Hydrogenation of pyrrolizin-3-ones; new routes to pyrrolizidines

Despinoy, Xavier L. M.; McNab, Hamish

doi:10.1039/b910199c

Cited by 22 publications

(18 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sporadic reports of 3H-pyrrolizin-3-ones have appeared in the literature but little remains known about their chemistry and biological activity. [8][9][10][11][12][13] Complex structures incorporating a 3H-pyrrolizin-3-one-type core have been reported, including tricyclic pyrrolo-indolones, pyrrolo-isoindolones, tetracyclic isoindoloindolones and other polycyclic heterocycles. [14][15] A number of these are marine natural products or their derivatives.…”

Section: Synthesis and Preliminarymentioning

confidence: 99%

Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Kirk

Bezos

Willis

et al. 2016

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (7), 1813-1816. Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors Abstract Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that nonindoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of nonindoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib; the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to semaxanib at 10 μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors. Disciplines Medicine and Health Sciences Publication DetailsKirk, N. S., Bezos, A., Willis, A. C., Sudta, P., Suksamrarn, S., Parish, C. R., Ranson, M. & Kelso, M. J. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors.

show abstract

Section: Synthesis and Preliminarymentioning

confidence: 99%

Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Kirk

Bezos

Willis

et al. 2016

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

show abstract

“…The elimination of 18 yields 21 , which has been converted to (±)-isoretronecanol in two steps in low yield. 23 Alternatively, reduction and elimination provides lactam 20 . Further reduction yields lactam ester 22 , which has been converted to (±)-isoretronecanol in one step.…”

Section: Resultsmentioning

confidence: 99%

“…Herein we report the development of anhydride Mannich reactions (AMRs) using sulfone-substituted anhydrides for the synthesis of γ- and δ-lactams as well as a six-step formal synthesis of (±)-isoretronecanol. 22,23 …”

Section: Introductionmentioning

confidence: 99%

Diastereoselective Synthesis of γ- and δ-Lactams from Imines and Sulfone-Substituted Anhydrides

et al. 2014

View full text Add to dashboard Cite

Sulfone-substituted γ- and δ-lactams have been prepared in a single step with high diastereoselectivity. Sulfonylglutaric anhydrides produce intermediates that readily decarboxylate to provide δ-lactams with high diastereoselectivity. Substituents at the 3- or 4-position of the glutaric anhydride induce high levels of stereocontrol. Sulfonylsuccinic anhydrides produce intermediate carboxylic acids that can be trapped as methyl esters or allowed to decarboxylate under mild conditions. This method has been applied to a short synthesis of the pyrrolizidine alkaloid (±)-isoretronecanol.

show abstract

“…A possible mechanism involves initial hydrogenation of the pyrrole ring to the tetrahydro compound 10 followed by reduction of the ketone function via a small amount of the enol tautomer at its less hindered face (Scheme 2). 17 The dione 4 shows extensive active methylene chemistry. The CH 2 group exchanges rapidly in [ 2 H 4 ]methanol but rather more slowly under acidic conditions ([ 2 H]TFA; t 1 2 ca.…”

Section: Methodsmentioning

confidence: 99%

Pyrrolizine-1,3-dione

et al. 2010

Self Cite

View full text Add to dashboard Cite

Pyrrolizine-1,3-dione 4 was made by oxidation of the alcohol 2 using pyridinium chlorochromate. The dione 4 shows ketone properties (e.g. formation of DNP derivative 11) and, in common with other pyrrolizinones, the lactam unit is readily ring-opened by methanol under basic conditions. The active methylene unit of 4 couples readily with diazonium salts to provide the hydrazone 15 whose structure was confirmed by X-ray crystallography. The 'Meldrumsated' derivative 18 exists exclusively as the tautomer 18F; flash vacuum pyrolysis (FVP) of 18 at 700 degrees C gives the pyronopyrrolizine 20 exclusively. Reaction of 4 with DMF acetal gives the dimethylaminomethylene derivative 22 which exists as a mixture of rotamers at room temperature.

show abstract

Hydrogenation of pyrrolizin-3-ones; new routes to pyrrolizidines

Cited by 22 publications

References 39 publications

Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Diastereoselective Synthesis of γ- and δ-Lactams from Imines and Sulfone-Substituted Anhydrides

Pyrrolizine-1,3-dione

Contact Info

Product

Resources

About