Department of Material Chemistry, Graduate School of Engineering
Kyoto University, Japan
京都大学大学院 工学研究科 材料化学専攻
The Chemistry of Organocatalysts
1. Mildness is powerful:
multipoint activation through weak interactions for selective transformations
Organocatalysts utilize various molecular interactions for catalysis. However, molecular interactions for organocatalysis are generally not as strong as those for metal-catalysis. Thus, this character often leads to the necessity of multiple activations to catalyze a reaction; however, in other words, it enables the use of multipoint interactions in the transition state of a catalytic reaction, even if it is a very rapid reaction. On the basis of this concept, we developed several synthetic methods for asymmetric construction of various heterocycles via hetero-Michael additions and applied synthetic transformations. In order to accomplish high enantioselectivity, we designed reactions utilizing different activation manners by organocatalysts depending on the substrate type; it is a key to utilize simultaneous multipoint interactions with a catalyst for the recognition of specific conformations of substrates.
Publications (Reviews)
A. Intramolecular hetero-Michael addition
Intramolecular hetero-Michael additions allow straightforward construction of heterocycles. However, such reactions proceed very fast, and it is difficult to attain the enantioselectivity. To address this issue, we focused on acid-base bifunctional catalysts (aminothioureas, phosphoric acids, and so on), enabling synergistic multipoint activations through mild hydrogen bonding. Multipoint recognition of the substrates provides an effective chiral environment. In addition, employing mild noncovalent interactions gives rise to an effective system like enzymes, in which reactions cannot proceed without simultaneous activations at multiple sites. By this strategy, we have synthesized various kinds of heterocycles.
Publications
B. Synthesis of axially chiral compounds
Bifunctional organocatalysts have significantly contributed to the field of asymmetric synthesis. In these catalysts, the (thio)urea and tertiary amino functional groups cooperatively realize the simultaneous recognition of a hydrogen-bond donor and a hydrogen-bond acceptor in a suitable spatial configuration. As mentioned above, we have used these organocatalysts for several asymmetric cyclization reactions via intramolecular hetero-Michael addition, in which multipoint interactions by the catalysts recognize the specific conformations of the substrates in the transition state before the construction of a chiral center. Inspired by the success of these results, we envisaged that the utility of this class of small-molecule catalysts could be expanded by translating the molecular conformations recognized by bifunctional organocatalysts into axial chirality; we found the novel competence of bifunctional organocatalysts as an efficient avenue for the asymmetric construction of axially chiral compounds.
Publications
C. α,β-Unsaturated acylammonium catalysis
Asymmetric hetero-Michael additions to α,β-unsaturated carboxylic acid derivatives have suffered from their low stereoselectivity. This is attributed to the complexity of the activation manners through noncovalent interactions by chiral Brønsted or Lewis acids, because carboxylic acid derivatives such as esters have several coordination sites (hetero atoms). Thus, for those substrates, we employed multipoint activations involving rigid covalent interactions; we utilized α,β-unsaturated acylammonium species as key intermediates, which are generated via the addition-elimination reaction by a chiral nucleophilic catalyst with a carboxylic acid derivative; highly enantioselective cyclizations via sulfa-Michael additions were realized. This method offers efficient routes to 1,5-benzothiazepines, representative pharmaceutical agents, and so on.
Publications
2. Development of a novel organocatalyst:
creation of a new functional group for organocatalysis
For creating new catalysis, there should be a number of approaches; among them we decided to design a new functional group for catalysis, which may provide new reactivity or selectivity in catalytic reactions. Currently, we focus on olefins as such functional groups; especially, we are interested in trans-cyclooctenes. This olefin has a highly strained structure, and it has high reactivity and planar chirality. In addition, the introduction of substituents makes it possible to precisely design the catalytic site. From such viewpoints, we are studying on the design of new catalysts using trans-cyclooctenes.
Thus far, the catalytic behavior of trans-cyclooctenes was for the first time demonstrated. These strained olefins efficiently facilitate halolactonizations, and the trans-cyclooctene framework is essential for good catalytic performance. Additionally, the substituents also play important roles in determining efficiency, and they have the potential for designing the environment around the catalytic site. Thus, these molecules would offer a new platform for designing unexploited molecular catalysts.
Publications
1) Einaru, S.; Shitamichi, K.; Nagano, T.; Matsumoto, A.; Asano, K.; Matsubara, S.
Angew. Chem., Int. Ed. 2018, 57, 13863–13867.
2) Nagano, T.; Einaru, S.; Shitamichi, K.; Asano, K.; Matsubara, S. Eur. J. Org. Chem. 2020, 7131–7133.
