Internationale Ausgabe: DOI: 10.1002/anie.201608758 Drug Discovery Deutsche Ausgabe: DOI: 10.1002/ange.201608758 Palladium-Catalyzed Arylation of Carbasugars Enables the Discovery of Potent and Selective SGLT2 Inhibitors Wai-Lung Ng, Kit-Man Lau, Clara B.-S. Lau, and Tony K. M. Shing* Dedicated to Professor Stephen L. Buchwald Abstract: Selective inhibition of the transporter protein sodium-glucose cotransporter 2 (SGLT2) has emerged as a promising way to control blood glucose level in diabetes patients. Reported herein is a short and convergent synthetic route towards some small-molecule SGLT2 inhibitors by a chemo- and diastereospecific palladium-catalyzed arylation reaction. This synthetic strategy enabled the discovery of two highly selective and potent SGLT2 inhibitors, thereby paving the way towards the development of carbasugar SGLT2 inhibitors as potential antidiabetic/antitumor agents. Palladium-catalyzed C À N coupling reactions have been used extensively in the synthesis of many important pharma- ceuticals. [1] It serves as a powerful method to synthesize amines which are not readily accessible by traditional synthetic transformations. Amino-carbasugars are biological- ly important compounds. For example, valienamine and acarbose were shown to exhibit strong glycosidase inhibitory activities. [2] Despite their biological importance, their synthe- ses remain challenging and are usually lengthy. The synthetic hurdle has prevented amino-carbasugars from being devel- oped into valuable drug candidates. Recently, we discovered a potent and selective inhibitor of the transporter protein sodium-glucose cotransporter 2 (SGLT2; [3] Figure 1, compound 4). It is a carbasugar which contains a metabolically stable C ÀO bond. We postulate that the syntheses of their aza-analogues (e.g. amino-carbasugars 5 and 6) could provide important insights into the structure– activity relationship (SAR) of these inhibitors, [4] thereby aiding the development of carbasugar SGLT2 inhibitors as antidiabetic [5] and antitumor [6] agents. The targeted amino- carbasugars 5 and 6, the carbocyclic analogues of sergliflozin (1) and dapagliflozin (2), contain a C ÀN bond which is not easily accessible by traditional synthetic transformations (Figure 1). Thus, palladium-catalyzed arylation is ideal for such a challenging transformation (Figure 2). The b-hydride elimination of the [L n Pd(NHAlkyl)Ar] intermediate is a potential complication which may lead to the epimerization at C1 on the carbasugar core (Figure 2, pathway V). However, we envisioned that, with judicious choice of ligand and reaction conditions, the undesired b-hydride elimination pathway could be suppressed. Figure 1. Retrosynthetic analysis of the two representative amino- carbasugars 5 and 6. Figure 2. Mechanism of palladium-catalyzed arylation of a polyhydroxyl- ated amino-carbasugar and potential complication by b-hydride elimi- nation. [*] Dr. W.-L. Ng, Prof. Dr. T. K. M. Shing Department of Chemistry, The Chinese University of Hong Kong Shatin, New Territories, Hong Kong SAR (China) E-mail: tonyshing@cuhk.edu.hk Dr. W.-L. Ng Department of Chemistry, Massachusetts Institute of Technology Cambridge, Massachusetts 02139 (USA) K.-M. Lau, Prof. Dr. C. B.-S. Lau Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China The Chinese University of Hong Kong Shatin, New Territories, Hong Kong SAR (China) Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.doi.org/10. 1002/anie.201608758. A ngewandte Chemi e Zuschriften 1 Angew. Chem. 2016, 128,1–5  2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Ü Ü