Combinatorial synthesis has developed within a few years from a laboratory curiosity to a method that is taken seriously in drug research. Rapid progress in molecular biology and the resulting ability to determine the activity of new substances extremely efficiently have led to a change in paradigm for the synthesis of test compounds: in addition to the conventional procedure of synthesizing one substance after another, new methods allowing simultaneous creation of many structurally defined substances are becoming increasingly important. A characteristic of combinatorial synthesis is that a reaction is performed with many synthetic building blocks at once—in parallel or in a mixture— rather than with just one building block. All possible combinations are formed in each step, so that a large number of products, a so‐called library, is obtained from only a few reactants. Several methods have been developed for combinatorial synthesis of small organic molecules, based on research into peptide library synthesis: single substances are produced by highly automated parallel syntheses, and special techniques enable targeted synthesis of mixtures with defined components. Many structures can be obtained by combinatorial synthesis, and the size of the libraries created ranges from a few individual compounds to many thousand substances in mixtures. This article gives an overview of the combinatorial syntheses of small organic molecules reported to date, performed both in solution and on a solid support. In addition, different techniques for identification of active compounds in mixtures are presented, together with ways to automate syntheses and process the large amounts of data produced. An overview of pionering companies active in this area is also given. The final outlook attempts to predict the future development of this exponentially growing area and the influence of this new thinking in other areas of chemistry.

No abstract

No abstract

No abstract

Under Palladium catalysis [Pd(OAc)2, K2CO3, LiCl, Bu4NBr, DMF] o‐bromo‐trans‐stilbene (trans‐7a) reacts to give 9,10‐dibenzylidene‐9,10‐dihydroanthracene (4a) with formation of a new six‐membered ring. The (Z) diastereomer crystallizes preferentially to give pure (Z)‐4a, as proved by X‐ray crystal structure analysis. A variety of substituted o‐bromostilbenes and heterocyclic analogs 7 were prepared by Wittig olefination of o‐bromobenzaldehyde with substituted benzyltriphenylphosphonium ylides, Wittig‐Horner‐Emmons olefination of arenecarbaldehydes with diethyl o‐bromobenzylphosphonate or Wittig olefination of substituted benzaldehydes with substituted (o‐bromobenzyl)‐diphenylphosphonium ylides, respectively. The cis‐o‐bromostilbenes were photoisomerized to the trans diastereoisomers trans‐7 by irradiation in the presence of diphenyl disulfide. All of these o‐bromo‐trans‐stilbenes trans‐7a–g and trans‐7j, k under palladium catalysis reacted to the corresponding 9,10‐bis(arylmethylene)‐9,10‐dihydroanthracenes 4, mostly as mixtures of (E) and (Z) diastereomers (50‐97 % yield). The (Z) diastereomer of the parent 4a and the alkyl‐substituted compounds 4c and 4e could be purified by simple crystallization, and in some runs, only (Z)‐4a, c, e were obtained. Among the heterocyclic analogs trans‐7h, i only the furyl derivative trans‐7h reacted (76 % yield) cleanly, whereas the pyridine analog trans‐7i gave a mixture of products from which the rather sensitive product 4i could not be isolated in pure form. The cis‐o‐bromostilbenes cis‐7a, c cyclized to phenanthrenes under the same conditions (70‐71 % yield). The UV spectra of compounds 4a, c–k are similar to that of anthracene, and so are the oxidation and reduction potentials of (Z)‐4a.