Expeditious Assembly of a 2‐Amino‐4H‐chromene Skeleton by Using an Enantioselective Mannich Intramolecular Ring Cyclization–Tautomerization Cascade Sequence

Abstract

The concept of a “privileged medicinal scaffold” has emerged as one of the most guiding principles in the process of drug discovery. The privileged scaffold commonly consists of a rigid hetero-ring system that assigns a well-defined orientation of appended functionalities for target recognition. In the light of this, the accessibility of convenient methods for the diversification of privileged scaffold functionalities impacts on the success in seeking potential drugs. Undoubtedly, the discovery of novel synthetic methodologies to facilitate the preparation of compound libraries is a pivotal focal point in modern medicinal chemistry. Chromene, as one of the privileged scaffolds, often appears as an important structural component in both biologically active and natural compounds. It has widely appeared in natural alkaloids, tocopherols, flavonoids, and anthocyanins. Moreover, in recent years functionalized chromenes have played an ever-increasing role in the field of synthetic and medicinal chemistry. Among the diverse chromene systems, 2-amino-4H-chromenes are particularly privileged medicinal scaffolds for the generation of small-moleculebased ligands with highly pronounced spasmolytic, diuretic, anticoagulant, and antianaphylactic activities. In particular, the current interest in 2-amino-4H-chromene derivatives with a nitrile functionality arises from their potential application in the treatment of human inflammatory tumor necrosis factor (TNF)a-mediated diseases, such as rheumatoid and psoriatic arthritis. The corresponding cyano-functionalized benzopyranopyridine (inhibitor of MK-2) originating from the 2-amino-4Hchromene scaffold was found to inhibit mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK-2) and suppress the expression of TNFa in U937 cells. In the case of cancer therapy, the tumor antagonist HA14-1 and a family of related alkyl (4H-chromen-4-yl)cyanoacetates are a new class of small molecules that exhibit a binding activity for the surface pocket of the cancer-implicated Bcl-2 protein and induce apoptosis or programmed cell death in follicular lymphoma B cells and leukemia HL-60 cells. The 2amino-3-cyano-4H-chromene MX58151, with a 3-bromo-4,5dimethoxyphenyl substituent at the 4-position, represents a promising class of proapoptotic small-molecule agents with multiple action modes against the breast cancer cell line T47D, the lung cancer cell line H1299, and the colorectal cancer cell line DLD-1. It induces caspase-mediated apoptosis in tumor cells and is about as potent as or slightly more potent than the commonly prescribed anticancer alkaloids Vinblastine and Paclitaxel in the caspase activation assay. Furthermore, compound MX58151 might have an advantage for the treatment of the drug-resistant cancers as it retains activity in tumor cells resistant towards current antimitotic agents, taxanes (including Taxol and Taxotere), and the Vinca alkaloids. The inhibition of tubuline polymerization and disruption of preformed endothelial cell capillary tubules constitute other significant activities of 2-amino-3cyano-4-aryl-4H-chromenes of type 3 that can place them in the row of effective anticancer therapeutics with an analogous mode of action. Most recently, another 2-amino-4aryl-4H-chromene compound (IRSP inhibitor) has been discovered as an insulin-regulated aminopeptidase inhibitor. In particular, this inhibitor is maybe useful in therapeutic application including enhancing memory and learning functions. In view of the significance of this framework, efficient syntheses of 2-amino-4H-chromenes are of great interest. [a] Q. Ren, W.-Y. Siau, Prof. Dr. J. Wang Department of Chemistry, National University of Singapore 3 Science Drive 3, Singapore 117543 Fax: (+65)6516-1691 E-mail : chmwangj@nus.edu.sg [b] Prof. Dr. Z. Du, Prof. Dr. K. Zhang Faculty of Engineering and Light Industry Guang Dong University of Technology Guang Dong, 510006 (P.R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100927.