Terminal Substituent Effects on the Reactivity, Thermodynamics, and Stereoselectivity of the 8 pi-6 pi Electrocyclization Cascades of 1,3,5,7-Tetraenes

摘要

M06-2X/6-31+G(d,p) computations are reported for the 8 pi-6 pi electrocyclization cascades of 1,3,5,7-tetraenes. The rate-determining step for these cascades is typically the second (6 pi) ring closure. According to experiment and theory, un- and monosubstituted tetraenes readily undergo 8 pi electrocyclic ring closure to form 1,3,5-cyclooctatrienes; however, the 6 pi electrocyclizations of these cyclooctatriene intermediates are slow and reversible, and mixtures of monocyclic and bicyclic products are formed. Computations indicate that di- and trisubstituted tetraenes undergo facile but less exergonic 8 pi electrocyclization due to a steric clash that destabilizes the 1,3,5-cyclooctatriene intermediates. Relief of this steric clash ensures the subsequent 6 pi ring closures of these intermediates are both kinetically facile and thermodynamically favorable, and only the bicyclic products are observed for the cascade reactions of naturally occurring tri- and tetrasubstituted tetraenes (in agreement with computations). The 6 pi electrocyclization step of these cascade electrocyclizations is also potentially diastereoselective, and di- and trisubstituted tetraenes often undergo cascade reactions with high diastereoselectivities. The exo mode of ring closure is favored for these 6 pi electrocyclizations due to a steric interaction that destabilizes the endo transition state. Thus, theory explains both the recalcitrance of the unsubstituted 1,3,5,7-octatetraene and 1-substituted tetraenes toward formation of the bicyclo[4.2.0]octa-2,4-diene products, as well as the ease and the stereoselectivity with which terminal di- and trisubstituted tetraenes are known to react biosynthetically.