Merrifield linker

For this solid-phase approach, conventional iPrOCH2-functionalized polystyrene resin (Merrifield linker) was employed. After attachment of the requisite substrate, the resin was pre-swollen in a solution of barium(II) hydroxide in N,N-dimethyl-formamide within an appropriate sealed microwave vial. The vial was heated in the microwave cavity for 5 x 2 min cycles (overall 10 min) with the reaction mixture being allowed to cool to room temperature in between irradiation cycles (Scheme 7.50), leading to comparatively modest isolated yields of hydantoins. 

MAMP (Merrifield, Alpha-MethoxyPhenyl) resin 44 is an alternative to aldehyde linkers to construct TV-substituted amides [53], Nucleophilic displacement of the benzylic chloride with an amine followed by acylation yielded a secondary amide which was released upon a low ( 10%) concentration of TFA (Scheme 16). 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

These authors developed the use of a 4-alkyloxybenzyl ether-type linker attached to the Merrifield resin via an ester function that allowed the cleavage of the oligosaccharides under two different conditions. Using the reactivity of the activated... 

In our first attempt to bind linker-modified bis(pyrazol-l-yl)acetic acids to a solid phase we used Merrifield resin, which is one of the most popular solid phase supports. Since Merrifield polymer was designed to bind carboxylic acids, we used the ester methyl 2,2-bis(3,5-dimethylpyrazol-l-yl)-3-hydroxypropionate (52) instead of the 2,2-bis(3,5-dimethylpyrazol-l-yl)-3-hydroxypropionic acid (49). 

Grafting on the resin was achieved via a nucleophilic substitution of the benzylic chlorine by the deprotonated OH-linker of 52 (Scheme 29) by using a mixture of KO Bu, 18-crown-6 and CsBr. Determining the nitrogen content of solid phase samples by elemental analyses was accomplished, to verify the functionalization of the polymer. This enables calculation of the degree of functionalization. Usually, an occupancy of more than 20 percent of the theoretical sites was achieved. Saponification of the functionalized Merrifield resin P-52 leads to the monoanionic NJ, 0 functionalized solid phase. Subsequent reaction with [ReBrtCOlsJ afforded the polymer mounted tricarbonyl rhenium complex P-52-Re (Scheme 29). 

As the pioneering development of Merrifield [21] and Wang [22] are based on the benzyl linker type, this type represents the starting point of modern linker development. 

Another variant of a polymer-bound methyl 2 -(4-hydroxybutyl)-2-chloro-2-cyclopropylideneacetate 280 was prepared using a Merrifield resin containing a hydroxyethyl end group with a hydroxymethyldihydropyranyl (DHP) linker 284... 

In preparing these various libraries, extensive use is made of solid phase synthetic methods. These methods are all derived from the solid phase peptide synthesis (SPPS) method developed by Merrifield in 1963. When performing a large number of syntheses, it is preferable to perform the synthetic steps on a solid bead rather than completing the entire synthesis in the solution phase. The solid-phase technique makes byproduct removal and final compound purification easier. The organic chemistry literature contains a wealth of different types of solid-phase supports and novel linkers for attaching the synthetic substrate to the bead. 

---