Synthesis of orthogonally protected 1-methylcyclobutane-1,3-diamines | Poster Board #3423

Conformationally limited moieties, especially small rings, are common motifs in drug discovery. Introduction of the methyl substituent to biologically active molecules tends to change their properties drastically; “magic methyl” effect has been reported recently. Hereby, we combined these two concept performing syntheses of conformationally limited 1,3-cyclobutane 1,3-diamines having a methyl group installed. Diagonal protection of the amino groups enables further chemoselective modifications. The substances were obtained as single diastereomers; relative configuration of the products was confirmed by NOE experiments.
The reaction sequence requires available starting materials and consists of easily performable steps. The procedure was scaled up to yield 30 g of the desired amines in a single run.
To prove the concept, we obtained methylated Abrocitinib analogues and compared their physicochemical and biochemical properties.