Several aspects of the heterogeneous actions of aqueous and gaseous HCl on the chemical behavior of 3,4‐epoxycyclopentanone (=6‐oxabicyclo[3.1.0]hexan‐3‐one; 1) included in the asymmetric cages of tri‐o‐thymotide (TOT) clathrates belonging to space groups P3₁21 are described, showing specific features strikingly at variance with those observed in liquid solutions. In a first step, the substrate underwent an acid‐promoted allylic isomerization, as already observed in our previous investigations, to give optically active 4‐hydroxycyclopent‐2‐en‐1‐one (2). In a consecutive step, a displacement of the OH group was accomplished by the Cl⁻ anion to afford the corresponding chloro compound 3. Polymorphism was encountered in the preparation of TOT/1 clathrates. Recrystallization of TOT in the pure guest 1 yielded micro‐twinned crystals belonging to the P3₁ space group (host/guest ratio 1 : 1), whereas the expected P3₁21 lattice grew from a mixture of TOT, 1, and MeOH. The structural determination of TOT/1 was carried out by X‐ray diffraction (Fig. 1). Kinetic measurements were achieved that shed light on some striking features of this type of heterogeneous reactions for solid‐liquid and solid‐gas systems. Several reactions of pure clathrate antipodes (+)‐TOT/1 with gaseous HCl were carried out under various conditions; concentration and enantiomer‐excess(ee) determinations of the products 2 and 3 allowed to establish a larger ee for 3, thus demonstrating the influence of the host‐guest diastereomeric association on the progression of the reaction. The correlation of optical activities of the host and products for the global reaction disclosed the sequence (+)‐(M)‐TOT/1→(−)‐2→(−)‐3. A new way for the preparation of 2 was devised. It was further demonstrated that the X‐ray structure analysis of the chiral clathrate (M)‐TOT/(+)‐2 (Fig. 4) associated with chiroptical measurements was an efficient and straightforward method to determine the absolute (+)‐(R)‐configuration of the guest. The enantioselectivity of the TOT clathrate for 2 was established by two different methods which allowed the appraisal of an accurate revised value of the specific rotation of 2. The enclathration of 3 occurred exclusively in the orthorhombic centrosymmetric host lattice Pbca, thus prohibiting the X‐ray structural determination of the guest absolute configuration. The problem of finding a pathway to the intended enantiomer enrichment of 3 was worked out through the action of aqueous HCl on microcrystalline (+)‐TOT/(−)‐(S)‐2 that gave an optically active mixture of unreacted 2 with 3 as sole product. The pure optically active 3 was isolated by subsequent TLC. The resolution of 3 was achieved by GC over a chiral column and its (unknown) specific rotation measured. The absolute configuration of 3 was established by the measurement of the enantiomer purity of the optically active mixture 3 obtained after the total conversion of (−)‐(S)‐2 in the presence of thionyl chloride in Et₂ O, dioxane, and benzene. It was deduced that the (−)‐3 enantiomer had the (S)‐configuration.