Synthesis of a novel polycyclic ring scaffold with antimitotic properties via a selective domino Heck–Suzuki reaction† †Electronic supplementary information (ESI) available: Full experimental details, 1H and 13C NMR spectra and X-ray crystallographic data for compound 4d. CCDC 936207. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc02547d Click here for additional data file. Click here for additional data file

• Published in: Chemical science (Cambridge) 2014-09, Vol.6 (1), p.390-396
• Main Authors: Alza, Esther, Laraia, Luca, Ibbeson, Brett M., Collins, Súil, Galloway, Warren R. J. D., Stokes, Jamie E., Venkitaraman, Ashok R., Spring, David R.
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c4sc02547d

The synthesis of a previously undescribed sp 3 -rich 6-5-5-6 tetracyclic ring scaffold using a palladium catalysed domino Heck–Suzuki reaction is reported. The synthesis of a previously undescribed sp 3 -rich 6-5-5-6 tetracyclic ring scaffold using a palladium catalysed domino Heck–Suzuki reaction is reported. This reaction is high-yielding, selective for the domino process over the direct Suzuki reaction and tolerant towards a variety of boronic acids. The novel scaffold can also be accessed via domino Heck–Stille and radical cyclisations. Compounds based around this scaffold were found to be effective antimitotic agents in a human cancer cell line. Detailed phenotypic profiling showed that the compounds affected the congression of chromosomes to give mitotic arrest and apoptotic cell death. Thus, a novel structural class of antimitotic agents that does not disrupt the tubulin network has been identified.