Parallel syntheses

3 Parallel Synthesis. Frank s group later turned its attention to peptide synthesis and applied the paper disk method to the synthesis of peptides. Methods of 

PRACTICAL ASPECTS OF COMBINATORIAL SOLID-PHASE SYNTHESIS 

Paper as a solid support fascinated Frank, and he later developed another unique and ingenious technique, the spot synthesis (SPOT). In SPOT synthesis, peptides are synthesized on functionalized membrane sheets as spots that could be as large as 10 mm or as small as 1 mm. The spot synthesis technique became a popular tool for peptide synthesis and was soon automated. The first semiautomated SPOT synthesizer, the ASP222, was launched by ABIMED Analysen-Technik of Germany in 1993. The automated method provided an economical way to synthesize very large numbers of peptides. The Intavis synthesizer Auto-Spot (www.intavis.com) allowed the simultaneous synthesis of 1600 peptides. The chemical and physical problems associated with the use of cellulose sheets as synthesis support were, for the most part, overcome by developing synthetic membranes from polypropylene and Teflon.  

The first synthesized array contained 1024 peptides in a 32 x 32 grid, with each peptide residing in a 400 pm x 400 0m area. In addition to peptides and oligonucleotides, light-directed synthesis has also been applied to prepare arrays of oligocarbamates.  

These discoveries introduced the combinatorial concept to the chemical society however, the scientific community in general had begun to accept the new combinatorial 

Combinatorial synthesis on solid supports is usually carried out by using either the parallel synthesis (see section 6.2.1) or the Furka split and mix procedures (see section 6.2.2). The precise method and approach adopted when using these methods will depend on the nature of the combinatorial library being produced and also the objectives of the investigating team. However, in all cases it is necessary to determine the structures of the components of the library by either keeping a detailed record of the steps involved in the synthesis or giving beads a label that can be decoded to give the structure of the compound attached to that bead (see section 6.3). The method adopted to identify the components of the library will depend on the nature of the synthesis. 

The grid consists of an array of wells sunk in a plastic plate 

One form of combinatorial chemistry involves parallel synthesis or array synthesis. In parallel synthesis, each new compound is formed in its own miniature reactor or well. If a new library is to contain 500 members, synthesis of the library will require 500 wells in the final step. For this reason, parallel synthesis is associated with the phrase one compound-one well. 

Managing a large number of individual reactions can be cumbersome. Reactions are often automated with a robotic liquid handler to minimize the tedium. The liquid handler does exactly what its name implies it dispenses solutions of reagents into racks of wells. Multiple racks are placed on the deck of the liquid handler. Some racks hold wells for reactions, and other racks hold solvents or solutions of reagents. The positions of all the reaction wells and solutions are programmed into a computer. The computer then directs a robotic arm. The robotic arm is suspended over the deck where it takes up and dispenses solvents and reagents as needed. 

The racks can include a number of features, including the ability to heat and cool the reaction as well as to exclude air and moisture. Furthermore, a liquid handler can also 

SCHEME 9.5 Parallel synthesis of an eight-member library 

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. 

Multiple nucleotide/peptide/saccharide synthesis refers to the simultaneous (parallel) synthesis of a multitude of nucleotide/peptide/saccharide sequences, irrespective of the chain 

This issue highlights the characterization difference between parallel synthesis and combinatorial synthesis. Parallel synthesis is automated traditional organic chemistry. Each compound is made in a separate reactor, purified and characterized. There is no excuse for not fully characterizing compounds made by parallel synthesis. Jonathan Ellman s laboratory at UC Berkeley has been a pioneering academic center for solid-phase chemistry development. His philosophy is to synthesize libraries of discrete compounds in a spatially separate fashion, rather than libraries of compound mixtures, to allow for rigorous analytical characterization [48,49], 

What parallel synthesis does is put a new burden on analytical throughput to keep up with the productivity of the automated synthesis laboratory. To illustrate the issue, Fig. 5 shows the increase in mass spectrometry samples analyzed at Affymax over the last 2 

NMR has trouble keeping up with these sampling requirements and should be used more selectively for new chemistry development and where thorough stereochemical outcomes are in question. Future developments in coupled LC/NMR may allow for fast, flow-injection NMR [52], 

Split/pool solid-phase libraries and solution-phase pools 

The quality control of larger libraries must take a systems approach [2], Building blocks must be checked rigorously [60], Chemistries must be extensively rehearsed with single compounds and small model libraries of a size where HPLC is likely to separate all of the members [61,62], Incorporation of a positive control is a good way to check on the successful synthesis of a library [63], Finally, steps should be taken to assure the completion of reactions in the actual library production and that good documented practices are followed in handling automated equipment. 

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The parallel synthesis of furans from a-hydroxycarbonyl compounds is frequently conducted using aldoses or ketoses as readily available sources of this functional grouping, especially as the resulting polyhydroxyalkyl side-chain can be removed easily by oxidative degradation (Schemes 67d and 67e) 56MI30300). 

D.L. Flynn, Phase-trafficking reagents and phase-switching strategies for parallel synthesis, Med Res Rev 19 408-431 1999. 

These two selectors terminated with a glycine were then prepared on a larger scale, their carboxyl groups reacted with 3-aminopropyltriethoxysilane, and the conjugate immobilized onto silica. Each CSP was packed into columns and used for the separation of racemic (l-naphthyl)leucine ester 17. Separation factors of 6.9 and 8.0 were determined for the columns with DNB-ala-gly and DNB-leu-gly selector respectively. These were somewhat lower than those found for similar CSPs using the parallel synthesis and attached through a different tether [87]. 

CHIRSOURCE aims to explore the use of chiral chromatography for combinatorial chemistry approaches. Combinatorial chemistry, as well as parallel synthesis. 

For a complete optimization of all factors, the above-described procedure is not practical. In order to perform this rapidly, parallel synthesis and screening techniques must be developed. These can consist of a scaled-down version of the MIPs in vials that can be handled automatically and analyzed in situ (Fig. 6-13) [85, 86]. 

Two main approaches to combinatorial chemistry are used—parallel synthesis and split synthesis. In parallel synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic instruments add different sequences of building blocks to tfie different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. 

Palmitic acid, structure of, 1062 Palmitoleic acid, structure of, 1062 PAM resin, solid-phase peptide synthesis and, 1037 Para (m), 519 Paraffin, 91 Parallel synthesis, 586 Parent peak (mass spectrum), 410 Partial charge, 36 Pasteur, Louis, 297, 307... 

A chemical library is a precisely defined collection of different chemical compounds. Chemical libraries can be either prepared by parallel synthesis or by split-and-recombine synthesis. 

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

If small or medium libraries for lead optimization are demanded and all synthetic products are to be screened individually, most often parallel synthesis is the method of choice. Parallel syntheses can be conducted in solution, on solid phase, with polymer-assisted solution phase syntheses or with a combination of several of these methods. Preferably, parallel syntheses are automated, either employing integrated synthesis robots or by automation of single steps such as washing, isolation, or identification. The latter concept often allows a more flexible and less expensive automation of parallel synthesis. 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

Microwave-assisted solid-phase parallel synthesis has also been reported using multi-well filter-bottom polypropylene plates [45,155]. However, it should be mentioned that the thermal instability of the polypropylene plates is a limitation of this setup. In addition, uneven heating across the plate results in higher temperatures (AT 10-20 °C) being observed at the center of the plate than at the edges. 

Recently, Murray and Gellman demonstrated that parallel synthesis in inexpensive 96-well polypropylene filter plates with microwave irradiation in a multimode reactor is a simple and effective method for the rapid preparation of j8-peptide hbraries on sohd support in acceptable purities [156]. 

Scheme 15 Parallel synthesis of 2-oxazolines from carboxylic acids and aminoalcohols using PS-Mukaiyama reagent...

As in the case of benzimidazole, a parallel synthesis of benzoxazoles was described. The authors report that mixing directly differently substituted o-amino phenols 193 with acylating agents 194 and heating at 200 °C for 10-15 min under microwave irradiation, a collection of benzoxazoles 195 was obtained (Scheme 70). With this reaction, a 48-member library of benzoxazoles with different substituents on the aromatic rings was obtained [125]. 

Solid-phase, parallel-synthesis approaches to the imidazole derivatives 49 <96TL937>, 50 and 51 <96TL835>, 52 <96TL751>, and 53 <96TL4865> were also reported in 1996. 

Referring to highly parallel synthesis, the smallness of the micro-channel dimensions enables one to combine several micro imit operations on one chip [23]. By using multi-layered chip architecture complicated fluidic circuits with nx m combinations of fluid streams can be made. By this means, truly combinatorial parallel processing can be achieved. 

OS 10] [R 10] [P 9] The feasibility of 2 x 2 parallel synthesis using two amines and two acid chlorides for a phase-transfer reaction was demonstrated [23]. This paves the way fornx m parallel reaction combinations as a new micro flow approach for combinatorial chemistry. 

Kikutani, Y, Horiuchi, T., Uchiyama, K., Hisamoto, H., Tokeshi, M., Kitamori, T, Glass microchip with three-dimensional microchannel network for 2x2 parallel synthesis. Lab. Chip 2 (2002) 188-192. 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

The protocol offers a direct and efficient method for the synthesis of the boronic ester in the solid phase, which hitherto met with little success using classical methodology (Scheme 1-42). A solid-phase boronate (113 [155], 114 [156]) is quantitatively obtained by treating a polymer-bound iodoarene with the diboron (82). The subsequent coupling with haloarenes furnishes various biaryls. The robot synthesis or the parallel synthesis on the surface of resin is the topic of further accounts of the research. 

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