Hydroxymethyl-based resins

The protocols described in this section are applicable to all linker-derivatized resins in which loading involves esterification of the first amino acid to a linker hydroxyl group. The ease of esterification with Fmoc-amino acids increases in the order 5 3= 4 6 1 =2. 

Formation of ester bonds is considerably more difficult than that of amide bonds harsher conditions than those normally used for chain elongation must be employed which, unless carried out under controlled conditions, can lead to low substitution, enantiomerization, and dipeptide formation. To ensure satisfactory results when using these protocols it is important that the following precautions are observed  

Owing to the basic character of DMAP, some enantiomerization and dipeptide formation can be expected the amount depends on the quantity used, the duration of the reaction, and the nature of the amino acid. Enantiomerization is particularly problematic with cysteine and histidine (6). For most other amino acids, however, the levels of enantiomerization can be generally controlled to within acceptable limits by keeping the amount of DMAP used to a minimum. Dipeptide formation can be a problem with this method, particularly during the loading of glycine (7). 

Protocol 2. Attachment to alcohol-based resins using symmetrical anhydrides 

Prepare the appropriate Fmoc-amino acid anhydride (5 eq) according to Protocols. Dissolve in minimum volume of DMF and add to resin. If necessary add extra DMF to ensure complete coverage of the resin bed. 

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Another alternative for incorporation of the first protected amino acid onto hydroxymethyl base resins without activation of the carboxy group is by a Mitsunobu reac-tion.f l The esterification of 4-hydroxymethylphenoxy-type resins by Fmoc-protected amino acids using this method was first reported by Sieber,P l who observed the presence of an unidentified hydrophobic impurity in the amino acids cleaved from the resin however, independent studies by the groups of Krchnak and Spatola l have shown that the esterification of 4-hydroxymethylphenoxy-type PSty and PEG-PS resins using this procedure proceeds rapidly with acceptable to good yields, with practically no racemization and without the presence of additional contaminants in the final product. On the other hand, this method did not provide satisfactory results for cellulose supports.P l... 

For anchoring of the first amino acid onto hydroxymethyl-based resin, which upon cleavage provides a C-terminal carboxylic acids, it is recommended to use a protocol without the use of tertiary bases, such as DIEA. This type of protocol is designed to minimize the degree of self-acylation, hence, donble incorporation, and racemiza-tion of the first residne. The most common hydroxymethyl-based resins are Wang-type linkers (fcc Table 2). Two different protocols are described below for loading of hydroxymethyl-based resins (1) the symmetrical anhydride method and (2) the MSNT/Melm method. The MSNT/Melm method is recommended for difficnlt sitnations, which inclndes the attachment of amino adds that are prone to epimerization. For the synthesis of C-terminal adds where the first residue is either Cys or Pro, it is recommended to use the trityl-based resins. Many ofthe resins with a hydroxymethyl linker can be obtained with the first amino acid already preloaded. 

Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

The carboxyl-based TL 1.43 (101) was easily prepared from hydroxymethyl PS resin and a trisubstituted aromatic compound its SP fimctionahzation on the amide carbonyl or on the chlorine atom is followed by cleavage with TMSl (trimethyl silyl iodide) for 72 h at 75 °C to obtain simultaneously ester hydrolysis and decarboxylation to 2-unsubstituted quinazolines. An expansion to other heterocyclic systems is easily foreseeable. 

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

Other highly acid-labile functionalized solid supports and handles incorporate one or two additional electron-donating substituents, such as methoxy groups in 4-alkoxybenzyl alcohol-base-resins. Among these systems, SASRIN resin (super acid sensitive resin, 11),[4 " ] 4-(4-hydroxymethyl-3-methoxyphenoxy)butanoic acid (HMPB, 12),t4 and 2,4,5-trichlorophenyl 5-(4-hydroxymethyl-3,5-dimethoxyphenoxy)valerate (13)f4 l handles are the most widely used. 

PAC-PS base resin 2b Tentagel chloroformate hydroxymethyl-PS base resin... 

The A/ [9-hydroxymethyl-2-fluorenyl]succinamic acid (HMFS) resin 5v [243,244] attached via a different spacer to the base resin was therefore developed and leads to improved performance in peptide syntheses with Boc-amino acids (using TFA-induced AT-deprotection). The final sequence was cleaved most effectively by use of morpholine-DMF (1 4), Other resins that cleave by /3-elimination are the nitrophenylethanols 5w but these supports have thus far been applied mainly for oligonucleotide syntheses [245,246], Peptides have also been assembled on resin 5u using Boc protecting groups and shown to be stable to DIEA-CH2CI2 (1 9) but cleaved by treatment with DBU [247],... 

Chem. Descrip. Hydroxymethyl dioxoazabicyclooctane CAS 6542-37-6 EINECS/ELINCS 229-457-6 Uses Crosslinking agent for resorcinol phenol-formaldehyde or protein-based resin systems, paints/coatings, adhesives, and inks raw material for synthesis... 

Hydroxymethyl dioxoazabicyclooctane CAS 6542-37-6 EINECS/ELINCS 229-457-6 Synonyms 7-Hydroxymethyl-1,5-dioxo-3-aza-bicyclooctane 1H,3H,5H-Oxazolo [3,4-c] oxazole-7a(7H)-methanol Oxazolo [3,4-c] oxazol-7a-yl-methanol Ciassification Heterocyclic organic compd. Empihcai CeHnNOs Properties M.w. 145.16 Toxicoiogy Irritant TSCA listed Uses Antimicrobial in cosmetics crosslinking agent for resorcinol phenol-formaldehyde or protein-based resin systems raw material for synthesis for paints, coatings, adhesives, and inks... 

The use of hydroxymethylated resorcinol (HMR) as an adhesion promoter to enhance solid wood bonding is a recent development that holds considerable promise in improving the durability of the bonds between solid wood and adhesives. HMR consists of a mix of methylolated resorcinol monomers and low molecular weight oligomers [1]. Its usefulness as an adhesion promoter has been shown for a number of different wood species and different adhesives formaldehyde-based resins, epoxies and polyurethanes [2-7]. 

The best adhesive formulation for phloroglucinolic tannins, such as pine tannin extracts is, instead, a comparatively new and is also capable of giving excellent results when using resorcinol tannins such as a wattle tannin extract [68-71]. The adhesive gluemix consists only of a mix of an unmodified tannin extract 50 per cent solution to which paraformaldehyde and polymeric nonemulsifiable 4,4 -diphenylmethane diisocyanate (commercial pMDI) are added [68-71]. The proportion of tannin extract solids to pMDI can be as high as 70/30 w/w, but can be much lower in pMDI content. This adhesive is based on the peculiar mechanism by which the pMDI in water, is hardly deactivated to polyureas because it reacts faster with the hydroxymethyl groups of a formaldehyde-based resin, be it a tannin or another resin [69,71]. 

Kennedy and cowoikers repOTted Ihe use of resin-bound isonitriles in the Ugi MCR to afford valuable 2,5-diketq)iperazines and l,4-benzodiazepine-2-5-diones [89]. They developed a resin-bound carbonate convertible isonitrile based on a hydroxymethyl polystyrene resin. As shown in Scheme 11.38, the Ugi reaction with these resin-bound convertible isonitiiles afforded, after several derivatizations, the desired 2,5-diketopiperazines in good yields 178. 

Other. 2-Nitro-1-butanol is an excellent solvent for many polyamide resins, cellulose acetate butyrate, and ethylceUulose. It can be utilized in paint removers for epoxy-based coatings. 2-Hydroxymethyl-2-nitro-l,3-propanediol is usebil for control of odors in chemical toilets. Its slow release of formaldehyde ensures prolonged action to control odor, and there is no reodorant problem which sometimes is associated with the use of free formaldehyde. 2-Hydroxymethyl-2-nitro-l,3-propanediol solutions are effective preservative and embalming fluids. The slow Uberation of formaldehyde permits thorough penetration of the tissues before hardening. 

Ethyleneurea Resins. One of the most widely used resins during the 1950s and 1960s was based on dimethylolethyleneurea [136-84-5] (l,3-bis(hydroxymethyl)-2-imidazohdinone) commonly known as ethyleneurea resin. This resin [28906-87-8] is most convenientiy prepared from urea, ethylenediamine, and formaldehyde. 2-Imidazohdinone [120-93-4] (ethyleneurea) is first prepared by the reaction of excess ethylenediamine [107-15-3] wiih. urea (38) in an aqueous medium at about 116°C. 

Glyoxal Resins. Since the late 1960s, glyoxal resins have dorninated the textile-finish market for use as wrinMe-recovery, wash-and-wear, and durable-press agents. These resins are based on l,3-bis(hydroxymethyl)-4,5-dihydroxy-2-imidazohdinone, commonly called... 

The use of phenolic polymers in photocrosslinkable systems usually involves multicomponent systems which incorporate polyfunctional low molecular weight crosslinkers. For example, Feely et al. [9] have used hydroxymethyl melamine in combination with a photoactive diazonaphthoquinone which produces an indene carboxylic acid upon irradiation to crosslink a novolac resin. Similarly, Iwayanagi et al. [10] have used photoactive bisazides in combination with poly(p-hydroxy-sty-rene) to afford a negative-tone resist material which does not swell upon development in aqueous base. 

The phosphonium and carbenium salts are efficient reagents for activating and coupling A-alkoxycarbonylamino acids as well as peptide acids. However, the requirement for tertiary amine to effect the reaction has several implications. The base renders hydroxyl groups subject to acylation. Hence, the side chains of serine and threonine and any hydroxymethyl groups of a resin that have not been derivatized... 

Urea-formaldehyde resins are generally prepared by condensation in aqueous basic medium. Depending on the intended application, a 50-100% excess of formaldehyde is used. All bases are suitable as catalysts provided they are partially soluble in water. The most commonly used catalysts are the alkali hydroxides. The pH value of the alkaline solution should not exceed 8-9, on account of the possible Cannizzaro reaction of formaldehyde. Since the alkalinity of the solution drops in the course of the reaction, it is necessary either to use a buffer solution or to keep the pH constant by repeated additions of aqueous alkali hydroxide. Under these conditions the reaction time is about 10-20 min at 50-60 C. The course of the condensation can be monitored by titration of the unused formaldehyde with sodium hydrogen sulfite or hydroxylamine hydrochloride. These determinations must, however, be carried out quickly and at as low temperature as possible (10-15 °C), otherwise elimination of formaldehyde from the hydroxymethyl compounds already formed can falsify the analysis. The isolation of the soluble condensation products is not possible without special precautions, on account of the facile back-reaction it can be done by pumping off the water in vacuum below 60 °C imder weakly alkaline conditions, or better by careful freeze-drying. However, the further condensation to crosslinked products is nearly always performed with the original aqueous solution. 

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