Sequential combinatorial synthesis

An outstanding feature of the cation flow method is that the method enables continuous sequential combinatorial synthesis by simple flow switching as shown in Figure 6. In the first step, the cation flow generated from precursor A1 is allowed to react with nucleophile Bl. Then, the cation flow is allowed to react with the nucleophile B2. In the third step, the cation flow is allowed to react with nucleophile B3. Then, the precursor of the cation is switched to A2, and the cation flow generated from A2 is allowed to react with nucleophiles Bl, B2, and B3 sequentially. Then, the precursor of the cation is switched to A3, and the... 

Figure 6. Sequential combinatorial synthesis based on the cation flow ...

The advantages of functional polymers are best realized when used in two situations— multistep sequential reactions and automated parallel combinatorial synthesis to produce libraries of compounds. In both situations there is a large savings in the time and expense of carrying out the many chemical reactions and their corresponding handling and purification steps. 

The examples shown in this review article demonstrate that a variety of methods for polymer synthesis have been developed in flow microreactors. Continuous flow synthesis enables serial combinatorial synthesis, in which a variety of polymers can be synthesized in a sequential way using a single flow reactor with a flow switch. Space integration, which enables the synthesis of structurally well-defined polymers without isolating living polymer ends, also enhances the power and speed of polymer synthesis. Because several test plants for continuous production have already been built, there is no doubt that flow microreactors can contribute to polymer production in industry. 

By combining several click reactions, click chemistry allows for the rapid synthesis of useful new compounds of high complexity and combinatorial libraries. The 2-type reaction of the azide ion with a variety of epoxides to give azido alcohols has been exploited extensively in click chemistry. First of all, azido alcohols can be converted into amino alcohols upon reduction.70 On the other hand, aliphatic azides are quite stable toward a number of other standard organic synthesis conditions (orthogonality), but readily undergo 1,3-dipolar cycloaddition with alkynes. An example of the sequential reactions of... 

All issues about the preparation of inorganic solid catalysts that we have discussed above apply for the rapid sequential synthesis of inorganic solids by automated methodologies. As for HTE - and combinatorial approaches in organic chemistry, technical solutions for compound synthesis can be obtained commercially for a number of synthetic problems [42-45] and it is beyond the scope of this chapter to discuss all the technical details. 

A -tritylaziridine-2-(5)-carboxaldehyde. The application of a novel, sequential, trans-acetalation oxonium ene cyclization has delivered a stereoselective synthesis of the C-aromatic taxane skeleton, and a combinatorial sequence of the regioselective propiolate-ene, catalytic enantioselective epoxidation and carbonyl-ene cyclization reactions has been used to complete the synthesis of the A-ring of a vitamin D hybrid analogue. 

In vitro multi-enzyme systems are set up by the combination of enzyme modules including pathway and even pathway-unrelated enzymes. Also, the synthesis of saccharides in combination with de novo enzymatic sugar synthesis can be accomplished. This so-called combinatorial biocatalysis can be performed in sequential reactors or in a one-pot reaction vessel which challenges further reaction engineering for optimization. Even the combination of an enzyme module with a chemical... 

Typically MCRs allow the synthesis of very many derivatives of a special scaffold. Since the number of possible products increases exponentially with the multiplicity of the MCR, very large chemical spaces can be inspected. These very large chemical spaces are not realistically accessible by classical sequential syntheses. As realized by Ugi in 1961 starting with 1000 each of the educts carboxylic acid, amines, aldehydes and isocyanides 10004 products are accessible [4]. In this seminal paper the roots of combinatorial chemistry are described. The authors noted that MCRs have huge variability. Although the paper describes the essentials of combinatorial chemistry, the time was not right for the great advances that only started 30 years later. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

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