B(C6F5)3-catalysed reactions of vinyl diazo esters with nitrones: synthesis of benzo[b]azepine and pyrrolidinone precursors Michael G. Guerzoni ,† , Katarina Stefkova † , Yara van Ingen, Dr Emma Richards and Prof. Rebecca L. Melen Cardiff University, UK, † Equal contribution The widespread occurrence of nitrogen-containing heterocycles in drug candidates triggers an unceasing development of new synthetic methods. To this end, numerous enantio- and/or diastereo-selective synthetic methodologies for pyrrolidine- and benzoazepine-containing drugs have been developed. However, these generally rely on multi-step syntheses and the use of precious transition metals. 1 In our group, we are interested in the utilisation of boron Lewis acids, such as B(C 6 F 5 ) 3 , to promote new or orthogonal reactivities to existing methods. 2 One property of B(C 6 F 5 ) 3 is its ability to activate diazo compounds to afford carbene equivalents; similar to transition metals, albeit without the formation of a metal-carbene intermediate. 3 We have also shown that, depending on the diazo structure, carbene formation can be thwarted hence allowing its formation at a later stage in the synthesis. 4 With this in mind, my poster will describe our recent discovery of a diastereoselective synthesis of isoxazolidine scaffolds from the reaction between nitrones and vinyldiazo esters catalysed by B(C 6 F 5 ) 3 , which crucially keeps the diazo functionality intact. 5 This method provides a useful tool to synthesise highly functionalised diazo compounds in moderate to good yields and with good diastereo-control over the two formed chiral centres. These products were then initially screened as carbene precursors to afford benzo[b]azepines through an intramolecular rearrangement using B(C 6 F 5 ) 3 or Rh 2 (OAc) 4 as catalyst. During our investigation of different diazo ester substrates, we observed that silylenol diazo esters undergo a Mukayiama-Mannich addition with nitrones, to form silyl-protected hydroxylamine diazo esters, again catalysed by B(C 6 F 5 ) 3 . These can then be subjected to a Rh 2 (OAc) 4 -catalysed diazo activation to access pyrrolidinones containing three chiral centres, of which one quaternary. In conclusion, this work highlights the ability to synthesise diazo-containing isoxazolidine and hydroxylamine scaffolds using catalytic B(C 6 F 5 ) 3 in good yield and d.r. . The obtained products can be conveniently interconverted to pyrrolidinone and benzo[b]azepine scaffolds using Rh 2 (OAc) 4 in just one step. Interestingly, preliminary results show that B(C 6 F 5 ) 3 can also trigger the intermolecular rearrangement, opening up the possibility to use only borane Lewis acids to access precious drug candidates starting from simple starting materials. References
1. R. D. Taylor, M. Maccoss and A. D. G. Lawson, J. Med. Chem., 2014, 57, 5845–5859. 2. G. Kumar, S. Roy and I. Chatterjee, Org. Biomol. Chem., 2021, 19, 1230–1267.
3. A. Dasgupta, R. Babaahmadi, B. Slater, B. F. Yates, A. Ariafard and R. L. Melen, Chem, 2020, 6, 2364–2381. 4. R. Babaahmadi, A. Dasgupta, C. J. T. Hyland, B. F. Yates, R. L. Melen and A. Ariafard, Chem. - A Eur. J., 2022, 28, e202104376 5. M. G. Guerzoni,† K. Stefkova,† Y. van Ingen, E. Richards and R. L. Melen, Org. Lett., 2023, 25, 3, 500–505.
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