Isothiourea catalysed enantioselective generation of point and axially chiral iminothia- and iminoselenazinanones

Symmetrical and unsymmetrical thioureas, as well as unsymmetrical selenoureas, are used in an isothiourea-catalysed Michael addition-lactamisation protocol using α,β-unsaturated pentafluorophenyl esters to generate iminothia- and iminoselenazinanone heterocycles with high enantioselectivity (up to 99 : 1 er). The scope and limitations of this process have been widely investigated (40 examples in total) with unsymmetrical thio- and selenoureas containing ortho-substituted N-aryl substituents giving atropisomeric products, leading to an effective process for iminothia- and iminoselenazinanones heterocyclic products containing both point and axially chiral stereogenic elements with excellent stereocontrol (up to >95 : 5 dr and 98 : 2 er). Mechanistic investigation showed that (i) the catalytically liberated aryloxide could deprotonate an electron-deficient thiourea; (ii) in the absence of an isothiourea catalyst, this leads to formation of racemic product; (iii) a crossover experiment indicates the reversibility of the thia-Michael addition. Computational analysis has identified the factors leading to enantioselectivity within this process, with stereocontrol arising from the lactamisation step within the catalytic cycle.