Spatially addressable

In the future, further studies should be addressed to improve the chemose-lectivity and diastereoselectivity of the reductive coupling process, especially searching for novel reagents and milder experimental conditions. As a matter of fact, a few novel reductive couphng procedures which showed improved efficiency and/or stereoselectivity have not been further apphed to optically active imines. For example, a new electrochemical procedure which makes use of the spatially addressable electrolysis platform with a stainless steel cathode and a sacrificial aluminum anode has been developed for imines derived from aromatic aldehydes, and the use of the N-benzhydryl substituent allowed 1,2-diamines to be obtained with good yields and dl-to-meso ratios... 

Fodor, S. P. (1991). Light-directed, spatially addressable parallel chemical synthesis. Science 251, 767-773. 

In a different approach three different structurally defined aza-crown ethers were treated with 10 different metal salts in a spatially addressable format in a 96-well microtiter plate, producing 40 catalysts, which were tested in the hydrolysis of /xnitrophenol esters.32 A plate reader was used to assess catalyst activity. A cobalt complex turned out to be the best catalyst. Higher diversity is potentially possible, but this would require an efficient synthetic strategy. This research was extended to include lanthanide-based catalysts in the hydrolysis of phospho-esters of DNA.33... 

Several combinatorial approaches to the discovery of transition metal based catalysts for olefin polymerization have been described. In one study Brookhart-type polymer-bound Ni- and Pd-(l,2-diimine) complexes were prepared and used in ethylene polymerization (Scheme 3).60,61 A resin-bound diketone was condensed with 48 commercially available aminoarenes having different steric properties. The library was then split into 48 nickel and 48 palladium complexes by reaction with [NiBr2(dme)] and [PdClMe(COD)], respectively, all 96 pre-catalysts being spatially addressable. 

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

As first practiced by Geysen and Houghton, the preparation of combinatorial libraries produced discrete compounds of known identity through a technique known as "spatial separation," which simply means that individual compounds in the library are produced discretely and are not mixtures. Such spatially addressable compound sets are produced in such a way as to keep separate the reaction flasks or resin beads containing the individual components of the library and perform bioassays on the discrete compounds, one at a time. Thus, if the "history" of the reaction conditions performed in each flask or on each solid support, the identity of the compounds produced is known, without resort to structure elucidation techniques. Initially, this technique, after typically an extensive reaction development stage, allowed the preparation of between 10 and 1000 discrete combinatorial products. 

Parallel synthesis is the term loosely applied to the preparation of discrete compounds in the format of a spatially addressable array. It is often used in contrast to "mixture-based" combinatorial synthesis. While it is hue that the term "parallel synthesis" may encompass the preparation of a fully combinatorial multidimensional array of compounds, in practice, it most... 

Their components are produced typically in a spatially addressable format requiring no deconvolution or encoding strategies for identification of active components making for very quick analysis of SAR. 

Pirrung, M.C., Spatially addressable combinatorial libraries, Chem. Rev., 1997, 97, 473-488. 

Direct electrochemical amide oxidation reactions have also been employed in parallel synthesis using a spatially addressable electrochemical platform [107]. In this work, an electrolysis platform was set up so that 16 electrochemical reactions could be run in parallel at the same time. The cells were set up in a 4 by 4 array in which each cell was equipped with a... 

In-situ photofabrication of OND arrays involves light-directed, spatially addressable, parallel (combinatorial) chemical synthesis [35,43,66-68]. A surface, usually a sihcon wafer or a glass slide, is coated with hnker molecules... 

Other terms also relate to the anatomy of the microarray (Figure 1.4). The probes are immobilized on the substrate at discrete (x, y) locations or spatially addressable sites. The probe spots [measured in microns (diameters) for a circular spotted array or as a side of a square for an in situ array] are often referred to as features or elements of an array. Thus, an array containing 10,000 features would have 10,000 probes arranged as an array on a substrate. 

I-odor. S P A. 01 at. "Light-Directed. Spatially Addressable Parallel Chemical Synthesis.". Vcienee, 767 (February IS. 19911 Jam>ld. M.F. "Nanosurfaee Clietnisiry on Size-Selected Silicon C liniers." Seitner. 1085 tMay 14. 1991). 

Scharn, D., Wenschuh, H., Reineke, U., Schneider-Mergener, J. and Germeroth, L., Spatially addressed synthesis of amino- and amino-oxy-substituted 1,3,5-triazine arrays on polymeric membranes, /. Comb. Chem., 2000, 2, 361. 

An alternative method for tracking the chemical history is encoding by spatial address. The identity of each entity is defined by its spatial address. A one-dimensional directed split-and-pool procedure, referred to as necklace coding, has been developed for synthesis carried out on SynPhase Crowns and Lanterns.13 Individual supports are strung on a Teflon thread and the position of a particle on the thread (necklace) encoded the previous chemical history (Fig. 1). A similar concept was later reported by Furka and co-workers14,15 Two-and three-dimensional encoding of the directed split-and-pool synthesis platform has been patented by Selectide Corp.16... 

In Scheme 9.4, a three-component synthesis using an amine, acid chloride, and alkyl halide is shown. If this process were started with two amines (Ai and A2), two acid chlorides (Cj and C2), and two alkyl halides (Hj and H2), eight (23) new amides may be formed (Scheme 9.5). Such a synthesis would require eight wells. The reagents would be dispensed in a pattern to generate all possible combinations. At the end of the synthesis, the exact position and contents of each well would be known. Therefore, parallel synthesis is often referred to as a spatially addressable method. Any particular compound may be accessed directly and immediately. 

Regardless of how the products are isolated and purified, all parallel syntheses hold to the concepts of one compound-one well and spatial-addressability. Differences between various parallel syntheses are discemable based on whether the synthesis is performed in a solution-phase or solid-phase manner. 

At the end of a split synthesis, because the beads have been pooled and mixed, the exact identity of a molecule on a given bead is unknown. Likewise, the identity and structure of compounds in wells is unknown. Split synthesis is not a spatially addressable method. Fortunately, the exact structure does not need to be known unless a compound shows activity in a screen. If active, the structure of the compound in the well will need to be elucidated through a process called deconvolution. Deconvolution is generally accomplished through one of two methods recursive deconvolution21 or binary encoding.22... 

The use of planar supports for presenting large arrays of spatially addressed molecules is one of the most powerful and versatile methods for creating combinatorial libraries.19,28-29... 

FIGURE 6.3. (a) A schematic representation of a 2 X 2 array of addressed supported fluid biomembranes with various components in each box. The right-hand side (b) An epifluorescence image of a 3 x 3 array of fluid biomembranes that have been addressed using the spatial addressing techniques described above. 

The experiments described above demonstrate the ability to deliver soluble analytes to bilayer arrays and to evaluate the ability of these species to prevent surface absorption of proteins. Therefore, we have demonstrated methods of creating spatially addressed arrays of aqueous solutions above phospholipid membranes as well as arrays of phospholipid membranes with unique chemistry in each bilayer.13 These two concepts were carried out in separate assays. To be able to control both surface chemistry and aqueous chemistry... 

FIGURE 6.8. (a) Schematic diagram of bilayer coated PDMS microchannels on a planar glass substrate. The bilayer coats both the glass and polymer surfaces. Protein solutions can then be injected into the channels as indicated by the arrows, (b) Epifluorescence image of a spatially addressed array of eight Egg PC bilayer coated microchannels. The channels are alternately coated with bilayers containing 1 mol% Texas Red and 3 mol% fluorescein labeled lipids. 

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