Organic synthesis and combinatorial chemistry

Historically, the more diverse chemistries and sample manipulations of general organic synthesis have hindered the design and use of automated systems. Recently, however, 

One of the earliest instruments for automated organic synthesis was developed at Takeda in the late 1980s [90], This system was later utilized to generate more than 200 derivatives of substituted /V-(carboxyalkvl)amino acids [72] by solution-phase chemistry. 

Since 1992, workers at Chiron have extended the use of their Zymark robot system from peptide synthesis to libraries containing up to 5000 peptoid [oligo(N-substituted glycines)] [56,91-94] analogues. 

Workers at Parke-Davis reported the DIVERSOMER method in 1993 [63,64] which utilized proprietary reactors in combination with a Tecan robot. This technology has been implemented to generate libraries ofhydantoins [63-66,95], benzodiazepines [63-66, 95], and quinolones [67,96,97] by solid-phase synthesis. 

Zeneca reported the execution of solution-phase chemistry with a Zymark robotic system, thereby generating 50 quinuclidine analogues to test for squalene synthetase inhibition [38], 

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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. 

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

GuilUer F, Orain D, Bradley M. Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem. Rev. 2000 100 2091-2157. 

Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry 00CRV2091. 

Sieber P (1987) A new acid-labile anchor group for the solid-phase synthesis of C-terminal peptide amides by the Fmoc method. Tetrahedron Lett 28 2107-2110 Mende F, Seitz O (2011) 9-Fluorenylmethoxycarbonyl-based solid-phase synthesis of peptide a-thioesters. Angew Chem Int Ed 50 1232-1240 Giiillier F, Grain D, Bradley M (2000) Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem Rev 100 2091-2158... 

N. K. Terret, Combinatorial Chemistry, Oxford University Press, New York, 1998 M. Winter, R. Warrass, Resins and Anchors for Solid-Phase Organic Synthesis, in Combinatorial Chemistry (Ed. H. Fenniri), Oxford University Press, New York, p. 117-138, 2000. 

Recent advances in the use of Lawesson s reagent include its application in microwave assisted solvent-free syntheses, solid-phase synthesis and combinatorial chemistry.165 Despite the ubiquity of Lawesson s reagent for organic thionation reactions, there are still some classes of compounds that it does not... 

Lew, A., Krutzik, P.O., Hart, M.E. and Chamberlin, A.R., Increasing rates of reaction microwave-assisted organic synthesis for combinatorial chemistry /. Comb. Chem., 2002, 4, 95-105. 

Parallel to these developments in solid-phase synthesis and combinatorial chemistry, microwave-enhanced organic synthesis has attracted much attention in recent years. As is evident from the other chapters in this book and the comprehensive reviews available on this subject [5, 6], high-speed microwave-assisted synthesis has been applied successfully in many fields of synthetic organic chemistry. Any technique which can speed the process of rather time-consuming solid-phase synthesis is of substantial interest, particularly in research laboratories involved in high-throughput synthesis. 

As carbene complexes have become proficient catalysts, their incorporation into recyclable catalyst systems has grown into a field of its own. The most common strategy for recovering a catalyst for subsequent use is to append it to a heterogeneous support (e.g., a PS bead), and both Fischer carbenes and NHCs have been incorporated into polymers for this purpose. The first polymer-bound Fischer carbene complexes were reported by Mariorana and Seneci in 1999 [51], for use in soHd-phase organic synthesis for combinatorial chemistry. These materials were prepared via the attachment of chromium carbene complexes to a polymer resin... 

In triphase catalysis, solvated resin supports are important carriers for solid-phase organic synthesis in combinatorial chemistry. The physical properties of resin, resin swelling, dynamic solvation, and solvated supports are important factors in affecting the synthesis. However, these factors are also affected by solvent. Selective solvation of resin alters the local reactivity and accessibility of the bound substrate and the mobility of the entrapped re-... 

Solid-phase reactions play an important role in parallel synthesis and combinatorial chemistry, particularly in the area of medicinal chemistry, where their potential has emerged as a result of the possibility of automation. Considerable attention has been focused on adapting and exploiting the advantages of solid-phase synthesis (SPS) to produce libraries of such organic compounds. In this context, transition metal-pro-... 

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