Scheme 1. Retrosynthetic Approach for the Key Intermediates 3a,b
search for agents able to target the NNRTIs drug-resistant
protected derivatives of compound 1. Two different synthetic
routes were then planned for the synthesis of the key
intermediates 3a,b (Scheme 1): according to route A, 3a,b
could be obtained after cyclization of S-methylisothiourea
(SMT) with the â-ketoesters 7a,b and final O-deacetylation.
The intermediates 7a,b could be achieved after condensation
of potassium ethyl 2-methyl malonate with 6a,b, which could
in turn be obtained via oxidation of 5a,b. According to route
B, the key intermediates 3a,b could be obtained via Grignard
reaction on the aldehyde 2, which could in turn be obtained
after deprotection of the acetal 12 resulting from the
cyclization of SMT with the â-ketoester 11.
mutants, many different modifications have been performed
on the pyrimidinone scaffold of the DABO-family during
the past 25 years: (i) introduction of different chains at
position C-2; (ii) substitution of the hydrogen in C-5 with
bulkier groups; (iii) introduction of different substituents on
the phenyl ring at position C-6; and (iv) substitution of the
phenyl ring in C-6 with different aromatic or heteroaromatic
moieties.6 However, few modifications of the arylmethyl
carbon at the C-6 position have been reported so far, and it
has been recently shown by Ji et al.7 that this kind of
functionalization led to potent anti-HIV-1 DABOs, although
only biological data for the HIV-1 (wt) infected MT-4 cells
were disclosed.8
Herein, we report a straightforward and versatile approach
for the synthesis of C-6 arylmethyl-functionalized S-DABO
analogues (general structure I, Figure 1) accessible by
consecutive functionalization of the C-6 hydroxy group in
the key intermediates 3a,b (Scheme 1). The identification
of a lead compound belonging to a new family of S-DABO
cytosine analogues is also disussed.
Scheme 2
In our original idea, the key intermediate 3a could be
obtained by two alternative pathways, namely the direct
lithiation in C-6 and reaction with the appropiate aldheyde9
or passing through the C-6-formyl intermediate 2 (Scheme
2).10 However these approaches were unsuccessful even
starting from the corresponding N3-benzyl- and O-benzyl-
(4) Botta, M.; Artico, M.; Massa, S.; Gambacorta, A.; Marongiu, M. E.;
Pani, A.; La Colla, P. Eur. J. Med. Chem. 1992, 27, 251-257.
(5) (a) Manetti, F.; Este´, J. A.; Clotet-Codina, I.; Armand-Ugo´n, M.;
Maga, G.; Crespan, E.; Cancio, R.; Mugnaini, C.; Bernardini, C.; Togninelli,
A.; Carmi, C.; Alongi, M.; Petricci, E.; Massa, S.; Corelli, F.; Botta, M. J.
Med. Chem. 2005, 48, 8000-8008. (b) Cancio, R.; Mai, A.; Rotili, D.;
Artico, M.; Sardella, G.; Clotet-Codina, I.; Este´, J. A.; Crespan, E.; Zanoli,
S.; Hu¨bscher, U.; Spadari, S.; Maga, G. ChemMedChem 2007, 2, 445-
448.
(6) Artico, M. Drugs Future 2002, 27, 159-175.
(7) Ji, L.; Chen, F.-E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J.
Med. Chem. 2007, 50, 1778-1786.
(8) The work cited in ref 7 was published during the preparation of the
present manuscript whose content was already disclosed in the MD thesis
of one of the authors: Contemori, L. MD thesis, University of Siena, Siena,
Italy, 2006.
Following the approach described in route A, 4-fluoroben-
zaldehyde 4a was converted in compound 5a via reaction
with ethynylmagnesium bromide and subsequent protection
of the R-hydroxy group as acetyl derivative (Scheme 3).
Compound 5a was then oxidized to the corresponding
carboxylic acid 6a, which was activated as imidazolide and
then reacted with potassium ethyl 2-methylmalonate to give
the â-ketoester 7a. Unfortunately, the subsequent condensa-
tion of 7a with SMT did not afford the expected pyrimidi-
none 8a, while the lactone 9a was obtained as the only
product. This synthetic pathway could represent, however,
an alternative approach for the synthesis of 3,5-disubstituted
(9) Petersen, L.; Jessen, C. H.; Pedersen, E. B.; Nielsen, C. Org. Biomol.
Chem. 2003, 1, 3541-3545.
(10) Megati, S.; Sodum, R.; Otter, G. M.; Klein, R. S.; Otter, B. A.
Bioorg. Med. Chem. Lett. 1994, 4, 469-472.
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