No abstract

An efficient approach to synthesis of various substituted 3‐azabicyclo[3.2.0]heptane‐derived building blocks based on [3+2] cycloaddition of cyclobut‐1‐eneraboxylic acid ester and in situ generated azomethine ylide was developed and applied on multigram scale. The utility of 1,3‐disubstituted 3‐azabicyclo[3.2.0]heptane scaffold was demonstrated by additional structural analysis using exit vector plot (EVP) tool, and tested in parallel synthesis of compound library.

A gram-scale synthesis, physico-chemical characterization, and lead-likeness assessment of 4-di/trifluoromethyl-2-heterabicyclo [2.1.1]hexanes as fluorinated bicyclic proline analogues and phenyl isosteres are disclosed. The key step of the synthesis included iodocyclization of fluorinated 3-hydroxy-/3aminomethyl methylenecyclobutanes; with the amino derivatives, the reaction was accompanied with carboxylation and further cyclization. Apart from the corresponding 4-di/ trifluoromethyl-2,4-methanoprolines, a series of fluorinated oxabicyclo[2.1.1]hexane-derived building blocks relevant to medicinal chemistry (i. e. primary iodides, carboxylic acids, alcohols, azides, primary amines, sulfonyl chlorides, and alkynes) were prepared. For representative derivatives of the resulting fluorinated 2-oxabicyclo[2.1.1]hexanes, pK a and logP values were measured to clarify their potential as the possible phenyl isosteres. Apart from the somewhat increased acidity, finetuned lipophilicity intermediate between that of non-fluorinated or aromatic counterparts was observed. Finally, the potential of the title building blocks was demonstrated by generation of virtual compound libraries using the LLAMA software. The resulting libraries fitted perfectly the lead-like chemical space, had higher three-dimensionality, and showed lower mean lead-likeness penalty as compared to those obtained from either non-fluorinated or aromatic derivatives.

Four new cyclobutane-containing building blocks were synthesized on a multigram scale starting from 3-methylene-1-(trifluoromethyl)cyclobutane-1-carbonitrile and 3-methylene-1-(trifluoromethyl)cyclobutane-1-carboxylic acid. The synthesized compounds contain trifluoromethyl group near the functional one (carboxylic or amino group) and are promising for further application in drug discovery