e Instituto de BiotecnologÍa de la Universidad de Granada, 18071 Granada (Spain)
Molecular mechanics calculations were done for compounds 1-18. These compounds are tricyclic diterpenes belonging to the enantio series (ent-), with ent-13-epi-manoyl oxide structure.
Compound 1 is the unfunctionalized skeleton of ent-13-epi-manoyl oxide. Compounds 2-15 are ent-13-epi-manoyl oxides with different hydroxyl groups at positions C-3, C-6, C-7, C-11 and/or C-12 with different ent-alpha or ent-beta arrangements. Compounds 16-18 are mono- or diketones at positions C-3 and C-12.
These compounds were chosen for molecular mechanics calculations for the following reasons:
b) experimental coupling constants are known;
c) the calculated theoretical coupling constants are helpful in assigning experimental coupling constants;
d) all the structures have three fused highly rigid rings, making investigations of their conformational behavior of interest.
Molecular mechanics methodology  was used throughout the study. Molecular mechanics modelling and conformational analyses of compounds 1-18 were done with the PC-MODEL program . Energy minimization was done with the program using an MMX force field, which was a modification of the MM2 (QCPE-395, 1977)  and MMP1 (QCPE-318) programs .
Conformational analysis of rings and hydroxyl orientation in structures 1-18 was done with the RANDOMIZE and MULTOR options of the PC-MODEL program. This conformational analysis provides the lowest energy conformations. From these conformations, steric energies and theoretical coupling constants were calculated using the PMR option of the PC-MODEL program. This option is based on an empirical generalization of the Karplus equation .
The energy differences for compounds 1-5, 8 and 18 are approximately of 3-7 kcal/mol in favor of those conformations with a C ring in a chair conformation. Therefore, we conclude that products 1-18 exist mainly in only one ring conformation, with the A, B and C rings very close to the chair conformations.
The unfunctionalized ent-13-epi-manoyl oxide skeleton has a steric energy of 47.9 kcal/mol. Compounds 2 (ent-3beta-hydroxy) and 3 (ent-12alpha-hydroxy) are mono-hydroxylated derivatives. Compounds 4, 5, 6 and 7 have two hydroxyl groups; compounds 4 and 5 are epimers at C-12 and compounds 6 and 7 are epimers at C-6. In both cases the equatorial arrangement (ent-6a or ent-12b) is energetically favorable in approximately 0.5 kcal/mol. Products 8-15 are trihydroxylated compounds. Some of them (9 and 12) have small steric energy values (47.3 and 46.5 kcal/mol, respectively). Both products 9 and 12 have the same functionalization at C-3, C-7 and C-12, although opposite arrangements at C-7 and C-12. Compounds 10 and 13 are epimers at C-12 and the equatorial arrangement is again favorable (0.3 kcal/mol). Compounds 16 and 17, epimers at C-1, have a carbonyl group at C-3. Diketone 18 is abnormally stable since its steric energy is 46.1 kcal/mol.
Cremer-Pople ring puckering parameters were calculated for the different rings of the most stable conformations for compounds 1-5, 8, 16-18.The B ring for all products (1-18), independently of the C ring conformation, has a chair conformation. The C ring for all the compounds presents a slightly distorted chair conformation.
The experimental data for products 2-18 indicate that the A, B and C rings are preferably in a chair conformation, with good concordance between the theoretical and experimental values of the coupling constants for the protons on C-2 and the geminal proton to the equatorial hydroxyl group on C-3 (for A ring), coupling constants for protons on C-6 and geminal proton to the axial or equatorial hydroxyl group on C-7 (for B ring) and coupling constants between H-9 and H-11 (for C ring).