A COMPREHENSIVE APPROACH TO THE CONFORMATIONAL-ANALYSIS OF CYCLIC-COMPOUNDS

Currently available strategies for the conformational analysis of cycl ic compounds include the molecular mechanics energy minimization of ra ndomly distorted previously optimized cyclic structures (Osawa, Raber, Saunders, Wilson) or minimization of the cyclic structures contained within a set of acyclic structures (Fromowitz, Hruby, Karplus, Pavitt, Scheraga, Still, Veber). Reported herein is a novel constrained stoch astic search strategy which affords large numbers of only cyclic initi al structures. The algorithm is based on a random variation of the dih edral angles of a chain within the range of angles that are compatible with ring closure. With efficiency defined as the number of cyclic pr obe structures lacking internal close contacts that can be produced pe r second, for 10-, 15-, 20-, 30-, and 50-membered rings our strategy p roduces these structures 40, 80, 160, 400, and 4500 times more efficie ntly than other methods tested. The structures generated in this way a ppear to be well distributed over the conformational space: all previo usly reported MM2 and MM3 minima for 9-, 10-, 11-, 12-, and 17-membere d cyclic hydrocarbons have been found by minimization of 50, 100, 1000 , 2500, and 60000 cyclic probe structures, respectively. Numerous prev iously unreported (usually high energy) minima have also been found. T hese include structures in which one or more hydrogens or methylene gr oups are directed toward the interior of the ring, one trefoil knot, a nd artifacts that contain pyramidal carbon. The latter are found only with MM2, because of the different expressions for bending employed in the MM2 and MM3 force fields, Using a version of the algorithm that a voids high energy structures, a total of 12513 MM2 minima has been fou nd for cycloheptadecane.