Linear and Convergent Syntheses of Bifunctional Hydroxy-Bisphosphonic Compounds as Potential Bone-Targeting Prodrugs

Sameh Aoun; Pierre Sierocki; Jacques Lebreton; Monique Mathé-Allainmat

doi:10.1055/s-0037-1611540

Synthesis, Table of Contents

Synthesis 2019; 51(18): 3556-3566
DOI: 10.1055/s-0037-1611540

paper

Linear and Convergent Syntheses of Bifunctional Hydroxy-Bisphosphonic Compounds as Potential Bone-Targeting Prodrugs

Sameh Aoun

,

Pierre Sierocki

,

Jacques Lebreton*

Université de Nantes, CNRS, Laboratoire CEISAM–UMR CNRS 6230, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France Email: monique.mathe@univ-nantes.fr Email: jacques.lebreton@univ-nantes.fr

,

Monique Mathé-Allainmat*

Université de Nantes, CNRS, Laboratoire CEISAM–UMR CNRS 6230, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France Email: monique.mathe@univ-nantes.fr Email: jacques.lebreton@univ-nantes.fr

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Abstract

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This article is dedicated to the memory of our colleague and friend Dr. Marc Padrines.

Abstract

The synthesis of two bifunctional compounds bearing a terminal hydroxy-bisphosphonic function (HBP) was achieved following a linear and a convergent strategy. In the linear approach, the free hydroxy-bisphosphonic function was introduced in the last step of the synthesis, under neutral conditions using an Arbuzov reaction with tris(trimethylsilyl) phosphite and a carboxylic acid precursor activated in situ with catecholborane. In the convergent approach, Huisgen type cycloaddition was studied starting from an HBP-functionalized alkyne partner to obtain the targeted bifunctional molecule. These complementary approaches allow for the preparation of complex bone-targeting molecules as potential prodrug candidates.

Key words

bisphosphonate - Arbuzov reaction - click reaction - bifunctional derivatives - prodrug

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References

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