HMPB resin

HMPB resin, an aminomethyl polystyrene resin acylated with 4-hydroxymethyl-3-methoxyphenoxybutyric acid cleavable by extremely mild acidolysis similar to SASRIN (super acid-sensitive resin). Detachment of the final product, even in form of the frilly protected peptides, is achieved with dilute acid (1% TFA/dichloromethane) to yield peptide... 

For the solid-phase experiments [115], the commercially available Wang and HMPB-AM resins were chosen due their stability under the applied reaction conditions and an easy cleavage with TFA/DCM mixtures. Moreover, a novel, tailor-made and readily available linker, derived from inexpensive syringaldehyde was designed and proven to be superior to both standard Wang and HMPB-AM resins. For an initial study, as a proof of concept , the Wang linker was mimicked with a 4-methoxybenzyl group at N-1 position of a pyrazinone, and the sequence was evaluated in solution (Scheme 41). 

Wang Ratio resin Min Yield (%) HMPB-AM resin Ratio Min Yield (%) Syringaldehyde resin Ratio Min Yield (%) ... 

Combinatorial solid-phase synthetic methodologies have been used extensively in drug development [8]. A new solid-phase synthesis of 2-imidazolidones has been discovered by Goff, based on a domino aminoacylation/Michael addition reaction [9]. Thus, when immobilized amine 10-26 (HMPB-BHA resin) was treated with phenylisocyanate in the presence of triethylamine, a smooth formation of 2-imida-zolidone took place. Acid-catalyzed removal from solid phase provided 10-27 in good yield (Scheme 10.6). 

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. 

Protected peptides for further convergent synthesis can be synthesized on hyperlabile Trt(2-Cl), HMPB, Rink, SASRIN, Sieber, or TGT resins (see Sections 4.3.1, 4.3.1.1, 4.3.2.2, and 4.3.3.2) and cleaved with dilute TFA to yield the fully blocked peptide acid. 

Figure 4 (a) Analysis of dansyl-Ile-Thr(0 Bu -Pro-Gln-Trp-LysCBocFWang-linker-resin, giving peptide dansyl-Ile-Thr-Pro-Gln-Trp-Lys (MH+, 1006.0). The peak at 772.6 represents a small amount of undansylated material, (b) Analysis of Fmoc-Cys(Trt)-Lys(Boc)-Ile-HMPB-linker-resin, giving Fmoc-Cys-Lys-Ile (MH+, 585.5), Fmoc-Cys(Trt)-Lys-Ile (MH+, 849.8), and Fmoc-Cys-Lys-Ile disulfide [(M-S-S-M)H+, 1168.3], (c)Analysis of the disulfide of Fmoc-Cys-Asn-Cys-Lys(Boc)-Ile-FIMPB-linker-resin giving the disulfide of Fmoc-Cys-Asn-Cys-Lys-Ile (MH+, 801.0). (Reprinted from Ref. 64.)... 

Hydroxymethyl-3-methoxyphenoxybutyryl-benzydrylamino resin (X=H, MPPB-BHA X CHs, HMPB-MBHA)... 

Deprotection-protection Aminomethyl resin Chloromethyl resin Wang resin 2-Chlorotrityl resin Benzoic acid resin HMPB-MBHA resin TentaGel... 

A number of other useful highly acid-labile handles are also available. Most of these linkers are formed by introducing electron-donating substituents into the benzyl groups that serve as the peptide-resin anchor. The first handle of this type, 4-hydroxymethyl-3-methoxyphenoxyacetic acid (HMPA), 3, was introduced by Sheppard and Williams [22,23]. A closely related and more widely used alternative is 4-(4-hydroxymethyl-3-methoxyphenoxy) butyric acid [24-26] (HMPB), 4. 

Wang resin HMPB-AM resin Syringaldehyde resin... 

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