Bispidine as a Privileged Scaffold

Abstract

Thediazabicyclic molecule bispidine named by the chemist Carl Mannich in 1930, is a naturally occurring scaffold with interesting features. Bispidine can form different conformers, has high basicity, can attack dichloromethane, has metal ion coordination properties and interacts with nicotinic acetylcholine receptors. In this review we will discuss important properties, synthetic pathways and biological activities of bispidine and some derivatives. Bispidine can function as a scaffold for compounds with very diverse biological activities, e.g. interacting with ion channels, G-protein coupled receptors, and enzymes, and is even used for the development of new in vivo radiotracers.

Chiral Amino Acids‐Derived Catalysts and Ligands

“…Bispidine is an interesting diamine via a combination of two piperidine molecules fused over three carbon atoms, which is found in quinolizidine alkaloids. [8] Since chiral amine-type compounds make a difference in asymmetric organocatalysis, we decided to design new primary/secondary amine-based chiral catalysts.…”

“…[32b,32c] Due to the conformational and basicity properties, bispidine has been a subject of considerable interest as a chelating ligand for the formation of metal complexes. [8] Our chiral diamines bearing a bispidine structure and two well positioned sp 3 -hybridized nitrogen atoms would enable them as potential chiral ligands and will be one of our further endeavor. Scheme 6 Bispidine-based diamines organocatalysis…”

“…Based on the above, we designed several types of chiral ligands and organocatalysts from primary and secondary amino acids in the past 20 years. They include C 2 -symmetric N,N'-dioxides, [6] guanidine-amides, [7] bispidine-based diamines, [8] and other organic salts [9] (Figure 1). These compounds share advantages of ready availability and easy modification.…”

Optimization of Hexadentate Bispidine Ligands as Chelators for 64CuII PET Imaging

“…Among the range of well‐established ligands used in this field, due to the facile synthesis, the large synthetic variability, the ease of derivatization with biological vectors and the relatively high complex stability and inertness, bispidines (3,7‐diazabicyclo[3.3.1]nonanes; see Figure for the bispidine ligands discussed in this manuscript) have been shown to have significant advantages for 64 Cu‐based PET imaging . Among other reasons, these arise from the rigid adamantane‐derived backbone—preorganized and complementary for tetragonally distorted octahedral geometries—that is well suited and selective for binding Cu II ; it is also for this reason that bispidines have been described as a favorable ligand platform for medicinal applications . In addition to radiopharmaceutical chemistry, applications of Cu–bispidines include aziridination catalysis, and hemocyanine and catecholase biomimetic chemistry …”

Supramolecular Organogels Based on N-Benzyl, N’-Acylbispidinols

“…requires use of poly/multifunctional chelating agents that should form covalent bonds with various biomolecules/vectors possessing high specificity and selectivity towards certain targets [5], [8][9][10][11]. 3,7-Diazabicyclo[3.3.1]nonanes (hereafter called bispidines) are one of the privileged scaffolds in medicinal chemistry [12] due to the number of advantages, e.g. (i) high basicity and solubility in water and/or organic solvents [13,14]; (ii) ability to diverse functionalization including chiral derivatives [15][16][17][18][19][20]; (iii) deeply studied conformational features which allow application of some rigid conformation [21][22][23].…”