Parallel library

The tremendous development of combinatorial chemistry during the last few years has contributed to increasing steadily the options for a chemist to synthesize a chemical library, and many excellent reviews have dealt extensively with different aspects of this exciting new discipline. Solid-phase [1] or solution-phase [2] libraries, parallel synthesis [3] or mixtures of compounds [4] and large or small libraries, are only a few of the alternatives, and each one of... 

The library was tested using a known competition assay (142), and binding activities for the 30 pools were acquired. While the pool complexity was low, as was therefore the possibility of false positives/artifacts, the extreme similarity of all the library components with known calcium channel blockers (compare the monomers in Fig. 7.19 leading to nifedipine. Mi = A, M2 = K, M3 = T, with all the others) meant a constant level of activity was to be expected for all pools. For such a small focused library, parallel synthesis would probably have been more suitable to acquire a refined SAR, but we will see how iterative deconvolution succeeded anyway in both identifying active individuals and showing significant activity differences for different pools. The screening results are reported in Table 7.1. Five pools showed activity > 1 xM, 12 pools had an activity between 100 nM and 1 xM, and 11 pools were active between 10 and 100 nM. Two pools showed an activity around 7-8 nM They both contained methyl acetoacetate (M2, K) as well as 2-fluorobenzaldehyde (M3, P) and 2-nitroben-zaldehyde (M3, T), respectively. 

Almost all of the analytical characterization tools (e.g., HPLC, NMR, FTIR, and LC/MS) are serial-based techniques, and parallel synthesis is inherently parallel. Consequently, this led rapidly to a new bottleneck in the discovery process (i.e., the analysis and purification of compound libraries). Parallel synthesis suffers from some of the same shortcomings of split and mix synthesis (e.g., the expected compound may not be pure, or even synthesized in suffi-... 

NWChem is part of the Molecular Science Software Suite (MS ) which has been recognized by R D Magazine as one of the 100 most technologically signihcant new products and processes of 1999. The other elements of MS are Ecce, which is a problem-solving environment, and ParSoft, which is the underlying libraries and tools for parallel communication and high-performance input/output. All of the MS components are available publicly. 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

Fig. 3-10. EUipticities measured at 260 nm for separations aehieved with the members of the parallel library of 16 dipeptide CSPs (Reprinted with permission from ref. [87]. Copyright 1999, Ameriean Chemieal Soeiety.)...

Our group also demonstrated another combinatorial approach in which a CSP carrying a library of enantiomerically pure potential selectors was used directly to screen for enantioselectivity in the HPLC separation of target analytes [93, 94]. The best selector of the bound mixture for the desired separation was then identified in a few deconvolution steps. As a result of the parallelism advantage , the number of columns that had to be screened in this deconvolution process to identify the single most selective selector CSP was much smaller than the number of actual selectors in the library. 

A chemical library is a precisely defined collection of different chemical compounds. Chemical libraries can be either prepared by parallel synthesis or by split-and-recombine synthesis. 

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

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. 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

As in the case of benzimidazole, a parallel synthesis of benzoxazoles was described. The authors report that mixing directly differently substituted o-amino phenols 193 with acylating agents 194 and heating at 200 °C for 10-15 min under microwave irradiation, a collection of benzoxazoles 195 was obtained (Scheme 70). With this reaction, a 48-member library of benzoxazoles with different substituents on the aromatic rings was obtained [125]. 

---