2018 Volume 76 Issue 8 Pages 781-791
Natural products are a rich source of biologically active compounds that are frequently developed into pharmaceutical medicines. Synthetic organic chemistry has contributed to bridge medicinal and natural product chemistries by broadening the accessible chemical entities based on the structure of natural products. In this article, we describe our recent achievements in catalytic asymmetric total synthesis of biologically active natural products with structural complexity.
Caprazamycin B was discovered as an anti-tuberculosis antibiotic, and was developed to CPZEN-45, which exhibited activity toward extensively drug-resistant strains (XDR-TB). Leucinostatin A exhibited selective antiproliferative activity against tumor cells in the presence of the corresponding stromal cells, which can be recognized as an anti-cancer seed. To facilitate structure activity relationship studies, synthetic routes to both natural products were established using catalytic asymmetric reactions as key transformations to regulate the absolute configuration. A nitroaldol reaction using Nd/Na-amide complex or LLB*, a thioamide-aldol reaction with Cu(I) complexed with a chiral bidentate phosphine ligand, alcoholysis of 3-glutaric anhydride employing a Ni2-Schiff base complex, a Zn-linked BINOL-catalyzed aldol reaction, and a Strecker-type reaction were effectively applied to the syntheses. It is noteworthy that the present syntheses revised the reported stereochemistry of leucinostatin A.
