Chiral pool strategy is a synthetic approach used to synthesize enantiomeric natural and unnatural products of biological significance. Naturally abundant enantiopure carbohydrates, amino acids, hydroxy acids are used as starting materials. The inherent chirality, susceptibility to broad functional group modifications make these small molecules as a good starting point and avoid tedious chemical methodologies in insertion of chirality. In living organisms various biochemical reactions also utilizes small molecules like amino acids for biosynthesis of several enzyme substrates, and coenzymes. For example, in sphingolipid biosynthesis, L-Serine is the starting material for <i>de novo </i>synthesis of central sphingolipid Ceramide. Cellular ceramide levels have been implicated in cell signaling, membrane stability and involved in several disease states including cancer. Sphingolipid flux is affected in perturbation of biosynthesis and metabolism.<br/>We have used different L- amino acids to synthesize various advanced chiral scaffolds in enantiopure gram quantities towards synthesis of sphingoid based natural products. Amino acid, amines and carboxylic acid functional group transformations including protection – deprotection chemistry is employed in synthesis of natural product Spisulosine, anhydrophytosphingosine, and biologically active analogs. These natural products have structural similarities with the intermediates of sphingolipid biochemistry and exhibited evidence of interfering with ceramide metabolism. Representative stereoselective synthesis methodology and biological evaluation studies will be discussed. The analogs of Jaspine b and Spisulosine were screened for biological activity and showed promising results both individually and in combination.

Chiral pool strategized synthesis of sphingoid based natural products using alpha amino acids

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ACS Fall 2022

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