Synthesis of 3-Azidopiperidine Skeleton Employing Ceric Ammonium Nitrate (CAN)-Mediated Regioselective Azidoalkoxylation of Enol Ether: Total Synthesis of D₂ Receptor Agonist (±)-Quinagolide

Abstract

The total synthesis of (±)-quinagolide, which is a D2 receptor agonist, was accomplished via a ceric ammonium nitrate (CAN)-mediated regioselective azidoalkoxylation of enol ether route. Key features of the synthesis include Claisen rearrangement, PPTS (pyridinium p-toluenesulfonate)-catalyzed one-pot acetal deprotection, followed by a diastereoselective Henry reaction, which enables construction of the required trans ring junction and CAN-mediated regioselective azidoalkoxylation of enol ether. The PPTS-catalyzed intramolecular diastereoselective Henry reaction to fix three contiguous stereocenters on tetrahydronaphthalene and the first-of-its-kind synthesis of the 3-azidopiperidine skeleton, using a CAN-mediated regioselective azidoalkoxylation of enol ether, are important findings of the present work.

Furan‐Derived Chiral Bicycloaziridino Lactone Synthon: Collective Syntheses of Oseltamivir Phosphate (Tamiflu), (S)‐Pipecolic acid and its 3‐Hydroxy Derivatives

“…[1] The inherent ring strain of aziridine ring allows the regioselective and stereoselective transformation of this small N-containing ring system for its elegant use in the synthesis of biologically activem olecules. [3] Due to our continued interest in the synthesis of biologically active compounds that are having societal importance, [4] synthetic studies towards tamiflu, pipecolic acid, andi ts 3-hydroxy derivatives were initiated in our group using chiral aziridine as ab uildingb lock. [3] Due to our continued interest in the synthesis of biologically active compounds that are having societal importance, [4] synthetic studies towards tamiflu, pipecolic acid, andi ts 3-hydroxy derivatives were initiated in our group using chiral aziridine as ab uildingb lock.…”

“…[2] In the past decade, considerable progress has been made in the field of stereoselective synthesis of aziridines.H owever,r egioselectivity and stereoselectivity,a sw ell as complexity associated with the catalysts to be prepared and, most importantly, synthesis of aziridine synthon, which is stable at room temperature for its practical use in the synthesis of bioactive compoundsa re the main challenges and need furtheri mprovement. [3] Due to our continued interest in the synthesis of biologically active compounds that are having societal importance, [4] synthetic studies towards tamiflu, pipecolic acid, andi ts 3-hydroxy derivatives were initiated in our group using chiral aziridine as ab uildingb lock. Tamiflu (1, oseltamivir phosphate) which is neuraminidase inhibitor was first developed by Gilead Sciences for the treatment of swine flu (H5N1 human flu), whereas pipecolic acida nd its 3-hydroxy derivatives (2, 3,a nd 4)a re impor-tant building blocks for the synthesis of various biologically active compounds (Figure 1).…”

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

“…Toward this, recently (2018), we reported an efficient synthesis of quinagolide, which features a Claisen rearrangement, PPTS-catalyzed one-pot acetal deprotection and intramolecular diastereoselective Henry reaction, and ceric ammonium nitrate-mediated regioselective azidoalkoxylation of enol ether as the key steps. 5 In that context, our group effectively utilized ring closing metathesis (RCM) as an important synthetic tool in the total synthesis of natural products. 6 Herein, we report our alternative synthetic approach for the total synthesis of quinagolide using RCM as the key reaction for the construction of 3-aminopiperidine skeleton of quinagolide.…”

“…Ester 7 in turn could be accessed from meta -hydroxybenzaldehyde using PPTS-catalyzed one-pot acetal deprotection followed by diastereoselective Henry reaction as a key step, which was reported earlier by our group. 5…”

“…With the aim of developing a practical route to this potent dopamine agonist, synthetic studies toward quinagolide were initiated in our group. Toward this, recently (2018), we reported an efficient synthesis of quinagolide, which features a Claisen rearrangement, PPTS-catalyzed one-pot acetal deprotection and intramolecular diastereoselective Henry reaction, and ceric ammonium nitrate-mediated regioselective azidoalkoxylation of enol ether as the key steps . In that context, our group effectively utilized ring closing metathesis (RCM) as an important synthetic tool in the total synthesis of natural products .…”