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

Abstract

A potent dopamine (D2) 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.

• Authors: Subhash P Chavan, Appasaheb L Kadam, Sanket A Kawale
• Journal: ACS omega (ACS Omega) Vol. 4 Issue 5 Pg. 8231-8238 (May 31 2019) ISSN: 2470-1343 [Electronic] United States
• PMID: 31459911 (Publication Type: Journal Article)