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Omar Ahmed, Peter B. Hitchcock and Douglas W. Young- Investigation of a route to ibotenic acid analogues via a reduced pyroglutamate template

Omar Ahmed, Peter B. Hitchcock and Douglas W. Young- Investigation of a route to ibotenic acid analogues via a reduced pyroglutamate template

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PAPER www.rsc.org/obc
| Organic & Biomolecular Chemistry
Investigation of a route to ibotenic acid analogues
via
a reducedpyroglutamate template
Omar Ahmed, Peter B. Hitchcock and Douglas W. Young*
Received 6th January 2006, Accepted 16th February 2006 First published as an Advance Article on the web 14th March 2006 
DOI: 10.1039/b600195e
Two alternative “ring switch” based syntheses have been shown to give access to the reduced protectedhomochiral analogues,
27
,
28
and
36
, of the CNS active compound ibotenic acid.
Introduction
(2
)-Glutamic acid is an excitatory neurotransmitter which in-teracts with a variety of ionotropic (ion channel controlling)and metabotropic (G-protein linked) receptors.
1
Analogues of glutamic acid have been shown to be specific in their action byinteracting with one or more of these receptors to give selectivephysiological effects. Thus,whilethenatural productibotenic acid
1
, an active constituent of the psychotropic fly agaric mushroom
Amanita muscaria
, acts at both ionotropic and metabotropicglutamate receptor sub-types,
1
analogues such as (
R
)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)-acetic acid [(
R
)-AMAA]
2
andDL-tetrazolylglycine
3
act specifically at the ionotropic
-methyl-
D
-aspartate (NMDA) receptor sub-type.
1
These compounds con-sist of a heterocyclic ring system fused to a glycine moiety.The homologue (
)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazoyl)-propionic acid (AMPA)
4
and many analogues which have aheterocyclic ring fused to the
-carbon of 
L
-alanine are activeat a different ionotropic glutamate receptor sub-type, the AMPAsite.
1
Glutamate receptors are involved in memory and learningprocesses and antagonists have been identified as potential drugsfor variety of neurodegenerative diseases,
2
including Alzheimer’sdisease,
2
epilepsy
2,3
and ischaemia.
2,4
Department of Chemistry, University of Sussex, Falmer, Brighton, UK BN19QJ 
Scheme 1
We have discovered a versatile and economical synthesis for alarge variety of homochiral compounds in which a heterocyclicring system is fused to the
-carbon atom of 
L
-alanine or the
c
-carbon atom of ethylglycine. These compounds were designed tohave potential for activity at individual receptors
5–9
and some haveshowninterestingCNSactivity.Thesynthesis,showninScheme1,involved reaction of aldehydes
5
of protected pyroglutamic acid(
n
=
1)
5–8
and of protected 6-oxopipecolic acid (
n
=
2),
9
withbisnucleophiles and involved a minimum of steps. We havechristenedthispowerfulsynthetictoola“ringswitching”reaction
5
and recently extended it to the use of 
-lactam aldehydes
12
fromwhich aplethoraofanalogues ofibotenicacid could beobtained
10
(Scheme 2).
1596
|
Org. Biomol. Chem.
, 2006,
4
, 1596–1603This journal is
©
The Royal Society of Chemistry 2006
 
Scheme 2
An alternative way of obtaining analogues of ibotenic acidmightbetoreactthepyroglutamate-3-aldehyde
19
withbisnucleo-philes and indeed reaction with a substituted hydrazine, as inScheme 3, might yield isomers
20
of the ibotenate analogues
15
,obtainedbythe
 b 
-lactamroute.
10
Further,reactionofanenone
21
Scheme 3Scheme 4Scheme 5
Reagents and conditions: (i) ref. 13; (ii) (a) O
3
, CH
2
Cl
2
,
78
C, 15 min (b) Ph
3
P, rt, 1 h (96%); (iii) (a) O
3
, CH
2
Cl
2
,
78
C, 15 min, (b) Zn,HOAc, rt, 1 h (18%); (iv) H
2
NNH
2
, MeOH, rt, 18 h (41%
27
); (v) MeNHNH
2
, MeOH, rt, 18 h (65%
28
); (vi) TBAF, THF, 0
C, then rt, 25 min (96%);(vii) RuO
2
·
H
2
O, NaIO
4
, H
2
O, CCl
4
 –CH
3
CN, rt, 18 h (35%).
with substituted hydrazines, as in Scheme 4, might yield the com-pounds
22
, reduced isomers of the ibotenate analogue
14
, whichwas obtained by the
-lactam route.
10
Unfortunately, synthesisof 3-substituted pyroglutamate derivatives such as the aldehydes
19
would best be approached
via
enones such as
21
, and we have
 This journal is
©
The Royal Society of Chemistry 2006
Org. Biomol. Chem.
, 2006,
4
, 1596–1603 |
1597
 
shown
11
thatsuchcompoundsareextremelypronetoracemisationanddimerisationunderverymildconditions.Wethereforedecidedto test the route using the reduced compounds
23
and
25
.
Results and discussion
The aldehyde
25
was prepared as shown in Scheme 5 by a similarroute to one we have previously used.
12
The 4-vinyl substitutedcompound
24
was prepared from the enone
23
by the method of HerdeisandHubmann.
13
Ozonolysisfollowedbyatriphenylphos-phine work-up then gave the aldehyde
25
. In an earlier ozonolysisreactionwherezincandaceticacidwereusedfollowedbymethanolin the work-up, the hemiacetal
26
was obtained. The structure of this compound was assigned on the basis of the spectral dataand confirmed by X-ray crystallography. The crystal structure isshown in Fig. 1, confirming the relative stereochemistry of two of thecentres,thehydroxylgroupbeingdisorderedovertwolocationsin the crystal, indicating a mixture of epimers.
Fig.1
X-Raystructuredeterminationof(4
,5
)-
-
tert
-butoxycarbonyl-5-
tert
-butyldiphenylsiloxymethyl-4-hydroxymethoxymethylpyrrolidin-2-one
26
.
Having prepared the desired aldehyde
25
, we were now in aposition to attempt the “ring-switching” reaction. We thereforereacted the aldehyde separately with hydrazine and with methyl-hydrazine and obtained the “ring-switched” products
27
and
28
in 41 and 65% yields, respectively. The urethane–lactam band at
ca.
1770cm
1
wasnolongerpresentintheinfra-redspectraofthesecompounds and the imine proton, H-6, appeared at
d
7.03 ppm inthe
1
HNMRspectrumofproduct
27
andat
 d
7.06ppmin
1
HNMRspectrum of product
28
. A characteristic exchangeable NHBocdoublet was present at
d
4.86 ppm in the
1
H NMR spectrum of product
27
andat
 d
4.74ppminthe
1
HNMRspectrumofproduct
28
.The “ring switch” reactions had, therefore, succeeded but,to prepare the desired ibotenic acid analogues
20
, it was nownecessary to deprotect the products to the corresponding alcoholsandthenoxidisethesetotheacids.The
-methylpyridazine
28
wasthereforetreatedwithtetrabutylammoniumfluorideintetrahydro-furantoaffordthealcohol
29
in96%yield.Whenthiswasoxidisedusing ruthenium oxide monohydrate and sodium periodate, noreaction was observed after 18 h at room temperature although,when2.2mol%ofcatalystand4.1equivalentsofsodiumperiodatewere used, a new, less polar product was obtained in 34% yield.This was evidently not the desired acid and the spectroscopic datasuggested that it might be the cyclic imino ether
30
. This, and therelative stereochemistry was confirmed by X-ray structure deter-mination (Fig. 2). An attempt to oxidise the primary alcohol
29
using ruthenium trichloride and periodate which had provedsuccessful in our hands
12
for oxidation of other protected aminoalcohols was unsuccessful, as was the use of oxygen and aplatinum catalyst.
Fig. 2
X-Ray structure determination of (4a
,5
)-5-
tert
-butoxycarbo-nylamino-2-methyl-3-oxo-2,3,4,4
a
,5,6-hexahydrofuro[2,3-
c
]pyridazine
30
.
The alternative “ring switching” reaction method of Scheme 4has already been carried out successfully on the reduced analogue
31
14
but when we reacted the TBDPS derivative
23
with hydrazinehydrate or with methylhydrazine no reaction ensued. We thereforedeprotected the TBDPS derivative
23
using tetrabutylammoniumfluorideandaceticacidintetrahydrofurantoobtainthealcohol
32
in quantitative yield as shown in Scheme 6. This was reacted with
tert
-butyldimethylsilyl triflate and lutidine in dichloromethane at
Scheme 6
Reagents and conditions: (i) TBAF, HOAc, THF, 0
C then rt, 18 h (quant.); (ii) TBDMSOTf, 2,6-lutidine, CH
2
Cl
2
,
78
C, then 0
C,30 min, then rt, 30 min (43%
31
+
43%
33
); (iii) TBDMSOTf, pyridine, CH
2
Cl
2
,
78
C, 30 min, then
10
C, 30 min then rt, 30 min (76%
31
);(iv) MeNHNH
2
, MeOH, H
2
O, rt, 18 h (80%); (v) aq. NaOH, MeOH, reflux, 18 h (48%); (vi) TBAF, HOAc, THF, 0
C, then rt, 18 h (61%).
1598
|
Org. Biomol. Chem.
, 2006,
4
, 1596–1603This journal is
©
The Royal Society of Chemistry 2006

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