trans -1,2-Disubstituted Cyclopropanes with CH 2 -Extended Functional Groups: Synthesis and Physicochemical Properties

An efficient multigram synthesis of trans -1,2-disubstituted cyclopropane derivatives bearing two functional groups (including fluoroalkyl substituents), with one or both of them attached to the ring through a CH 2 spacer, was developed. The strategy was based on a Michael-initiated ring closure reaction (MIRC), followed by functional group transformations to provide a series of over 70 structurally diverse building blocks, including free carboxylic acids, amines, and other synthetically relevant derivatives, on up to 370 g scale. The methodology also enabled the preparation of fluorinated derivatives bearing CH 2 CF 3 , CH 2 CHF 2 , and CH 2 CH 2 F substituents. The combined effect of fluorination and the CH 2 spacer on key physicochemical properties was investigated through acidity/basicity (p K a ) and lipophilicity (Log P ) measurements. It was found that insertion of the spacer between the fluoroalkyl group and the cyclopropane ring increased pKa by 0.5–0.7 units for the carboxylic acids and by 1.1–1.5 units for the protonated amines, whereas its contribution to lipophilicity was lower than expected from additivity. Enumeration of a virtual library based on the proposed building blocks allowed us to demonstrate their potential for lead-oriented synthesis in drug discovery.