Synthesis of mixtures

The situation may be different for lead optimization where more reliable biological data are required, e.g., for deriving more detailed structure-activity relationships. At that stage, the libraries mostly comprise fewer compounds so that erroneous biological data have a much higher impact. 

Nevertheless, the achievable purity will remain an important criterion for whether or not a reaction is suitable for solution-phase combinatorial synthesis. The extent to which this criterion can be fulfilled depends on the uniformity of the reaction and on the efficiency with which the products can be purified. Therefore, this chapter will focus on reactions that have been more or less successfully applied to solution-phase combinatorial chemistry (including parallel synthesis), and particularly on the purification techniques that have been used. 

As with solid-phase combinatorial synthesis, libraries can be prepared either as mixtures or in the form of single compounds. Nowadays, the latter strategy seems to be preferred. 

From the point of view of synthetic effort, preparation of combinatorial mixtures is by far the most economical approach. It can be done with ordinary laboratory equipment and does not take more time than the synthesis of any one of the individual components of the library. This simplicity, however, has its price firstly, the more components a mixture contains the more difficult it becomes to follow the reaction analytically and to determine the actual composition of the reaction product. Secondly, if hits are found in a biological assay, deconvolution is required. In most cases this is done via resynthesis either of the individual components or of subsets of the mixture. If the composition of the initial mixtures was carefully planned it may be possible to identify the active component(s) by simply comparing the composition of the active mixtures with those of the inactive ones. Corresponding procedures have been reported in the literature (e.g., the techniques of indexed [1,2] and orthogonal [3] chemical libraries have been used in solution-phase synthesis). However, the biological effect of a mixture may also be due to a combined action of several weakly active members, with the result that deconvolution does not identify a significantly active compound. Finally, the problem of impurities multiplies with the complexity of the mixtures. 

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The synthesis of mixture-based libraries in any of the various formats relies on the divide, couple, and recombine paradigm (Fig. 1) to assemble the mixture [13-15], In this method, the solid support is divided into appropriate portions, each portion is coupled... 

Although not identical, both the orthogonal and positional scan formatted libraries share the features that all mixtures are made at the start of the library process and only individual compound synthesis is required after the first screening of mixtures. This is an extra initial effort with regard to the synthesis of mixtures when compared to an iterative method. The advantage is that no intermediate mixture syntheses will be required. If prepared in sufficient quantity, the library can be screened over a large number of assays, and the added effort of initial mixture syntheses will be translated into an efficiency in deconvolution relative to the continual resynthesis of mixtures with iterative deconvolution. 

Synthesis of mixture libraries and deconvolution of active sublibraries... 

Synthesis of mixtures of peptides further enhanced the speed and convenience of library construction but required development of devolution methods so that active components in the mixtures could be identified. Direct methods of sequence analysis are available. Mass spectrometry is popular as are NMR methods (involving magic angle methods on single beads). Edman degradation of peptides can also be performed. These methods are popular when iterative methods result in linear polymers. 

In the proposed vapor phase processes for organic acid synthesis, carbon monoxide is passed with the vaporized aliphatic alcohol over catalysts similar in nature to those employed in the pressure synthesis of higher alcohols from hydrogen-carbon monoxide mixtures. Pressures on the order of 200 atmospheres are employed. Temperatures of about 200° to 300° C. are preferred but it is necessary to use somewhat higher ones in order to obtain sufficient reaction. Mixtures of the oxides of zinc and chromium or copper, promoted with alkali or alkaline earth oxides, are suitable catalysts for the formation of carbon-carbon linkages.97 Catalysts composed of an alkali, chromium, and molybdenum have been claimed for the synthesis of mixtures of higher alcohols, aldehydes, acids, esters, etc., from carbon monoxide and vaporized aliphatic alcohols as methanol, ethanol, etc., at temperatures of about 420° C. and a pressure of 200 atmospheres.98... 

Determinataion of optical purity synthesis of mixture of 2-phenylpropionic... 

DETERMINATAION OF OPTICAL PURITY SYNTHESIS OF MIXTURE OF 2-PHENYLPROPIONIC ACID AND 3 -PHENYLPROPIONIC ACID... 

Working at high pressures I.G. came first to a synthesis of mixtures of different organic compounds and later to the specific synthesis of methanol. 

E. Positional Scanning Solid-Phase Synthesis of Mixture-Based Organic and Heterocyclic Libraries from Amino Acids and Linear Peptides... 

A major problem associated with the synthesis of mixtures is that not all the reaction partners will couple with the same reaction rate and this will give rise to a non-equimolar distribution of the products. This problem could be solved more or less efficiently in the field of peptide and oligonucleotide chemistry by adjusting the concentrations of the amino acid- and nucleic acid components according to their respective reaction rates. In the field of combinatorial synthesis of small molecules this problem is much more severe. 

A synthesis of mixtures of Cg to C,2 hydrocarbons, their separation, hydrofonnyla-tion, and hydrogenation to produce alcohols having different number of caibon atoms is described in the invention. Some fractions of these alcohols are used for a production of plasticizers with the remaining hydrocarbon stock being used as a motor fuel." ... 

Scheme 3. Synthesis of mixture of 9Z- and 9E-dodecenylacetates Enarmonia formasana).

Tri(cyclopentyl)borane in diglyme added at 0° to Li-n-hexylacetylide under hexane, the volatile solvent removed, methyl tosylate added at -78°, the cooling bath removed, warmed 2 hrs. at 40°, then oxidized with alkaline H2O2 -> product. Y 88%. F. e., also with other alkylating agents such as bromides, sulfates, or oxonium salts, protonation with methanesulfonic acid, and synthesis of mixtures of cis- and trans-ethylene derivs., s. A. Pelter, C. R. Harrison, and D. Kirkpatrick, Chem. Commun. 1973, 544. 

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