Pyrrole-library

Application of the Ugi reaction to the synthesis of diverse pyrrole libraries has been limited by a lack of commercially available isocyanides. To circumvent this problem, Armstrong has... 

Figure 8.46 Synthesis and purification of the solution-phase, discrete pyrrole libraries L22 and L23 using the supported reagents 8.48, 8.58, 8.76, 8.92, 8.95, 8.97.

Table 17.3. Building blocks for the pyrrole library synthesis.

Figure 17.17. Automated HPLC-MS-analysis of ten pyrrole libraries (PYL-1-PYL-I0).

Appendix 17.1. Mass spectrometric data of the pyrrole library PYL-1. 

Pyrrole is one of the most prominent heterocycles, having been known for more than 150 years, and it is the structural skeleton of several natural products, synthetic pharmaceuticals, and electrically conducting materials. A simple access to the pyrrole ring system involves the conversion of cyclic anhydrides into five-membered imides. Mortoni and coworkers have described the conversion of 2-methylquinoline-3,4-dicarboxylic acid anhydride to a quinoline-3,4-dicarboximide library by treatment of the anhydride with a diverse set of primary amines under microwave conditions (Scheme 6.180) [341]. The authors studied a range of different conditions, including dry media protocols (see Section 4.1) whereby the starting materials were adsorbed onto an inorganic support and then irradiated with microwaves. For the transforma-... 

Most practical cases of parallel synthesis are, of course, considerably more complex than this example. For instance, in 2004, researchers at the University of Cologne in Germany and the Chemspeed Company reported on their efforts to obtain a better understanding of the way in which cell receptors work. They synthesized a library of 24 forms of a compound called 2-(guanidiniocarbonyl)-lFI-pyrroles, known to bind... 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Fig. 2.3.8. A tripeptide-based library of cationic guanidinio-carbonyl pyrrole receptors 7 designed for the binding of Val-Val-lle-Ala, a tetrapeptide representing the C-terminus of Ap.

Workers at Ontogen [82,83] reported the use of the OntoBLOCK system which utilizes a Tecan robot. They have implemented this technology for solid-phase synthesis to generate over 50 000 compounds corresponding to libraries of pyrroles, phosphonates, phosphinates, lactams, imidazoles, hydantoin imides and thioimides, oxazoles, and b-lac-tams. These libraries have resulted in potent and selective inhibitors of iNOS, PTPases and cdc25 phosphatase and compounds that reverse the P-glycoprotein (Pgp)-based multiple drug resistance (MDR) phenomenon in cellular assays and in animal models [98],... 

Scheme 5, Preparation of an array of tri-substituted pyrrole derivatives 4. An example of increased efficiency - Library Synthesis...

The Paal-Knorr synthesis of furans as well as thiophenes and pyrroles has been carried out on solid support and a library of heterocyclic compounds has been prepared <2003SL711>. It has been shown that the acid-catalyzed synthesis of 2,3>4-substituted furans from 1,4-diketones can be assisted by microwave irradiation <20040L389>. 

A Comprehensive Example Synthesis and Purification of Libraries of Tri- and Tetrasubstituted Pyrroles... 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

Scheme 4 Human NK-1 libraries based on a spiropyrrolo-pyrrole template with the inclusion of the bis-trifluoromethyl benzoyl moiety to provide the desired selectivity...

Furo[3,2-fe]pyrroles were synthesized from commercially available 5-bromofuran-2-carbaldehyde via a 4-step transformation <03TL4257>. These procedures show the divergence and allow for the potential for the construction of compound libraries. 

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