Intramolecular Diaza-Diels–Alder Protocol: A New Diastereoselective and Modular One-Step Synthesis of Constrained Polycyclic Frameworks

Vunnam Srinivasulu, Amarnath Reddy, Ralph Mazitschek, Amanda K. Lukens, Dyann F. Wirth, Liang Li, Pance Naumov, Matthew O'Connor, Taleb H. Al-Tel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4137-4148
Number of pages12
JournalChemistry - A European Journal
Volume23
Issue number17
DOIs
StatePublished - Jan 1 2017

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Keywords

  • antimalarial activity
  • cycloaddition
  • polycycles
  • structure–activity relationships
  • synthesis design

ASJC Scopus subject areas

  • Chemistry(all)

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