Combinatorial synthesis solid-phase

The use of microwaves was first reported in 1996 for both homogeneous883 and solid-phase coupling reactions of arylboronic acids (Equation (208)).884 Microwave irradiation significantly increases the efficiency of ligandless palladium acetate, solid-phase coupling for combinatorial synthesis, solid-phase coupling using KF-y-alumina,... 

Some interesting procedures are being developed to make the present protocol more useful as a synthetic tool. Directing to the combinatorial synthesis, solid-phase syntheses have currently been under development using polymer-supported stannanes (Scheme 69) [263-268] or electrophiles (Scheme 70, Scheme 71) [149, 269-272]. In the latter case, unreacted organotin reagent as... 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Two general methods are used to build a library of compounds by the general techniques of combinatorial chemistry solid-phase synthesis (SPS) and solution-phase synthesis. 

Continuing with the approach of this chapter from previous years metal-mediated reactions, cycloadditions, radical processes and asymmetric applications will be highlighted. Syntheses using traditional approaches will not be covered, unless improvements are reported. Due to the volume of publications concerning pyridines and associated heterocycles many subject areas could not be covered. Combinatorial or solid-phase synthesis will not represented since the area is rather specialized and many of the processes utilize existing methodology. The synthesis and reactions of polyaza-fused systems of the pyridine class will also not be included in this review. 

The current chemical space is occupied by compounds isolated from nature, synthesised by conventional solution phase synthesis, solid phase combinatorial synthesis and by smaller fragment based libraries. These libraries vary significantly both in their size and complexity. The comparison of diversity of these libraries and their impact as drug leads is reviewed in this chapter. 

Amino Acids, Chemical Properties of Click Peptides, Design and Application of Peptide Combinatorial Libraries Solid-Phase Synthesis of Biomolecules... 

Fukase K (2001) Combinatorial and solid-phase methods in oligosaccharide synthesis. In Fraser-Reid B, Tatsuta K, Thiem J (eds) Glyco-science II. Springer, Berlin Heidelberg New York,... 

K. Fukase, Oligosaccharides Synthesis Combinatorial and solid phase methods in oligosaccharide synthesis, in B. Fraser-Reid, K. Tatsuta, and J. Thiem, (Eds.), Glycoscience Chemistry and Chemical Biology, Vol. 2, Springer, Berlin, 2001, pp. 1621-1660. 

Chipeta Way Salt Lake City, Utah 84108 Fax 801-583-4961 E-mail jobs npsp.com Internet site www.npsp.com combinatorial chemistry, solid-phase organic synthesis solicits r4sumfis by surface or e-mail... 

Solid-phase combinatorial peptide synthesis, combinatorial peptide synthesis, solid-phase peptide synthesis. 

The recent interest in organic solid phase synthesis, triggered by the advent of chemical combinatorial methods (1-7), also accelerated methodology development. Simplification of chemical protocols, their robustness, and amenability to handling large arrays of compounds, prepared by combinatorial/ parallel solid phase synthesis, is one area that witnessed numerous novel contributions. This chapter describes an apparatus and method for gaseous cleavage of compounds from solid phase supports. 

Combinatorial chemistry has significantly increased the nurnjjers of molecules that can be synthesised in a modern chemical laboratory. The classic approach to combinatorial synthesis involves the use of a solid support (e.g. polystyrene beads) together with a scheme called split-mix. Solid-phase chemistry is particularly appealing because it permits excess reagent to be used, so ensuring that the reaction proceeds to completion. The excess... 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

K. Gordon and S. Balasubramanian, Solid phase synthesis - designer linkers for combinatorial chemistry A review J Chem Technol Biotechnol 74 835-851 7999. 

F. Guillier, D. Grain and M. Bradley, Linkers and Cleavage Strategies in Solid-phase Organic Synthesis and Combinatorial Chemistry, Chem Rev 100 2091-2157 2000. 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

The Biginelli reaction has also been extended to solid phase and combinatorial synthesis. In a recent combinatorial approach Kappe and coworkers used 4-chloroacetoacetate as a building block to create a library of diverse DHPMs under... 

Preparation of Memfield resin-bound nitro acetates, which is a suitable bndding block for the development of combinatorial solid phase synthesis, is repotted. The anion of ethyl nitro acetate is generated in DMF by an electrochemical method using Pt cathode, magnesium rod anode, and tetrabutylairunonium bromide as an electrolyte. Alkylaton of this anion with alkyl hahdes gives mono-alkylated products in 80% yield." ... 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

Solid-Phase Organic Synthesis and Combinatorial Chemistry. 80... 

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