Synthesis of new carbocyclic C-nucleoside analogs

                Prashant Khirsariya^*1, 2, Lukáš Maier^1^, 2 and Kamil Paruch^1^, 2

                                                 ^

  ^1Masaryk University, Faculty of Science, Department of Chemistry, Kamenice 5/A8, 623 00 Brno,
                                          Czech Republic

^2International Clinical Research Center, St. Anne’s University Hospital Brno, Pekarska 53, 656 91
                                       Brno, Czech Republic

                                      *prashant@mail.muni.cz


The chemical modification of nucleosides has been – and will continue to remain – a major research
topic in medicinal chemistry. Classical nucleoside analogs (A) constitute an important class of
biologically active compounds, which has promising antiviral and anticancer properties^1. Since
they possess labile hemiaminal motif, extensive effort has been invested into the identification of
more stable substances while preserving the biological activity, e.g. C-nucleosides (B) or
carbocyclic N-nucleosides (C).


It is conceivable that, at least in some cases, carbocyclic C-nucleosides (D) might be even more
robust versions of nucleoside analogs B and C. In addition, installation of certain substituents
(e.g. R^1 = OH) is meaningful only in this class as this would lead to chemically unstable ketals
and aminals in the series A, B and C. However, analogs D are quite rare and most published
syntheses only produced single target compounds^2.


Our recently developed flexible synthesis of compounds D enables selective manipulation of
individual positions around the cyclopentane ring, including highly diastereoselective installation
of carbo - and heterocyclic substituents at position 1´, orthogonal functionalization of position
5´, and efficient inversion of stereochemistry at position 2´, which are important for subsequent
SAR development. Some of the newly prepared carbocyclic C-nucleosides inhibit human DNA
glycosylases.


References:

1 a) Modified Nucleosides in Biochemistry, Biotechnology and Medicine; Ed.: P.       Herdewijn,
Wiley-VCH, 2008. (b) Chemical Synthesis of Nucleoside Analogues;     Ed.: P. Merino, Wiley, 2013.

2 a) Just, G.; Reader, G. Tetrahedron Lett. 1973, 14, 1524. b) Just, G.; Kim, S.     Tetrahedron
Lett. 1976, 17, 1063. c) Just, G.; Ouellet, R. Can. J. Chem. 1976, 54,     2925. d) Chun, B. K.;
Song, G. Y.; Chu, Ch. K. J. Org. Chem. 2001, 66, 4852. e)     Rao, R. J.; Schinazi, R. F.; Chu, Ch.
K. Bioorg. Med. Chem. 2007, 15, 839. f)     Maier, L.; Hylse, O.; Nečas, M.; Trbušek, M.; Arne, M.
Y.; Dalhus, B.; Bjoras, M.;     Paruch, K. Tetrahedron Lett., 2014, 55, 3713.