Curriculum-based undergraduate research experiences (CUREs) have been shown to increase student retention in STEM fields and are starting to become more widely adopted in chemistry curricula. Here we describe a 10-week CURE that is suitable for a second-semester organic chemistry laboratory course. Students synthesize small molecules and use protein-observed 19F (PrOF) NMR to assess the small molecule's binding affinity to a target protein. The research project introduced students to multistep organic synthesis, structure-activity relationship studies, quantitative biophysical measurements (measuring Kd from PrOF NMR experiments), and scientific literacy. Docking experiments could be added to help students understand how changes in a ligand structure may affect binding to a protein. Assessment using the CURE survey indicates self-perceived skill gains from the course that exceed gains measured in a traditional and an inquiry-based laboratory experience. Given the speed of the binding experiment and the alignment of the synthetic methods with a second-semester organic chemistry laboratory course, a PrOF NMR fragment-based ligand discovery lab can be readily implemented in the undergraduate chemistry curriculum.

As fragment-based drug discovery has become mainstream, there has been an increase in various screening methodologies. Protein-observed 19F (PrOF) NMR and 1H CPMG NMR are two fragment screening assays that have complementary advantages. Here, we sought to combine these two NMR-based assays into a new screening workflow. This combination of protein- and ligand-observed experiments allows for a time- and resource-efficient multiplexed screen of mixtures of fragments and proteins. PrOF NMR is first used to screen mixtures against two proteins. Hit mixtures for each protein are identified then deconvoluted using 1H CPMG NMR. We demonstrate the benefit of this fragment screening method by conducting the first reported fragment screens against the bromodomains of BPTF and Plasmodium falciparum (Pf) GCN5 using 467 3D-enriched fragments. The hit rates were 6%, 5% and 4% for fragments binding BPTF, PfGCN5, and fragments binding both proteins, respectively. Select hits were characterized, revealing a broad range of affinities from low µM to mM dissociation constants. Follow-up experiments supported a low-affinity second binding site on PfGCN5. This approach can be used to bias fragment screens towards more selective hits at the onset of inhibitor development in a resource- and time-efficient manner.

Course-based undergraduate research experiences (CUREs) provide significant benefits to students compared to prescriptive ("cookbook") laboratory curricula. However, carrying out research on the scale of an undergraduate course can present logistical challenges. Fortunately, the CURE format provides significant flexibility to tailor curricula to meet the needs of various class sizes, disciplines, and student groups, and to fit with the resources available in the institutional environment. Here we present a diversity of experiences and perspectives on the implementation of CUREs, with the goal of offering examples and practical advice to current or prospective CURE practitioners while highlighting the numerous approaches available for incorporating authentic research into undergraduate laboratory courses.

The preparation of heterocyclic compounds using 1,3-dipolar cycloaddition chemistry is now well recognized in the fields of organic synthesis, drug discovery efforts, polymer chemistry, and materials science. As highlighted in this review, a growing area of interest in organic synthesis involves the enantioselectivity aspects of dipolar cycloaddition chemistry for the preparation of many different classes of natural products. Asymmetric synthesis of natural products using chiral substrates has been elegantly accomplished over the past decade using an assortment of dipole intermediates and represents the focus of this review article.

The synthesis of heterocyclic compounds has attracted significant attention for decades. Among the various heterocycles isolated from nature, alkaloidal natural products have received significant attention due to their diverse bioactivity. As highlighted in this minireview, a growing area of interest in organic synthesis involves the use of substituted 1,3-dipoles for the preparation of different alkaloidal natural products. Cascade reactions proceeding by an intramolecular 1,3-dipolar cycloaddition chemistry are of particular interest to the synthetic organic community because of the increase in molecular complexity involved and the high isolated yields. The synthesis of numerous alkaloids has been elegantly accomplished in recent years using an assortment of synthetic dipole intermediates.

AbstractReview: 54 refs + subrefs.

The synthesis of heterocyclic compounds has attracted significant attention for decades. Among the various heterocycles isolated from nature, alkaloidal natural products have received significant attention due to their diverse bioactivity. As highlighted in this minireview, a growing area of interest in organic synthesis involves the use of substituted 1,3-dipoles for the preparation of different alkaloidal natural products. Cascade reactions proceeding by an intramolecular 1,3-dipolar cycloaddition chemistry are of particular interest to the synthetic organic community because of the increase in molecular complexity involved and the high isolated yields. The synthesis of numerous alkaloids has been elegantly accomplished in recent years using an assortment of synthetic dipole intermediates.

The Polonovski, Pummerer, and Nef reactions have found wide application, and considerable effort has been invested in expanding the scope and selectivity of these reactions. Each of these reactions formally transfers the oxidation of a heteroatom to an adjacent carbon atom, and new methods seek to facilitate the formation of reactive intermediates or to divert the reactive intermediates toward new reaction paths. This chapter details the mechanisms, including stereo- and regiochemistry where appropriate and significant advances have expanded the utility of each reaction. Examples where alternative products were isolated, such as those resulting from Grob-type fragmentation or molecular rearrangements, are provided as well.

Increasing the size of the silyl group on 2-trialkylsilyloxyfurans reduces the rate of Diels–Alder reactions with maleic acid derivatives. While the exo-adduct resulted from the reaction between 2-silyloxyfurans and maleic anhydride, endo-adducts resulted from the reactions with maleate esters. Analysis of transition state structures for the cycloaddition, calculated at the B3LYP/6-31G∗ level of theory, revealed significant stretch-mode asynchronicity in the forming bonds, with selectivity arising from steric interactions that affect torsional strain about the shorter of the forming bonds.

This chapter contains sections titled Introduction Ammonium 1,3-Ylides 1,2-Ammonium Ylides Conclusion References

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While allylic migrations are well known, 1,3-sulfur shifts are relatively rare. These shifts occur through a variety of mechanisms depending upon the substrate type and the reaction conditions. Radical-chain, ion-pair, dipolar, and symmetry-forbidden 1,3-sigmatropic mechanisms have all been proposed. Allylic sulfur shifts have been used in the synthesis of sulfides and sulfones of higher complexity, the stereospecific synthesis of alkenes, and the construction of ketones. This comprehensive survey of 1,3-sulfur migrations pays particular attention to the reported mechanisms and synthetic application.

Sequential transformations enable the facile synthesis of complex target molecules from simple building blocks in a single preparative step. Their value is amplified if they also create multiple stereogenic centers. In the ongoing search for new domino processes, emphasis is usually placed on sequential reactions which occur cleanly and without forming by-products. As a prerequisite for an ideally proceeding one-pot sequential transformation, the reactivity pattern of all participating components has to be such that each building block gets involved in a reaction only when it is supposed to do so. The development of sequences that combine transformations of fundamentally different mechanisms broadens the scope of such procedures in synthetic chemistry. This mini review contains a representative sampling from the last 15 years on the kinds of reactions that have been sequenced into cascades to produce heterocyclic molecules.

Through a novel sequence of aminodiene Diels-Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an intramolecular Diels-Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered such that it participates in the cycloaddition as the 2pi component. A convenient way to construct the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal's diene. The presence of this activating group not only prevents the isomerization of the advanced ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle's ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately, our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid.

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