Conformational restriction is a renowned approach to design of analogues in bioorganic and medicinal chemistry. A desirable feature of this methodology is possibility of molecular structure modification without significant perturbation of the compound properties. Small rings can provide such possibility; in particular, cyclopropane-containing conformationally restricted analogues (“methanologues”) have been widely used to date. However, the cyclopropane moiety can significantly affect electronic properties and chemical reactivity of the molecule due to its partially unsaturated nature. Cyclobutane ring does not have such drawbacks; on the other hand, it is small enough to satisfy the above-mentioned criteria as a conformational restriction tool. In this report, we shall describe case studies from our research on cyclobutane-derived conformationally restricted compounds. In the first part, design and synthesis of cyclobutane-derived amino acids, as well as their incorporation into cell-penetrating peptides, will be described. In particular, fluorinated analogues of polar amino acids (such as lysine (1) and serine (2) analogues) which can be used as 19F NMR labels will be discussed. The second part of this presentation will include examples of using cyclobutane-derived scaffolds (such as spiro[3.3]heptane) in design of building blocks for medicinal chemistry. With the use of exit vector plot (EVP) tool, we will show that such building blocks (e.g. 3) provide unusual but controllable spatial arrangements of the functional groups mounted onto the cyclobutane ring(s) and can be used as promising surrogates of common (hetero)aliphatic rings. The presentation will include published and unpublished results obtained in our groups in the last 10 yeas.

Synthesis of functionalized cyclobutanes as a conformational restriction tool for the medicinal chemistry

2019 Spring National Meeting

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