Synthesis of Biselyngbyaside and Biselyngbyolide A

• Applicant: Professor Dr. Martin E. Maier
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249973799

Aim of the project is the total synthesis of the two related 18-membered macrolides biselyngbyaside (1) or its aglycon, respectively, and of biselyngbyolide A (2). The macrolactone rings contain several secondary hydroxyl functions and double bonds, with two of them being part of a conjugated system. The side chain having a length of six carbon atoms contains two double bonds, separated by a methylene group (skipped diene). Biological studies showed that both of the target molecules have growth inhibition activity, whereby biselyngbyolide A (2) was the most active with an IC50 value of 12 nM (HL60 cell line). In preliminary work we already developed a synthesis for the C1-C13 part of biselyngbyaside (1). It is planned to couple this fragment, featuring a terminal vinyl iodide, with a C14-C23 building block via a Stille coupling reaction to obtain the seco acid and ultimately to the macrolactone. Our preliminary studies also showed that it might be advantageous to replace the terminal propenyl part of the side chain during the synthesis with a corresponding allylic alcohol which is more stable towards double bond isomerization. For the C1-C13 part of biselyngbyolide A (2) we can use an advanced building block from the biselyngbyaside synthesis. It is planned to establish the polyol subunit of biselyngbyolide A (2) through a dithiane strategy or a vinylogous aldol approach. In order to introduce structural modifications, the side chain positions at C19 and C23 appear suitable. If modifications in this region should be tolerated, some derivatives for use in chemical biology studies will be prepared. Alternatively, the 3-OH group might be used for attaching linker type fragments since in biselyngbyaside (1) this OH group is glycosylated and the compound is still active.

• DFG Programme: Research Grants