Automated library synthesis

Tetrasubstituted thiophenes obtained by the Gewald reaction serve as templates for structural diversification and semi-automated library synthesis. Thiophene 31, prepared from 3-ketoester 29 and t-butylcyanoacetate 30, could be selectively derivatized at three of the four substituents to maximize library diversity. This procedure represents an improvement over previously published methods for utilizing 1,3-dicarbonyl compounds in the Gewald reaction. 

I 2 Supported Reagents and Scavengers in Multi-step Organic Synthesis Automated library synthesis using solid-supported reagents... 

The T2 linker has recently been shown to be a versatile backbone amide anchor. Immobilized disubstituted triazenes were acylated with carboxylic acid anhydrides or chlorides to give amide derivatives. These amides were cleaved under very mild conditions using trimethyl chlorosilane. This sequence thus employs the T2 system as backbone amine linker and was demonstrated in the automated library synthesis of substituted amide derivatives.54... 

Combinatorial chemistry technology and the merging of automated library synthesis with the traditional medicinal chemistry principles to provide a more rational approach to library generation are providing pharmaceutical companies with millions of... 

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

ChemOvation Ltd., founded in 1998, focuses on providing an integrated drug discovery support service via collaborative programs, and the manufacture of innovative compound libraries. Apart from that, their range of services includes chemistry development, automated parallel synthesis, scale-up, process development, and screening. 

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively, deserves special comment. While the parallel set-up allows for a considerably higher throughput achievable in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature/pressure is limited. In the parallel mode, all reaction vessels are exposed to the same irradiation conditions. In order to ensure similar temperatures in each vessel, the same volume of the identical solvent should be used in each reaction vessel because of the dielectric properties involved [86]. As an alternative to parallel processing, the automated sequential synthesis of libraries can be a viable strategy if small focused libraries (20-200 compounds) need to be prepared. Irradiating each individual reaction vessel separately gives better control over the reaction parameters and allows for the rapid optimization of reaction conditions. For the preparation of relatively small libraries, where delicate chemistries are to be performed, the sequential format may be preferable. This is discussed in more detail in Chapter 5. 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

Keywords Automated parallel synthesis Block copolymers experimentation Polymer libraries Random copolymers... 

Automated carbohydrate synthesis allows for the production of complex carbohydrates orders of magnitude faster than other approaches. This advance has the potential to parallel the breakthroughs achieved by researchers in the peptide and DNA fields that opened up the pro-teomic and genomic eras in biotechnology. By increasing the scope of the carbohydrate building block library and streamlining the reaction conditions further we anticipate that automated solid-phase carbohydrate synthesis will become the method of choice for carbohydrate production. 

DeWitt reviews automated synthesis from 1990 to the present, and concludes that full exploitation of automation in the chemistry laboratory has not yet been realized. However, many of the important, but repetitive, manipulations needed to perform an effective library preparation are now routinely automated. As library synthesis becomes commonplace in the industry, the chemist will require even more automated systems. Clearly, we can expect exciting advances in this area in the future. 

This simple and versatile combinatorial one-pot method will surely provide, in future, many diverse libraries, and its use in combination with solution purification techniques (see the next sections) will help in automating the experimental procedures. A thorough search for new multicomponent condensations should even increase their applications in combinatorial library synthesis. 

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