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

Abstract

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.

Ring Opening of Donor–Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N‐Heterocycles

“…In terms of bioactivities, spirooxindole‐3,3′‐pyrrolidin‐2‐one derivatives were shown to be efficient antagonists of the CRTH2 (DP2) receptor, with the corresponding K i values at the nanomolar level 43. They also demonstrate moderate cytotoxicity against selected cancer cells 44. Moreover, the ability of the pyrrolidone moiety to undergo selective reduction45 as well as the tendency of the NH 2 group to undergo easy substitution by H or various functional groups through diazonium salt formation enables compound 13 to be transformed into more complex structures of biological relevance 46…”

Partially Saturated Bicyclic Heteroaromatics as an sp3‐Enriched Fragment Collection

“…Examples of previous studies aiming to synthesize collections of sp 3 ‐enriched fragments have been limited. Diversity‐oriented synthesis and natural product derivatives have been used to generate 3D fragment collections, but there remains an unmet need to access new scaffold types. Recently there have been calls for new approaches and methodologies for designing fragments with multiple synthetically accessible growth vectors in three dimensions, to allow rapid and efficient elaboration of hits to leads after initial screening, with some early success …”

Diversity-Oriented Asymmetric Synthesis

“…They described a reagent-based DOS to afford spirocyclic and fused heterocyclic ring systems. 10,28,29 This strategy afforded biologically relevant molecular scaffolds such as cyclotryptamines, spirooxoindolones, tetrahydroquinolines, spiroindolanes and fused N-heterocycles. 30 The two-step sequence starts with bicy-…”