Combinatorial strategy

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

A. Beck-Sickinger and P. Weber, Combinatorial Strategies in Biology and Chemistry, Wiley, Chichester, 2002. 

Figure 3.2 Schematic of Miller s metal complexation/affmity reagent dynamic combinatorial strategy. A series of monomers is allowed to rapidly equilibrate by metal complexafion. Addition of an immobilized receptor drives the selection of metal complexes with affinity for the immobilized receptor.

The cyclic pentapeptoid skeleton 23a was assembled after three consecutive U-4CRs, two of them to prepare the linear precursor b and the final one for the ring closure. The approach has been shown to be straightforward and opens the possibility for a combinatorial strategy toward a wide range of cyclic oligopeptoids. This was the first report where the peptoid backbone and the macrocycle closure were performed by consecutively employing MCRs. 

An asymmetric C-C coupling, one of the most important and challenging problems in synthetic organic chemistry, seems to be most appropriate for the creation of a complete set of diastereomers because of the applicability of a convergent, combinatorial strategy [38-40]. In Nature, such reactions are facilitated by lyases which catalyze the (usually reversible) addition of carbo-nucleophiles to C=0 double bonds, in a manner mechanistically most often categorized as aldol and Claisen additions or acyloin reactions [41], The most frequent reaction type is the aldol reaction, and some 30 lyases of the aldol type ( aldolases ) have been identified so far [42], of which the majority are involved in carbohydrate, amino acid, or hydroxy acid metabolism. This review will focus on the current state of development of this type of enzyme and will outline the scope and limitations for their preparative application in asymmetric synthesis. 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

Very generally, the identification of a molecule of interest by a combinatorial strategy requires (i) the random synthesis of a balanced library in which the different candidates are statistically equi-represented, (the over-representation of some compounds and the under-representation of others will bias the population and subsequently may affect the outcome of the selection) (ii) the efficient partitioning of candidates which display the desired property depends upon a carefully adjusted selection pressure combined with an effective procedure allowing the physical separation of the winners, and (iii) the identification of these winning molecules and their defined synthesis at high yield and low cost for further use. This means either a very sensitive analytical method to determine the chemical structure of the selected molecules must be used... 

Combinatorial Strategies for Speeding up Discovery and Optimization of Heterogeneous Catalysts on the Academic Laboratory Scale A Case Study of Hydrogen Purification for Feeding PEM Fuel Cells... 

Combinatorial Strategies for Speeding up Discovery and Optimization of Heterogeneous Catalysts... 

This third strategy aims at designing HT data acquisition procedure in such a way that more advanced information is collected, such as mechanistic and kinetic insights, as compared with the limited information obtained with the previous strategies. This newly acquired knowledge can be used in turn for further combinatorial strategies, as above described (ES or DoE) [12]. 

Pros Parallel testing has been rather widely described for decades, long before the appearance of the combinatorial strategy [26]. Therefore, even if the technology remains essentially home-made at the academic level, as stressed above, a rather satisfactory control of performances has been demonstrated simply by reproducibility tests or testing the same catalysts in all the channels of the reactor. 

As mentioned in Section 10.2.3.1, explaining the general outlines of the search strategies, HT data acquisition may also be used to obtain more advanced fundamental information, such as mechanistic and kinetic insights, than the somewhat limited information found with the previously described combinatorial strategies... 

The choice of combinatorial strategies, including the domain of investigation, the space of parameters, data management and processing techniques, appears as crucial. One option, as shown here, is to try and test sets of diverse catalyst for-... 

Diversity-oriented Synthesis of Chromophores by Combinatorial Strategies and Multi-component Reactions"... 

With optimized synthetic protocols, this combinatorial strategy was then transposed to 3-bromocoumarin derivatives 25 (Fig. 5.9) as coupling partners. 

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