LATE-STAGE · Palladium catalyzed C(sp3)‒H late-stage diversification of biologically active molecules
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-03-01 → 2018-02-28
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Palladium catalyzed C(sp3)‒H late-stage diversification of biologically active molecules
Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods that enable the functionalization of bioactive compounds are surprisingly limited, and so the development of directed catalytic methods remains an important challenge. This project entailed the development of novel palladium-catalyzed C–H methodologies to introduce functionalizations on simple aliphatic amines and the application of these new methods on more complex and important bioactive molecules. In the first year, a method for the C-H carbonylation of methylene beta C-H bonds in secondary aliphatic amines to form trans-disubstituted β-lactams was successfully developed and applied to drug analogues as a β-adrenergic antagonist (also known as β blocker) Propanolol. In the second year, a Pd(II)-catalyzed γ-C–H amination process was developed, in which a series of cyclic secondary alkyl amines are converted into highly substituted chiral drug-like azetidines. The novel chiral azetidine derivatives are currently under biological evaluation.
Data: CORDIS, © European Union
Project objective
Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods that allow their late-stage functionalization directly on the bioactive compound is surprisingly limited, and so the development of directed catalytic methods remains an important challenge. Metal catalysed C–H activation represents a versatile tool for late-stage functionalization. It mostly relies on directing functional groups to functionalize C–H bonds. Recently, Professor Gaunt at the University of Cambridge has uncovered a new C–H activation mode that enables the conversion of hindered amines into β-lactams and aziridines. The first objective of this proposal aims to directly apply the transformations developed by Gaunt, e.g. carbonylation, aziridination and acetoxylation reactions, to a precise class of drugs that contain the secondary amine motif as central function, i.e. β-adrenergic drugs. The use of the oxidative Pd(II)/(IV) catalytic cycle will then allow the development of a novel fluorination. The second objective relies on a new methodological concept, which seeks to merge palladium catalysis with radical chemistry, opening a route to develop novel perfluoroalkylation, amination and methylation reactions via a new Pd (II)/(III)/(IV) catalytic cycle. Finally, the third aim will be to apply all the methods developed to four important anticancer drugs, in collaboration with the new AstraZeneca oncology unit in Cambridge, to prepare novel analogues for biological testing.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
- View on CORDIS
- DOI: 10.3030/702462
- http://web.archive.org/web/20180221051351/http://www-gaunt.ch.cam.ac.uk/publications.shtml
Data: CORDIS, © European Union