Structural Studies of Diterpenes: Conformational Analysis of ent-13-epi-manoyl oxides by Molecular Mechanics

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:

a) they are related to the experimental work carried out by our research group, since they arise from natural, chemical or microbiological sources;

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 [1] was used throughout the study. Molecular mechanics modelling and conformational analyses of compounds 1-18 were done with the PC-MODEL program [2]. Energy minimization was done with the program using an MMX force field, which was a modification of the MM2 (QCPE-395, 1977) [3] and MMP1 (QCPE-318) programs [4].

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 [5].

Cremer-Pople [6] ring puckering parameters were calculated for the different rings of the most stable conformations for compounds 1-5, 8, 16-18, using the CONPUC program [7,8].

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).