Combinatorial chemistry solid-phase techniques

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. 

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... 

Some other aspects of nitrile oxide chemistry that will grow in importance in the future involve the use of high pressure (> 10 kbar) to enforce hitherto slow or not feasible cycloadditions. Of particular relevance for nitrile oxides will be to find substantial improvements for practical, cost-efficient, large-scale reactions (351). Solid-phase techniques, adaptation for combinatorial chemistry, or improved versions for dehydrating nitroalkanes will all play an increasingly important role. 

The solid-phase technique has been applied in this field with the amino component linked to a polymer/7,9 To meet the requirements of combinatorial chemistry the coupling conditions of resin-bound Asp with carbazic acid chloride of Fmoc-AzSar-OH and Fmoc-AzAla-OH were individually optimized. Remarkably, the carbazic acid chloride of Fmoc-AzSar-OH proved to be much more reactive than the activated Fmoc-AzAla-OH/9 ... 

As recent as three years ago, the synthetic chemist had a limited portfolio of reactions which could be conducted on solid phase and most of the useful reactions involved carbon-heteroatom bond formation, in particular, carbon-nitrogen bonds. An explosion in interest in combinatorial chemistry techniques has brought solid-phase synthesis back into the spotlight. During the past 18 months, a number of groups have published on the solid-phase synthesis of complex, functionality-rich small molecules. At the current rate of progress, one would expect that, within a few years, the synthetic chemist will have the ability to tackle nearly any synthesis using solid-phase techniques. 

Since the introduction of sohd-phase peptide synthesis (SPPS) on lightly crosslinked polystyrene (PSty) by Merrifield in 1962,this technique has been optimized in all its aspects and has subsequently found widespread application in many other fields of organic chemistry, e.g. for the synthesis of oligonucleotides, for catalysis, for the immobilization of enzymes in biotechnology, and for the preparation of polymeric reagents. A new but very rapidly growing field of application of this revolutionary method is the use of solid-phase techniques in combinatorial chemistry for the synthesis of hbraries of compounds whose constituents differ widely in their chemical nature. ... 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this prupose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. Combinatorial chemistry had its beginning with the Merrifield synthesis, particularly when applied to peptide synthesis, and continues as an important part of modem organic chemistry. ... 

The field of combinatorial chemistry covers a wide range of interdependent concepts and techniques as diverse as solid-phase synthesis, supported reagents, parallel homogeneous-phase chemistry, solid-phase extractions and adapted analytical methods. They were designed and developed both to address specific problems, libraries synthesis, and to help chemists in their everyday work. 

A novel methodology employing aza-Payne rearrangement and OJ<[-intramolecular acyl transfer reactions was reported by Tamamura et for the synthesis of peptidomimetics containing hydroxyethylamine dipeptide isosteres (87). This method is also applicable for the synthesis of hydroxyethylamine dipeptide isosteres containing pseudopeptides and also for combinatorial chemistry using solid-phase techniques. 

However, since its implementation, solution- and solid-phase techniques have been competing with each other, and although many companies started their combinatorial chemistry program with solid-phase techniques, solution-phase combinatorial methods have taken over and now account for approximately 25% of all combinatorial efforts. 

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. 

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. 

---