Design and Synthesis of Natural Product-Inspired Small Molecule Collections will be discussed focusing two approaches as follows.

1) Chemo-enzymatic Synthesis of Macrolactone Library Inspired by Quinoxaline Antibiotics
Although enzymatic cyclization is advantageous as it allows site-selective ring-closure of functionalized precursors, thioesterase (TE)-catalyzed cyclization is often precluded due to hydrolysis and product inhibition especially when used with synthetic substrates. To circumvent the obstacles, we focused on the DNA-binding properties of quinoxaline antibiotics, and devised an unprecedented strategy: enzymatic synthesis employing DNA to capture and thereby exclude the cyclic product from the active site of the enzyme. This co-incubation with DNA successfully suppressed undesired hydrolysis and prevented product inhibition, and resulted in a three-fold improvement in the yield of cyclized products (19-23%?67-74%). This chemoenzymatic strategy making use of DNA will be useful for other quinoxaline/quinoline antibiotics and is also generally applicable for small molecules with DNA binding properties.

2) Expeditious Synthesis of Artemisinin-inspired Small Molecules
Inspired by the common tricyclic system of naturally occurring anti-malarial artemisinin and Ca²⁺-ATPase inhibitor transtaganolides, we designed sesquiterpene-inspired small molecule libraries with rich three-dimensional structural diversity. We devised an expeditious synthetic process that controls not only the stereochemical relationships of ring-junctions (trans-cis, cis-cis and trans-trans fused skeletons) but also the modes of cyclization by tandem RCM of dienynes, which entails formation of six types of tricyclic skeletons in a systematic fashion. Furthermore, installations of endoperoxides were demonstrated to construct a collection of artemisinin analogs and increase structural diversity of the small molecule library. A preliminary screening of anti-parasitic activities will also be presented.