Benchtop nuclear magnetic resonance (NMR) spectroscopy has enabled the monitoring and optimization of chemical transformations while simultaneously providing kinetic, mechanistic, and structural insight into reaction pathways, with quantitative precision. The complementary application of benchtop NMR in the synthesis of fluorinated chemical entities has drawn significant interest from medicinal chemists since fluorinated motifs can also significantly alter the biological profiles of drugs, improving their pharmacokinetic properties. In this study, <sup>19</sup>F NMR spectroscopy was utilized to monitor the synthesis of novel trifluorinated analogs of monastrol, an antiproliferative small molecule kinesin Eg5 inhibitor, and to probe the mechanism of the Biginelli cyclocondensation, the multicomponent reaction used to synthesize dihydropyrimidine and related scaffolds. After isolating a trifluorinated hexahydropyrimidine product that did not dehydrate through the Biginelli cyclocondensation, we performed this final dehydration step, and optimized dehydration conditions, to obtain 6-trifluoromonastrol. This workflow was also applied to the synthesis of a trifluorinated analog of LaSOM 63, a compound previously reported to induce apoptotic cell death through the inhibition of ecto-5’nucleotidase activity. To further our studies, we used computational approaches to model the energetic pathways for the final dehydration in the formation of monastrol, LaSOM 63, and their respective trifluorinated analogs. Here, we present discoveries regarding the fluorination of both monastrol and LaSOM 63, while applying benchtop <sup>19</sup>F NMR spectroscopy to analyze their reaction kinetics.

Benchtop nuclear magnetic resonance (NMR) spectroscopy enables the discovery and optimization of novel trifluorinated 2,4-dihydropyrimidine compounds as novel antiproliferative agents

ACS Fall 2021

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