1,3,5,7-tetraenes can undergo 8p-6p electrocyclization cascades to form bicyclo[4.2.0]octa-2,4-diene. Terminal substitution of 1,3,5,7-tetraene is known to have a profound effect of the reactivity of these substrates and in some cases the stereoselectivity of the 6p ring closure. To better understand how terminal substitution influences these aspects of tetraene chemistry we have modeled the 8p-6p electrocyclization of a number of substituted tetraenes computationally. According to our computations, the rate-determining step for these cascades is typically the 6p ring closure. For the un- and monosubstituted tetraenes, this step is slow and either thermoneutral or only slightly exergonic. Substitution at both ends of 1,3,5,7-tetraene destabilizes the 1,3,5-cyclooctadiene (8p ring closure product), rendering the subsequent 6p ring closure both kinetically facile and thermodynamically favorable. While trisubstituted compounds readily undergo the 8p-6p electrocyclization cascades, tetrasubstitiution of the tetraene renders the second ring closure endergonic. For those cascade reactions involving a stereoselective 6p ring closure, only di- and trisubstituted tetraenes undergo the cascade reaction with a high degree of diastereoselectivity. The exo mode of ring closure is favored for these ring closures because endo transition states are destabilized by a steric clash. Thus, theory explains the recalcitrance of the unsubstituted octatetraene and 1-substituted octatetraenes towards formation of bicyclo[4.2.0]octadiene, the ease with which terminal di- and trisubstituted tetraenes are known to undergo the 8p-6p ring closure in Nature, and the stereoselectivity of diastereoselective 6p ring closure. 

Computational survey of 8p-6p electrocyclization cascades of 1,3,5,7-tetraenes: Understanding the influence of terminal substitution on reactivity and selectivity

248th National Meeting (2014)

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