Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

Abstract

<p></p><p>We have discovered and studied a <i>tele</i>substitution reaction in a biologically important heterocyclic ring system. Conditions that favour the <i>tele</i>-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the <i>in vivo </i>active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium.</p> <p> </p> <p>Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link <a href="https://ses.library.usyd.edu.au/handle/2123/21890">https://ses.library.usyd.edu.au/handle/2123/21890</a> . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds. </p><br><p></p>

tele-Substitution Reactions in the Synthesis of a Promising Class of 1,2,4-Triazolo[4,3-a]pyrazine-Based Antimalarials

“…Under some circumstances, however, a leaving group may be displaced from an aromatic system by a nucleophile entering at a different position on the ring, for example, at the carbon adjacent to the leaving group ( cine -substitution) or even further away ( tele -substitution, Figure A). We report here our discovery, and mechanistic studies, of a tele -substitution reaction in a [1,2,4]­triazolo­[4,3- a ]­pyrazine system, which is at the core of a series of molecules with significant potential for the future treatment of malaria…”