A Molecular Electron Density Theory Study of the Chemoselectivity, Regioselectivity, and Diastereofacial Selectivity in the Synthesis of an Anticancer Spiroisoxazoline derived from α-Santonin

The [3 + 2] cycloaddition (32CA) reaction of an α-santonin derivative, which has an exocyclic C–C double bond, with p-bromophenyl nitrile oxide yielding only one spiroisoxazoline, has been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. Analysis of the conceptual density functional theory (CDFT) reactivity indices and the global electron density transfer (GEDT) account for the non-polar character of this zwitterionic-type 32CA reaction, which presents an activation enthalpy of 13.3 kcal·mol−1. This 32CA reaction takes place with total ortho regioselectivity and syn diastereofacial selectivity involving the exocyclic C–C double bond, which is in complete agreement with the experimental outcomes. While the C–C bond formation involving the β-conjugated carbon of α-santonin derivative is more favorable than the C–O one, which is responsible for the ortho regioselectivity, the favorable electronic interactions taking place between the oxygen of the nitrile oxide and two axial hydrogen atoms of the α-santonin derivative are responsible for the syn diastereofacial selectivity.


32CA reactions of the simplest nitrile oxide 13 with methyl acrylate 10 and 3methylene lactone 16
In order to characterize the origin of the total regioselectivity found in the 32CA reaction of α-santonin derivative 2 with p-bromophenyl nitrile oxide 3, the 32CA reactions of the simplest nitrile oxide 13 with methyl acrylate 10 and 3-methylene lactone 16 were studied in gas phase at the MPWB1K/6-311G(d,p) computational level (see Scheme S1). For the 32CA reaction between the simplest nitrile oxide 13 and methyl acrylate 10, the meta TS8 was found to be 1.4 kcal·mol -1 higher in energy than the ortho TS7, indicating that this non-polar zw-type 32CA reaction is poorly regioselective. A similar poor regioselectivity was found for the 32CA reaction between benzonitrile oxide 9 and methyl acrylate 10 at the B3LYP/6-31G(d) (see Scheme 2). Scheme S1. 32CA reactions of the simplest nitrile oxide 13 with methyl acrylate 10 and 3-methylene lactone 16. Relative MPWB1K/6-311G(d,p) gas phase energies are given in kcal·mol -1 . Relieve energies in THF are given in parentheses.
Interestingly, when the 32CA reaction of the simplest nitrile oxide 13 with the simplest 3-methylene lactone 16 is analyzed, while the activation energy associated with the ortho TS9 decreases to 11.9 kcal·mol -1 , the energy difference with the meta TS10 increases to 5.4 kcal·mol -1 , which is in clear agreement with the energy results found in the 32CA reaction of α-santonin derivative 2 with p-bromophenyl nitrile oxide 3 (see Scheme 3). Considering that only minor steric factors exist along the approach of the S3 simplest nitrile oxide 13 to the exocyclic C−C double bond of lactone 16, the total regioselectivity found in this 32CA reaction can be exclusively associated with electronic factors related to the bonding changes along the reaction.
The inclusion of solvent effects of THF increases the activation energies by between 1.2-1.6 kcal·mol -1 , and decreases the exothermic character of the reaction by between 1.0-1.5 kcal·mol -1 as a consequence of a better solvation of the reagents than TSs and cycloadducts.
The geometries of the ortho and meta regioisomeric TSs associated with the 32CA reaction between the simplest nitrile oxide 13 and 3-methylene lactone 16 are given in Figure S1. A comparison of the distances between the nuclei involved in the formation of the new C−C and C−O single bonds at these TSs with those involved in the 32CA reaction of α-santonin derivative 2 with p-bromophenyl nitrile oxide 3 (see Figure S1) indicates that while the more favorable ortho TSs show a very similar bond formation pattern, the meta TSs involving p-bromophenyl nitrile oxide 3 are slightly more asynchronous as a consequence of the presence of the phenyl substituent in nitrile oxide 3. Inclusion of the solvent effects of THF scarcely modifies the gas phase geometries. Finally, in order to evaluate the polar nature of the 32CA reaction of the simplest nitrile oxide 13 with 3-methylene lactone 16, the GEDT at the gas phase TSs was analyzed. The computed GEDT values, 0.05 e at TS9 and 0.00 e at TS10, emphasize the non-polar character of this zw-type 32CA reaction. In spite of the electrophilic character S4 of simplest 3-methylene lactone 16, ω = 1.54 eV, the very low nucleophilic character of simplest nitrile oxide 13, N = 1.17 eV, accounts for the non-polar character of this 32CA reaction (the global reactivity indices of nitrile oxide 13 and 3-methylene lactone 16 are given in Table 1).

ELF topological analysis of C−C and C−O bond formation along the 32CA reaction
of α-santonin derivative 2 with p-bromophenyl nitrile oxide 3 In order to characterize the C-C and C-O bond formation along the 32CA reaction of αsantonin derivative 2 with p-bromophenyl nitrile oxide 3, a topological analysis of the ELF along the IRC associated with the most favorable ortho/syn reaction path was performed, with the aim of finding the structures directly involved in the bond formation processes. The populations of the most relevant ELF valence basins, GEDT, relative energies, C-C and C-O forming bond distances, and IRC values of the selected structures of the IRC are gathered in Table S1, while the ELF valence basin attractor positions are represented in Figure S2.
The ortho/syn reaction path begins at structure S1, d(C1−C4) = 3.480 Å and d(O3−C5) = 3.241 Å. Thus, it is expected that its ELF topological features will be very similar to those of the separated reagents. While the two V(C1,N2) and V′(C1,N2) disynaptic basins of the nitrile oxide framework and the two V(C4,C5) and V′(C4,C5) disynaptic basins of the santonin exocyclic ethylene moiety have total populations of 5.97e and 3.43e, respectively, the V(N2,O3) disynaptic basin and the V(O3) monosynaptic basin integrate 1.84e and 5.69e. Therefore, these populations show a similar bonding pattern to that of the separated reagents; i.e. a C1−N2 triple bond, an N2−O3 single bond, an O3 oxygen non-bonding electron density equivalent to three lone pairs, and an underpopulated C4−C5 double bond (Section 3.1).
At TS1, d(C1−C4) = 2.130 Å and d(O3−C5) = 2.362 Å, together with the strong depopulation of the two V(C1,N2) and V′(C1,N2) disynaptic basins to 4.08e, which allows relating the C1−N2 bonding region to a double bond, a new V(N2) monosynaptic basin is observed with a population of 1.90e. This V(N2) monosynaptic basin can be related to the N2 non-bonding electron density present at the final spiroisoxazoline 4.
Parallel, the depopulation of the V(C1,C1') disynaptic basin associated with the C1−C1' bonding region (not shown in Table S2), has caused the appearance of a V(C1) S5 monosynaptic basin integrating 0.40e at TS1, which can be associated with a C1 pseudoradical center. On the other hand, at the santonin framework, the C4−C5 bonding region has been depopulated by 0.27e, in such a manner that the two V(C4,C5) and V′(C4,C5) disynaptic basins have merged into a single V(C4,C5) disynaptic basin integrating 3.16e. Otherwise, although the total population associated with the O3 oxygen has decreased by only 0.09e, the V(O3) monosynaptic basin has split into two V(O3) and V′(O3) monosynaptic basins, integrating 2.85e and 2.75e. At TS2, no disynaptic basin associated with the new C1−C4 or O3−C5 single bonds are found.
At structure S2, which is exactly before the formation of the first C1−C4 single bond, d(C1−C4) = 1.973 Å and d(O3−C5) = 2.265 Å, while the V(C1) monosynaptic basin reaches 0.66e, and a new V(C4) monosynaptic basin, integrating 0.37e, is observed at the ethylene system of the santonin framework (see Figure S2). This monosynaptic basin, which can also be related with a C4 pseudoradical center, entirely comes from the depopulation of the V(C4,C5) disynaptic basin to 2.80e. At S2, the two C1 and C4 pseudoradical centers demanded for the corresponding C1−C4 bond formation by sharing electron density are observed.
At structure S5, d(C1−C4) = 1.590 Å and d(O3−C5) = 1.865 Å; while the total population of the two V(O3) and Vʹ(O3) monosynaptic basins decreases by 0.31e and the V(C5) monosynaptic basin disappears, a new V(O3,C5) disynaptic basin is created with S6 an initial population of 0.56e (see Figure S2). This relevant topological change indicates that the formation of the second O3−C5 single bond takes place at an O−C distance of ca.
1.86 Å, by sharing the non-bonding electron densities of the O3 oxygen and the C5 pseudoradical center. Interestingly, the extremely low population of the V(O3,C5) disynaptic basin, which is half that of the V(C1,C4) disynaptic basin at S3, suggests an incipient remarkably polarized O3−C5 single bond. Note that the population associated with the O3 oxygen is 5.42e.
Finally, at spiroisoxazoline 4, d(C1−C4) = 1.494 Å and d(O3−C5) = 1.433 Å, as the total population of the two V(O3) and Vʹ(O3) monosynaptic basin decreases to 4.96e, the population of the V(O3,C5) disynaptic basin strongly increases to 1.34e, but remains low compared to that of the V(C1,C4) disynaptic basin, which reaches 1.99e. Similarly, the V(N2,O3) disynaptic basin ends up integrating only 1.06e, while the V(N2) monosynaptic basin reaches 2.87e. Figure S2. Attractor positions of the ELF valence basins for the selected structures associated with the formation of the C1−C4 and O3−C5 single bonds along the most favorable ortho/syn reaction path of the non-polar zw-type 32CA reaction between αsantonin derivative 2 and p-bromophenyl nitrile oxide 3. The electron populations, in average number of electrons, e, are given in brackets. Table S1. ELF valence basin populations, intrinsic reaction coordinate (IRC) values, internuclear distances along the single bond formation, relative a electronic energies and global electron density transfer (GEDT) of the selected structures associated with the formation of the C1−C4 and O3−C5 single bonds along the most favorable ortho/syn reaction path of the non-polar zw-type 32CA reaction between α-santonin derivative 2 and p-bromophenyl nitrile oxide 3, yielding spiroisoxazoline 4. IRC values are given in atomic unities, a.u., distances in angstroms, Å, GEDT values and electron populations are given in average number of electrons, e, and relative energies are given in kcal·mol -1 .  (a) Relative to the first structure of the reaction path, S1 S8 Figure S3. NCI gradient isosurfaces of TS1r and TS2r, as reduced models for the interacting quantum atoms (IQA) calculations of TS1, and TS2, respectively. Surfaces are colored in the [-0.02, 0.02] a.u. range of sign(λ 2 )ρ (isosurfaces = 0.5 a.u.). Table S2. MPWB1K/6-311G(d,p) total (E, in a.u.) and relative a (∆E, in kcal·mol -1 ) energies, in gas phase and in THF, of the stationary points involved in the 32CA reaction between α-santonin derivative 2 and p-bromophenyl nitrile oxide 3.