Jimmy Wu

We report a new method for the synthesis of indolyl‐7‐azanorbornanes. The process involves the generation of a meta‐stable tetrahydro‐1,2,3‐triazepine intermediate that decomposes by extrusion of molecular nitrogen and ultimately leads to the formation of the observed products. The intermediacy of the triazepine intermediate was substantiated by trapping with allyl bromide to give an allylated triazepine compound that was sufficiently stable to be fully characterized in the usual ways.

We report a collection of “selectivity rules” for the dearomative (3+2) annulation reaction between substituted indoles and oxyallyl cations. The application of these rules enables us to synthesize four different regioisomeric permutations of the annulation products in a stereoselective fashion. We demonstrated that these products could be further transformed into hexahydro‐ and tetrahydrocarbazoles by nucleophile‐intercepted Beckmann fragmentation (NuBFr) and Beckmann fragmentation (BFr).

Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors.

The Beckmann elimination and nucleophile-intercepted Beckmann fragmentation (NuBFr) of oximes starting from regioisomeric indolinyl bicyclic ketones lead to products that are subjected to further synthetic manipulations and ultimately result in the stereospecific formation of densely functionalized hexahydrocarbazoles. The Pd-catalyzed Suzuki-Miyaura cross-coupling reaction of a key alkenyl bromide intermediate with various boronic acids gives arylated products.

We report a new method for the regiodivergent dearomative (3 + 2) reaction between 3-substituted indoles and oxyallyl cations.

The nucleophile-intercepted Beckmann fragmentation (NuBFr) has the potential to be broadly applicable to the synthesis of indoline alkaloid based natural products. However, the reaction has not been widely adopted, in part, because of limitations associated with the availability of appropriate promoter–Nu reagents. We have devised a stereospecific Ag(I)-promoted reaction for functionalizing NuBFr products to give novel compositions-of-matter that may be useful in synthesis and medicinal chemistry. With unhindered amine nucleophiles, structurally unique [2.2.2]-bicycloamidines are generated. We also disclose for the first time detailed density functional theory (DFT) studies which shed light on the mechanism of the NuBFr and Ag-promoted substitution reaction that supports an unusual aziridinium ion as a key intermediate.

We describe the first examples of nucleophile-intercepted Beckmann fragmentations of indoline oximes. This reaction uses MsCl as a promoter to give cyano chlorides and is believed to proceed through an aziridinium intermediate via a double stereoinvertive process. Mechanistic insights have led to the further discovery that oxygen, nitrogen, and bromide nucleophiles can be employed for this fragmentation by the use of other promoters. We envision that these products may be useful in the syntheses of members of the akuammiline and koumine families of indoline alkaloids.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

We report the first example of the rhenium-catalyzed allylation reaction of indolyl compounds by means of cross-coupling with propargyl ethers as non-obvious allylating reagents.

The first examples of (3 + 2) annulations between azaoxyallyl cations and cyanamides and nitriles to give the corresponding 2-aminoimidazolones and imidazolones are reported. On the basis of the isolation of unexpected imidate products with certain substrates, it is proposed that the reaction proceeds via fast kinetic O-alkylation followed by rearrangement to the thermodynamically favored 2-aminoimidazolones and imidazolones. The method was applied to the formal synthesis of the antihypertensive drug irbesartan.