Abstract
Hetero-Diels-Alder (HDA) reaction is an important synthetic method for many natural products. An iron(III) catalyst was developed to catalyze the challenging HDA reaction of unactivated aldehydes and dienes with high selectivity. Here we report extensive density-functional theory (DFT) calculations and molecular dynamics simulations that show effects of iron (including its coordinate mode and/or spin state) on the dynamics of this reaction: considerably enhancing dynamically stepwise process, broadening entrance channel and narrowing exit channel from concerted asynchronous transition states. Also, our combined computational and experimental secondary KIE studies reveal unexpectedly large KIE values for the five-coordinate pathway even with considerable C–C bond forming, due to equilibrium isotope effect from the change in the metal coordination. Moreover, steric and electronic effects are computationally shown to dictate the C=O chemoselectivity for an α,β-unsaturated aldehyde, which is verified experimentally. Our mechanistic study may help design homogeneous, heterogeneous and biological catalysts for this challenging reaction.
Highlights
Hetero-Diels-Alder (HDA) reaction is an important synthetic method for many natural products
The Diels–Alder (DA) reaction has long been one of the most popular, classical, and atom-economical chemical and biological synthetic methods for forming sixmembered carbocycles[1,2,3,4,5,6]. This important cycloaddition reaction was extended to the addition of other substrates containing C=X bonds (e.g., X=O; i.e., oxa-Diels–Alder (ODA) reaction) to give various six-membered heterocyclic molecules, which are very useful in the synthesis of carbohydrates and many natural products[1,2,7,8,9]
Our combined computational and experimental secondary kinetic isotope effect (KIE) studies supported that the five- and six-coordinate mode pathways in the quartet and sextet states can be involved in the reaction through a concerted asynchronous mechanism
Summary
Hetero-Diels-Alder (HDA) reaction is an important synthetic method for many natural products. An iron(III) catalyst was developed to catalyze the challenging HDA reaction of unactivated aldehydes and dienes with high selectivity. The reaction mechanism of the unique reactivity and high selectivity of the Fe(III)-catalyzed challenging ODA of unactivated aldehydes and dienes (Fig. 1) remains unclear and is much more complicated than that of the uncatalyzed ODA reaction due to various possible spin states and coordinate modes of Fe. the reaction dynamics of metal-catalyzed DA or HDA reactions, including this Fe-catalyzed ODA reaction, are completely unknown
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