Chemoselective multicomponent one-pot assembly of purine precursors in water

The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination.     

Multicomponent assembly of cavitand-based polyacylhydrazone nanocapsules

The thermodynamically controlled syntheses of different di-, tetra-, and hexacavitand polyacylhydrazone nanocapsules are reported. [2+4]-, [4+8]-, and [6+12]-nanocapsules assemble upon reacting a tetraformyl cavitand with two equivalents of isophthalic dihydrazide, or terephthalic dihydrazide in the presence of trifluoroacetic acid, whereby the building blocks are linked together through 8, 16, or 24 newly formed acylhydrazone bonds. Futhermore, the reaction of the tetraformylcavitands with different trigonal planar trihydrazides, simultaneously leads to the formation of [2+4]- and [6+8]-nanocapsules in varying ratios that depend on the cavitand to trihydrazide ratio and the nature of the cavitand and trihydrazide building blocks. The product ratios are rationalized with the different conformational strain of the acylhydrazone linkages in these nanocapsules. Diffusion NMR experiments with the hexacavitand polyacylhydrazone nanocapsules yield solvodynamic radii that range from 1.6 to 2.5 nm, consistent with estimates from force field calculations, and support, that these capsules have solvent filled, spherical interiors, the sizes of which approaches those of smaller proteins.     

Multicomponent assembly of boron-based dendritic nanostructures

A new synthetic strategy for the construction of boron-based macrocycles and dendrimers is described. Condensation of aryl- and alkylboronic acids with 3,4-dihydroxypyridine is shown to give pentameric macrocycles in which five boronate esters are connected by dative B-N bonds. Three macrocycles have been characterized crystallographically. The boron atoms of these assemblies represent chiral centers, and the assembly process is highly diastereoselective. Attachment of amino or aldehyde groups in the meta position of the arylboronic acid building blocks does not interfere with macrocyclization. This allows performing multicomponent assembly reactions between functionalized boronic acids, dihydroxypyridine ligands, and amines or aldehydes, respectively. Reaction of 3,5-diformylphenylboronic acid, 3,4-dihydroxypyridine, and a primary amine R-NH2 (R=Ph, Bn) gives dendritic nanostructures having a pentameric macrocyclic core and 10 amine-derived R groups in their periphery. Combination of 3,5-diformylphenylboronic acid with 2,3-dihydroxypyridine and the dendron 3,5-(benzyloxy)benzylamine, on the other hand, results in formation of a dendrimer with a tetrameric macrocyclic core and eight dendrons in its periphery.     

Multicomponent dynamic covalent assembly of a rhombicuboctahedral nanocapsule

Molecular container compounds have a range of potential applications in chemical and biological sciences, most notably as nanoreactors, drug delivery devices, and storage materials. We report a highly efficient dynamic covalent chemistry approach for the synthesis of covalent rhombicuboctahedral nanocapsule 1 from 14 square- and triangular-shaped molecular components. The nanocapsule is obtained in a one-pot reaction in high yield and high purity, and has a solvodynamic diameter of 3.9 nm. In our approach, six formyl cavitands and eight 1,3,5-tris(p-aminophenyl)benzene molecules are assembled into a molecular rhombicuboctahedron through twenty four newly formed dynamic imine bonds. Binding studies show that 1 encapsulates tetraalkylammonium salts in toluene. We also discuss the growth mechanism of this nanocapsule.     

Multicomponent reactions are accelerated in water

Two multicomponent reactions, the Ugi and Passerini reactions, are accelerated by the use of aqueous solutions. The rate enhancements compared to those by organic solvents can approach 300-fold. Reactions performed in water offer another advantage that products are often insoluble, permitting direct isolation by precipitation. The methods were applied to the preparation of three small combinatorial libraries.     

Bioconversion of proposed precursors into theobroxide and related compounds

We have previously reported a tetraketide origin for theobroxide and its related compound. In the present study, bioconversion of natural and deuterium-labeled precursors of this proposed biosynthetic pathway by Lasiodipoldia theobromae was investigated. Theobroxide was quantified after bioconversion from each proposed precursor. The transformation of the isotopically labeled precursor to products was tracked by 2H NMR measurement.     

Multicomponent assembly strategies for the synthesis of diverse tetrahydroisoquinoline scaffolds

Several novel multicomponent assembly processes have been developed for the rapid and efficient assembly of various heterocyclic scaffolds bearing a tetrahydroisoquinoline core, each of which allows for facile derivatization to access a diverse array of compounds. This work led to the serendipitous discovery of a new method for the synthesis of a fused quinazolone ring system, which was applied to a one-step total synthesis of the quinazolinocarboline alkaloid rutaecarpine.     

Supramolecular DNA assembly

The powerful self-assembly features of DNA make it a unique template to finely organize and control matter on the nanometre scale. While DNA alone offers a high degree of fidelity in its self-assembly, a new area of research termed 'supramolecular DNA assembly' has recently emerged. This field combines DNA building blocks with synthetic organic, inorganic and polymeric structures. It thus brings together the toolbox of supramolecular chemistry with the predictable and programmable nature of DNA. The result of this molecular partnership is a variety of hybrid architectures, that expand DNA assembly beyond the boundaries of Watson-Crick base pairing into new structural and functional properties. In this tutorial review we outline this emerging field of study, and describe recent research aiming to synergistically combine the properties inherent to DNA with those of a number of supramolecular scaffolds. This ultimately creates structures with numerous potential applications in materials science, catalysis and medicine.     

Multicomponent assembly and diversification of novel heterocyclic scaffolds derived from 2-arylpiperidines

A collection of structurally diverse, polyheterocyclic scaffolds comprising a 2-arylpiperidine subunit were synthesized using a Mannich-type multicomponent assembly process, followed by appropriately sequenced ring-forming reactions. An improved procedure for removal of N-4-pentenoyl groups was developed; one-pot sequences for tandem urea/thiourea formation and cyclization and tandem enolate arylation/alkylation were discovered. A novel entry to bridged tetrahydroquinoline scaffolds exploiting A(1,3) strain was also invented. Derivatization of several scaffolds was achieved by cross-coupling and N-functionalization.     

Multicomponent assembly of anionic and neutral decanuclear copper(II) phosphonate cages

A multicomponent synthetic strategy involving copper(II) ions, tert-butylphosphonic acid (t-BuPO(3)H(2)) and 3-substituted pyrazole ligands has been adopted for the synthesis of soluble molecular copper(II) phosphonates. The use of six different 3-substituted pyrazoles, 3-R-PzH [R = H, Me, CF(3), Ph, 2-pyridyl (2-Py), and 2-methoxyphenyl (2-MeO-C(6)H(4))] as ancillary ligands afforded nine different decanuclear cages, [Cu(5)(μ(3)-OH)(2)(O(3)P-t-Bu)(3)(3-R-Pz)(2)(X)(2)](2)·(Y) where R = H, X = t-BuPO(3)H, and Y = (Et(3)NH(+))(4)(solvent) (1); R = Me, X = 3-MePzH, and Y = solvent (2); R = Me, X = t-BuPO(3)H, and Y = (Et(3)NH(+))(4)(solvent) (3); R = CF(3), X = t-BuPO(3)H, and Y = (Et(3)NH(+))(4)(solvent) (4); R = Ph, X = 3-PhPzH, and Y = solvent (5); R = 2-Py, X = 0.5 MeOH, and Y = solvent (6); R = 2-Py, X = none, and Y = solvent (7); R = 2-Py, X = H(2)O, and Y = (Et(3)NH(+)·PF(6)(-))(2)(solvent) (8); R = 2-MeO-C(6)H(4), X = MeOH or 0.5:0.5 MeOH/H(2)O, and Y = solvent (9). Compounds 1-6, 8, and 9 were isolated using a direct synthetic method which involves the reaction of copper(II) salts and the ligands, while 7 was obtained from an indirect route involving the reaction of preformed copper-pyridylpyrazolate precursor complexes and t-BuPO(3)H(2). The decametallic compounds 1-9 possess a butterfly shaped core. The core of the cages 1, 3, and 4 are tetraanionic and contain more phosphonates than pyrazole ligands, while the other cages are neutral and contain more pyrazoles than phosphonate ligands. Compounds 1-6 have been studied by electrospray ionization-high-resolution mass spectrometry (ESI-HRMS). The decanuclear cage 6 was shown to be a good plasmid modifier.     

Multicomponent reactions for the synthesis of new cyclopentadienephosphonate derivatives in water

A series of polysubstituted cyclopentadienephosphonate derivatives were synthesized via one-pot multicomponent reactions of primary amines and phosphites with activated acetylenic compounds in water as the solvent at room temperature.

Particularly valuable features of this method include high yields of products, broad substrate scope, short reaction time and a straightforward procedure.     

Multicomponent analysis of drinking water by a voltammetric electronic tongue

A voltammetric electronic tongue is described that was used for multicomponent analysis of drinking water. Measurements were performed on drinking water from a tap and injections of the compounds NaCl, NaN₃, NaHSO₃, ascorbic acid, NaOCl and yeast suspensions could be identified by use of principal component analysis (PCA). A model based on partial least square (PLS) was developed for the simultaneously prediction of identification and concentration of the compounds NaCl, NaHSO₃ and NaOCl. By utilizing this type of non-selective sensor technique for water quality surveillance, it will be feasible to detect a plurality of events without the need of a specific sensor for each type of event.     

New potentialities of electrophilic addition in the assembly of polyfunctional compounds from simple precursors

A novel methodology of the multicomponent coupling based on the controlled sequence of the kinetically independent electrophilic additions is suggested and its promise as an efficient protocol for the short synthesis of the structurally diverse polyfunctional compounds from simple precursors is demonstrated.     

Multicomponent,Mannich-type assembly process for generating novel,biologically-active 2-arylpiperidines and derivatives

A multicomponent, Mannich-type assembly process commencing with commercially available bromobenzaldehydes was sequenced with [3+2] dipolar cycloaddition reactions involving nitrones and azomethine ylides to generate collections of fused, bicyclic scaffolds based on the 2-arylpiperidine subunit. Use of the 4-pentenoyl group, which served both as an activator in the Mannich-type reaction and a readily-cleaved amine protecting group, allowed sub-libraries to be prepared through piperidine N-functionalization and cross-coupling of the aryl bromide. A number of these derivatives displayed biological activities that had not previously been associated with this substructure. Methods were also developed that allowed rapid conversion of these scaffolds to novel, polycyclic dihydroquinazolin-2-ones, 2-imino-1,3-benzothiazinanes, dihydroisoquinolin-3-ones, and bridged tetrahydroquinolines.     

Ligand inducible assembly of a DNA tetrahedron

Here we show that a small synthetic ligand can be used as a key building component for DNA nanofabrication. Using naphthyridinecarbamate dimer (NCD) as a molecular glue for DNA hybridization, we demonstrate NCD-triggered formation of a DNA tetrahedron.