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Description: The present PhD-research proposal fits in one of the main research topics of the Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC) dealing with the investigation of the synthesis of medium-sized ring containing natural products and analogues, which is known to be rather difficult. Therefore the application of microwave irradiation – the core business of LOMAC1 - plays a key role in these investigations. The expected rigidity of the medium-sized ring in the proposed compounds, makes these systems excellent candidates to be elaborated as privileged structures en route to the development of novel drugs. This nicely fits into another main research topic of LOMAC: the development of novel small and rigid molecules to be investigated as privileged structures for the generation of peptidomimetics in the light of drug design.
Among natural compounds and important pharmaceuticals the 3-benzazepine framework is abundantly present. Considerable efforts have been made towards the synthesis of alkaloids as aphanorphine2, lennoxamine3 and cephalotaxine4 (Figure) because of their challenging chemical structures and interesting biological activity. The renal vasodilator Fenoldopam relates to the class of 1-substituted tetrahydro-3-benzazepines and is a peripheral dopamine D1 receptor agonist.5 The tetracyclic MK-801 (Dizocilpine) represents a non-competitive NMDA receptor antagonist and has been extensively studied for treatment of neurodegenerative diseases such as Huntington's, Alzheimer's, and amyotrophic lateral sclerosis.6 Variously substituted at position 1, the 3-benzazepine structure has also been studied for the synthesis of potent NMDA receptor antagonists.7
Most often the construction of the medium-sized ring of the 3-benzazepine scaffold is achieved via intramolecular Friedel-Crafts alkylation.2b-d,6b,8 However, this method demands an excess of Lewis acid and lacks flexibility for variation of substituents. Alternatively, ring closure is accomplished upon formation of the C-N bond via intramolecular reductive amination.7a Intramolecular radical cyclization was successfully applied for the synthesis of the 7-membered ring in aphanorphine.2a,e Particularly useful for the syntheses of natural compounds and analogues is the corresponding 3-benzazepinone structure, as alkylation allows further introduction of substituents, for example, giving rise to bridged structures.2c,d,9 Transition metal-catalyzed reactions were also used for generating the 3-benzazepine scaffold. Thus, the Heck reaction of olefins proved to be high yielding and reliable.4a,b,7b,10 Though this approach regioselectively leads to 7-membered rings, a problem with the geometry and location of the resulting double bond still remains, due to the unselective elimination of palladium-hydrogen species at the final step of the Heck reaction.2e,4a,10a On the contrary, as a result of the mechanism, our approach via intramolecular Heck reductive cyclization on a triple bond assures full control over the ring size and the geometry of the double bond.11 A regioselective synthesis of 4-substituted 3-benzazepinones via intramolecular hydroamidation of the triple bond incorporated in the noncyclic precursor has also recently been reported.12a,b
However, to the best of our knowledge the 3-benzazepine structure has not been regarded as a potential privileged scaffold and no studies are available for generating diversity oriented small combinatorial libraries of this and related medium-sized ring scaffolds. Moreover, the fact that medium-sized rings are generally considered to be the most difficult ring sizes to synthesize (due to their associated torsional, transannular and large-angle strain, which makes these rings relatively conformationally rigid), adds additional challenges to the proposal.13
The term “privileged structure” was originally coined by B. E. Evans at Merck, who recognized that benzodiazepine structures do not only bind to benzodiazepine receptors of the CNS, but also to cholecystokinin receptors, even though the natural ligands bear little resemblance to this class of compounds.14 According to the definition of Evans, privileged structures are a compound class that can bind to various protein-receptor surfaces with high affinity. These structures appear to contain common structural features. Since the term privileged structure was introduced, a variety of organic scaffolds including biphenyl, have been described as privileged structures.15 The expected rigidity of the medium-sized ring in the proposed compounds, makes these systems excellent candidates to be elaborated as privileged structures. The specificity for the different receptors depend on the substituents introduced on the scaffold. Therefore combinatorial libraries have to be constructed and screened. Libraries based on privileged structures as scaffolds, displaying a diversity of appended pharmacophoric groups, have much greater probability for generating hits in a screening against various drug targets.
A diversity oriented synthesis of small combinatorial libraries of 3-benzazepines and related medium-sized ring analogues will be investigated in solution phase and on solid support. We will rely on a previously developed strategy of our Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), for the synthesis of 1-substituted 3-benzazepinones11, based on a microwave-assisted intramolecular Heck reductive cyclization reaction on a triple bond (Scheme). The applied strategy assures the exclusive generation of compounds possessing the Z-conformation of the exocyclic double bond as well as the exclusive formation of the 7-membered ring. The presented PhD-research proposal aims at the further evaluation of this new microwave-assisted protocol for the diversity oriented synthesis of 3-benzazepines and related medium-sized ring analogues.
- The scope and limitations of the procedure will be investigated by variation of the tether.
- Alternative “domino protocols” such as Heck reaction followed by Suzuki/Miyaura, Heck or Sonogashira reaction will be investigated.
- New precursors for our Heck intramolecular reductive cyclization reaction on a triple bond will be generated via an enantioselective A3-coupling procedure or via a post-Ugi 4-component reaction (U-4CR)/Heck reductive cyclization, ensuring diversity.
- The á,â-unsaturated carbonyl of the generated benzazepinones will be evaluated for the further decoration of the scaffold via radical cyclization. This will be exemplified by the synthesis of a natural product analogue, the methylated (+/-)-O-methyl-thalisopavine.
- The post-U-4CR/Heck reductive cyclization will be translated to solid phase organic synthesis (SPOS).
The application of microwave irradiation will play a central role in this PhD-project, although without having the intention to determine the existence of special, non-thermal microwave effects. Microwave irradiation will be used purely as a technique.
This research will result in the generation of a number of new compounds with hitherto unknown skeletons which will be evaluated as privileged structures by in-house (K. U. Leuven, i.a. at the Rega-Institute), broad screening for biological activity. Possible lead compounds will be further investigated and optimized on the way of drug development. This will be done in close collaboration with the screening partners at K.U.Leuven.
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