To understand why acylation of lactol 1 was favoured over acyclic alcohol 76, their ground states were evaluated (Figure ). The cyclic lactol 1 was thermodynamically favoured by 1.3 kcal/mol, and the interconversion between them was rapid compared to the acylation process (∆G ‡ = 11.7 kcal/mol, ~3-4 kcal/mol lower) -i.e. a Curtin-Hammett scenario is operative. Thus the barriers of TS-I and TS-II determine the cyclic vs acyclic preference (∆G ‡ = 13.7 and 15.6 kcal/mol, respectively), not the thermodynamic stability of the starting materials 1 and 76. The favoured TS-II possessed a stabilizing interaction between the acyl isothiouronium ion and the more Lewis basic lactol N-C=O carbonyl donor (C•••O=C = 2.83 Å, interaction highlighted in green). In comparison, in the disfavoured acyclic alcohol acylation TS-I, the isothiouronium and carbonyl are much further apart (C•••O=C = 4.05 Å, interaction highlighted in grey), resulting in a weaker interaction (Figure ). Consistent with this hypothesis, the Wiberg bond index of this interaction in TS-II was 0.0102, suggesting significantly greater bonding interaction compared to that of TS-I (0.0006). The origins of enantiodiscrimination in the acylation of cyclic ester products were also investigated (Figure ). Acylation of the (R)-lactol via TS-III had a barrier of 15.3 kcal/mol that leads to the minor (S)-ester product 2. This barrier was 1.6 kcal/mol higher than TS-II (94:6 er), which is in good agreement with experiment (97:3 er). The key interactions responsible for the observed enantiodiscrimination are shown in Fig 3, bottom. In the disfavoured TS-III, the isothiouronium interacts with the less Lewis basic lactol ether O (C•••OC = 3.05 Å, interaction highlighted in blue). This contrasts with the favoured TS-II, where the more Lewis basic lactol N-C=O carbonyl donor participates (C•••O=C = 4.05 Å, interaction highlighted in grey).