UC Davis

Neuronal atrophy and decreased dendritic spine density in the cortex are key pathological features of a variety of neuropsychiatric disorders. Lysergic acid diethylamide (LSD), a semi-synthetic ergoline alkaloid and psychoplastogen, possesses the remarkable ability to promote cortical neuron growth and increase spine density; however its full therapeutic potential is limited by its induction of powerful, long-lasting hallucinations. Naturally occurring lysergic acid is used to produce LSD via semi-synthesis, narrowing the scope of structure-activity relationship studies that may elucidate methods to modulate hallucinogenic activity. While a variety of synthetic strategies for accessing ergoline alkaloids have emerged, the complexity of the tetracyclic ring system results in distinct challenges in preparing analogs with novel substitution patterns. Accordingly, we designed versatile total synthesis methodology towards LSD and related tetracyclic ergoline structures to allow for functionalization at previously inaccessible substitution sites. Key strategies including intramolecular α-arylation, C-H insertion, and borrowing hydrogen alkylation are used to construct the tetracyclic ergoline core, and highlight unique stability challenges and rearrangements faced by a variety of late-stage ergoline precursors. Subsequently, we discovered isotryptamine isosteres of ergoline alkaloids, a new class of fully synthetic ergolines which possess substantial improvements in both synthetic strategies and therapeutic profiles relative to their natural ergoline counterparts.