Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Abstract

In the context of drug discovery, novel spirocyclic pyrrolidines have been synthesized in two steps from common three- to seven-membered-ring (hetero)alicyclic ketones. The key transformation is a reaction between an electron-deficient exocyclic alkene and an in situ generated N-benzyl azomethine ylide. The developed method has been used to synthesize the central diamine core of the known antibacterial agents Sitafloxacin and Olamufloxacin.

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…Despite its chemical elegance it suffers from the waste intensiveness and high toxicity of the used precursors, reagents, and produced waste (tributyltin compounds). Mykhailiuk from Enamine Ltd. proposed a spirocyclization method based on [3+2]‐cycloaddition reaction between electron‐deficient alkenes and in situ generated highly reactive azomethine ylide [38,39] . However, the lack of stereocontrol during the key cycloaddition step is the main weakness of this strategy.…”

“…Mykhailiuk from Enamine Ltd. proposed a spirocyclization method based on [3 + 2]-cycloaddition reaction between electrondeficient alkenes and in situ generated highly reactive azomethine ylide. [38,39] However, the lack of stereocontrol during the key cycloaddition step is the main weakness of this strategy. Recently Mykhailiuk reported a unified spirolactam synthesis from α-aminoesters, relying on Dieckmann condensation (Scheme 1b).…”

Recent synthesis of thietanes

“…This review covers the methods outlined in Figure 2 and also some miscellaneous methods for the synthesis of various thietane derivatives. A special focus is on the construction of the thietane ring, excluding methods for the simple modifications of the thietane rings and their side chains [26][27][28][29][30][31].…”

1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long–sought-after mimetics for ortho / meta -substituted arenes

“…Specifically, C(sp 3 )-rich structures, where the venerable benzene ring is replaced with saturated bioisosteres, have started to rapidly populate the patent literature, compound libraries, and the toolbox of medicinal chemistry tactics (1,2). These three-dimensional moieties often exhibit improved biological activities, physicochemical properties and metabolic profiles compared to the parent benzene ring (3)(4)(5)(6)(7)(8). These singular characteristics have encouraged several academic and industrial groups, including the Pfizer/Scripps team, to achieve the functionalization of these small structures (for some recent examples, see refs.…”