Liquid-phase synthesis supports

Geckeler, K, E, Soluble Polymer Supports for Liquid-Phase Synthesis. VoL 121, pp. 31-80. Gehrke, S, H. Synthesis, Equilibrium Swelling, Kinetics Permeability and Applications of Environmentally Responsive Gels. Vol. 110, pp. 81 -144. de GenneSy P.-G> Flexible Polymers in Nanopores. VoL 138, pp. 91-106. 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

A related support frequently used for liquid-phase synthesis is methoxy-polyethyl-ene glycol (MeO-PEG). The group of Taddei has presented a general procedure for... 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

Geckeler, K. E. Soluble Polymer Supports for Liquid-Phase Synthesis. Vol. 121, pp. 31-80. 

Initially, the term Hquid-phase synthesis was used to contrast the differences between soHd-phase peptide synthesis and a method of synthesis on soluble polyethylene glycol (PEG) [5, 6]. Although soluble polymer-supported synthesis is less ambiguous than Hquid-phase synthesis, the latter term is more prevalent in the Hterature. In-keeping with previous reviews [7-12], the phrases classical or solution synthesis will be used to describe homogeneous reaction schemes that do not employ polymer supports while liquid-phase synthesis will be reserved... 

Traditionally, soluble polymers have received less attention as polymeric supports than their insoluble counterparts. A perceived problem with the use of soluble polymers rested in the ability to isolate the polymer from all other reaction components. Yet, in practice this separation is not difficult and several methods have capitalized on the macromolecular properties of the soluble support to achieve product separation in liquid-phase synthesis. Most frequently the homogeneous... 

A frequent complication in the use of an insoluble polymeric support lies in the on-bead characterization of intermediates. Although techniques such as MAS NMR, gel-phase NMR, and single bead IR have had a tremendous effect on the rapid characterization of solid-phase intermediates [27-30], the inherent heterogeneity of solid-phase systems precludes the use of many traditional analytical methods. Liquid-phase synthesis does not suffer from this drawback and permits product characterization on soluble polymer supports by routine analytical methods including UV/visible, IR, and NMR spectroscopies as well as high resolution mass spectrometry. Even traditional synthetic methods such as TLC may be used to monitor reactions without requiring preliminary cleavage from the polymer support [10, 18, 19]. Moreover, aliquots taken for characterization may be returned to the reaction flask upon recovery from these nondestructive... 

Fig. 5.1 Soluble polymers used as supports for liquid-phase synthesis.

Blettner, C. G. Konig, W. A. Stenzel, W. Schotten, T. Polyfethylene glycol) Supported Liquid Phase Synthesis of Biaryls, Synlett 1998, 295-297. 

Sauvagnat, B., Lamaty F., Lazaro, R. and Martinez, J., Polyethylene glycol (PEG) as polymeric support and phase-transfer catalyst in the soluble polymer liquid phase synthesis of ct-amino esters, Tetrahedron Lett., 1998, 39,821. 

Conventional liquid phase synthesis suffers from the limitation that each product or intermediate has to be separated from the other components of the reaction mixture. An elegant answer to this problem is to use a solid phase synthesis (SPS) approach. In such an approach the compounds are synthesized on a solid support and simple washing steps replace the laborious work up and isolation procedures. At the end of the synthesis the product is released from the solid support. The SPS of oligomers of amino acids or nucleotides is well estabilished and task chemists are facing now is the development of SPS routes for small organic molecules. 

Liquid injection molding, for silicone rubbers, 3, 674—675 Liquid ligands, in metal vapor synthesis, 1, 229 Liquid-phase catalysis, supported, for green olefin hydroformylation, 12, 855 Lithiacarbaboranes, preparation, 3, 114 Lithiation, arene chromium tricarbonyls, 5, 236 Lithium aluminum amides, reactions, 3, 282 Lithium aluminum hydride, for alcohol reductions, 3, 279 Lithium borohydride, in hydroborations, 9, 158 Lithium gallium hydride, in reduction reactions, 9, 738 Lithium indium hydride, in carbonyl reductions, 9, 713—714... 

Additionally, this methodology was transposed to liquid-phase synthesis of 2,6-dicyanoanilines using polyethylene glycol) (PEG) as support, starting with a... 

The use of supported reagents offers an attractive option for improving the quality of products prepared using solution-phase chemistry. Additionally, liquid-phase synthesis, for example using PEG, provides opportunities to combine some of the benefits of solid-phase approaches with the versatility of solution-phase synthesis. Smart methods such as resin capture for isolating specific compounds from mixtures of products will also help to increase the utility of solution-based approaches. This chapter encompasses developments in each of these areas. 

As already mentioned, components of libraries produced by the original split-mix method are discrete compounds. If the libraries are cleaved from the solid support, however, mixtures are formed. The products of the liquid phase synthesis are always mixtures. At the beginnings, finding an active component in a mixture of thousands, or millions of structurally related compounds seemed to be a task like finding a needle in a haystack. Later on, however, reliable methods have been developed to solve this problem. All these methods are based on preparation and screening of properly designed partial libraries. 

Wyndham KD, Feher FJ, Polyfunctional silsesquioxanes as supports for liquid phase synthesis, Book of Abstracts, 214th ACS National Meeting, Las Vegas, September 7-11, 1997, American Chemical Society, Washington. 

Aminomethyl-3-nitrobenzoylpolyethyleneglycols are another class of photosensitive soluble polymeric supports designed for the liquid phase synthesis of protected peptide amides 192,193) (scheme 8). These supports have been very recently used for efficient synthesis of three biologically active 14-peptideamides corresponding to the wasp venom peptides, mastoparan, mastoparan X and Polistes mastoparan 198). 

Monofunctional polyethyleneglycol supports containing benzyloxycarbonylhydra-zide, p-benzyloxybenzyloxycarbonylhydrazide and t-butyloxycarbonylhydrazide anchoring groups, 22, 23 and 24 respectively have been developed recently for the liquid phase synthesis of protected peptide hydrazides 199). 

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