Strategies for the synthesis of spiropiperidines – a review of the last 10 years

Abstract

Spiropiperidines have gained in popularity in drug discovery programmes as medicinal chemists explore new areas of three-dimensional chemical space. This review focuses on the methodology used for the construction of 2-, 3- and 4-spiropiperidines, covering the literature from the last 10 years. It classifies the synthesis of each of the types of spiropiperidine by synthetic strategy: the formation of the spiro-ring on a preformed piperidine ring, and the formation of the piperidine ring on a preformed carbo- or heterocyclic ring. While 3- and 4-spiropiperidines are predominantly synthesised for drug discovery projects, 2-spiropiperidines are synthesised en route to natural products. The lack of 2-spiropiperidines in drug discovery is presumably due to limited general procedures for their synthesis.

Oxetanes and Oxetenes: Fused-Ring Derivatives

“…124 Researchers at Merck reported an optimized synthetic route towards spiro-oxetane containing piperidines and pyrrolidines via a simple intramolecular SN2-type displacement of a primary tosylate. 128,129 The latter is prepared in situ from diol 183 using n-butyllithium and tosyl chloride; the addition of a second equivalent of n-butyllithium then delivered the desired spiro-oxetane piperidine 185 in 66% yield on a 37 g scale. Similar strategy led to compounds 186 and 187 from ethyl nipecotate and methyl 1-benzylpyrrolidine-3-carboxylate (respectively).…”

Exploration of the Mechanism, Chemospecificity, Regiospecificity and Stereoselectivity of the Cycloaddition Reaction between Hydroxyparthenolide and Nitrilimine: MEDT Study

“…Spiro products are bi-cyclic molecules whose two rings are connected by an atom (scheme1), which can be considered as very important compounds in industry and in biological application [18][19][20]. Spiro derivatives have been used to produce polymers, dyes, plastic foams, drugs, pesticides and herbicides [21].…”

Synthesis and Modeling Studies of Furoxan Coupled Spiro-Isoquinolino Piperidine Derivatives as NO Releasing PDE 5 Inhibitors

“…The spirocycles with distinct structural features are important scaffolds often found in natural products and display numerous bioactivities. In particular, spiropiperidines are considered as privileged structures and have received considerable attention in medicinal chemistry as the skeleton displays a wide array of activities [40,41].…”