Asymmetric intramolecular α-arylation of polar amino acids bearing β-leaving groups Ö. Taşpınar, D.J. Leonard, A. Mayo, C. Göcke, N. Picois, J. Clayden University of Bristol, UK Quaternary amino acids are important building blocks for a wide range of pharmaceuticals, agrochemicals, and natural products. They are typically prepared by α-functionalization of their naturally occurring tertiary precursors. While α-alkylation is a well-established method, the only general method for the preparation of α-arylated variants was published previously by our group in 2018. However, this did not include polar amino acids possessing aβ- leavinggroup such as serine, threonine, or cysteine. 1a
Here, we report further development of our original transition-metal-free arylation protocol for polar amino acid substrates by incorporating a γ-heteroatom into the ring system of chiral oxazolidines or thiazolidines as ideal templates for highly diastereoselective arylations. The reaction is based on a unique N→C rearrangement chemistry that was first established in the Clayden group 1b combined with Seebach’s self-regeneration of stereocentres (SRS) methodology. 2 In this process, the arene is delivered to the α-carbon of the amino acid enolate in an intramolecular fashion. The reaction is facilitated by a urea tether, which promotes spontaneous cyclisation to form a wide range of α-arylated bicyclic hydantoins. The reaction can be further modified to produce highly enantioenriched quaternary amino acids and hydantoins. The asymmetric arylation route described in the previous and this work is unique in its avoidance of transition metals and chiral auxiliaries, and gives the opportunity to access a variety of arenes with different electron densities. These compounds have a wide range of potential applications in medicinal, agrochemical, and peptidomimetic chemistry. References 1. a) D. J. Leonard, J. W. Ward, J. Clayden, Nature 2018 , 562 , 105–109; b) J. Clayden, J. Dufour, D. M. Grainger, M. Helliwell, J. Am. Chem. Soc. 2007 , 129 , 7488–7489. 2. D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. Int. Ed. 1996 , 35 , 2708–2748.
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