Piperazines are among the most common structures found in modern-day drug compounds. They are found in the anti-histamine, Citizirine, which is used to treat hay fever, and Indinavir, one of the first antiretroviral therapies developed to combat HIV/AIDS.
However, there has been a major bottleneck in the development of new piperazine drugs. Piperazines with groups attached to the carbon backbone, rather than nitrogen atoms, are particularly challenging to synthesise in a laboratory.
To address this key limitation, PhD student James Firth in York’s Department of Chemistry developed a new method for the functionalisation of the piperazine structure so it can be chemically modified at will.
Funded by the Engineering and Physical Sciences Research Council (EPSRC) in collaboration with pharmaceutical company AstraZeneca, the project utilised organolithium chemistry and involved an in-depth mechanistic study of the reaction pathway, including the use of infra-red spectroscopy.
Ultimately, an efficient method was optimised and proven to work in a formal synthesis of Indinavir.
Professor Peter O’Brien, supervior of James Firth’s project, in the Department of Chemistry, said: “Our new approach simplifies the synthesis of single enantiomers of substituted piperazines and this could find numerous applications in the pharmaceutical industry.
“It should be stressed that only a blue-sky fundamental mechanistic study coupled with James’ tenacity and creativity allowed the development of this new practical synthetic method.”
The research is published in the Journal of the American Chemical Society.
- Synthesis of Enantiopure Piperazines via Asymmetric Lithiation–Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent by James D. Firth, Peter O’Brien, and Leigh Ferris can be read here: http://pubs.acs.org/doi/abs/10.1021/jacs.5b11288
- For more information about the Department of Chemistry at the University of York, visit: http://www.york.ac.uk/chemistry/