https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Helicenes: synthesis and applications.

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

Department of Natural Products for Chemical Genetic Research, Key Laboratory of Brain Functional Genomics, Ministry of Education & Shanghai Key Laboratory of Brain Functional Genomics (MOE & SBFG), East China Normal University, Shanghai, 200062, China and Department of Pharmacognosy and National Center for Natural Products Research (NCNPR), School of Pharmacy, The University of Mississippi, Oxford, Mississippi 38677

Lamellarins and related pyrrole-derived alkaloids from marine organisms.

The emerging inverse electron demand Diels–Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.

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Inverse electron demand Diels–Alder reactions in chemical biology

A concise (nine-step) and effective (19% overall yield) total synthesis of ningalin D (1a) is disclosed and is based on a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole Diels-Alder strategy to assemble a fully substituted pyrrole core central to its structure. Additional highlights of the synthesis include a double Dieckmann condensation to introduce the C and D aryl rings enlisting substituents judiciously placed on the dienophile and intrinsic to the widely used tetrazine 2, a highly effective Suzuki coupling of the resulting C and D phenol triflates for introduction of the sterically demanding F and G aryl rings, and an unusually effective formal oxidative decarboxylation reaction cascade initiated by a Curtius rearrangement to directly provide the biphenylene quinone methide found imbedded in the structure of ningalin D. The cytotoxic and multidrug resistance (MDR) reversal activity of ningalin D, its derivatives, and the key synthetic intermediates are detailed.

Total synthesis of ningalin D.

The synthesis of 3,6-bis(3,4-dimethoxybenzoyl)-1,2,4,5-tetrazine (2) and the scope of its reactivity in inverse electron demand Diels-Alder reactions are disclosed representing the first systematic study of the [4 + 2] cycloaddition reactions of 3,6-diacyl-1,2,4,5-tetrazines.

Synthesis and inverse electron demand Diels-Alder reactions of 3,6-bis(3,4-dimethoxybenzoyl)-1,2,4,5-tetrazine.

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Jeffrey M. Zimpleman

Papers

Total synthesis of ningalin D.

Synthesis and inverse electron demand Diels-Alder reactions of 3,6-bis(3,4-dimethoxybenzoyl)-1,2,4,5-tetrazine.

Synthesis and Inverse Electron Demand Diels—Alder Reactions of 3,6-Bis(3,4-dimethoxybenzoyl)-1,2,4,5-tetrazine.