Total synthesis of pachastrissamine together with its 4-epi-congener via [3,3]-sigmatropic rearrangements and antiproliferative/cytotoxic evaluation

Abstract

Synthesis of the HCl salts of two anhydrophytosphingosines, jaspine B (1) and its 4-epi-congener 5 from easily available dimethyl l-tartrate and/or l-arabinose, is described. The key transformations are the efficient incorporation of a chiral amino group via [3,3]-sigmatropic rearrangements, a Wittig olefination for the instalment of the carbon backbone and the acid-promoted building-up of a tetrahydrofuran framework. Evaluation for in vitro antiproliferative/cytotoxic activity with a panel of human tumour cell lines using a MTT assay revealed for some compounds of our strategy noteworthy activity. Compound 1·HCl (IC50: 0. 41-2.35 μM), its antipode ent-1·HCl (IC50: 4.07-5.69 μM) and also stereoisomer 4·HCl (IC50: 4.28-6.10 μM) exhibited significant potency compared with clinically available anticancer drugs such as cisplatin (IC50: 11.4-14.7 μM) and etoposide (IC50: 1.2-21.2 μM) on MDA-MB-231, MCF-7 and Jurkat cells.

Keywords: Anhydrophytosphingosines; Anticancer activity; Jaspine B; Pachastrissamine; Stereoselective synthesis; [3,3]-Heterosigmatropic rearrangements.