In contrast to nature, who generates structurally complex, cyclic secondary metabolites in a direct, highly controlled manner starting from linear precursors, the corresponding transformations are difficult to achieve in the laboratory. A breakthrough in this area was reported by Snyder in 2009 with the preparation of the antimonypentachloride-diethylsulfide-bromine complex BDSB, which, for the first time, was capable of cyclizing a wide range of linear 1,5-dienes. However, BDSB does not confirm to the requirements of modern halogenating agents, such as sustainability and atom economy. Within our work concerning selective and catalytic halogenation methods of alkenes, we discovered that standard X+-sources such as N-bromosuccinimide (NBS), NIS and 1,3-dichloro-5,5-dimethylhydanthoin (DCDMH) together with an unprecedented Lewis acid/base combination of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and morpholine were exceptionally well suited to promote biomimetic halonium-induced polyene cyclization reactions of a wide range of substrates. The method tolerates electron poor and –rich substrates, aromatic and O- nucleophiles as well as intermolecular nucleophilic quenching with water yielding mono, di, tri and tetracyclic products. In-depth mechanistic studies and control experiments with a plethora of fluorinated and standard solvents revealed interesting insights into the mode of action, underlining the unique and indispensable role of NBS, morpholine and HFIP in the success of these reactions. The presented method employs standard bench-stable reagents and is atom economic, scalable and easily conductible, paired with high yields and excellent diastereoselectivities, which makes it widely applicable to access halonium cyclized polyenes.

Biomimetic haliranium-induced polyene cyclizations

255th National Meeting (2018)

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