Gel-phase 13C NMR Research Articles

Solid-Phase Biomimetic Synthesis of Polyketide.

Solid-phase biomimetic polyketide synthesis has been developed. This method is composed of (i) carbon chain elongation of resin-bound carboxylic acid via decarboxylative Claisen condensation with malonic acid half thioester, (ii) stepwise transformation of the resulting β-ketothioester, and (iii) hydrolysis of thioester to regenerate the carboxylic acid for the next iteration cycle. Colorimetric tests were available for convenient monitoring of the solid-phase reactions; malachite green (basic dye) and iron(III) chloride successfully detected the carboxylic acid and the β-ketothioester, respectively. In addition, gel-phase 13C NMR could be utilized to confirm the progress of substrate immobilization. The established method was applied to the synthesis of the natural products, xylapyrone C and kavain. The present method could be further extended to the synthesis of (R)-kavain with catalytic diastereoselective asymmetric transfer hydrogenation as a key step.

Novel monodisperse PEG-grafted polystyrene resins: synthesis and application in gel-phase 13C NMR spectroscopy

A series of novel polystyrene-oligo(oxyethylene) graft copolymers containing monodisperse PEG units ( n = 2–12) have been synthesized and examined concerning their applicability for gel-phase 13C NMR spectroscopy. A strong correlation between the graft length and the line widths in the gel-phase spectra was observed. By grafting a PEG chain with only eight units, it was possible to obtain results similar to TentaGel resin. Additionally, TOF-SIMS images were recorded in order to evaluate the homogeneity of the resin.

Regio- and stereoselective hydrosilylation of immobilized terminal alkynes

Regio- and stereoselective hydrosilylation of terminal alkynes on solid support using diisopropyl hydrosilanes yielding β-( E)-vinyl silanes with excellent selectivity is reported. The hydrosilylation is catalyzed by Pt(DVDS)/P( i BuNCH 2CH 2) 3N (DVDS = 1,3-divinyl-1,1,3,3-tetramethyl-disiloxane), in which the bulky proazaphosphatrane ligand plays a key role for the selectivity. The immobilized products are characterized with gel phase 13C NMR and 1H high resolution magic angle spinning NMR.

Exploring the Solid-Phase Synthesis of 3,4-Disubstituted β-Lactams: Scope and Limitations

This work describes a comprehensive study on the solid-phase synthesis of 3,4-disubstituted beta-lactams. In situ generated ketenes react with immobilized aldimines under mild conditions to generate libraries of beta-lactams in good to very good overall isolated yields. Different commercially available solid supports were studied, with the cost-effective Wang resin proving to be the most effective. The utility of the protocol was also demonstrated by the highly efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. A practical technique for the preparation of manual solid-phase parallel libraries of biologically interesting beta-lactam compounds, using Mukaiyama's salt as dehydrating agent, is also presented. Reactions were easily monitored by FT-IR and gel-phase 13C NMR using conventional equipment.

Synthesis of a Shark Repellent Peptide Toxin, Pardaxin (16-33) on a Highly Flexible Polymer Support: Clpser

A high swelling resin, CLPSER has been developed and utilized for the solid phase synthesis of Pardaxin, which is an 18-residue peptide. The resin was characterized by gel phase (13)C NMR, IR and SEM. The utility of the new polymer support in polypeptide synthesis was further established by the comparative synthesis of pardaxin with commercially available Merrifield resin. The MALDI TOF MS, amino acid analysis and the HPLC revealed the superior quality of CLPSER.

Synthesis of Poly(aryl benzyl ether) Dendrimers on Solid Support

Dendronized supports, combining core Wang resin and poly(aryl benzyl ether) dendrons, were prepared using a novel route. Employing a dimethyl 5-hydroxyisophthalate module and a Mitsunobu condensation/ester reduction iterative sequence, the dendrimer was cleanly and efficiently prepared to the third generation. The synthesis was monitored using gel-phase 13C NMR and acidolytic cleavage, followed by 1H NMR. Gel-phase NMR and swelling experiments demonstrated that the behavior of the dendronized resins in various solvents is strongly influenced by the peripheral functional groups. Synthesis of a cinnamate derivative (via Mitsunobu and Heck reactions) and of a tripeptide demonstrated suitability of the dendronized support for solid-phase synthesis.

Synthesis of Hydrophilic Polar Supports Based on Poly(dimethylacrylamide) via Copper-Mediated Radical Polymerization from a Cross-Linked Polystyrene Surface: Potential Resins for Oligopeptide Solid-Phase Synthesis

A series of cross-linked polystyrene-based resins, Wang, Merrifield, and primary amino functional beads, have been transformed into initiators for transition-metal-mediated radical polymerization. Wang and amino functional resins have been condensed with 2-bromoisobutyryl bromide to give approximately quantitative conversion to initiator groups as monitored by FTIR and gel-phase 13C NMR spectrometry. In each case efficient polymerization of N,N-dimethylacrylamide (DMAc) has been demonstrated. Polymerization occurs with the RuCl2(PPh3)3 system in conjunction with Al(OiPr)3 with the reaction proceeding most efficiently with a toluene/ethanol solvent mixture which gives the best swelling of the composite particle. Surprisingly, copper(I) bromide with the pyridine imine type catalysts also led to efficient polymerization. Polymerization proceeds effectively directly from chloromethyl functional Merrifield resins given a 75% increase in weight at 130 °C after 55 h. Yields are significantly greater for derivati...

Solid-phase syntheses of N-substituted carbamates. Reaction monitoring by gel-phase 13C NMR using a 13C enriched BAL-linker

The solid-phase synthesis of N-substituted carbamates using the tris(alkoxy)benzyl (BAL) resin is reported. The incorporation of the primary amine was carried out by reductive amination, which was followed by reaction with an alkyl succinimidyl carbonate prepared in situ from the alcohol and N,N′-disuccinimidyl carbonate (DSC). Final cleavage with trifluoroacetic acid rendered the target compounds. Scope and limitations of these methods are discussed. The reactions were controlled by gel-phase 13C NMR using a 13C enriched BAL resin.

Living Radical Polymerization Immobilized on Wang Resins: Synthesis and Harvest of Narrow Polydispersity Poly(methacrylate)s

Wang resin has been transformed into an initiator for copper(I)-mediated living radical polymerization of methacrylates at initiator loading of 0.9 and 3.5 mmol g-1. The immobilized initiator was characterized by ATR FTIR, gel phase 13C NMR, and solid-state CP/MAS 13C NMR using two different spinning frequencies as well as a TOSS pulse sequence. The immobilized initiator has been used to prepare poly(methyl methacrylate), PMMA, homopolymer, and poly(methyl methacrylate)-block-poly(benzyl methacrylate-co-methyl methacrylate), P(MMA)-block-P(BzMA-co-MMA), block copolymers. The poly(methacrylate)s have been harvested from the insoluble resin by a simple trifluoroacetic acid, TFA, wash which selectively cleaved the activated benzyl ester linkage, so as to facilitate analysis. At an initiator loading of 0.9 mmol g-1 the Mn increases linearly with conversion with kinetics following first-order behavior in monomer as would be expected for living polymerization. After 3 h a 61.9% conversion of MMA is reached, wit...

Use of Quinic Acid as Template in Solid-Phase Combinatorial Synthesis

The use of pentafunctional quinic acid as a polyoxygenated scaffold for combinatorial synthesis is described. Simple protecting group chemistry is used to allow the selective formation of difunctionalized and tetrafunctionalized compounds. The reactions are followed by gel-phase 13C NMR and yield cleaved products of high purity.

On the Development of New Poly(styrene-oxyethylene) Graft Copolymer Resin Supports for Solid-Phase Organic Synthesis

With the aim of creating new, improved solid supports for organic synthesis, a series of poly(styrene-oxyethylene) graft copolymers 6a - d was synthesized by anionic polymerization of ethylene oxide from a polystyrene-supported 1,3-diol 5b. Graft lengths were varied from 29 to 58 repeat units (67-82 wt % polyoxyethylene). The so-formed alcohols 6a - d were further transformed into chlorides 7a - d, amines 8a - d, and two commonly used linkers, Wang 9a - d and HMPB 10a - d. These functional group interconversions were efficiently monitored using gel-phase 13C NMR, and the solid-state properties of all copolymers were characterized by differential scanning calorimetry. Thermal properties of these materials were found to be dominated by the polyoxyethylene composition. A correlation between the melting point associated with the graft lengths and the physical properties of the resins was observed. The optimum graft copolymer composition, determined by balancing the degree of functional group loading with resi...

Approaches to combinatorial synthesis of heterocycles: Solid phase synthesis of pyridines and pyrido[2,3-d]pyrimidines

An efficient solid phase synthesis of diverse pyridines and pyrido[2,3-d]pyrimidines is described. O-Immobilized keto esters 2 react with aldehydes to afford Knoevenagel derivatives 3. These undergo Hantzsch-condensation with α-oxo enamines to generate 1,4-dihydropyridines 4 that are oxidized with CAN to produce immobilized pyridines 5. The method has been extended to synthesis of fused pyrido[2,3-d]pyrimidines employing 6-aminouracils as the α-oxo enamine component. The course of the reaction on solid phase was studied by gel-phase 13C NMR spectrosopy. The synthesis is designed to be amenable for combinatorial libraries preparation.

A novel method for the functionalization of polystyrene resins through long aliphatic spacers

The preparation of functionalized polystyrene-divinylbenzene resins containing functional groups bonded to the polymeric matrix by a long alkyl chain has been accomplished in a two-step procedure from unfunctionalized resins and the acid chloride of a monoalkyl ester of an alkanedioic acid. The procedure is useful for the preparation of spacer-modified polymers of variable crosslinking degrees, including highly crosslinked macroreticular resins such as XAD-4. The high mobility of the chains is revealed by the easy analysis of the polymers by gel-phase 13C-NMR spectroscopy.

Solution of problems in ultra-high load solid-phase peptide synthesis by gel-phase 13C NMR spectroscopy : R. Epton, Wolverhampton Polytechnic, Wolverhampton, Great Britain

Solution of problems in ultra-high load solid-phase peptide synthesis by gel-phase 13C NMR spectroscopy : R. Epton, Wolverhampton Polytechnic, Wolverhampton, Great Britain

Gel phase 13C NMR spectroscopy as an investigative tool in ultra-high load solid (gel) phase peptide synthesis

Gel phase 13C NMR spectroscopy as an investigative tool in ultra-high load solid (gel) phase peptide synthesis

Application of gel-phase 13c-nmr to monitor solid phase peptide synthesis

The results presented in this article show the general applicability of gel-phase 13C-NMR to monitor solid phase peptide synthesis on the most commonly used polystyrene-based resins. The optimal conditions to acquire gel-phase 13C-NMR spectra of copoly(styrene-l%-divinylbenzene) has been determined. The technique proved to be applicable to characterize polystyrene-based starting supports as well as to the determination of their degree of functionality and purity. The stage-by-stage 13C-NMR characterization of the growing peptide chain during the synthesis of tripeptide H-Asn-(N-Me)Ala-Thr-NH 2 on a benzhydrylamine resin is described. The structural information, derived from this technique is relevant for the synthetic process as the spectra can be acquired under similar conditions. The characteristics of the spectra facilitate monitoring of coupling and deprotection reactions.