Reagent selection approaches

As we mentioned earlier, the time that is available for each diversity task will likely depend on the nature of the task. Reagent selection may need to be done in a hurry, whereas compound acquisition studies may be afforded rather more time. In the former case, it is clear that the computer time required for diversity analysis/library design must not exceed that available (possibly only days if the library chemistry is already developed, longer if the chemistry is new). For many product-based reagent selection approaches, CPU time is at present a very real obstacle to what might be done. It is to be hoped that more efficient algorithms and exploitation of parallel computation techniques will help alleviate the current difficulties. More fundamentally, the development of approaches based on Markush representations may offer a solution in instances where only simple 2-D descriptors are employed. ... 

CF3C02Et, Et3N. CH3OH, 25°, 15-45 h, 75-95% yield. A polymeric version of this approach has also been developed. This reagent selectively protects a primary amine in the presence of a secondary amine. ... 

A potentially more sensitive and selective approach involves reaction of formic acid with a reagent to form a chromophore or fluorophore, followed by chromatographic analysis. A wide variety of alkylating and silylating reagents have been used for this purpose. Two serious drawbacks to this approach are that inorganic salts and/or water interfere with the derivatisation reaction, and these reactions are generally not specific for formic acid or other carboxylic acids. These techniques are prone to errors from adsorption losses, contamination, and decomposition of the components of interest. Enzymic techniques, in contrast, are ideal for the analysis of non-saline water samples, since they are compatible with aqueous media and involve little or no chemical or physical alterations of the sample (e.g., pH, temperature). 

With the aid of electron tunneling it appears possible to regulate the selectivity of redox conversions. For practically important reactions this has not been realized so far, but that this approach may prove to be useful is demonstrated, e.g. by the data presented in Table 6. In this table, a comparison is made between the rate constants for reactions of three different acceptors with hydrated electrons in liquid water at 298 K and the characteristic times, t, for reactions of the same acceptors with trapped electrons in solid water-alkaline glasses at 77 K. The values of x have been calculated using the values of ve and ae from Ref. [21]. It can be seen in the liquid, when due to diffusion the reagents can approach to within short distances of each other (direct collisions), that the rate constants for all three... 

Remarkably, Schreiber was able to use every single functionality of 46. Seven different highly selective pairing reactions were performed, to obtain seven different scaffolds (A-G), which is quite remarkable since they are all obtained from one single substrate. To come back to a term earlier introduced, this is an example of a reagent-based approach since a single substrate is converted by different reaction conditions, producing a diversity of scaffolds [42]. 

Fluorescence has been also selected as a detection mode for an improved sensitivity and selectivity in the HPLC determination of microcystins and nodnlarin (James and James 1991). This method uses a post-colunm system, whereby the arginine residne of microcystin-LR was derivatized with a fluorescent reagent. This approach obviously hmits the application to toxins containing atgitune, e g., nticrocystin-LR, and toxins snch as microcystin-LA. 

The isotope-coded affinity tag (ICAT) technique involves differential labeling of two different protein populations on the side chain of reduced cysteinyl residues using one of two chemically identical but isotopically different ICAT reagents (19). By incorporating a biotin affinity tag into the ICAT reagents, selective isolation and purification of labeled peptides substantially reduces sample complexity. The ICAT approach has been applied successfully to the systematic identification and quantification of proteins contained in the microsomal fraction of cells... 

There are two different approaches that can be taken to reagent selection. In reagent-based selection, each pool of reagents is handled independently. An alter-... 

To obtain catalytically active compounds, a phosphine or a sulfide substituent has to be introduced in the position adjacent to the amine in the cyclopentadienyl ring. This is achieved by a metalation/substitution sequence. The metalation with alkyllithium reagents is a highly diastereoselective process which produces the diastereomers in a ratio of 96 421 22. Thus, from the (R)-amine, the (/ ,p/ )-lithioamine is obtained in high yield. As an alternative to the lithiation procedure, mercuration and cyclopalladation have been used for the preparation of phosphine derivatives32, however, this is a less convenient and less selective approach. 

A very mild and selective approach to aryl- and hetaryliodonium chlorides 282 is based on the reaction of aryllithium 280 (generated in situ from bromoarenes and butyllithium) with ( )-chlorovinyliodine(in) dichloride (18) (Scheme 2.82) [71,88,89,403,404]. Tlie iodonium transfer reagent 18 is prepared by the reaction of iodine trichloride with acetylene in concentrated hydrochloric acid (Scheme 2.8 in Section 2.1.3.2) [403] caution this compound is highly unstable and should be handled and stored with proper safety precautions [71]. However, the iodonium transfer procedure with reagent 18 is particularly useful for the preparation of bis(hetaryl)iodonium chlorides 283 from the appropriate nitrogen heterocycles 282 (Scheme 2.82) [71]. 

The reversal of facial selectivity was ensured by two rationally designed structural features i) the methyl substituent at C2, which imposes a fixed enamine conformation (Figure 11.4A) and ii) the distal carbo>ylic acid at C4, which successfully directs the facial-selective approach of the reagents (Figure 11.4B). 

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