Practical Catalytic Asymmetric Synthesis of a Promising Drug Candidate

Abstract

Cellular glucose is mostly metabolized by the glycolytic pathway in vivo, and only a small amount of nonphosphorylated glucose enters into the polyol pathway, an alternative route of glucose metabolism [1]. The reduction of glucose to sorbitol is rate-determining step of the polyol pathway, which is catalyzed by aldose reductase [2]. Under hyperglycemic conditions, the increased flux of glucose enters into the polyol metabolic pathway [2], inducing various metabolic imbalances such as the accumulation of sorbitol and facilitated consumption of NADPH because of the enhanced activity of aldose reductase [3]. These imbalances eventually lead to the onset and progression of diabetic complications such as neuropathy, nephropathy, and vascular disorders. Therefore, the development of an aldose reductase inhibitor is important from the clinical aspect as diabetic disorders are a major health concern in the world [4]. Clinical development of aldose reductase inhibitors has suffered from side effects, however. AS-3201 (1: ranirestat) was identified as a spirosuccinimide-type aldose reductase inhibitor with remarkable efficacy and safety (Scheme 1) [5]. 1can be administered orally, and its clinical development (phase III in the United States and Canada) for the potential treatment of diabetic nephropathy is ongoing. Currently, inefficient optical resolution is required for asymmetric synthesis of 1, and the development of an efficient catalytic asymmetric synthesis of 1is a formidable task for future therapeutic development and efficient commercial production [5]. The key structural feature of 1is a tetra-substituted stereogenic center bearing nitrogen, and the construction of this chiral center via atom-economical and scalable catalytic asymmetric reaction would streamline the large-scale synthesis of 1. Toward this end, we have focused on the catalytic asymmetric amination of succinimide 2with azodicarboxylate to afford 3. Initial efforts have been devoted to catalytic asymmetric amination of β-ketoesters in the reaction with succinimide 2with known catalysts [6, 7], but none of the catalysts provided product 3with satisfactory enantioselectivity; this was likely the result of the unique chemical properties of succinimide substrate 2, which exhibits multiple coordination modes.