title: A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine.
abstract: Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated.
authors.affiliation: Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: J J
authors.initials: JJ
authors.lastname: Ciardiello
authors.affiliation: Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: H L
authors.initials: HL
authors.lastname: Stewart
authors.affiliation: Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: H F
authors.initials: HF
authors.lastname: Sore
authors.affiliation: Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: W R J D
authors.initials: WRJD
authors.lastname: Galloway
authors.affiliation: Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom. Electronic address: spring@ch.cam.ac.uk.
authors.forename: D R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D011803:Quinine / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D047028:Macrocyclic Compounds; D011803:Quinine
keywords: Chemical space; Complexity-to-diversity; Diversity-oriented synthesis; Library synthesis; Macrocycles; Natural products; Scaffold