Library pyrrolidines

Fig. 34 Preparation of a 4-thiazolidinone library using an ionic liquid support. Reagents and conditions a MW 100 °C, l-2h, open vessel b R"NH2, t-BuOK, MW 100-150°C, 10-20 min. R = H, Me, CH2COOH R = Pr, i-Pr, i-Bu, Bn, piperonyl, CH2CH(OMe)2, CH2CH CH2 R" = Pr, Bu, Bn, or cyclic derivatives as piperonyl, piperidine, pyrrolidine,...

A spiro[pyrrolidine-2,3 -oxindole] library <1998TL2235> has been synthesized via a three-component 1,3-dipolar cycloaddition in the solution phase. Isatins 432 were treated with L-proline or L-thiaproline and chalcone 433 in a MeOH-H20, CH3CN-H20, or dioxane-H20 solution. Spiropyrrolidines 49 (Scheme 96) were obtained as the sole products in good yield and high purity (Table 15). 

E. M., Gallop, M. A. (1995) Combinatorial organic synthesis of highly functionalized pyrrolidines identification of a potent angiotensin converting enzyme inhibitor from a mercaptoacyl proline library. J Am Chem Soc 117, 7029-7030. 

Maclean, D. Schullek,J. R. Murphy,M. M. Ni,Z-J. Gordon,E. R. Gallop, M. A. Encoded Combinatorial Chemistry Synthesis and Screening of a Library of Highly Functionalized Pyrrolidines, Proc. Natl. Acad. Sci. USA... 

Polymer-supported azomethine ylids generated from a-silylimines through a 1,2-silatropic shift, are shown to be versatile reagents suitable for the synthesis of libraries of pyrrolidine derivatives after 1,3-dipolar cycloaddition with a series of dipolarophiles. Effectively substituents R1, R2 and dipolarophiles A=B and A=B can be chosen to get the desired adduct.146... 

Rosania et al. [19] have shown this straightforward preparation to be advantageous for the transposition to a diversity-oriented, combinatorial approach to an organelle-targeted fluorescent library. Therefore, the condensation of 9 and 10 (Fig. 5.4) with pyrrolidine as a catalyst was performed in 96-well plates and the dehydration reaction was accelerated by microwave irradiation for 5 min to give 10-90% conversion. The resulting library compounds were analyzed using an LC-MS system with diode-array and fluorescence detectors and a fluorescence plate-reader to determine the absorption and emission maxima and the emission colors. 

The selected example by Maclean et al. [40] reported a 240-member encoded pyrrolidine library, whose synthetic scheme is reported in Figure 9.12. Coupling of the resin bound acid labile linker FIMPB (4-hydroxymethyl-3-methoxyphenoxybutyric acid) with the first monomer set (four Fmoc amino acids, A) was followed by its coding (tags Ti-T3), and by coding of the second monomer set B (tags T4-T6) then the second monomer set (four aldehydes, B) was added and the reactive imines were immediately reacted with the third... 

It is much easier, though, to compare encoding techniques with direct deconvolution (see elsewhere in this book) [1, 6], The two main classes of structure determination methods for pool libraries are significantly different, and clear distinctions about their usefulness can be made. The example of a 240-member (without considering diastereoisomers) mercaptoacyl pyrrolidine library, which was prepared as an encoded (secondary amine tags) [40] or as a nonencoded library and then submitted to iterative deconvolution [88], will be used for this comparison. The following considerations were either reported by MacLean et al. [40] or derived from the critical analysis of the results obtained. 

Maclean D, Schullek JR, Murphy MM, Ni ZJ, Gordon EM, Gallop MA, Encoded combinatorial chemistry synthesis and screening of a library of highly functionalized pyrrolidines, Proc. Natl. Acad. Sci. USA, 94 2805-2810, 1997. 

Of course, unities are themselves labile at neutral pH, and therefore in principle one should be able to obtain an identical result by simply mixing salicylaldehyde, amines, and zinc in buffer in the presence of DNA. In a second report in 1999, we examined exactly this possibility [6]. Once again as expected, the pyrrolidine was the amine most retained by the DNA resin in the presence of salicylaldehyde and zinc. An inherent complication of this strategy, however, is that the labile library constituents made analysis and understanding of the results of library selection difficult. Furthermore, while useful as a proof of concept study, there is no clear pathway from the metal complexes identified in these studies to compounds suitable for use in structural studies or in vivo. As we will discuss later, consideration of such issues has been an important aspect of the design of more recent libraries targeting RNA recognition. 

An Example Synthesis of a Spiro[Pyrrolidine-2,3 -Oxindole] Library... 

TABLE 8.1 Spiro [pyrrolidine-2,3-oxindole] Discrete Library L5 Chemistry Assessment and Monomer Rehearsai... 

Figure 9.7 Process/BB representation of a h)rpothetical pyrrolidine library regio- and stereochemical issues.

We screened our library to identify protein prenyltransferase inhibitors other than GGTI. To do this, we focused on P5-H6 that exhibited a slight inhibition of RabGGTase at concentrations higher than 10,000 nM. We rescreened dihydropyrroles and pyrrolidines that are related to P5-H6... 

Two enz)mies of pyrrolidine alkaloid formation responsible for the conversion of putrescine to the N-methylpyrrolinium ion have been investigated in some detail. PMT, partially purified from cultures of Hyoscyamus niger and fully characterized from Datura stramonium, has been cloned by differential screening of complementary deoxyribonucleic acid (cDNA) libraries from high- and low-nicotine-yielding N. tabacum plants (Hibi et ah, 1994). The enzyme shows considerable sequence homology to spermidine synthase but is distinct from this enz)mie as it only shows PMT activity when expressed in Escherichia coli. MPO has been isolated in pure form from N. tabacum transformed root cultures (McLauchlan et ah, 1993). It is quite widely spread in... 

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