Organic Reaction Chemistry Laboratory

Yoshinosuke Usuki (Associate Professor)

1. Current Research and Principal Research Interests

My research interests are all concerned with bio-organic chemistry of natural products. Natural products chemistry is still of great importance as a basic science since natural products have made significant contributions to development of new drugs as well as progress in basic studies of life sciences. The main focus of the research is on the design and synthesis of natural and non-natural products of biological importance, and the development of new synthetic methodologies towards fluorinated bio-molecule mimics. Current research projects include:

Microbial-derived natural products with novel biological activities: Microbial species have a capability to produce a wide variety of bioactive compounds with novel structures and various biological activities. Since UK-2A, an antimycin class antibiotic, was first isolated in 1996 from a soil sample collected at Sugimoto campus, we have been engaged in studies toward synthesis and biological evaluation of di/tri/tetra lactone antibiotics.

1) Splenocins were isolated from organic extract of marine-derived Streptomyces strain CNQ431 as potent anti-inflammatory antibiotics in 2009, which displayed low nanomolar activity in the suppression of cytokine production by OVA stimulated splenocytes. The structures of splenocins are similar to those of antimycin A3 (AA) and UK-2A. We have achieved total synthesis of sprenocin B, a hybrid molecule combining certain structural features of both UK-2A and AA, via macrolactonization using ethoxyvinyl ester as a key reagent for furnishing the 9-membered dilactone ring skeleton.[1] Investigations into the application of the developed protocol to the structure–activity relationship are currently underway.

2) Neoantimycin is a rare and unusual ring-extended member of the antimycin class. First isolated in 1967 from a South American soil isolate of Streptomyces orinoci. Literature references were limited, but the recent discovery of prunustatin A as a selective GRP78 molecular chaperone down-regulator, which could lead to the development of new approaches toward combatting cancer, highlights the potential of this class as research probes. The total synthesis of prunustatin A and neoantimycin have been achieved via trans-esterification as a key step for furnishing the 15-membered tetralactone ring skeleton.[2, 3]

Fluorinated Biomimetics: The ability of fluorine to impart unique properties to organic molecules has been exploited in the design of fluorine-containing bioactive compounds. Functionalized fluoroolefins are particularly important, with current applications in the synthesis of biologically active materials such as peptide isosteres. In our continuing studies on synthetic organofluorine chemistry towards fluorinated biomimetics, we have been interested in replacement of side-chain amide moieties of asparagine and glutamine with fluoroolefins, which are proposed to be aprotic mimic for amides due to their electronic properties. Asparagine and glutamine residues play important structural roles in proteins because their side-chain amide groups could act as both hydrogen bond acceptors and donors. We have developed a new access to fluorine-containg asparagine and glutamine analogues via formate reduction.[5]

Exploration of plant-derived natural products with novel structures and biological activities: Natural products, such as plants extract, provide unlimited opportunities for new drug discoveries because of the unmatched availability of chemical diversity. We are now focusing on the chemical constituents of plants grown in the Hengduan Mountains area of China.

2. Selected Publications

1. "Total synthesis of splenocin B, a potent inhibitor of the pro-inflammatory cytokine from marine-derived Streptomyces sp.", K.-I. Yoshida, M. Ijiri, H. Iio, Y. Usuki, Tetrahedron, 71, 9626–9629 (2015).

2. "First Total Synthesis of Neoantimycin", H. Ogawa, H. Iio, Y. Usuki, Chem. Lett., 44, 1214–1216 (2015).

3. "A New Total Synthesis of Prunustatin A", Y. Usuki, H. Ogawa, K.-I. Yoshida, T. Inaoka, H. Iio, Asian J. Org. Chem., 4, 737–740 (2015).

4. "A New Concise Synthesis of (+)-Ipomeamarone, (–)-Ngaione and their stereoisomers", T. Deguchi, H. Iio, Y. Usuki, Chem. Lett., 43, 1882–1884 (2014).

5. "A New Access to Fluorine-containing Asparagine and Glutamine Analogues via Pd-catalyzed Formate Reduction", Y. Usuki, Y. Wakamatsu, M. Yabu, H. Iio, Asian J. Org. Chem., 3, 1270–1272 (2014).