Harnessing the intrinsic photochemistry of isoxazoles for the development of chemoproteomic crosslinking methods.

The intrinsic photochemistry of the isoxazole, a common heterocycle in medicinal chemistry, can be applied to offer an alternative to existing strategies using more perturbing, extrinsic photo-crosslinkers. The utility of isoxazole photo-crosslinking is demonstrated in a wide range of biologically relevant experiments, including common proteomics workflows.

Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput in silico screening.

Small molecules that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple molecules with nanomolar affinity for αS fibrils and moderate specificity for αS over Aß fibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to αS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified molecule. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging molecular targets.

Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives.

Discovery of enantioselective catalytic reactions for the preparation of chiral compounds from readily available precursors, using scalable and environmentally benign chemistry, can greatly impact their design, synthesis, and eventually manufacture on scale. Functionalized cyclobutanes and cyclobutenes are important structural motifs seen in many bioactive natural products and pharmaceutically relevant small molecules. They are also useful precursors for other classes of organic compounds such as other cycloalkane derivatives, heterocyclic compounds, stereodefined 1,3-dienes, and ligands for catalytic asymmetric synthesis. The simplest approach to make cyclobutenes is through an enantioselective [2 + 2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction which has a long history. Yet known reactions of this class that give acceptable enantioselectivities are of very narrow scope and are strictly limited to activated alkynes and highly reactive alkenes. Here, we disclose a broadly applicable enantioselective [2 + 2]-cycloaddition between wide variety of alkynes and alkenyl derivatives, two of the most abundant classes of organic precursors. The key cycloaddition reaction employs catalysts derived from readily synthesized ligands and an earth-abundant metal, cobalt. Over 50 different cyclobutenes with enantioselectivities in the range of 86-97% ee are documented. With the diverse functional groups present in these compounds, further diastereoselective transformations are easily envisaged for synthesis of highly functionalized cyclobutanes and cyclobutenes. Some of the novel observations made during these studies including a key role of a cationic Co(I)-intermediate, ligand and counterion effects on the reactions, can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates that are accessible by this route.

Tandem catalysis for asymmetric coupling of ethylene and enynes to functionalized cyclobutanes.

Transformation of simple precursors into structurally complex cyclobutanes, present in many biologically important natural products and pharmaceuticals, is of considerable interest in medicinal chemistry. Starting from 1,3-enynes and ethylene, both exceptionally inexpensive starting materials, we report a cobalt-catalyzed route to vinylcyclobutenes, as well as the further enantioselective addition of ethylene to these products to form complex cyclobutanes with all-carbon quaternary centers. These reactions can proceed in discrete stages or in a tandem fashion to achieve three highly selective carbon-carbon bond formations in one pot using a single chiral cobalt catalyst.

Gold-catalyzed α-furanylations of quinoline N-oxides with alkenyldiazo carbonyl species.

Gold-catalyzed α-furanylations of 8-alkylquinoline N-oxides have been achieved using alkenyldiazo carbonyl species as nucleophiles. The reactions are applicable to a reasonable range of alkenyldiazo species and 8-alkylquinoline N-oxides. The reaction mechanism is postulated to involve an initial nucleophilic addition of diazocarbonyl species at 8-alkylquinoline N-oxides, followed by diazo decomposition.

Gold-catalyzed cycloaddition reactions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl compounds: synthesis of isoxazolidine and benzo[b]azepine derivatives.

Gold-catalyzed cycloadditions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl species to yield isoxazolidine derivatives stereoselectively are described. Treatment of these isoxazolidine products with the same catalyst results in a novel 1,2-H shift/[3,3] rearrangement to give benzo[b]azepine compounds. The mechanism of this skeletal rearrangement is elucidated with deuterium-labeling experiments.

Zinc(II)-catalyzed intermolecular hydrative aldol reactions of 2-en-1-ynamides with aldehydes and water to form branched aldol products regio- and stereoselectively.

This work describes zinc(II)-catalyzed hydrative aldol reactions of 2-en-1-ynamides with aldehydes and water to afford branched aldol products regio- and stereoselectively. The anti and syn selectivity can be modulated by the sizes of sulfonamides to yield E- and Z-configured zinc(II) dienolates selectively. This new reaction leads to enantiopure aldol products by using a cheap chiral sulfonamide. The mechanistic analysis reveals that the sulfonamide amides of the substrates can trap a released proton to generate dual acidic sites to activate a carbonyl allylation reaction.

Gold-catalyzed oxa-Povarov reactions for the synthesis of highly substituted dihydrobenzopyrans from diaryloxymethylarenes and olefins.

Oxa-Povarov reactions involving readily available diaryloxymethylarenes and aryl-substituted alkenes are reported. Their [4+2] cycloadditions were efficiently catalyzed by IPrAuSbF6 (IPr=1,3-bis(diisopropylphenyl)imidazol-2-ylidene) with high diastereoselectivity. Product analysis revealed that the reactions likely proceed by a stepwise ionic mechanism, because both E- and Z-configured ß-methylstyrene gave the same cycloadducts in the same proportions.

Gold-catalyzed reactions between alkenyldiazo carbonyl species and acetals.

In the presence of catalyst IPrAuSbF6 catalyst (IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene), alkenyldiazo carbonyl species react with organic acetals to give E-configured alkyl 3,5-dimethoxy-5-pent-2-enoates stereoselectively. This reaction sequence comprises an initial Prins-type reaction, followed by gold carbene formation.

Gold-catalyzed formal [3 + 3] and [4 + 2] cycloaddition reactions of nitrosobenzenes with alkenylgold carbenoids.

We report two new formal cycloaddition reactions between nitrosobenzenes and alkenylgold carbenoids. We obtained quinoline oxides 3 in satisfactory yields from the gold-catalyzed [3 + 3]-cycloadditions between nitrosobenzenes and alkenyldiazo esters 1. For propargyl esters 5, its resulting gold carbenes react with nitrosobenzene to give alkenylimine 8, followed by a [4 + 2]-cycloaddition with nitrosobenzene.