Wrecking Bonds

In the article by Kirti Devi, Asad Shehzad, and Mario P. Wiesenfeldt, the researchers tackle a significant challenge in drug design: converting benzene rings, which are common in many drugs, into more useful and stable compounds called cyclohexenes. Benzene rings are abundant but often limit the effectiveness and stability of drugs due to their aromatic nature. The goal is to reduce these benzene rings to cyclohexenes, which are more versatile and resistant to rearomatization, meaning they don't easily revert back to their original benzene form.

The researchers developed a new method to achieve this reduction using a process called organophotocatalytic reduction. This involves creating a special complex called an electron-donor-acceptor (EDA) complex, which is excited by light. This complex facilitates a mild reduction of the benzene ring without damaging other sensitive groups present in the molecule. A key component of this process is the use of a dihydrobenzimidazole (DHBI) thiophenolate as the donor, which helps in stabilizing the intermediate radicals and preventing unwanted back reactions. Additionally, an oxidized thioquinone methide plays a crucial role in isomerizing the intermediate cyclohexadienes into more stable and reducible forms.

The new method is significant because it can tolerate a wide range of functional groups and heteroarenes commonly found in drugs, which previous methods could not. This makes it highly applicable for late-stage modifications in drug synthesis, allowing for the creation of diverse libraries of C(sp3)-rich compounds. The reaction conditions are optimized using Rongalite as a terminal reductant, and the resulting cyclohexenes are produced in high yields and with good regioselectivity. This work opens up new avenues for medicinal chemists to design more effective and stable drugs by converting readily available benzene rings into valuable cyclohexene motifs.