Synthesis of tyrosyl-DNA phosphodiesterase i inhibitors

Article abstract of DOI:10.1016/j.tetlet.2016.05.017

The first report for the synthesis of tyrosyl-DNA phosphodiesterase I inhibitors 3,4-dimethoxyphenol-1-β-d-(6′-O-galloyl)glucopyranoside 3 and 3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol 2-β-d-(6′-O-galloyl) glucopyranoside 5 has been accomplished starting from readily available d-glucose as a starting material. An efficient and general approach has been reported for the synthesis of compounds 3 and 5 with an overall yield of 26% and 27%, respectively.

Full text of DOI:10.1016/j.tetlet.2016.05.017

Accepted Manuscript
Synthesis of Tyrosyl-DNA Phosphodiesterase I Inhibitors
Sagar D. Nale, Vrushali H. Jadhav
PII:
S0040-4039(16)30530-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.017
TETL 47635
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 April 2016
3 May 2016
4 May 2016
Please cite this article as: Nale, S.D., Jadhav, V.H., Synthesis of Tyrosyl-DNA Phosphodiesterase I Inhibitors,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.017
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Graphical Abstract
Synthesis of Tyrosyl-DNA Phosphodiesterase I
Inhibitors
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Sagar D. Nale and Vrushali H. Jadhav*

1
Tetrahedron Letters
Synthesis of Tyrosyl-DNA Phosphodiesterase I Inhibitors
Sagar D. Nale and Vrushali H. Jadhav*
Division of Organic Chemistry, National Chemical Laboratory (CSIR-NCL), Pune-411008, India. Email: vh.jadhav@ncl.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
The first report for the synthesis of tyrosyl-DNA phosphodiesterase I inhibitors 3,4-
dimethoxyphenol-1-β-D-(6′-O-galloyl)glucopyranoside 3 and 3-(4-hydroxy-3-methoxyphenyl)
Received in revised form
Accepted
Available online
propane-1,2-diol 2-β-D-(6′-O-galloyl) glucopyranoside 5 has been accomplished starting
from readily available D-glucose as a starting material. An efficient and general approach has
been reported for the synthesis of compounds 3 and 5 with an overall yield of 26% and 27%
respectively.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Tyrosyl-DNA
inhibitors
glycosylation
Topoisomerase I (Top1) tyrosine residue is covalently bound
to the 3′-phosphate moiety of DNA. Tyrosyl-DNA
phosphodiesterase I (Tdp1) is an enzyme that repairs DNA
lesions.1-5 Neurological disorders such as spinocerebellar ataxia
are caused due to mutation of Tdp1 gene. Hence there is a need
to study and synthesize Tdp1 inhibitors that could act
synergistically. Recently Tian et. al in 20156 isolated compounds
macropteranthol 1, alongwith with four analogues, namely,
O-galloyl) glucopyranoside 5a showed good inhibitory activity
against tyrosyl-DNA phosphodiesterase I with IC50 value of 1 M.
Due to the interesting biological property of compounds 3 and 5a
we report a first synthetic route to compounds 3 and 5 starting
from D-glucose.
mallophenol
galloyl)glucopyranoside 3, 3,4,5-trimethoxyphenol-1-β-D-(6′-O-
galloyl) glucopyranoside 4, and (S)-3-(4-hydroxy-3-
A
2,
3,4-dimethoxyphenol-1-β-D-(6′-O-
We visualized the retro synthesis of compounds 3 and 5
starting from D-glucose (Scheme 1). Compounds 3 and 5 can be
obtained by esterification of compounds A and B with tri-benzyl
protected acid followed by debenzylation whereas compounds A
and B can in turn be obtained by glycosylation with C, which can
methoxyphenyl)propane-1,2-diol-2-β-D-(6′-O-galloyl)
glucopyranoside 5a (Figure 1) from a bark of Australian plant
Macropteranthes leichhardtii and reported its inhibitory activity
against tyrosyl-DNA phosphodiesterase I. Among all the natural
products isolated by Tian et. al, compounds 3, 4-
inturn be obtained from D-glucose over
transformations.
a
series of
dimethoxyphenol-1-β-D-(6′-O-galloyl)glucopyranoside
3
and
(S)-3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol-2-β-D-(6′-

2
Tetrahedron
neighbouring group effect of the acetate in 75% yield.
Deacetylation of acetates in compound 17 using sodium
methoxide afforded compound 18 in 98% yield. Selective
esterification of primary hydroxyl in compound 18 using 3,4,5-
tribenzyloxybenzoic acid by insitu formation of 3,4,5-
tribenzyloxybenzoyl chloride afforded compound 19 in 52%
yield. Benzyl deprotection using ammonium formate in presence
of 10% Pd/C in methanol under reflux conditions afforded the
target compound 3 in good yield.
2,3,4,6-tetra-O-acetyl-D-glucopyranosyl
trichloroacetimidate 6 was prepared from D-glucose using the
reported procedure.7 Synthesis of 1-(benzyloxy)-3-(4-
(benzyloxy)-3-methoxyphenyl)propan-2-ol 10 was started from
eugenol 7 (Scheme 2). Protection of free hydroxyl in eugenol
using benzylbromide afforded benzyl protected eugenol 8 in 96%
yield.8 Dihydroxylation using osmium tetraoxide gave diol 9
which on monoprotection of primary hydroxyl using
benzylbromide afforded compound 10 in good yield.
Similarly synthesis of compound
5
was also
accomplished from 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl
trichloroacetimidate 6 (Scheme 4). Glycosylation of eugenol
derived compound 10 with trichloroacetimidate 6 in presence of
BF3OEt2 gave -glycosylated product 20 in 1:3 diastereomeric
Synthesis of 3,4,5-tribenzyloxybenzoic acid 14 was
achieved from gallic acid over series of transformations (Scheme
3). Esterification of gallic acid 11 using methanol in acidic
conditions afforded ester 12 in 92% yield, which on tri-
benzylation gave compound 13 in 90% yield. Hydrolysis of ester
in compound 13 under basic conditions afforded 3,4,5-
tribenzyloxybenzoic acid 14 in good yield.
1
ratio at C-2 centre as seen from H NMR spectrum. It was not
possible to separate the diastereomers of compound 20 on
column chromatography. Deacetylation using sodium methoxide
in methanol afforded compound 21 (1:3 diastereomeric ratio) in
98% yield. Selective esterification of primary alcohol in
compound 21 with 3,4,5-tribenzyloxybenzoic acid by insitu
formation of 3,4,5-tribenzyloxybenzoyl chloride afforded
compound 22 (1:3 diastereomeric ratio) in 56% yield.
Deprotection of the benzyl groups in compound 22 using
ammonium formate in presence of 10% Pd/C in methanol at
reflux conditions completed the synthesis of target compound 5
Synthesis of compound 3 was accomplished from
2,3,4,6-tetra-O-acetyl-D-glucopyranosyl trichloroacetimidate 6
over a series of transformations (Scheme 4). Glycosylation of
3,4-dimethoxyphenol with trichloroacetimidate 6 using BF3OEt2
afforded selectively the -glycosylated compound 17 due to the
1
in good yields. The H NMR spectrum showed 1:3 ratio of

3
stereoisomer at C-2 position. Both isomers in compound 5
showed same Rf on TLC and hence continuous efforts to separate
the isomers using various solvent system failed. HPLC was
recorded for compounds 5 and 20. It showed presence of two
isomers but no proper separation of isomers was seen even after
continuous efforts. It was thus difficult for us to separate the
isomers at every step in synthesis of compound 5. Thus we report
the synthesis of compound 5 as a 1:3 diasteromeric mixture at C-
V.H.J. thanks DST, New Delhi for the INSPIRE Faculty
Award (IFA 12, CH-44) and Fast Track Grant (CS-041/2013).
V.H.J also thanks Director, NCL for providing all the infra-
structural facilities.
References and notes
1.
2.
3.
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Pommier, Y. J. Biol. Chem. 2012, 287, 12848-12857.
Walker, S.; Meisenberg, C.; Bibby, R. A.; Askwith, T.; Williams,
G.; Rininsland, F. H.; Pearl, L. H.; Oliver, A.W.; Khamisy, S. El.;
Ward, S.; Atack, J. R. Anal Biochem. 2014, 454, 17-22.
Zhou, T.; Lee, J. W.; Tatavarthi, H.; Lupski, J. R.; Valerie,
Kristoffer.; Povirk L. F. Nucl. Acids Res. 2005, 33, 289-297.
Nguyen, T. X.; Morrell, A.; Sheridan, M. C.; Marchand, C.;
Agama, K.; Bermingam, A.; Stephen, A. G.; Chergui, A.;
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Cushman M. J. Med. Chem. 2012, 55, 4457–4478.
Tian, L. W.; Feng, Y.; Tran, T. D.; Shimizu, Y., Pfeifer, T.;
Forster, P. I, Quinn, R. J. J. Nat. Prod. 2015, 78, 1756-1760.
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68.
1
2 position. The spectral data ie. IR, H, 13C NMR and HRMS of
4.
5.
synthesized tyrosyl-DNA phosphodiesterase I inhibitors 3 was
found to be in good agreement with those reported in the
isolation paper9 and peaks in the 1H and 13C NMR that of 5 was
found to be in agreement with one of the isomer i.e 5a.10, 11
In conclusion, we have completed the total synthesis of
tyrosyl-DNA phosphodiesterase I inhibitors 3 and 5 in 7 steps
with an overall yield of 26% and 27% respectively in a simple
and efficient manner. The present approach towards the synthesis
of compounds 3 and 5 in general would be useful for the
synthesis of similar types of analogs and congeners of these
bioactive natural products.
6.
7.
8.
9.
Yadav, Y.; Owens, E. A.; Sharma, V.; Aneja, R.; Henary, M. Eur.
J. Med. Chem. 2014, 75, 1-10.
Saijo, R.; Nonaka, G. I.; Nishioka, I. Phytochemistry 1989, 28,
2443-2446.
10. Kikuzaki, H.; Sato, A.; Mayahara, Y.; Nakatani, N. J. Nat. Prod.
2000, 63, 749-752.
11. Zhoul, Y.; Chen, H.; Wang, B.; Liang, H.; Zhao, Y.; Zhang, Q.
Planta Med 2011, 77, 1944-1946.
Supplementary Material
Supplementary data (detailed experimental procedure,
characterization of the products and copies of spectra are
provided) associated with this article can be found, in the online
version.
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Acknowledgments

Highlights
Efficient glycosylation.
Synthesis of tyrosyl inhibitors using cheap and readily available starting
materials.
Simple and efficient synthesis of compounds 3 and 5 with good overall yield.