One-pot synthesis of azanucleosides from proline derivatives

doi:10.1016/j.tetlet.2007.11.113

Tetrahedron Letters

Volume 49, Issue 3, 14 January 2008, Pages 455-458

https://doi.org/10.1016/j.tetlet.2007.11.113 Get rights and content

Abstract

Common cyclic amino acids, derived from proline and hydroxyproline, can be readily transformed into azanucleosides. The mildness of the reaction conditions, and the good yields obtained, make this procedure an interesting alternative to the conventional processes.

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Acknowledgments

This work was supported by the Research Programs PPQ2003-01379 and CTQ2006-14260/PPQ (Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerios de Ciencia y Tecnología y de Educación y Ciencia, Spain). We also acknowledge financial support from FEDER funds. D.H. thanks the Ministerio de Educación y Ciencia for a FPU fellowship and Gobierno de Canarias (Consejería de Industria)-CSIC for a research contract.

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Hydroxylated seco-analogs of cytotoxic phenanthroindolizidine alkaloids were prepared in good yields from inexpensive 4-hydroxyproline derivatives, in just two steps. Thus, a sequential oxidative radical scission–oxidation was used for the direct conversion of the proline derivative into a 2-(2-aryl-oxoethyl)pyrrolidine with a variety of aryl and heteroaryl groups. The 4R-stereogenic center allowed ready isomer separation, and stereocontrol in the introduction of new chains (interestingly, the 2,4-cis isomers predominated). In the second step, a cyclization reaction afforded alkaloid analogs with an indolizidinone core; a partial isomerization took place but the isomers were readily purified. Then the cytotoxic activity of the bicyclic indolizidinones and the simpler pyrrolidine derivatives was compared against tumorogenic human neuronal SHSY-5Y and breast cancer MCF7 cells. All the biphenyl derivatives displayed a potent activity (one derivative caused >80% cell death in both tumor lines at micromolar dosis), being comparable in the pyrrolidine and indolizidinone series.
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One-pot synthesis of azanucleosides from proline derivatives

Abstract

Graphical abstract

Section snippets

Acknowledgments

Tetrahedron

Synthesis

Angew. Chem., Int. Ed. Engl.

J. Am. Chem. Soc.

Org. Biomol. Chem.

Org. Lett.

Bioorg. Med. Chem. Lett.

J. Org. Chem.

Tetrahedron Lett.

Org. Lett.

Eur. J. Org. Chem.

J. Org. Chem.

J. Med. Chem.

Eur. J. Org. Chem.

Eur. J. Org. Chem.

J. Org. Chem.

Top. Curr. Chem.

J. Org. Chem.

J. Org. Chem.

Acta Biochem. Pol.

J. Chem. Soc., Perkin Trans. 1