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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.

In this review we highlight the general cyclization strategies currently available to organic chemists for the concurrent and stereoselective installation of multiple Quaternary Stereogenic Centers (QSC) atoms in cyclic or polycyclic architectures. QSCs embedded in rigid cyclic architectures are motifs found in many blockbuster drugs and important bioactive natural product classes, and yet, direct access to these structures stereoselectively from simple precursors remains a significant challenge. Underscoring the difficulty associated with their synthesis, such topologically three‐dimensional molecules are underrepresented in existing small molecule compound libraries, which are instead dominated by linear or flat molecules. This review focuses on methods disclosed in both natural product synthesis and methodology studies since the turn of the 21st century. The cases to be examined successfully achieve these challenging transformations: (1) one‐step assembly of the cyclized architecture; and (2) concurrent stereoselective installation of multiple (≥2) new QSCs. These cyclization strategies, which address the aforementioned fundamental challenges in complex molecule synthesis, have been categorized into five broad groups: i) Biomimetic Polyene Cyclization Cascades; ii) Cyclization Cascades of Prochiral Alkenes; iii) Cycloadditions; iv) Dearomatizations; v) Electrocyclizations. [ABSTRACT FROM AUTHOR]

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.

The successful development of Michael addition reaction sequence, which gives cyclopentenones directly from precursors alkylidene beta-ketoester substrates in high yield, creating three contiguous stereocenters with excellent diastereoselectivity, is reported. The sequence is efficiently catalyzed by Ir[Me(CO)(dppe)(DIB)](super 2 +) and occurs with high diastereoselectivity, creating new stereocenters.

The electrophilic Ir(III) complex having a labile DIB chelate is a very reactive catalyst for promoting the Nazarov cyclization of aryl and divinyl ketones. This is the first example of catalysis of the Nazarov cyclization using a well-defined cationic metal complex having two adjacent substrate sites.

A mild, Lewis acid-catalyzed procedure for Nazarov cyclization of polarized divinyl ketones is reported. Polarization in the cyclization, by utilizing Lewis acid with chiral ligands to promote enentioselective cyclization and synthetic applications of the methodology is highlighted.

A diastereoselective two-step strategy for the synthesis of densely functionalized 1-halocyclopentenes with several chiral centers has been developed. In the first step, a multicomponent alkynyl halo-Prins reaction joins an enyne, a carbonyl derivative, and either a chloride, bromide, or iodide to produce a cyclic ether intermediate. In the subsequent step, the intermediate is ionized to generate a halopentadienyl cation, which undergoes an interrupted halo-Nazarov cyclization. The products contain three new contiguous stereogenic centers, generated with a high level of stereocontrol, as well as a vinyl halide allowing for additional functionalization. The strategy creates two new carbon-carbon bonds, one carbon-halide bond, and one carbon-oxygen bond. [ABSTRACT FROM AUTHOR]

Oxygen heterocycles were synthesized via tandem palladium-catalyzed reactions.

The stereocontrolled total synthesis of hispidospermidin, a phospholipase C inhibitor, was reported. It was found that the 400MHz nuclear magnetic resonance spectrum of a true sample and that of the synthetic racemate were comparable. The total synthesis venture is believed to be of great potential for the generation of a wide range of analogs that will eliminate delicate SAR profiles.

A 1,6 conjugate addition/Nazarov electrocyclization/internal redox cyclization sequence was developed. Various 5-hydroxycyclopentenones were made through the 1,6-conjugate addition initiated Nazarov reaction with excellent diastereoselectivities. Under thermal conditions, these underwent a through-space 1,5-hydride-transfer/ring-closure reaction to form bridged bicyclic N-heterocyclic compounds with up to four stereogenic centers. It was also possible to convert simple acyclic dienyl diketones into the bicyclo[3.2.1] products in a one-pot process (with a solvent switch). [ABSTRACT FROM AUTHOR]

It has been possible to obtain two concise syntheses of the interleukin-8 receptor antagonist (+/-)-frondosin B from commercially available 5-methoxysalicylaldehyde. The absolute configuration of the secondary methyl centre in frondosin B was established as R.

The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum-based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization. [ABSTRACT FROM AUTHOR]

A wide variety of electron-rich arenes were efficiently converted into the corresponding iodinated compounds via a gold(I)-catalyzed reaction under mild conditions. [ABSTRACT FROM AUTHOR]

The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediates central to the cyclization. Methods reviewed include carbon-heteroatom ionization, double bond functionalization, nucleophilic addition, or electrocyclic ring opening. Additional variations, such as iso- and imino-Nazarov cyclization, employ unconventional substrates to produce new pentacycles. Here we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization. [ABSTRACT FROM AUTHOR]

Alkynones were treated with boron trifluoride diethyl etherate to generate β-iodoallenolates, which underwent intramolecular aldol reactions to produce cycloalkenyl alcohols. Diastereoselective oxa-Michael ring closure could then be induced by treatment with a catalytic amount of gold(III) chloride, affording highly functionalized tetrahydropyranone-containing ring systems. [ABSTRACT FROM AUTHOR]

An approach toward the carbon framework of various sesquiterpenes from the herbertane and cuparane families is described, including the concise total synthesis of enokipodin B. The key step is the construction of the vicinal quarternary centers of the skeleton through a tandem Nazarov cyclization/Wagner-Meerwein rearrangement mediated by a copper(II) complex. During this study, it was also found that changing the ligand architecture on the copper(II) promoter improved the chemoselectivity of the cationic rearrangement. [ABSTRACT FROM AUTHOR]

The discovery and elucidation of a new Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways. [ABSTRACT FROM AUTHOR]

The scope of the cycloaromatization of propargylic ethers was explored using operationally simple air- and moisture-insensitive conditions. Highly substituted phenol derivatives were obtained in high yields. Mechanistic experiments indicate that the reaction occurs by an electrocyclization followed by 1,3-proton transfer. [ABSTRACT FROM AUTHOR]