Generation of multimillion chemical space based on the parallel Groebke-Blackburn-Bienaymé reaction

Evgen V Govor; Vasyl Naumchyk; Ihor Nestorak; Dmytro S Radchenko; Dmytro Dudenko; Yurii S Moroz; Olexiy D Kachkovsky; Oleksandr O Grygorenko

doi:10.3762/bjoc.20.143

Generation of multimillion chemical space based on the parallel Groebke-Blackburn-Bienaymé reaction

Beilstein J Org Chem. 2024 Jul 16:20:1604-1613. doi: 10.3762/bjoc.20.143. eCollection 2024.

Authors

Evgen V Govor^{1

2}, Vasyl Naumchyk^{1

2}, Ihor Nestorak^{1

3}, Dmytro S Radchenko¹, Dmytro Dudenko¹, Yurii S Moroz^{1

2}, Olexiy D Kachkovsky³, Oleksandr O Grygorenko^{1

2}

Affiliations

¹ Enamine Ltd., Winston Churchill Street 78, Kyїv 02094, Ukraine.
² Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyїv 01601, Ukraine.
³ V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, Akademik Kukhar Street 1, Kyїv 02094, Ukraine.

Abstract

Parallel Groebke-Blackburn-Bienaymé reaction was evaluated as a source of multimillion chemically accessible chemical space. Two most popular classical protocols involving the use of Sc(OTf)₃ and TsOH as the catalysts were tested on a broad substrate scope, and prevalence of the first method was clearly demonstrated. Furthermore, the scope and limitations of the procedure were established. A model 790-member library was obtained with 85% synthesis success rate. These results were used to generate a 271-Mln. readily accessible (REAL) heterocyclic chemical space mostly containing unique chemotypes, which was confirmed by comparative analysis with commercially available compound collections. Meanwhile, this chemical space contained 432 compounds that already showed biological activity according to the ChEMBL database.

Keywords: fused rings; heterocycles; imidazoles; isonitrile; multicomponent reactions.

Grants and funding

The work was funded by Enamine Ltd. and NIH (Grant No. GM133836 to Prof. John Irwin and Y.S.M.). O.O.G. was also funded by Ministry of Education and Science of Ukraine (Grant No. 0122U001962 (22BF037-02)).