Merging rearrangement with radical reactions is a largely unexplored field but may hold promise for approaching scaffolds that are inaccessible by other methodology. Here a tandem nucleophilic substitution/Brook rearrangement/singleelectron transfer oxidation/radical oxygenation strategy is presented, through which α,γ-dioxygenated ε, -unsaturated amides are efficiently prepared in a single step from enantiomerically enriched allylepoxides and 2-silylacetamides. The resulting compounds can be easily transformed by persistent [a] 2854 radical effect-based 5-exo-trig or 6-endo-trig radical cyclization reactions to functionalized carbocycles bearing three or four stereocenters. The stereochemical outcome of the cyclization reactions can predicted by the Beckwith-Houk model. The cyclic compounds can be easily diversified by post-cyclization modifications. The tandem process can be further extended by an acylation step leading to -dicarbonyl enolates, which were also transformed to cyclopentane and cyclohexane derivatives under oxidative conditions. Scheme 1. (A) Connectivity change and chirality transfer in a sigmatropic rearrangement. (B) Anionic rearrangement types. (C) Known rearrangementradical reaction sequences and the proposed strategy.atom has been recently frequently used to trigger further nucleophilic transformations with alkyl halides, [13] epoxides, [14] al-Full Paper

Pyrrolidones are common heterocyclic fragments in various biologically active compounds. Here, a two-step radical-based approach to γ-lactams bearing three to four stereocenters starting from epoxides, N-allylic silylacetamides and TEMPO is reported. The sequence starts with a new tandem nucleophilic substitution/Brook rearrangement/single electron transfer-induced radical oxygenation furnishing orthogonally protected α,γ-dioxygenated N-allylamides with wide scope, mostly good yields, and partly good diastereo- and enantioselectivity for defined combinations of chiral epoxides and chiral amides. This represents a very rare example of an oxidative geminal C–C/C–O difunctionalization next to carbonyl groups. The resulting dioxygenated allylic amides are subsequently subjected to persistent radical effect-based 5-exo-trig radical cyclization reactions providing functionalized pyrrolidones in high yields as diastereomeric mixtures. They converge to 3,4-trans-γ-lactams by base-mediated equilibration, which can be easily further diversified. Stereochemical models for both reaction types were developed.

Brefeldin A is an important natural product and biochemical tool with cell‐modulating and other diverse biological activities. To explore its chemical space, a generally applicable strategy for total syntheses of naturally occurring (+)‐brefeldin A (BFA), 2‐epi‐BFA, their diastereomers and analogs with varying macrocyclic ring size is reported. The five‐membered ring fragment was constructed by a short three‐step sequence consisting of tandem nucleophilic epoxide opening/Brook rearrangement/radical oxygenation and subsequent thermal radical cyclization based on the persistent radical effect. Further key steps are asymmetric aldehyde vinylation, which enables control of the absolute configuration at the allylic hydroxy group of BFA, cross‐metatheses reactions for attachment of the northern and southern side chains to the cyclopentane unit and final Shiina macrolactonization. The cytotoxic activity of all compounds was determined, and several analogs proved to be similarly active as BFA, providing insight about regions of the skeleton that can be varied or have to be conserved with respect to their biological activities. Fluorescence microscopy revealed that BFA and some non‐natural analogs disassemble the Golgi apparatus in cells with large variation of the disassembly and subsequent reassembly times.