ABSTRACT
The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1â er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35â examples in total). The DKR process is amenable to scale-up on a 1â g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=Oâ â â isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.