Synthetic and Computational Study of Tin-Free Reductive Tandem Cyclizations of Neutral Aminyl Radicals.

5- exo, 5- exo Cyclizations of conformationally unbiased propargylic aminyl radicals proceed with excellent yield, chemoselectivity, and diastereoselectivity under tin-free reductive cyclization conditions, regardless of the electronic environments and intermediate radical stabilization resulting from various olefin substituents. These conditions avoid the need for slow addition of initiator and reductant. By contrast, analogous 6- exo, 5- exo cyclizations require substituents capable of intermediate radical stabilization to avoid premature reduction products. These experimental results are corroborated by computations that further establish the reactivity of these aminyl radicals upon exposure to tin-free cyclization conditions.

Tin-Free Access to the ABC Core of the Calyciphylline A Alkaloids and Unexpected Formation of a D-Ring-Contracted Tetracyclic Core.

A tin-free strategy for the successful cyclization of a variety of internal alkyne-containing N-chloroamine precursors to the ABC core via cyclization of a neutral aminyl radical is established. Deuterium labeling experiments confirm that the solvent is the primary source of the final H atom in the cyclization cascade. These conditions enabled a streamlined route to a ß-ketoester intermediate poised for intramolecular Knoevenagel condensation to construct the seven-membered D-ring of calyciphylline A alkaloids. However, exposure to CsF in t-BuOH at elevated temperatures led to an unexpected decarboxylation to form a D-ring-contracted tetracyclic core.