Oxidative cyclizations of cyclic amidines
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OXIDATIVE CYCLIZATIONS OF CYCLIC AMIDINES. Raymond C F Jones , †a James N Iley b & Janet E Smith b a Dept. of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UK b Dept. of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK

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Oxidative cyclizations of cyclic amidines

OXIDATIVE CYCLIZATIONSOF CYCLIC AMIDINES

Raymond C F Jones,†a James N Ileyb & Janet E Smithb

aDept. of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UK

bDept. of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK

†e-mail [email protected]; fax: ++44(0)1908223926


Cyclic amidines as pseudopeptides
Cyclic amidines as pseudopeptides

  • The use of amide bond replacements is a well-known tactic in the search for agonists or antagonists at peptide receptors.

  • We have explored cyclic amidines as conformationally restricted amide bond replacements, and have prepared imidazolines (1)1 and TETRAHYDROPYRIMIDINES (2)2 as pseudodipeptides.

  • 1. R.C.F. Jones and J. Dickson, J. Peptide Sci., 2001, 7, 220, and refs. therein.

  • 2. R.C.F. Jones and A.K. Crockett, Tetrahedron Lett., 1993, 34, 7459.


Pyoverdins and the tetrahydropyrimidines
Pyoverdins and the tetrahydropyrimidines

  • We were intrigued to find the tetrahydropyrimidine (THP) amino acids (2) as components of the PYOVERDIN family of yellow-green fluorescent siderophores and of the co-occurring desferriferribactin siderophores found in Pseudomonas bacteria such as P. fluorescens.


Tetrahydropyrimidine amino acids
Tetrahydropyrimidine amino-acids

  • We have prepared in protected form some THP amino acids, including some that appear in the pyoverdin and related natural products.2


The chromophore oxidised thp amino acid
The chromophore: oxidised THP amino-acid

  • The Pyoverdin chromophore is also derived from a THP amino-acid after oxidative cyclization, as indicated below. This is consistent with:

    • co-isolation of siderophores having both uncyclized and cyclized tyrosine-based THP amino-acids (see sheet 3)

    • isolation of the isopyoverdins, having the isomeric chromophore

    • isolation of the 5,6-dihydro derivatives.


Model substrates for oxidative cyclisation
Model substrates for oxidative cyclisation

  • To model a biomimetic approach to the chromophore of pyoverdins, we prepared the aryl tetrahydropyrimidine (3) and imidazoline (4).


Oxidation with a hypervalent iodine reagent
Oxidation: with a hypervalent iodine reagent

  • The cyclic amidine substrates (3) and (4) were oxidised in alcohol solvents to give cyclohexadienones, that cyclized on alumina to afford pyrimido and imidazolo[1,2-a]quinolines.


Cyclisation to fused quinolines
Cyclisation to fused quinolines

  • X-Ray crystal structures confirm the structures and stereochemistry (cis ring junction) of the 6a-alkoxy-2,3,5,6,6a,9,10,10a-octahydro-1H-pyrimido[1,2-a]quinolin-9-ones.


Aromatisation the chromophore nearly
Aromatisation - the chromophore (nearly!)

  • Elimination of the “bridgehead” alcohol in strong acid leads to aromatisation of the benzene ring, and the ring system of the chromophore in reduced form, as found in the 5,6-dihydropyoverdins. Dehydrogenation is currently under investigation.


Acknowledgements
Acknowledgements

  • We wish to thank the Engineering and Physical Science Research Council and The Open University for funding to JES and for facilities.

  • We thank the National Service for X-Ray Crystallography (Southampton) for the X-ray crystal structures (Dr Simon Coles)

  • and the EPSRC National Mass Spectrometry Service Centre (Swansea) for MS data


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