Abstract
Medium-sized heterocycles exist in a broad spectrum of biologically active natural products and medicinally important synthetic compounds. The construction of medium-sized rings remains challenging, particularly the assembly of different ring sizes from the same type of substrate. Here we report palladium-catalyzed, regiodivergent [5 + 4] and [5 + 2] annulations of vinylethylene carbonates and allylidenemalononitriles. We describe the production of over 50 examples of nine- and seven-membered heterocycles in high isolated yields and excellent regioselectivities. We demonstrate the synthetic utility of this approach by converting a nine-membered ring product to an interesting polycyclic caged molecule via a [2 + 2] transannulation. Mechanistic studies suggest that the [5 + 2] annulation proceeds through palladium-catalyzed ring-opening/re-cyclization from the [5 + 4] adducts.
Highlights
Cyclic molecular frameworks have special importance in chemical research and industry.[1]
Our investigations began with a reaction between the accessible diene 1a and vinylethylene carbonate 2a
With a series of synthesized molecule fused pharmacologically privileged frameworks in hand and motivated by the pharmaceutical properties of nitrile,16a–c oxygen heterocycles1f and caged-skeletons,16d–h we preliminarily evaluated their ability to inhibit the proliferation of a panel of cancer cell lines (Scheme 3b)
Summary
Cyclic molecular frameworks have special importance in chemical research and industry.[1]. MSRs are challenging to prepare because of their inherent entropic factors and transannular interactions. Most established methods to generate MSRs are based on a xed reaction site and suitable only for rings of the same size;[4] changing the size of the ring usually requires changing the substrate design.[5] Such a substrate-controlled strategy can be quite costly and inefficient because of the need to prepare the necessary substrate variants and optimize them in the ring-forming reactions. It could be much more efficient to develop a way to generate medium-sized rings of various sizes from the same set of substrates, by altering the reaction conditions. To our knowledge, controlling the regioselectivity of mediumsized ring cyclization is notoriously difficult and remains underdeveloped[6] (Scheme 1a)
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