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Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small-molecule inhibition of macromolecular machines.

An interdisciplinary course called "The Chemistry of Poisons" was created, featuring organic chemistry, biology, pharmacology, and toxicology content. This exploratory chemistry elective course was created by an instructor with a background in synthetic organic chemistry and a teaching assistant with a background in pharmacy practice. "The Chemistry of Poisons" features an interdisciplinary, student-centered approach to learning that provides a foundation for future academic initiatives to deliver chemical, pharmacological, and humanistic content in a manner that is both enjoyable for students and demonstrably facilitates knowledge and application level learning. Student course feedback and a retrospective survey were used to gauge student-perceived learning achievement. Survey results and feedback were consistent with knowledge and application level learning of course content and preference for interdisciplinary course design. These results warrant further development and study of interdisciplinary strategies for chemical education.

The total synthesis of racemic merrilactone A is described, which has featured a simultaneous and stereospecific creation of the C4 and C5 stereocenters via silyloxyfuran Nazarov cyclization. The results have suggested the participation of Lewis acidic silicon species in the Nazarov cyclization.

Research is presented concerning the total synthesis of racemic hispidospermidin. The four important steps leading up to the synthesis and the results of a preliminary SAR profile are discussed.

This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization- processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing- saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019. 1 Introduction 1.1 Alkyne-Carbonyl Coupling Pathways 1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction 2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles) 2.1 Early Work 2.2 Halide as Terminal Nucleophile 2.3 Oxygen as Terminal Nucleophile 2.4 Arene as Terminal Nucleophile (Intermolecular) 2.5 Arene Terminal Nucleophile (Intramolecular) 2.6 Cyclizations Terminated by Elimination 3 Synthetic Utility of Alkynyl Prins Annulation 3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo-- addition--Oxidation Sequence 3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors 3.3 Alkynyl Prins Cyclization in Natural Product Synthesis 4 Alkynyl Aza-Prins Annulation 4.1 Iminium Electrophiles 4.2 Activated Iminium Electrophiles 5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis 6 Summary and Outlook [ABSTRACT FROM AUTHOR]

The total syntheses of aglafolin, rocagloic acid, and rocaglamide are described by using Nazarov cyclization. The generation of the oxyallyl cation intermediate is accomplished by peracid oxidation of allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization.

The effects of the dienone substitution pattern on the reactivity and selectivity of the Nazarov cyclization are discussed.

A chiral auxiliary is employed to obtain, via Nazarov cyclization, a synthetic intermediate crucial to our previously reported synthesis of the tetrapetalone A core. This indane derivative, corresponding to the A and B rings of the tetrapetalone natural product skeleton, is then used to test an endgame strategy for installation of the β-rhodinosyl group on ring B. A palladium-catalyzed decarboxylative coupling is described that effects the exclusive formation of the desired β-glycosidic linkage, and the target rhodinose moiety can be obtained via hydrogenation. [ABSTRACT FROM AUTHOR]

A Nazarov cyclization/Wagner-Meerwein rearrangement pathway that produces unusual spirocyclic products is described. The transformations are found to be highly stereoselective, efficient for a range of substrate types and are capable of creating adjacent quaternary centers.

The synthesis of a ring-expanded bryostatin analogue is described, which has retailed all the functionalities in the byrostatins and their biological activities against many cancer cell lines. The main features of this analogue include a Ru-catalyzed tandem tetrahydropyran formation, a Pd-catalyzed tandem dihydropyran formation and a ring-closing metathesis.

An efficient stereoselective synthesis of (plusmin)-merrilactone A via catalytic Nazarov cyclization is described. The method involves Nazarov cyclization of a silyloxyfuryl enone as the key step.