Download Good & Bad Behaviour: Expected & Unexpected Annulations of

OXIDATIVE CYCLIZATIONS
OF CYCLIC AMIDINES
Raymond C F Jones,†a James N Ileyb & Janet E Smithb
aDept.
bDept.
of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UK
of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
†e-mail
[email protected]; fax: ++44(0)1908223926
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.
R2
O
H
N
R1
H
N
N
H
O
a dipeptide unit


N
N
R1
H
N
N
H
O
(1)
R1
N
H
O
(2)
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.
2
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.
O
HN
H
N
H2N
OH
N
H
N
+
N
O
O
Gly–Ser– D-threo-HOAsp–Ala–Gly–D-Ala–Gly
N
H
OH
NH
O
O
OH
Pyoverdin Pf CCM 2798
OH
CO2H
NOH
O
N
H
N
H2N
O
D-Ser–Lys–Gly–NH
N
H
NH
O
O
O
N
OH
N
H
N
H
CHO
OH
N
OH
CHO
OH
Desferriferribactin ATCC 13525
3
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
H2N
N
Tyr
I
H
N
H2N
O
ZHN
CO2Me
N
ZHN
H
N
N
H
SMe
EtOH, reflux
CO2Me
O
OCH2Ph
OCH2Ph
+
N
Ser
ZHN
N
I
SMe
OCH2Ph
ZHN
H
N
N
H
CO2Me
O
OCH2Ph
4
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.
O
N
H
N
HN
H
N 5
N
H
HN
H
N
N
O
5
N
O
6
6
OH
OH
OH
pyoverdin chromophore
OH
OH
isopyoverdin chromophore
5
Model substrates for oxidative cyclisation

To model a biomimetic approach to the chromophore of pyoverdins, we
prepared the aryl tetrahydropyrimidine (3) and imidazoline (4).
O
1. MeOSO 2CF3, DCM, 20ÞC
2. H 2N(CH 2)3NH2, EtOH reflux
3. H 2, Pd–C, MeOH
O
HN
N
H
CF3SO3
(quantitative)
4 steps
OH
NH2
OH
(3)
OH
OCH2Ph
1. MeOSO 2CF3, DCM, 20ÞC
2. H2N(CH 2)2NH2, MeOH reflux
3. H2, Pd–C, MeOH
HN
N
H
CF3SO3
(92%)
OH
(4)
6
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.
I(COCF3)2
HN
N
H
HN
CF3SO3
HN
N
H
CF3SO3
N
H
(R = Me, Et )
ROH, 20ÞC, 5 mins
(R = Me, Et, Pr i, Bu t)
CF3SO3
alumina
column
RO
RO
OH
O
O
(3)
HN
HN
N
H
CF3SO3
HN
N
H
CF3SO3
CF3SO3
N
H
(R = Me )
MeO
MeO
OH
(4)
O
O
7
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[1,2a]quinolin-9-ones.
N
HN
CF3SO3
N
H
N
MeO
O
8
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
N
HN
CF3SO3
N
CF3SO3H
H
dehydrogenation?
N
workup at pH8
N
6
MeO
O
5
OH
OH
OH
pyoverdin
chromophore model
9
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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