Predicting Regioselectivity in Nucleophilic Aromatic Substitution

We have investigated practical and computationally efficient methods for the quantitative prediction of regioisomer distribution in kinetically controlled nucleophilic aromatic substitution reactions. One of the methods is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. We show that predictions from this method can be used quantitatively both for anionic nucleophiles with F^– as leaving group, as well as for neutral nucleophiles with HF as leaving group. The σ-complex approach failed when the leaving group was Cl/HCl or Br/HBr, both for anionic and neutral nucleophiles, because of difficulties in finding relevant σ-complex structures. An approach where we assumed a concerted substitution step and used such transition state structures gave quantitatively useful results. Our results are consistent with other theoretical works, where a stable σ-complex has been identified in some cases, whereas others have been indicated to proceed via a concerted substitution step

Route Design in the 21st Century: The IC<i>SYNTH</i> Software Tool as an Idea Generator for Synthesis Prediction

The new computer-aided synthesis design tool IC<i>SYNTH</i> has been evaluated by comparing its performance in predicting new ideas for route design to that of historical brainstorm results on a series of commercial pharmaceutical targets, as well as literature data. Examples of its output as an idea generator are described, and the conclusion is that it adds appreciable value to the performance of the professional drug research and development chemist team

Substituted 7‑Amino-5-thio-thiazolo[4,5‑<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX₃CR1)

We have developed two parallel series, A and B, of CX₃CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo­[4,5-<i>d</i>]­pyrimidine core structure, we were able to achieve compounds with high selectivity for CX₃CR1 over the closely related CXCR2 receptor. The structure–activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds <b>18a</b> and <b>24h</b>. We show the preparation of the first potent and selective orally available CX₃CR1 antagonists