The approach of the morpholine nucleophile from either the Reor the Si-face of either β-lactone diastereoisomer was modelled (Figure and 2D), with calculations revealing a strong preference towards addition to the Si-face of both diastereoisomers, due to a stabilising hydrogen bonding interaction between the pyrazolone C=O and morpholine N-H. This stabilising interaction was observed for all structures, with increasing elongation of the N-H bond relative to free morpholine as the reaction progresses (Table ). In contrast, reactivity through the disfavoured Re-face of the β-lactone (Figure and 2D, dashed lines) does not benefit from a stabilising intramolecular hydrogen-bond, and instead a strongly asynchronous concerted process is followed, with no distinct tetrahedral intermediate located connecting the reactant encounter complex to the product. This pathway is calculated to be significantly energetically disfavoured and predicts a reversal of selectivity towards the observed minor diastereoisomeric product. The stabilising hydrogen bond interacRon mediates nucleophilic aoack from the Si-face of the (3R,4R)-7 and (3S,4R)-8 β-lactones via TS1major and TS1minor, respecRvely, to generate the corresponding tetrahedral intermediates 18/19. The presence of this hydrogen bond is also apparent from the non-covalent interaction (NCI) plot inset in Figure . Subsequent ring opening via TS2major and TS2minor is predicted to be stereodetermining (DD ‡ G = 0.9 kcal/mol), preferenRally generaRng the β-hydroxyamide products (1'R,4R)-11 and (1'S,4R)-20 in a calculated 83:17 dr that is in close agreement with the observed 88:12 dr. Subsequent proton transfer, likely facilitated by an excess of morpholine, generates the product.