Synthesis of pipecolic acid: an integral fragment of antimitotic tubulysins

Abstract

Cancer is the second savage cause of deaths worldwide. Currently, finding a cure to such a deadly disease is a matter of concern. Antimitotic compounds provide promising solution to the aforementioned problem. The primary aim of antimitotic compounds is to interfere with the polymerization of tubulin components of microtubules. This results in hindrance of cell division, an essential process of cell life cycle, leading to apoptosis. Therefore, inhibiting tubulin polymerization directly leads to cell death, which makes them crucial targets by cytotoxic compounds. Tubulysin family of natural products is one such example of those prominent antimitotic compounds, isolated from myxobacteria culture extracts. Due to their commendable cytotoxic activity, tubulysins have become a center of attraction for research in the field of chemotherapy.Structurally, tubulysins are tetrapeptides consisting of four unusual amino acids, N-methyl pipecolic acid (Mep), isoleucine (Ile), tubuvaline (Tuv) and tubutyrosine (Tut) or tubuphenylalanine (Tup). Among these, pipecolic acid is an interesting fragment to analyze since tubulysin family of compounds bind to tubulin protein primarily through pipecolic acid and it is least tolerant to modifications. All these factors provide a growing opportunity for discovering new and better methodologies for synthesis of pipecolic acid.In this work, we have reported two different synthetic routes which might be used for the gram scale synthesis of pipecolic acid. We started our synthesis using naturally occurring L-serine as the chiral source and successfully synthesized advanced intermediates which can be used for furnishing the final target pipecolic acid in future.All the intermediates are well characterized using various spectroscopic techniques.