High-performance liquid combinatorial synthesis

As in other organic synthesis laboratories, high-performance liquid chromatography (HPLC) is also intensively used for separations in combinatorial chemistry laboratories. Using standard detectors such as ultraviolet (UV),... 

The purity control and the structure verification of compound collections from automated synthesis and combinatorial chemistry play an essential role in the success of medicinal chemistry programs. High performance liquid chromatography (HPLC), mass spectrometry (MS), and liquid chromatography-mass spectrometry (LC-MS) techniques are generally accepted as the most appropriate means of characterization (1,2). While these analytical methods are fast and easy to automate, they do not provide sufficient structural and quantitative data about the desired products. 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

The simplicity of these transformations and high yields in both steps indicate that the preparation of compounds of type 106 from 1, 2 can easily be automated and performed as liquid phase parallel synthesis. The starting materials 1,2 can also be put on a polymer support to obtain combinatorial libraries of l,l -di-, l,r,2 -tri-, l,l, 2, 2 -tetra-, l,r,2, 3 -tetra-, l,r,2, 2, 3 -penta- and... 

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