Versatile Design Principles for Facile Access to Unstrained Conjugated Organoborane Macrocycles

A facile and versatile approach was developed to access ambipolar boron‐containing macrocycles. Two examples of new conjugated cyclic motifs are presented with carbazole moieties as donors and borane moieties as acceptors embedded into the ring system. They were first predicted using computational methods. Possible targets with appropriately shaped π‐conjugated bridges that minimize the overall ring strain were identified and their geometry was optimized by DFT methods. The synthetic demonstration was then accomplished using organometallic condensation reactions under high dilution conditions. The resulting monodisperse macrocycles provide important insights into the design principles necessary for the preparation of new unstrained macrocycles with interesting optical and electronic characteristics. The current research also offers a more general approach to conjugated ambipolar B/N macrocycles as a promising new family of (opto)electronic materials.     

Phormidolides B and C,Cytotoxic Agents from the Sea: Enantioselective Synthesis of the Macrocyclic Core

New cytotoxic polyketide macrolides named phormidolides B and C were isolated from a marine sponge of the Petrosiidae family collected off the coast of Pemba (Tanzania). The isolation, structure elucidation, and enantioselective synthesis of three diastereomers of the macrocyclic core is described herein. The described synthetic methodology started from 2‐deoxy‐D ‐ribose or 2‐deoxy‐L ‐ribose and afforded the desired macrocycles with high enantiomeric purity. The key step of the synthesis is the formation of the Z‐trisubstituted double bond using a Julia–Kocienski olefination. The versatility of the synthetic methodology may provide access to other enantiopure macrocycles by making changes in the starting materials or chiral inductors.     

Enzymatic Macrocyclization of 1,2,3‐Triazole Peptide Mimetics

The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme‐mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4‐substituted 1,2,3‐triazole moieties. The introduction of non‐peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non‐natural triazole‐containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.     

β‐Octamethoxy‐Substituted 22π and 26π Stretched Porphycenes: Synthesis,Characterization, Photodynamics,and Nonlinear Optical Studies

Three meso‐expanded tetrapyrrolic aromatic macrocycles, including 22π and 26π acetylene–cumulene bridged stretched octamethoxyporphycenes and octamethoxy[22]porphyrin‐(2.2.2.2), are reported, for the first time, by modification of previously reported synthetic methods. This strategy led to an enhancement in the overall yield of their corresponding octaethyl analogues. The methoxy‐substituted expanded porphycenes display slightly blueshifted absorption relative to their ethyl analogues, along with very weak fluorescence, probably due to efficient intramolecular charge transfer (ICT). Additionally, the two‐photon absorption (TPA) cross sections of these macrocycles were evaluated; these are strongly related to core expansion of the porphyrin aromaticity through increased meso‐bridging carbon atoms as well as conformational flexibility and substitution effects at the macrocyclic periphery. In particular, the octamethoxy stretched porphycenes display strong TPA compared with the octaethyl analogues due to the dominant ICT character of methoxy groups with a maximum TPA cross section of 830 GM at 1700 nm observed for 26π‐octamethoxyacetylene–cumuleneporphycene.     

Curved Oligophenylenes as Donors in Shape‐Persistent Donor–Acceptor Macrocycles with Solvatofluorochromic Properties

Many optoelectronic organic materials are based on donor–acceptor (D–A) systems with heteroatom‐containing electron donors. Herein, we introduce a new molecular design for all‐carbon curved oligoparaphenylenes as donors, which results in the generation of unique shape‐persistent D–A macrocycles. Two types of acceptor‐inserted cycloparaphenylenes were synthesized. These macrocycles display positive solvatofluorochromic properties owing to their D–A characteristics, which were confirmed by theoretical and electrochemical studies.     

Synthesis of 15‐, 16‐, and 17‐Membered Bis‐C‐Pivot Macrocycles Consisting of N2O2 Donor‐Type Crown Ethers and Dialkyl Phosphonates

Bis‐C‐pivot macrocycles containing aminophosphonate functions ( 5–10 ) have been synthesized and characterized by elemental analysis, FTIR, MS, 1D ¹H, ¹³C and ³¹P NMR, and 2D HETCOR techniques. The phosphorylation reaction of dibenzo‐bis‐imino crown ethers ( 1–4 ) with dimethyl and diethyl phosphite used here has the potential to provide bis‐C‐pivot macrocycles ( 5–10 ), which possess two stereogenic C‐centers giving rise to diastereoisomers (meso and racemic). Detailed spectral assignments for the meso and racemic forms of the compounds are reported on the basis of chemical shifts, signal intensities, spin–spin coupling constants, and splitting patterns. The bis‐C‐pivot macrocycles ( 5–10 ) may serve as a potential new class of supramolecular host molecules.     

Co‐Conformational Distribution of Nanosized [2]Catenanes Determined by Pulse EPR Measurements

The co‐conformational ensembles of three differently sized [2]catenanes were studied by measuring pair correlation functions corresponding to the separation of nitroxide spin labels—one attached to each of the two macrocycles—with the double electron–electron resonance (DEER) experiment. A geometric model for the [2]catenanes was derived that approximates the macrocycles by circles and takes into account the topological constraint. Comparison of the experimental to the theoretically predicted pair correlation functions gives insight into the co‐conformational distribution and the size of the macrocycles. It was found that the macrocycles of the medium‐ and large‐sized catenanes in chloroform are close to fully expanded, while they are partially collapsed in glassy o‐terphenyl. For the small‐sized catenane, moderate interaction between the unsaturated sections of the macrocycles in chloroform is indicated by a slight overrepresentation of short label‐to‐label separations in the pair correlation function.     

Substrate‐Induced Dimerization Assembly of Chiral Macrocycle Catalysts toward Cooperative Asymmetric Catalysis

An artificial system of substrate‐induced dimerization assembly of chiral macrocycle catalysts enables a highly cooperative hydrogen‐bonding activation network for efficient enantioselective transformation. These macrocycles contain two thiourea and two chiral diamine moieties and dimerize with sulfate to form a sandwich‐like assembly. The macrocycles then adopt an extended conformation and reciprocally complement the hydrogen‐bonding interaction sites. Inspired by the guest‐induced dynamic assembly, these macrocycles catalyze the decarboxylative Mannich reaction of cyclic aldimines containing a sulfamate heading group. The imine substrate can be activated toward nucleophilic attack of β‐ketoacid by a cooperative hydrogen‐bonding network enabled by sulfamate‐induced dimerization assembly of the macrocycle catalysts. Highly efficient (>95 % yield in most cases) and enantioselective (up to 97.5:2.5 er) transformation of a variety of substrates using only 5 mol % macrocycle was achieved.     

One‐Pot Approach to Organo‐Phosphorus–Chalcogen Macrocycles Incorporating Double OP(S)SCn or OP(Se)SeCn Scaffolds: A Synthetic and Structural Study

The development of new methodology for the preparation of functional macrocycles with practical applications is an important research area in macromolecular science. In this study, we report a new one‐pot route for the synthesis of a series of macro‐heterocycles by incorporating two phosphorus atoms and two chalcogen atoms and two oxygen atoms (double OP(S)SC_n or OP(Se)SeC_n scaffolds). The three‐component condensation reactions of 2,4‐diferrocenyl‐1,3,2,4‐diathiadiphosphetane 2,4‐disulfide ( FcLR , a ferrocene analogue of Lawesson's reagent) or 2,4‐bis(4‐methoxyphenyl)‐1,3,2,4‐dithiadiphosphetane 2,4‐disulfide ( LR , Lawesson's reagent), or 2,4‐diphenyl‐1,3,2,4‐diselenadiphosphetane 2,4‐diselenide ( WR , Woollins’ reagent), disodium alkenyl‐diols, and dihalogenated alkanes are performed, giving rise to soluble and air or moisture‐stable macrocycles in good‐to‐excellent yields (up to 92 %). This is the first systemically preparative and readily scalable example of one‐pot ring opening/ring extending reaction of three‐components to prepare phosphorus–chalcogen containing macrocycles. We also provide a systematic crystallographic study.     

A Modular Synthetic Strategy for Functional Macrocycles

Reported here is a molecule‐Lego synthetic strategy for macrocycles with functional skeletons, involving one‐pot and high‐yielding condensation between bis(2,4‐dimethoxyphenyl)arene monomers and paraformaldehyde. By changing the blocks, variously functional units (naphthalene, pyrene, anthraquinone, porphyrin, etc.) can be conveniently introduced into the backbone of macrocycles. Interestingly, the macrocyclization can be tuned by the geometrical configuration of monomeric blocks. Linear (180°) monomer yield cyclic trimers and pentamers, while V‐shaped (120°, 90° and 60°) monomers tend to form dimers. More significantly, even heterogeneous macrocycles are obtained in moderate yield by co‐oligomerization of different monomers. This series of macrocycles have the potential to be prosperous in the near future.     

Dynamics of Synthetic Membraneless Organelles in Microfluidic Droplets

Cells can form membraneless organelles by liquid–liquid phase separation. As these organelles are highly dynamic, it is crucial to understand the kinetics of these phase transitions. Here, we use droplet‐based microfluidics to mix reagents by chaotic advection and observe nucleation, growth, and coarsening in volumes comparable to cells (pL) and on timescales of seconds. We apply this platform to analyze the dynamics of synthetic organelles formed by the DEAD‐box ATPase Dhh1 and RNA, which are associated with the formation of processing bodies in yeast. We show that the timescale of phase separation decreases linearly as the volume of the compartment increases. Moreover, the synthetic organelles coarsen into one single droplet via gravity‐induced coalescence, which can be arrested by introducing a hydrogel matrix that mimics the cytoskeleton. This approach is an attractive platform to investigate the dynamics of compartmentalization in artificial cells.     

Metallomacrocycles That Incorporate Cofacially Aligned Diimide Units

Pyromellitic diimide and naphthalene diimide moieties were incorporated into hemilabile phosphanylalkyl thioether ligands. These ligands reacted with [Cu(CH₃CN)₄]PF₆ and [Rh(NBD)Cl]₂ (NBD=norbornadiene) by the weak‐link approach to form condensed intermediates. Upon reaction of each diimide ligand with these transition‐metal precursors, the two diimide units became cofacially aligned within a supramolecular macrocyclic architecture. The introduction of ancillary ligands to each of these condensed intermediates caused the weak thioether–metal bonds to break, thus generating a large macrocycle in which the distance between diimide units is significantly larger than for the condensed intermediates. The two Rh^I cationic condensed intermediates were characterized by single‐crystal X‐ray diffraction studies, and the electrochemical activity of these macrocycles was demonstrated with the naphthalene diimide–Cu^I macrocycles.     

Photophysical Characterization of the Naturally Occurring Dioxobacteriochlorin Tolyporphin A and Synthetic Oxobacteriochlorin Analogues

Tolyporphins are tetrapyrrole macrocycles produced by a cyanobacterium‐containing culture known as HT‐58‐2. Tolyporphins A–J are free base dioxobacteriochlorins, whereas tolyporphin K is an oxochlorin. Here, the photophysical characterization is reported of tolyporphin A and two synthetic analogues, an oxobacteriochlorin and a dioxobacteriochlorin. The characterization (in toluene, diethyl ether, ethyl acetate, dichloromethane, 1‐pentanol, 2‐butanone, ethanol, methanol, N,N‐dimethylformamide and dimethylsulfoxide) includes static absorption and fluorescence spectra, fluorescence quantum yields and time‐resolved data. The data afford the lifetime of the lowest singlet excited state and the yields of the nonradiative decay pathways (intersystem crossing and internal conversion). The three macrocycles exhibit only modest variation in spectroscopic and excited‐state photophysical parameters across the solvents. The long‐wavelength (Q_y) absorption band of tolyporphin A appears at ~680 nm and is remarkably narrow (full‐width‐at‐half‐maximum ~7 nm). The position of the long‐wavelength (Q_y) absorption band of tolyporphin A (~680 nm) more closely resembles that of chlorophyll a (662 nm) than bacteriochlorophyll a (772 nm). The absorption spectra of tolyporphins B–I, K (which were available in minute quantities) are also reported in methanol; the spectra of B–I closely resemble that of tolyporphin A. Taken together, tolyporphin A generally exhibits spectral and photophysical features resembling those of chlorophyll a.     

The Supramolecular Chemistry of Strained Carbon Nanohoops

Since 1996, a growing number of strained macrocycles, comprising only sp²‐ or sp‐hybridized carbon atoms within the ring, have become synthetically accessible, with the [n]cycloparaphenyleneacetylenes ( CPPAs ) and the [n]cycloparaphenylenes ( CPPs ) being the most prominent examples. Now that robust and relatively general synthetic routes toward a diverse range of nanohoop structures have become available, the research focus is beginning to shift towards the exploration of their properties and applications. From a supramolecular chemistry perspective, these macrocycles offer unique opportunities as a result of their near‐perfect circular shape, the unusually high degree of shape‐persistence, and the presence of both convex and concave π‐faces. In this Minireview, we give an overview on the use of strained carbon‐rich nanohoops in host–guest chemistry, the preparation of mechanically interlocked architectures, and crystal engineering.     

Specific Noncovalent Association of Chiral Large‐Ring Hexaimines: Ion Mobility Mass Spectrometry and PM7 Study

Ion mobility mass spectrometry and PM7 semiempirical calculations are effective complementary methods to study gas phase formation of noncovalent complexes from vaselike macrocycles. The specific association of large‐ring chiral hexaimines, derived from enantiomerically pure trans‐1,2‐diaminocyclohexane and various isophthaldehydes, is driven mostly by CH–π and π–π stacking interactions. The isotrianglimine macrocycles are prone to form two types of aggregates: tail‐to‐tail and head‐to‐head (capsule) dimers. The stability of the tail‐to‐tail dimers is affected by the size and electronic properties of the substituents at the C‐5 position of the aromatic ring. Electron‐withdrawing groups stabilize the aggregate, whereas bulky or electron‐donating groups destabilize the complexes.     

A facile and efficient synthetic approach to novel lariat macrocyclic diamides and bis macrocyclic diamides

The hydroxy macrocycles 8, 19a‐c were prepared in 40–55% yields by reacting the dipotassium salts 2a‐c with each of epichlorohydrin ( 7 ) and bis(chloromethyl) derivative 18 . Acylation of the hydroxyl group of each of 8, 19a‐c with 2‐chloroacetylchloride ( 9 ) in DMF gave the corresponding esters 10, 20a,b . Reaction of the latter with different amines as well as phenoxides furnished exclusively the target lariat macrocycles 13a‐c, 22a‐c and 23a‐c in 60–63% and 50–55% yields, respectively. Amination of two equivalents of the chloroacetyloxy derivative 10 and 2a,b with 1 equiv. of piperazine ( 12c ) afforded the corresponding bismacrocycles 14 and 26a,b respectively, in 60–65% yields. Moreover, the novel bis(macrocycles) 27–29 were prepared in 45–50% yields, respectively, by reacting each of 20a,b with the dipotassium salts 2b, 24 and 25 respectively, in DMF.     

Homodiselenacalix[4]arenes: Molecules with Unique Channelled Crystal Structures

A synthetic route towards homodiselenacalix[4]arene macrocycles is presented, based on the dynamic covalent chemistry of diselenides. The calixarene inner rim is decorated with either alkoxy or tert‐butyl ester groups. Single‐crystal X‐ray analysis of two THF solvates with methoxy and ethoxy substituents reveals the high similarity of their molecular structures and alterations on the supramolecular level. In both crystal structures, solvent channels are present and differ in both shape and capacity. Furthermore, the methoxy‐substituted macrocycle undergoes a single‐crystal‐to‐single‐crystal transformation during which the molecular structure changes its conformation from 1,3‐alternate (loaded with THF/water) to 1,2‐alternate (apohost form). Molecular modelling techniques were applied to explore the conformational and energetic behaviour of the macrocycles.     

Cooperative Self‐Assembly of Pyridine‐2,6‐Diimine‐Linked Macrocycles into Mechanically Robust Nanotubes

Nanotubes assembled from macrocyclic precursors offer a unique combination of low dimensionality, structural rigidity, and distinct interior and exterior microenvironments. Usually the weak stacking energies of macrocycles limit the length and mechanical strength of the resultant nanotubes. Imine‐linked macrocycles were recently found to assemble into high‐aspect ratio (>10³), lyotropic nanotubes in the presence of excess acid. Yet these harsh conditions are incompatible with many functional groups and processing methods, and lower acid loadings instead catalyze macrocycle degradation. Here we report pyridine‐2,6‐diimine‐linked macrocycles that assemble into high‐aspect ratio nanotubes in the presence of less than 1 equiv of CF₃CO₂H per macrocycle. Analysis by gel permeation chromatography and fluorescence spectroscopy revealed a cooperative self‐assembly mechanism. The low acid concentrations needed to induce assembly enabled nanofibers to be obtained by touch‐spinning, which exhibit higher Young's moduli (1.33 GPa) than many synthetic polymers and biological filaments. These findings represent a breakthrough in the design of inverse chromonic liquid crystals, as assembly under such mild conditions will enable the design of structurally diverse and mechanically robust nanotubes from synthetically accessible macrocycles.     

Chiral Macrocycles as Reagents and Catalysts

Ionophores, whether of natural or synthetic origin, encapsulate their ionic “guests” using noncovalent bonding. This encapsulation process resembles, at least superficially, the bonding of a substrate by an enzyme-active site. The analogy to enzymes can be extended further if the ionophore is provided with functional groups that can react with a suitable guest molecule bound in the cavity of the ionophore. We have embedded in the periphery of a macrocycle a 1,4-dihydropyridine, a mimic of the coenzyme NADH. The macrocycle, in addition to having (weak) ionophoric properties, is chiral. The strategy has led to compounds that react as artificial hydrogenases and which are capable of distinguishing, in a predictable fashion, between the prochiral faces of suitable carbonyl substrates. Ancillary developments from this approach have been many. A remarkably general method for the preparation of a wide variety of macrocycles has been developed which depends on some remarkable chemical idiosyncrasies of the cesium ion. In attempts to exploit the chemical possibilities of these macrocycles, unusual chemistry, possibly relevant to the action of the enzyme, 3-phosphoglyceraldehyde dehydrogenase, has been uncovered. In a similar vein, study of macrocycles has led to variants of the aldol condensation on chiral templates. Finally, catalytic CC bond formation mediated by transition metals is revealed to be an area in which chiral macrocycles can play a useful role by acting as chiral ligands for the transition metal.     

Ring‐opening polycondensations

Ring‐opening polycondensation is a novel synthetic strategy using heterocycles of any ring size having two reactive bonds as bifunctional monomers in step‐growth polymerizations. The first part of this article reviews previous publications. The previous studies mainly dealt with syntheses of polyesters from tin‐containing macrocycles including cyclic polylactones. These tin‐containing cyclic oligomers or polymers were easily obtained in two ways, either by ring‐closing polycondensation of dibutyltin compounds with preformed diols or by ring‐expansion polymerizations of lactones by means of cyclic tin‐initiators. The second part of this article presents new results which deal with ring‐opening polycondensations of silicon containing macrocycles derived from oligo(ethylene glycol)s. In these cases the chain growth proceeds by elimination of dimethyl dichlorosilane. In addition to syntheses of homopolyesters, copolycondensations with silylated or stanylenated monomers were studied. Finally, the thermodynamical aspects of ring‐opening polycondensations will be discussed.