Cyclobutane amino nitriles (CBANs), as a class of sterically hindered α,α- disubstituted unnatural amino acid derivatives, have attracted extensive attention in drug discovery. However, traditional synthetic strategies substantially restrict the exploration of CBANs' chemical space, especially for more sterically hindered vicinal tetrasubstituted derivatives.

In a new study published in NatureChemistry on June 1, a research team led by Prof. ZHANG Lumin from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences has developed a modular diastereoselective approach to constructing hindered cyclobutane amino nitriles through a triplet nitrene-mediated ring expansion reaction.

This transformation involves a triplet-nitrene enabled ring expansion of alkylidenecyclopropanes (ACPs) combined with a titanium (IV)-catalysed cyanylation step. Artful harnessing of the unique reactivity of triplet nitrene is the key to address the synthetic challenge. 2,2-Dialkyl-substituted alkylidenecyclopropanes (ACPs) were readily prepared from structurally diverse ketones via classical Wittig or Tebbe olefination, demonstrating the generality of this strategy.

The researchers used pyridin-1-yl(tosyl)amide (Py⁺NTs^-) as a less conventional nitrene precursor, tetrakis(9H-carbazol-9-yl) isophthalonitrile (4CzIPN) as an organic photocatalyst under visible light irradiation, in conjunction with titanium(IV) isopropoxide (Ti(Oi-Pr)₄) as a Lewis catalyst, trimethylsilyl cyanide (TMSCN) as a nitrile source, and dichloromethane (DCM) as a solvent, to obtain the desired CBANs.

Mechanistic experiments and density functional theory calculations revealed that Py⁺NTs^- forms a triplet nitrene under irradiation, and that the ACP is converted into the in situ generated cyclobutanimine intermediate via a diradical-mediated ring expansion pathway. This strategy demonstrates remarkable structural diversity and broad functional group compatibility.

In addition, the diverse applications of this strategy have been explored. The researchers devised a two-step synthetic route, aimed at incorporating their bioisostere fragment, 5-amino-2-azaspiro[3.3]heptane-5-carbonitriles, into complex bioactive molecules to expand the chemical space of this valuable drug fragment.

Besides forming the gem-NHTs-CN framework, the researchers examined the versatility of this diradical-mediated ring expansion gem-difunctionalization strategy using various functionalized pyridinium ylides as nitrene precursors. Furthermore, they constructed a versatile platform by trapping the in situ generated cyclobutanimines intermediate with a wide spectrum of nucleophiles, thereby enabling the generation of structurally diverse congested motifs.

The researchers believe that this strategy will significantly expand the available chemical space of sterically congested CBANs and its diverse applications, which will have both synthetic and mechanistic implications. More broadly, their diverse products, which feature hindered unnatural amino acid derivatives that are rigid, sp³-rich, and three-dimensional, will attract significant attention from medicinal chemists for drug discovery.