Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction.

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g., P1, P1', P2, and P2') of the darunavir framework have been structurally modified. An alternate route for the synthesis of darunavir and three related P1 and P1' derivatives has been developed. This synthetic pathway involves the use of a Crimmins titanium tetrachloride-mediated oxazolidine-2-thione-guided asymmetric glycolate aldol addition reaction. The resultant aldol adduct introduces the P1 fragment of darunavir via an aldehyde. Transamidation with a selected amine (isobutylamine or 2-ethyl-1-butylamine) to cleave the auxiliary yields an amide wherein the P1' component is introduced. From this stage, the amide is reduced to the corresponding ß-amino alcohol and the substrate is then bis-nosylated to introduce the requisite p-nitrobenzenesulfonamide component and activate the secondary alcohol for nucleophilic substitution. Treatment with sodium azide yielded the desired azides, and the deprotection of the p-methoxyphenoxy group is achieved with the use of ceric ammonium nitrate. Finally, hydrogenation to reduce both the aniline and azide functionalities with concurrent acylation yields darunavir and its derivatives.

Diastereoselective and Enantioselective Synthesis of α-p-Methoxyphenoxy-ß-Lactones: Dependence on the Stereoelectronic Properties of the ß-Hydroxy-α-p-Methoxyphenoxycarboxylic Acid Precursors.

Treatment of ß-hydroxy-α-p-methoxyphenoxy carboxylic acids derived from the asymmetric glycolate aldol addition reaction with p-nitrobenzenesulfonyl chloride yielded divergent results depending on the nature of the ß-substituent of the carboxylic acid. Substrates bearing either alkyl substituents (R = -n-butyl, -n-octyl, -benzyl, isopropyl, -tert-butyl) or aryl systems bearing electron-withdrawing substituents (R = -p-C6H4Cl, -p-C6H4Br, -p-C6H4NO2) yielded ß-lactones. In contrast, α-p-methoxyphenoxy-ß-hydroxycarboxylic acids bearing electron-donating aryl groups or the sterically demanding 2-naphthyl group formed (Z)-alkenes.

A Dual-Pronged Approach: A Ruthenium(III) Complex That Modulates Amyloid-ß Aggregation and Disrupts Its Formed Aggregates.

Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-ß (Aß) are now recognized as the neurotoxic species. Metal-based therapeutics are uniquely suited to target Aß, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of Aß in solution, where the inclusion of a primary amine proximal to the ligand coordination site improved the activity of the complexes. To advance these structure-activity relationships, a series of oxazole-based Ru complexes were prepared and evaluated for their ability to modulate Aß aggregation. From these studies, a lead candidate, Oc, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble Aß and diminishing its cytotoxicity. Further evaluation of Oc demonstrated its ability to disrupt formed Aß aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for Aß has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success.

Telluracarbaporphyrins and a Related Palladium(II) Complex: Evidence for Hypervalent Interactions.

The reaction of a carbatripyrrin with a tellurophene dicarbinol in the presence of BF3·Et2O, followed by oxidation with DDQ, afforded the first example of a telluracarbaporphyrin. Although this system exhibits strongly aromatic characteristics, it is prone to air oxidation, giving rise to a hydroxy derivative that was characterized by X-ray crystallography. The initial telluracarbaporphyrin reacted with palladium(II) acetate to give a stable organometallic complex, and X-ray crystallography showed that the palladium cation was coordinated to all four atoms in the CNTeN core. An oxacarbatripyrrin was also reacted with a tellurophene dialcohol to give an air-stable porphyrin analogue with a CNTeO core. Nonmetalated telluracarbaporphyrins showed relatively short Te-N separations that strongly implied the involvement of hypervalent tellurium interactions. Furthermore, despite the presence of a very large tellurium atom, the tellurophene subunit is not strongly pivoted away from the mean macrocyclic plane as would be expected in the absence of these interactions. The aromatic properties of heterocarbaporphyrins were assessed by proton NMR spectroscopy, NICS calculations, and AICD plots. In addition, the relative stability of hydroxytelluraporphyrins in comparison to their tellurophene oxide tautomers was investigated and the aromatic characteristics of these oxidized structures were evaluated.

Rhodium Complexes of Carbaporphyrins, Carbachlorins, adj-Dicarbaporphyrins, and an adj-Dicarbachlorin.

The macrocyclic cavities in carbaporphyrins are well suited for the formation of metalated derivatives. A carbaporphyrin diester and a naphthocarbaporphyrin reacted with [Rh(CO)2Cl]2 to give good-to-excellent yields of rhodium(I) complexes, and these were fully characterized by X-ray crystallography. Both rhodium(I) derivatives were converted into rhodium(III) complexes in refluxing pyridine, albeit in moderate yields. Carbachlorins also formed rhodium(I) complexes, but these could not be further transformed into rhodium(III) products. The rhodium(III) complexes incorporate two axial pyridine ligands, which exhibit strongly shielded resonances in their 1H NMR spectra, and the rhodium(III) carbaporphyrin diester was further characterized by X-ray crystallography. adj-Dicarbaporphyrins also formed rhodium(I) complexes, but these reactions involved the relocation of a proton to generate an internal methylene unit. The environments associated with the two faces of the resulting macrocycles are very different from one another, and this results in the 1H NMR chemical shifts for the two internal methylene protons being separated by well over 3 ppm. Although the diatropicities of rhodium(I) complexes for monocarbaporphyrins and carbachlorins are comparable to those of the parent ligands, the chemical shifts for rhodium(I) dicarbaporphyrins are consistent with a significant reduction in the porphyrinoid aromaticity. A dicarbachlorin also gave a rhodium(I) complex, but this species fully retained the diatropic characteristics of the parent ligand. Nevertheless, the internal CH2 unit still gave two widely separated doublets indicative of radically differing environments for the two faces of the macrocycle. Rhodium(I) dicarbaporphyrin and dicarbachlorin complexes were further characterized by X-ray crystallography.

Synthesis and Properties of Carbaporphyrin and Carbachlorin Dimethyl Esters Derived from Cyclopentanedialdehydes.

Norbornenes with two ester substituents were prepared by Diels-Alder cycloadditions of cyclopentadiene with dimethyl fumarate and dimethyl 1,1-ethylenedicarboxylate. Oxidation with potassium permanganate gave good yields of related diols that were oxidatively ring-opened to afford cyclopentane dialdehydes. MacDonald-type "3 + 1" condensations with a tripyrrane, followed by oxidation with DDQ in refluxing toluene, gave carbaporphyrin or carbachlorin products in good yields. The macrocyclic products were highly diatropic and produced porphyrin-like UV-vis spectra. The carbaporphyrin was converted into silver(III) and gold(III) organometallic derivatives. Reaction with methyl iodide in the presence of potassium carbonate gave mono- and dialkylation products, and treatment of the former with Ni(OAc)2 or Pd(OAc)2 afforded nickel(II) and palladium(II) complexes. The free base carbaporphyrin and carbachlorin, and the nickel and palladium complexes, were characterized by X-ray crystallography. The carbachlorin also reacted with silver(I) acetate to give a silver(III) derivative. Carbaporphyrins and carbachlorins underwent deuterium exchange at the meso-positions with deuteriated TFA, and this observation indicates that protonation is occurring at the bridging carbons. The new route to carbaporphyrins and carbachlorins has enabled detailed studies on the properties of these systems and provides the foundations for future investigations.

Metalation and Selective Oxidation of Diphenyl-23-oxa-, -thia-, and -selena-21-carbaporphyrins.

The availability of diphenyl-23-oxa-, -thia-, and -selena-21-carbaporphyrins has enabled the reactivity of these systems to be investigated and contrasted. All three heterocarbaporphyrins reacted with palladium(II) acetate in refluxing chloroform-acetonitrile to give organometallic palladium(II) derivatives in good yields. These structures are stable and give UV-vis spectra that show increasing broadening and bathochromic shifts as the size of the heteroatom increases. Nickel(II) acetate in refluxing N,N-dimethylformamide reacted with the oxa- and thiacarbaporphyrins under nitrogen to give the corresponding nickel(II) complexes, but the selenacarbaporphyrin did not metalate under these conditions. The NMR spectra for all of the metal complexes showed that they possess strong diamagnetic ring currents, although the palladium complexes gave larger downfield shifts that were slightly diminished when larger heteroatoms were present in the porphyrinoid cavity. Reactions of the oxacarbaporphyrin with nickel(II) acetate in the presence of air led to a unique oxidation reaction that afforded a weakly diatropic 21-oxycarbaporphyrin, and low yields of a related product were also obtained from the thiacarbaporphyrin.

Regioselective oxidation and metalation of meso-unsubstituted azuliporphyrins.

Azuliporphyrins are intriguing porphyrin analogues that incorporate an azulene ring in place of a pyrrolic unit. This system undergoes regioselective oxidation reactions and favors the formation of stable organometallic derivatives. Reaction of meso-unsubstituted azuliporphyrins with Co2(CO)8 or CoCl2·6H2O gave 21-oxyazuliporphyrins, while Cu(OAc)2 produced the corresponding copper(ii) complexes. Treatment of an oxyazuliporphyrin with Ni(OAc)2 or Pd(OAc)2 afforded analogous nickel(ii) and palladium(ii) derivatives. Silver(i) acetate in pyridine reacted with azuliporphyrins to give moderate yields of silver(iii) benzocarbaporphyrins, and the prevalence of structures with a formyl moiety at the sterically crowded 21-position suggested that the ring contraction reactions were triggered in part by intramolecular attack from an axial peroxide ligand. Related thiaazuliporphyrins reacted with palladium(ii) acetate to give palladium(ii) benzothiacarbaporphyrins but this chemistry did not give rise to structures with 21-formyl groups, suggesting that the ring contraction reactions occurred by a different mechanistic pathway. These results demonstrate the existence of a rich tapestry of oxidation and metalation reactions for azuliporphyrin systems.

Preparation, structural characterization, assessment of potential antiaromaticity and metalation of 21-oxyazuliporphyrins.

Oxidation of tetraarylazuliporphyrins with silver(I) acetate in refluxing chloroform-acetonitrile afforded good yields of 21-oxyazuliporphyrins. Although hydroxyazuliporphyrin tautomers can be considered for this system, spectroscopic results and density functional theory calculations indicate that the keto form is favored, and this was confirmed by single-crystal X-ray diffraction. Oxyazuliporphyrins formally possess a 24π electron delocalization pathway, but the proton NMR spectra are consistent with macrocycles that have diatropic ring currents. Nucleus independent chemical shift and anisotropy of induced current density calculations also confirmed the diatropic nature of these macrocycles, although these results indicated that the seven-membered ring is antiaromatic. However, while the NMR spectra showed the azulene protons at atypically high field values, the results are consistent with a nonaromatic cycloheptatrienyl unit. Protonation gave dicationic products that exhibited enhanced diatropic character. Oxyazuliporphyrins readily form metalated derivatives with Ni(II), Pd(II), and Pt(II), and these complexes exhibited significant diatropic character even though the macrocycle is highly distorted. X-ray diffraction characterization of palladium(II) and platinum(II) complexes demonstrated that these derivatives are structurally virtually identical to a previously reported copper(II) oxyazuliporphyrin.

Role of noncovalent interactions in vanadium tellurite chain connectivities.

Structural differences in [V2Te2O10]n(2n-) chain metrics are directly ascribed to variations in noncovalent interactions in a series of organically templated vanadium tellurites, including [C6H17N3][V2Te2O10]·H2O, [C5H16N2][V2Te2O10], and [C4H14N2][V2Te2O10]. The noncovalent interaction (NCI) method was used to locate, quantify, and visualize intermolecular interactions in [C4H14N2][V2Te2O10] and [C5H16N2][V2Te2O10]. Variations in the van der Waals attractions between [1,4-diaminobutaneH2](2+) and [1,5-diaminopentaneH2](2+) result in divergent packing motifs for these cations, which causes a reorganization of N-H···O hydrogen bonding and variances in the [V2Te2O10]n(2n-) chain metrics. The application of the NCI method to this type of solid-state structure provides a direct method to elucidate the structural effects of weak noncovalent interactions.

Synthesis of an adj-dicarbaporphyrin and the formation of an unprecedented tripalladium sandwich complex.

An adj-dicarbaporphyrin was prepared by carrying out a base-catalyzed MacDonald reaction between bis(3-indenyl)methane and a dipyrrylmethane dialdehyde. The porphyrinoid system exhibited highly diatropic characteristics, and the proton NMR spectrum gave resonances at -5.74 and -6.24 ppm for the internal NH and CH protons, respectively. The UV-vis spectrum was also porphyrin-like, giving a Soret band at 455 nm and a series of Q bands at longer wavelengths. Addition of trifluoroacetic acid gave a C-protonated monocation, and at higher acid concentrations a dicationic species was observed. Addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) afforded a monodeprotonated porphyrinoid anion. All of these species retained highly diatropic characteristics. Density functional theory calculations showed that a nonplanar tautomer with four internal hydrogens was favored, in agreement with the spectroscopic data. Nucleus-independent chemical shift calculations also confirmed the aromatic characteristics of the free-base, cationic, and anionic structures. The dicarbaporphyrin reacted with palladium(II) acetate in refluxing acetonitrile to give an unusual tripalladium sandwich complex consisting of two dianionic palladium(II) dicarbaporphyrin units surrounding a palladium(IV) cation with unique η(5) interactions involving meso-carbon atoms.

Synthesis and metalation of dimethoxybenziporphyrins, thiabenziporphyrins, and dibenziporphyrins.

Dimethoxybenzitripyrranes were prepared in excellent yields by reacting benzene dicarbinols with BF3·Et2O and excess pyrrole in refluxing 1,2-dichloroethane. Reaction with a pyrrole dialdehyde in the presence of TFA, followed by oxidation with DDQ, afforded good yields of meso-diphenyldimethoxybenziporphyrins. These dimethoxyporphyrinoids exhibited weakly diatropic properties that were enhanced upon protonation. The dimethoxybenzitripyrranes also reacted with a thiophene dicarbinol to give dimethoxythiabenziporphyrins, and the nonplanar nature of this system was demonstrated by X-ray crystallography. The dimethoxybenziporphyrins reacted with palladium(II) acetate to give the related organometallic derivatives, but the thiabenziporphyrins underwent a demethylation to afford palladium(II) thiaoxybenziporphyrins. Related palladium(II) complexes were also prepared from previously reported thiacarbaporphyrinoids. The X-ray structure for one of the complexes showed that the six-membered ring is very distorted and the thiophene ring is strongly tilted out of the plane of the macrocycle. The dimethoxybenzitripyrranes also reacted with dimethoxybenzene dicarbinols to give the first examples of dibenziporphyrins, thereby further demonstrating the versatility of this synthetic methodology.

Synthesis, structural characterization, aromatic characteristics, and metalation of neo-confused porphyrins, a newly discovered class of porphyrin isomers.

Neo-confused porphyrins represent a unique family of porphyrin isomers that retain overall aromatic characteristics by virtue of a 17-atom 18π electron delocalization pathway. These porphyrin analogues have a pyrrolic subunit linked in a 1,3-fashion so that a nitrogen atom is directly connected to a meso-bridging carbon. Pyrrole-3-carbaldehydes were shown to react with sodium hydride and 5-acetoxymethylpyrrole-2-carbaldehydes in DMF to give the crucial neo-confused dipyrrolic dialdehyde intermediates. MacDonald "2 + 2" condensation of the dialdehydes with a dipyrrylmethane afforded a dihydroporphyrinoid, and subsequent oxidation with 0.2% aqueous ferric chloride generated a series of fully conjugated neo-confused porphyrins. Unusual dihydroporphyrin byproducts were also identified. Reaction of neo-confused porphyrins with nickel(II) or palladium(II) acetate in refluxing acetonitrile gave excellent yields of the corresponding organometallic derivatives. Proton NMR spectroscopy demonstrates that the diatropic character of this system is diminished compared to regular porphyrins, although neo-confused porphyrins retain porphyrin-like UV-vis spectra. Protonation led to the sequential formation of mono- and dicationic species. Proton NMR spectra for the dications showed the presence of enhanced diamagnetic ring currents.

Controllable formation of heterotrimetallic coordination compounds: systematically incorporating lanthanide and alkali metal ions into the manganese 12-metallacrown-4 framework.

The inclusion of Ln(III) ions into the 12-MC-4 framework generates the first heterotrimetallic complexes of this molecular class. The controllable and deliberate preparations of these compounds are demonstrated through 12 crystal structures of the Ln(III)M(I)(OAc)4[12-MCMn(III)(N)shi-4](H2O)4·6DMF complex, where OAc(-) is acetate, shi(3-) is salicylhydroximate, and DMF is N,N-dimethylformamide. Compounds 1-12 have M(I) as Na(I), and Ln(III) can be Pr(III) (1), Nd(III) (2), Sm(III) (3), Eu(III) (4), Gd(III) (5), Tb(III) (6), Dy(III) (7), Ho(III) (8), Er(III) (9), Tm(III) (10), Yb(III) (11), and Y(III) (12). An example with M(I) = K(I) and Ln(III) = Dy(III) is also reported (Dy(III)K(OAc)4[12-MCMn(III)(N)shi-4](DMF)4·DMF (14)). When La(III), Ce(III), or Lu(III) is used as the Ln(III) ions to prepare the Ln(III)Na(I)(OAc)4[12-MCMn(III)(N)shi-4] complex, the compound Na2(OAc)2[12-MCMn(III)(N)shi-4](DMF)6·2DMF·1.60H2O (13) results. For compounds 1-12, the identity of the Ln(III) ion affects the 12-MCMn(III)(N)shi-4 framework as the largest Ln(III), Pr(III), causes an expansion of the 12-MCMn(III)(N)shi-4 framework as demonstrated by the largest metallacrown cavity radius (0.58 Å for 1 to 0.54 Å for 11), and the Pr(III) causes the 12-MCMn(III)(N)shi-4 framework to be the most domed structure as evident in the largest average angle about the axial coordination of the ring Mn(III) ions (103.95° for 1 to 101.69° for 11). For 14, the substitution of K(I) for Na(I) does not significantly affect the 12-MCMn(III)(N)shi-4 framework as many of the structural parameters such as the metallacrown cavity radius (0.56 Å) fall within the range of compounds 1-12. However, the use of the larger K(I) ion does cause the 12-MCMn(III)(N)shi-4 framework to become more planar as evident in a smaller average angle about the axial coordination of the ring Mn(III) ions (101.35°) compared to the analogous Dy(III)/Na(I) (7) complex (102.40°). In addition to broadening the range of structures available through the metallacrown analogy, these complexes allow for the mixing and matching of a diverse range of metals that might permit the fine-tuning of molecular properties where one day they may be exploited as magnetic materials or luminescent agents.

Synthesis, structural characterization and reactivity of heteroazuliporphyrins.

A series of hetero-azuliporphyrins have been prepared by the "3 + 1" variant on the MacDonald condensation. Azulitripyrranes with tert-butyl and phenyl substituents reacted with thiophene or selenophene dialdehydes in the presence of TFA to give, following an oxidation step, thia- and selena-azuliporphyrins in 45-55% yield. Two of these compounds gave crystals suitable for X-ray crystallographic analysis and the data were consistent with the presence of a 17-atom delocalization pathway. The hetero-azuliporphyrins have significant diatropic character that is enhanced by the presence of an electron-donating tert-butyl substituent. The aromatic character is further increased in polar solvents such as DMSO, which are believed to stabilize dipolar resonance contributors with 18π electron delocalization pathways. Protonation also greatly increases the diatropic characteristics of these macrocycles. The porphyrinoids underwent an oxidative ring contraction with t-BuOOH-KOH to give moderate yields of benzoheterocarbaporphyrins. Reaction of azulitripyrranes with 2,5-furandicarbaldehyde afforded oxa-azuliporphyrins, a class of carbaporphyrinoids that had previously been inaccessible. These "missing links" in the study of heteroazuliporphyrins were isolated as the dihydrochloride salts. Protonated oxa-azuliporphyrins are stable aromatic compounds, but the free base forms underwent rapid decomposition in solution.

Synthesis of benziporphyrins and heterobenziporphyrins and an assessment of the diatropic characteristics of the protonated species.

Benzitripyrranes were prepared by reacting diphenyl-substituted benzenedicarbinols with excess pyrrole in the presence of BF3·Et2O. These dipyrrolic compounds underwent acid-catalyzed condensations with a pyrrole dialdehyde to afford good yields of diphenylbenziporphyrins, and further reaction with palladium(II) acetate gave stable organometallic derivatives. The X-ray crystal structure of a palladium(II) benziporphyrin showed that the system deviates significantly from planarity. Although the benzitripyrranes failed to give stable macrocyclic products with furan or thiophene dialdehydes, they afforded tetraphenyl heterobenziporphyrins upon reaction with diphenyl-substituted furan- or thiophenedicarbinols and BF3·Et2O. Benziporphyrins and their heteroanalogues showed no indication of a diamagnetic ring current by proton NMR spectroscopy, but addition of TFA gave rise to the formation of weakly diatropic dications.

6-Phenyl-oxane-2,4-dione.

The title compound, C11H10O3, is a phenyl-subsituted dihydro-pyran-dione in which the heterocycle adopts a boat conformation with the phenyl substituent canted 72.14 (5)° relative to the mean plane of the heterocycle.

CSD Communications of the Cambridge Structural Database.

The Cambridge Structural Database (CSD) is a collection of over one million experimental three-dimensional structures obtained through crystallographic analyses. These structures are determined by crystallographers worldwide and undergo curation and enhancement by scientists at the Cambridge Crystallographic Data Centre (CCDC) prior to their addition to the database. Though the CSD is substantial and contains widespread chemical diversity across organic and metal-organic compounds, it is estimated that a significant proportion of crystal structures determined are not published or shared through the peer-reviewed journal mechanism. To help overcome this, scientists can publish structures directly through the database as CSD Communications and these structural datasets are made publicly available alongside structures associated with scientific articles. CSD Communications contribute to the collective crystallographic knowledge as nearly two thirds are novel structures that are not otherwise available in the scientific literature. The primary benefits of sharing data through CSD Communications include the long-term preservation of scientific data, the strengthening of a widely data-mined world repository (the CSD), and the opportunity for scientists to receive recognition for their work through a formal and citable data publication. All CSD Communications are assigned unique digital object identifiers (DOIs). Contributions as CSD Communications currently comprise about 3.89% of the total CSD entries. Each individual CSD Communication is free to view and retrieve from the CCDC website.

A Ru(II)-arene-ferrocene complex with promising antibacterial activity.

The evolution of high virulence bacterial strains has necessitated the development of novel therapeutic agents to treat resistant infections. Metal-based therapeutics represent a promising avenue for advancement, given their structural variability and unique modes of action relative to classical organic molecules. One strategy that has seen marked success is the incorporation of ferrocene into the framework of established antibacterial agents, while ruthenium-based complexes have also shown promise as bioactive compounds. This work focused on the preparation of novel ruthenium(II)-arene complexes containing Schiff base ligands with an attached ferrocene, and evaluation of their antibacterial activity. Structure-activity relationships identified the importance of having a phenyl group between the Schiff base imine and the appended ferrocene. This complex, C2, showed prominent activity against several clinically relevant bacterial strains, including a minimum inhibitory concentration of 16 µg mL-1 for methicillin-resistant Staphylococcus aureus (MSRA). Overall, the results of this study represent a promising new lead for future development of novel antibacterial agents.

Synthesis of a series of aromatic benziporphyrins and heteroanalogues via tripyrrane-like intermediates derived from resorcinol and 2-methylresorcinol.

Tripyrrane analogues were prepared by reacting resorcinol or 2-methylresorcinol with 2 equiv of an acetoxymethylpyrrole in the presence of p-toluenesulfonic acid and calcium chloride. Following removal of the benzyl ester protective groups, the resorcinol-derived benzitripyrrane was reacted with a pyrrole dialdehyde to give an aromatic hydroxyoxybenziporphyrin. However, furan and thiophene dialdehydes gave highly insoluble products that could not be fully characterized. The methylresorcinol-derived tripyrrane analogue reacted with pyrrole, furan, thiophene, and selenophene dialdehydes to give unstable porphyrinoids that were further oxidized with [bis(trifluoroacetoxy)iodo]benzene to give stable benziporphyrin derivatives. These oxidized benziporphyrins showed strongly diatropic properties by proton NMR spectroscopy where the differences in chemical shifts (Δδ) were >18 ppm in some cases. The selenophene-derived system was further characterized by X-ray crystallography, and these results showed that one of the pyrrole subunits in this crowded structure was tilted by 21° relative to the mean macrocyclic plane. The tripyrrolic system reacted with silver(I) acetate to give the corresponding silver(III) organometallic complex. Regioselective alkylation with methyl or ethyl iodide and potassium carbonate gave diastereomeric mixtures of N-alkyl derivatives, and the N-ethyl substitution products showed highly diastereotopic characteristics.