Alkoxyallene‐Based LANCA Three‐Component Synthesis of 1,2‐Diketones, Quinoxalines, and Unique Isoindenone Dimers and a Computational Study of the Isoindenone Dimerization

A series of β‐alkoxy‐β‐ketoenamides was prepared by the well‐established LANCA three‐component reaction of lithiated 1‐(2‐trimethylsilylethoxy)‐substituted allenes, nitriles, and α,β‐unsaturated carboxylic acids. The α‐tert‐butyl‐substituted compounds were smoothly converted into the expected 1,2‐diketones by treatment with trifluoroacetic acid. A subsequent condensation of the 1,2‐diketones with o‐phenylenediamine provided the desired highly substituted quinoxalines in good overall yield. Surprisingly, the α‐phenyl‐substituted β‐alkoxy‐β‐ketoenamides investigated afford not only the expected 1,2‐diketones, but also pentacyclic compounds with an anti‐tricyclo[4.2.1.12,5]deca‐3,7‐diene‐9,10‐dione core. These interesting products are very likely the result of an isoindenone dimerization which was mechanistically studied with the support of DFT calculations. Under the strongly acidic reaction conditions, a stepwise reaction is likely leading to a protonated isoindenone as reactive intermediate. It may first form a van der Waals complex with a neutral isoindenone before the two regio‐ and diastereoselective ring forming steps occur. Interestingly, two neutral or two protonated isoindenones are also predicted to dimerize giving the observed pentacyclic product

Regioselective Reactions of Highly Substituted Arynes

The fully regioselective reactivity of four new highly substituted silyl aryl triflate aryne precursors in aryne acyl-alkylation, acyl-alkylation/condensation, and heteroannulation reactions is reported. The application of these more complex arynes provides access to diverse natural product scaffolds and obviates late-stage functionalization of aromatic rings

Practical Spectrophotometric Assay for the \u3cem\u3edapE\u3c/em\u3e-Encoded \u3cem\u3eN\u3c/em\u3e-Succinyl-L,L-Diaminopimelic Acid Desuccinylase, a Potential Antibiotic Target

A new enzymatic assay for the bacterial enzyme succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) is described. This assay employs N6-methyl-N2-succinyl-L,L-diaminopimelic acid (N6-methyl-L,L-SDAP) as the substrate with ninhydrin used to detect cleavage of the amide bond of the modified substrate, wherein N6-methylation enables selective detection of the primary amine enzymatic product. Molecular modeling supported preparation of the mono-N6-methylated-L,L-SDAP as an alternate substrate for the assay, given binding in the active site of DapE predicted to be comparable to the endogenous substrate. The alternate substrate for the assay, N6-methyl-L,L-SDAP, was synthesized from the tert-butyl ester of Boc-L-glutamic acid employing a Horner-Wadsworth-Emmons olefination followed by an enantioselective reduction employing Rh(I)(COD)(S,S)-Et-DuPHOS as the chiral catalyst. Validation of the new ninhydrin assay was demonstrated with known inhibitors of DapE from Haemophilus influenza (HiDapE) including captopril (IC50 = 3.4 [± 0.2] μM, 3-mercaptobenzoic acid (IC50 = 21.8 [±2.2] μM, phenylboronic acid (IC50 = 316 [± 23.6] μM, and 2-thiopheneboronic acid (IC50 = 111 [± 16] μM. Based on these data, this assay is simple and robust, and should be amenable to high-throughput screening, which is an important step forward as it opens the door to medicinal chemistry efforts toward the discovery of DapE inhibitors that can function as a new class of antibiotics

Rhodium-catalysed hydroformylation of N-(2-propenyl)-β-lactams as a key step in the synthesis of functionalised N-[4-(2-oxoazetidin-1-yl)but-1-enyl]acetamides

Biologically relevant functionalised N-[4-(2-oxoazetidin-1-yl)but-1-enyl]acetamides have been prepared in a two-step approach starting from N-(2-propenyl)-beta-lactams, involving initial rhodium-catalysed hydroformylation followed by subjection of the obtained aldehydes to Staudinger reaction conditions after initial imination

Enantioselective and Regiodivergent Copper-Catalyzed Electrophilic Arylation of Allylic Amides with Diaryliodonium Salts.

A catalytic enantioselective and regiodivergent arylation of alkenes is described. Chiral copper(II)bisoxazoline complexes catalyze the addition of diaryliodonium salts to allylic amides in excellent ee. Moreover, the arylation can be controlled by the electronic nature of the diaryliodonium salt enabling the preparation of nonracemic diaryloxazines or β,β'-diaryl enamides.We are grateful to EPSRC, GSK and the University of Cambridge (E.C., H.P.J.M. & M.T.) and the ERC and EPSRC for fellowships (M.J.G.). Mass spectrometry data were acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University.This is the final version of the article. It first appeared from ACS via http://dx.doi.org/10.1021/jacs.5b0393

Highly efficient synthesis of trans-β,γ-unsaturated-α-keto amides

International audienceA highly efficient, metal-free, and selective access to trans-β,γ-unsaturated-α-keto amides is described via peptidic coupling, involving easy to prepare trans-β,γ-unsaturated-α-keto acids and commercially available amines

[Cp*Ru]-catalyzed selective coupling/hydrogenation

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