Intramolecular Diaza‐Diels–Alder Protocol: A New Diastereoselective and Modular One‐Step Synthesis of Constrained Polycyclic Frameworks. Issue 17 (17th February 2017)

• Record Type: Journal Article
• Authors: Srinivasulu, Vunnam; Reddy, Amarnath; Mazitschek, Ralph; Lukens, Amanda K.; Wirth, Dyann F.; Li, Liang; Naumov, Panče; O'Connor, Matthew John; Al‐Tel, Taleb H.
• Is Part Of: Chemistry. Volume 23:Issue 17(2017)
• Page Start: 4137
• Page End: 4148
• Publication Date: 2017-02-17
• Subjects: antimalarial activity -- cycloaddition -- polycycles -- structure–activity relationships -- synthesis design; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201605231
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Phenotype‐based screening of diverse compound collections generated by privileged substructure‐based diversity‐oriented synthesis (pDOS) is considered one of the prominent approaches in the discovery of novel drug leads. However, one key challenge that remains is the development of efficient and modular synthetic routes toward the facile access of privileged small‐molecule libraries with skeletal and stereochemical complexity and drug‐like properties. In this regard, a novel and diverse one‐pot procedure for the diastereoselective synthesis of privileged polycyclic benzopyrans and benzoxepines is described herein. These unexplored chemotypes were accessed by utilizing an acid‐mediated diaza‐Diels–Alder reaction of 2‐allyloxy‐ and/or homoallyloxy benzaldehyde with 2‐aminoazine building blocks. Profiling of representative analogues against blood‐stage Plasmodium falciparum parasites identified three lead candidates with low micromolar antimalarial activity. Abstract : Privileged process : A one‐step protocol for the diastereoselective synthesis of privileged polycyclic benzopyrans and benzoxepines is described. These unexplored chemotypes were accessed by utilizing an acid‐mediated diaza‐Diels–Alder reaction of 2‐allyloxy‐ and/or homoallyloxy benzaldehyde with 2‐aminoazine building blocks (see scheme; TFA=trifluoroacetic acid, IM=intramolecular, Boc= tert ‐butyloxycarbonyl).