Solution phase libraries

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Recently, a novel method for the synthesis of a library of substituted prolines with microwave technology [95] has been described. In the first step, 1 equivalent of an amine is added to 1.1 equivalents of an aldehyde in 1,2-dichloroethane (DCE), with subsequent irradiation at 180 °C for 2 min. In the second step, 0.85 equivalents of the maleimide are added and the resulting solution is heated at 180 °C for an additional 5 min. This methodology allowed the production of a solution-phase library of 800 compounds with a crude purity between 65 and 82% (Scheme 9.45). The compounds were purified by solid-supported reagent scavenging to afford the final products with a purity between 90 and 98% and in 79-85 % yield [96]. 

For solution-phase libraries that are composed of mixtures of compounds, the difficulty of analysis escalates with increasing numbers of compounds. Typically, large mixtures of compounds are not analyzed before screening, whereas small ones may be analyzed for reaction completeness using mass spectrometry, HPLC, NMR, or combinations thereof. The identification and analysis of active compounds from these mixtures is painstakingly tedious, and often complete characterization is possible only after deconvolution procedures and resynthesis of the active compound. For solid-phase libraries, the methods currendy developed are discussed below. 

Solution-phase library Resin scavenging Resin capture Split and mix... 

In a soluble polymer strategy comparable to resin-capture [145], Janda reported a MeO-PEGsooo-supported dialkyl borane reagent (31) that was used in the purification of a solution-phase library of y9-amino alcohols [146]. Purification was achieved by simply adding (31) to the crude reaction mixture followed by subsequent precipitation of the polymer with diethyl ether to give polymer-supported 1,3,2-oxazaboroU-dine (32) (Scheme 5.2). The /9-amino alcohol product could then be released from the soluble support by treatment with acid. In a two-step synthetic strategy that is readily amendable to automation, the isolation of a small library of /9-amino alcohols was accomplished with all compounds obtained in >80% purity. 

As an example, the bifimctional epoxy ester core (+)-2 was reacted with building blocks 3-18 to yield solution-phase library NGL127A443 containing nominally 512 substitutionally and stereochemically unique compounds (Figs. 3.3, 3.4). Of these, 82% have a molecular weight unique to 0.050 amu. This library was combined with four other 500-member libraries to form a 2500-member primary library that was screened against the important antibacterial target dihydrofolate reductase (DHFR, also known as Fol-A). 

In practice, this array-based method is ineffective, primarily because there is insufficient material on the surface of the array to compete with solution-phase library members. As discussed in Chapter 3, however, implementing the RBDCC concept on resin beads produced a viable method for... 

Anionic resin capture of solution-phase library products has also been reported. The anion exchange resin A-26 hydroxide 6 was used in a dual capacity to mediate Dieckmann condensations of solution-phase library intermediates and also to affect resin capture of the formed tetramic acids as polymer-bound intermediates (Scheme 7).79 Rinsing, followed by tri-... 

Khmelnitsky YL, Michels PC, Dordick JS, Clark DS, Generation of solution-phase libraries of organic molecules by combinatorial biocatalysis, in Molecular Diversity and Combinatorial Chemistry (Eds. I.W. Chaiken, K.D. Janda), pp. 144-157, 1996, American Chemical Society, Washington. 

Synthetic Organic Libraries Solution-Phase Libraries... 

The previous chapters have shown how combinatorial technologies have always been associated with chemistry in the SP and how this chemistry is flexible enough to provide libraries in many formats. More recently, there has been growing interest in libraries of small organic molecules prepared under homogeneous reaction conditions. These libraries are usually called solution-phase libraries and will be discussed in this chapter to demonstrate how they present a useful alternative to SP libraries and how they can provide the chemist with more options with regards to the choice of library format. 

SYNTHETIC ORGANIC LIBRARIES SOLUTION-PHASE LIBRARIES... 

Having said this, the synthesis of solution-phase libraries is possible, and indeed is more appropriate, than the corresponding SP chemistry under certain circumstances. The value of such libraries is discussed in the following sections, but it is appropriate to stress the concept of complementarity, rather than mutual exclusivity of the solution and SP library formats. The goal for a combinatorial chemist is always to select the best library format according to the needs of the project without exclusion of individual options due to personal preference. 

SYNTHETIC ORGANIC LIBRARIES SOLUTION-PHASE LIBRARIES 8.2 SOLUTION-PHASE DISCRETE LIBRARIES... 

Figure 8.5 Logical steps to a successful solution-phase library synthesis.

The synthetic scheme used to prepare the library is shown in Fig. 8.10. The reaction steps, amide coupling, ozonization, reductive amination, and catalytic reduction, are trivial for carbohydrate substrates, and the authors decided that assessment of the chemistry for the library synthesis would not have been necessary. The availability of 8.19 in multigram quantities reduced the significance of potentially low-yielding steps. The rehearsal of the monomers was also avoided because of the small size of the two monomer sets Mi (four Fmoc-protected a-amino acids, Fig. 8.10) and M2 (six amines. Fig. 8.10), which were inspired by a model for the interaction between paromomycin and RNA (55). Finally, such a small array could be considered as a model library for a much larger solution-phase library of potential RNA binding molecules. 

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