Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid

Abstract

Ergot is the spore form of the fungus Claviceps purpurea. Ergot alkaloids are indole compounds that are biosynthetically derived from L-tryptophan and represent the largest group of fungal nitrogen metabolites found in nature. The common part of ergot alkaloids is lysergic acid. This review shows the importance of lysergic acid as a representative of ergot alkaloids. The subject of ergot and its alkaloids is presented, with a particular focus on lysergic acid. All methods of total lysergic acid synthesis—through Woodward, Hendrickson, and Szantay intermediates and Heck coupling methods—are presented. The topic of biosynthesis is also discussed.

One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel–Crafts Alkylation of γ-Hydroxybutyrolactams

“…Nevertheless, as such multicyclic skeletons are frequently part of bioactive natural substances, there is significant scientific interest toward them. Thus, Ergot alkaloids, for instance, have been the subject of various studies in recent years [ 14 , 15 , 16 , 17 ], including a number of total syntheses of Lysergic acid 3 [ 18 , 19 , 20 , 21 ]. Herein we would like to present a convenient route to a principally new type of polycyclic indole moiety 4 , which resembles the skeletons of the Ergot alkaloids and may possess some potent bioactivities as well.…”

Migraine drugs

“…Hendrickson (1928Hendrickson ( -2018 [338] from Brandeis University published the ninth total synthesis of racemic lysergic acid, but the first one entirely avoids protecting group chemistry [326]. To increase step economy, Hendrickson considered the assembly of the framework [313,314]. However, also some recent formal syntheses of lysergic acid [315][316][317][318] as well as Peter Vollhardt's total synthesis of racemic LSD in 1994, starting from commercial 4-bromoindole in just seven steps and 1.1% overall yield, might also be appreciated [319] a Ring construction/introduction sequence [320] 1976 AB→C→D (+/-) 19 1.5 Oppolzer [321] 1981 AB→CD (+/-) 17 0.9 Ninomiya [322] 1982 AB→C→D (+/-) 20 0.03 Rebek [323] 1983 AB→C→D (+/-) 14 4.4 Kurihara [324] 1986 AB→C→D (+/-) 14 2.0 Ortar [325] 1988 AB→C→D (+/-) 12 1.3 Hendrickson e [326] 2004 AB→D→C (+/-) 9 14.5 Szántay [327] 2004 AB→C→D (+) 15 0.7 Fujii, Ohno [328] 2008 AB→DC (+/-) 21 3.1 Fukuyama [329] 2009 D→A→BC (+) 34 0.9 Fukuyama [330] 2009 D→AB→C (+) 24 0.08 Fujii, Ohno [331] 2011 AB→ DC (+) 16 5.9 Fujii, Ohno [332] 2011 AB→ DC (+) 17 1.8 Jia [333] 2011 AB→D→C (+) 20 5.1 Fukuyama [334] 2013 AB→D→C (+) 19 12.0 Jia [335] 2013 D→AB→C (+) 12 1.0 Fukuyama [336] 2018 A→B→C→D (+) 30 0.07 Smith [337] 2022 AB→D→C (+/-) 6 12.0 from readily available indole and nicotinic acid starting materials as the most efficient route and avoided also the initial reduction of the indole, which was frequently performed in previous syntheses (Scheme 4).…”

General Access to Clavine Alkaloids via a Rhodium(I)‐Catalyzed Diastereoselective Hayashi‐Miyaura Reaction

“…Construction of the ergoline ring system typically begins with the indole or indoline AB-ring system followed by cyclization or annulation to forge the Cring (with the piperidine D-ring already present or closing afterward), with some elegant exceptions (Figure 1A, left). [8] In particular, synthetic routes to enantiomerically pure ergoline derivatives feature a Cring that is closed through either transition metal catalysis relying on the stereochemistry that is set before the cyclization reaction or asymmetric organocatalysis whereby the stereochemistry is set, building complexity from there. Of the transition metal-catalyzed cross-coupling reactions, the intramolecular Heck reaction has been used most frequently, whereas other palladium coupling reactions are scarcely reported in comparison (Figure 1A, centre).…”