Directed Synthesis of Biologically Interesting Heterocycles with Squaric Acid 34Dihydroxy3cyclobutene12dione Based Technology

Masatomi Ohno1 (K) • Shoji Eguchi2

1 Department of Advanced Science and Technology, Toyota Technological Institute, 2-12-1 Hisakata, Tempaku, 468-8511 Nagoya, Japan [email protected]

2Department of Molecular Design & Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, 464-8603 Nagoya, Japan

1 Chemistry of Squaric Acid with 3-Cyclobutene-1,2-Dione Skeleton 2

2 Derivatization of Squaric Acid to 4-Hydroxy-2-Cyclobutenone Skeleton . . 3

3 Ring Transformation of the Derivatized Cyclobutenone 5

3.1 Varied Reactivity in Ring Opening and Ring Closure 5

3.2 Thermal Concerted Process 9

3.3 Reactive Intermediate Induced Process 21

4 Squaric Acid Bioisostere 27

5 Concluding Remarks 32

References 32

Abstract A variety of methods for organic transformation starting from squaric acid have been developed in this decade. These are based on conversion of pseudoaromatic 3,4-dihydroxy-3-cyclobutene-1,2-dione into the more reactive 4-hydroxy-2-cyclobutenone by introduction of the required (or desired) functional groups followed by key ring transformation, the rearrangement being stimulated thermally or induced by a reactive intermediate. These strategies can construct a variety of bioactive heterocycles when functional groups contain heteroatoms or heterocycles. Interestingly, squaric acid is rendered as an acid part, for example, of an amino acid, and this bioisostere concept is extended to various heterocycle-containing squaramides (3,4-diamino-3-cyclobutene-1,2-dione derivatives) as bioactive conjugate compounds. This review article covers biologically interesting heterocyclic compounds accessible with the squaric acid based technology.

Keywords Bioisostere • Cyclobutenone • Electrocyclic reaction • Reactive intermediate • Squaric acid

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