Journal
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Volume 2017, Issue 34, Pages 5015-5024Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.201701030
Keywords
Cyclopropanes; Sulfoxides; Small ring systems; Homogeneous catalysis; Molecular diversity
Categories
Funding
- Royal Society
- Engineering and Physical Sciences Research Council (EPSRC) [EP/J001538/1, EP/K503733/1]
- Eli Lilly (UK)
- Imperial College London
- Engineering and Physical Sciences Research Council [EP/K503733/1, EP/J001538/1] Funding Source: researchfish
- EPSRC [EP/J001538/1] Funding Source: UKRI
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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 degrees 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 (ALogP), 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.
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