In conclusion, a highly enantioselective isothioureacatalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols has been developed. High enantioselectivity and good to excellent product yields (up to 88%, 99:1 er) are observed across a broad range of substrate derivatives incorporating substitution at N-( ) and C(2), di-and spirocyclic substitution at C(5)-and C(6)-, as well as benzannulation. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O •••isothiouronium interaction identified as key to producing lactol ester products with high enantioselectivity. Ongoing work from within our laboratory is aimed at developing further effective DKR processes using isothioureas as catalysts and its broad application to heterocycle synthesis.