Six-Step Synthesis of (±)-Lysergic Acid

Abstract

This article describes a concise synthesis of lysergic acid from simple aromatic precursors. The successful strategy relies on the coupling, dearomatization, and cyclization of a halopyridine with a 4-haloindole derivative in 6 total synthetic steps from commercial starting materials. In addition to highlighting the advantages of employing dearomative retrosynthetic analysis, the design is practical and anticipated to enable the synthesis of novel neuroactive compounds as exemplified by the synthesis of a novel natural product derivative, 12-chlorolysergic acid.

Revolutions in Chemistry: Assessment of Six 20th Century Candidates (The Instrumental Revolution; Hückel Molecular Orbital Theory; Hückel’s 4n + 2 Rule; the Woodward–Hoffmann Rules; Quantum Chemistry; and Retrosynthetic Analysis)

“… This graphic is a recent explicit example of the utilization of retrosynthetic analysis in a total synthesis, in this case, of lysergic acid. 260 Reproduced from ref ( 260 ). Copyright 2023 American Chemical Society.…”

Synthetic Strategies toward Lysergic Acid Diethylamide: Ergoline Synthesis via α-Arylation, Borrowing Hydrogen Alkylation, and C–H Insertion

“…20−23 Initial efforts employing this strategy were relatively inefficient, though several recent useful improvements have streamlined this approach and should be considered for future efforts toward LSD analogues. 24,19 In sharp contrast, strategies that join rings A and D prior to the closure of ring C have received relatively little attention. Only a single example has been reported using this strategy, and subsequent evidence questioned whether lysergic acid could be produced using this synthetic route (Figure 1B).…”

“…The biological activities of simpler tryptamine-based compounds can be dramatically altered by A-ring substitution; however, such analogues of LSD have not materialized. Since the first total synthesis of lysergic acid over 60 years ago, dozens of ergoline alkaloid synthetic strategies have emerged, yet only two examples of A-ring substituted analogues have been reporteda C13-fluorinated analogue of lysergol and a recently reported C12-chlorinated lysergic acid derivative. , Moreover, no methods published to date have enabled the reliable introduction of substituents on the C-ring. The limited study of unnatural ergoline analogues, including those with A- and C-ring substitutions, is unsurprising given the synthetic complexity of the ergoline scaffold.…”

“…Structurally, LSD and related ergolines are composed of an indole (ring AB) and a tetrahydropyridine (ring D) bridged by a central C-ring (Figure A). Many strategies have emerged for synthesizing this tetracyclic ring system, with the majority of modern syntheses joining rings A and D via sp 2 –sp 2 coupling in the final stage. − Initial efforts employing this strategy were relatively inefficient, though several recent useful improvements have streamlined this approach and should be considered for future efforts toward LSD analogues. , In sharp contrast, strategies that join rings A and D prior to the closure of ring C have received relatively little attention. Only a single example has been reported using this strategy, and subsequent evidence questioned whether lysergic acid could be produced using this synthetic route (Figure B).…”

Solving a Mystery with Classical and Dual Photoredox Catalysis: Application of Nickel in the Synthesis of Ergot Alkaloids

“…Hendrickson’s subsequent intermediate 7 remained elusive to date, yet the procedure is still mentioned and discussed in recent literature. , The strategy is not without risks due to a thermodynamic problem also observed by Nichols: Manipulations on the methylene bridge with the pyridine and indole moiety being intact may lead to an isomerization of the 2,3-indole double bond into conjugation to produce the more favorable benzo­[ f ]­quinoline system in 6 . , Therefore, such manipulations should be avoided, and an early introduction of the methylene bridge is advisable.…”