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Review

Metal Complexes of Bispidine Derivatives: Achievements and Prospects for the Future

by
Altynay B. Kaldybayeva
1,2,*,
Valentina K. Yu
2,*,
Feyyaz Durap
3,4,
Murat Aydemir
3,4 and
Khaidar S. Tassibekov
1,2
1
Faculty of Chemistry and Chemical Technology, Al Farabi Kazakh National University, 71 Al-Farabi Ave, Almaty 050040, Kazakhstan
2
Laboratory of Chemistry of Synthetic and Natural Medicinal Substances, A.B. Bekturov Institute of Chemical Sciences, 106 Sh. Ualikhanov St., Almaty 050010, Kazakhstan
3
Department of Chemistry, Faculty of Science, Dicle University, 21280 Diyarbakir, Türkiye
4
Science and Technolgy, Application and Research Center (DUBTAM), Dicle University, 21280 Diyarbakir, Türkiye
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(5), 1138; https://doi.org/10.3390/molecules30051138
Submission received: 6 February 2025 / Revised: 22 February 2025 / Accepted: 24 February 2025 / Published: 3 March 2025
(This article belongs to the Special Issue Organometallic Compounds: Design, Synthesis and Application)
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Abstract

:
Multidentate bispidine ligands, including tetra-, penta-, hexa-, hepta-, and octadentate variants, exhibit strong coordination tendencies due to their intrinsic rigidity, significant reorganization potential, and ability to efficiently encapsulate metal ions. These structural attributes profoundly influence the thermodynamic stability, metal ion selectivity, redox behavior, and spin-state configuration of the resulting complexes. Metal ions, in turn, serve as highly suitable candidates for coordination due to their remarkable kinetic inertness, rapid complex formation kinetics, and low redox potential. This review focuses on ligands incorporating the bispidine core (3,7-diazabicyclo[3.3.1]nonane) and provides an overview of advancements in the synthesis of metal complexes involving p-, d-, and f-block elements. Furthermore, the rationale behind the growing interest in bispidine-based complexes for applications in radiopharmaceuticals, medicinal chemistry, and organic synthesis is explored, particularly in the context of their potential for diagnostic and catalytic drug development.

1. Introduction

Bispidine 1 (3,7-diazabicyclo[3.3.1]nonane), composed of two condensed piperidine rings, was first synthesized by Mannich and Moss in the 1930s through the condensation of piperidine with paraformaldehyde and primary amines [1]. Its coordination with transition metals was later established by Stetter and Haller in 1957 and 1969, respectively [2]. Since then, the bispidine framework has been extensively studied in coordination chemistry [3,4,5], organic synthesis [6,7], radiopharmaceuticals [8,9,10,11], and medical chemistry [12]. Naturally occurring bispidine derivatives are found in Genista and Lupinus species in the form of the cyclic alkaloids such as cytisine 2, spartein 3, and lupanin 4 (Figure 1), which exhibit antiarrhythmic, anticonvulsant, and antimicrobial properties [13,14,15].
Derivatives of 3,7-diazabicyclo[3.3.1]nonane can typically be synthesized through five distinct methods (Scheme 1):
Molecules 30 01138 sch001
Scheme 1. Synthesis methods of 3,7-diazabicyclo[3.3.1]nonanes. (I) Mannich reaction-based synthesis from carbonyl compounds and aliphatic amines [16]; (II) transformation of 4-piperidones into 3,7-diazabicyclo[3.3.1]nonanes [17]; (III) acid hydrolysis of carboxylic acid nitrile derivatives, reduction and, in some cases, alkylation (or acylation with subsequent reduction) of the obtained 3,7-diazabicyclo[3.3.1]nonanes [18]; (IV) cyclization of 3,5-bifunctional piperidine derivatives [13]; (V) ring-opening of the 1,3-diazaadamantane cycle [19].
Scheme 1. Synthesis methods of 3,7-diazabicyclo[3.3.1]nonanes. (I) Mannich reaction-based synthesis from carbonyl compounds and aliphatic amines [16]; (II) transformation of 4-piperidones into 3,7-diazabicyclo[3.3.1]nonanes [17]; (III) acid hydrolysis of carboxylic acid nitrile derivatives, reduction and, in some cases, alkylation (or acylation with subsequent reduction) of the obtained 3,7-diazabicyclo[3.3.1]nonanes [18]; (IV) cyclization of 3,5-bifunctional piperidine derivatives [13]; (V) ring-opening of the 1,3-diazaadamantane cycle [19].
Molecules 30 01138 sch001

2. The Structure of Bispidine Ligands

The bispidine frame can adopt three primary conformations: armchair–armchair, armchair–boat (or boat–chair), and boat–boat. Among these, the armchair–armchair conformation is generally the most energetically favorable and is particularly suitable for capturing one or two protons via intramolecular hydrogen bonding (N–H···N and N–H···Cl···H–N). This conformation also facilitates efficient metal chelation. The donor centers, specifically N7 and N3, contribute to the rigidity of the ligand framework, while the incorporation of additional donor groups, such as pyridyl moieties at C2 and C4, introduces structural flexibility. Furthermore, bispidine ligans can exhibit configurational isomerism (Figure 2), resulting in different ligand orientations: endo/endo ligands (fully equatorial), exo/endo (axial and equatorial), and exo/exo (fully axial). The endo/endo configuration is particularly advantageous for creating a well-organized coordination environment, ensuring optimal donor positioning for metal complexation [20,21,22].
Studies have demonstrated that NMR spectroscopy can effectively determine the cis/trans configurations (Figure 3) of substituents at the 2nd and 4th positions [23]. In the armchair–armchair conformation, phenyl substituents at C2 and C4 adopt equatorial positions, resulting in a cis-symmetric configuration. However, the introduction of bulky substituents or hydrogen bonds accepting groups at N3 induces a transition to the trans-configuration.
The structures of all ligands and the characteristics of their metal intermediates discussed in the article are shown in Figure 4 and in Table 1.

3. Synthesis of Metal Complexes with a Fragment of Bispidine

3.1. Bispidine Complexes of d-Block Transition Metals

Bispidine-type ligands (3,7-diazabicyclo[3.3.1]nonane) exhibit significant rigidity; as tetra-, penta-, and hexadentate bispidine derivatives originate from the highly rigid diazaadamantane framework. Transition metal complexes often require structural support from rigid multidentate ligands, making bispidine an ideal candidate for imparting unique coordination geometries. A representative copper-containing complex (5) was synthesized by stirring L 1 in methanol (MeOH) at room temperature for 2 h with a methanolic solution of CuCl2·2H2O, followed by ether diffusion. The reaction yielded the desired complex with a 72% efficiency (Figure 4, Table 1, Scheme 2) [24].
Solvent evaporation is commonly used to isolate target complexes following the interaction of a ligand with an inorganic salt, allowing for subsequent crystallization and solvent diffusion. However, this method may be ineffective when complexes exhibit high water solubility, preventing their formation. An alternative approach, demonstrated in [25], involves synthesizing copper complexes with an acidic N2O2-chelate. In this method, aqueous solutions of ligands L 2–5 and malachite were mixed and stirred overnight, yielding copper complexes 6 a–d with high efficiency (Scheme 3).
Radioactive tracers play a crucial role in cancer diagnosis, particularly through positron emission tomography (PET). In this technique, a positron-emitting isotope binds to a biological carrier and selectively accumulates in cancerous cells. While 62Cu is primarily limited to perfusion studies due to its short half-life [56,57], 64Cu serves as an optimal positron emitter for both PET and targeted radiotherapy as, in its turn, it is an ideal [58,59,60,61]. In a related study, ligands L 6–8 were combined with a Cu(OAc)2·2H2O solution and stirred overnight at room temperature, yielding copper complexes 7 a–c with an efficiency of 56% (Scheme 4) [26].
The oxidation of 3,5-di-tert-butylcatechin with oxygen was carried out using bispidine–copper complex catalysts 8 a–d (bispidines with donor groups such as bis-tertiary amine-bispiridyl or bis-tertiary amine-trispiridyl). The catalysts 8 a–d, featuring bispidine fragments, were synthesized by reacting L 12, 3,4,5,6-tetrachlorocatechin (tcc), and Cu(BF4)2 in the presence of acetonitrile and methanol. These reactions yielded the desired complexes with a 58% efficiency (Scheme 5) [27].
When using bispidine ligands with copper as a catalyst in the Henry reaction, the product yield can be enhanced to 96%. To achieve this, complex 9 was synthesized reacting L 13 with copper chloride (CuCl2) under continuous stirring for 5 h at 25 °C (Scheme 6) [28]. The yield of reaction products between nitromethane and 4-nitrobenzaldehyde in the presence of a copper complex 9 (20 mol % of each) reaches to 95%, and when using keratin as a catalyst, only 66% [62].
Oligonuclear transition metal complexes are of significant interest in photochemistry due to their ability to facilitate photoinduced energy and electron transfer. Ru(II) polypyridyl complexes serve as effective photoactive components, exhibiting favorable photophysical properties, such as a long excited-state lifetimes and high quantum luminescence yields. However, their application is limited by the high resistance of Ru(II) complexes to photodegradation. To address this issue, an intermediate copper complex 10, based on the rigid bispidine ligand L 14, has been introduced as a potential alternative [29].
Comba and colleagues (Scheme 7) designed novel ligands L 15 and L 16, 3-(2-methylpyridyl)-7-(bis-2-methylpyridyl)-3,7-diazabicyclo[3.3.1]nonane, featuring two tertiary amine and four pyridine donor groups. These ligands can form both heteronuclear and mononuclear metal complexes and coordinate in different modes acting as pentadentate, hexadentate, or monodentate ligands. This versatility enables the formation of seven-coordinate pentagonal pyramidal and bipyramidal structures. The reaction of L 15 with Cu(BF4)2 in acetonitrile yields copper complex 11 with an efficiency of 74% [30].
Supramolecular metallogels (SMG) are utilized in film production, nanowire synthesis, and the removal of organic contaminants. To facilitate SMG isolation, research has focused on synthesizing bispidine ligands and their complexes, which can form coordination polymers. In this context, complexes 12 a–e were synthesized with yields ranging from 51% to 95% by reacting L 17 and a hydrate copper salt in ethanol, followed by boiling for 2 h (Scheme 8) [31].
The aziridination reaction catalyzed by transition metals holds significant importance in organic synthesis, particularly in the dihydroxylation and epoxidation of nonfunctionalized alkenes. A highly promising approach involves the transfer of nitrenes to olefins in the presence of transition metal catalysts. In [32], the synthesis of copper complexes 13 a–c, based on tetra- and pentadentate bispidine ligands L 1, L 18, L 19, is reported for use as catalysts.
The redox potentials and stability constants of Cu(II) complexes derived from tetradentate bispidine ligands can be changed by substituting pyridine rings. To achieve this, a suspension of L 18 and Cu(ClO4)2·6H2O in acetonitrile was stirred for 2 h at room temperature, followed by ether diffusion, resulting in the isolation of complex 14 (Scheme 9) [63].
Pentadentate bispidine ligands L 20–22 (3,7-diazabicyclo[3.3.1]nonanes) have been demonstrated to enhance complex stability and readily interact with biological molecules and fluorescent particles for PET imaging. Additionally, these ligands rapidly form stable complexes with Cu(II). In a representative synthesis, a reaction mixture of L 21 and copper(II) perchlorate hexahydrate in acetonitrile was stirred overnight at room temperature, followed by ether diffusion, yielding complex 15 b as blue crystals with a 69.4% yield (Scheme 10) [33].
Bispidine ligands have demonstrated excellent efficiency in forming coordination conjugates with dyes, making them valuable for optical sensor development and imaging systems. Complexes 16 a, b were synthesized from a ligand L 22 derivative, reduced with sodium borohydride, and reacted with copper(II) acetate hexahydrate in a mixture of methanol and acetonitrile (Scheme 11) [64].
Nitrogen atoms within the rigid bicyclic framework contribute to the selectivity and stability of complex formation with metal cations and even neutral atoms [65,66,67]. Vatsadze et al. [34] synthesized metal complexes 17 a–d by reacting copper(II) chloride and perchlorate with L 23–26 in appropriate solvents, followed by heating the mixtures and subsequently crystallizing the products (Scheme 12).
The remarkable stability of radioactive copper complexes with bispidine-picolinates offers significant potential not only for PET imaging but also for radionuclide therapy using the therapeutic isotope copper-67 [68,69,70]. Radiopharmaceuticals based on Cu(II) ions have been synthesized through the formation of copper-containing compounds 18 a, b, facilitated by the strong complexing properties of hexadentate picolinate-based bispidine ligand L 27 (Scheme 13) [35].
Bispidinone Cu(II) complexes have been extensively studied for PET imaging due to their exceptional stability and ease of bioconjugation [71]. In addition, bispidinone-based metal chelates have been explored as catalysts for various reactions, including aziridination [72], olefin oxidation [73,74], hydroxylation of CH groups [75], halogenation [76], sulfoxidation [77], and their role in non-heme enzyme models [78,79]. Mononuclear Fe(II) coordination complexes, which exhibit low-spin, high-spin, or spin-crossover states, have found applications in biomimetic studies and magnetic resonance imaging (MRI) [80,81,82]. The reaction of L 28–30 and L 36 with iron(II) tetrafluoroborate hexahydrate or iron(II) perchlorate hydrate in degassed anhydrous acetonitrile underan argon atmosphere leads to the formation of metal complexes 19 a–d with yields ranging from 17% to 71%. These complexes hold the potential to design responsive off–on probes (Scheme 14) [36].
Iron-containing metalloproteins are well known for their essential role in mediating oxidative transformations within the human body [83,84,85]. To investigate the influence of equatorial heteroatom substitution on chlorite oxidation, Sahoo et al. [37] synthesized iron-containing complexes 20 a–c by reacting L 31–33 with Fe(MeCN)2(OTf)2 in acetonitrile (MeCN) at room temperature, followed by slow vapor diffusion of diethyl ether, yielding 84–88%. The complexes demonstrated the ability to oxidize ClO2− to ClO2 under ambient conditions at pH 5.0 in an acetate buffer solution (Scheme 15).
High-valent iron complexes serve as catalysts in oxidation and halogenation reactions, while low-valent complexes are widely utilized in autooxidation processes within the paint industry. In a representative synthesis, iron (II) 2-ethylhexanoate was reacted with L 34 in acetonitrile at room temperature. Following vacuum evaporation, product 21 was isolated with a 57% yield (Scheme 16) [38].
The coordination chemistry of iron is remarkable due to its wide range of oxidation states, which play a crucial role in spin crossover phenomena and the modeling of electron and oxygen transfer enzymes. Iron(II) complexes 22 a–f were synthesized using bispidine ligands L1, L34–37, containing two tertiary amines and two, three, or four additional donor groups (pyridine, phenolate, or alcoholate), in reaction with iron(II) salts. The resulting complexes were obtained with yields ranging from 40% to 70% (Scheme 17) [39].
Certain bispidine iron–oxo complexes served as catalysts for the oxidation of non-heme iron [86,87]. Currently, several synthetic methods have been developed for such compounds, including the preparation of iron(II) complexes 23 a, b. In a representative synthesis, L 38 was reacted with iron(II) triflate in acetonitrile, yielding iron complex 23a with a yield of 73% (Scheme 18) [40].
A reaction mixture of dimethyl 7-(di(pyridine-2-yl)methyl)-9-hydroxy-3-methyl-2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonan-1,5-dicarboxylate L 16 and ferric chloride (FeCl2) in dry acetonitrile was stirred at room temperature overnight. The resulting yellow solution was subjected to diethyl ether diffusion, yielding yellow needle-like crystals of complex 24 with a 52% yield (Scheme 19) [30].
Bispidine Mn(II) complexes with tetradentate ligands typically adopt an octahedral geometry, whereas heptacoordinated Mn(II) complexes can exhibit pentagonal bipyramidal or trigonal prismatic structures. In a representative synthesis, L 15 and MnCl2·4H2O were suspended in an equimolar acetonitrile–methanol mixture and stirred overnight at room temperature, followed by diethyl ether diffusion. The reaction yielded complex 25 with an efficiency of 56% (Scheme 20) [30].
The platinum complex cisplatin (cis-(NH3)2PtCl2) exhibits significant pharmacological properties, including alkylating, immunosuppressive, antitumor, and cytostatic effects. This has driven extensive research into the properties of platinum complexes and the development of efficient synthetic methods. In the pursuit of Pt complexes with cytotoxic activity, Cui et al. [41] synthesized platinum complexes 26 a–c by reacting (1,5-hexadiene)PtCl2 with bispidine L 40 in dimethylformamide (DMF) at 70 °C for 3 h (Scheme 21).
Researchers [42] synthesized (spiro[bispidin-9.2′-[1,3]dioxolan])platinum (II) dichloride (27) by reacting L 41 with (C6H10)PtCl2 in dimethylformamide (DMF). The reaction was conducted at 100 °C for 2 h, yielding the product with an efficiency of 97% (Scheme 22).
Pyrazole rings, macrocyclic amides, and oxygen-containing substituents (such as alcohols or carboxylate groups) can enhance the number of coordination sites within the bispidine core [88]. To expand its coordination capacity, a, palladium-containing complex (28) was synthesized by reacting PdCl2 with L 42, which was obtained via the CuAAC click reaction, in acetonitrile at room temperature for 48 h (Scheme 23) [43].
The ligand L 43 has been found to be a highly organized bidentate ligand, with its alkyl substituents providing functional groups for further modifications. Nickel acetylacetonate Ni(acac)2 was reacted with 3,7-Diallyl-3,7-diazabicyclo[3.3.1]nonane L 43 in the presence of pentane for 1 h at room temperature, yielding (C7H12N2allyl2)Ni(acac)2 29 with an efficiency of 99% (Scheme 24) [44].
The formation of C(sp2)–C(sp3) bonds is a fundamental transformation in organic synthesis. It has been established that sp, sp2, and sp3 carbon atoms can be effectively linked using nickel catalysts. The (bispidine)Ni(NO3)2 complex 30, which exhibits strong reactivity towards various aryl halides with benzylzine bromides or dialkylzine reagents, was synthesized with a 98% yield by reacting L 1 with nickel nitrate hydrate (Scheme 25) [45].
The stability of metal complexes under physiological conditions is a critical factor in nuclear medicine, which can be achieved using rigid ligands with metal-binding capabilities. The coordination chemistry of hexadentate ligands L 44–45 with various metals ions (Zn(II), Co(II), and Ga(III)) was investigated. The reaction of L 44 and L 45 with metal salts resulted in the formation of complexes 31–33 with yields ranging from 32 to 98% (Scheme 26) [46].
Positron emission tomography (PET) combined with X-ray computed tomography (CT) provides highly accurate information on tumor progression in various cancers, including lymphoma and epithelial malignancies affecting the lungs, esophagus, cervix, head, and neck [89,90,91]. However, a key limitation arises from the slow redistribution kinetics of bioconjugates, which may not always align with non-metallic isotopes. To overcome this challenge, the development of metal radioisotopes, specifically metal complexes 34 a–d, with longer half-lives and simplified radiochemistry, is essential [92]. In pursuit of such compounds, a recent study synthesized coordination complexes of Zn(II), Co(II), Cu(II), and Ni(II) with L 46 (Scheme 27) [47,48].
Mercury-197 (197Hg) complexes have been clinically utilized in diagnostics imaging of the kidneys and brain, particularly in the form of chloroperodrine with a radioactive label, due to their stability and the radiochemical properties used. Mercury complexes with a bispidine framework (35 a, b) demonstrated high chemical stability in the presence of an excess of sulfur-containing compounds and exhibited strong in vivo stability (Scheme 28) [49].

3.2. Complexes of p-Block Elements with Bispidines

There is a significant demand for bismuth-based complexes, driven by the demonstrated effectiveness of targeted cancer radiotherapy using actinium-225, whose daughter isotopes (bismuth-211 and bismuth-213) exhibit high therapeutic potential. The synthesis of complexes 36 a–e was achieved by reacting bispidine ligands L48–51 with bismuth nitrate hydrate in the presence of methanol, yielding 60% to 99% (Scheme 29) [50].
Gallium-68 (68Ga) complexes are widely utilized in PET/PDT for early disease detection, allowing diagnosis before physical symptoms manifest, as gallium nuclides facilitate efficient targeting of disease sites. Complexes 37 a, b were synthesized with a 90% yield by reacting ligands L 52 and L 53 with GaCl3 in aqueous suspension overnight at 100 °C (Scheme 30) [51].
Since the first clinical studies in 1925 demonstrated the effectiveness of bismuth-214 complexes for measuring blood flow between hands, scientific efforts have focused on developing new methods for utilizing other complexes in single-photon emission computed tomography (SPECT), positron emission tomography (PET), and targeted therapies (including alpha, beta, and electron therapy). In a representative synthesis, indium complex 38 was obtained with a 39% yield by reacting bispidine ligand L 54 with indium perchlorate hydrate In(ClO4)3·8H2O at room temperature for 5 h (Scheme 31) [52].

3.3. Bispidine-Containing Lanthanide Complexes

The reaction of L 51 with indium, lanthanum and lutetium salts resulted in the formation of complexes 39–41, with yields ranging from 81% to 88% (Scheme 32) [53].
The bispidine ligand L 51, functioning as an antenna, effectively transferred energy to the lanthanides metal centers, which exhibited high radiation intensity and extended luminescence lifetimes. This highlights the potential of complexes 42–44 for use in fluorescent probe fabrication. A notable example is the terbium complex 42, synthesized through the reaction of L 51 with terbium nitrate (Scheme 33) [54].
Lanthanide complexes 45–47, featuring a bispidine framework with photophysical properties, were synthesized using readily available materials, including L 55 and methanol in an aqueous solutions of lanthanide salts. The resulting products were obtained with yields ranging from 40% to 70% (Scheme 34) [55].
The rigid framework and tunable basicity of bispidine ligands significantly influence the stability and selectivity of their metal complexes, enabling the synthesis of tetra-, penta-, hexa- and octadentate metal complexes incorporating a bispidine fragment. These complexes have been applied in various catalytic and biomedical fields. In organic synthesis, bispidine-based copper(II) complexes catalyze aziridination reactions [25,93,94], while nickel (II) pre-catalyst facilitate C-C bond formation [95]. Additionally, copper(II) complexes play a role in the enantioselective Henry reaction [96,97,98]. Other notable applications include oxygen activation using copper (I) and cobalt (II) [99,100] and oxidation reactions mediated by high-valent iron and manganese complexes with bispidine ligands [101,102]. In medicine, bispidine complexes are explored as potential cytostatic agents in cancer therapy [103]. In radiopharmaceuticals, they are widely used for PET/PDT imaging [104,105].

4. Conclusions

Bispidines constitute a diverse class of ligands well-established in coordination chemistry, exhibiting coordination numbers ranging from 4 to 8. Their adaptability in terms of coordination geometry, donor group variability, and structural rigidity allows for the tailored design of bispidine ligands for specific metal ions and diverse applications.
In radiopharmaceutical development, key factors include efficient radiolabeling, complex stability, and the ease of functionalization for conjugation with biological vectors. This review highlights recent advances in the chemistry of bispidine–metal complexes, demonstrating their high efficiency and broad practical applicability. These developments underscore the significant potential of bispidine complexes in medical and radiopharmaceutical chemistry, particularly for drug development and catalytic systems that mimic natural enzymes. Furthermore, ongoing research in coordination chemistry is expected to yield new discoveries, expanding the scope of bispidine applications.

Author Contributions

Conceptualization, V.K.Y. and M.A.; methodology, V.K.Y. and M.A.; software, V.K.Y., A.B.K. and F.D.; validation, K.S.T.; formal analysis, V.K.Y. and M.A.; investigation, A.B.K. and F.D.; resources, V.K.Y. and M.A.; data curation, V.K.Y., A.B.K. and F.D.; writing—original draft preparation, V.K.Y., A.B.K. and F.D.; writing—review and editing, A.B.K. and F.D.; visualization, A.B.K. and F.D.; supervision, V.K.Y. and M.A.; project administration, A.B.K., K.S.T. and M.A.; funding acquisition, A.B.K., K.S.T. and M.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research has been funded by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan, Grant number AP22688235 and BR27101179. Partial support for this work by Dicle University (Project number: FEN.24.025) is gratefully acknowledged.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Acknowledgments

We also thank the Faculty of Science of Dicle University for partial support for F.D. and A.M.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 01138 g001
Figure 1. Bispidine framework and natural alkaloids containing it.
Figure 1. Bispidine framework and natural alkaloids containing it.
Molecules 30 01138 g001
Molecules 30 01138 g002
Figure 2. Possible configuration isomers of bispidine.
Figure 2. Possible configuration isomers of bispidine.
Molecules 30 01138 g002
Molecules 30 01138 g003
Figure 3. Structural conformations of bispidons. (a) cis-chair–chair, (b) cis-chair–boat, (c) trans-chair–boat, (d) trans-boat–chair.
Figure 3. Structural conformations of bispidons. (a) cis-chair–chair, (b) cis-chair–boat, (c) trans-chair–boat, (d) trans-boat–chair.
Molecules 30 01138 g003
Molecules 30 01138 g004aMolecules 30 01138 g004b
Figure 4. Structures of bispidine ligands.
Figure 4. Structures of bispidine ligands.
Molecules 30 01138 g004aMolecules 30 01138 g004b
Molecules 30 01138 sch002
Scheme 2. Synthesis of complex 5.
Scheme 2. Synthesis of complex 5.
Molecules 30 01138 sch002
Molecules 30 01138 sch003
Scheme 3. Synthesis of copper complexes 6 a–d.
Scheme 3. Synthesis of copper complexes 6 a–d.
Molecules 30 01138 sch003
Molecules 30 01138 sch004
Scheme 4. Reaction of L 6 with copper salt.
Scheme 4. Reaction of L 6 with copper salt.
Molecules 30 01138 sch004
Molecules 30 01138 sch005
Scheme 5. Reaction of bispidine containing ligand L 12 with copper salt.
Scheme 5. Reaction of bispidine containing ligand L 12 with copper salt.
Molecules 30 01138 sch005
Molecules 30 01138 sch006
Scheme 6. Synthesis of complex 9.
Scheme 6. Synthesis of complex 9.
Molecules 30 01138 sch006
Molecules 30 01138 sch007
Scheme 7. Synthesis of copper complex 11.
Scheme 7. Synthesis of copper complex 11.
Molecules 30 01138 sch007
Molecules 30 01138 sch008
Scheme 8. Reaction of L 17 with copper salts.
Scheme 8. Reaction of L 17 with copper salts.
Molecules 30 01138 sch008
Molecules 30 01138 sch009
Scheme 9. Synthesis of copper-based complex 14.
Scheme 9. Synthesis of copper-based complex 14.
Molecules 30 01138 sch009
Molecules 30 01138 sch010
Scheme 10. Synthesis of complex 15 b.
Scheme 10. Synthesis of complex 15 b.
Molecules 30 01138 sch010
Molecules 30 01138 sch011
Scheme 11. Synthesis of hexacoordinate Cu complexes 16 a, b.
Scheme 11. Synthesis of hexacoordinate Cu complexes 16 a, b.
Molecules 30 01138 sch011
Molecules 30 01138 sch012
Scheme 12. Reaction tetradentate bispidine ligand L 23 with copper salt.
Scheme 12. Reaction tetradentate bispidine ligand L 23 with copper salt.
Molecules 30 01138 sch012
Molecules 30 01138 sch013
Scheme 13. Synthesis of copper complex 18 a.
Scheme 13. Synthesis of copper complex 18 a.
Molecules 30 01138 sch013
Molecules 30 01138 sch014
Scheme 14. Synthesis of complex 19 a.
Scheme 14. Synthesis of complex 19 a.
Molecules 30 01138 sch014
Molecules 30 01138 sch015
Scheme 15. Reaction of L 31–33 with an iron salt.
Scheme 15. Reaction of L 31–33 with an iron salt.
Molecules 30 01138 sch015
Molecules 30 01138 sch016
Scheme 16. Synthesis of heptacoordinate Fe complex 21.
Scheme 16. Synthesis of heptacoordinate Fe complex 21.
Molecules 30 01138 sch016
Molecules 30 01138 sch017
Scheme 17. Reaction tetradentate bispidine ligand L 35 with an iron salt.
Scheme 17. Reaction tetradentate bispidine ligand L 35 with an iron salt.
Molecules 30 01138 sch017
Molecules 30 01138 sch018
Scheme 18. Synthesis of iron-based complex 23a.
Scheme 18. Synthesis of iron-based complex 23a.
Molecules 30 01138 sch018
Molecules 30 01138 sch019
Scheme 19. Synthesis of complex 24.
Scheme 19. Synthesis of complex 24.
Molecules 30 01138 sch019
Molecules 30 01138 sch020
Scheme 20. Reaction of L 15 with manganese salt.
Scheme 20. Reaction of L 15 with manganese salt.
Molecules 30 01138 sch020
Molecules 30 01138 sch021
Scheme 21. Reaction of L 40 with a platinum salt.
Scheme 21. Reaction of L 40 with a platinum salt.
Molecules 30 01138 sch021
Molecules 30 01138 sch022
Scheme 22. Synthesis of tetracoordinate Pt complex 27.
Scheme 22. Synthesis of tetracoordinate Pt complex 27.
Molecules 30 01138 sch022
Molecules 30 01138 sch023
Scheme 23. Reaction of L 42 with palladium salt.
Scheme 23. Reaction of L 42 with palladium salt.
Molecules 30 01138 sch023
Molecules 30 01138 sch024
Scheme 24. Synthesis of nickel complex 29.
Scheme 24. Synthesis of nickel complex 29.
Molecules 30 01138 sch024
Molecules 30 01138 sch025
Scheme 25. Synthesis of complex 30.
Scheme 25. Synthesis of complex 30.
Molecules 30 01138 sch025
Molecules 30 01138 sch026
Scheme 26. Reaction of L 44 with various metal salts.
Scheme 26. Reaction of L 44 with various metal salts.
Molecules 30 01138 sch026
Molecules 30 01138 sch027
Scheme 27. Reaction of L 46 with metal salts.
Scheme 27. Reaction of L 46 with metal salts.
Molecules 30 01138 sch027
Molecules 30 01138 sch028
Scheme 28. Synthesis of mercury complexes 35 a, b.
Scheme 28. Synthesis of mercury complexes 35 a, b.
Molecules 30 01138 sch028
Molecules 30 01138 sch029
Scheme 29. Synthesis of bismuth-based complex 36 a.
Scheme 29. Synthesis of bismuth-based complex 36 a.
Molecules 30 01138 sch029
Molecules 30 01138 sch030
Scheme 30. Synthesis of complex 37 b.
Scheme 30. Synthesis of complex 37 b.
Molecules 30 01138 sch030
Molecules 30 01138 sch031
Scheme 31. Reaction heptadentate bispidine ligand L 54 with an indium salt.
Scheme 31. Reaction heptadentate bispidine ligand L 54 with an indium salt.
Molecules 30 01138 sch031
Molecules 30 01138 sch032
Scheme 32. Reaction hexadentate bispidine ligand L 51 with a lutetium salt.
Scheme 32. Reaction hexadentate bispidine ligand L 51 with a lutetium salt.
Molecules 30 01138 sch032
Molecules 30 01138 sch033
Scheme 33. Synthesis of terbium complex 42.
Scheme 33. Synthesis of terbium complex 42.
Molecules 30 01138 sch033
Molecules 30 01138 sch034
Scheme 34. Synthesis of complexes 45–47.
Scheme 34. Synthesis of complexes 45–47.
Molecules 30 01138 sch034
Table 1. Some characteristics of various metal complexes containing bispidine framework.
Table 1. Some characteristics of various metal complexes containing bispidine framework.
NoSaltsLig. (L)Complex, Solventλmax
{ε(M−1 cm−1)} 		Yield, %The Color of the SolidSynthesis MethodApplicationRef.
1CuCl2·2H2OL 1[Cu(L)Cl]Cl·2H2O, MeOH656 {90}72Blue Diffusion of ether [24]
2Cu2(OH)2CO3L 2–5[L2Cu(OH)2],
H2O		602–612 {247–252} Blue Neutralization with acidic chelate N2O2Radiopharmaceuticals, positron emission tomography (PET)[25]
3Cu(OAc)2·2H2OL 6
L 7–8		[Cu(L)(O)], MeOH
[Cu(L)(OH2)],
MeOH		483 {149}
476 {117}
524 {189}		56Red and purple Recrystallization64Cu PET visualization[26]
4Cu(BF4)2L 1,
L 9–12		[Cu(L)NCMe)]2+, MeCN
[Cu2(L)NCMe)]4+, MeCN, MeOH		450 {510}
453 {577}
456 {685}
468 {651}
532 {1640}		58 Catalytic enzymatic oxidation of catecholamines[27]
5CuCl2L 13[Cu(L)Cl]Cl, MeOH 55Green RecrystallizationThe catalyst for Henry’s enantioselective reaction[28]
6Cu(ClO4)2·6H2OL 14[Cu(L)](ClO4)2, MeOH:H2O412 70Green Heating, concentration at low pressureThe aziridination reaction[29]
7Cu(BF4)2L 15
L 16		[Cu(L)](BF4)2·3H2O, MeCN
[Cu(L)](BF4)2·2H2O, MeCN		626 {119}
630 {112}		74
54		Blue Evaporation, diffusion of ether
heating, diffusion of ether		The aziridination reaction[30]
8Cu(ClO4)2·6H2O
CuCl2·2H2O
CuBr2·2H2O
Cu(NO3)2·3H2O
Cu(CF3COO)2·4H2O		L 17[Cu(L)2](ClO4)2, EtOH
[Cu(L)2Cl]Cl, EtOH
[Cu(L)2Br]Br, EtOH
[Cu(L)2](NO3)2, EtOH
[Cu(L)2](CF3COO)2, EtOH		284 {450}
273 {462}
272 {482}
288 {450}
284 {485}		95
-
68
51
-		Pink
Blue
Purple
Yellow 		Concentration at low pressure, recrystallizationDevelopment of supramolecular coordination polymers[31]
9Cu(CF3SO3)2
Cu(BF4)2·6H2O		L 1
L 18
L 19		[Cu(L)](CF3SO3)2, MeCN
[Cu(L)](BF4)2·3H2O, MeCN
[Cu(L)](BF4)2·4H2O, MeCN		-
624 {25}
881 {60}		83
88
89		 Diffusion of etherThe aziridination reaction[32]
10Cu(ClO4)2·6H2OL 20–21
 
L 22		[Cu(L)](ClO4)2, MeCN
 
[Cu(L)](ClO4), MeCN		629
627
564		84
69
92		Blue
Blue
Purple 		Diffusion of ether64Cu PET visualization[33]
11CuCl2
Cu(ClO4)2
Cu(OH)2		L 23
L 24
L 25
L 26		[Cu(L)]Cl2, EtOH
[Cu(L)](ClO4)2, CHCl3
[Cu(L)](OH)2,
DMF		 Blue
Purple
Dark-
blue 		Heating, recrystallization Catalysts for enantioselective reactions[34]
12CuX2L 27[Cu(L)X]X For the synthesis of radiopharmaceuticals based on Cu(II) ions[35]
13Fe(BF4)2·6H2O
 
Fe(ClO4)2·H2O
Fe(BF4)2·6H2O		L 36
L 28
L 29
L 30		[Fe(L)] 2BF4,
MeCN
[Fe(L)]·2ClO4, MeCN
[Fe(L)(MeCN)]·2BF4, MeCN		458 {5560}
455 {10,870}
443 {12,570}
444 {7144}		71
36
25
17		Red-black
Dark-brown
-
Dark-brown		Diethyl ether diffusion, heating, recrystallizationFor the design of responsive off–on probes[36]
14Fe(MeCN)2(OTf)2L 31
L 32
L 33		[Fe(L) MeCN)]2+, MeCN37 {1061]
380 {1057}
373 {1112}		88
84
88		Yellow
Brown
Light-yellow		Slow vapor diffusion with diethyl etherFor oxidizing ClO2− to ClO2[37]
15Fe(OOCC7H15)2L 34[Fe(L)OOCC7H15] (OOCC7H15)40057Canary Evaporation, recrystallizationCatalyst for the auto-oxidation process[38]
16[Fe(NCCH3)2·(CF3SO3)2]
Fe(SCN)2
FeSO4
FeCl2
Fe(ClO4)2
FeCl2		L 1
 
L 1
L 34
L 35
L 36
L 37		[Fe(L)(CF3SO3)2], CD3CN
 
[Fe(L)(SCN)2], CD3CN
[Fe(L)SO4], MeOH
[Fe(L)Cl]Cl, MeOH
[Fe(L)](ClO4)2, MeOH
[Fe(L)Cl]Cl, MeOH		392
 
375
404
412 {1819}
564 {215}
579 {948}		40–70 Ether diffusion, recrystallizationCatalysts[39]
17[Fe(NCCH3)2]·(CF3SO3)2L 38
 
L 39		[Fe(L)(CF3SO3)] (CF3SO3), MeCN
[Fe(L)(CF3SO3)] (CF3SO3)·3H2O, MeCN		 73
 
33		Yellow RecrystallizationA catalyst for bioinspired catalysis[40]
18FeCl2
Fe(ClO4)2
 
Fe(BF4)2·6H2O		L 16
L 15
 
L 15		[Fe(L)Cl]Cl, MeCN
[Fe(L)(OCH3)](ClO4)2, MeOH
[Fe(L)(OCH3)](BF4)2, MeOH		412 {1381}
-
 
364 {1245}		52
49
 
54		Yellow Diffusion of etherThe activation process[30]
19MnCl2·4H2OL 15[Mn(L)Cl]2[MnCl4], MeCN: MeOH 56Colorless Evaporation, diffusion of etherPET visualization[30]
20(C6H10)PtCl2L 40[Pt(L)Cl]Cl, DMF
[Pt(L)Cl]Cl·C3H7NO, DMF
[Pt(L)Cl]Cl·3H2O, H2O		 87
87
60		Yellow Recrystallization, cooling
heating, recrystallization		Cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer)[41]
21(C6H10)PtCl2L 41[Pt(L)Cl]Cl, DMF 97Yellow Heating, recrystallizationPreparation of compounds with cytotoxic activity[42]
22PdCl2L 42[Pd(L)Cl]Cl, MeCN Might be used as catalysts under
microwave irradiation		[43]
23Ni(acac)2L 43[Ni(L)](acac)2, C5H12 99Blue CoolingImmobilization of metal heterogeneous surfaces[44]
24Ni(NO3)2·6H2OL 1[Ni(L)(NO3)](NO3), MeCN: MeOH 98Pink Evaporation, recrystallizationA catalyst for bond formation C(sp2)-C(sp3)[45]
25Zn(OAc)2·2H2OL 44
L 45		[Zn(L)](TFA), TFA,
MeOH		 98
61		Colorless Evaporation, diffusion of etherBifunctional Chelators for 64Cu PET[46]
26ZnCl2L 46[Zn(L)Cl], THF, H2O Evaporation, centrifugationChelator for radiolabeling studies with 64Cu[47,48]
27Co(OAc)2·2H2OL 44
L 45		[Co(L)](TFA), TFA,
MeOH		470 {123}
475 {117}		32
67		Red
Brown 		Evaporation, diffusion of etherBifunctional Chelators for 64Cu PET[46]
28197HgCl2
NatHgCl2		L 47[Hg(L)], EtOH
[Hg(L)], THF		 Heating, evaporationTheranostic applications in radiopharmaceuticals[49]
29Bi(NO3)3·5H2OL 48
L 49
L 50
L 51		[Bi(L)](NO3)2, MeOH
[Bi(L)(NO3)](NO3), MeOH
[Bi(L)(Br)0,5(NO3)0,5], MeOH
[Bi(L)(NO3)], MeOH
[Bi(L)(NO3)](NO3), MeOH		 93
99
60
95
67		 Recrystallization
 

Evaporation, recrystallization		Targeted 213Bi alpha therapy[50]
30GaCl3L 52
L 53		[Ga(L)]Cl, H2O-
422 {240}		90White
Purple 		Heating, recrystallizationPET visualization,
creating stable theranostic probes for PET/PDT		[51]
31Ga(NO3)3L 48[Ga(L)](TFA)(NO3), TFA, MeOH:H2O 65Colorless Heating, evaporationBifunctional Chelators for 64Cu PET[46]
32In(ClO4)3·8H2OL 54[In(L)](ClO4), MeOH 39Orange Concentration in a vacuumCreation of a chelating component in radiopharmaceuticals based on In[52]
33In(OAc)3·5H2O
 
Lu(OAc)3·4H2O
 
LaCl3·7H2O		L 51[In(L)](TFA), TFA, MeOH, H2O
[Lu(L)](TFA), TFA, MeOH
 
[La(L)](TFA), TFA, MeOH		 88
 
84
 
81		Colorless Evaporation
 
Evaporation, diffusion of ether
Evaporation, concentration in vacuum		Chelators in nuclear medicine used in single-photon emission computed tomography (SPECT)[53]
34Nd(OAc)3
 
Tb(NO3)3
 

Dy(OAc)3		L 51[Nd(L)(OH)2](TFA)·(MeOH), TFA, MeOH
[Tb(L)(OH)2](TFA)·2H2O·MeCN, TFA, H2O, MeCN
[Dy(L)(OH)2](TFA)·1.5H2O·MeCN, TFA, H2O, MeCN		-
 
491
 

-		 Colorless Evaporation, diffusion of etherActing as an antenna for energy transmission[54]
35Tb(NO3)3
 
Eu(OAc)3
 
Yb(NO3)3		L 55[Tb(L)](NO3) MeOH·H2O, MeOH:H2O
[Eu(L)](OAc), EtOH:MeOH
 
[Yb(L)] (NO3) MeOH, H2O, MeOH,		261
 
261
 
262		40–70 Heating, evaporationBiological fluorescent probes with red-shifted absorption[55]
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Kaldybayeva, A.B.; Yu, V.K.; Durap, F.; Aydemir, M.; Tassibekov, K.S. Metal Complexes of Bispidine Derivatives: Achievements and Prospects for the Future. Molecules 2025, 30, 1138. https://doi.org/10.3390/molecules30051138

AMA Style

Kaldybayeva AB, Yu VK, Durap F, Aydemir M, Tassibekov KS. Metal Complexes of Bispidine Derivatives: Achievements and Prospects for the Future. Molecules. 2025; 30(5):1138. https://doi.org/10.3390/molecules30051138

Chicago/Turabian Style

Kaldybayeva, Altynay B., Valentina K. Yu, Feyyaz Durap, Murat Aydemir, and Khaidar S. Tassibekov. 2025. "Metal Complexes of Bispidine Derivatives: Achievements and Prospects for the Future" Molecules 30, no. 5: 1138. https://doi.org/10.3390/molecules30051138

APA Style

Kaldybayeva, A. B., Yu, V. K., Durap, F., Aydemir, M., & Tassibekov, K. S. (2025). Metal Complexes of Bispidine Derivatives: Achievements and Prospects for the Future. Molecules, 30(5), 1138. https://doi.org/10.3390/molecules30051138

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