Charting the Chemical Reaction Space around a Multicomponent Combination: Controlled Access to a Diverse Set of Biologically Relevant Scaffolds

Abstract

Charting the chemical reaction space around the combination of carbonyls, amines, and isocyanoacetates allows the description of new multicomponent processes leading to a variety of unsaturated imidazolone scaffolds. The resulting compounds display the chromophore of the green fluorescent protein and the core of the natural product coelenterazine. Despite the competitive nature of the pathways involved, general protocols provide selective access to the desired chemotypes. Moreover, we describe unprecedented reactivity at the C-2 position of the imidazolone core to directly afford C, S, and N-derivatives featuring natural products (e.g. leucettamines), potent kinase inhibitors, and fluorescent probes with suitable optical and biological profiles.

Keywords: Green Fluorescent Protein Chromophore; Heterocycles; Isocyanides; Multicomponent Reactions; Reaction Discovery.

Figure 1

Charting the chemical reaction space of an MCR to generate alternative scaffolds.

Scheme 1

A) MCR to yield 2‐imidazolines by Orru. B) 4‐Imidazolone synthesis by Zhu. C) Sequential synthesis of 4‐imidazolones by Bischoff. D) This work: charting of the chemical space around the interaction of carbonyls, amines, and isocyanoacetates.

Figure 2

A) Possible outcomes of the MCR between carbonyls, amines, and isocyanoacetates. B) Role of additives and solvents in the process and selected standard conditions. C) Scope of the MCR under the standard conditions [MCR; AgNO₃ (10 mol %); MeOH (0.2 M); rt for 17 h or 40 °C (μW) for 20 min]. D) Proposed reaction pathways and putative mechanisms.

Figure 3

Photocatalyzed dimerization of compounds 5 to give cyclobutanes 8.

Figure 4

MCR with 1,2‐diamines: access to analogues of the natural product coelenterazine. A) General reaction Scheme and structure of coelenterazine. B) Scope of the process. C) Isolated intermediates and conversion to the coelenterazine derivatives 9. D) Proposed reaction mechanism for the formation of adducts 9. E) The C−H activation reaction. F) Formation of bis‐imidazolone adduct 5‐bis‐a.^[a]Standard conditions: MCR; AgNO₃ (10 mol %); MeOH (0.2 M); rt for 17 h or 40 °C (μW) for 20 min.^[b]Unoptimized yield: the reaction was performed with a 1 : 1 : 1 ratio of reactants.

Figure 5

Addition of nucleophiles to the GFP core. A) New MCR with 1,3‐diaminopropane. B) Use of an excess of methylamine in the MCR. C) Examples derived from the new MCR‐oxidation process. D) Sequential protocol leading to adducts 12 and 13. E) Scope of the sequential protocol.^[a]Standard conditions: MCR; AgNO₃ (10 mol %); MeOH (0.2 M); rt for 17 h or 40 °C (μW) for 20 min.^[b]Unless otherwise stated, [o]=TEMPO.^[c]Yield calculated over 2 steps (MCR‐oxidation).

Figure 6

Photophysical studies. A) Normalized absorption spectra of compounds 5 i, 5 o′, 5 j, and 12 d in EtOH (100 μM). B) Emission spectra of 5 i and 12 d in EtOH (100 μM, λ _ext: 360 nm). C) Emission spectra of 12 d in increasing concentrations of phosphatidylcholine (PC)‐liposome in PBS (100 μM, λ _ext: 360 nm). D) Synthesis of probe 12 j and conjugation with biologically relevant carboxylic acids. E) Fluorescence images of MDA‐MB‐231 human cancer cells after incubation with compound 12 d (100 μM, 1 h, green) and DRAQ5 (red) as a nuclear counterstain. Scale bar: 10 μm.