Formal Synthesis of (−)-Quinagolide: Diastereoselective Ring Expansion via a Bicyclic Aziridinium Ion Strategy to Access the Octahydrobenzo[g]quinoline Architecture

Abstract

The diastereoselective formal synthesis of (−)-quinagolide, a D2 receptor agonist, has been achieved. The synthesis started from l-pyroglutamic acid and relied on utilization of (a) a stereospecific catalytic hydrogenation and diastereoselective Horner–Emmons–Michael cascade to obtain functionalized prolinate, (b) a Lewis acid mediated Pummerer cyclization to construct a tricyclic fused ring system, and (c) a diastereoselective ring expansion via a bicyclic aziridinium intermediate to access the required 3-substituted piperidine scaffold.

Recent advances in the accessibility, synthetic utility, and biological applications of aziridines

“…In one of the described procedures, cis -aziridine ( 7 ) was employed as a chiral synthon (Scheme 2). 7…”

Rapid Synthesis of the epi-Biotin Sulfone via Tandem S,N-Carbonyl Migration/aza-Michael/Spirocyclization and Haller–Bauer Reaction

“…The Goldberg and Sternbach approach has been thoroughly modified for several years. With our ongoing interest and endeavors in the synthesis of biologically active compounds, 11 we were interested in exploring an efficient synthesis of (+)-biotin.…”

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

“…In continuation, we recently used this methodology to construct the octahydrobenzo[g]indole skeleton. [5] Herein, we explored it to directly achieve the octahydrobenzo[g]quinoline skeleton for the synthesis of quinagolide (1).…”

“…As tools for synthesis, the Pummerer rearrangement continues to find widespread application en route to various biologically active natural products. In continuation, we recently used this methodology to construct the octahydrobenzo[g]indole skeleton [5] . Herein, we explored it to directly achieve the octahydrobenzo[g]quinoline skeleton for the synthesis of quinagolide ( 1 ).…”