Scott G. Stewart

Stereoselective Synthesis of 2,3-Dihydropyrroles from Terminal Alkynes, Azides, and α,β-Unsaturated Aldehydes via N-Sulfonyl-1,2,3-triazoles

A stereoselective method for synthesis of trans-2,3-disubstituted 2,3-dihydropyrroles is reported. N-Sulfonyl-1,2,3-triazoles prepared from terminal alkynes generate α-imino rhodium carbene complexes, which when combined with α,β-unsaturated aldehydes produce trans-2,3-disubstituted dihydropyrroles. The method can be successfully applied to a one-pot process starting from terminal alkynes.

Norcantharidin analogues: Synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition

Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide–acid norcantharidin analogues (15–26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC50 values of ∼15 and ∼3 μm, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC50 values in the range of 15–10 μM (PP1) and 11–5 μM (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.

Domino Heck-Aza-Michael Reactions: Efficient Access to 1-Substituted Tetrahydro-β-carbolines

A simple and efficient palladium-catalyzed domino reaction for the synthesis of a series of C1-substituted tetrahydro-beta-carbolines is described. This domino process involves a Heck reaction at the indole 2-position of a halogenated tryptamine precursor, followed by intramolecular aza-Michael addition.

A general approach to N-heterocyclic scaffolds using domino Heck-aza-Michael reactions.

Palladium-catalyzed domino Heck-aza-Michael reactions for the synthesis of a series of C1-substituted tetrahydro-β-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process involves the initial intermolecular Heck reaction of an aryl bromide with an electron deficient alkene, followed by an intramolecular aza-Michael reaction to form the new N-heterocycle in high yield.

New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles

A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFkappaB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.

Scalable synthesis of catalysts for the Mizoroki–Heck cross coupling reaction: palladium nanoparticles assembled in a polymeric nanosphere

Palladium nano-spheres 160 nm in diameter, as an assembly of uniform 5 nm nanoparticles, are accessible using a facile one step method under continuous flow on a spinning disc with hydrogen gas as the reducing agent. The stable colloidal system is an effective catalyst for the Mizoroki–Heck reaction, as established for the reaction between several aryl halides and n-butyl acrylate, and can be readily recycled without a change in their catalytic activity.

Biogenic production of palladium nanocrystals using microalgae and their immobilization on chitosan nanofibers for catalytic applications

Spherical palladium nanocrystals were generated from aqueous Na2[PdCl4] via photosynthetic reactions within green microalgae (Chlorella vulgaris). Electrospun chitosan mats were effective for immobilizing these biogenic nanocrystals, as a material for recycling as a catalyst for the Mizoroki–Heck cross-coupling reaction. This photosynthetically-driven metal transformation system can serve as a good candidate for an environmentally-friendly method for the synthesis of metal nanocatalysts.

The antiplasmodial activity of norcantharidin analogs

The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 μM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 μM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 μM, representing a fivefold enhancement over norcantharidin.

Inspiration from old dyes: tris(stilbene) compounds as potent gram-positive antibacterial agents.

Herein we describe the preparation and structure-activity relationship studies on range of stilbene based compounds and their antibacterial activity. Two related compounds, each bearing carboxylic acid moieties, exhibit good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12-0.25 μg mL(-1) and against Staphylococcus spp. with MICs ranging from 2-4 μg mL(-1). The derivative 17 showed increased activity with MICs of 0.06-0.25 μg mL(-1) against M. catarrhalis and 0.12-1 against Staphylococcus spp. This level of activity is similar to that reported for S. aureus for antibiotics, such as vancomycin, with MICs of ≤2.0 μg mL(-1) and clindamycin with MICs of ≤0.5 μg mL(-1). As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of tris(stilbene) compounds as antibacterial agents providing suitable properties for further development.

Formation and reactions of azepino[4,5-b]indoles: an unprecedented ozone reaction in the formation of novel benzo[c]naphthyridinones.

Herein we report the formation and interesting reactivity of several azepino[4,5-b]indole heterocycles. Initially, a key intramolecular Heck reaction is used to efficiently create the azepino[4,5-b]indole seven membered ring containing an exocyclic double bond. Treatment of the olefin with ozone results in an unprecedented secondary reaction of the Criegee intermediate, through intramolecular olefin trapping, to afford a benzo[c]naphthyridione containing a bridging cyclic peroxide.