Scalable Synthesis of All Stereoisomers of 2-Aminocyclopentanecarboxylic Acid─A Toolbox for Peptide Foldamer Chemistry.

Although the construction of peptides with well-defined three-dimensional structures and predictable functions, including biological activity, using conformationally constrained ß-amino acids has been shown to be a very successful strategy, their broad application is limited by access to the appropriate building blocks. In particular, trans- and cis-stereoisomers of 2-aminocyclopentanecarboxylic acid (ACPC) are of high interest. The scalable synthesis of all four stereoisomers of Fmoc derivatives of ACPC is presented with NMR-based analysis methods for their enantiomeric purity.

Controlling chirality in the synthesis of 4 + 4 diastereomeric amine macrocycles derived from trans-1,2-diaminocyclopentane and 2,6-diformylpyridine.

A few suitably long dialdehyde and primary diamine building blocks of a predetermined chirality have been designed and synthesized to enable controlled and efficient synthesis of all six possible diastereomers of 4 + 4 macrocyclic amine derived from trans-1,2-diaminocyclopentane (DACP) and 2,6-diformypyridine (DFP) units. Although two out of six diastereomers have been reported recently, their synthesis presented here is more direct and occurs with an improved yield. This family of 4 + 4 macrocycles contains one pair of homochiral enantiomers of identical RRRRRRRR and SSSSSSSS configurations of DACP units, two different meso forms (meso I of alternating RRSSRRSS and meso II of neighboring RRRRSSSS configuration of DACP moieties) as well as one pair of heterochiral enantiomers, where configuration of one diamine fragment is opposite to the other three diamine parts, RRRRRRSS and SSSSSSRR, respectively. The structures of each type of macrocycle in solid state have been confirmed by single crystal analyses of a macrocyclic amine in its suitable protonated form. The different symmetry of each type of macrocycle in solutions has been proved by 1H and 13C NMR spectra of their hydrochloride derivatives. The chiral nature of two different pairs of optically active enantiomers has been established by circular dichroism spectra. These chiral 4 + 4 diastereomeric macrocycles are receptors for chiral guests and recognize in solution 10-camphorsulfonic acid as well as chiral tartaric acid.

Magnetic Nanoparticles Functionalized with Copper Hydroxyproline Complexes as an Efficient, Recoverable, and Recyclable Nanocatalyst: Synthesis and Its Catalytic Application in a Tandem Knoevenagel-Michael Cyclocondensation Reaction.

A novel catalyst has been afforded by attaching of a Cu(proline)2 complex to magnetic nanoparticles through cheap, simple, and readily available chemicals. This catalyst was characterized by Fourier transform infrared, energy-dispersive X-ray, X-ray diffraction, vibrating-sample magnetometry, transmission electron microscopy, scanning electron microscopy, and inductively coupled plasma analyses. The catalytic activity of the Fe3O4@NH2@TCT@HProCu nanocatalyst was investigated in a green and effective synthesis of pyran derivatives in high yields by applying three-component reactions of malononitrile, dimedone, and aldehydes in ethanol. Conversion was high under optimal conditions. The obtained nanocatalyst could be easily separated from the mixture of the reaction and was recyclable nine times via a simple magnet without considerable reduction of its catalytic efficiency. Operational simplicity, high product yields, environmental friendliness, ecofriendliness, economical processing, and easy workup are the features of this methodology.

Sorting Phenomena and Chirality Transfer in Fluoride-Bridged Macrocyclic Rare Earth Complexes.

The reaction of fluoride anions with mononuclear lanthanide(III) and yttrium(III) hexaaza-macrocyclic complexes results in the formation of dinuclear fluoride-bridged complexes. As indicated by X-ray crystal structures, in these complexes two metal ions bound by the macrocycles are linked by two or three bridging fluoride anions, depending on the type of the macrocycle. In the case of the chiral hexaaza-macrocycle L1 derived from trans-1,2-diaminocyclohexane, the formation of these µ2-fluorido dinuclear complexes is accompanied by enantiomeric self-recognition of macrocyclic units. In contrast, this kind of recognition is not observed in the case of complexes of the chiral macrocycle L2 derived from 1,2-diphenylethylenediamine. The reaction of fluoride with a mixture of mononuclear complexes of L1 and L2, containing two different Ln(III) ions, results in narcissistic sorting of macrocyclic units. Conversely, a similar reaction involving mononuclear complexes of L1 and complexes of achiral macrocycle L3 based on ethylenediamine results in sociable sorting of macrocyclic units and preferable formation of heterodinuclear complexes. In addition, formation of these heterodinuclear complexes is accompanied by chirality transfer from the chiral macrocycle L1 to the achiral macrocycle L3 as indicated by CPL and CD spectra.

Dicarba[26]hexaporphyrinoids(1.1.1.1.1.1) with an Embedded Cyclopentene Moiety-Conformational Switching.

Invited for the cover of this issue is Lechoslaw Latos-Grazynski and co-workers at University of Wroclaw. The image depicts two essential conformations of 31,34-dicarba[26]hexachlorins: dumbbell and rectangular with regular or doubly inverted carbocyclic rings, respectively. Read the full text of the article at 10.1002/chem.202002603.

Dicarba[26]hexaporphyrinoids(1.1.1.1.1.1) with an Embedded Cyclopentene Moiety-Conformational Switching.

Incorporation of cyclopentene fragments into a skeleton of parental [26]hexaphyrin(1.1.1.1.1.1) afforded extended carbaporphyrinoids: 31,34-dicarbahexa[26]chlorin and its derivatives: the first externally substituted by ethoxy and 2,4,6-trimethylbenzylidene groups and the second one formed by selective oxidation of one cyclopentene ring. Macrocycles adopt dumbbell-shaped conformations with two meso hydrogen atoms located inside the macrocyclic cavity. Protonation of 31,34-dicarba[26]hexachlorins provided dications existing in dumbbell-shaped and rectangular conformations.

Mixed Macrocycles Derived from 2,6-Diformylpyridine and Opposite Enantiomers of trans-1,2-Diaminocyclopentane and trans-1,2-Diaminocyclohexane.

The condensation reaction of 2,6-diformylpyridine with an equimolar mixture of opposite enantiomers of trans-1,2-diaminocyclopentane and trans-1,2-diaminocyclohexane using a dynamic combinatorial chemistry approach has been examined. In nonmetal-templated reactions, depending on reaction conditions, mixed 2 + 1 + 1 macrocyclic imine or bigger mixed 4 + 2 + 2 imine macrocycle are formed selectively. The 2 + 1 + 1 imine used as a precursor in the templated by CdII ions produces a library of enlarged chiral mixed imines coordinated with metal cations among which the hexanuclear CdII complex of 6 + 3 + 3 imine was isolated and characterized. All macrocyclic imine compounds have been reduced to the corresponding macrocyclic amines, which have been further transformed into their hydrochlorides. Each macrocyclic compound has been obtained as two enantiomers. For imine macrocycles and for the hydrochloride derivatives of macrocyclic amines, their X-ray crystal structures have been determined. In particular, the crystals of protonated 4 + 2 + 2 macrocyclic amine, which contains two types of diastereomeric cations differing in terms of inverted twists of pyridine moieties, and hexanuclear CdII complex of 6 + 3 + 3 imine, which gives a deeper insight into the expansion reaction, have been investigated. A heterochiral self-sorting of 2 + 2 and 2 + 1 + 1 macrocyclic imines has been confirmed by a competition reaction of 2,6-diformylpyridine, racemic trans-1,2-diaminocyclopentane, and racemic trans-1,2-diaminocyclohexane and theoretical calculations.

Trinuclear and Hexanuclear Lanthanide(III) Complexes of the Chiral 3+3 Macrocycle: X-ray Crystal Structures and Magnetic Properties.

A new triphenolic hexaaza chiral macrocyclic amine L forms trinuclear complexes 1-3 with rare earth metal lanthanide(III) ions (Ln = Dy, Eu, and Y) with the general formula [Ln3L(µ3-OH)2(NO3)4(H2O)2]· xCH3OH. The crystal structures of the nitrate derivatives of this type reveal the presence of a {Ln3(µ3-OH)2} core within the macrocycle. For the chloride derivative of dysprosium(III) 4, a duplex of the trinuclear compound is formed to give the hexanuclear [Dy6L2(µ3-OH)3(µ3-O)(µ2-Cl)3Cl4(H2O)2] compound, in which two trinuclear macrocyclic units are linked by bridging chloride anions, supplemented by a hydrogen bond connecting the central oxo and hydroxo bridges as well as by weak interactions at the periphery of the macrocycle. The nuclear magnetic resonance spectra of these complexes reveal a dynamic behavior in solution related to exchange of axial ligands and hindered rotation of phenyl substituents. Magnetic studies of the nitrate (1-3) and chloride (4) dysprosium(III) complexes suggest the presence of weak ferromagnetic interactions between neighboring metal centers. The interaction is strongest for compound 1, and for the related duplex compound 4, it appears to be somewhat weaker. The ac susceptibility measurements for complexes 1 and 4 confirm their field-induced single-molecule magnet behavior with the following characteristics: Ueff = 10.6 cm-1 (15.2 K), τ0 = 2.05 × 10-4 s under 2500 Oe dc fields for 1; Ueff = 7.9 cm-1 (11.4 K), τ0 = 1.68 × 10-4 s under a 3000 Oe dc field for 4.

Chiral Cryptates Derived from a Hexaazamacrocycle.

The reactions of hexaazamacrocycle 1 with 2,6-bis(bromomethyl)pyridine or 2,6-bis[(tosyloxy)methyl)]pyridine in the presence of appropriate carbonates result in the formation of derivatives of cryptand 6: enantiopure azacryptates of sodium and potassium. Crystal structures of these compounds indicate interaction of a metal ion with four pyridine nitrogen atoms and four tertiary amine atoms. The competition reactions monitored by NMR spectroscopy indicate preferential binding of Na+ over K+ as well as higher affinity of 6 for Na+ in comparison with the [2.2.1] cryptand.

Hexanuclear and Trinuclear Metal Complexes of a Giant Octadecaaza Macrocycle.

A large macrocyclic ligand containing six pyridine fragments and six diaminocyclopentane fragments is able to form hexanuclear Zn(II) and Ni(II) complexes as well as a trinuclear Zn(II) complex. X-ray crystal structures of these complexes indicate quite different ligand conformations. In the hexanuclear Zn(II) derivative with chloride counteranions metal ions have a distorted-trigonal-bipyramidal geometry and occupy loop sections formed by the highly folded macrocycle, which adopts a globular shape. In the hexanuclear Ni(II) derivative with nitrate counteranions metal ions exhibit a distorted-octahedral geometry and the ligand conformation is much more open, while in the trinuclear Zn(II) complex the macrocycle wraps around the octahedral metal ions. The last highly entangled conformation of the trinuclear complex is also present in solution, as confirmed by the NOESY spectra. The NMR data indicate that the hexanuclear Zn(II) complex partially dissociates in water solutions to form the trinuclear complex, while the 1H NMR titration of the free macrocycle with zinc(II) chloride indicates that the formation of a trinuclear complex corresponds to cooperative binding of metal ions.

From 2 + 2 to 8 + 8 Condensation Products of Diamine and Dialdehyde: Giant Container-Shaped Macrocycles for Multiple Anion Binding.

The combination of 2,6-diformylpyridine and trans-1,2-diaminocyclopentane fragments results in 2 + 2, 3 + 3, 4 + 4, 6 + 6, and 8 + 8 macrocyclic imine condensation products. These imines can be reduced to the corresponding 2 + 2, 3 + 3, 4 + 4, 6 + 6, and 8 + 8 macrocyclic amines. The X-ray crystal structures of their protonated derivatives show a rich variety of macrocycle conformations ranging from a stepped 2 + 2 macrocycle to a multiply folded 8 + 8 macrocycle of globular shape. These compounds bind anions via hydrogen bonds: two chloride anions are bound above and below the macrocyclic ring of the 2 + 2 amine, one chloride anion is bound approximately in the center of the 3 + 3 macrocycle, and two chloride anions are deeply buried inside a folded container-shaped 4 + 4 macrocycle, while in the case of the previously reported 6 + 6 amine four chloride anions and two solvent molecules are buried inside a container-shaped macrocycle. Yet another situation was observed for a multiply folded protonated 8 + 8 macrocycle which binds six sulfate anions; two of them are deeply buried inside the container structure while four anions interact with the clefts at the surface of the container.

Structural Analogues of Selfotel.

A small library of phosphonopiperidylcarboxylic acids, analogues of NMDA antagonist selfotel (CGS 19755), was synthesized. First, the series of aromatic esters was obtained via a palladium-catalyzed cross-coupling reaction (Hirao coupling) of dialkyl phosphites with bromopyridinecarboxylates, followed by their hydrolysis. Then, hydrogenation of the resulting phosphonopyridylcarboxylic acids over PtO2 yielded the desired phosphonopiperidylcarboxylic acids. NMR studies indicated that the hydrogenation reaction proceeds predominantly by cis addition. Several compounds were obtained as monocrystal structures. Preliminary biological studies performed on cultures of neurons suggest that the obtained compounds possess promising activity toward NMDA receptors.

Zwitterionic phosphorylated quinines as chiral solvating agents for NMR spectroscopy.

Because of their unique 3D arrangement, naturally occurring Cinchona alkaloids and their synthetic derivatives have found wide-ranging applications in chiral recognition. Recently, we determined the enantioselective properties of C-9-phosphate mixed triesters of quinine as versatile chiral solvating agents in nuclear magnetic resonance (NMR) spectroscopy. In the current study, we introduce new zwitterionic members of this class of molecules containing a negatively charged phosphate moiety (i.e., ethyl, n-butyl and phenyl hydrogen quininyl phosphate). An efficient approach for synthesizing these compounds is elaborated, and full characterization, including conformational and autoaggregation phenomena studies, was performed. Therefore, their ability to induce NMR anisochrony of selected enantiomeric substrates (i.e., primarily N-DNB-protected amino acids and their methyl esters) was analyzed compared to uncharged diphenyl quininyl phosphate and its positively charged quaternary ammonium hydrochloride salt. In addition, (1) H and (13) C NMR experiments revealed their enantiodiscrimination potential toward novel analytes, such as secondary amines and nonprotected amino acids.

Anion and solvent induced chirality inversion in macrocyclic lanthanide complexes.

A series of the lanthanide(III) or yttrium(III) complexes of the type [LnL(NO3)(H2O)2](NO3)2, [LnL(NO3)(H2O)](NO3)2, [LnL(H2O)2](NO3)3, and [LnLCl(H2O)2]Cl2 where L is an all-R or all-S enantiomer (L(R) or L(S)) of the chiral hexaaza macrocycle, 2(R),7(R),18(R),23(R)- or 2(S),7(S),18(S),23(S)-1,8,15,17,24,31-hexaazatricyclo[25.3.1.1.0.0]-dotriaconta-10,12,14,26,28,30-hexaene, and Ln(III) = Sm(III), Tb(III), Ho(III), Er(III), Tm(III), Yb(III), Lu(III), or Y(III), have been synthesized and structurally characterized. The crystal structure of the free macrocycle shows a highly twisted molecule, preorganized for the formation of helical complexes. The crystal structures of the lanthanide(III) complexes show two different diastereomeric forms of the macrocycle with different configurations at the stereogenic amine nitrogen atoms: (RRRR) or (RSRS) (denoted as L(RI) and L(RII), respectively). The L(RI) diastereomeric form of the nitrate derivatives [LnL(NO3)(H2O)](NO3)2 (Ln = Ho, Er) and [LnL(H2O)2](NO3)3 (Ln = Tm, Yb, Lu) convert slowly to the L(RII) form in methanol or acetonitrile solutions, while this process is not observed for the L(RI) diastereomers of analogous chloride derivatives [LnL(H2O)2]Cl3 (Ln = Tm, Yb, Lu). On the other hand, the L(RI) → L(RII) conversion for these Tm(III), Yb(III), and Lu(III) chloride derivatives can be triggered by the addition of external nitrate anions. The circular dichroism (CD) and (1)H NMR data indicate initial fast exchange of axial chloride for axial nitrate ligand, followed by slow chirality inversion of the equatorial macrocyclic ligand.

Incorporation of trinuclear lanthanide(III) hydroxo bridged clusters in macrocyclic frameworks.

A cluster of lanthanide(III) or yttrium(III) ions, Ln3(µ3-OH)2, (Ln(III) = Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Yb(III), or Y(III)) can be bound in the center of a chiral macrocyclic amines H3L1(R), H3L1(S), and H3L2(S) obtained in a reduction of a 3 + 3 condensation product of (1R,2R)- or (1S,2S)-1,2-diaminocyclohexane and 2,6-diformyl-4-methylphenol or 2,6-diformyl-4-tertbutylphenol. X-ray crystal structures of the Nd(III), Sm(III), Gd(III), Dy(III), and Y(III) complexes reveal trinuclear complexes with Ln(III) ions bridged by the phenolate oxygen atoms of the macrocycle as well as by µ3-hydroxo bridges. In the case of the Nd(III) ion, another complex form can be obtained, whose X-ray crystal structure reveals two trinuclear macrocyclic units additionally bridged by hydroxide anions, corresponding to a [Ln3(µ3-OH)]2(µ2-OH)2 cluster encapsulated by two macrocycles. The formation of trinuclear complexes is confirmed additionally by (1)H NMR, electrospray ionization mass spectrometry (ESI MS), and elemental analyses. Titrations of free macrocycles with Sm(III) or Y(III) salts and KOH also indicate that a trinuclear complex is formed in solution. On the other hand, analogous titrations with La(III) salt indicate that this kind of complex is not formed even with the excess of La(III) salt. The magnetic data for the trinuclear Gd(III) indicate weak antiferromagnetic coupling (J = -0.17 cm(-1)) between the Gd(III) ions. For the trinuclear Dy(III) and Tb(III) complexes the χ(M)T vs T plots indicate a more complicated dependence, resulting from the combination of thermal depopulation of mJ sublevels, magnetic anisotropy, and possibly weak antiferromagnetic and ferromagnetic interactions.

Geometric changes around an N atom due to a urethane-type bis(tert-butoxycarbonyl) substituent.

Two crystal structures of urethane-protected derivatives of aspartic acid dimethyl ester are presented, namely dimethyl (2S)-2-[(tert-butoxycarbonyl)amino]butanedioate, C(11)H(19)NO(6), and dimethyl (2S)-2-{bis[(tert-butoxycarbonyl]amino}butanedioate, C(16)H(27)NO(8). The geometry at the N atom is discussed and compared with similar structures. The analysis of singly and doubly N-substituted derivatives reveals an elongation of all bonds involving the N atom and conformational changes of the amino acid side chain due to steric interactions with two bulky substituents on the amino group.

A 1:2 cocrystal of genistein with isonicotinamide: crystal structure and Hirshfeld surface analysis.

Genistein, a naturally occurring polyphenolic compound, was combined with isonicotinamide, a pharmaceutically acceptable coformer, to yield a 1:2 cocrystal [systematic name: 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one-pyridine-4-carboxamide (1/2)], C15H10O5·2C6H6N2O. The molecules in the cocrystalline phase are present in their neutral forms, and assemble a molecular layer by means of hydrogen bonding.

Hexa- and octanuclear copper(II) complexes with a tetraeicosaaza amine macrocycle.

One hexa- and two octanuclear Cu(II) complexes were synthesised from different metal salts and a very large (8 + 8) tetraeicosaaza macrocycle. These nitrate, chloride and sulphate coordination compounds were characterised by taking elemental analysis, spectroscopy, crystallography and magnetic susceptibility measurements. Their crystal structures revealed different interesting coordination modes of Cu(II) cations and nuclearity in these centrosymmetric complexes. For the sulphate complex two different, homo- vs. heterochiral, arrangements of the same macrocycle L3 around the same Cu(II) cations take place.

SO3H-Functionalized Epoxy-Immobilized Fe3O4 Core-Shell Magnetic Nanoparticles as an Efficient, Reusable, and Eco-Friendly Catalyst for the Sustainable and Green Synthesis of Pyran and Pyrrolidinone Derivatives.

A SO3H-functionalized epoxy-immobilized Fe3O4 core-shell magnetic nanocatalyst was prepared through a simple three-step procedure, and it was identified by various analyses such as Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), differential thermal gravity (DTG), Brunauer-Emmett-Teller (BET) analysis, transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA), vibration sample magnetometry (VSM), and powder X-ray diffraction (PXRD). BET analysis showed that the as-prepared nanocatalyst was synthesized with a mesoporous structure and high specific area (35.45 m2 g-1). The TEM image clearly showed that the particle size distribution was in the range of 47-65 nm. The designed magnetic nanocatalyst was used successfully in the synthesis of pyran derivatives via the reaction of dimedone, malononitrile, and various aromatic aldehydes and synthesis of pyrrolidinone derivatives via the reaction of various aromatic aldehydes, aniline, and diethyl acetylenedicarboxylate. The nanocatalyst was simply isolated from the reaction mixture utilizing an external magnet and reused several times according to the model reactions without significant loss in its efficiency.

Crystallization as a selection force at the polymerization of nucleotides in a prebiotic context.

Accumulation and selection of nucleotides is one of the most challenging problems surrounding the origin of the first RNA molecules on our planet. In the current work we propose that guanosine 3',5' cyclic monophosphate could selectively crystallize upon evaporation of an acidic prebiotic pool containing various other nucleotides. The conditions of the evaporative crystallization are fully compatible with the subsequent acid catalyzed polymerization of this cyclic nucleotide reported in earlier studies and may be relevant in a broad range of possible prebiotic environments. Albeit cytidine 3',5' cyclic monophosphate has the ability to selectively accumulate under the same conditions, its crystal structure is not likely to support polymer formation.