Laboratory of Synthetic Organic Chemistry

Research Outline

Our mission is to 1) develop a novel catalytic asymmetric reaction based on a new concept and 2) apply it to the efficient synthesis of therapeutics. We focus specifically on the development of C–C bond-forming reactions that proceed via proton transfer between substrates, achieving perfect atom economy. These processes should be sufficiently robust to be amenable to industrial application and to streamline the synthetic routes of optically active therapeutics. We believe our collection of state-of-the-art asymmetric catalysts enables the production of a myriad of compounds that enhance human health and improve society.

Theme outline

1. Development of asymmetric reactions catalyzed by rareearth metal/amide-based ligand complexes

Fig.1 Proposed transition state model for asymmetric amination.

We have focused on the development of catalytic asymmetric reactions based on the unique characteristics of rare-earth metal/amide-based ligand complexes: rare-earth metals can adopt multiple coordination modes, and amide-based ligands can exhibit appropriate structural rigidity and flexibility. These complexes have exhibited high performance in reactions with highly coordinative substrates. Their structural flexibility permitted in-situ switching of catalytic functions through dynamic structural changes. Combination with an alkali metal produced a heterobimetallic heterogeneous catalyst, which is effective for anti-selective catalytic asymmetric nitroaldol reactions.

2. Soft Lewis acid/hard Brønsted base cooperative catalysis

Fig.2 Deprotonation by cooperative catalysis.

We have focused on the development of catalytic asymmetric reactions using soft Lewis basic substrates, e.g., alkyl nitrile, thioamide, and terminal alkynes. When the designed soft Lewis acid/hard Brønsted base cooperative catalysts are used, the soft Lewis acid selectively activates soft Lewis basic functionalities, and the hard Brønsted basic alkali metal aryloxide deprotonates pronucleophiles activated in-situ under mild basic conditions. This strategy of cooperative catalysis allows us to develop atom-economical catalytic C–C bondforming methodologies to construct a chiral tetrasubstituted carbon center and synthetically useful chiral building blocks.

3. Catalytic asymmetric synthesis of therapeutically important compounds and their medicinal chemistry

We have applied the arsenal of catalytic asymmetric reactions developed in our group to the efficient catalytic asymmetric synthesis of therapeutics. We have synthesized the neuraminidase inhibitor Tamiflu (anti-influenza), Relenza(anti-influenza) and the aldose reductase inhibitor Ranirestat (for the treatment of diabetic neuropathy). We are also interested in the medicinal chemistry of the targets based on our synthetic methodology.

Fig.3 Structures of therapeutic targets.

4. Studies of asymmetric synthesis of caprazamycin-related compounds

We participate in the CPZEN-45 project and confront the asymmetric total synthesis of caprazamycins, from which CPZEN-45 has been chemically derived. To stereoselectively construct the key substructures of caprazamycin B, depicted in the figure below (red), the synthesis utilizes the multimetallic asymmetric catalysts we have developed. A diverse array of caprazamycin analogs inaccessible from the natural sources will be prepared by this synthetic procedure for the screening for anti-extremely drug-resistant tuberculosis medicines.

Fig.4 Structure of caprazamycin B.