Open-chain Precursor Research Articles

On-Surface Pseudo-High-Dilution Synthesis of Macrocycles: Principle and Mechanism.

Macrocycles have attracted much attention due to their specific "endless" topology, which results in extraordinary properties compared to related linear (open-chain) molecules. However, challenges still remain in their controlled synthesis with well-defined constitution and geometry. Here, we report the successful application of the (pseudo-)high-dilution method to the conditions of on-surface synthesis in ultrahigh vacuum. This approach leads to high yields (up to 84%) of cyclic hyperbenzene ([18]-honeycombene) via an Ullmann-type reaction from 4,4″-dibromo-meta-terphenyl (DMTP) as precursor on a Ag(111) surface. The mechanism of macrocycle formation was explored in detail using scanning tunneling microscopy and X-ray photoemission spectroscopy. We propose that the dominant pathway for hyperbenzene (MTP)6 formation is the stepwise desilverization of an organometallic (MTP-Ag)6 macrocycle, which forms via cyclization of (MTP-Ag)6 chains under pseudo-high-dilution conditions. The high probability of cyclization on the stage of the organometallic phase results from the reversibility of the C-Ag bond. The case is different from that in solution, in which cyclization typically occurs on the stage of a covalently bonded open-chain precursor. This difference in the cyclization mechanism on a surface compared to that in solution stems mainly from the 2D confinement exerted by the surface template, which hinders the flipping of chain segments necessary for cyclization.

Cyanobacterial ent-Sterol-Like Natural Products from a Deviated Ubiquinone Pathway.

Natural products from marine animals show high potential for the development of new medicines, but drug development based on these compounds is commonly hampered by their low natural abundance. Since many of these metabolites are suspected or known to be produced by uncultivated bacterial symbionts, the rapidly growing diversity of sequenced prokaryotic genomes offers the opportunity to identify alternative, culturable sources of natural products computationally. In this work, we investigated the potential of using this sequenced resource to facilitate the production of meroterpenoid-like compounds related to those from marine sources. This genome-mining strategy revealed a biosynthetic gene cluster for highly modified cytotoxic meroterpenoids related to pelorol and other compounds isolated from sponges. Functional characterization of the terpene cyclase MstE showed that it generates an ent-sterol-like skeleton fused to an aryl moiety from an open-chain precursor and is therefore a promising tool for the chemoenzymatic preparation of synthetically challenging chemical scaffolds.

Total Synthesis of Nannocystin A.

Nannocystin A is a 21-membered cyclodepsipeptide showing remarkable anticancer properties. Described is the total synthesis of nannocystin A, which features an asymmetric vinylogous Mukaiyama aldol reaction for efficient assembly of the penultimate open-chain precursor and a pivotal intramolecular Heck cross-coupling for the final macrocyclization.

Macrocycle Synthesis by Chloride-Templated Amide Bond Formation.

A new family of pseudopeptidic macrocyclic compounds has been prepared involving an anion-templated amide bond formation reaction at the macrocyclization step. Chloride anion was found to be the most efficient template in the macrocyclization process, producing improved macrocyclization yields with regard to the nontemplated reaction. The data suggest a kinetic effect of the chloride template, providing an appropriate folded conformation of the open-chain precursor and reducing the energy barrier for the formation of the macrocyclic product.

The Role of the Amino Acid-Derived Side Chain in the Preorganization of C2-Symmetric Pseudopeptides: Effect on SN2 Macrocyclization Reactions

A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br(-) has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds.

Synthesis of Cyclic Polystyrenes Using Living Anionic Polymerization and Metathesis Ring-Closure

A combination of living anionic polymerization and metathesis ring-closure provides an efficient method for synthesis of well-defined, macrocyclic polymers over a broad molecular weight range. A series of well-defined, α,ω-divinylpolystyrene precursors (Mn = 2800, 8600, 17000, and 38000 g/mol) were synthesized by 4-pentenyllithium-initiated polymerization of styrene followed by termination with 4-chloromethylstyrene. Efficient cyclization of these α,ω-divinylpolystyrene precursors was effected in CH2Cl2 and CH2Cl2/cyclohexane mixtures using a Grubb’s catalyst, bis(tricyclohexylphosphine)benzylidine ruthenium(IV) chloride. As the precursor Mn increased, more cyclohexane was added and the concentration of the precursor was decreased from 1.41 × 10–4 to 2.15 × 10–6 M. The macrocyclic polymers were uniquely characterized by MALDI–TOF mass spectrometry in terms of peaks that appeared characteristically 28 m/z units lower than those of the corresponding open-chain precursor peaks, corresponding to the loss of an ethylene unit. Relative to linear analogues, the macrocycles exhibited longer SEC retention volumes, lower intrinsic viscosities, and higher Tgs at the lower Mn values.

First Total Synthesis of the Marine Natural Product Viscosamine

Pyridinium alkaloids are widely distributed in marine sponges of the order Haplosclerida. The cyclic trimeric 3-alkylpyridinium alkaloid viscosamine, from the Arctic sponge Haliclona viscosa, was synthesised through a ten-step synthesis starting from pyridylalcohol in 8% overall yield. Key steps involved the simultaneous activation and deprotection of an open chain precursor, followed by cyclisation under highly dilution conditions. Viscosamine is the first cyclotrimeric 3-alkylpyridinium natural product obtained by total synthesis.

Facile Intramolecular Cyclization in Oxidative Coupling of Acetylenes Linked to 1,3-Positions of Benzene: Strained [12]Metacyclophanedienetetrayne System

Oxidative coupling of ethynylpropellane linked to 1,3,5-position of a benzene core 3b did not give the cage dimer 2 but the dimer 4 having a strained [12]metacyclophanedienetetrayne system. The spectral and structural features of the novel ring system were revealed for the simple dibenzo derivative 6, which was also prepared efficiently by the intramolecular cyclization of the open-chain precursor.

Detours en route to a total synthesis of (+)-cassiol

A synthesis of the antiulcerogenic compound (+)-cassiol 1b has been achieved in 43% yield starting with lactol ( S)- 2 and sulfone 26. This short and efficient synthesis features the one-pot Julia olefination reaction of the sodium anion of ( S)- 2 with 26, through the key intermediate (−)- 9. This synthesis has been developed as a result of exploratory experiments including different olefination reactions on 2. An attempt to synthesize the intermediate 9 by an intramolecular aldol condensation approach of the open chain precursor 4 is also described.

De novo synthesis of a methylene-bridged Neu5Ac-alpha-(2,3)-gal C-disaccharide.

A general strategy toward the synthesis of C-ketosides of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of methylene-bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2. The key strategic element of this novel approach is a stereoselective, 6-exo-trig selective, electrophilic cyclization of the appropriate open chain precursor 4 by means of phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18 accessible from D-galactose to open chain aldehyde 5a obtained from D-glucono-delta-lactone by chain elongation. Subsequent C1-incorporation using Tebbe-reagent, formation of a cyclic carbonate, and deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with phenylselenyl triflate, was stereoselectively cyclized in a 6-exo-trig selective manner. A selena-Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after deacetylation, could be regioselectively tetrabenzoylated with benzoyl cyanide. Triflate activation of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of configuration afforded azide 41, which was reduced with hydrogen and Pearlman's catalyst. Concomitant removal of the benzyl ethers and subsequent saponification of all ester moieties successfully completed the de novo synthesis of the desired methylene bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2.

Biosynthetic Studies on the α-Glucosidase Inhibitor Acarbose in Actinoplanes sp.: 2-epi-5-epi-Valiolone Is the Direct Precursor of the Valienamine Moiety

The biosynthetic pathway leading to the mC7N cyclitol (valienamine) moiety of acarbose (1) in Actinoplanes sp. strain SN 223/29 has been studied using 3H-, 2H-, and 13C-labeled cyclitols. These precursors were synthesized from d-glucose or d-mannose as starting materials. The feeding experiments demonstrated that cyclitols having the same stereochemistry at C-2 as the valienamine moiety of acarbose; i.e., valienone, valienamine, valiolone, valiolamine, and 1-epi-valienol, were not incorporated and thus are not plausible intermediates in 1 biosynthesis. 2-epi-Valiolone (10b), which has the same stereochemistry as the presumed open-chain precursor, sedoheptulose 7-phosphate, was also not incorporated. However, its C-5 epimer (10a) was incorporated efficiently and specifically into the valienamine moiety of 1. Surprisingly, the dehydrated form of 2-epi-5-epi-valiolone, 2-epi-valienone, was not incorporated. This suggests that 2-epi-5-epi-valiolone must be converted directly into the pseudodisaccharide moiety of acarbose without the intervention of other free cyclitol intermediates. This may occur by linkage to the amino group of TDP-4-amino-4,6-dideoxyglucose to form the imine, epimerization at C-2 to the correct stereochemistry, dehydration between C-5 and C-6 aided by enamine formation, and finally reduction to the amine. It is proposed that these reaction steps all take place on a single enzyme without free intermediates. Alternative mechanistic possibilities are also discussed.

Ladder-type materials

Materials with a ribbon- or ladder-type framework possess a two-dimensional geometry and are thus intermediate between linear and three-dimensional systems. The limited conformational freedom of ladder polymers is particularly relevant in the case of conjugated ladder-type materials since the steric inhibition of electron delocalization is drastically reduced.Up until today two general routes have been used to prepare ladder-type materials: (1) the polymerisation of multifunctional monomers, in which both strands of the ladder structure are generated in a single reaction; and (2) the cyclisation of suitably functionalized open-chain (single-stranded) precursor polymers in a polymer-analogous process. Both strategies pre-suppose certain essentials to arrive at structurally defined ladder polymers, especially the exclusion of side-reactions and an almost quantitative conversion of the starting materials.The main attention of this article is focused on an active physical function of ladder-type materials. Among others, ladder-type poly( p-phenylene)s (LPPPs) represent an outstanding class of ladder-type materials. They are characterized by an extraordinarily low concentration of active traps (topological defects, impurities) and display a set of attractive electronic properties (very intensive photo- and electroluminescence, high charge carrier mobilities). This unique performance has established the solution processable LPPPs as standard materials for organic polymer based light emitting diodes (LEDs) and optically pumped solid state lasers.

The electron impact and fast atom bombardment mass spectrometry of aziridines and their 2-chloroethylamine precursors

A mass spectrometric method for the analysis of aziridines and their 2-chloroethylamine precursors is described. These compounds are characterized by their highly labile interconvertible nature. The capabilities of electron impact and fast atom bombardment (FAB) mass spectrometry as ionizaton techniques for structure confirmation studies were explored. A new technique using FAB mass spectrometry to distinguish between an aziridine and its open-chain precursor is described.

The photofragmentation of naphthalene and azulene monocations in the energy range 7–22 eV

Photoion mass spectrometry was used to study the fragmentation of naphthalene and azulene monocations over the excitation energy range 7–22 eV. Fifteen fragmentation processes in naphthalene and twelve in azulene have been examined in detail. The photoionization mass spectra at 20.58 eV are quasi-identical for the two isomers. This, and the constant value of the difference between the fragment appearance energies (AE) for naphthalene and azulene, equal to the difference in the heats of formations of the neutral parents, suggest that identical products are formed. The unimolecular dissociations fall mainly into (i) a “low energy” group, (AE<16 eV) and (ii) a “high energy” group (AE > 18 eV). The reactions in (i) have in common the bicyclic precursor C 10H + 8 ion 18 which decays via rupture of one ring. The group (ii) reactions involve rupture of both rings to give an open chain precursor, the 1,6-bis-ethinyl-hexatriene radical cation 20. Thermodynamic and mechanistic arguments are given to propose specific reaction pathways and product structures. Two general schemes rationalize the low-energy and high-energy ionic decompositions.

Calyculin synthetic studies. Stereoselective construction of the C(14)-C(25) spiroketal subunit

A convergent, stereocontrolled synthesis of the spiroketal fragment of calyculins A-H has been achieved. Key transformations include the noel iodine monobromide-induced iodocarbonate cyclization of (+)- 19, efficient coupling epoxide (+)- 4 with the sterically hindered dithiane 15, and a multi-step, one-pot conversion of open-chain precursor (−)- 13 to spiroketal (+)- 11.

Synthesis and characterization of new electroactive polymers

Optical quality thin films of polyquinoxaline ladder polymers have been prepared by thermal treatment of open-chain precursor polymers derivatized with a variety of substituents to improve solubility. Polycondensation synthesis is employed to avoid problems of polymer branching and disorder. Both alkyl derivatization which improves solubility with little effect upon electronic properties and derivatization with vinylamine side groups which influences both physical and electronic properties are discussed. The planar conformation of ladder polymers optimizes π-orbital overlap; thus, large optical nonlinearities are anticipated. Third order susceptibilities as high as 3 x 10 −9 esu for pristine polymers have been measured by degenerate four wave mixing and third harmonic generation.

Synthetic studies relevant to biosynthetic research on vitamin B12. Part 9. Synthesis of 20-methyl and 20-cyano isobacteriochlorins

Isobacteriochlorins carrying a C-methyl group at C-20 of the macrocycle are important for research on the biosynthesis of vitamin B12. Several different approaches are studied which allow the introduction of a C-20 methyl group into model isobacteriochlorins, the most successful involving the stepwise reduction of a nitrile residue to a methyl group. Successful syntheses are described of two 20-methylisobacteriochlorins and two 20-cyanoisobacteriochlorins. All the routes used depend finally on the photochemical cyclisation of an 18π-electron open-chain precursor.

Preparation and properties of azopolyimides‐I

AbstractA new class of aromatic and heterocyclic polyimides were synthesized from benzothiazoleamines benzidine, 4,4′‐diaminodiphenyl ethane and 4,4′‐diamino diphenyl sulfone with 4,4′‐azodipthalic anhydride and/or pyromellitic dianhydride. The synthesis involved the reaction of the dianhydride with the respective diamine to yield an intermediate, soluble, open chain precursor polymer, the polyamic acid, which on cyclodehydration yielded the less soluble, heat resistant polyimides. All these polyimides were characterized by IR and NMR. Solubility, density, viscosity, and thermal stability of these polymers were also studied.

Human calcitonin. V. Synthesis and characterization of the protected calcitonin M-(1-10)-decapeptide

AbstractThe present report describes in detail the synthesis and characterisation of the protected Calcitonin M decapeptide 1–10, , a key intermediate in the synthesis of Calcitonin M. I. was obtained from the openchain precursor Boc‐Cys (Trt)‐Gly‐Asn‐Leu‐Ser (But)‐Thr (But)‐Cys (Trt)‐Met‐Leu‐Gly‐OH (II) by oxidation with iodine in a yield of 70%, after purification by counter‐current distribution.II was prepared by fragment coupling of the sequences 1–4 and 5–10.The free calcitonin M (1–10)‐decapeptide, obtained from I by removal of the protecting groups by acidolysis, has no hypocalcaemic activity and does not inhibit specific binding of calcitonin M to its antibodies in rabbit serum.

Cyclopolycondensations. VIII. New Thermally Stable Aromatic Polybenzoxazinones by Solution Polymerization in Polyphosphoric Acid

Abstract High molecular weight polybenzoxazinones have been prepared by cyclo-polycondensation reaction of 4,4′-diamino-3,3′-biphenyldicarboxylic acid with a variety of aromatic carbonyl compounds using a solution polymerization technique in polyphosphoric acid. From the model reactions of anthranilic acid, and 4,4′-diamino-3,3′-biphenyldicarboxylic acid with benzoyl chloride in polyphosphoric acid, it is established that the cyclopolycondensation proceeds through the formation of an open-chain tractable precursor, polyamic acid of high molecular weight (ninh = 2.66) in the first step, which subsequently undergoes thermal or chemical cyclodehydration along the polymer chain, to yield, in the second step, a fully aromatic polybenz-oxazinone. Polybenzoxazinones thus obtained have excellent thermal stability both in nitrogen and in air. The optimum polymerization conditions for obtaining polyamic acid of high molecular weight are determined by the study of reaction variables such as polymerization temperatur...