Copper-catalysed dehydrogenation or lactonization of C(sp3)-H bonds.

Cytochrome P450 enzymes are known to catalyse bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation1,2. Developing analogous catalytic systems for remote C-H functionalization remains a significant challenge3-5. Here, we report the development of Cu(I)-catalysed bimodal dehydrogenation/lactonization reactions of synthetically common N-methoxyamides through radical abstractions of the γ-aliphatic C-H bonds. The feasibility of switching from dehydrogenation to lactonization is also demonstrated by altering reaction conditions. The use of a readily available amide as both radical precursor and internal oxidant allows for the development of redox-neutral C-H functionalization reactions with methanol as the sole side product. These C-H functionalization reactions using a Cu(I) catalyst with loading as low as 0.5 mol.% is applied to the diversification of a wide range of aliphatic acids including drug molecules and natural products. The exceptional compatibility of this catalytic system with a wide range of oxidatively sensitive functionality demonstrates the unique advantage of using a simple amide substrate as a mild internal oxidant.

Emerione A, a novel fungal metabolite as an inhibitor of New Delhi metallo-ß-lactamase 1, restores carbapenem susceptibility in carbapenem-resistant isolates.

OBJECTIVES: Bacterial strains that produce New Delhi metal-ß-lactamase 1 (NDM-1) are a worldwide health threat. It remains a challenging task to find a potent NDM-1 inhibitor for clinical practice. METHODS: Molecular docking and virtual screening of an in-house fungal natural product database for NDM-1 inhibitors were performed. Based on the screening results, the affinity and inhibition ability of potential NDM-1 inhibitors were determined using purified NDM-1. The efficacy of compounds in combination with four ß-lactam antibiotics (meropenem, imipenem, ceftriaxone and ampicillin) was evaluated. Morphological changes in Klebsiella pneumoniae ATCC BAA-2146 after treatment with the compounds were visualised by transmission electron microscopy. RESULTS: In silico screening led to the identification of four fungal products as potential NDM-1 inhibitors. Emerione A (1), a methylated polyketide with bicyclo[4.2.0]octene and 3,6-dioxabicyclo[3.1.0]hexane functionalities, has significant activity in cells (Kd = 11.8 ± 0.6 µM; IC50 = 12.1 ± 0.9 µM) and potentiates the activity of meropenem against two kinds of NDM-1-producing Enterobacteriaceae. To the best of our knowledge, emerione A (1) is the second fungal metabolite reported to exhibit NMD-1 inhibitory activity. According to the structural novelty of our database, we also found a new structural compound, asperfunolone A (2), with potential NMD-1 inhibitory activity. CONCLUSION: Considering the low toxicity of emerione A (1), it may represent a potential lead compound for anti-NDM-1 drug development.

Asymmetric Total Synthesis of Arcutinidine, Arcutinine, and Arcutine.

We have accomplished the asymmetric total synthesis of arcutinidine, arcutinine, and arcutine, three arcutine-type C20-diterpenoid alkaloids. A pentacyclic intermediate was rapidly assembled by using two Diels-Alder reactions. We developed a cascade sequence of Prins cyclization and Wagner-Meerwein rearrangement to construct the core of arcutinidine, which was then elaborated into an oxygenated pentacycle through a scalable route. Chemoselective reductive amination followed by spontaneous imine formation furnished the pyrroline motif in the final stage. We clarified the S configuration of the α-carbon of the acyl group within arcutine through chemical synthesis and crystallographic analysis.

Total Synthesis of Septedine and 7-Deoxyseptedine.

Septedine (2) is a hetidine type C20-diterpenoid alkaloid bearing an oxygenated heptacyclic scaffold. We have accomplished the first and asymmetric total synthesis of 2 and its 7-deoxy analogue 3. A functionalized tricyclic intermediate was prepared with excellent enantiopurity by using Carreira polyene cyclization. An unusual anionic Diels-Alder reaction was responsible for the construction of the bicyclo[2.2.2]octane. The α-methyl ketone was furnished by iridium-catalyzed allylic alcohol isomerization. Sanford Csp3-H oxidation was exploited to install the secondary hydroxy group of 2. The oxazolidinopiperidine was assembled by selective reductive amination and spontaneous N, O-ketalization at a final stage.

Identification and Mechanistic Studies of a Cell Cycle Regulator JP18 from a Library of Synthetic Indole Terpenoid Mimics.

We constructed a small library of indole terpenoid mimics using a hybridizing strategy to link various indole and α,ß-unsaturated enone building blocks together. Prepared compounds were evaluated for the cytotoxicity against a panel of cancer cell lines. An indolyl ketone called JP18 was identified as a cell cycle regulator, and the underlying mechanism was investigated.

Asymmetric total synthesis of mycoleptodiscin A.

The first total synthesis of mycoleptodiscin A, a structurally unusual indolosesquiterpenoid possessing an ortho-benzoquinone motif, has been accomplished. A sulfone alkylation coupled two readily available fragments to give an aryl triene intermediate. The tetracyclic core of the molecule was assembled through a highly enantioselective iridium-catalyzed polyene cyclization. The benzylic homologation was achieved by a cationic cyanation. The indole motif was constructed via a copper-mediated intramolecular C-N bond formation at a late stage.

Synthesis of indole terpenoid mimics through a functionality-tolerated Eu(fod)3 -catalyzed conjugate addition.

The chemical synthesis of indole terpenoids of structural and biological interests has attracted remarkable attention. Here we report an Eu(fod)3 -catalyzed indole conjugate addition reaction, which tolerates various acid-sensitive functional groups. A collection of indole terpenoid mimics have been prepared from natural product-derived α,ß-unsaturated enones on the basis of this reaction. The further conversion of the indole adducts into more complex natural product-like molecules has also been demonstrated.

Total synthesis of taiwaniadducts B, C, and D.

The first total syntheses of taiwaniadducts B, C, and D have been accomplished. Two diterpenoid segments were prepared with high enantiopurity, both through Ir-catalyzed asymmetric polyene cyclization. A sterically demanding intermolecular Diels-Alder reaction promoted by Er(fod)3 assembled the scaffold of taiwaniadducts B and C. A carbonyl-ene cyclization forged the cage motif of taiwaniadduct D at a late stage, providing over 200 mg of this compound.

Divergent total synthesis of taiwaniaquinones A and F and taiwaniaquinols B and D.

A divergent approach was developed toward the total synthesis of taiwaniaquinoids. An advanced intermediate 5a with trans A/B ring junction was concisely assembled by employing a Bi(OTf)3-catalyzed cationic cyclization and a Wolff-type ring contraction as key steps. This common intermediate was readily converted to racemic taiwaniaquinones A and F and taiwaniaquinols B and D, respectively.