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

Marine natural products.

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.

Biaryls (two directly connected aromatic rings, Ar 1 -Ar 2 ) are common motifs in pharmaceuticals, agrochemicals, and organic materials. Current methods for establishing the Ar 1 -Ar 2 bond are dominated by the cross-coupling of aryl halides (Ar 1 -X) with aryl metallics (Ar 2 -M). We report that, in the presence of 1 to 2 mole percent of a gold catalyst and a mild oxidant, a wide range of arenes (Ar 1 -H) undergo site-selective arylation by arylsilanes (Ar 2 -SiMe 3 ) to generate biaryls (Ar 1 -Ar 2 ), with little or no homocoupling (Ar 1 -Ar 1 /Ar 2 -Ar 2 ). Catalysis proceeds at room temperature and tolerates a broad range of functional groups, including those incompatible with cross-coupling. These features expedite biaryl preparation, as demonstrated by synthesis of the nonsteroidal anti-inflammatory diflunisal.

/pdf/gold-catalyzed-direct-arylation-4qzj90ch1s.pdf

Gold-Catalyzed Direct Arylation

The design of synthetic routes by retrosynthetic logic is decisively influenced by the transformations available. Transition-metal-catalyzed C-H activation has emerged as a powerful strategy for C-C bond formation, with myriad methods developed for diverse substrates and coupling partners. However, its uptake in total synthesis has been tepid, partially due to their apparent synthetic intractability, as well as a lack of comprehensive guidelines for implementation. This Review addresses these issues and offers a guide to identify retrosynthetic opportunities to generate C-C bonds by C-H activation processes. By comparing total syntheses accomplished using traditional approaches and recent C-H activation methods, this Review demonstrates how C-H activation enabled C-C bond construction has led to more efficient retrosynthetic strategies, as well as the execution of previously unattainable tactical maneuvers. Finally, shortcomings of existing processes are highlighted; this Review illustrates how some highlighted total syntheses can be further economized by adopting next-generation ligand-enabled approaches.

Advancing the Logic of Chemical Synthesis: C-H Activation as Strategic and Tactical Disconnections for C-C Bond Construction.

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dual-specificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

https://www.mdpi.com/1660-3397/6/4/514/pdf

Tomohiro Yamaguchi

Papers

Total synthesis of lamellarins D, L, and N

The first total synthesis of lamellarin α 20-sulfate, a selective inhibitor of HIV-1 integrase

Total Synthesis of Lamellarins D (Ia), L (II), and N (Ib).