Synthesis of Thiangazole Analogs. [1]
Miroslav KRÍŽa), Vladimír BOBOŠÍK a), Ján ŠRAGA a)†, Juerg EHRLERb),
Thomas FRUEHb), Saleem FAROOQb)
a) Synkola, Areál PrivF UK, Pavilón CH-2, Mlynská dolina, 842 15 Bratislava,
Slovakia E-Mails:miro.kriz@post.sk, mkriz@pobox.sk
b) Novartis Crop Protection AG., CH-4002 Basel, Switzerland
The synthesis of analogs is one method for the improvement of biological
activity of natural products. The isolation, structure elucidation and biological activity
of thiangazole-a tris-thiazoline-oxazole metabolite isolated from the cell-extract of
Polyangium spec.-has been recently described [2,3,4]. It belongs to a family of natural
product known as tantazole and mirabazole [5,6,7] all having as characteristic structural
feature the linear assembly of tree thiazoline rings followed by an oxazole or thiazole
ring. In this contribution we describe the synthesis of some analogs of thiangazole
where the hydrophobic styryl part is replaced by various aromatics and heteroaromatics
moieties.
H
N
O
N
O
N
N
S
N
S
S
Thiangazol
e
The synthesis route involves 16 steps and follows basically the route of our published
total synthesis of thiangazole [8] by the stepwise formation of the three thiazoline rings
and final assembly of the oxazole ring (cf. Scheme 1). Condensation of enantiomerically pure methyl (R)-2-methylcysteine hydrochloride with various aryl and
heteroaryl carboxylic acid chlorides yielded the corresponding amide esters that were
cyclized to thiazolines similar Heathcoock's synthesis [9].Introduction of the second and
third thiazoline rings were accomplished by transformation to the corresponding acid
chloride, condensation with (R)-4 and subsequent cyclisation with TiCl4.
The terminal oxazole ring was formed by a slight modification of Masamune's [10]
procedure starting from the amide 16. Reaction of 16 with ethyl 3-bromo-2-oxo-butyrate
in the presence of cyclohexene oxide gave the corresponding 4-hydroxy-oxazoline that
was dehydrated by TFA in pyridine. Transformation of the oxazole esters with
methylamine in MeOH and KCN-catalysis yielded the corresponding oxazole amides.
(R)- 4
5 (a-h)
6 (a-h)
7 (a-h)
9 (a-h)
10 (a-h)
11 (a-h)
13 (a-h)
14 (a-h)
1 5 (a-h)
1 6 (a-h)
1 7 (a-h)
18 (a-h)
19 (a-h)
Enantiomerically pure methyl (R)- 2-methylcysteine was prepared by preparative
HPLC-separation on cellulose triacetate of ethyl 4-methyl-2-phenyl-thiazoline-4carboxylate (cf. Scheme 2) [8].
1
2
(R)-3
(R)-4
3
(S)-3
(S)-4
References:
[1]
This contribution was also published in the proceedings on VIIth Blue Danube
Symposium in Eger 1998, Hungary
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