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Zhong Jin- Muscarine, imidazole, oxazole, and thiazole alkaloids

Zhong Jin- Muscarine, imidazole, oxazole, and thiazole alkaloids

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Muscarine, imidazole, oxazole, and thiazole alkaloids
Zhong Jin
Institute and State Key Laboratory of Elemento-organic Chemistry, Nankai University,Tianjin 300071, P. R. China. E-mail:jinzhong2000@263.net; Fax:
(00)86-(0)22-23503438
Received (in Cambridge, UK) 14th April 2003First published as an Advance Article on the web 16th October 2003
Covering: July 2001–December 2002. Previous review:
Nat. Prod. Rep.
, 2002,
19
, 454The occurrence, structure determination, biological activities, as well as total syntheses of muscarine, imidazole,oxazole and thiazole alkaloids have been reviewed. The literature covers from the middle of 2001 to the end of 2002,and 149 references are cited.
1 Introduction2 Muscarine alkaloids3 Imidazole alkaloids4 Oxazole and isoxazole alkaloids5 Thiazole alkaloids6 References
1 Introduction
Living organisms have proven to be a rich source of noveland structurally diverse natural products containing imidazole-, oxazole-, or thiazole-derived units and displaying a widevariety of biological activities. In particular, molecules iso-lated from marine organisms constitute an ever-growingsubset of all natural products collected, and among themare some of the most potent antitumor and cytotoxic agentsyet discovered.
1
The structural challenge and signi
cant bio-logical importance of these secondary metabolites havedriven the search for ever more e
cient approaches to theirsynthesis.This review covers the literature from the middle of 2001 tothe end of 2002, following on from the previous review
2
in theseries.
Born in Nanjin, P. R. China in 1973, Zhong Jin started to studyorganic chemistry at Nankai University in 1991. After graduation from Nankai University in 2000, he joined the research group of Professor Runqiu Huang as a lecturer. His research interestsinclude the discovery of novel bioactive substances, thedevelopment of selective and e
 ffi
cient organic syntheticmethodologies, and the total syntheses of natural products,especially alkaloids.
Zhong Jin
2 Muscarine alkaloids
During the past decades, much attention has been paid to themuscarine alkaloids, which were
rst isolated from
Amanitamuscaria
, a poisonous mushroom found in pinewoods, byreason of their ability to act as an acetylcholine agonist in theperipheral nervous system. More recently, the characterizationof many subtypes of muscarinic receptors has further enhancedthis interest. The naturally occurring diastereomers of muscarine are (
)-(2
,3
R
,5
)-muscarine
1
, (
)-(2
,3
R
,5
R
)-
allo
-muscarine
2
, (
)-(2
,3
,5
)-
epi 
-muscarine
3
, and (
)-(2
,3
,5
R
)-
epiallo
-muscarine
4
. Their cholinomimetic activityand simple but challenging structure has interested chemistsand biologists over the years.A formal short synthesis of (
)-muscarine
1
has beenaccomplished starting from methyl (
)-lactate.
3
The
O
-silylaldehyde
5
was prepared from methyl (
)-lactate in two e
cientsteps by sequential
O
-silylation and DIBAL-H reduction. Non-chelation controlled and highly
anti 
-selective addition of lithi-ated
O
-TBDPS propargyl alcohol favoured formation of theprotected yne-diol
6
. Lindlar reduction then provided the key
anti 
-(
) cyclization precursor
7
. 5-
endo
-Trig iodocyclisation of the protected (
)-ene-diol
7
, without removal of the protectinggroup, gave almost exclusively the iodo-tetrahydrofuran
8
.Removal of the iodine by hydrogenolysis proceeded unevent-fully to give the trisubstituted tetrahydrofuran
9a
, which was
nally deprotected to give the tetrahydrofuran-2-methanol
9b
.The diol
9b
was converted e
ciently into (
)-muscarine bysequential selective tosylation of the primary alcohol andthermolysis with trimethylamine in methanol at 80
C (Scheme1). A stereoselective synthesis of tetrahydrofurans has beenachieved by formal [3
2]-cycloaddition of allyl and crotyl-silanes with
α
-triethylsilyloxy aldehydes.
4
The methodologyprovided a concise pathway for the synthesis of (
)-
allo
-muscarine
2
and (
)-
epi 
-muscarine
3
.
3 Imidazole alkaloids
Six novel imidazole compounds, catharsitoxins A-F
10
 –
15
,have been isolated from the Chinese remedy qiung laug, which
584
Nat. Prod. Rep.
, 2003,
20
, 584605DOI:10.1039/b304142p
This journal is © The Royal Society of Chemistry 2003
 
has been used in China for more than 500 years to treat spas-modic contractions.
5
To con
rm their structures and ensure anadequate supply for further biological studies, catharsitoxins Aand D were synthesized.Alkaloid
16
has been isolated from the aerial part of 
Nitrariasibirica
Pall., along with a decahydroquinoline alkaloid.
6
Theirstructures were determined using chemical transformations andspectral data.Enantiomeric marine natural products are uncommon, and itis rare to
nd enantiomers with two or more chiral centers.Bioassay-directed fractionation of extracts of the delicate pinkstalked ascidian,
Hypsistozoa fasmeriana
collected at Tutukaka,North Island, New Zealand, a
ff 
orded the new (
)-enantiomerof 
trans
-5-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-4-(2-imid-azolyl)-1,2,3-trithiane
17
.
7
A second collection of 
H. fasmeriana
made at Leigh Harbor, Northland, a
ff 
orded (
)-
17
and twonovel dithiane alkaloids
18
and
19
. All spectroscopic dataobserved for (
)-
17
were identical to the literature valuesoriginally reported for (
)-
17
isolated from
Aplidium
species
Scheme 1
Reagents and conditions:
a) TBDPS propargyl ether,
n
-BuLi, 12-crown-4,
78
C, 4 h; b) H
2
, 5% Pd
 –
CaCO
3
, quinoline,MeOH, 20
C, 1 h; c) IBr (2 eq.), MeCN,
10
C, 5 h; d) H
2
, 5% Pd
 –
C,Et
3
N, MeOH, 20
C, 5 h; e) NH
4
F, MeOH, 20
C, 12 h.
and
Distaplia stylifera
, with the exception of the chiropticalproperties, which were equal in magnitude and opposite in signat every wavelength measured. Both enantiomers of 
17
exhib-ited identical biological activities in a range of assays, includingmodest cytotoxicity and antimicrobial properties.The symmetrical disul
de-linked marine alkaloid, poly-carpine
20
, which has a signi
cant inhibitory e
ff 
ect on thereverse transcriptase of avian myeloblastosis virus (and is there-fore a potential anti-HIV agent) and moderate antitumoractivity, has been isolated from the tropical ascidian
Polycarpaaurata
.
8
The cytotoxic and antitumor activities of polycarpinewere compared with those of some synthetic analogues.A series of novel antibiotics with activity against methicillin-resistant staphylococci and vancomycin-resistant enterococcihas been puri
ed from a strain of 
Streptomyces hygroscopicus
,LL-AC98, and their structures have been characterized usingspectroscopic analyses and chemical conversions.
9
These anti-biotics, designated mannopeptimycins
α
 –
ε
 
21
 –
25
, are glyco-sylated cyclic hexapeptides containing two stereoisomers of anunprecedented amino acid,
α
-amino-
β
-[4
-(2
-iminoimidazol-idinyl)]-
β
-hydroxypropionic adid (Aiha), as a distinguishingfeature. The cyclic peptide core of these antibiotics is attachedto a mannosyl monosaccharide moiety in
22
and to mannosylmonosaccharide and disaccharide moieties in
21
,
23
,
24
, and
25
. The presence and position of an isovaleryl group in theterminal mannose (Man-B) in
23
 –
25
are critical for retainingantibacterial potency.Wainunuamide
26
, isolated from the Fijian marine sponge
Stylotella aurantium
, is a new histidine-containing cyclicpeptide.
10
The peptide contains three proline residues and ahistidine residue, which is rare in cyclic peptides and has onlypreviously been reported in a cyclic peptide isolated fromthe cyanobacterium
Oscillatoria agardhii 
, suggesting a possiblesource of the peptide.
Nat. Prod. Rep.
, 2003,
20
, 584
 –
605
585
 
Further investigation of the extract of the seeds of 
Celosiaargentea
(Amaranthaceae) resulted in the isolation of three newbicyclic peptides, celogentins A
27
, B
28
, and C
29
, togetherwith a known related bicyclic peptide, moroidin
30
, originallyisolated from
Laportea moroides
(Labiatae).
11
A structure
 –
activity relationship study using moroidin derivatives as well ascelogentins A
 –
C and moroidin indicates that the bicyclic ringsystem, including the unusual connections between Leu, Trp,and His residues, the ring size and the conformation areimportant for their interaction with tubulin.Bromopyrrole alkaloids are characteristic secondary metab-olites found in marine Porifera belonging to several generaincluding
Axinella
,
Agelas
,
Acanthella
,
Pseudaxinyssa
and
Hymeniacidon
. Bioassay-guided fractionation of the methanolextract of the marine sponge
Stylissa caribica
, collected o
ff 
thecoast of Sweetings Cay, Bahamas, resulted in the isolation of two known bromopyrrole alkaloids containing 2-amino-imidazole or -imidazoline rings: dibromoisophakellin
31
andageliferin
32
, as well as a new compound
-methyl dibromo-isophakellin
33
.
12
Dibromoisophakellin
31
has also beenisolated from the marine sponge
Axinella carteri 
, collected on areed slope of Talakanen Island, Phillipines, along with a newisomeric 9,10-
seco
derivative, called ugibohlin.
13
Bioassay-monitored isolation of marine sponge
Axinella brevistyla
a
ff 
orded four new alkaloids: 3-bromomaleimide, 3,4-dibromo-maleimide, 12-chloro-11-hydroxydibromoisophakellin
34
and
-methylmanzacidin C along with the known dibromo-isophakellin
31
, tauroacidin
35
, taurodispacamide A
36
, girol-line
37
and 4,5-dibromopyrrole-2-carboxylic acid.
14
Thedichloromethane
 –
methanol extract of the sponge
Agelassventres
, collected o
ff 
the coast of North Cat Cay, Bimini,Bahamas, resulted in the isolation of three known alkaloids:hymenidin
38
, oroidin
39
, 4,5-dibromopyrrole-2-carboxylicacid, and a new bromopyrrole-derived alkaloid, sventrin
40
.
15
Four brominated compounds have been isolated from a Carrib-bean specimen of 
Agelas
sp. and one of them was identi
ed as anew bromopyrrole metabolite, monobromoisophakellin
41
.
16
Anew dimeric bromopyrrole alkaloid, bromosceptrin
42
, hasbeen obtained from a Florida keys specimen of 
Agelas conifera
along with
ve other known dimeric bromopyrrole alkaloids.
17
Their structures were established by MS spectrometry, and 1Dand 2D NMR spectroscopy.
586
Nat. Prod. Rep.
, 2003,
20
, 584
 –
605

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