesized in 1956 starting from 3ß-carboxyethylindole, and numerous processes have been published since: see this 2022 review for full details.

External links

• Reconstituting the complete biosynthesis of D-lysergic acid in yeast. Wong et al. Nature Communications 2022-02.
• Biosynthesis, total synthesis, and biological profiles of ergot alkaloids. Tasker & Wipf. The Alkaloids: Chemistry and Biology 2020.
• Total Synthesis of Lysergic Acid. Umekazi et al. Organic Letters 2013.
• The Chemistry of Peptide Ergot Alkaloids. Komarova & Tolkachev. Pharmaceutical Chemistry Journal 2001-02, translated 2001-09.
• List of Precursors and chemicals frequently used in the illicit manufacture of narcotic drugs and psychotropic substances under International Control. International Narcotics Control Board 2022-01. Also known as the "Red List".
• Tryptamine and Ergoline Chemistry on the Hive (archived at Erowid)