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), MW and molecular shape by using the LLAMA (Lead‐Likeness and Molecular Analysis) software, to illustrate the success in generating lead‐like compounds and fragments.

We thank the EC FP6 (Marie Curie EST Fellowship to PDD; Contract: MEST-CT-2005-020744), The University of Edinburgh and Eli Lilly for funding. Supporting information:Experimental procedures for the synthesis of compounds 3, 4c, 4h-m and 6d-g; spectroscopic data for Evans-Tishchenko minor diastereomers and RAAT products 5e-g. This material is available free of charge via the Internet at http://pubs.acs.org Graphical abstract: AbstractThe low temperature Evans-Tishchenko coupling of a range of functionalised heteroaryl aldehydes with -hydroxy ketones in the presence of a Sm(III) catalyst has been achieved with high yields (90-99%) and good to excellent diastereoselectivity (90:10->95:5 dr). However, at room temperature a retro-aldol aldol-Tishchenko reaction was found to compete with the desired Evans-Tishchenko reaction. Identification of these byproducts has allowed the corresponding aldol-Tishchenko reaction to be optimised for several heteroaryl aldehydes.

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Norepinephrine Transporter. -Selective and potent norepinephrine reuptake inhibitors, containing a tertiary alcohol motif, are synthesized via a highly diastereoselective addition of an appropriately substituted benzyl Grignard reagent, e.g. (VI), to ketone (V) as the key step. Compound (VIIa) shows the greatest binding affinity to the NET and is stable under aqueous acidic conditions. Despite extensive metabolism in specified liver microsomes, (VIIa) displays potent oral in vivo activity in the α-MMT pharmacodynamic model of NET inhibition (some yields not given). -(CASES-THOMAS*, M. J.; et al.; Bioorg.