Reagent-Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic- and Fused Heterocyclic Ring Systems

• Published in: Chemistry, an Asian journal an Asian journal, 2012-10, Vol.7 (10), p.2351-2360
• Main Authors: Damerla, V. Surendra Babu, Tulluri, Chiranjeevi, Gundla, Rambabu, Naviri, Lava, Adepally, Uma, Iyer, Pravin S., Murthy, Y. L. N., Prabhakar, Nampally, Sen, Subhabrata
• Format: Article
• Language: English
• Subjects: bicyclic compounds; biological activity; Bridged Bicyclo Compounds - chemistry; Chemistry; Crystallography, X-Ray; Cyclization; fused-ring systems; Heterocyclic Compounds - chemistry; lactams; Lactams - chemistry; Molecular Conformation; spiro compounds; Spiro Compounds - chemistry; Static Electricity; Stereoisomerism
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201200385

Herein, we report a diversity‐oriented‐synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N‐heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N‐heterocycles. The two‐step sequence starts with a chiral‐bicyclic‐lactam‐directed enolate‐addition/substitution step. This step is followed by a ring‐closure onto the built‐in scaffold electrophile, thereby leading to stereoselective carbocycle‐ and spirocycle‐formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug‐like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell‐lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry. Uno, DOS, tres: An enolate‐mediated strategy was used to synthesize biologically relevant cyclic scaffolds. In silico analysis was used to evaluate the compounds in terms of, for example, polar surface area and chemical diversity.