Organocatalytic asymmetric synthesis of α-aminophosphinates Cáoimhe J. Niland 1,2 , Joseph J. Ruddy 1 , Martin P. Ó Fearraigh 1 , Eoghan M. McGarrigle 1,2 1 Centre for Synthesis and Chemical Biology, University College Dublin, Ireland, 2 SSPC, the SFI Research Centre for Pharmaceuticals, University of Limerick, Ireland P -Stereogenic organophosphorus compounds have found widespread use as chiral ligands and are important molecules in medicinal and synthetic chemistry. α-Aminophosphinate derivatives are used as surrogates for α-amino acids, so it would be desirable to access P -stereogenic aminophosphinates. Jacobsen and co-workers showed that the enantioselective addition to acyl-activated isoquinolines could be achieved through anion-binding catalysis. [1,2] The Mukherjee group successfully applied this method to the synthesis of ɑ-aminophosphonates by using silyl phosphites as nucleophiles in the enantioselective dearomatisation of isoquinolines catalysed by a chiral thiourea. They achieved high enantioselectivities for the C -stereogenic products. [3] Here, we report the organocatalytic additions of prochiral phosphonites to acyl-activated isoquinolines, giving access to α-aminophosphinates which bear both C - and P -stereogenic centres. [4] An enantiopure chiral thiourea catalyst gave phosphinate products in moderate-to-excellent yields (up to 99%) and enantioselectivities (up to 96%). The scope of the reaction, including a gram-scale example, has been demonstrated. The reactions are suggested to proceed via P-C bond formation, followed by Arbuzov-type collapse at phosphorus. Our efforts to develop and understand this new route to enantioenriched α-aminophosphinates will be described.
References 1. M. S. Taylor, N. Tokunaga, E. N. Jacobsen, Angew. Chem., Int. Ed. 2005 , 44 , 6700–6704. 2. S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc. 2008 , 130 , 7198–7199. 3. A. Ray Choudhury, S. Mukherjee, Chem. Sci. 2016 , 7 , 6940–6945. 4. C. J. Niland, J. J. Ruddy, M. P. Ó Fearraigh, E. M. McGarrigle, manuscript submitted.
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