Design and Synthesis of Conformationally Diverse Pyrimidine-Embedded Medium/Macro- and Bridged Cycles via Skeletal Transformation

The rigidity and flexibility of small molecules are complementary in 3-dimensional ligand-protein interaction. Therefore, the chemical library with conformational diversity would be a valuable resource for investigating the influence of skeletal flexibility on the biological system. In this regard, we designed and synthesized ten conformationally diverse pyrimidine-embedded medium/macro- and bridged cyclic scaffolds covering 7- to 14-member rings via an efficient skeletal transformation strategy. Their high conformational and shape diversity was confirmed by chemoinformatic analysis.


General synthetic procedure for the preparation of 1a-1b
Scheme S1. Synthetic scheme for starting tricycles 1a-1b.
To a solution of di-tert-butyl hydrazodicarboxylate in toluene/50% aq. NaOH=2:1 solution (0.1 M), tetraethylammonium bromide (TEAB, 0.15 equiv.) and alkyl dibromide (1.5 equiv.) were added at room temperature. The resulting mixture was vigorously stirred at 100 o C. After the completion of the reaction was checked by TLC, the resulting solution was quenched with deionized water and saturated aq. NaCl, and the organic material was extracted twice with ethyl acetate (EA). The combined organic extracts were dried over anhydrous Na2SO4(s) and filtered. After the solvent was evaporated under reduced pressure, the residue was purified by silica-gel flash column chromatography to obtain the desired Boc-protected cyclic hydrazines [82% (n=1) and 83% (n=2)]. The resulting Boc-protected cyclic hydrazines were dissolved in dichloromethane (DCM) and mixed with trifluoroacetic acid (TFA). The reaction mixture was stirred at room temperature. After the completion of the reaction was checked by TLC, the resulting solution was concentrated under reduced pressure to obtain the desired cyclic hydrazines (quantitative yields).
To a ethanol solution (0.1 M) of 4-chloro-6-(4-methoxybenzylamino)pyrimidine-5-carboxaldehyde that was prepared by using the reported synthetic procedure (Choi et al., 2015), cyclic hydrazines (1.1 equiv.) and triethylamine (TEA, 5 equiv.) were added at room temperature. The resulting mixture was stirred at 80 o C. After the complete consumption of pyrimidine was checked by TLC, the reaction mixture was cooled down to room temperature. Then, NaBH4 (3 equiv.) was added to the reaction mixture, and the resulting mixture was stirred at room temperature. When the completion of the reaction was checked by TLC, the resulting mixture was concentrated under reduced pressure, quenched with deionized water and saturated aq. NaCl, and the organic material was extracted three times with EA. The combined organic extracts were dried over anhydrous Na2SO4(s) and filtered. After the solvent was evaporated under reduced pressure, the residue was purified by silica-gel flash column chromatography to obtain the desired compounds 1a-1b.
To a solution of 2a-2d in ethanol (0.05 M), NaOEt (1.5 equiv.) and NaBH4 (20 equiv.) were added at room temperature. The resulting mixture was stirred at 60 °C. After the completion of the reaction was checked by TLC, the reaction mixture was concentrated under reduced pressure, quenched with deionized water and saturated aq. NaHCO3, and the organic material was extracted three times with ethyl acetate (EA). The combined organic extracts were dried over anhydrous Na2SO4(s) and filtered. After the solvent was evaporated under reduced pressure, the residue was purified by silica-gel flash column chromatography to obtain desired compounds 3a-3d.
To a solution of 3a-3d in ACN (0.05 M), benzyl bromide (1.10 equiv.) was added at room temperature with stirring. When the completion of the reaction was checked by TLC, the resulting mixture was concentrated under reduced pressure, quenched with deionized water and saturated aq. NaHCO3, and the organic material was extracted three times with EA and three times with DCM. The combined organic extracts were dried over anhydrous Na2SO4(s) and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica-gel flash column chromatography to obtain the desired compounds 3a′-3d′.

General synthetic procedure for the preparation of 4a-4d
Scheme S4. Synthetic scheme for bridged cycles 4a-4d.
3a′-3d′ were treated with HF/pyridine/tetrahydrofuran (5/5/90) solution (0.1 M), and the reaction mixture was stirred at room temperature. When the completion of the reaction was checked by TLC, ethoxytrimethylsilane was added and the reaction mixture was allowed to quench any excess HF. The resulting mixture was concentrated under reduced pressure. To a solution of the resulting residue in DCM (0.05 M) and TEA (2.0 equiv.), methanesulfonyl chloride (1.5 equiv.) were added at room temperature with stirring. When the completion of the reaction was checked by TLC, the resulting mixture was concentrated under reduced pressure. The residue and NaH (2.0 equiv.) were dissolved in dry DMF (0.05 M) under an argon atmosphere with stirring at room temperature. After the reaction completion monitored by TLC, the resulting mixture was quenched with deionized water and saturated aq. NaHCO3, and the organic material was extracted three times with EA and three times with DCM. The combined organic extracts were dried over anhydrous Na2SO4(s) and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica-gel flash column chromatography to obtain desired compounds 4a-4d.