Chemotherapeutic agents must be sufficiently aggressive to kill tumor cells, yet inactive against healthy cells. Among the few chemical classes that come close to these idealized agents are highly unsaturated hydrocarbons such as enyne-allenes. These 10 π electron polyunsaturated systems undergo easy (often spontaneous) cycloaromatization by converting two σ bonds into a π bond (the so-called Myers-Saito cyclization) to form a α,3-didehydrotoluene biradical (α,3-DHT, a σ,π-biradical). These radicals are known to be aggressive and able to abstract hydrogen atoms from deoxyribose residues in DNA, finally causing oxidative DNA cleavage and cell death.

This approach, however, requires a multistep synthesis of complex structures, which limits the overall viability. Furthermore the generation of DHTs from the Myers-Saito cyclization led exclusively to α,3-didehydrotoluenes. We recently developed a completely different approach that obtains the same DHT active intermediates by supplying a large amount of energy to a stable, easily synthesized compound, rather than from an unstable precursor obtained through an expensive synthesis. The breakthrough of our research is arriving to α,n-DHTs by two consecutive eliminations from a ring-substituted benzyl derivative (Ar-LG) via a phenyl cation intermediate. In the enyne-allene system, aromaticity is arrived at the same time as biradical formation, whereas our approach starts from an aromatic, and the required high energy activation is conveniently supplied by irradiation.The adoption of stable precursors broadens the field of accessible structures that can thus be tailor-made for specific actions and, furthermore, the photochemical activation has practical advantages in the application of the therapy.

Thus, Ar-LG is an aromatic compound having a leaving group (LG) and a -CH₂EG group (EG = an electrofugal group) that reacts under irradiation in solution. In the first step, a triplet phenyl cation (³Ar⁺) is generated by fragmentation of the triplet excited state of the aromatic (³Ar-LG) and in turn loses the EG group forming the desired (α,n-DHT).

Future developments

We are now planning to synthesize different DHT precursors, characterized by different LG and EG groups. Likewise we are exploring the effect of further functional groups conjugated with the aromatic core.

References

1. Protti, S.; Ravelli, D.; Mannucci, B.; Albini, A.; Fagnoni, M. “α,n-Didehydrotoluenes by Photoactivation of (Chlorobenzyl)trimethylsilanes: An Alternative to Enyne-Allenes Cyclization” Angew. Chem. Int. Ed. 2012, 51, 8577-8580. DOI: 10.1002/anie.201202794
2. Ravelli, D.; Protti, S.; Fagnoni, M.; Albini, A. “From Phenyl Chlorides to α,n-Didehydrotoluenes via Phenyl Cations. A CPCM–CASMP2 Investigation” J. Org. Chem. 2013, 78, 3814-3820. DOI: 10.1021/jo400269s