Asymmetric Synthesis of Lysergic Acid via an Intramolecular (3+2) Dipolar Cycloaddition/Ring-Expansion Sequence

Abstract

An effective, potentially scalable asymmetric synthesis of lysergic acid, a core component of the ergot alkaloid family, is reported. The synthesis features the strategic combination of an intramolecular azomethine ylide cycloaddition and Cossy–Charette ring expansion to assemble the target’s C- and D-rings. Simple functional group manipulation produced a compound that had been converted to lysergic acid in four steps, thus constituting a formal synthesis of the natural product. The strategy may be used to prepare novel ergot analogues that include unnatural antipodes and may be more amenable to analogue generation relative to prior approaches.

Six-Step Synthesis of (±)-Lysergic Acid

“…The minor undesired isomer (25a) could again be recycled to afford higher quantities of 25b, which proceeded through the Heck cyclization to generate enoate 26 in 71% yield. Hydrolysis of this mixture gave 12-chlorolysergic acid (27)…”

“…While our initial approach was initially thwarted by tactical limitations, the inversion of polar synthons enabled the construction of the final tetracyclic core. Furthermore, the synthesis of 12chlorolysergic acid (27) was accomplished through the adaptation of the successful second-generation approach, demonstrating entry into novel molecular space unlocked by this synthetic blueprint. We contend that this synthetic advance holds great promise for the increased utilization of psychedelics and their derivatives as new neuropharmacological treatments.…”

“…Like many before us, targeting lysergic acid ( 2 ) was a starting point toward synthesizing and validating any psychoactive LSD derivatives. − Prior to our studies, the most concise approach was the controversial synthesis of 2 reported by Hendrickson which was later disputed by both Nichols and Boger . Overall, we considered two retrosynthetic strategies to allow quick access to lysergic acid ( 2 ).…”

Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid

“…In 2021, Garner and Rathnayake published a study that used Szantay’s intermediate to obtain lysergic acid [ 74 ]. This is a novel approach that involves carrying out an intramolecular cycloaddition reaction of an azomethine ylide, generated in situ, followed by ring expansion to Szantay’s ketone.…”

A Concise and Malleable Synthesis of (±)-Lysergic Acid

“…Targeting lysergic acid (2), the synthetic precursor to LSD, was a starting point towards synthesizing and validating any psychoactive LSD derivatives. 16,17,[26][27][28][29][30][31][32][33][34][35][18][19][20][21][22][23][24][25] This includes the controversial short synthesis of 2 reported by Hendrickson 25 which was later disputed by both Nichols 36 and Boger. 37 Overall, two retrosynthetic strategies were considered to allow quick access to 2.…”