Chemoselective flow hydrogenation approaches to isoindole-7-carboxylic acids and 7-oxa-bicyclio[2.2.1]heptanes

Hizartzidis, Lacey; Tarleton, Mark; Gordon, Christopher P.; McCluskey, Adam

doi:10.1039/c3ra47657j

Cited by 17 publications

(24 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is known that removal of the 7‐O atom and modifications to the 5,6‐bridge of the bicyclo[2.2.1]heptane moiety decrease analogue potency . Based on our prior development of norcantharidin analogues we envisaged two potentially facile routes to modified norcantharidins; Route A would afford a family of octahydroepoxyisoindole‐7‐carboxlic acids ( 7 a – n ; Scheme ), and Route B would result in the incorporation of furanyl amines into a second series of novel norcantharidin analogues ( 13 a – c ; Scheme ) . Route B offered the possibility of developing chimeric molecules combining features from our prior reports of cytotoxic norcantharidin analogues and cytotoxic acrylamide analogues .…”

Section: Resultsmentioning

confidence: 99%

“…[31,32] Based on our prior developmento fn orcantharidin analogues we envisaged two potentially facile routest om odified norcantharidins; Route A would afford af amily of octahydroepoxyisoindole-7-carboxlic acids (7a-n;S cheme 1), [33] and Route B would result in the incorporation of furanyl amines into a second series of novel norcantharidin analogues (13 a-c; Scheme2). [34] Route B offered the possibility of developing chimeric moleculesc ombining features from our prior reports of cytotoxic norcantharidin analogues and cytotoxic acrylamide analogues. [35][36][37] We first explored the synthesis of af ocused library of octahydroepoxyisoindole-7-carboxylic acids (7a-n).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues

et al. 2019

View full text Add to dashboard Cite

Octahydroepoxyisoindole analogues of norcantharidin were accessed through a Diels–Alder reaction of an amine‐substituted furan with maleic anhydride and subsequent reduction of the bicyclo[2.2.1]heptene olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity to norcantharidin, none of these analogues displayed notable cytotoxicity against the 11 cell lines examined: HT29 (colon), MCF‐7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2‐C (neuroblastoma), SJ‐G2 and U87 (glioblastoma), MIA (pancreatic), and SMA (spontaneous murine astrocytoma). The incorporation of an amino‐substituted system post‐synthesis of norcantharidin afforded facile access to 14 acid/amide‐substituted norcantharidin analogues. Of these, only four displayed sufficient activity at the initial 25 μm compound screening dose to warrant full evaluation of growth inhibition. Common to these analogues was the presence of a 4‐biphenyl moiety, and in particular 3‐(2‐(furan‐2‐ylmethyl)‐3‐(4‐biphenylamino)‐3‐oxopropylcarbamoyl)‐7‐oxabicyclo[2.2.1]heptane‐2‐carboxylic acid (13 c) and 3‐(2‐(pyrrole‐2‐ylmethyl)‐3‐(4‐biphenylamino)‐3‐oxopropylcarbamoyl)‐7‐oxabicyclo[2.2.1]heptane‐2‐carboxylic acid (24) displayed high levels of cytotoxicity, returning GI50 values of 15 nm (HT29) to 2.9 μm (U87) and 17 nm (SMA) to 2.8 μm (U87), respectively. These are the most cytotoxic norcantharidin analogues reported to date.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues

et al. 2019

View full text Add to dashboard Cite

show abstract

“…hydrogenation of 56 at 70°C resulted in reduction of olefin and ketone moieties affording 57, and reduction at room temperature gave 58 in an excellent yield (Scheme 16). 24 Catalyst selection imparts variations in the chemoselectivity of alkyne reductions with Lindlar or Pd impregnated γ-Al 2 O 3 catalysts facilitating partial hydrogenation of alkyne bonds. By contrast in the same system and a RANEY® Ni catalyst resulted in olefin and nitrile hydrogenation to 20 in a quantitative yield (Scheme 17).…”

Section: Chemoselective Olefin and Alkyne Hydrogenationmentioning

confidence: 99%

“…Homogenous organometallic catalysts, such as Rh-, Ru-and Ircomplexes, occupy the same phase as the reagent offering greater catalyst reactant contact but often prove difficult to partition from a reaction mixture and difficult to recycle. [22][23][24][25][26] Further, while the initial costs of catalyst cartridges is perceived by some as high, the economic, environmental and safety advantages quickly outweigh the initial cost. Pt, Pd, Ru, Re, Rh and Ir, all of which show excellent activity as activated charcoal, zeolite, alumina and silica supported reagents.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The expanding utility of continuous flow hydrogenation

et al. 2015

View full text Add to dashboard Cite

There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations. Moreover flow reactors enhance laboratory safety with pyrophoric catalysts contained in sealed cartridges and hydrogen generated in situ from water. This mini-review focuses on recent applications of flow chemistry to mediate nitro, imine, nitrile, amide, azide, and azo reductions. Methodologies to effect de-aromatisation, hydrodehalogenation, in addition to olefin, alkyne, carbonyl, and benzyl reductions are also examined. Further, protocols to effect chemoselective reductions and enantioselective reductions are highlighted. Together these applications demonstrate the numerous advantages of performing hydrogenation under flow conditions which include enhanced reaction throughput, yields, simplified workup, and the potential applicability to multistep and cascade synthetic protocols.

show abstract

Chemoselective Flow Hydrogenation Approaches to Diversify the Cytotoxic Tetrahydroepoxyisoindole Carboxamide Scaffold

et al. 2018

View full text Add to dashboard Cite

An Intramolecular Diels-Alder cycloaddition reaction between a furan diene and an alkynic dienophile was performed within a flow hydrogenator fitted with an inert titanium column at 150 8C, no H 2 , under 100 bar pressure. A single column pass (t R = 1.6 min) afforded % 55% conversion to the tetrahydroepoxyisoindole carboxamide scaffold with a product turnover of % 0.035 g/h, a 95% improvement over batch procedures. The cycloaddition protocol is performed in water and ethanol, and does not require catalysts or other additives. Quantitative hydrogenation of the resulting dual p-bonds within the oxabicyclo system was effected with either a 10% Pd/Al 2 O 3 or 10% Pd/CaCO 3 catalyst at 20 8C, 20 bar, with full H 2 whereas utilisation of a Raney Ni catalyst under these conditions resulted in a quantitative mono-olefin reduction of the C4-C5 double-bond. With regard to di-olefin reduction, a degree of stereoselectivity was observed with the aforementioned palladium-based catalysts yielding exclusive formation of (R) configuration at C7 while utilisation of a 5% Pt/C (sulfided) catalyst at temperatures below 60 8C promoted the formation of the (S)isomer at C7. Hence this work further highlights that flow-hydrogenation provides unprecedented convenience for establishing robust protocols to effect chemoselective transformations.

show abstract

Chemoselective flow hydrogenation approaches to isoindole-7-carboxylic acids and 7-oxa-bicyclio[2.2.1]heptanes

Cited by 17 publications

References 47 publications

Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues

Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues

The expanding utility of continuous flow hydrogenation

Chemoselective Flow Hydrogenation Approaches to Diversify the Cytotoxic Tetrahydroepoxyisoindole Carboxamide Scaffold

Contact Info

Product

Resources

About