Turning hydrogen bonding catalysts into enantioenriched iminothiazinanone heterocycles using isothiourea catalysis Alastair J. Nimmo, Aidan McKay, Andrew D. Smith* EaStCHEM, School of Chemistry, University of St Andrews, UK Since Schreiner demonstrated the ability of N , N’ -bis[3,5-bis(trifluoromethyl)phenyl]thiourea to catalyse the Diels-Alder cycloaddition reaction, 1 electron-deficient thioureas have become ubiquitous motifs in modern organocatalysis. 2 Their bench stability and facile synthesis from inexpensive starting materials make them an attractive choice of catalyst and they have been applied in a plethora of transformations. However, despite their frequent use, electron‑deficient thioureas have been overlooked as substrates. While in principle thioureas contain a nucleophilic sulfur atom, this property has not been harnessed in enantioselective catalysis to date, with S-adducts only characterised as catalyst deactivation pathways. 3,4 Isothiourea-catalysed Michael additions have been used extensively to achieve enantioselective C-C bond formation. 5,6 However, their use to selectively form C-X bonds through Michael addition of non-carbon nucleophiles is extremely limited. Recent work has demonstrated the elegance of electron-deficient aryl esters in the generation of C(1)-ammonium enolate reactive intermediates. The aryloxide liberated upon catalyst acylation is required to fulfil multiple roles in the catalytic cycle, including that of Brønsted base. 7,8 The excellent hydrogen bond donor ability of electron-deficient thioureas is concomitant with a p K a acidic enough to enable facile deprotonation by a catalytically liberated aryloxide. 9 Herein, catalytically generated aryloxide activates electron- deficient thioureas to be competent dinucleophiles in an isothiourea-catalysed thia-Michael addition-lactamisation protocol. This methodology has allowed the first enantioselective synthesis of chiral 2-imino-1,3-thiazinan-4-ones with good to excellent yields (up to 95% yield) and enantioselectivity (up to 98:2 er) using as little as 5 mol% of the isothiourea catalyst. The scope and limitations of this protocol, alongside mechanistic insight, will be presented.
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