Incorporation of the bioactive moiety of leinamycin into thymidine

Article abstract of DOI:10.1016/j.tetlet.2004.04.011

A simple synthesis of 1,2-dithiolan-3-ones from α,β-unsaturated thiophenyl esters has been elaborated. With the aim of introducing the biologically active 1,2-dithiolan-3-one-1-oxide moiety of leinamycin into a nucleoside, the method was successfully appl

Full text of DOI:10.1016/j.tetlet.2004.04.011

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4307–4309
Incorporation of the bioactive moiety of leinamycin into thymidine
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Akos Szilagyi, Istvan F. Pelyvas, Orsolya Majercsik and Pal Herczegh
*
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ꢀ
ꢀ
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Department of Pharmaceutical Chemistry and Research Group for Antibiotics of the Hungarian Academy of Sciences,
University of Debrecen, PO Box 70, H-4010 Debrecen, Hungary
Received 27January 2004; revised 22 March 2004; accepted 2 April 2004
Dedicated to Professor Ferenc Sztaricskai, on the occasion of his 70th birthday
Abstract—A simple synthesis of 1,2-dithiolan-3-ones from a,b-unsaturated thiophenyl esters has been elaborated. With the aim of
introducing the biologically active 1,2-dithiolan-3-one-1-oxide moiety of leinamycin into a nucleoside, the method was successfully
applied to thymidine-50-aldehyde.
Ó 2004 Elsevier Ltd. All rights reserved.
Leinamycin was isolated1 from the fermentation broth
Me
H
S
N
O
of a Streptomyces species, and besides antibacterial
activity, possesses anticancer activity on experimental
tumors in mice. It was shown that leinamycin inhibits
the synthesis of bacterial DNA and in vitro causes sin-
gle-strand cleavage of supercoiled double-helical plas-
mid DNA.2 The compound is built up3 from a thiazole-
containing 18-membered lactam to which a spiro-linked
1,2-dithiolan-3-one-1-oxide moiety is attached. This
sulfur-containing heterocycle, hitherto unknown in
natural compounds, was recognized as the ‘warhead’
responsible4 for the DNA-cleaving effect of the antibi-
otic. In addition to the total synthesis5 of leinamycin, the
preparation of various dithiolanone type compounds
has also been studied6–10 in order to develop simple
analogues of the parent antibiotic (Fig. 1).
O
S
N
H
S
O
OH
Me
H
OH O
Me
Figure 1. Structure of leinamycin.
Firstly, in a model reaction, 3-phenylpropionaldehyde
(1) was transformed by a Wittig reaction into the a,b-
unsaturated active ester 2, which was then treated with
hydrogen sulfide in dioxane in the presence of triethyl-
amine. Conjugate addition and nucleophilic substitution
by the SHÀ ion resulted in the formation of a mercap-
tothio acid 3, which was oxidized, without isolation,
with iodine into the disulfide, that is, the dithiolanone 4
(Scheme 1).
As Hara et al.2 have suggested that ‘a combination of
the 1,3-dioxo-1,2-dithiolane DNA-cleaving moiety with
a DNA recognition element might provide a novel
approach for the design of new cancer chemotherapeutic
agents’ we thought that this principle might be realized
by the incorporation of the foregoing, small heterocycle
into a nucleoside molecule. Although synthesis of the
1,2-dithiolan-3-one ring has been accomplished, we
intended to develop an alternative, new, simple metho-
dology allowing incorporation of this moiety into
nucleosides.
By applying this strategy to aldehydo-D
-arabinose11 (5),
compound 7 was obtained as a diastereoisomeric mix-
ture (Scheme 2).
Our goal was to incorporate the dithiolanone moiety
into uridine. Thus, a Wittig reaction of the aldehyde 9,
prepared12 from isopropylidene uridine (8), with phen-
ylthiocarbonylmethylenetriphenylphosphorane gave the
thioester 10, (Scheme 3) but subsequent thiolysis and
oxidation led to a complex reaction mixture.
Keywords: Leinamycin; DNA cleaving; Wittig reaction; Conjugate
addition; Ring closure.
* Corresponding author. Tel.: +36-52-512-900/2463; fax: +36-52-512-
914; e-mail: herczeghp@tigris.klte.hu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.011

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A. Szilꢀagyi et al. / Tetrahedron Letters 45 (2004) 4307–4309
SH SH
O
CHO
b
a
O
S
2
1
O
S
3
c
S
4
Scheme 1. Reagents and conditions: (a) (C6H5)3PCHCOSC6H5, toluene, rt, 48 h, 80%; (b) Et3N, H2S, 1,4-dioxane, rt, 2 h; (c) Et3N, I2, 1,4-dioxane,
rt, 1 h, 60% (b þ c).
S
S
O
S
O
O
O
O
O
O
a
b,c
O
CHO
H
O
O
O
O
O
O
7
6
5
Scheme 2. Reagents and conditions: (a) (C6H5)3PCHCOSC6H5, toluene, rt, 48 h, 78%; (b) Et3N, H2S, 1,4-dioxane, rt, 2 h; (c) Et3N, I2, 1,4-dioxane,
rt, 1 h, 63% (b þ c).
O
O
O
O
O
O
O
OHC
N
N
N
NH
NH
NH
a
HO
S
O
O
O
O
O
O
O
O
O
8
9
10
Scheme 3. Reagents and conditions: (a) (C6H5)3PCHCOSC6H5, toluene, rt, 48 h, 71%.
HS
S
O
O
O
11
O
O
N
N
NH
NH
O
O
O
O
O
O
'
11
HS
O
O
S
HSOC
O
O
N
N
NH
HSOC
NH
O
O
O
O
O
'
12
12
Scheme 4.
When oxidizing the 50-thio derivative 11 of uridine,
Goodman and co-workers13 observed the formation of
compound 110 (Scheme 4). In our case the presumed
intermediate 12 might also be in equilibrium with the
adduct 120. Goodman explained the transformation
11!110 in terms of the strained conformation of the
sugar carrying the dioxolane ring, which places the SH
group at an appropriate distance to the double bond to
permit addition.
We supposed that in the absence of the dioxolane ring
the intramolecular addition would be inhibited. There-

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A. Szilꢀagyi et al. / Tetrahedron Letters 45 (2004) 4307–4309
4309
O
O
O
S
O
O
N
OHC
N
NH
NH
a
b,c
O
O
O
13
TBDMSO
TBDMSO
14
O
S
S S
S
O
O
O
N
O
N
O
NH
NH
d,e
O
O
HO
TBDMSO
16
15
Scheme 5. Reagents and conditions: (a) (C6H5)3PCHCOSC6H5, toluene, rt, 48 h, 74%; (b) Et3N, H2S, 1,4-dioxane, rt, 2 h; (c) K3[Fe(CN)6], 1,4-
dioxane, rt, 16 h, 42% (b þ c); (d) p-TsOH, 1,4-dioxane–H2O ¼ 9:1, rt, 18 h, 47%; (e) dimethyl dioxirane, acetone, rt, 2 h, 96%.
fore, the thymidine derivative14 13 was converted into
2. Hara, M.; Saitoh, Y.; Nakano, H. Biochemistry 1990, 29,
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tion with phenylthiocarbonylmethylenetriphenylphos-
phorane. After treatment with hydrogen sulfide,
4. Asai, A.; Hara, M.; Kakita, S.; Kanda, Y.; Yoshida, M.;
oxidation of the intermediate with iodine gave a com-
Saito, H.; Saitoh, Y. J. Am. Chem. Soc. 1996, 118, 6802–
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6803.
oxidation was accomplished with potassium hexa-
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cyanoferrate(III) the expected dithiolanone 15 could be
isolated (Scheme 5). Desilylation under acidic condi-
tions, followed by oxidation8 with dimethyl dioxirane
then furnished the desired substance 16,15 biological
investigation of which are in progress.
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Acknowledgements
The authors thank the Hungarian Scientific Research
Fund for financial support (OTKA T 42512, 42567).
13. Reist, E. J.; Benitez, A.; Goodman, L. J. Org. Chem. 1964,
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References and notes
€
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15. All new compounds have been characterized by combus-
tion analysis and/or spectroscopic methods (MS, NMR).
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