| Allinger's MM2 program was used in an evaluation of the molecular mechanics method as a tool in synthetic and mechanistic organic chemistry. From the synthetic standpoint, the evaluation was made on the basis of a comparison with detailed "classical" conformational analyses of A/B- and B/C ring juncture isomers in alternate synthetic pathways in the formal total synthesis of fusidic acid. It was found that, while Dreiding models and careful conformational analysis often differed significantly from molecular mechanics regarding the favored conformation of a molecule, the qualitative conclusions drawn regarding thermodynamic isomer stabilities were usually in agreement. However, given the subjectivity of "classical" conformational analysis and the complexity of the molecules under study, it was felt that the molecular mechanics method is nearly as convenient and much more reliable for evaluating potential synthetic pathways.;Molecular mechanics was applied to mechanistic studies of both thermodynamic and kinetically controlled reactions. The use of Li/NH(,3) reductions to establish the A/B ring juncture stereochemistry in two related fusidan enones was studied, using MM2 to evaluate the ring system thermodynamics. It was shown that, while the A/B-cis ring juncture was more stable in both systems, a stereoelectronic effect could overcome the unfavorable thermodynamics in a (DELTA)('9,11) system, allowing the trans ring fusion to predominate. For kinetically controlled reactions, a transition state modeling method using molecular mechanics in conjunction with linear regression analysis was devised. This method was applied to the Li/EtNH(,2) and the Li/NH(,2)CH(,2)CH(,2)NH(,2) reductions of epoxides, providing evidence for a revised mechanism and suggesting that the transition state geometries are significantly different in the two solvents. The method was also applied to the kinetic deprotonation of acyclic ketones and esters, which was shown to proceed through a cyclic transition state. The use of the transition state modeling technique for the quantitative prediction of alcohol regioisomers in the epoxide reduction and of cis : trans enolate ratios in kinetic enolate formation was proposed. |
