1. development new catalytic asymmetric reactions by the use of organic catalysis
2. development and application of high pressure induced by water-freezing to the organic synthesis
3. total synthesis of biologically interesting molecules

1) Development new catalytic asymmetric reactions by the use of organic catalysis

 The catalytic asymmetric reaction is one of the important topics in modern organic synthesis. I have found the following two highly enantioselective reactions using easily available proline-catalyst.

The direct and enantioselective, one-pot, three-component cross-Mannich reaction of aldehydes:
 The direct and diastereo- and enantio-selective, one-pot, three-component cross-Mannich reaction of two different aldehydes has been developed, in which one aldehyde is employed as the Mannich donor, and the other aldehyde is utilized as a component of the Mannich acceptor, affording a b-aminoaldehyde in a highly syn-diastereo- and enantio-selective manner.


The direct proline catalyzed asymmetric a-aminoxylation of aldehydes and ketones:
 Aldehydes and ketones are reacted with nitrosobenzene in the presence of a catalytic amount of proline, affording a-aminoxylated aldehydes and ketones in good yield with high enantioselectivity, which are easily converted into synthetically important a-hydroxy aldehydes and ketones.

2) Development and application of high pressure induced by water-freezing to the organic synthesis

  Pressure is one important factor affecting the rate of organic reactions and many reactions with a large, negative volume of activation have been accelerated using high pressure. The volume of water increases about 10% on freezing. When water is frozen in a sealed autoclave, a high pressure of up to about 200 MPa can be realized. We have applied this high pressure method to several reactions such as the Michael reaction of alcohols with a,b-enones, and the Baylis-Hillmann reaction, proline-catalyzed Mannich reaction of ketone, and proline-catalyzed aldol reaction. Especially in the proline-mediated Mannich reaction under the high pressure induced by water-freezing, Mannich adducts were obtained in better yield and higher enantioselectivity than the reaction under normal pressure.

3) Total synthesis of biologically important molecule

  There are many natural products which have interesting biological properties, but their biological studies can not be developed because of the shortage of supply from the natural sources. Chemical synthesis is one of the methods for the production of these natural products. I have been engaged in the total synthesis of such rare compounds with unique and complicated structures based on the highly original methodology.
Angiogenesis inhibitors are promising drugs for the treatment of angiogenesis-related diseases including cancer. Epoxyquinols A and B are unique pentaketide dimers which show anti-angiogenic activity. Though structurally epoxyquinols A and B have a highly functionalized and complicated heptacyclic ring system containing 12 stereo-centers, biosynthetically it is proposed they are formed via an unusual oxidative dimerization of the much simpler epoxycyclohexenone. We have developed the first total synthesis of the naturally-occurring enantiomers of (+)-epoxyquinols A and B using the postulated biomimetic oxidative dimerization, along with determination of their absolute stereochemistry.

 Azaspirene is a new angiogenesis inhibitors, containing a highly oxygenated 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skele­ton with benzyl and hexadiene substituents. I have accomplished the first total synthesis of (-)-azaspirene, establishing its absolute stereochemistry. The key steps are a MgBr2•OEt2-mediated, diastereoselective Mukaiyama aldol reaction, a NaH-promoted, intramolecular cyclization of an alkynylamide, and the aldol reaction of a ketone containing functionalized g-lactam moiety without protection of tert-alcohol and amide functionalities. We has also synthesized pseurotin A for the first time by the similar methodology.

 Epolactaene is a microbial metabolite, which is effective in promoting neurite outgrowth and arresting the cell cycle at the G1 phase in a human neuroblastoma cell line, so that it is regarded as a potential treatment for various neurodegenerative diseases such as dementia. We have accomplished a stereocontrolled total synthesis of both enantiomers of (+)- and (-)-epolactaene from tetrahydropyran-2-ol. Key reactions are as follows: 1) The stereoselective construction of the conjugated (E,E,E)-triene by a combination of kinetic deprotonation and thermodynamic equilibration. 2) The (E)-selective Knoevenagel condensation of b-ketonitrile with a chiral 2-alkoxyaldehyde. 3) A diastereoselective epoxidation achieved using a bulky nucleophile (TrOOLi) and an appropriate protecting group. 4) The mild hydrolysis of an a-epoxy nitrile by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular assistance. We have also synthesized NG-391 which shows neurotrophic activity and an effect on neurite outgrowth by our original methodology.