OXIDATIVE CYCLIZATIONS

OF CYCLIC AMIDINES

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

aDept. of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UKbDept. of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK

†e-mail r.c.f.jones@lboro.ac.uk; fax: ++44(0)1908223926

2

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.

HN

NH

N

R1 O

HN

NH

O

R1 O

HN

NH

N

R1 O

R2

a dipeptide unit (1) (2)

3

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.

NOH

ONHO

HN

OH

OH

OH

O

HN

NH

N

O

N

HN + Gly–Ser–D-threo-HOAsp–Ala–Gly–D-Ala–Gly

Pyoverdin Pf CCM 2798

HN

NH

NH

OH

O

OO

N

NH

OH

H2N

O

CO2H

NCHO

OH

NH

NCHO

OH

O

D-Ser–Lys–Gly–NH

OH

O

H2N

Desferriferribactin ATCC 13525

4

ZHN

OCH2Ph

N

SMe NH

NHN CO2Me

O

ZHN

OCH2Ph

ZHN

OCH2Ph

N

SMe NH

NHN CO2Me

O

ZHN

OCH2Ph

+

I

I

Tyr

H2N

H2NHN CO2Me

O

EtOH, reflux

Ser

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

5

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.

N

NH

HN

OH

O O

HN

OH

OH

N

HN

HN

OH

OH

N

HN

O

pyoverdin chromophore isopyoverdin chromophore

5

6

5

6

6

Model substrates for oxidative cyclisation

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

OH

O

OH

NH

HN

OH

OCH2Ph

O

NH24 steps

1. MeOSO2CF3, DCM, 20˚C2. H2N(CH2)3NH2, EtOH reflux3. H2, Pd–C, MeOH

1. MeOSO2CF3, DCM, 20˚C2. H2N(CH2)2NH2, MeOH reflux3. H2, Pd–C, MeOH

OH

NH

HN

(quantitative)

(92%)

(3)

(4)

CF3SO3

CF3SO3

7

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.

ROH, 20˚C, 5 mins

I(COCF3)2

NH

HN

O

O

NH

HN

RO

MeO

(R = Me, Et, Pri, But)

(R = Me)

aluminacolumn

(R = Me, Et)

HN

O

RO

O

MeO

N

N

NH

HN

OH

OH

NH

HN

(3)

(4)

CF3SO3

CF3SO3

CF3SO3

CF3SO3

HN

CF3SO3

CF3SO3

H

H

8

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.

HN

O

MeO

N

CF3SO3

H

N

N

9

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.

HN

O

MeO

N

CF3SO3

HCF3SO3H

N

OH

N

workup at pH8

dehydrogenation?

HN

OH

OH

N

pyoverdinchromophore model

5

6

10

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