2-Substituted and 1,2-Disubstituted Piperidines

Vardanyan, Ruben

doi:10.1016/b978-0-12-805157-3.00003-x

Cited by 3 publications

(1 citation statement)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reaction conditions directly adapted from previously reported protocols 17,23 led to moderate-to-good yields of the desired cross coupling products. The resulting compounds incorporate prominent structural motifs in medicinal chemistry, including sugar fragments (A08-1, A15-1) 35 , a phosphonate (A18-1) 36 , spirocyclic and heteroaryl ureas (A08-2, A12-2, A12-3) 37, 38 , piperidine and pyrrolidine (A06-1, A16-2) 39 , amino acid fragments (A06-2, A08-3), and a polyamine derivative (A13-1) 40 . As evident from the PCA plots in Fig.…”

Section: Synthetic Implementationmentioning

confidence: 99%

Accessing 3D molecular diversity via benzylic C–H cross coupling

Chen

Kong

et al. 2022

Preprint

View full text Add to dashboard Cite

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C(sp2)-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties. Benzylic C(sp3)–H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C(sp3)-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C–H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space.

show abstract