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

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.

Scheme 1

Groebke–Blackburn–Bienaymé (GBB) reaction.

Figure 1

Marketed drugs comprising imidazo[1,2-a]azine scaffolds.

Figure 2

Yields of library members 4 synthesized using both Sc(OTf)₃ and TsOH as the catalysts.

Figure 3

Amino heterocycles 1{1–27} demonstrating poor performance in the parallel GBB reaction.

Figure 4

(Hetero)aromatic aldehydes 2{1–6} illustrating electronic and steric effects on the parallel GBB reaction.

Scheme 2

A) Parallel GBB reaction and B) examples of library members 4 obtained (relative configurations are shown).

Figure 5

Physicochemical properties of the chemical space of 271 Mln. members obtained by virtual GBB reaction (MW – molecular weight; HAcc/HDon – H-bond acceptor/donor count; F(sp³) – fraction of sp³-hybrid carbon atoms; RotB – rotatable bond count); compounds complying with specific Lipinski/Veber rules (MW ≤ 500, log P ≤ 5, HDon ≤ 5, HAcc ≤ 10, RotB ≤ 10 [38,41]) as well as compounds with F(sp³) > 0.5 are highlighted in blue, the rest of the compounds are shown in yellow.

Figure 6

Distribution of maximal values among pairwise-calculated Tanimoto similarities T (MFP2 fingerprints [46]) of extended Bemis–Murcko scaffolds for the generated chemical space members (5.60 Mln. scaffolds) to the extended Bemis–Murcko scaffolds of A) ChEMBL compounds (v. 33); B) PubChem compounds (due to the large size of the dataset, a preliminary clusterization was performed to achieve ca. 5-fold size reduction); C) ZINC15 drug-like compounds, and D) enamine’s stock screening collection. Average T values are shown by dotted lines.

Figure 7

t-Distributed stochastic neighbor embedding (t-SNE) comparative analysis of 50,000 randomly selected molecules picked from the generated chemical space and A) ChEMBL compounds; B) PubChem compounds; C) ZINC15 compounds; and D) enamine’s stock screening collection.

Figure 8

Some biologically active representatives of the generated GBB chemical space found in the ChEMBL database.