Since the inception of sulfur-fluoride exchange (SuFEx) reactions through the works of the recently awarded two-time Nobel laureate in Chemistry, Sharpless, and his group, sulfur(VI) fluorides were found to have versatile properties and extensive applications in the chemical and medicinal sciences. Among the derivatives of sulfur(VI) fluorides, sulfamides were noted as the most difficult to synthesize via SuFEx reactions within the works of Ball and his group at Pomona College and also the least present in FDA-approved drugs due to the weakened electrophilicity of the sulfur atoms bonded to the respective nitrogen atoms. To circumvent the challenges of synthesizing sulfamides and identify untapped applications of the molecular motif, a chemoinformatics workflow is implemented to discover the chemical space of sulfamides and develop a model formed from computational works that predicts what kind of amines can react into sulfamides based on generalizable conditions of SuFEx reactions. To this end, a library consisting of primary and secondary amines was retrieved and filtered based on reactivity factors of SuFEx reactions and was analyzed computationally via multidimensional modeling, principal component analysis (PCA), and Mordred spaces to identify the synthetic accessibility, drug-likeness, physical-organic properties, and model of the amines in the library. In identifying the trends of reactive and non-reactive amines in the library, a series of experiments will be conducted to synthesize the sulfamides based on the general conditions outlined in Ball and his group and record not only the successful reactions of the experiment but also the failures. These results will be fed in to our computational analysis for machine learning and help hone in on the optimal conditions and substrate type necessary for the successful access to the chemical space of sulfamides. The end goal of the series of experiments is to access the chemical space of sulfamides and identify the ideal and non-ideal settings of the substrate scope and reactive conditions to form sulfamides; in reporting both the successful and failed reactions to synthesize sulfamides, later works on the reaction may refer to this work as a starting ground and develop further models to better discover the successful reactivities and therefore additional applications to the molecular motif, serving future scientific advances.

Developing computational models for the access of sulfamides via sulfur-fluoride exchange (SuFEx) reactions

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