Synthesis of linear D-alt-L peptidomimetics starting from a carbohydrate precursor

SOL C. PARAJÓN PUENZO; ADRIANA A. KOLENDER; SANDRA E. MARTÍN; OSCAR VARELA

Blucher Chemistry Proceedings

Editora Blucher

Lugar: San Pablo; Año: 2011 vol. 1

2318-4043

Synthesis of linear D-alt-L peptidomimetics starting from a carbohydrate precursor Sol C. Parajón Puenzo, Adriana A. Kolender, Sandra E. Martín, Oscar Varela* Dpto. Química Orgánica, CIHIDECAR-CONICET-UBA, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina ? INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina *e-mail varela@qo.fcen.uba.ar Keywords: peptidomimetics, oligopeptides, carbohydrates INTRODUCTION Fundamental building blocks used by nature are amalgamated to produce natural-like, yet unnatural, structural entities with multifunctional groups anchored in a single ensemble. For example, hybrid molecules that maintain the basic structure of a carbohydrate have been obtained. This hybrids include amino and carboxyl functional groups, characteristic of amino acids. Diverse arrays of peptidic templates have been employed for the construction of homo- and heterooligomers that behave as peptidomimetics. These molecules are sometimes able to associate themselves spontaneously (self-assembly process) to form complex architectures.1 The novel materials find useful applications as microelectronics, drug delivery and tissue engineering. The linear oligopeptides are also precursor of cyclic peptoids (carbopeptoids) useful as molecular receptors.2 We describe herein the synthesis of an amino acid building block starting from inexpensive D-Glucono-1,5-lactone. As the amino containing stereocenter possesses the S configuration, the molecule is combined with Dalanine (R configuration) to give D-alt-L peptides to favor self-assembly processes. RESULTS AND DISCUSSION Treatment of D-Glucono-1,5-lactone (1) with 2,2- dimethoxypropane led to conversion into the methyl ester and simultaneous protection as the 3,4:5,6-diO-isopropylidene derivative (2). The free hydroxyl group was substituted by azide to obtain 4, via the triflate 3. Treatment of 4 with bis(tribultyltin) oxide [(Bu3Sn)2O] gave the free carboxylic acid 5, without racemization or elimination at C-2, as happened with other bases. Coupling of 5 with D-alanine in the presence of 1-hydroxybenzotriazole (HOBt), N,Ndiisopropylethylamine (DIPEA) and a carbodiimide (EDCI) afforded the dipeptide 6. This key intermediate was used as precursor of both the acid 7 (by reaction with (Bu3Sn)2O) and the amine 8 (under Staudinger conditions). Condensation of 7 and 8 gave the D-alt-L-tetrapeptide 9. Scheme 1. Synthesis of oligopeptides 6-10. CONCLUSION The sugar-based amino acid precursor 5 has been synthesized straightforward from D-Glucono-1,5- lactone. This building block was employed as key intermediate in the stereocontrolled synthesis of linear D-alt-L oligopeptides. ACKNOWLEDGEMENTS We are indebted to ANPCyT, UBA, UNC and CONICET for financial support. REFERENCES 1 Börner, J. C. Prog. Polym. Sci. 2009, 34, 811. 2 Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. Rev. Drug Discovery 2008, 7, 608.