Combinatorial libraries Solid phase organic synthesis

The advent of combinatorial techniques and solid phase organic synthesis may lead to preparation of large numbers of structurally related molecules in short periods of time. This is important especially for the optimization of lead structures in the pharmaceutical industry [40]. It is now well established and documented that the combinatorial technology and solid phase techniques could offer sufficient latitude for preparation of corresponding chemical libraries with broad structural diversity. The diverse potentiality of (3-lactam moiety as specific pharmacophores and scaffolds has attracted ample interests from pharmaceutical industries for the synthetic methods based on polymer-supported techniques. 

Many laboratories have investigated alternative solution-phase strategies for preparing combinatorial libraries to overcome these limitations of solid-phase organic synthesis.This chapter reviews advances that have been made over the last two years in polymer-assisted syntheses. This... 

M. Winter, Support for solid-phase organic synthesis, in G. Jung, (Ed.), Combinatorial Peptide and Nonpeptide Libraries, VCH, Weinheim, 1996, pp. 465-510. 

Recent years has seen a buigeoning interest in solid-phase organic synthesis protocols for the production of combinatorial libraries of new molecules [76,77]. A challenging factor in this approach is the analysis of the newly synthesised materials for which, ideally, direct structural analysis of the material would be carried out whilst still attached to the solid support and thus still available for further chemistry. The direct NMR analysis of such materials, even when solvated, is complicated by two principal factors which can severely degrade spectrum resolution ... 

In recent years, combinatorial chemistry has proved to be one of the best approaches for acceleration in drug development [1-6]. Solid-phase organic synthesis (SPOS) [7-9] plays a most important role for production of combinatorial libraries. 

Although the combinatorial and parallel synthesis of compound libraries devoted to screening, lead finding and lead optimisation purposes have initiated a real burst of interest for solid-phase organic synthesis (SPOS), there are numerous other applications and opportunities for SPOS emerging from related areas. This chapter will summarise the fields of interest for SPOS and some of those will be discussed more extensively in the following chapters. 

One of the most developed methods used in combinatorial chemistry libraries preparation is solid-phase organic synthesis (SPOS) based on the Merrifield method for peptide synthesis [128]. A great number of such libraries have been prepared on a solid support, generally a functionalized polystyrene resin cross-linked with a small amount of divinylbenzene. Recently, it was demonstrated that micro-wave irradiation can be applied to solid-phase immobilized reagents to reduce significantly the reaction time. Those readers who are interested in such processes we would like to refer to more extensive reviews published by Chamberlin et al. [129] and Kappe [130], while in this chapter we are giving most common examples. 

Some other aspects of catalysis like control of stereochemistry with chiral ligands have not yet been widely explored in solid phase organic synthesis. Up to now most compound libraries simply contained racemates and freqnently even mixtures of diastereomers. For sure, to address stereoselectivity will be one of the next challenges in combinatorial solid phase synthesis. 

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