Traceless and stereoselective synthesis of tetrahydro-beta-carbolinethiohydantoins by microwave irradiation.

Combinatorial chemistry provides a powerful tool for an incessant demand of novel chemical entities from medicinal chemistry and has greatly influenced the whole gamut of drug discovery process. In recent years it has been experiencing a paradigm shift with special emphasis laid on liquidphase methodologies.1,2 Though the idea of a macromolecule acting as a support for organic reactions was born with the synthesis of peptides,3 it has now grown into an independent methodology for creating a variety of nonpeptidic, drug-like molecular libraries,4,5 signaling new vistas in classical and combinatorial synthesis.6 In an inimitable way the soluble polymer supported organic synthesis retains the advantage of the homogeneity of the classical organic reaction whose progress can be monitored by conventional analytical techniques.7 In addition to this, the easy product isolation by precipitation, high yields, and compatibility with microwave (MW) irradiation8,9 have made this method highly suitable for a multistep organic synthesis involving a variety of functional group interconversions. Polymer supported reactions in which the macromolecular carrier does not leaVe behind any structural imprint on the target molecules are referred to as traceless syntheses, which are a new trend in both solid-phase10 and liquid-phase11 methodologies. Heterocycles are versatile molecular scaffolds, on to which meaningful structural diversity can be introduced to vary the stereochemical and physicochemical properties of the resulting compounds, thus tailoring them for better membrane transport and receptor binding in biological systems. Tetrahydro-â-carbolines are one such class of semirigidized tricyclic heterocycles,12 which are found to occur as mammalian13 and plant alkaloids, like jafraine,14 exhibiting a wide range of biological activities.15-17 The tetrahydro-â-carbolines such as demethoxyfumitremorgins have been isolated from the fungal species, some of which have been found to exhibit antiviral,18 topoisomerase II inhibiting,19 and protein kinase and cell cycle inhibiting20 activities (Figure 1). Because of their potential biological properties, these tetraand polycyclic â-carbolines have been synthesized by classical21,22 as well as solid-phase23-26 methods. The design concept of the presently synthesized molecular library has originated from the recognition of the biological role of the thiohydantoin moiety. A large number of thiohydantoins have been associated with calcium mobilization,27 inhibition of glycogen phosphorylases,28 aldose reductase inhibition,29 anti-HIV,30 and anti-leukemic31 activities. Thus the generation of a combined tetracyclic skeleton ressembling drug-like molecules has a substantial intellectual appeal. The present paper demonstrates successful application of liquid-phase methodologies toward the parallel stereoselective synthesis of thiohydantoin fused tetrahydro-â-carbolines powered by the microwave irradiation. Application of microwave irradiation for organic reactions has emerged as a practical technique to reduce reaction times and enhance the yields, thus speeding up the drug discovery process.32,33 It has been applied by our group, leading to the generation of the molecular libraries of thioxotetrahydro pyrimidinones34 and hydantoins.35 The enhanced loading capacity of the dihydric poly(ethylene glycol), PEG-4000(1), has been used in the stepwise synthesis toward the target molecular libraries (Scheme 1). The synthesis was initiated by the generation * Corresponding author: cmsun@mail.nctu.edu.tw. © Copyright 2006 by the American Chemical Society