Combinatorial and Solid-Phase Syntheses

Institutfur Organische Chemie, Universitat Karlsruhe (TH), Fritz-Haber-Weg 6, D-76131 

Transition-metal-mediated transformations play an important role in combinatorial synthesis on solid supports because they allow C-C bond formation under mild, neutral conditions and tolerate a broad range of functional groups. In particular, the palladium-mediated cross-coupling reactions, more precisely the Mizoroki-Heck, the Suzuki and the Stille reactions received a lot of attention due to their enormous derivatization potential of functional structures [5]. Although Stille coupling was the first to be explored on and 

The Mizoroki-Hedc Reaction Edited by Martin Oestreich 2009 John Wiley Sons, Ltd. ISBN 978-0-470-03394  

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Polymer-Supported Stannanes and Fluorous Stannane. Some interesting procedures are being developed to make the present protocol more useful as a synthetic tool. Directed toward combinatorial synthesis, solid-phase syntheses have currently been under development using polymer-supported stannanes.t t In these cases trialkyltin halide is released during the course of the reactions. More recently, a new version was developed with inversed strategy. In this process, the stannyl group remains on the polystyrene support and could be recovered for reuse. ... 

Several reviews of P-lactam chemistry have appeared including a general survey with 407 references <99MI335>. Other reviews include discussions of thioester enolate-imine reactions , enantio- and diastereo-selective routes to azetidinones <99MI221>, the use of diazoketones in diastereoselective synthesis <99MI43>, and solid-phase and combinatorial syntheses of p-lactams <99MI955>. 

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. 

A Versatile Synthetic Strategy Enabling Solid-Phase Syntheses of 1,5-Ben-zothiazepines, 1,5-Benzodiazepines and Related Structures, Schwarz, M. K., Lecture presented at the 2nd Canadian Conference of Combinatorial Chemistry, Montreal, Canada, Oct. 6-7, 1997. 

Solid-phase methods are applicable to syntheses of sequence-specific oligomers and dendritic structures. The triazene chemistry developed for this specific purpose may also be useful in other types of syntheses. Further development of solid-phase syntheses of this type into combinatorial synthesis of oligomers is the next logical step. Solid-phase methods will never completely replace solution-phase approaches to oligomers, but either technique should be considered with respect to the special characteristics and requirements for the system under investigation. 

Recent strategies in CSP development and optimization related to the Pirkle concept and to low molecular weight synthetic chiral selectors. In the attempt to proceed more effectively with the development of new tailor-made CSPs, solid-phase syntheses and combinatorial chemistry approaches involving SO and/or CSP libraries have been tested. 

In conclusion, two combinatorial dapoxyl dye libraries were synthesized in both solution and solid phase methods and a fluorescence-based screening identified the highly sensitive and selective binding dye (A41-S) toward site I of HSA, demonstrating that this dapoxyl dye library has a great potential to sense macromolecules with fluorescence intensity changes. 

The realm of combinatorial chemistry is covered by a wide umbrella of techniques that include both solution phase and solid phase synthesis. The revival of solid phase synthesis has led to great interest in the development of analytical methods to monitor the reaction directly on the polymer support during the course of combinatorial syntheses. These techniques have a significant advantage compared to cleave-and-analyze characterization, particularly for optimizing reaction conditions. 

Some of the syntheses of pyrimidines and quinazolines were automated so that combinatorial libraries of compounds could be generated. For instance, 2-thioxo-4-dihydropyrimidinones were prepared in this fashion by reductive alkylation of p-amino acids with aldehydes, addition of isothiocyanates, and then cyclization <97JOC9358>. The use of highly fluorinated substrates in the Ugi and Biginelli multicomponent reactions led to a combinatorially-suitable preparation of dihydropyrimidines 15 <97JOC2917>, and efficient solid phase syntheses of chiral quinazoline-... 

Xu J, Szakal CW, Martin SE, Peterson BR, Wueher A, Winograd N. Molecule-speeifie imaging with mass speetrometry and a buekminsterfullerene probe Appheation to characterizing solid-phase synthesized combinatorial libraries. J Am Chem Soc 2004 126 3902-3909. 

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