Studies towards the total syntheses of the callipeltins

Angel I Morales-Ramos, Purdue University

Abstract

Callipeltin A, a novel cyclic depsidecapeptide was shown to possess antifungal and anti-HIV activity and cytotoxicity against selected human carcinoma cell lines, as well as powerful inhibition of the Na +/Ca2+ exchanger in guinea pig left atria. It contains three novel amino acid residues, one of them being a β-methoxytyrosine (β-MeOTyr) with stereochemistry that could not be determined due to its sensitivity to acidic hydrolysis conditions. In efforts to complete the total synthesis of callipeltin A, the syntheses of the residue (2R,3 R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE) and two diastereomers of callipeltin E have been pursued. Syntheses of the fully protected (2R,3R,4 S) and (2S,3S,4S) diastereomers of the non-proteinogenic amino acid AGDHE have been carried out in 13 steps and 15% overall yield each, from a commercially available Boc-L-Orn(Z)-OH. The stereochemical configuration of the residue was confirmed to be (2R,3R,4S) by 1H NMR comparison of the two diastereomers with natural products callipeltin A and D. Studies of the protecting groups in the residue suggested that the acetonide is not suitable for the synthesis of callipeltin A. A second generation asymmetric synthesis of AGDHE from a vinyl sulfone is three steps away from being completed. Key steps in the synthesis are a regio- and diastereoselective amination of an epoxide vinyl sulfone and a diastereospecific dihydroxylation of a vinyl sulfone. The developed methodology is flexible enough to generate any configurational isomer of AGDHE as well as other amino acids, amino alcohols and other residues with similar functionality. The strategy for the solid phase synthesis of callipeltin A and the stereochemical elucidation of β-MeOTyr has been studied by synthesizing a model and two diastereomers of callipeltin E.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry

COinS