Homogeneous soluble polymeric supports

An extension of the combinatorial synthesis in solution is achieved by the use of soluble polymeric supports [80, 81], which combines some of the advantages of chemistry in solution and on solid phase. The so-called liquid-phase combinatorial synthesis is based on the physical properties of poly (ethylene glycol) monomethyl ether. The polymer is soluble in a variety of aqueous and organic solvents, which allows reactions to be conducted in homogeneous phase whereas the propensity to crystallize in appropriate solvents facilitates the isolation and purification of the compound at each step of the combinatorial synthesis. 

Wandrey and co-workers pioneered the use of homogeneous catalysts bound to soluble supports in continuously operating membrane reactors (CFMRs). In 1996 Kragl and Dreisbach reported on a chiral polymer-enlarged homogeneous catalyst, which was used for the enantioselective addition of diethylzinc to benzaldehyde [Eq. (3)] [9]. The catalyst consisted of a soluble polymeric support, a copolymer of 2-hydroxyethylmethacrylate and octadecyl methacrylate, combined with a,a-diphe-nyl-L-prolinol as the active organocatalytic site (2). 

Polymeric supports of variable solubility have been investigated as an alternative to insoluble supports used in solid-phase synthesis. Reactions are performed in homogeneous media by choosing an appropriate solvent that solubilizes the polymer, and purification is performed by precipitation. This methodology benefits both solution-phase and solid-phase syntheses. Moreover compound characterization can be easily undertaken at any stage of the synthesis, since the support is soluble in standard spectroscopic solvents. A direct real-time control is possible, whereas a solid-phase protocol relies on a cleave and analyze strategy that consumes compound, imparts delay, and thus can only be accomplished at the end of synthesis. For these reasons soluble polymeric supports are preferred to conventional insoluble supports (resins, plastic pins), and they are compatible with analytical techniques such as NMR and mass spectrometry. 

Another occasionally useful alternative to the above-described methods is to employ a liquid-phase synthesis on soluble polymeric supports. In this case, the reactive molecules such as poly(ethyleneoxide) are coupled to a polymer backbone and brought into contact with reagents within a homogeneous medium (solvent). On completion of the reaction, the polymeric matrix is separated from the system... 

Soluble polymers have also been used as support. These exploit the combined advantage of homogeneous with those of soHd-phase chemistry [36]. PEG linked 5-bromothiophene-2-carboxyUc acid was cross-coupled with several arylboronic acids under microwave irradiation (constant power of 75 W) using water as the solvent (Scheme 17). Interestingly, microwave irradiation gave less ester cleavage than classical heating (70 °C). The polymeric support remained stable under both conditions. 

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... 

POE 6000 was used as polymeric support, a soluble polyethylene glycol derivative functionalized at both termini with an amino group and with an average molecular mass of 6000 Da [62-63]. After completion of the homogeneous reactions it can be precipitated, filtered off, and washed with diethyl ether, thereby facilitating the separation of surplus reagents and the side products. Furthermore it allows for NMR spectroscopic monitoring of the reactions [64]. 

In addition to titanium-based Ziegler-Natta catalysts, vanadium-based systems have also been developed for PE and ethylene-based co-polymers, particularly ethylene-propylene-diene rubbers (EPDM). Homogeneous (soluble) vanadium catalysts produce relatively narrow molecular mass distribution PE, whereas supported V catalysts give broad molecular mass distribution.422 Polymerization activity is strongly enhanced by the use of a halogenated hydrocarbon as promoter in combination with a vanadium catalyst and aluminum alkyl co-catalyst.422,423... 

The most common polymer supports used for chiral catalyst immobilization are polystyrene-based crosslinked polymers, although poly(ethylene glycol) (PEG) represents an alternative choice of support. In fact, soluble PEG-supported catalysts show relatively high reactivities (in certain asymmetric reactions) [le] which can on occasion be used in aqueous media [le]. Methacrylates, polyethylene fibers, polymeric monoliths and polynorbornenes have been also utilized as efficient polymer supports for the heterogenization of a variety of homogeneous asymmetric catalysts. 

POE 6000 was used as the polymeric support, a soluble polyethyleneglycol derivative functionalized at both termini with an amino group and with an average molecular mass of 6000 Da[323-3241. After completion of the homogeneous reactions... 

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