Solution-phase parallel synthesis

The high level of diversity possible in each of the three conqmnents coiq>led with our desire to rapidly develop a structure activity relationship and identify potential field candidates led us to choose a positional scanning approach to nanow each reactant set We would fiien do combinatorial crosses of the best amines wifii the best carbonyl conqmnents with the best olefins to identify the optimally active analogs. The synthesis was carried out in parallel using solution phase liquid handling methods and filtration blocks to collect die precipitated products. 

If small or medium libraries for lead optimization are demanded and all synthetic products are to be screened individually, most often parallel synthesis is the method of choice. Parallel syntheses can be conducted in solution, on solid phase, with polymer-assisted solution phase syntheses or with a combination of several of these methods. Preferably, parallel syntheses are automated, either employing integrated synthesis robots or by automation of single steps such as washing, isolation, or identification. The latter concept often allows a more flexible and less expensive automation of parallel synthesis. 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Scheme 3.56. Solution-phase parallel synthesis of rac-homosilatecan analogues (3-216).

Tietze and coworkers developed two new domino approaches in the field of combinatorial chemistry, which are of interest for the synthesis of bioactive compounds. Combinatorial chemistry can be performed either on solid phase or in solution using parallel synthesis. The former approach has the advantage that purification of the products is simple and an excess of reagents can be used. This is not possible for reactions in solution, but on the other hand all known transformations can be used. The Tietze group has now developed a protocol which combines the... 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

A parallel solution-phase asymmetric synthesis of a-branched amines has been reported by Ellman and coworkers based on stereoselective addition of organomag-nesium reagents to enantiomerically pure tert-butanesulfinyl imines [156]. Micro-wave heating was utilized in two of the steps of this synthesis of asymmetric amines, both for the imine formation and for the resin capture (Scheme 7.128). 

Kirschning A, Monenschein H, Wittenberg R (2001) Functionalized polymers - emerging versatile tools for solution-phase chemistry and automated parallel synthesis. Angew Chem Int Ed 40 650-679... 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

Many of these new techniques are especially suited to the preparation of combinatorial libraries by solution phase parallel synthesis. This chapter provides a brief introduction to the concepts of strategy level purification, and then introduces fluorous chemistry with representative examples of reactions, reagents and techniques. 

D. L. Boger, C. M. Tarby, P. L Myers, L H. Caporale, Generalized Dipeptidomimetic Template Solution Phase Parallel Synthesis of Combinatorial Libraries , J. Am Chem. Soc. 1996,118,2109. 

Although it uses an all-liquid environment, like traditional procedures, the methods of solution-phase synthesis (also called parallel synthesis or multiple parallel synthesis ) are distinct. The difference is illustrated below. 

An important difference between combinatorial or parallel DOS and, for example, total synthesis is the high number of synthesized compounds, which renders conventional purification procedures such as flash chromatography impractical, at least if they have to be performed after every step. Synthesis on solid support avoids these problems to some extent if high conversions can be achieved with excess reagent or selective release strategies (see above). To do solution phase DOS, selective, high yield reactions or selective purification processes are required. 

---