A Short Synthesis of Ergot Alkaloids and Evaluation of the 5-HT_1/2 Receptor Selectivity of Lysergols and Isolysergols

Abstract

Key transformations in a four-step synthesis of the ergot alkaloid scaffold include a novel cesium carbonate-mediated hydrogen autotransfer alkylation to generate the C(3)–C(4) bond and an intramolecular Heck reaction that directly establishes the C(9)–C(10) alkene of methyl lysergate. An ester reduction and a streamlined experimental procedure establish a readily scalable, expedient total synthesis of all four stereoisomers of lysergol and isolysergol, including the previously unknown (−)-lysergol, for pharmacological evaluation at 5-HT1A and 5HT2A,B,C receptors. A bicyclic scaffold is also characterized for the first time in the intramolecular Heck coupling.

Six-Step Synthesis of (±)-Lysergic Acid

“…While similar transformations have been reported, ,, low yields and/or stoichiometric amounts of Pd have been required to affect this annulation, attesting to its challenging implementation. Simultaneous with our investigation, Wipf also reported a similar strategic implementation of this cyclization . The stereochemistry of the center alpha to the ester in 12b was crucial to the success of this reaction, allowing for syn -beta-hydride elimination to proceed following the migratory insertion of the putative arylpalladium­(II) intermediate.…”

“…Simultaneous with our investigation, Wipf also reported a similar strategic implementation of this cyclization. 45 The stereochemistry of the center alpha to the ester in 12b was crucial to the success of this reaction, allowing for syn-beta-hydride elimination to proceed following the migratory insertion of the putative arylpalladium(II) inter-mediate. Finally, saponification and isomerization of the mixture of 21, 22a, and 22b was executed as previously reported to generate lysergic acid (2) in 50% yield.…”

Total Synthesis of (+)-Isolysergol

“…(2S)-(+)-phenylbut-3en-1-yl tosylcarbamate (17) was obtained via [CuCl(COD)] 2catalyzed ring-opening vinylation of (2R)-(+)-phenyloxirane 24 and a subsequent esterification with p-tosyl isocyanate (p-Ts-NCO) with 69% yield in 2 steps. Compound (+)-17 then underwent Pd-catalyzed aminoalkynylation with TIPS-EBX (18) to afford the desired 4,5-trans-substituted product (−)-16. The efficient reduction of the cyclic carbamate (−)-16 with LiAlH 4 resulted in amino alcohol (−)-19 with 99% yield via deprotection of the carbamate moiety.…”

“…The D-ring of (+)-3 was constructed by Baylis−Hillman reaction with formaldehyde followed by an acid-catalyzed 6endo-trig cyclization. In 2022, Wipf and Tasker 18 developed a short, scalable four-step synthesis of methyl lysergates. Key transformations include a novel cesium carbonate-mediated hydrogen autotransfer alkylation to generate the C (3)-C (4) bond and an intramolecular Heck reaction that directly establishes the C (9)-C (10) alkene of methyl lysergate.…”

Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid

“…According to the latest reports, structure 51 can also be obtained in three–five steps from a nicotinic acid ester 60 ( Scheme 23 ) [ 63 ].…”