A Practical Synthesis of Differentially Protected 2-(Hydroxymethyl)piperazines

An efficient and scalable synthesis of three differentially protected 2-(hydroxymethyl)piperazines is presented, starting from optically active and commercially available (2S)-piperazine-2-carboxylic acid dihydrochloride. These synthetic building blocks are useful in the preparation of biologically active compounds and as chemical scaffolds for the construction of combinatorial libraries

Synthesis of Substituted Pyridines via Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates

Diels−Alder cycloadditions of oximinosulfonate 8 with a variety of 1,3-dienes proceed with regiochemistry opposite to that observed with conventional imino dienophiles, providing expeditious synthetic routes to substituted pyridines, tetrahydropyridines, and pyrrolines. The oximinosulfonate 8 is prepared in one convenient synthetic operation from Meldrum's acid and reacts with conjugated dienes at −78 °C in the presence of 2 equiv of dimethylaluminum chloride to afford [4 + 2] cycloadducts in good to excellent yield. Exposure of these cycloadducts to the action of NaOMe and N-chlorosuccinimide in methanol−THF at room temperature then produces substituted pyridines. The utility of this new two-step annulation protocol is demonstrated in total syntheses of the pyridine alkaloids fusaric acid and (S)-(+)-fusarinolic acid. Heating the [4 + 2] cycloadducts derived from 8 in a mixture of acetonitrile and pH 7 phosphate buffer induces an unusual Stieglitz-type rearrangement leading to the formation of interesting spirobicyclic pyrrolines

Self-Complementary Cavitands

Self-Complementary Cavitand

Efficient and Stereocontrolled Synthesis of 1,2,4-Trioxolanes Useful for Ferrous Iron-Dependent Drug Delivery

Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67–71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a <i>trans</i> relationship between the 3″ substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3″-substituted 4-nitrobenzoate analogue

Intramolecular [4 + 2] Cycloadditions of Iminoacetonitriles: A New Class of Azadienophiles for Hetero Diels−Alder Reactions

Iminoacetonitriles participate as reactive dienophiles in stereoselective intramolecular hetero Diels−Alder reactions which afford substituted quinolizidines. The cycloadduct with exo-oriented cyano group is obtained as the major or exclusive product of the reaction as a consequence of the α-amino nitrile anomeric effect The α-amino nitrile moieties incorporated in the cycloadducts constitute latent iminium ions, which upon exposure to mild protic or Lewis acids are unmasked, setting the stage for further useful synthetic transformations. For example, reductive decyanation with NaBH3CN excises the cyano group, while Bruylants reaction with Grignard reagents and acetylides lead to α-substituted amines. The substrates for these [4 + 2] cycloadditions are prepared from readily available alcohols via a Mitsunobu coupling reaction with the previously unknown, easily prepared reagent HN(Tf)CH2CN followed by cesium carbonate promoted elimination of trifluoromethanesulfinate

Simple One-Pot Synthesis of Disulfide Fragments for Use in Disulfide-Exchange Screening

Disulfide exchange screening is a method for evaluating the binding of small molecule fragments to proteins that have at least one accessible cysteine. While operationally simple, it does require a large library of small fragment molecules bearing disulfide-containing side chains. These specialized fragments are not available commercially and this has limited the adoption of the method. We report here a convenient one-pot procedure that enables facile preparation of disulfide screening fragments while also producing less of an environmental impact. The new synthetic method involves the initial formation of symmetric disulfides, followed by a disulfide exchange reaction in which the symmetrical dimer is converted into the final screening fragment by introduction of a solubilizing ‘cap’. The method is amenable to parallel synthetic methods and can be carried out in air without the need for the specialized equipment typically required for performing organic synthesis

Simple One-Pot Synthesis of Disulfide Fragments for Use in Disulfide-Exchange Screening

Disulfide exchange screening is a method for evaluating the binding of small molecule fragments to proteins that have at least one accessible cysteine. While operationally simple, it does require a large library of small fragment molecules bearing disulfide-containing side chains. These specialized fragments are not available commercially and this has limited the adoption of the method. We report here a convenient one-pot procedure that enables facile preparation of disulfide screening fragments while also producing less of an environmental impact. The new synthetic method involves the initial formation of symmetric disulfides, followed by a disulfide exchange reaction in which the symmetrical dimer is converted into the final screening fragment by introduction of a solubilizing ‘cap’. The method is amenable to parallel synthetic methods and can be carried out in air without the need for the specialized equipment typically required for performing organic synthesis

Simple Plate-Based, Parallel Synthesis of Disulfide Fragments using the CuAAC Click Reaction

Disulfide exchange screening is a site-directed approach to fragment-based lead discovery that requires a bespoke library of disulfide-containing fragments. Previously, we described a simple one-pot, two-step synthesis of disulfide fragments from amine- or acid-bearing starting materials. Here, we describe the synthesis of disulfide fragments that bear a 1,4-substituted-1,2,3-triazole linkage between disulfide and molecular diversity element. This work establishes the compatibility of copper­(I)-catalyzed azide–alkyne cycloaddition (CuAAC) chemistry with a one-pot, two-step reaction sequence that can be readily parallelized. We performed 96 reactions in a single deep-well microtiter plate, employing 48 alkynes and two different azide linker reagents. From this effort, a total of 81 triazole-containing disulfide fragments were obtained in useful isolated yields. Thus, CuAAC chemistry offers an experimentally convenient method to rapidly prepare disulfide fragments that are structurally distinct from fragments accessed via amide, sulfonamide, or isocyanate chemistries

Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

Clinical development of the antimalarial artefenomel was recently halted due to formulation challenges stemming from the drug’s lipophilicity and low aqueous solubility. The symmetry of organic molecules is known to influence crystal packing energies and by extension solubility and dissolution rates. Here we evaluate RLA-3107, a desymmetrized, regioisomeric form of artefenomel in vitro and in vivo, finding that the regioisomer retains potent antiplasmodial activity while offering improved human microsome stability and aqueous solubility as compared to artefenomel. We also report in vivo efficacy data for artefenomel and its regioisomer across 12 different dosing regimens

Synthesis of Aza-, Oxa-, and Thiabicyclo[3.1.0]hexane Heterocycles from a Common Synthetic Intermediate

An efficient and stereospecific approach to the synthesis of structurally constrained aza-, oxa-, and thiabicyclo[3.1.0]hexane heterocycles has been achieved through application of the intramolecular cyclopropanation reaction of diazoacetates. The various constrained heterocycles (X = N, O, or S) are conveniently prepared from a common diol intermediate accessible from readily available cinnamyl alcohols. Application of the methodology to the synthesis of conformationally constrained oxazolidinone antibacterials is also discussed