Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment‐Based Drug Discovery

Abstract

In recent years the pharmaceutical industry has benefited from the advances made in fragment‐based drug discovery (FBDD) with more than 30 fragment‐derived drugs currently marketed or progressing through clinical trials. The success of fragment‐based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2‐rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three‐dimensional scaffolds. Herein, we report step‐efficient routes to a number of biologically relevant, fragment‐like heterocyclic spirocycles. The use of both electron‐deficient and electron‐rich 2‐atom donors was explored in complexity‐generating [3+2]‐cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.

Chemical Biology Toolsets for Drug Discovery and Target Identification

“…In the early twentieth century, drug development started with the advancements in pharmacology and synthetic and therapeutic chemistry. In the 1950s and 1960s, enzyme kinetics has provided methods for accurate computation of compound's effectiveness and enzyme competence [17].…”

“…They may or may not get paid for their participation in drug trial studies. This mini trial is useful in determining the absorption and side effect of drug in relation to its dose concentration [17].…”

Quantum Chemical Investigation of the Formation of Spiroheterocyclic Compounds Via the (3 + 2) Cycloaddition Reaction of 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one with Diazomethane and Nitrone Derivatives

“…Their fascinating molecular framework and their presence in a variety of natural products are of special interest to chemists [1][2][3][4][5][6][7][8]. Within a three-dimensional fragment space, spirocycles are an essential class of molecular ring systems [5,9,10]. Their quaternary atomic center avails an inherent three-dimensionality to this class of scaffolds whereas their cyclic nature provides all the benefits of reduced flexibility.…”

“…Their quaternary atomic center avails an inherent three-dimensionality to this class of scaffolds whereas their cyclic nature provides all the benefits of reduced flexibility. These characteristics are largely responsible for their biological activity [9,11,12]. Over the years, many synthetic procedures have been developed to construct spirocycles, most of which are usually based on cycloaddition reactions or condensation reactions [13].…”

“…The construction of a spirocyclic framework commonly involves the formation of a new ring on an existing ring system [1]. Synthesis of spiroheterocycles is particularly challenging; however, they present an under-explored area of the chemical library with outstanding potential in drug design [9]. Cycloaddition reactions are important synthetic procedures for the transformation of both cyclic and acyclic precursors into complex spirocyclic compounds [14].…”