Schaap’s dioxetanes

In the late 1980s, A. Paul Schaap and co-workers at Wayne State University (Detroit) reported the synthesis of dioxetane derivatives that trigger bright chemiluminescence when activated by alkaline phosphatase enzymes (see image). These compounds came to be known as “Schaap’s dioxetanes”.

One of Schaap’s compounds, 3-(2′-spiroadamantane)-4-methoxy-4-(3″-phosphoryloxy)phenyl-1,2-dioxetane¹—known as PPD marketed by Lumigen² (Southfield, MI)—is of particular interest. It is stable at ambient temperature; and in 1989, Schaap*, Hashem Akhavan, and Louis J. Romano reported that it is suitable for ultrasensitive enzyme-linked immunoassays and DNA probes. The same year, Irena Bronstein and co-workers at Tropix³ (Bedford, MA) described its use in immunoassays of the thyroid-stimulating hormone thyrotropin. Typically, PPD’s more stable disodium salt is used in immunoassays rather than the free acid.

PPD is used in more than 2 billion chemiluminescent immunoassays per year for clinical diagnosis, food safety, pharmaceutical analysis, and environmental monitoring. In 2018, Roland Lindh at Uppsala University (Sweden) and Harvard University (Cambridge, MA) and coauthors around the world wrote a comprehensive review of the chemiluminescence and bioluminescence of cyclic peroxides, including Schaap’s dioxetanes. The following year, Nir Hananya and Doron Shabat*⁴ at Tel Aviv University reported that adding an electron-withdrawing group to one of the dioxetanes increased its chemiluminescence quantum yield by 3000-fold.

1. SciFinder: phenol, 3-(4-methoxyspiro[1,2-dioxetane-3,2′-tricyclo[3.3.1.13,7]decan]-4-yl)-, 1-(dihydrogen phosphate).
2. Now part of Beckman Coulter (Brea, CA).
3. Now part of PerkinElmer (Waltham, MA).
4. Shabat was one of the early coiners of “Schaap’s dioxetanes”.