No abstract

Nitrogen heterocycles (azacycles) are common structural motifs in numerous pharmaceuticals, agrochemicals, and natural products. Many powerful methods have been developed and continue to be advanced for the selective installation and modification of nitrogen heterocycles through C–H functionalization and C–C cleavage approaches, revealing new strategies for the synthesis of targets containing these structural entities. Here, we report the first total syntheses of the lycodine-type Lycopodium alkaloids casuarinine H, lycoplatyrine B, lycoplatyrine A, and lycopladine F as well as the total synthesis of 8,15-dihydrohuperzine A through bioinspired late-stage diversification of a readily accessible common precursor, N -desmethyl-β-obscurine. Key steps in the syntheses include oxidative C–C bond cleavage of a piperidine ring in the core structure of the obscurine intermediate and site-selective C–H borylation of a pyridine nucleus to enable cross-coupling reactions.

No abstract

Antilipoperoxidant protein dysfunction is associated with many human diseases, suggesting that bilayer lipid peroxidation may contribute broadly to pathogenesis. Small molecule inhibitors of this membrane-localized chemistry could in theory enable better understanding and/or treatment of such diseases, but currently available compounds have important limitations. Many biological questions thus remain unanswered, and clinical trials have largely been disappointing. Enabled by efficient, building block-based syntheses of three atypical carotenoid natural products produced by microorganisms that thrive in environments of extreme oxidative stress, we found that peridinin is a potent inhibitor of nonenzymatic bilayer lipid peroxidation in liposomes and in primary human endothelial cells. We also found that peridinin blocks monocyte-endothelial cell adhesion, a key step in atherogenesis. A series of frontier solid-state NMR experiments with a site-specifically 13C-labeled isotopolog synthesized using the same MIDA boronate building block-based total synthesis approach revealed that peridinin is completely embedded within and physically spans the hydrophobic core of POPC membranes, maximizing its effective molarity at the site of the targeted lipid peroxidation reactions. Alternatively, the widely used carotenoid astaxanthin is significantly less potent and was found to primarily localize extramembranously. Peridinin thus represents a promising and biophysically well-characterized starting point for the development of small molecule antilipoperoxidants that serve as more effective biological probes and/or therapeutics.