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The first comprehensive book focusing on synthesis and applications of macrocyclic polyamines and their derivatives
Macrocyclic polyamines are a class of widely used important compounds. This is the first book that systematically summarizes the synthesis and applications of macrocyclic polyamines and their analogues, including the properties and synthetic methods of macrocyclic polyamines, chemical nucleases based on macrocyclic polyamines, the derivatives of macrocyclic polyamines as nano-vector materials, macrocyclic polyamines derivatives for bio-imaging, chemical sensors based on macrocyclic polyamines, and other applications of macrocyclic polyamines.
Macrocyclic Polyamines: Synthesis and Applications includes most of the studies involving macrocyclic polyamines and their derivatives, and may be used as a reference for the researchers in related fields. It offers in-depth coverage of cyclization modes; special procedures for tetraza macrocyclic compounds; diacids-diamines condensation; oxidative DNA cleaving by macrocyclic polyamines; lipids with cationic MPA headgroups; the derivatives of DOTA, DO3A, and PCTA; receptors for anions; sensors for bioactive molecules; macrocyclic polyamines for solvent extraction and membrane transport of amino acids and their derivatives, electrophoretic separation, and open-tubular CEC; and much more.
?The first book that systematically summarizes the chemistry of macrocyclic polyamines and their derivatives in terms of synthetic methods for their preparation, functionalization, and application in the main fields of chemical sensors, chemical nucleases, drug-delivery, bio-imaging and vector materials
?Provides a comprehensive reference for the researchers working on macrocyclic polyamines
?Offers train of thought in related research fields such as organic chemistry, coordination chemistry, analytical chemistry, supramolecular chemistry, biomaterials, etc.
Macrocyclic Polyamines: Synthesis and Applications will not only provide a reference for the researchers working on macrocyclic polyamines, but also offer opportunities for researchers in related research fields to understand the benefits of these key compounds.
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Table of Contents
Cover
Title Page
Copyright
Preface
Chapter 1: Introduction
1.1 Classification of Macrocyclic Polyamines
1.2 Properties of Macrocyclic Polyamines
1.3 Applications of Macrocyclic Polyamines
References
Chapter 2: Synthetic Methods for Macrocyclic Polyamines
2.1 Ring-Closure Modes
2.2 The Synthesis of Saturated Macrocyclic Polyamines
2.3 Aromatic Subunit-Containing Polyazamacrocycles
2.4 Macrocyclic Polyimines (Schiff Bases)
2.5 Macrocyclic Amides
2.6 Cryptands
References
Chapter 3: Chemical Nucleases Based on Macrocyclic Polyamines
3.1 Hydrolysis of Nucleic Acids
3.2 Oxidative Cleavage of Nucleic Acids
3.3 Summary
References
Chapter 4: Derivatives of Macrocyclic Polyamines as Nanovector Materials
4.1 Derivatives of MPAs as Nonviral Gene Vectors
4.2 Multifunctional Materials for Both Drug Delivery and Bio-Imaging
4.3 Summary
References
Chapter 5: Macrocyclic Polyamine Derivatives for Bio-Imaging
5.1 Typical Macrocyclic Polyamines for Magnetic Resonance Imaging (MRI)
5.2 Other Derivatives of Macrocyclic Polyamines for MRI
5.3 MPAs for PET Imaging
References
Chapter 6: Chemical Sensors Based on Macrocyclic Polyamines
6.1 Sensors for Metal Cations
6.2 Receptors for Anions
6.3 pH Indicator
6.4 Sensors for Bioactive Molecules
6.5 Summary
References
Chapter 7: Other Applications of Macrocyclic Polyamines
7.1 Macrocyclic Polyamines as Ionophores
7.2 Macrocyclic Polyamines for Electrophoretic Separation
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 2: Synthetic Methods for Macrocyclic Polyamines
Figure 2.1 Intramolecular cyclization.
Figure 2.2 [1 + 1] Cyclization.
Figure 2.3 [2 + 2] Cyclization.
Figure 2.4 A typical example of the Richman–Atkins reaction.
Figure 2.5 The effect of leaving groups.
Figure 2.6 The synthesis of tetraaza macrocycles.
Figure 2.7 Synthons of dihalomethyl arenes.
Figure 2.8 Pd-catalyzed N-arylation for the synthesis of aromatic polyazamacrocycles.
Figure 2.9 Effect of metal on cyclization.
Figure 2.10 Metal-induced ring contraction or ring expansion.
Figure 2.11 Routes to synthesize unsymmetrical compartmental ligands.
Figure 2.12 Automatic condensation of 2,6-diformyl phenols with diamines.
Figure 2.13 Acid-assisted condensation of diamines with a shorter chain length.
Figure 2.14 Selected aromatic dicarbonyls.
Figure 2.15 Synthesis of crab-like bis-α-chloroamide.
Figure 2.16 Synthesis of MPAs via crab-like cyclization.
Figure 2.17 Synthesis of cyclen/cyclam derivatives via crab-like cyclization.
Figure 2.18 Crab-like cyclization of primary amines.
Figure 2.19 Synthesis of pyridine-containing macrocyclic amides.
Figure 2.20 Condensation of diesters bearing β-heteroatoms.
Figure 2.21 Condensation of malonate diesters with amines.
Figure 2.22 Condensation reagent-assisted cyclization.
Figure 2.23 Alkylation of unprotected amines for the synthesis of cryptands.
Figure 2.24 Coupling of tripodal aldehydes and amines followed by reduction in the synthesis of cryptands.
Figure 2.25 Coupling of tripodal esters with amines.
Figure 2.26 Examples of cryptands generated by the condensation of a tripodal amine with dicarbonyls.
Figure 2.27 Multistep synthesis of a spherical cryptand.
Chapter 3: Chemical Nucleases Based on Macrocyclic Polyamines
Scheme 3.1 The mechanisms for substrate activation by metal complexes.
Scheme 3.2 Proposed catalytic cycle for the hydrolysis of BNPP by Cu(II)-[9]aneN
3
.
Chapter 5: Macrocyclic Polyamine Derivatives for Bio-Imaging
Figure 5.1 Structure of DOTA and its Gd complex (Gd–DOTA).
Figure 5.2 Structures of DOTApnB, DOTASA, and DOTAGA.
Figure 5.3 Interconversion of [Ln-DOTA]
−
stereoisomeric structures in solution.
Figure 5.4 Schematic diagram of a metalloradiopharmaceutical and a tumor receptor.
Figure 5.5 Structures of DO3A, DO3ABn, and DO3MA.
Figure 5.6 Metal-responsive MRI contrast agents for calcium.
Figure 5.7 Metal-responsive MRI contrast agents for zinc.
Figure 5.8 Metal-responsive MRI contrast agents for copper.
Figure 5.9 β-Galactose-responsive MRI contrast agent.
Figure 5.10 MRI contrast agent interaction with esterase.
Figure 5.11 Structures of PCTA, PCTGA, and BP2A.
Figure 5.12 Structures of TETA and NOTA.
Chapter 6: Chemical Sensors Based on Macrocyclic Polyamines
Figure 6.1 Illustration of two interaction mechanisms of chemical sensors with analytes.
Figure 6.2 X-ray crystallographic structure of the
6-20-Zn
(
II
) complex.
Figure 6.3 Structures of
6-23
and
6-24
and X-ray crystallographic structure of
6-24-Zn(II)
.
Figure 6.4 Compound
6-47
and X-ray crystallographic structure of
6-47-Ag(I)
.
Figure 6.5 Compounds
6-13-Zn(II)
and
6-48-Zn(II)
coordinate with PPi.
Figure 6.6 Structure of the complex
6-61-Cd(II)
and its interaction with PPi.
Figure 6.7 Cascade mechanism for the consecutive inclusion of two Cu(II).
Figure 6.8 Schematic representation of the complex formed between receptor
6-84
and ATP by means of hydrogen bonding and electrostatic and π-stacking interactions.
Figure 6.9 Scheme of the interaction between the
6-86-Zn(II)
complex and deprotonated deoxythymidine.
Figure 6.10 Schematic detection of poly dT by the chemosensing ensemble of
6-93-Zn(II)
with phenol red.
Figure 6.11 X-ray crystal structures of
6-99
and
6-100
.
Figure 6.12 Chirality integration based on self-aggregation of cholesterol-armed cyclen–metal complexes.
Chapter 7: Other Applications of Macrocyclic Polyamines
Figure 7.1 Two typical membrane systems for cation transport: symport and antiport. I or I
−
: ionophore; M
+
: guest cation; X
−
: symport anion; N
+
: antiport cation.
Figure 7.2 Transport of Cu
2+
ions through a liquid membrane system mediated by the dioxocyclam carrier
7-1
.
Figure 7.3 Reaction of dioxocyclam
7-1
with Pt
II
.
Figure 7.4 Acidity of Au
III
-cyclam.
Figure 7.5 Liquid membrane system for the transport of amino acid esters. A
+
, guest ammonium cation; X
−
, co-transported anion; L, macrocyclic ligand carrier.
Figure 7.6 Liquid membrane system for transport of anions by the protonated carrier
7-26
.
Figure 7.7 Liquid membrane system for transport of organic anions: S
−
, organic anion; X
−
, antiport anion; L, neutral ligand.
Figure 7.8 Structures of [9]aneN
3
and [14]aneN
4
and NS isomers.
Figure 7.9 Structures of dioxo[13]aneN
4
and its analytes.
Figure 7.10 Procedures for covalent surface modification of a fused-silica capillary column.
Figure 7.11 Organic analytes separated using a [24]ane-N
6
modified capillary column.
Figure 7.12 Structure of the [28]ane-N
6
O
2
-modified fused-silica capillary.
Figure 7.13 Structures of arsenic and selenium oxyanions.
Figure 7.14 Structures of aromatic acids.
Figure 7.15 Structures of aliphatic acids.
Figure 7.16 Structures of the monophosphorylated nucleoside isomers.
Figure 7.17 Structures of four selenium forms.
Figure 7.18
[
32]aneN
8
-modified fused silica capillary.
Figure 7.19 The structures of the derivatized carbohydrates.
Figure 7.20 Dioxo[13]aneN
4
-modified fused silica capillary.
Figure 7.21 Reaction scheme for the synthesis of the poly(GMA-
co
-EDMA) monolith and postmodification with MPA.
Figure 7.22 Structures of benzoic acid derivatives.
List of Tables
Chapter 4: Derivatives of Macrocyclic Polyamines as Nanovector Materials
Table 4.1 Cyclen-based cationic lipids with a single hydrophobic chain.
Chapter 5: Macrocyclic Polyamine Derivatives for Bio-Imaging
Table 5.1 Metal radionuclei commonly used in PET
Chapter 7: Other Applications of Macrocyclic Polyamines
Table 7.1 Carrier-mediated transport of metal cations
Table 7.2 Sequences of eleven peptides
Macrocyclic Polyamines
Synthesis and Applications
Xiaoqi Yu and Ji Zhang
Authors
Professor Xiaoqi Yu
Sichuan University
College of Chemistry
No. 29 Wangjiang Road
610064 Chengdu
China
Professor Ji Zhang
Sichuan University
College of Chemistry
No. 29 Wangjiang Road
610064 Chengdu
China
Cover
(Foreground image) © cdascher/Gettyimages;
(Background image) © Ensuper/Shutterstock
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Preface
Although macrocyclic organic compounds have been studied for nearly half a century, the discovery and study of novel macrocyclic compounds continue to be of high importance to chemists, especially in the field of supramolecular chemistry. The awarding of two separate Nobel prizes over the past 30 years is an evidence for this assertion. First, the 1987 Nobel Prize in Chemistry was awarded to American chemists Charles J. Pedersen and Donald J. Cram, along with French chemist Jean-Marie Lehn, for their development and use of molecules with structure-specific interactions of high selectivity. The macrocyclic molecules developed by these pioneering researchers may help people to achieve the goal of finding synthetic organic chemicals with functions similar to natural proteins. The most recent Nobel Prize in Chemistry (2016), awarded to Jean-Pierre Sauvage, J. Fraser Stoddart, and Bernard L. Feringa for the design and synthesis of molecular machines, is also highly reliant on the facile synthesis and host–guest properties of macrocyclic organic compounds. The most commonly known functional macrocyclic compounds are crown ethers, which were developed by Professor Charles J. Pedersen in 1967. Macrocyclic polyamines are a family of aza-crown ethers. The nitrogen atoms on the macrocycle make the molecules allow for greater flexibility with regard to modifications and performance. In this book, some properties and applications of macrocyclic polyamines, which may not be possessed by crown ethers, are described and reviewed.
Macrocyclic polyamines are a class of cyclic crown ether-like organic compounds that possess more than two nitrogen atoms in the ring. Because the nitrogen atoms in the cyclic structures can be modified with different functional groups to form various derivatives with different physical and chemical properties, these derivatives can be used over a diverse collection of areas. Although macrocyclic polyamines have been studied for decades, books or chapters focusing on their synthesis and applications are relatively rare. Herein, we aim to summarize some research advances of macrocyclic polyamines including the following contents: the properties of and synthetic methods toward macrocyclic polyamines, chemical nucleases based on macrocyclic polyamines, derivatives of macrocyclic polyamines as nano-vector materials, macrocyclic polyamines derivatives for bio-imaging, chemical sensors based on macrocyclic polyamines, as well as several other applications. This text includes most of the studies involving macrocyclic polyamines and their derivatives, and we believe that it may be used as a reference for the researchers in related fields.
It would have been impossible for us to write a comprehensive monograph on so many aspects of macrocyclic polyamines without support from many coworkers and colleagues. Accordingly, we would like to thank all the people who worked together so enthusiastically on this book, including Drs Shan-Yong Chen (Chapter 2), Qiang Liu (Chapter 3), Wen-Jing Yi (Chapter 3), Li-Jian Ma (Chapter 5), Kun Li (Chapter 6), and Shan-Shan Yu (Chapter 7). We are also grateful to funding agencies such as the National Natural Science Foundation of China for supporting our research about this project
Xiao-Qi Yu and Ji Zhang
Chengdu, P. R. ChinaMay 2017
Chapter 1Introduction
1.1 Classification of Macrocyclic Polyamines
Macrocyclic polyamines (MPAs) are important complexing agents for cations, anions, and neutral molecules. In this book, MPAs are defined as having at least three nitrogen atoms and nine atoms in the ring. Although polyazamacrocycles containing amide and imine functional groups cannot be named amines strictly, these macrocycles are also included here. According to the functional groups in the ring, MPAs can be divided into aliphatic MPAs, aromatic-containing MPAs, macrocyclic polyimines, macrocyclic polyamides, and cryptands.
1.1.1 Aliphatic Macrocyclic Polyamines
In an aliphatic macrocycle, all carbon and hetero atoms are sp3-hybridized. Cylen and cyclam are the most used aliphatic MPAs. One or more nitrogen atoms can be substituted with other heteroatoms, such as oxygen or sulfur, to afford heteroatom-substituted MPAs (compound 1-1).
1.1.2 Aromatic-Containing Macrocyclic Polyamines
To adjust the rigidity of MPAs, aromatic motifs such as benzene and pyridine are introduced. Most aromatic-containing MPAs have a linker between the aromatic motif and the nitrogen atom (compounds 1-2 and 1-3). Modern transition metal catalysis enables the direct combination of the aromatic motif with the nitrogen atom through the formation of CAr−N bonds (compound 1-4).
1.1.3 Macrocyclic Polyimines
Macrocyclic polyimines have at least one imine bond in the ring. Because aliphatic macrocyclic Schiff bases have rather low hydrolytic stability, they often complex with a suitable metal template (compound 1-5). Aromatic-containing macrocyclic polyimines are hydrolytically stable to a certain extent in the absence of a template (compound 1-6).
1.1.4 Macrocyclic Polyamides
Macrocyclic polyamides have at least one amide bond in the ring (compounds 1-7 and 1-8). Macrocyclic polyamides possess the dual features of cyclic peptides and MPAs. Amide-containing macrocycles are usually prepared by cyclocondensation of acids with amines or coupling of the amide-containing precursors.
1.1.5 Cryptands
Cryptands (compound 1-9) are three-dimensional analogs of crown ethers but offer much better selectivity and strength of binding. Spherical cryptands (compound 1-10) can be described as twice-bridged azamacrocycles.
1.2 Properties of Macrocyclic Polyamines
1.2.1 Acid–Base Properties
Except for the nitrogens on the aromatic ring, the amino groups on MPAs are mainly aliphatic secondary amines, which always have relatively strong basicity, and the pKa values of their protonated species are in the range of 9–11. However, the secondary amines on MPAs have a much wider pKa range. Generally, the first protonation steps of MPAs are much easier (pKa 9–11, similar to common secondary amines) than the last protonation steps (pKa 1–3, low basicity). This behavior might be attributable to charge-repulsion effects [1] due to the higher positive charge density on the cycle compared with open-chain polyamines. Some typical aliphatic MPAs with their pKa values for each amine are listed below; for detailed data, the reader may refer to the review by Izatt and coworkers [2]. The positive charge of MPAs under neutral conditions facilitates their interaction with negatively charged biomolecules such as nucleic acids and some proteins. MPA derivatives may bind to nucleic acids through electrostatic interaction, protect the nucleic acid cargo from degradation, and deliver the cargo to target cells or tissues (Chapter 4). Moreover, the wider pKa range of amines may afford the vector materials special pH buffering capability in the intracellular environment, leading to enhanced endosomal escape.
1.2.2 Coordination Property
Macrocyclic structures are extremely favorable for metal complexation. Similar to crown ethers, the nitrogens on MPAs may coordinate to metal ions of appropriate size. They show a pronounced ability to bind a wide variety of metals and, in many cases, undergo marked conformational changes during binding [3]. The increased stability of a metal coordination complex of a tetra-amine macrocyclic ligand over that of similar noncyclic tetra-amine ligands has been called the macrocyclic effect. 1,4,7-Triazacyclononane (TACN) has a smaller cavity, and the binding ability is weaker than that of cyclen or compound 1-11. Cyclen may coordinate well to first-row transition elements such as Cu2+ and Zn2+, and the resultant metal complexes are widely used as artificial nucleases (Chapter 3), chemical sensors (Chapter 6), ionophores (Chapter 7), or chemical catalysts. MPA 1-11 has a larger cycle, which facilitates its binding with larger metal ions such as Cd2+ and Hg2+. In addition, MPAs with a cavity larger than that of 1-11 may also coordinate with more than one first-row transition metal ion [2]. The analogs of 1-12 with 7–9 nitrogens can form dinuclear complexes, whereas those with 11 or 12 nitrogens can form even trinuclear complexes. In addition, pendant coordinating groups can also be attached to the nitrogens on the macrocycle, resulting in more extensive metal coordination properties and applications [4]. For example, some MPA derivatives with carboxylic groups on the arms may act as chelating agents to coordinate with lanthanide metal ions. For example, the Gd-complexes of cyclen derivatives are used intensively in the field of bio-imaging, as described in detail in Chapter 5.
Although most applications involving MPAs employ their metal complexes, the polyamine itself may also serve as a bioactive species. Certain MPAs might act as promising cytotoxic agents by depleting the ATP level of tumor cells [5]. Combinatorial chemistry studies have also found that polyazapyridinophanes possess potent antimicrobial activities [6]. These findings are not included in this book.
1.3 Applications of Macrocyclic Polyamines
As mentioned earlier, most MPA applications employ their metal complexes, which have been used (i) as enzyme mimics, especially artificial nucleases for the cleavage of nucleic acids, (ii) as magnetic resonance imaging (MRI) contrast agents for advanced diagnosis, (iii) as carrier molecules in studies of the selective uptake and transport of metal ions in biological systems, (iv) as gene carriers, (v) as chemical sensors or receptors for metal ions or bioactive molecules, and (vi) in metal recovery that depends on selective extraction. In addition, non-metal chelating MPAs have been used as nucleic acid carriers due to their positive charge in aqueous solution.
The main application areas are reviewed in detail in this book. Chapter 3 presents recent progress on metal or metal-free chemical nucleases based on MPAs, which cleave nucleic acids through a hydrolytic or oxidative mechanism; Chapter 4 introduces non-viral nucleic acid vectors, including cationic lipids and polymers, based on the MPA structure; Chapter 5 presents the use of MPA derivatives as contrast agents in bio-imaging studies; Chapter 6 focuses on the design and synthesis of fluorescent chemosensors for metal ions and bioactive molecules; and Chapter 7 introduces other applications, such as the use of MPA derivatives as ionophores or electrophoretic separation agents.
References
1 Bartolini, M., Bianchi, A., Micheloni, M., and Paoletti, P.J. (1982)
J. Chem. Soc., Perkin Trans. 2
, (11), 1345–1348.
2 Izatt, R.M., Pawlak, K., Bradshaw, J.S., and Bruening, R.L. (1991)
Chem. Rev.
,
91
, 1721–2085.
3 Liang, X. and Sadler, P.J. (2004)
Chem. Soc. Rev.
,
33
, 246–266.
4 Wainwright, K.P. (1997)
Coord. Chem. Rev.
,
166
, 35–90.
5 Frydman, B., Bhattacharya, S., Sarkar, A., Drandarov, K., Chesnov, S., Guggisberg, A., Popaj, K., Sergeyev, S., Yurdakul, A., Hesse, M., Basu, H.S., and Marton, L.J. (2004)
J. Med. Chem.
,
47
, 1051–1059.
6 An, H., Cummins, L.L., Griffey, R.H., Bharadwaj, R., Haly, B.D., Fraser, A.S., Wilson-Lingardo, L., Risen, L.M., Wyatt, J.R., and Cook, P.D. (1997)
J. Am. Chem. Soc.
,
119
, 3696–3708.
Chapter 2Synthetic Methods for Macrocyclic Polyamines
Cyclization and polymerization reactions employ the same starting materials and compete with each other in most cases. Therefore, the major effort in the synthesis of macrocyclic compounds is to manipulate the orientation of the reactive sites to afford macrocyclic products rather than acyclic polymers. There are two general means to improve the ring-closure reaction: (i) performing the reaction in high-dilution conditions and (ii) using a suitable metal template to interact with the heteroatoms. Chemists have also developed a variety of other efficient strategies of accessing polyazamacrocycles without the use of high dilution or templates, such as the Richman–Atkins reaction, the crab-like cyclization, and the condensation of diacids with diamines. MPAs are not limited to macrocycles bearing amine functional groups but also include imine, amide, and other functional groups. In this chapter, we divide MPAs into five categories: saturated MPAs, aromatic subunit-containing MPAs, macrocyclic amides, macrocyclic imines, and polyaza cryptands. Although the synthesis of MPAs has been summarized well in one book [1] and multiple reviews [2], these treatments have discussed only some of the categories of MPAs. We will introduce some frequently used methods to prepare all five categories.
2.1 Ring-Closure Modes
2.1.1 Intramolecular Cyclization
A linear compound bearing reactive groups on each end can undergo intramolecular cyclization to afford a cyclic compound (Figure 2.1a). This intramolecular cyclization has been widely applied for the synthesis of cyclic peptides. It can also be used for the synthesis of MPAs. For example, nitrobenzyl-substituted cyclen was prepared by intramolecular nucleophilic substitution in DMF at 60 °C (Figure 2.1b) [3]. The most used 1 + 1 cyclization was not applicable to the synthesis of this product.
Figure 2.1 Intramolecular cyclization.
2.1.2 1 + 1 Cyclization
The most often used ring-closure mode for the synthesis of macrocycles is the 1 + 1 cyclization (Figure 2.2a). Each precursor has two reactive functional groups on the end. The 1 + 1 cyclization has been extensively used for the synthesis of polyazamacrocycles. The Richman–Atkins reaction is a typical 1 + 1 type cyclization (Figure 2.2b) [4].
Figure 2.2 [1 + 1] Cyclization.
2.1.3 2 + 2 Cyclization
In the synthesis of polyazamacrocycles, the 2 + 2 cyclization (Figure 2.3a) is often a side reaction of a 1 + 1 cyclization. The concentration of the substrates affects the type of cyclization. A higher concentration favors the 2 + 2 cyclization by favoring polymerization. For example, 36-membered MPAs were prepared by 2 + 2 cyclization (Figure 2.3b) [5]. When the reaction was conducted at 0.02 M, the 1 + 1 cyclization process was largely preponderant (95 : 5); by contrast, at 0.5 M, the 2 + 2 mode was greatly favored (10 : 90).
Figure 2.3 [2 + 2] Cyclization.
2.1.4 Other Cyclization Modes
There are many less used ring-closure modes for the synthesis of polyazamacrocycles, such as 3 + 3, 4 + 4, and 2 + 1. The 3 + 3 and 4 + 4 cyclizations occur as side reactions in the 1 + 1 or 2 + 2 cyclization mentioned earlier. The yields decrease as the size of the ring increases. These products can be isolated by careful chromatography.
2.2 The Synthesis of Saturated Macrocyclic Polyamines
2.2.1 Ring Closure Using Sulfonamides
The utilization of sulfonamides for ring closure was reported early. The introduction of a sulfonyl group to the nitrogen atom not only increases the acidity, thus facilitating the formation of salts with bases, but also forces the open-chain compounds into macrocycle-like conformations. The sulfonyl groups (nearly always tosyl moieties) of the resulting sulfonyl-substituted polyamines are cleaved to form saturated MPAs.
The 24-membered tetraazamacrocycle 2-1 was first prepared in 1954 via a 1 : 1 cyclization between disodium salts of sulfonamide with a dibromide compound in a high dilution in DMF [6]. The 10- to 12-membered triaza compounds were prepared in less than 30% yields using a similar method [7]. Cyclization between sulfonamide salts with a terminal dihalide is usually performed under high-dilution conditions and affords products in low yield. Remarkable progress was made in 1974, when Richman and Atkins utilized a terminal disulfonate rather than a terminal dihalide for this cyclization [4]. The reaction was conducted by reacting disodium salts of sulfonamide with a terminal ditosylate or dimesylate in DMF at elevated temperature without the use of high-dilution techniques or templates, and 9- to 21-membered rings containing three to seven heteroatoms were obtained in 40–90% yields.
The so-called Richman–Atkins reaction is the cyclization of dimetal salts of sulfonamide with a terminal ditosylate or dimesylate in a dipolar aprotic solvent at elevated temperature without the use of high-dilution techniques or templates (Figure 2.4). However, the reaction of dimetal salts of sulfonamide with a terminal dihalide is also occasionally called the Richman–Atkins reaction. The Richman–Atkins reaction is probably the most widely used process for the synthesis of MPAs, especially for saturated MPAs.
Figure 2.4 A typical example of the Richman–Atkins reaction.
The tosylation of polyamines or glycol to prepare pertosylamides or terminal ditosylates is not complicated, but both precursors must be purified by crystallization or column chromatography before use. DMF, DMSO, and HMPA are good solvents for the cyclization, but DMF is more convenient. Purification of DMF is usually required. Dimethylamine, formaldehyde, and water impurities in DMF will decrease the yields of macrocyclic products.
The sulfonamide salts are prepared by adding sodium, sodium hydride, sodium methoxide or ethoxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide, or caesium carbonate to the solution of sulfonamide. The resultant salts can be isolated but are usually prepared in situ and used immediately because they are moisture sensitive. The nature of the bases affects the cyclization reaction. Caesium and potassium carbonate are the best bases for this reaction [8]. From an economic perspective, potassium is a good choice. The stronger bases accelerate the decomposition of the nucleophilic ditosylate precursor, thus decreasing the yield of the macrocyclic product. When the temperature is elevated, the decomposition occurs more quickly.
The leaving group X has a marked effect on the cyclization. As shown in Figure 2.5, the ditosylate and the dimesylate partner afforded 2-2 in good yields (80% and 66%, respectively), whereas dihalides gave lower yields of the product [9]. However, in another experiment, the leaving group had a different effect on the cyclization [8]. Bromides and mesylates gave the products in 70% and 75% yields, respectively, after 24 h at 30 °C. Chlorides and tosylates reacted more slowly under the same conditions; comparable yields were obtained at 50 °C. The requirement for different conditions may be due to the different effects of the leaving group. Usually, in a typical Richman–Atkins reaction, a terminal ditosylate or dimesylate gives better results than halides.
Figure 2.5 The effect of leaving groups.
Although most of the reactions were conducted at high temperature (100 °C), lower temperatures (room to ∼50 °C) gave better results than high temperatures. Twelve macrocycles (17–35-membered rings, 4–8 nitrogen atoms) were prepared by condensation of sulfonamide salts with ditosylates in DMF at ambient temperature [10]. The yield was high, up to 99% (for [17]ane N4).
Usually, there is more than one possible synthetic pathway to produce the same final product. The choice of one preparative method over another depends mainly on the availability and ease of synthesis of the precursors. Iwata and Kuzuhara found that the coupling of the nucleophile containing the longest chain length with the electrophile containing the shortest chain length gave the best yields [10]. For example, products of macrocycles 2-3, 2-4, and 2-5 prepared through method (a) were higher than those through method (b). By employing this rule, a 52-membered MPA bearing 12 nitrogen atoms in the ring was obtained in 72% yield using 1,4-dibromobutane as the electrophile [11].
2.2.2 The Removal of Tosyl Protecting Groups
The tosyl groups can be removed by three general methods: (i) acid hydrolysis with concentrated sulfuric acid, (ii) cleavage with a HBr/acetic acid mixture, and (iii) reduction with other reducing agents, such as sodium in liquid ammonia and lithium aluminum hydride.
The most used detosylation method is acid hydrolysis with concentrated (90–97%) sulfuric acid. Impurities and water have obvious negative effects on the final yields. Deprotection is usually performed at elevated temperature (∼100 °C). Removing more tosyl groups requires a longer reaction time. Fast detosylation was achieved by heating at 180 °C [12]. This method works very well with peraza macrocycles. However, acid hydrolysis does not always give good yields [13] and is less satisfactory for oxygen- and sulfur-containing macrocycles. Acid hydrolysis also leads to the decomposition of some aromatic subunit-containing macrocycles. For example, concentrated H2SO4 leads to the decomposition of the acridine moiety [14].
Reductive cleavage of the tosyl group with a HBr/acetic acid mixture is another widely used method to obtain free cyclic amines [15]. This procedure is performed using 33–47% HBr in acetic acid in the presence or absence of phenol. The reaction can be conducted at room temperature, under reflux or at higher temperature in a sealed tube. Carbon–oxygen or carbon–sulfur bonds can be cleaved by HBr/acetic acid under reflux conditions. The subsequent purification is easier than that using concentrated H2SO4.
Other reducing agents, including sodium in liquid ammonia [16], lithium aluminum hydride [17], and lithium in liquid ammonia [18], have also been used. The tosyl group in p-toluenesulfonamides can be removed by cathodic cleavage of N−S bonds [19]. Cyclen was obtained in 80% yield by electrochemical detosylation of tetratosylcyclen in an aprotic solvent at a carbon cathode [20].
A major problem with the sulfonamide cyclization process is the removal of the sulfonyl groups. The tosyl group is usually removed under fairly drastic conditions.
2.2.3 The Use of Easily Removable Protecting Groups
Protecting groups, such as benzoyl [21], benzyl [22], 2,4-dinitro-benzesulfonyl [23], naphthalene-2 sulfonyl [24], tert-butylsulfonyl [25], diethoxyphosphoryl (DEP) [26], nitrobenzenesulfonyl (Nosyl) [27], β-trimethylsilylethanesulfonyl (SES) [28], tert-butoxycarbonyl (t-Boc) [29], and trifluoroacetyl [30], have also been applied to protect/activate amines.
The DEP protecting group can be removed quantitatively under mild conditions (HCl/dioxane at room temperature) and can be applied to the synthesis of selectively protected polyazamacrocycles. The condensation of DEP-protected amines with tosylated triazaoligoethylene glycol afforded polyazamacrocycles 2-6 in moderate to good yields. The removal of DEP afforded tosyl-protected 2-7 in near quantitative yields [26a]. A modified procedure involving the DEP protecting group [31] was developed for the synthesis of polyazamacrocycles using t-BuOK as the base and THF as the solvent.
The cyclization of SES-protected amines in DMF at room temperature provided polyazamacrocycles 2-8 in good yields (68–84%). Removal of the SES group occurs smoothly upon treatment of the macrocyclic tris-sulfonamides with CsF in DMF at 95 °C for 24 h, affording macrocycles 2-9.
Despite the availability of many alternative protecting groups, all suffer from disadvantages such as difficult synthesis of the precursors, expensive starting materials, unsatisfactory yields, and limited scope of substrates. Therefore, these groups are not as widely employed to synthesize polyazamacrocycles as the tosyl group.
2.2.4 Special Procedures for Tetraaza Macrocyclic Compounds
An efficient synthesis of tetraaza macrocycles starting from a linear tetra-amine and a dicarbonyl compound is shown in Figure 2.6. The key feature of this method is the use of butanedione as the rigidifying and protecting reagent [32]. Butanedione reacted with tetra-amines to give the tricyclic bis-aminals 2-10, which were alkylated with 1,2-dibromoethane or 1,3-dibromopropane to afford the key tetracyclic bis-aminal intermediates 2-11. Acid hydrolysis of 2-11 with dilute HCl solution released the corresponding hydrochloride salts of macrocycles 2-12 quantitatively. Cyclam was obtained in an overall yield of 77%. This strategy also provided a convenient way to prepare regioselective C-functionalized tetraazamacrocycles after minor modification [33].
Figure 2.6 The synthesis of tetraaza macrocycles.
A bis-amidine-involved approach for the synthesis of tetraazamacrocycles was reported by Weisman and Reed [34]. Reductive ring expansion of bis-amidine 2-13 with DIBALH in refluxing toluene provided cyclen in good yield with high purity. The tricyclic bis-amidine intermediate was obtained by condensation of triethylenetetra-amine with the bis-thioimido ester salt or dithiooxamide [35] in alcohol. This two-step procedure afforded cyclen at gram scale in an overall yield of 57%. The disadvantages of this reaction include the generation of toxic H2S and the use of an expensive and highly flammable metal reagent. A three-step approach addressed these shortcomings. The tricyclic bis-amidine intermediate 2-13 was obtained by condensation of triethylenetetra-amine with DMF-DMA rather than dithiooxamide. Alkylation of this tricyclic bis-amidine with 1,2-dibromoethane afforded the tetracyclic intermediate 2-14, which underwent caustic hydrolysis to give cyclen [36]. The overall yield of cyclen was high, up to 88%. It is straightforward to produce 50 g of cyclen in 2 days, which represents the largest scale for the synthesis of cyclen thus far.
2.3 Aromatic Subunit-Containing Polyazamacrocycles
Aromatic subunits are often introduced as integral parts of receptors, where they play significant roles other than that in simple charge–charge interactions. The insertion of nitrogen units into the macrocycle can even provide further binding sites.
2.3.1 Alkylation of Sulfonamide Salts with Dihalomethyl Arenes
Aromatic polyazamacrocycles can be easily prepared by the alkylation of sulfonamides using dihalomethyl arenes. Usually, when a flexible terminal dihalide is applied to the reaction with sulfonamide salts, high-dilution techniques are required. However, when a dihalomethyl arene (Figure 2.7) is used, high-dilution conditions are not necessary. A large number of such receptors have been synthesized using dihalomethyl arenes as the electrophilic reagents. The most used solvents are DMF and acetonitrile. The sizes of the sulfonamide salts and dihalides are crucial for this cyclization.
Figure 2.7 Synthons of dihalomethyl arenes.
MPAs 2-15 containing a 1,4-benzo unit were prepared from bis(bromomethyl)benzene and sulfonamide salts [37]. The cyclization step was very efficient, affording the products in 40–96% yields after purification by chromatography or crystallization. The smallest compound, 2-15a, was obtained in a lower yield compared with the larger ring. Increasing the concentration of reactants from 10−3 to 10−2 M did not significantly decrease the final yield. Moreover, the dibromide compounds can be added all in one portion, and the yields are only slightly decreased compared with the dropwise addition of compounds. The effect of bases was also investigated. No obvious product formation was observed for Li2CO3 because its basicity is too low. The caesium salt, the most basic of the carbonates, promoted a faster reaction compared with other carbonates. For Na2CO3, K2CO3, and Cs2CO3, the nature of the base affects the rate of the reaction but does not affect the final yields. For example, K2CO3 and Cs2CO3 afforded 2-15d in similar yields when the reaction time of the former was doubled. For the same macrocycle, the utilization of Na2CO3 gives a comparable yield after stirring for 120 h compared to 24 h for K2CO3. Therefore, considering both efficiency and cost, K2CO3 is the best choice. 1,3-Benzo-containing macrocycles 2-16 were obtained by dripping the solution of the dibromide compound in acetonitrile (0.1 M) into a refluxing suspension of Na2CO3 and the sulfonamide salts in acetonitrile (0.04 M) over 4 h. Heteroaromatic units, such as pyridine, bipyridine, and terpyridine, were also introduced by similar reactions. The 15-membered pyridine-containing cycle 2-17 was synthesized using 2,6-bis(bromomethyl)pyridine and disodium salts of tetratosyltriethylenetetramine [38]. Pyridine-containing triaza cycles 2-18 were synthesized in moderate yield by reacting 2,6-bis(chloromethyl)-pyridine with the disodium salt of 1,4,8-tritosyl-1,4,8-triazaoctane or 1,4,7-tritosyl-1,4,7-triazaheptane in anhydrous dimethylformamide. The authors found that the yields of 2-18 increased obviously (90% for 2-18a and 75% for 2-18b) when anhydrous acetonitrile was used as the solvent and potassium carbonate as the base under heterogeneous conditions [39]. This improved procedure can be easily performed at gram scale (up to 30 g). Reaction of the dibromomethyl acridine with the tosylated tetra-amine in CH3CN using K2CO3 as the base afforded acridine-containing polyazamacrocycle 2-19 [14]. Bipyridine-containing cycles 2-20 were obtained by cyclization of 6,6′-bis(halomethyl)-2,2′-bipyridine with the corresponding sulfonamide salts in DMF [40].
2.3.2 Metal-Catalyzed N-arylation
N-arylation provides a direct strategy for the synthesis of aromatic subunit-containing polyazamacrocycles [41], especially rigid aromatic macrocycles [42]. This approach is conducted by reacting an aryl dihalide and a free polyamine in the presence of a Pd catalyst (Figure 2.8). A variety of aromatic polyazamacrocycles 2-23 were obtained in synthetically useful yields by reacting tetra-amine with the corresponding aromatic dihalides 2-22 in dilute conditions using Pd(dba)2 as the catalyst [43]. The yield depended on the nature of the polyamines and aromatic dihalides. For example, the reaction of tetra-amine 2-21a with 1,3-dibromobenzene afforded the corresponding product in 29% yield, whereas tetra-amine 2-21b gave the desired product in 56% yield [44]. The Pd-catalyzed diamination of dihalobenzenes, in addition to the targeted 1 + 1 macrocycles, can produce 2 + 2 and 3 + 3 ring-closure macrocycles as by-products.
Figure 2.8 Pd-catalyzed N-arylation for the synthesis of aromatic polyazamacrocycles.
The Pd-catalyzed diamination of aromatic dihalides enables the preparation of rigid aromatic polyazamacrocycles. Pd-catalyzed diamination of dihalide 2-24 with N1,N3-dimethylbenzene-1,3-diamine in refluxing toluene afforded calixaromatic compound 2-25a in 26% yield. In addition to the 1 + 1 cyclization, the 2 + 2 cyclization also occurred, giving 2-25b in 22% yield. Calixaromatic compound
2-25b was synthesized selectively in an improved yield of 39.5% by performing the reaction at 80 °C in 1,4-dioxane [45]. A variety of azacalix[n]pyridines 2-26 (n = 4–10) were prepared by employing the same procedures [46]. This strategy was not effective for the direct synthesis of NH-bridged calixpyridines. To address this problem, N-allyl groups were introduced as protecting groups prior to ring formation, and the deprotection of the allyl groups of 2-27 afforded 2-28 [47].
