Solid-and Solution-Phase Synthesis of Natural Product-Based Libraries

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Biologically active natural products have served as effective biochemical probes for discovery of not only new drug targets but also new biomarkers. The synthesis of small molecules based upon the structure of biologically active natural products would be an effective and promising way for identification of new biochemical probes. Combinatorial chemistry can assist the high-speed synthesis of these focused liberties. The combinatorial approach might not be an economic route in comparison with the traditional approach based on elucidating the best fragment at each diverse site because fully combinatorial liberties contain many redundant compounds. However, in traditional approach the compounds composed of the best fragments would not often exhibit the strongest biological activity in cell-based assay since cell-permeability of the small molecules would largely influence their biological activity. In this research project, we investigated the development of effective approaches for the solid- and solution-phase synthesis of natural product-based libraries.Research for the solid-phase synthesis of natural product-based libraries resulted in the syntheses of 25 aurilide derivatives, 122 macrosphelide A derivatives, 74 clavulone derivatives, 24 aeruginosin derivatives. In addition, bidirectional solid-phase semisynthesis of vancomycin derivatives was accomplished based on donor-bound glycosylation strategy. On the other hand, for the solution-phase synthesis of natural product-based libraries, we investigated one-pot sequential glycosylation approaches, that are effective not only for high speed synthesis of target oligosaccharides but also for the synthesis of combinatorial libraries. As the results, we succeeded in the development of one-pot glycosylation for the synthesis of a heptasaccharide exhibiting phytoalexin elicitor activity, core 2 type glycosyl amino acids and sialo-containing glycosyl amino acids.