Solid automated synthesizer

One widely used method involving protected compounds is solid-phase synthesis (polymer-supponed reagents). This method has the advantage of requiring only a simple workup by filtration such as in automated syntheses, especially of polypeptides, oligonucleotides, and oligosaccharides. 

These results demonstrate that O-glycosyl trichloroacetimidate-based oligosaccharide synthesis on solid support may eventually become a valuable alternative to solution-phase synthesis because useful experience is available for the selection of the polymer support and choice of the linker system and the glycosyl donor. Further standardization of the building blocks and the protective group pattern will finally provide the yields and the anomeric control in order to successfully plan automated syntheses of oligosaccharides also in a combinatorial manner. 

Despite the obstacles discussed above, solid-phase syntheses of oligomers do have two significant advantages over solution techniques. First, purifications in solid-phase techniques are easier and faster than in solution and are more likely to be amenable to automation. Second, hetero-oli-gomerizations are relatively easy to arrange if one component is anchored to a solid phase. Overall, the advantages of solid-phase syntheses of oligomers, as well as other products, can be appreciable for reproducible, reliable, and easily monitored reaction schemes. 

Amines are both valuable synthetic intermediates and interesting target molecules. A number of solid-phase syntheses have been developed, most of which are also suitable for the automated, parallel synthesis of this class of compound. 

The split-and-pool synthesis not only simplifies the complexity of the combinatorial synthetic process, but also offers additional important benefits. To undertake a full range of solid-phase chemical reactions, elaborate reaction conditions are needed for some chemical transformations. These include, but are not limited to, low temperature and inert atmosphere conditions. Parallel synthesis of a thousand compounds requires handling of a thousand reaction vessels. The timely addition of sensitive reagents (e.g., butyl lithium) at low temperature (—78°) under inert atmosphere during parallel synthesis is not a trivial task. It can be done if sophisticated automated synthesizer equipment is designed to handle and tolerate such reaction conditions. Such a synthesis can alternatively be performed easily in a manual fashion using a split-and-pool method that requires only a limited number of reaction vessels. Examples from Nicolaou s17 and Schrei-ber s18,19 laboratories have shown that the split-and-pool method is the methodology of choice for the synthesis of complex and diversity-oriented combinatorial libraries. 

For the fast identification of lead compounds for novel, small molecule enzyme inhibitors or other ligands for proteins, the screening of large and diverse arrays of compounds prepared on insoluble supports is one of the most efficient approaches.1-8 Parallel solid-phase synthesis has been found to be particularly well suited for the preparation of such arrays of diverse compounds since multistep synthetic sequences on insoluble supports can be conducted on fully automated synthesizers. 

Abarelix was synthesized by the solid phase method using an automated synthesizer (e.g. Beckman Model 990). The amino acid residues used can be purchased from commercial sources (e.g. Aldrich Chemical Co., Milwaukee, Wis.), or can be produced from commercially available starting materials according to known methods. Amino acids which are not obtained commercially can be synthesized in a protected form for coupling, or, if appropriate, can be coupled to form a peptide and subsequently modified to the desired form. 

First, a peptide synthesizer was modified to allow solid-phase oligosaccharide synthesis. This platform had the basic function of an automated synthesizer and allowed repeating cycles of glycosylation and deprotection to be mostly software controlled (Fig. 7.2a) [38], This robust pressure-driven system relies on an established... 

Like the solid phase peptide synthesis, this process has also been automated. Commercial automated synthesizers are available that can prepare polynucleotides containing more than 150 bases with a cycle time of about 10 minutes per base. 

The first step in the chemical synthesis is to investigate the scope and limitations of the synthetic reactions [32, 40], since different clusters of compounds, or even compounds within a cluster, may require different experimental settings. Even with automated solid state syntheses using polymer beads as carriers of compounds, the synthetic steps need to be optimised so that reasonable yields are obtained for all compounds in the library. Otherwise unbalanced test data will result, with subsequent loss of information. Such optimisation is easy to accomplish with few compounds. Recently, robots that optimise organic syntheses on the basis of statistical... 

Solid-phase synthesis has been shown to be ideal for the preparation of hbraries of potential drugs, and the advantages involved are likely to pertain to platinum drugs. In this respect, our group reported the solid-phase synthesis of dichloroplatinum(II) tripeptide complexes and dinuclear platinum(II) complexes. Using this technique, a library of complexes was generated in an automated synthesizer and conveniently screened for cytotoxicity via an adapted MTT assay. ... 

Solid phase synthesis lends itself easily to automation. This faet was readily apparent to Merrifield, who built the first automated synthesizer (S,5S,5P). Merri-field s pioneering effort was soon followed by other laboratories (60-87) and several synthesizers appeared on the market. The development of the Fmoe synthetic strategy (88,89) allowed for the substantial simplification of automatic synthesizers, since handling of the very unfriendly reagent, hydrofluoric acid, was no longer necessary. Cambridge Research Biochemicals was the first to introduce a Fmoc-based synthesizer, PEPSYNthesizer, to the market. This machine was capable of only one step of the synthesis, but it applied the... 

The ease, simplicity, and repetitive nature of solid-phase synthesis led to the development of automated synthesizers (Section 4.3.6). In addition, the advent of solid-phase peptide synthesis laid the groundwork for the development of combinatorial synthesis of peptide libraries that are now being used for the discovery of lead analogues for drug discovery (Section 4.3.7)... 

A further limitation of general organic synthesis on sohd supports arises from the limited types of support materials that are available. These also restrict the use of different types of solvents, as only those solvents can be employed whic that lead to a sufficient swelling of the polymer and hence to an acceptable reaction rate. As a result of the aforementioned restrictions, it became clear that synthesis on sohd supports requires a somewhat careful and time-consuming optimization of fhe reachon coridi lions. However, once properly developed - and with fhe scope of fhe perhnent reactions carefully evaluated - solid-support-based synthesis offers highspeed preparations of compound libraries whic that can also be carried out also by automated synthesizers. 

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