Divergent Synthesis of Cyclopropane-Containing Lead-Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide.

ABSTRACT: Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane-containing lead-like compounds, fragments and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)-ethyl 2-(phenylsulfanyl)-cyclopropane-1-carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt-catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide-magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 °C for > 2 h, which enables trapping with various electrophiles and Pd-catalyzed Negishi cross-coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALog?P), M_W and molecular shape by using the LLAMA (Lead-Likeness and Molecular Analysis) software, to illustrate the success in generating lead-like compounds and fragments.

SUBMITTER: Chawner SJ 

PROVIDER: S-EPMC5601191 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature