Editorial: Heterodienes in organic synthesis

methionine-containing peptides


Introduction
Vinylogous systems have always been in focus of organic chemists due to their unique reactivity, structure, and synthetic application (Curti et al., 2020).Heterodienes are among the most simple and valuable vinylogous systems in organic chemistry.The presence of heteroatoms in the conjugated diene induces specific polarization of the π-system leading to versatile reactivity patterns (Lopes et al., 2018).
The Frontiers Research Topic "Heterodienes in Organic Synthesis" comprises a Research Topic of original research articles dealing with the chemistry and applications of heterodienes.This Research Topic consists of four articles, which reflect on modern trends in the synthetic chemistry of the azoalkenes, nitrosoalkenes, as well as α,βunsaturated carbonyl compounds and imines.

Stability of heterodienes
Heterodienes are known to be reactive and chemically labile species.Thus, azoalkenes and nitrosoalkenes, unless stabilized with bulky or strong EWG groups, are prone to dimerization and polymerization reactions.These heterodienes are generated in situ from the corresponding stable precursors (α-halohydrazones, α-halooximes and their silyl ethers, ene-nitroso acetals, Figure 1C).In contrast, conjugated nitroalkenes are normally bench-stable, yet highly reactive heterodienes.Michael addition to nitroalkenes affords βfunctionalized nitro derivatives that can be further transformed into amines (via reduction of NO 2 group), carbonyls (via Nef reaction), oximes (via interrupted Nef and Meyer reactions), and other useful products (Ballini et al., 2007;Sukhorukov, 2023).Nitroalkenes are recognized for their stability and versatile chemistry, making them essential building blocks in organic synthesis along with enones (Halimehjani et al., 2014).

Heterodienes in biosynthesis
Apart from organic synthesis, heterodienes play a crucial role in the fields of biochemistry and biotechnology, with continuously expanding applications.Recent research on the biosynthesis of natural compounds has shown that Nature extensively exploits the versatile chemistry of heterodienes.The biosynthetic machinery utilizes the conjugate addition of enolate-type nucleophiles to α,β-unsaturated carbonyl compounds to synthesize structurally diverse natural products, for example, polyketides (Miyanaga, 2019).More surprisingly, the hetero-Diels-Alder reaction of unstable ortho-quinone methides (o-QMs) catalyzed by specific enzymes (in particular, hetero-Diels-Alderases) was recently discovered to be a key stage in the biosynthesis of cannabinoids (Purdy et al., 2022) and some sesquiterpenes (Chen et al., 2019) (Figure 1D).Heterodiene chemistry offers extensive possibilities for bioconjugation via fast and catalyst-free "click"-like reactions compatible with in vivo conditions, for example, [4 + 2]cycloaddition of 1,2,4,5-tetrazines (s-tetrazines) (Oliveira et al., 2017;Zare et al., 2022).Moreover, a reversible character of the Michael addition to heterodienes has been utilized to design "clip" reactions for controllable reversible bioconjugation chemistry (Diehl et al., 2016) (Figure 1E).

Azoalkenes
Conjugated azoalkenes are highly promising intermediates in organic synthesis since they are synthetic equivalents of enolonium cation (reversely polarized synthon to enolate anion) (Attanasi et al., 2009;Uteuliyev et al., 2015).Being powerful Michael acceptors, azoalkenes react with a variety of nucleophiles leading to αsubstituted hydrazones that can be further hydrolyzed to ketones.However, the use of P-nucleophiles in these reactions is very limited.The report by Alexey Sukhorukov et al. describes a convenient protocol for the Michael addition of phosphine oxides R 2 P(O)H to the in situgenerated azoalkenes.The developed method provides a convenient route to β-hydrazonophosphine oxides that are precursors to important organophosphorus compounds, including phosphorylated N-heterocycles, α-aminophosphonates, and vinylphosphonates.

Other heterodienes
Multi-component one-pot reactions using heterodienes are currently undergoing significant development.In this Research Topic, Yue Zhang et al. report new photocatalytic trichloromethyl radical-triggered annulative reactions of amide-linked 1,7-diynes with polyhalomethanes.This process involves a cascade of Kharasch-type addition/nucleophilic substitution/elimination reactions leading to densely substituted polyhalogenated quinolin-2(1H)-one derivatives.In another report in this field, Fabiana Nador et al. developed a Cucatalyzed A3-type coupling between pyridine-2-carbaldehyde, an aromatic alkyne, and a substituted tetrahydroisoquinoline to give new indolizine-dihydroisoquinoline hybrid dyes.The obtained products exhibit pH-dependent changes in the UV-Vis spectra and color which makes them attractive candidates to use as pH indicators.

Conclusion
The cutting-edge research articles published in this Frontiers Research Topic highlight that the chemistry of heterodienes continues to be an exciting and challenging research area, in which many more discoveries will be made.