Partially Saturated Bicyclic Heteroaromatics as an sp³‐Enriched Fragment Collection

Abstract

Fragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

Divergent Synthesis and Real-Time Biological Annotation of Optically Active Tetrahydrocyclopenta[c]pyranone Derivatives

“…1−4 Inclusion of diverse molecular shapes has been suggested as a key factor for library performance. 5−9 However, in contrast to natural products, many synthetic libraries contain only a few sp 3 -rich scaffolds. 8−11 Bridging this gap requires the development of efficient and scalable synthetic methods to access sp 3 -rich small molecules.…”

Synthesis of Structurally Diverse N‐Substituted Quaternary‐Carbon‐Containing Small Molecules from α,α‐Disubstituted Propargyl Amino Esters

“…In addition to PMI analysis, calculation of the mean values for physicochemical properties related to the “rule of three” guidelines commonly adopted within fragment library generation (Table ) was conducted. Notably the DOS library featured a low mean SlogP (1.37), higher mean number of chiral centres (1.1) and low fraction of aromatic atoms per molecule (0.29), compared to commercial libraries (see Supporting Information), demonstrating the amenability of the DOS library to fragment‐based drug discovery approaches …”

“…Notably the DOS library featured al ow mean SlogP (1.37),h igherm ean number of chiral centres (1.1) and low fraction of aromatic atoms per molecule (0.29),c ompared to commercial libraries (see Supporting Information), demonstrating the amenability of the DOS library to fragment-based drugdiscovery approaches. [38] Whilst PMIs are ac ommon way of assessing shape diversity, the relationship to bioactivity coverage appears to be more Comparative PMI plot analysis of DOS library (blue circles), Maybridge core 1000-member "Ro3" Fragmentl ibrary(greent riangles) and the DOS Ph virtual library (red squares). Compounds within "flatland" (represented by npr1 + npr2 value < 1.1, dashed line) could also be identified;t he further from this area the molecules move the morethey extend into three-dimensional space.…”

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

“…DOS is focused on using short and divergent synthetic sequences from simple starting materials to generate structurally complex and diverse scaffolds . DOS would provide the ideal strategy to expand fragment libraries into three‐dimensional chemical space, and this challenge has been taken up across industry and academia …”