Chemo- and Stereoselective Alpha-Sulfurylation of Amides

The late-stage functionalization of small molecules aiming for the formation of bioactive compounds has become an increasingly valuable tool in modern drug discovery. Despite the high abundance of the amide motif in pharmaceuticals, the modification of peptide bonds in the presence of other chemically related moieties is rather challenging, limiting the scope of chemical reagents. For this purpose, a general chemo- and stereoselective a-sulfurylation of amides is proposed, which allows the step-economical formation of a central subclass of small molecules with expected bioactive potency under essentially neutral conditions. Based on an intramolecular rearrangement as key transformation with the possibility for the installation of different sulfur-substituents, this strategy will not only overcome the limitations of other methods, but also enlarges the diversity of modifications by another important factor.

New methods for the introduction of carbon-sulfur bonds are of interest in the synthesis and diversification of bioactive compounds for the pharmaceutical industry. Throughout April 2020, the "U.S. Food and Drug Administration" (FDA) has approved over 250 structures with carbon-sulfur bonds for the treatment of human ailments.[1-3] From a synthetic standpoint, it is desirable to diversify molecules as late as possible. This so-called "late-stage functionalization" is seeking methods that allow the selective modification of the structural pattern of a molecule in the presence of others. On the one hand, this strategy allows a quicker formation of compound libraries, from which molecules can be tested on their bioactivity towards enzymes and receptors. On the other hand, the production process of selected compounds can be shortened. Considering this postdoctoral research stay, we developed a novel method to introduce carbon-sulfur bonds in the vicinity to a peptide bond under transition metal-free conditions. Characteristic for this method is a chemically selective peptide bond activation in connection with a charge-accelerated functionalization. Moreover, partial reaction steps can be controlled via the temperature profile of this modification. This method does not only overcome limitations of other functionalizations but also expands the diversity of modifications by another important factor.[4] In conclusion, the complemental and selective character of this method shares the potential to transfer this strategy to other chemically related groups to explore novel reactivities. The results of these studies will deliver significant contributions towards transitions metal-free "late-stage functionalization" of critical functional groups in pharmaceutical chemistry, and will also provide a more direct access for fine chemical synthesis. [1] (a) Scott, K. A.; Njardarson, J. T. Top. Curr. Chem. 2018, 376, 1-34. (b) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem. 2014, 57, 2832-2842. (c) Center for Drug Evaluation and Research. Orange book: Approved drug products with therapeutic equivalence evaluations, 40th ed.; U.S. Dept. of Health and Human Services: Rockville, Md., 2020. [2] Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Curr. Top. Med. Chem. 2016, 16, 1200-1216. [3] For recent reviews on strategies for carbon-sulfur bond formation, see: (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596-1636. (b) Eichman, C. C.; Stambuli, J. P. Molecules 2011, 16, 590-608. (c) Chauhan, P.; Mahajan, S.; Enders, D. Chem. Rev. 2014, 114, 8807-8864. (d) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem. Soc. Rev. 2015, 44, 291-314. (e) Wimmer, A.; König, B. Beilstein J. Org. Chem. 2018, 14, 54-83. [4] Leypold, M.; D'Angelo, K. A.; Movassaghi, M. ChemRxiv 2020, Preprint. https://doi.org/10.26434/chemrxiv.12755879.v1.