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

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

“…To utilize a reductive ring closure strategy, NHPI-ester 13b was prepared following a known procedure. , The photoreductive coupling yielded 14b , although a drop in yield and formation of minor amounts of the undesired regioisomer was observed (see the SI for further optimization attempts, other halogenation patterns, and protecting groups tested). Gratifyingly, 14b could be cyclized to 7 under various reductive conditions with the methodology of Kishi et al working most reliably. ,, NMR spectroscopy confirmed the structure of 7 …”

“…A particularly popular variant connects a tetrahydropyridine moiety to a 4-haloindole unit, which had previously been connected via a methylene bridge . A less common option is the closure of the C-ring at the methylene bridge on either side. , To this end, the A- and D-rings are typically coupled via an early Suzuki–Miyaura reaction or related methodologies.…”

“…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.…”

“…As a new route to the carbon skeleton had been established, we sought to extend it to the synthesis of other ergot alkaloids. Olson et al recently reported an elegant method for the formal total synthesis of lysergic acid diethylamide ((±)-LSD, 16 ) via a hydrogen borrowing approach.…”