Parallel Synthesis and Combinatorial Chemistry

Parallel synthesis and combinatorial chemistry are two closely related concepts, result of intentions to automatically perform more synthetic reactions. Parallel synthesis enables preparation of a set of defined compounds in a number of physically separated reaction vessels or micro-departments. Combinatorial chemistry instead uses a combinatorial process for preparation of a large number of compounds from a defined set of building blocks. Combinatorial chemical synthesis generates a large number of compounds, so-called libraries, at the same time and in predictable mode. 

Example 6.2 Using parallel synthesis, a series of 4(3H)-pyrimidinone derivatives IV was prepared. According to previous knowledge from these compounds, anti-HIV activity was expected [15]. 

The synthetic protocol characterizes the use of solid support with a carbonate unit and flexible linker (Merrifield resin) to construct library V. All compounds are screened on binding to the non-nucleoside binding pocket (NNBP). In vitro binding constants 5 kcal/mol are regarded as indicators of potential in vivo anti-HIV activity. 

This method characterizes the use of polymer-bound phopshine as a scavenger of the excess of hydroxyl azide in the reaction solution. The library of ca. 60 compounds is prepared with ca. 40 % average yield and ca. 90 % purity of isolated compounds meeting the criteria for high-throughput screening of their biological activity. 

---

Advances in parallel synthesis and combinatorial chemistry have given pharmaceutical companies the ability to generate an unprecedented number of compounds. In lead compound optimization efforts. 

Traditional medicinal chemistry laboratories are beginning to practice parallel synthesis and combinatorial chemistry more often. The development of manual and semiautomated devices, which improve the productivity of the synthesis process, is a reflection of this recent trend. Fully automated systems are expensive, and it is also not always easy to find adequate space in the laboratory to locate such systems. The synthesizers may have counterintuitive software and require a lot of maintenance therefore, it is often necessary to have dedicated users to operate them. Ad hoc usage by everyone in need is difficult due to the complexity of the software and scheduling issues, but the market is beginning to respond by offering smaller, substantially less expensive devices that are easy to use without learning complex software. 

Solid-phase reactions play an important role in parallel synthesis and combinatorial chemistry, particularly in the area of medicinal chemistry, where their potential has emerged as a result of the possibility of automation. Considerable attention has been focused on adapting and exploiting the advantages of solid-phase synthesis (SPS) to produce libraries of such organic compounds. In this context, transition metal-pro-... 

This issue highlights the characterization difference between parallel synthesis and combinatorial synthesis. Parallel synthesis is automated traditional organic chemistry. Each compound is made in a separate reactor, purified and characterized. There is no excuse for not fully characterizing compounds made by parallel synthesis. Jonathan Ellman s laboratory at UC Berkeley has been a pioneering academic center for solid-phase chemistry development. His philosophy is to synthesize libraries of discrete compounds in a spatially separate fashion, rather than libraries of compound mixtures, to allow for rigorous analytical characterization [48,49],... 

Parallel to these developments in solid-phase synthesis and combinatorial chemistry, microwave-enhanced organic synthesis has attracted much attention in recent years. As is evident from the other chapters in this book and the comprehensive reviews available on this subject [5, 6], high-speed microwave-assisted synthesis has been applied successfully in many fields of synthetic organic chemistry. Any technique which can speed the process of rather time-consuming solid-phase synthesis is of substantial interest, particularly in research laboratories involved in high-throughput synthesis. 

Solid-phase combinatorial synthesis can be performed using the split-and-pool technique based on the combination of variously substituted compounds together for the same reaction in an appropriate reaction step, as well as by parallel synthesis, in which all compounds are segregated during all the reaction steps (see next chapters). Although parallel synthesis is an efficient way to prepare arrays of structurally unrelated compounds, it is not necessarily a combinatorial approach conventionally based on substituent modifications of one structural motif. Thus, combinatorial chemistry is not parallel synthesis, albeit combinatorial chemistry can be performed in parallel fashion. 

Two main approaches to combinatorial chemistry are used—parallel synthesis and split synthesis. In parallel synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic instruments add different sequences of building blocks to tfie different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. 

Parallel processing of synthetic operations has been one of the cornerstones in combinatorial chemistry for years [1-6]. In the parallel synthesis of combinatorial libraries, compounds are synthesized using ordered arrays of spatially separated reaction vessels adhering to the traditional one vessel-one compound philosophy. The defined location of the compound in the array provides the structure of the compound. A commonly used format for parallel synthesis is the 96-well microtiter plate, and today combinatorial libraries comprising hundreds to thousands of compounds can be synthesized by parallel synthesis, often in an automated fashion [6]. 

As demonstrated in the previous sections of this review, microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis and/or combinatorial chemistry applications. The first example of parallel reactions performed under micro-wave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 12.22) [71]. Reactions were performed in a multimode microwave reactor in individual sealed polypropy-... 

There are two basic combinatorial chemistry techniques (1) parallel synthesis and (2) split and mix methods. They are illustrated next. 

These libraries contain a relatively small number of individuals (typically tens to hundreds) and are almost always prepared as discrete libraries using parallel synthesis and automated or semiautomated devices. Focused libraries are predominantly prepared in solution because of the easier shift from classical organic synthesis to solution-phase combinatorial chemistry, while automated purification procedures for relatively small arrays of discrete compounds in solution are common nowadays. The... 

TOOLS Program for combinatorial chemistry and parallel synthesis and custom chemical synthesis and manufacturing. 

In conclusion, parallel synthesis and more generally, combinatorial chemistry, seems to be an attractive approach in aroma research to help identifying new odorants with interesting sensory properties. It allows rapid synthesis of a large number of components in a reasonable time. The reference compoimds can be very usefril for structure elucidation of unknown odorants. 

---