Enantiospecific synthesis of (2S, 5S)-5-hydroxypipecolic acid and a tetrahydrofuran sugar amino acid from D-galactose.

UHRIG, M. L.; BALMACEDA, G.; VARELA, O.

Oslo, Noruega

Simposio; XXIV International Carbohydrate Symposium; 2008

International Carbohydrate Organization

The amino acid 5-hydroxypipecolic acid (1) is a natural product that has been found in various plants (acacia, palm-dates) and microorganisms (i.e, Pseudomonas fluorescens). This amino acid has been described as a powerful inhibitor of platelet aggregation. We report here an enantioselective synthesis of 1 starting from D-galactose, via its 2-acetoxyglycal derivative 3. Additionally, one of the intermediates in the synthetic sequence was employed as precursor of the tetrahydrofuran amino acid 2. Pyranoid and furanoid sugar amino acids (SAA) are extensively used as conformational constrained scaffolds in peptidomimetic studies. Natural or synthetic cyclic amino acids incorporated into peptides confer rigidity, influencing cell recognition events. Lactone 7, the key intermediate in the synthesis of both amino acids 1 and 2, was readily prepared from 3. Thus, glycosylation of 3 with 2-(S)-octanol in the presence of SnCl4 gave the enone 4, which on hydrogenation, O-deacetylation, reduction of the carbonyl and tosylation of the resulting diol afforded 5. Regioselective substitution of the primary tosyloxy group by azide led to 6. Hydrolysis of the glycoside followed by oxidation of the lactol afforded 7, which on hydrogenolysis of the azide gave 8. Under alkaline conditions, 8 underwent cyclization to the expected 1, which appeared accompanied with the SAA 2. The latter was formed by competition of the hydroxyl group at C-5 in the intramolecular displacement of the tosylate. The synthesis of the target pipecolic acid 1 could be accomplished via the intermediate 9, prepared from 7. The SAA 2 was selectively obtained by alkaline treatment of 7, to give 10, and further hydrogenolysis of the azide.