Beta Substituents Research Articles

ChemInform Abstract: Rational Synthesis of meso-Substituted Chlorin Building Blocks.

Chlorins bearing synthetic handles at specific sites about the perimeter of the macrocycle constitute valuable building blocks. We previously developed methodology for preparing meso-substituted chlorin building blocks and now present methodology for preparing several complementary beta-substituted chlorin building blocks. The chlorins bear one or two beta substituents, one meso substituent, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. New routes have been developed to two beta-substituted bromo-dipyrromethane monocarbinols (Eastern halves). A new beta-substituted Western half was prepared following the method for preparing an unsubstituted Western half (3,3-dimethyl-2,3-dihydrodipyrrin). Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. beta-Substituted chlorins have been prepared in 18-24% yield bearing a 4-iodophenyl group at the 8-position, a 4-iodophenyl group or a 4-[2-(trimethylsilyl)ethynyl]phenyl group at the 12-position, and a 4-iodophenyl group and a 4-[2-(trimethylsilyl)ethynyl]phenyl group at diametrically opposed beta-positions (2, 12). The latter building block makes possible the stepwise construction of linear multi-chlorin architectures. The chlorins exhibit typical absorption and fluorescence spectra. A systematic shift in the absorption maximum (637-655 nm for the free base chlorins, 606-628 nm for the zinc chlorins) and intensity of the chlorin Q(y)() band (epsilon up to 79 000 M(-)(1) cm(-)(1)) is observed depending on the location of the substituents. The characteristic spectral features and location of substituents in defined positions make these chlorins well suited for a variety of applications in biomimetic and materials chemistry.

Synthesis of Mono‐ and Disubstituted Porphyrins: A‐ and 5,10‐A2‐Type Systems

General syntheses have been developed for meso-substituted porphyrins with one or two substituents in the 5,10-positions and no beta substituents. 5-Substituted porphyrins with only one meso substituent are easily prepared by an acid-catalyzed condensation of dipyrromethane, pyrrole-2-carbaldehyde, and an appropriate aldehyde using a "[2+1+1]" approach. Similarly, 5,10-disubstituted porphyrins are accessible by simple condensation of unsubstituted tripyrrane with pyrrole and various aldehydes using a "[3+1]" approach. The yields for these reactions are low to moderate and additional formation of either di- or monosubstituted porphyrins due to scrambling of the intermediates is observed. However, the reactions can be performed quite easily and the desired target compounds are easily removed due to large differences in solubility. A complementary and more selective synthesis involves the use of organolithium reagents for S(N)Ar reactions. Reaction of in situ generated porphyrin (porphine) with 1.1-8 equivalents of RLi gave the monosubstituted porphyrins, while reaction with 3-6 equivalents of RLi gave the 5,10-disubstituted porphyrins in yields ranging from 43 to 90 %. These hitherto almost inaccessible compounds complete the series of different homologues of A-, 5,15-A(2)-, 5,10-A(2)-, A(3)-, and A(4)-type porphyrins and allow an investigation of the gradual influence of type, number, and regiochemical arrangement of substituents on the properties of meso-substituted porphyrins. They also present important starting materials for the synthesis of ABCD porphyrins and are potential synthons for supramolecular materials requiring specific substituent orientations.

Solvolysis of vinyl iodonium salts. New insights into vinyl cation intermediates.

Solvolysis of some vinyl iodonium salts carrying an excellent leaving group is examined, focusing on whether or not a classical primary vinyl cation can be generated. Formation of the primary cation is avoided, when possible, by participation of the beta substituent in the heterolysis to form a vinylenebenzenium ion or a secondary vinyl cation. Definitive evidence against a primary vinyl cation is provided by a chirality probe approach in the solvolysis of 4-methylcyclohexylidenemethyl iodonium salt.

Rational synthesis of beta-substituted chlorin building blocks.

Chlorins bearing synthetic handles at specific sites about the perimeter of the macrocycle constitute valuable building blocks. We previously developed methodology for preparing meso-substituted chlorin building blocks and now present methodology for preparing several complementary beta-substituted chlorin building blocks. The chlorins bear one or two beta substituents, one meso substituent, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. New routes have been developed to two beta-substituted bromo-dipyrromethane monocarbinols (Eastern halves). A new beta-substituted Western half was prepared following the method for preparing an unsubstituted Western half (3,3-dimethyl-2,3-dihydrodipyrrin). Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. beta-Substituted chlorins have been prepared in 18-24% yield bearing a 4-iodophenyl group at the 8-position, a 4-iodophenyl group or a 4-[2-(trimethylsilyl)ethynyl]phenyl group at the 12-position, and a 4-iodophenyl group and a 4-[2-(trimethylsilyl)ethynyl]phenyl group at diametrically opposed beta-positions (2, 12). The latter building block makes possible the stepwise construction of linear multi-chlorin architectures. The chlorins exhibit typical absorption and fluorescence spectra. A systematic shift in the absorption maximum (637-655 nm for the free base chlorins, 606-628 nm for the zinc chlorins) and intensity of the chlorin Q(y)() band (epsilon up to 79 000 M(-)(1) cm(-)(1)) is observed depending on the location of the substituents. The characteristic spectral features and location of substituents in defined positions make these chlorins well suited for a variety of applications in biomimetic and materials chemistry.

Rational synthesis of meso-substituted chlorin building blocks.

Chlorins provide the basis for plant photosynthesis, but synthetic model systems have generally employed porphyrins as surrogates due to the unavailability of suitable chlorin building blocks. We have adapted a route pioneered by Battersby to gain access to chlorins that bear two meso substituents, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. A 3,3-dimethyl-2,3-dihydrodipyrrin (Western half) was synthesized in four steps from pyrrole-2-carboxaldehyde. A bromodipyrromethane carbinol (Eastern half) was prepared by sequential acylation and bromination of a 5-substituted dipyrromethane followed by reduction. Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. The latter reaction has heretofore been performed with copper templates. Investigation of conditions for this multistep process led to copper-free conditions (zinc acetate, AgIO(3), and piperidine in toluene at 80 degrees C for 2 h). The zinc chlorin was obtained in yields of approximately 10% and could be easily demetalated to give the corresponding free base chlorin. The synthetic process is compatible with a range of meso substituents (p-tolyl, mesityl, pentafluorophenyl, 4-[2-(trimethylsilyl)ethynyl]phenyl, 4-iodophenyl). Altogether four free base and four zinc chlorins have been prepared. The chlorins exhibit typical absorption spectra, fluorescence spectra, and fluorescence quantum yields. The ease of synthetic access, presence of appropriate substituents, and characteristic spectral features make these types of chlorins well suited for incorporation in synthetic model systems.

Structural and conformational properties of (Z)-beta-(1-naphthyl)- dehydroalanine residue.

To understand how chemical structure of beta-substituted alpha, beta-dehydroalanine (particularly size and pi conjugation of beta substituent) affects conformational property, x-ray crystallographic analysis was performed on Boc-Ala-Delta(Z) Nap-Val-OMe [Boc: t-butoxycarbonyl; Delta(Z) Nap: (Z)-beta-(1-naphthyl)dehydroalanine; OMe: methoxy] having the naphthyl group as a bulky beta substituent. Single crystals were grown by slow evaporation from an ethanol solution in the triclinic space group P1 with a = 9.528 (3) A, b = 12.410(4) A, c = 5.975(2) A, alpha = 96.77(3) degrees, beta = 102. 81(2) degrees, gamma = 88.74(3) degrees, V = 684.1(4) A3, and Z = 1. Phase determination was carried out by a direct method (SHELEXS), and the final structure was refined to R = 8.1% and R(w) = 9.0% for 1964 observed reflections. The bond lengths and bond angles of the Delta(Z)Nap residue, characterized by a sp(2) hybridized C(alpha) atom, did not differ from those of other dehydroresidues such as Delta(Z) Phe, Delta(Z) Leu, and DeltaVal essentially. The peptide backbone took a type II beta-turn conformation involving an intramolecular hydrogen bond between CO(Boc) and NH(Val), similar to di- or tripeptides containing a Delta(Z) Phe or Delta(Z) Leu residue in the second positions. Here the naphthyl group was found to be nonplanar [chi(2) = 55(1) degrees ] relative to the C(alpha)==C(beta)==C(gamma) plane. The nonplanarity was supported by conformational energy calculation. The molecular packing was stabilized by two kinds of intermolecular hydrogen bonds and van der Waals interactions. Naphthyl groups were arranged in a partially overlapped face-to-face orientation with a center-to-center distance of 5.97 A. For additional information, peptide Boc-(Ala-Delta(Z) Nap-Leu)(2)-OMe was synthesized and its solution conformation was investigated by (1)H-NMR spectroscopy. The hexapeptide showed the tendency to form a 3(10)-helical conformation in solution essentially. Conformational properties of Delta(Z) Nap residue, characterized by a type II beta-turn and 3(10)-helix, were supported by a conformational energy contour map of the Delta(Z)Nap residue.

Conformational characteristics of peptides containing α,β‐dehydroamino acid residues

The structural preferences of synthetic peptides containing alpha, beta-dehydroamino acid residues, as determined by theoretical studies, x-ray diffraction analyses, and spectroscopic studies, are reviewed. The role of delta ZPhe residues in stabilizing type II beta-turn structures in small peptides and in nucleating helical structure in longer peptides is exemplified by several crystal as well as solution structural studies. From the few studies reported so far it appears that delta ZLeu influences the peptide backbone, much like the delta ZPhe residue, whereas delta Ala prefers the extended conformation, suggesting that the nature of beta substituents might influence the conformation restriction behavior of the dehydroresidues. Conformational studies on synthetic peptides containing delta E, delta ZAbu, and delta Val have also been described.

Structure and stereochemistry of brianolide, a new antiinflammatory diterpenoid from the Okinawan gorgonianBriareum sp.

Brianolide (1), a new antiinflammatory diterpenoid of the briarein class, possessing a beta substituent at C-12 (R), has been isolated from the Okinawan gorgonian Briareum sp. Its structure has been established from spectral data in conjunction with a single crystal X-ray analysis.

MTD Approach to Quantitative Structure-Activity Relationships for Cardiotonic Steroids

A minimal topological difference (MTD) approach is made to describe quantitative structure-activity relationships (QSAR) for the Na+, K+-ATPase inhibitory activity of cardiotonic steroids. The calculations take into account 20 derivatives of digitoxigenin, digoxigenin, and gitoxigenin with small substituents at different sites of the steroid backbone. A multiple correlation coefficient of r = 0.916 is obtained using the MTD and an indicator variable for the presence of a 15 beta substituent. The corresponding receptor map reveals receptor wall vertices in the C11, C12, C15, and C22 regions. Both 3 beta and 16 beta substituents are found to contain receptor cavity vertices. The MTD results are discussed with respect to lactone-ring conformational investigations presented and they are compared with findings of previous structure-activity studies.

Structure-activity relationships on the terminal D-amino acid moiety of a novel cephamycin MT-141.

The effect of chemical modification of the D-amino acid function, which represents the C-7 beta substituent of cephamycin MT-141 on in vitro antibacterial activity was examined. MT-141 was more active on Gram-negative organisms than Gram-positive ones. It showed strong bacteriolytic activity on Gram-negative organisms. Lysis of Escherichia coli K-12 strain JE1011 treated with a low concentration of this antibiotic was preceded by frequent formation of multiple bulges from the cells. Amidation or decarboxylation, removing the acidic function from the D-amino acid of MT-141, resulted in an increase in activity against Gram-positive bacteria, and a decrease against Gram-negative ones. Cells treated with the amide or the decarboxylate did not form multiple bulges but formed single bulges. N-Acetylation of the D-amino acid moiety removing the basic function, caused a marked drop in activity against both Gram-positive and Gram-negative bacteria. The bacteriolytic activity on E. coli was reduced, and cells treated with the N-acetate became filamentous. Conversion of the D-amino acid function of MT-141 to the L configuration caused a moderate drop in activity against both Gram-positive and Gram-negative organisms. Both bacteriolytic and bactericidal activities against E. coli were reduced in the L-congener. Cefoxitin, cefmetazole and latamoxef used as reference antibiotics were less active than MT-141 in the bactericidal activity against E. coli, and induced single bulge formation or filamentation of the cells around MIC levels. Cell-surface permeability, stability to beta-lactamases, and binding affinity to PBPs of E. coli did not differ between MT-141 and its derivatives.

The NMR spectra of porphyrins—19: 13C and proton NMR spectra of metal-free porphyrins with the Type-IX substituent orientation, and of their zinc(II) complexes

The 13C and proton NMR spectra of six porphyrins bearing the substituent orientation characteristic of the natural “Type-IX” arrangement are reported and assigned. Significant concentration effects in the spectra of the free base porphyrins, together with the broadening of the C α (and occasionally C β) carbon resonances due to NH tautomerism caused a significant loss of data in these spectra. However, the spectra of the corresponding zinc(II) porphyrins (with addition of excess pyrrolidine) show that both these extraneous effects are completely removed to give well-resolved spectra with accurately reproducible chemical shifts. These spectra are assigned and an analysis of the chemical shifts allows the deduction of substituent chemical shift (SCS) parameters for the peripheral substituents at the beta and meso carbons. There is no global effect of these beta substituents, the beta carbon SCS being confined to the immediate pyrrole ring, and the meso carbon SCS to the two adjacent pyrrole rings. The SCS parameters are analyzed and it is shown how they can be used to predict the peripheral and meso carbon chemical shifts of any porphyrin bearing the substituents discussed.

Oxidative and cardiovascular studies on natural and synthetic catecholamines.

The cyclic voltammometric behavior of epinephrine, norepinephrine, dopamine, epinine, alpha-methyldopamine, beta-methyldopamine, beta-methylepinine, and beta-methoxyepinine has been examined in order to evaluate substituent effects on cyclization rates of the electrochemically generated quinones. We observed that alpha and beta substituents caused a modest enhancement of cyclization rates while an N-methyl group dramatically increased cyclization rates. No correlation was observed between calculated amine pKa values, suggesting that differences in cyclization rates between the primary and secondary amine series were due to inherent nucleophilicity, a measure of which would be gas-phase proton affinities. The acute pressor effects of the newly synthesized catecholamines were compared with the native amines.

Some reflections on prebiotic porphyrins and their complexes with other primordial compounds.

SOME REFLECTIONS ON PREBIOTIC PORPHYRINS AND THEIR COMPLEXES WITH OTHER PRIMORDIAL COMPOUNDS Z. J. PETRYKA and C. J. WATSON* Extensive evidence has now been presented of the prebiotic genesis of organic compounds of potential biological utility [I]. The appropriate combination of certain of these might have provided simple photosynthetic or other systems essential for primeval life. Except for viruses (whose status in respect to the definition of life may be debatable) and certain prokaryotes, all forms of life require porphyrins for chlorophylls and/or hemes, in addition to amino and nucleic acids and proteins of various types. Under simulated geochemical conditions of primordial type [2] (i.e., an atmosphere of methane, ammonia, and water) the formation of formaldehyde and pyrrols has been noted [3-7]. In this environment , porphyrins have also been observed to form upon irradiation, heating, or electrical discharge [8-10]. Under similar conditions, the formation of other primeval compounds essential to the origin of life has been observed, including amino acids [11, 12], di- [13, 14] and polypeptides [15], as well as polyamino acid complexes with adenylate [16]. When amino acids are formed under such conditions, glycine is dominant in the mixture; this is of special interest, since, with succinate, glycine is essential for the biosynthesis of the porphyrins via 8-aminolevulinic acid and porphobilinogen. However, long before there was knowledge of porphyrin biosynthesis, as first provided in the now classical studies of Shemin and co-workers [17], Fischer and Fink [18] observed that acetylacetic ester and glycine condensed to yield a carboxypyrrol, which they considered as a possible model for porphyrin biosynthesis. * From the University of Minnesota Medical Research Unit, Northwestern Hospital, Chicago Avenue at 27th Street, Minneapolis, Minnesota 55407. Aided by a grant from the American Cancer Society. Perspectives in Biology and Medicine · Spring 1972 I 443 More recently, Calvin [19] has shown decisively that, under appropriate conditions, acetic acid and succinic acid are formed sequentially on irradiation of CO., with molecular hydrogen. Thus, it may be, as Calvin suggests, that porphyrin biosynthesis recapitulates prebiotic synthesis. We will return in a moment to certain aspects of this question. The observations by Hanada and Fox [20] and by Ponnamperuma [21] on the formation of ATP and nucleotides, respectively, in a simulated primeval atmosphere supplement the foregoing information and indicate that the most important constituents of living matter can arise in prebiotic fashion. The recent observation by PaechtHorowitz et al. [16], that certain prebiotic clays provide a suitable surface for polymerization of amino acids and combination with adenylate, confirms an earlier suggestion of Bernai [22], at the same time permitting insight into one of the most significant facets of the problem of life's origin. Porphyrins are believed to represent the first organic compounds absorbing the energy of visible light [23], although open-chain tetrapyrryl pigments, such as the phycocyanin or phycoerythrin of the blue or red algae might be permitted to compete for this honor. Evidence that they are derived from heme [24, 25] would nevertheless appear to give primacy to the porphyrins. Fossil blue-green algae have been found in rock at least 1.5 billion years old [19]. The phycocyanin- and chlorophyll-type compounds which may be presumed responsible for their color were in all likelihood biosynthetic in origin, since the algae, even at that early period, though simple, were in some measure organized living forms. In contrast to the porphyrins, there is no evidence to suggest a prebiotic formation of the open-chain tetrapyrryl compounds. Furthermore, algal pigments are of the IXa configuration, thus indicating a probable origin from heme(s) [24, 25] or chlorophyll. Hodgson [10] noted that the porphyrins generated in his discharge system (methane-ammonia-water atmosphere) exhibited a fairly ready solubility in water, possibly due to carboxylic side chains. This observation at least suggests the presence of (polar) beta substituents on the porphine ring, as in the porphyrins of living organisms. If, as mentioned in the foregoing, porphyrin biosynthesis recapitulates prebiotic synthesis, the presence of the hydrophilic uroporphyrin(s) might be anticipated. Actually, prebiotic porphyrins or porphyrins formed under simulated prebiotic conditions, such as those of Hodg444 I 7- J. Petryka and C. J. Watson · Prebiotic Porphyrins son, have...

Studies on phenazines. 28. Nuclear magnetic resonance studies. II. Ring protons of halogenophenazines and methyl, methoxylprotons of substituted phenazines.

The NMR spectra of chlorophenazines were measured and analyzed as the one of representative examples of substituted phenazines. Comparing with previously reported methoxyphenazines, ring protons of chlorophenazines showed weakly influenced signal patterns in which the anisotropic effects of chlorine atoms were observed in opposite sign to the methoxyl's. The significant abnormality in its shielding power of beta substituent on phenazine ring is conceivable to propose an additional interest for clarification of the reactivity and the polarizability of beta substituent. Concerning to the reactivity of substituent, methyl and methoxyl proton shifts of alpha and beta substituted phenazines were examined giving explicit descrimination in their absorption region as were seen in ring protons.