1‐Substituted 2‐Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery

Abstract

The 2-substituted piperidine core is found in drugs (18 FDA-approved drugs), however,t heir spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2-substituted piperidines and ademonstration of their validation in drug discovery.

Oxa-spirocycles: synthesis, properties and applications

“…5 Since that time, spirocyclic molecules have been playing an important role in chemistry. 6,7 In fact, more than 10.000 research manuscripts and 50.000 patents on the topic appeared during the last decade (Figure 1). 8 >50.000 patents since 2010 O Bioisoster es [cyclic] [spiro] Earlier, we reported on the preparation of oxa-bridged bicycles via iodocyclization of alkenyl alcohols.…”

Unexpected Discovery of Saturated Pyridine Mimetics

“…Spirocycles are currently popular in chemistry, 6 and we have several ongoing projects on making them. 7 One of those projects relies on the double alkylation of acetonitriles and the subsequent reduction of the nitrile group. For example, the reduction of nitrile 1 with LiAlH4 in tetrahydrofuran at room temperature gave the spirocyclic amine 2.…”

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.…”

“…Only recently have reports emerged delineating creative approaches to fill this gap [an initial disclosure of this study was deposited on ChemRxiv (21); subsequently, two additional reports (22,23) have appeared describing different and orthogonal strategies]. This is certainly due to the absence of synthetic methods to achieve 1,2-difunctionalization of BCPs rather than the lack of desire to replace orthoand metadisubstituted benzenes in bioactive molecules, which has been regularly mentioned over the years (3)(4)(5)(6)(7)(8). [According to incomplete statistics on "Drug Bank" (24), there are about 100 approved drugs that contain ortho-disubstituted benzene system and 50 approved drugs that contain meta-disubstituted benzene systems, respectively.]…”