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

• The total synthesis of pachastrissamine and its 4-epi-congener was accomplished.
• The cornerstone of this strategy was a [3,3]-heterosigmatropic rearrangement.
• Crystallographic analysis of a key structure was performed.
• A series of synthesized compounds was evaluated for the anticancer activity.

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.

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