Total Synthesis of (±)-Quinagolide: A Potent D₂ Receptor Agonist for the Treatment of Hyperprolactinemia

Abstract

A potent dopamine (D 2 ) receptor agonist (±)-quinagolide, which is used for the treatment of hyperprolactinemia, was synthesized using the ring closing metathesis (RCM) approach from meta -hydroxybenzaldehyde as the starting material. The key features of this synthesis are pyrolytic elimination, late-stage expedient synthesis of functionalized trans-fused tetrahydropyridine-3-carboxylates from olefin 6 , via conjugate addition–elimination upon acetate 11 , followed by RCM and phenyliodine bis(trifluoroacetate) (PIFA)-mediated Hofmann rearrangement of piperidine-3-carboxamide, which enables the synthesis of 3-aminopiperidine skeleton of quinagolide. For the total synthesis of natural products such as ergot alkaloids, late-stage synthesis of functionalized trans-fused tetrahydropyridine-3-carboxylates using RCM and PIFA-mediated Hofmann rearrangement of piperidine-3-carboxamide, which allows quick access to the synthetically challenging 3-aminopiperidine skeleton, are the main achievements of the present work.

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Whileas, the total synthesis of (�)-quinagolide 405 (Scheme 55), used for the treatment of hyperprolactinemia was accomplished by Chavan and co-workers reported under the influence of metathetic synthetic approach. [236] Deprotection of Boc group from terminal alkene compound 400 with TFA followed by alkylation with acetate 401 under conjugate addition-elimination reaction afforded a diene 402. Next, Npropylation of 402 with propyliodide in presence of K 2 CO 3 produced a suitable RCM precursor 403, which upon RCM afforded a tricyclic compound 404 in notetable yield.…”

Revisiting Classical Pummerer Cyclization Reaction: A Key Strategy for the Synthesis of (±)‐Quinagolide

“…Recently, our group reported the total synthesis of (�)-quinagolide (1) using meta-hydroxybenzaldehyde as the starting material and also reported a first enantioselective synthesis of its (À )-eutomer utilizing organocatalyzed Diels-Alder reaction. [10,11] Herein, we report an intramolecular classical Pummerer reaction based simple and efficient strategy to synthesize (�)-quinagolide (1).…”

Enantioselective Formal Total Synthesis of (−)-Quinagolide

“…Subsequently, in 2000, scalable synthesis of quinagolide intermediate was reported by Banziger et al from Novartis Ltd . Recently, our group reported the entirely different approach for the total synthesis of (±)-quinagolide . Though Nordmann et al resolved the intermediate of (±)-quinagolide and found that the dopaminomimetic activity is entirely associated with the (−)-enantiomer, to date, enantioselective total synthesis of (−)-quinagolide is not reported in the literature.…”