Laboratory of Organic and Medicinal Chemistry



Research Topics

1. Synthesis of New Compounds Exhibiting Characteristic Structural Features:

Creation of Stable Helical Molecules Based on N-pyramidal Amide We revealed the structural features of N-π-group-substituted 7-azabicyclo[2.2.1]heptane derivatives which induce N-pyramidalization of amides, sufonamides and nitrosamines and other related functional groups (Scheme 1).
We showed that amides of bicyclic 7-azabicyclo[2.2.1]heptane are intrinsically nitrogen-pyramidal. Single-crystal X-ray diffraction structures of some relevant bicyclic amides, including the prototype N-benzoyl-7-azabicyclo[2.2.1]heptane, exhibited nitrogen-pyramidalization in the solid state. We also evaluated the rotational barriers about the amide bonds of various N-benzoyl-7-azabicyclo[2.2.1]heptanes in solution. The observed reduction of the rotational barriers of the bicyclic amides, as compared with those of the monocyclic pyrrolidine amides, is consistent with a nitrogen-pyramidal structure of 7-azabicyclo[2.2.1]heptane amides in solution.

Scheme 1. Intrinsic Feature of Nitrogen-pyramidalization of Amides of 7-bicyclo[2.2.1]heptanes

Octamer         Side view of Helix        Top view of Helix
Scheme 2. Helical Structures of Homo-octamer of β-Proline Mimics based on Amides of 7-bicyclo[2.2.1]heptanes

We imagined that 7-azabicyclo[2.2.1]heptane amides can mimic ?-proline. Bridgehead substitution effectively controls amide cis-trans isomerization. Homo-octamer (8-mer) takes a helical structure, this ordered structure being robust in any solvents including water (Scheme 2).
Transnitosation of N-Pyramidal Nitrosamines to Thiol N-Nitrosamines can be considered as potential NO/NO+ donors. We showed that aliphatic N-nitrosoamines of 7-azabicyclo[2.2.1]heptanes could undergo heterolytic N-NO bond cleavage. Based on the observation of reduced rotational barriers of the N-NO bonds in solution and nitrogen-pyramidal structures of the N-nitroso group in the solid state, we postulate that N-NO bond cleavage of N-nitrosamines is enhanced by a reduction of the resonance in the N-NO group. The N-NO bond of the N-nitroso derivatives of 7-azabicyclo[2.2.1]heptanes tends to be weak. We described the S-transnitrosation reaction of aliphatic N-nitroso derivatives of 7-azabicyclo[2.2.1]heptanes, which resemble conformationally constrained proline derivatives, and its chemical features, i.e., reactivity and chemoselectivity. These N-nitroso derivatives of 7-azabicyclo[2.2.1]heptanes do not act as NO donors themselves, but can transnitrosate thiols (Scheme 3a). Also we found visible light irradiation releases NO under controlled manners (Scheme 3b). The new basic chemistry opened the door to new control of NO (nitric oxide)-biology, some of which were exemplified by us.

Scheme 3. Transnitrosation of N-pyramidal Nitrosamines to Thiols

2. Intrinsic Mechanistic Studies of Organic Reactions.

New Approach to Functionalizing Aromatic Compounds Based on Designed Superelectrophiles: Aromatic structures provide basic architecture for developing functionalized materials such as medicines. However, tools for chemoselective, regioselective and stereoselective introduction of various functional groups onto aromatic rings are still limited in their applicability. This project aims to provide a novel approach to functionalizing aromatic compounds by means of development of the chemistry of newly designed superelectrophiles (dications and recently monocations).
The following example of our reactions represented an oxyfuctionalization of aromatic ring by using an oxygen atom of a nitro group (Scheme 4). This reaction was facilitated by the intervention of dicationic species. Please imagine the reaction mechanism in particular of dication intervention.

Scheme 4. Oxy-fuctionalization of Substituted Aromatic Rings through Cyclization to 4H-1, 2-Benzoxazines.

3. Design and Synthesis of Molecules Interacting with Membrane Proteins.

Design and synthesis of chemical modulators relevant to membrane protein functions have been aggressively pursued in our laboratory, which include openers of ion channels, inhibitor of transporters and agonists of membrane receptors. The following compounds were among our previous achievements related to potassium ion channels, that is, openers of BK channels (large conductance calcium dependent potassium ion channels) (Scheme 4). We have also great interest in the molecular mechanism how these compounds open potassium ion channels, which was also studied and proposed together with ion channel experts (Scheme 5).

Scheme 4. Our Generation of Potent BK Channel Openers

Scheme 5. Proposed Channel Opening Mechanisms of Large-conductance voltage- and Ca2+-activated K+ (Slo1 BK) channels

4. Computational Studies of Organic Reactions, Structural Basis and Drug Design.

Application of ab initio (DFT) molecular orbital calculations have been carried out to understand the structural features, reaction selectivities, and reaction mechanisms. Combination of computational works with experimental observations is encouraged. Computer-assisted design of molecules is also intriguing.


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