Merrifield polymer

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). 

A control experiment with the unfunctionalized methyl bis(3,5-dimethylpyrazol-l-yl)acetate (51) showed no occupancy of the polymer sites and subsequently no A and A" signals but a typical IR spectrum of Merrifield polymer. Therefore, the results of our experiments prove a facial coordination of rhenium(I) by the monoanionic NJ), 0 tripod ligand as well as a solid phase fixation of the ligand and the resulting tricarbonyl complex (68). 

S)-2-Aminopropyl benzyl ether, polymer-supported reagent. The polymer is prepared by reaction of the N-phthaloyl derivative of (S)-2-aminopropanol with the Merrifield polymer in the presence of KH and 18-crown-6 in THF/HMPT followed by hydrazinolysis. 

The first report of a polymer-supported approach to this reaction appeared in 1987 [48]. Enantiopure amino alcohols such as ephedrine, prolinol, and 3-exo-amino-isoborneol were attached to Merrifield polymer. The use of polymer-supported 3-exo-aminoisoborneol 40 resulted in quite high enantioselectivity ( 95 % ee) in the ethylation of aldehydes with diethylzinc (Eq. 15), a result comparable with those obtained from the corresponding low-molecular-weight catalyst system (Eq. 16). A similar system was also reported in 1989, this time using ephedrine derivatives (41,42) and prolinol derivative (43) [49]. A methylene spacer was introduced between the polymer and the amino alcohol to improve activity [50]. Despite this the selectivity was always somewhat lower than that obtained from the low-molecular-weight catalyst (44). These chiral polymers were all prepared by the chemical modification method using Merrifield polymer. 

A mixture of 10.0 g of chloromethylated polystyrene (Merrifield polymer) (2.36 mmol of Ci g) and 11.7 g (70.8 mmol) of (-)-(lR,2S)-ephedrinc in 80 mL of DMF is stirred at 85 C for 4 d. The polymer is then filtered and washed repeatedly with EtOH, H20, and THF/H20 1 1, until no chloride is found in the wash liquid. Washing is then continued with THF and EtOH. After drying at 40 JC, 13.01 g of polymer are obtained. Nitrogen analysis indicates a loading of ephedrine corresponding to 1.81 mmol/g, while no chlorine remains on the polymer. 

Norbornadiene may undergo cycloaddition either once or twice the latter process is not usually a major complication 30-60 l o yields with simple acetylenes are typical and are further improved by adding a phosphine oxide [3, 99]. Under thermal conditions yields of cyclopentenones are limited by side-reactions of both diene and acetylene with the cobalt reagent. Cycloaddition with 4-pentyn-l-ol is such a case [Eq. (40)]. Much better yields, at the expense of some stereoselectivity, are obtained using an amine oxide to facilitate CO loss and alkene coordination [100]. Prior attachment of the alkynol to a Merrifield polymer is another method to suppress interfering processes and improve yields (Eq. (41)] (101). 

An example of the first type is the nthesis of cystine peptides. Tri-Cys-Cys-Ala-0-CHj-( was synthesized on a Merrifield polymer. 

Merrifield polymer resins are often used as substrates for polymer brush synthesis using NMP. To achieve this, TEMPO is reduced with sodium ascorbate. 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

Metal ion complexes. These classic CSPs were developed independently by Davankov and Bernauer in the late 1960s. In a typical implementation, copper (II) is complexed with L-proline moieties bound to the surface of a porous polymer support such as a Merrifield resin [28-30]. They only separate well a limited number of racemates such as amino acids, amino alcohols, and hydroxy acids. 

A number of studies have recently been devoted to membrane applications [8, 100-102], Yoshikawa and co-workers developed an imprinting technique by casting membranes from a mixture of a Merrifield resin containing a grafted tetrapeptide and of linear co-polymers of acrylonitrile and styrene in the presence of amino acid derivatives as templates [103], The membranes were cast from a tetrahydrofuran (THF) solution and the template, usually N-protected d- or 1-tryptophan, removed by washing in more polar nonsolvents for the polymer (Fig. 6-17). Membrane applications using free amino acids revealed that only the imprinted membranes showed detectable permeation. Enantioselective electrodialysis with a maximum selectivity factor of ca. 7 could be reached, although this factor depended inversely on the flux rate [7]. Also, the transport mechanism in imprinted membranes is still poorly understood. 

Difficulties due to side reactions (cyclization) and a broad molecular weight distribution accompanying the polycondensation of active esters led to the application of methods wherein the polymers are built up stepwise. In 1968, Sakakibara et al.31) introduced the solid-phase technique using Merrifield s resin. By stepwise addition of tert-pentyloxycar-bonyl tripeptides, they have synthesized (Pro-Pro-Gly)n with n = 5, 10, 15 and 20. 

Dipeptides and longer peptides are typically synthesized by solid-phase chemistry at polymer beads, a route discovered by and named after Merrifield [5, 88]. Disadvantages of this approach are that the polymer support is expensive and additional steps for linkage to and cleavage from the polymer are required. Hence solution chemistries are an alternative to the Merrifield approach. 

The Kumada-Corriu reaction is characterized by mild conditions and clean conversions [2]. A disadvantage of previous Kumada-Corriu reactions was due to the use of homogeneous catalysts, with more difficult product separation. Recently, an unsymmetrical salen-type nickel(II) complex was synthesized with a phenol functionality that allows this compound to be linked to Merrifield resin polymer beads (see original citation in [2]). By this means, heterogeneously catalyzed Kumada-Corriu reactions have become possible. 

In the synthesis of polypeptides with biological activity on a crosslinked polymer support as pioneered by Merrifield (1 2) a strict control of the amino acid sequence requires that each of the consecutive reactions should go virtually to completion. Thus, for the preparation of a polypeptide with 60 amino acid residues, even an average conversion of 99% would contaminate the product with an unacceptable amount of "defect chains". Yet, it has been observed (13) that with a large excess of an amino acid reagent —Tn the solution reacting with a polymer-bound polypeptide, the reaction kinetics deviate significantly from the expected exponential approach to quantitative conversion, indicating that the reactive sites on the polymer are not equally reactive. 

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